A Phase III Randomized Trial Comparing Physician/Patient Choice of Either High Dose Interferon or Ipilimumab to MK-3475 (Pembrolizumab) in Patients With High Risk Resected Melanoma
Phase: PHASE3
Conditions: Clinical Stage III Cutaneous Melanoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Cutaneous Melanoma, Metastatic Mucosal Melanoma, Metastatic Non-Cutaneous Melanoma, Non-Cutaneous Melanoma, Recurrent Cutaneous Melanoma, Recurrent Mucosal Melanoma, Recurrent Non-Cutaneous Melanoma
Sponsor: National Cancer Institute (NCI)

 
 
 
November 27, 2023 
Larissa Korde, MD, MPH  
National Institutes of Health  
National Cancer Institute 
Bethesda, Maryland 20892 
 
RE: 
Amendment #27 of Protocol #S1404: “A Phase III Randomized Trial Comparing Physician/Patient 
Choice of Either High Dose Interferon or Ipilimumab to MK-3475 (Pembrolizumab) in Patients 
with High Risk Resected Melanoma” Primary Study Chair:  Sapna P. Patel, MD. 
 
Dear Dr. Korde: 
Thank you for your review of the above-referenced SWOG protocol.  The following concerns were 
expressed in the letter of 10/24/2023.  We would like to take this opportunity to respond to these 
concerns. 
 
I. Comments Requiring a Response – Major Issues: 
# 
Section 
Comments 
1. 
1.4 
The translational medicine objectives must be stated in the body of the protocol. 
Please add these back to the Objectives Section.  
PI Response: The section has been updated with the translational medicine 
objectives. 
2. 
18.8 c 
This section states, “No specimens, demographic data, or PHI will be provided to 
Thermo Fisher.” However, the amended text of the section clearly states that the 
assays will now be performed at Thermo Fisher. Please reconcile. 
PI Response: The section has been updated to clarify that the assays will now 
be performed at Thermo Fisher. 
 
 
II. Recommendations: 
# 
Section 
Comments 
3. 
CTSU 
Address 
and 
Contact 
Informa
tion 
Table 
Page 5 
Revise the text in this section, as shown below, to reflect the updated CTSU 
template language. 
For patient enrollments: 
Refer to the patient enrollment section of the protocol for instructions on using 
the Oncology Patient Enrollment Network (OPEN). OPEN is 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 by phone or 
email: 1-888-823-5923 or at ctsucontact@westat.com 

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# 
Section 
Comments 
PI Response: The section has been updated. 
4. 
CTSU 
Address 
and 
Contact 
Informa
tion 
Table 
Page 5 
Replace the text in this section with the following updated CTSU template 
language. 
 
The most current version of the study protocol and all supporting documents 
must be downloaded from the protocol-specific page located on the CTSU 
members’ website (https://www.ctsu.org).  
 
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 Roster 
Maintenance application and in most cases viewable and manageable via the 
Roster Update Management System (RUMS) on the CTSU members’ website. 
PI Response: The section has beenwas updated. 
5. 
Section 
13.2.a 
CTEP 
Investig
ator 
Registra
tion 
Procedu
res 
Page 85 
Replace this paragraph in this section with the following updated CTSU 
template language. 
Food and Drug Administration (FDA) regulations require sponsors to select 
qualified investigators. National Cancer Institute (NCI) policy requires all 
individuals contributing to NCI-sponsored trials to register with their 
qualifications and credentials and to renew their registration annually. To register, 
all individuals must obtain Cancer Therapy Evaluation Program (CTEP) 
credentials necessary to access secure NCI Clinical Oncology Research Enterprise 
(CORE) systems. Investigators and clinical site staff who are significant 
contributors to research must register in the Registration and Credential 
Repository (RCR). The RCR is a self-service online person registration 
application with electronic signature and document submission capability. 
PI Response: The section has beenwas updated. 
6. 
Section 
13.2.a 
CTEP 
Investig
ator 
Registra
tion 
Procedu
res 
Page 85 
Revise the text in this section, as shown below, to reflect the updated CTSU 
template language. 
 
An active CTEP-IAM user account with a linked ID.me account (the latter 
required immediately for new CTEP-IAM accounts, and by July 1, 2023 for all 
users) is required to participate in NCI clinical trials supported by the Cancer 
Trials Support Unit (CTSU) and to access all CTEP and CTSU websites and 
applications.  In addition, IVRs and NPIVRs must list all clinical practice sites and 
Institutional Review Boards (IRBs) covering their practice sites on the FDA Form 
1572 in RCR to allow the following: 

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# 
Section 
Comments 
x Addition to a site roster; 
x Selection as the treating, credit, or drug shipment investigator or consenting 
person in OPEN; 
x Ability to be named as the site-protocol Principal (PI) on the IRB approval; 
and 
x Assignment of the Clinical Investigator (CI) task on the Delegation of Tasks 
Log (DTL).     
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on 
the IRB approval), consenting/treating/drug shipment investigator in OPEN, or 
as the CI on the DTL must be rostered at the enrolling site with a participating 
organization.  
 
Additional 
information 
is 
located 
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.  
PI Response: The section has been updated. 
7. 
Section 
13.2.c 
CTEP  
Registra
tion 
Procedu
res 
Page 86 
Replace these paragraphs in this section with the following updated CTSU 
template language. 
 
This study is supported by the NCI CTSU. 
 
IRB Approval   
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central 
Institutional Review Board (NCI CIRB) in order to participate in Cancer Therapy 
Evaluation Program (CTEP) and Division of Cancer Prevention (DCP) studies 
open to the National Clinical Trials Network (NCTN) and NCI Community 
Oncology Research Program (NCORP) Research Bases. In addition, U.S.-based 
sites must accept the NCI CIRB review to activate new studies at the site after 
March 1, 2019. Local IRB review will continue to be accepted for studies that are 
not reviewed by the CIRB, or if the study was previously open at the site under 
the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific 
regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet 
(SSW) for Local Context to the CIRB using IRBManager to indicate their intent 
to open the study locally. The NCI CIRB’s approval of the SSW is automatically 

S1404 
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Page 4 
 
# 
Section 
Comments 
communicated to the CTSU Regulatory Office, but sites are required to contact 
the CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site 
preferences for applying NCI CIRB approvals across their Signatory Network. 
Site preferences can be set at the network or protocol level. Questions about 
establishing site preferences can be addressed to the CTSU Regulatory Office by 
email or calling 1-888-651-CTSU (2878). 
Include the following (highlighted) paragraph for trials that will include sites 
using their local IRB or REB as well as for trials with non U.S.-based NCTN and 
NCORP sites.  
Sites using their local IRB or REB, must submit their approval to the CTSU 
Regulatory Office using the Regulatory Submission Portal located in the 
Regulatory section of the CTSU website. Acceptable documentation of local 
IRB/REB approval includes: 
x Local IRB documentation; 
x IRB-signed CTSU IRB Certification Form; and/or 
x Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on 
the IRB/REB approval) must meet the following criteria for the site to be able to 
have an Approved status following processing of the IRB/REB approval record: 
x Have an active CTEP status; 
x Have an active status at the site(s) on the IRB/REB approval (applies to 
US and Canadian sites only) on at least one participating organization’s 
roster; 
x If using NCI CIRB, be active on the NCI CIRB roster under the applicable 
CIRB Signatory Institution(s) record; 
x Include the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile;  
x List all sites on the IRB/REB approval as Practice Sites in the Form FDA 
1572 in the RCR profile; and 
x Have the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
x An active Federal Wide Assurance (FWA) number; 

S1404 
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# 
Section 
Comments 
x An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
x An active roster affiliation with the NCI CIRB roster under at least one 
CIRB Signatory Institution (US sites only); and 
x Compliance with all applicable protocol-specific requirements (PSRs). 
PI Response: The section has been updated. 
8. 
Section 
13.2.c 
CTEP  
Registra
tion 
Procedu
res 
Page 87 
Revise the text in this section, as shown below, to reflect the updated CTSU 
template language. 
 
Downloading Site Registration Documents:   
 
Download the site registration forms from the protocol-specific page located on 
the CTSU members’ website. Permission to view and download this protocol 
and its supporting documents is restricted to institutions and their associated 
investigators and staff on a participating roster. To view/download site 
registration forms:   
x Log in to the CTSU members’ website (https://www.ctsu.org) using your 
CTEP-IAM username and password or linked ID.me account (ID.me 
accounts are required for all newly created CTEP-IAM accounts and by 
July 1, 2023 for all users); 
x Click on Protocols in the upper left of the screen: 
o Enter the protocol number in the search field at the top of the 
protocol tree; or 
o Click on the By Lead Organization folder to expand, then select 
[Corresponding Organization], and protocol number S1404. 
x Click on Documents, Protocol Related Documents, and use the Document 
Type filter and select Site Registration to download and complete the forms 
provided. (Note: For sites under the CIRB, IRB data will load automatically 
to the CTSU.)  
PI Response: The section has been updated. 
9. 
Section 
13.4 
Registra
tion 
Procedu
Replace the text in this section with the following updated CTSU template 
language. 

S1404 
Revision #17 (contd.) 
Page 6 
 
# 
Section 
Comments 
res 
Page 90 
 
Patient Enrollment 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration 
system available on a 24/7 basis. OPEN is integrated with CTSU regulatory and 
roster data and with the LPOs’ registration/randomization systems or the 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
x Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; 
x To perform enrollments or request slot reservations: Must be on an LPO 
roster, ETCTN corresponding roster, or participating organization roster 
with the role of Registrar. Registrars must hold a minimum of an 
Associate Plus (AP) registration type; 
x If a Delegation of Tasks Log (DTL) is required for the study, the 
registrars must hold the OPEN Registrar task on the DTL for the site; and 
x Have an approved site registration for the protocol prior to patient 
enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the 
treating, crediting, consenting, drug shipment (IVR only), or receiving 
investigator for a patient transfer in OPEN, the IVR or NPIVR must list the IRB 
number used on the site’s IRB approval on their Form FDA 1572 in RCR. If a 
DTL is required for the study, the IVR or NPIVR must be assigned the 
appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
x Patient has met all eligibility criteria within the protocol stated 
timeframes; and  
x All patients have signed an appropriate consent form and Health 
Insurance Portability and Accountability Act (HIPAA) 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for your 
records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU 
members’ website. Further instructional information is in the OPEN section of 

S1404 
Revision #17 (contd.) 
Page 7 
 
# 
Section 
Comments 
the CTSU website at https://www.ctsu.org or https://open.ctsu.org. For any 
additional questions, contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
PI Response: The section has been updated. 
10. 
Section 
14.3 
Data 
Submiss
ion 
Require
ments 
Page 91 
Replace the text in this section with the following updated CTSU template 
language. 
 
Medidata Rave is the clinical data management system being used for data 
collection for this trial/study. Access to the trial in Rave is controlled through the 
CTEP-IAM system and role assignments.  
Requirements to access Rave via iMedidata: 
x 
Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; 
and 
x 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: 
Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or 
Rave Investigator.  
Rave role requirements: 
x 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
x 
Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
x 
Rave Read Only or Rave SLA role must have at a minimum an Associate 
(A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required. 
 
Upon initial site registration approval for the study in the Regulatory application, 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation email from iMedidata. To accept the invitation, site staff must either 
click on the link in the email or log in to iMedidata via the CTSU members’ 
website under Data Management > Rave Home and click to accept the invitation 
in the Tasks pane located in the upper right corner of the iMedidata screen. Site 
staff 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 eLearning link in 
the Tasks pane located in the upper right corner of the iMedidata screen. If an 

S1404 
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# 
Section 
Comments 
eLearning is required for a study and has not yet been taken, the link to the 
eLearning will appear under the study name in the Studies pane located in the 
center of the iMedidata screen; once the successful completion of the eLearning 
has been recorded, access to the study in Rave will be granted, and a Rave EDC 
link will replace the eLearning link under the study name.  
Site staff who have not previously activated their iMedidata/Rave account at the 
time of initial site registration approval for the study in the Regulatory application 
will receive a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account 
Activation and Study Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ website in the Data 
Management > Rave section or by contacting the CTSU Help Desk at 1-888-823-
5923 or by email at ctsucontact@westat.com.   
PI Response: The section has been updated. 
11. 
13.4 b 
Include this language in the protocol, as applicable. 
 
x If this is a study with a radiation and/or imaging (RTI) component, add 
the following to the protocol if applicable.  
This is a study with a radiation and/or imaging (RTI) component and the 
enrolling site must be aligned to an RTI provider. To manage provider 
associations or to add or remove associated providers, access the Provider 
Association page from the Regulatory section on the CTSU members’ website at 
https://www.ctsu.org/RSS/RTFProviderAssociation. Sites must be linked to at 
least one Imaging and Radiation Oncology Core (IROC) provider to participate 
on trials with an RTI component. Enrolling sites are responsible for ensuring that 
the appropriate agreements and IRB approvals are in place with their RTI 
provider. An individual with a primary role on a treating site roster can update the 
provider associations, though all individuals at a site may view provider 
associations. To find who holds primary roles at your site, view the Person Roster 
Browser under the RUMS section on the CTSU members’ website. 
x If IROC Houston will conduct RT modality credentialing, add the 
following to the protocol:  
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC 
Houston to verify credentialing status or to begin a new modality credentialing 
process.  
x If this study uses the IROC integration suite to document that the 
enrolling site is associated with a radiation or imaging (RTI) provider 
credentialed for the study modalities, add the following to the protocol:  

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# 
Section 
Comments 
To complete protocol-specific credentialing the RTI provider or enrolling site 
should follow instructions in the protocol to submit documentation or other 
materials to the designated IROC Quality Assurance (QA) center. Upon the 
IROC QA center approving the RTI provider for the study modality, IROC will 
automatically send the approval to the Regulatory and Roster Maintenance 
applications to comply with the protocol-specific requirement, unless otherwise 
noted at the bottom of the IROC Credentialing Approval notification. IROC will 
continue to copy the provider and/or enrolling site on modality approvals. 
 
Upon site registration approval in the Regulatory application, the enrolling site 
may access Oncology Patient Enrollment Network (OPEN) to complete 
enrollments. If the study is using the IROC integration suite, the enrolling site 
will select their credentialed provider treating the subject in the OPEN 
credentialing screen and may need to answer additional questions related to 
treatment in the eligibility checklist.   
PI Response: The section has been updated. 
12. 
Section 
15.6.a 
TRIAD 
Digital 
Image 
Submiss
ion 
Page 
106 
 
Replace the text in this section with the following updated CTSU template 
language. 
 
Transfer of Images and Data (TRIAD) is the American College of 
Radiology’s (ACR) image exchange application. TRIAD provides sites 
participating in clinical trials a secure method to transmit images. TRIAD 
anonymizes and validates the images as they are transferred. 
TRIAD Access Requirements: 
x Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; 
x Registration type of: Associate (A), Associate Plus (AP), Non-
Physician Investigator (NPIVR), or Investigator (IVR). Refer to 
the CTEP Registration Procedures section for instructions on how 
to request a CTEP-IAM account and complete registration in 
RCR; and 
x TRIAD Site User role on an NCTN, ETCTN, or other relevant 
roster. 
All individuals on the Imaging and Radiation Oncology Core provider 
roster have access to TRIAD and may submit images for credentialing 
purposes, or for enrollments to which the provider is linked in OPEN. 
 

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# 
Section 
Comments 
TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will 
need to install the TRIAD application on their workstation. TRIAD 
installation documentation is available at 
https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM account 
and RCR registration. 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
PI Response: The section has been updated. 
13. 
14.3 d 
Our records indicate that this study uses the Data Quality Portal (DQP). 
Please confirm and include the following CTSU template language. 
 
Data Quality Portal 
x Include only if study will use Data Quality Portal. 
x Include within the data submission/reporting section of the protocol.  
The Data Quality Portal (DQP) provides a central location for site staff to 
manage unanswered queries and form delinquencies, monitor data quality 
and timeliness, generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data 
Management. The Rave Home section displays a table providing 
summary counts of Total Delinquencies and Total Queries. DQP Queries, 
DQP Delinquent Forms, DQP Form Status and the DQP Reports modules 
are available to access details and reports of unanswered queries, 
delinquent forms, forms with current status, and timeliness reports. Site 
staff should review the DQP modules on a regular basis to manage 
specified queries and delinquent forms. 
The DQP is accessible by site staff who are rostered to a site and have 
access to the CTSU website. Staff who have Rave study access can access 
the Rave study data via direct links available in the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at 
sites twice a month. These notifications serve as alerts that queries and/or 
delinquent forms require site review, providing a summary count of 
queries and delinquent forms for each Rave study that a site is 
participating in. Additional site staff can subscribe and unsubscribe to 
these notifications using the CTSU Report and Information Subscription 
Portal on the CTSU members’ website. 

S1404 
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Page 11 
 
# 
Section 
Comments 
To learn more about DQP use and access, click on the Help Topics button 
displayed on the Rave Home, DQP Queries, DQP Delinquent Forms, 
DQP Form Status, and DQP Reports modules. 
Include the following (highlighted) only if study is not using the 
Calendaring functionality in Rave: 
This study does not use the Rave Calendaring functionality, and therefore 
the DQP Delinquent Forms module will not include details for this study, 
and the DQP Summary table on the Rave Home page will display N/A for 
the Total Delinquencies summary count.  
PI Response: The section has been updated. 
 
III. Other Edits 
 
# 
Section 
Comments 
1. 
Protocol 
and 
Consent 
The version date was updated.  
2. 
13.3h 
Removed the sentence “Patient SSN (SSN is desired, but optional.  Do not enter 
invalid numbers.)” 
 
 
 
 

 
 
 
Version Date: 
November 27, 2023 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) PARTICIPANTS 
 
FROM: 
SWOG Operations Office (protocols@swog.org) 
 
RE:    S1404, “A Phase III Randomized Trial Comparing Physician/Patient Choice of Either 
High Dose Interferon or Ipilimumab to MK-3475 (Pembrolizumab) in Patients with High 
Risk Resected Melanoma."  Study Chair:  Dr. S. Patel. 
 
REVISION # 17 
 
Study Chair:  Sapna Pradyuman Patel, M.D. 
Phone number: 713/792-2921 
E-mail: S1404SCquestion@swog.org  
 
 
IRB Review Requirements 
( ) 
Expedited review allowed 
 
 
Protocol changes 
(√)         Other: Additional Translational Medicine 
(√)         Editorial / Administrative changes 
 
  
Sites using the CIRB as their IRB of record: The protocol and/or informed consent form 
changes have been approved by the CIRB and must be activated within 30 days of the 
CIRB posting of this notice. 
 
Sites not using the NCI CIRB: Per CTMB Guidelines, the protocol updates and/or 
informed consent changes must be approved by local IRBs within 90 days of distribution 
of this notice. 
 
 
REVISION #17 
 
The above-referenced protocol has been updated as follows to incorporate additional translational medicine 
details: 
   
1. Protocol and Model Consent Form: The version date of these documents has been updated. No 
additional changes were made to the Model Consent Form. 
 
2. Kenneth F. Grossman, M.D., Ph.D. has been removed as a study chair and has been replaced by 
Sapna Pradyuman Patel, M.D. throughout the protocol document and contact information updated 
accordingly. 
 
3. Table of Contents: The Table of Contents has been updated. 
 
4. Contact Information Table: Sapna Pradyuman Patel, M.D was replaced Kenneth F. Grossmann, 
M.D., Ph.D. as the contact person for treatment or toxicity related questions. 
 
5. Cancer Trials Support Unit (CTSU) Address and Contact Information: The CTSU Contact Information 
has been updated throughout. 
 
6. Section 13.2, 13.3, and 13.4 :These sections have been updated to reflect new CTSU template 
language. 
 
7. Section 13.3h: This section has been revised per CTSU updates to the protocol template. The 
following sentence was removed “Patient SSN (SSN is desired, but optional.  Do not enter invalid 
numbers.)” 

S1404 
Revision #17 (contd.) 
Page 2 
 
 
8. Section 14.2 Master forms location has been updated. 
 
9. Section 14.3 and 15.15.6a.:Throughout this section the CTSU template language has been updated. 
 
10. Appendix 18.8c-d.: This section has been updated, Retrospective T-Cell Receptor Beta Chain 
Sequencing assays will be performed at Thermo Fisher, replacing MD Anderson laboratory.  
 
11. Appendix 18.8 f.: This section has been updated. Thermo Fisher mailing address, contact information 
has been added, and The University of Texas MD Anderson Cancer Center contact information was 
updated.  
 
12. Section 18.9 b: This section has been updated, the bank instructions for distribution has been changed 
to Thermo Fisher and MD Anderson laboratory was removed. 
 
The updated protocol and model informed consent form can be accessed from the CTSU website 
(www.ctsu.org ). Please discard any previous versions of the documents and replace with the updated 
versions. Please contact melanomaquestion@crab.org  or 206/652-2267 with any questions. 
 
This study has been reviewed and approved by the NCI’s Central Institutional Review Board (CIRB). 
 
This memorandum serves to notify the NCI, and SWOG Statistics and Data Management Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
 
Teresa Petrella, M.D. – CCTG  
 
 
Karen Favata – Merck 
Maria Edwards – PPD 
TaNisha Evans – PPD 
             Loni Pickle-Thermo Fisher Scientific 
 
 
 
 
 
 
 

 
S1404 
 
Page 1 
 
Version Date 11/27/2023 
 
 
 
PRIVILEGED COMMUNICATION 
Activated October 15, 2015 
FOR INVESTIGATIONAL USE ONLY 
 
 
SWOG 
 
TITLE 
A PHASE III RANDOMIZED TRIAL COMPARING PHYSICIAN/PATIENT CHOICE OF EITHER 
HIGH DOSE INTERFERON OR IPILIMUMAB TO MK-3475 (PEMBROLIZUMAB) IN PATIENTS 
WITH HIGH RISK RESECTED MELANOMA. 
 
NCT#02506153 
 
This is an FDA Registration Trial.  Additional site requirements include maintenance of a Trial 
Master File (https://www.swog.org/sites/default/files/docs/2017-
10/Guidance%20on%20FDA%20Inspection.pdf) and additional monitoring (see Appendix 18.6). 
 
STUDY CHAIRS: 
AGENTS: 
 
Sapna Pradyuman Patel, M.D. (Medical Oncology) 
NCI Supplied Investigational Agents 
MD Anderson Cancer Center 
(DCTD-sponsored): 
Melanoma Medical Oncology 
 
1515 Holcombe Blvd., Unit 0430 
MK-3475 
(Pembrolizumab) 
(NSC 
776864) 
Houston, TX 77030 
  
Phone: 713/792-2921 
 
FAX: 713/745-1046 
Commercially Supplied Agent: 
E-mail: S1404SCquestion@swog.org 
 
 
Interferon alfa 2b (NSC 377523) 
Michael V. Knopp, M.D., Ph.D. (Imaging) 
Ipilimumab (NSC 732442) 
The Ohio State University 
 
395 W 12th Ave, Suite 430 
CCTG STUDY CHAIR 
Columbus, OH 43210 
 
 
Phone:  614/293-9998 
Teresa Petrella, M.D. 
E-mail:  knopp.16@osu.edu 
Odette Cancer Centre 
 
Sunnybrook Health Sciences Centre 
Vernon K. Sondak, M.D.  (Surgery) 
2075 Bayview Avenue 
H. Lee Moffitt CC  
Toronto, Ontario, Canada M4N 3M5 
MKC-CutProg  
Phone:  416/480-5248 
10920 N. McKinley Dr  
FAX:  416/480-6002 
Tampa, FL 33612 
                                                             E-mail:  
teresa.petrella@sunnybrook.ca  
Phone:  813/745-8788 
 
FAX:  813/745-7211 
 
E-mail:  vernon.sondak@moffitt.org  
 
ECOG-ACRIN STUDY CHAIR 
BIOSTATISTICIANS: 
 
 
Ahmad Tarhini, M.D., Ph.D. 
Megan Othus, Ph.D. 
University of Pittsburgh Cancer Institute 
James Moon, M.S. 
UPMC Cancer Pavilion 
Hongli Li, M.S. 
5150 Centre Avenue, 5th Floor 
SWOG Statistical Center 
Pittsburgh, PA 15232 
1100 Fairview Ave N, M3-C102 
Phone: 412/648-6578 
P.O. Box 19024 
FAX: 412/648-6579 
Seattle, WA 98109-1024 
E-mail: tarhiniaa@upmc.edu  
Phone:  206/667-4623 
 
FAX:  206/667-4408 
 
E-mail:  mothus@fredhutch.org  

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E-mail: jmoon@fredhutch.org  
 
E-mail:  hongli@fredhutch.org  
 
 
PARTICIPANTS 
 
SWOG/SWOG 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
CCTG/Canadian Cancer Trials Group 
NRG/NRG Oncology 
 
 

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TABLE OF CONTENTS 
 
TITLE  ............................................................................................................................................ 1 
PARTICIPANTS ............................................................................................................................... 2 
TABLE OF CONTENTS .................................................................................................................. 3 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION .......... 5 
SCHEMA .......................................................................................................................................... 6 
1.0 
OBJECTIVES ..................................................................................................................... 7 
1.1 
Primary Objectives .............................................................................................................. 7 
1.2 
Secondary Objectives ......................................................................................................... 7 
1.3 
Additional Objectives .......................................................................................................... 7 
2.0 
BACKGROUND .................................................................................................................. 7 
3.0 
DRUG INFORMATION ..................................................................................................... 13 
3.1 
Interferon alfa-2b (Intron® A) ............................................................................................ 13 
3.2 
Ipilimumab (BMS-734016, MDX-010, YERVOY®) (NSC 732442) .................................... 16 
3.3 
MK-3475 (Pembrolizumab) (NSC-776864) ....................................................................... 24 
4.0 
STAGING CRITERIA (AJCC 7TH EDITION, 2010)........................................................... 35 
5.0 
ELIGIBILITY CRITERIA ................................................................................................... 35 
5.1 
STEP 1 REGISTRATION .................................................................................................. 35 
5.2 
STEP 2 REGISTRATION (Randomization) ...................................................................... 39 
6.0 
STRATIFICATION FACTORS .......................................................................................... 39 
7.0 
TREATMENT PLAN ......................................................................................................... 40 
7.1 
Treatment .......................................................................................................................... 40 
7.2 
Prohibited and Cautionary Medications ............................................................................ 43 
7.3 
Drug Compliance Documentation ..................................................................................... 44 
7.4 
Criteria for Removal from Protocol Treatment .................................................................. 45 
7.5 
Discontinuation of Treatment ............................................................................................ 45 
7.6 
Follow-Up Period, End of Study ........................................................................................ 45 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS ................................. 46 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................... 46 
8.2 
Dose Modification Considerations for Patients Receiving Interferon (Arm 1) ................... 46 
8.3 
Dose Modification Considerations for Patients Receiving Ipilimumab (Arm 1) ................. 50 
8.4 
Dose Modification Considerations for Patients Receiving MK-3475 (pembrolizumab) (Arm 
2) ....................................................................................................................................... 54 
8.5 
Use of Transfusion and/or EPO ........................................................................................ 61 
8.6 
Use of G-CSF .................................................................................................................... 61 
8.7 
Anti-infectives .................................................................................................................... 62 
8.8 
Dose Modification Contacts .............................................................................................. 62 
8.9 
Adverse Event Reporting .................................................................................................. 62 
9.0 
STUDY CALENDARS ...................................................................................................... 63 
9.1 
Arm 1: Interferon alfa-2b ................................................................................................... 63 
9.2 
Arm 1: Ipilimumab ............................................................................................................. 67 
9.3 
Arm 2: MK-3475 (Pembrolizumab) ................................................................................... 71 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS ................................... 75 
10.1 
Progression/Relapse ......................................................................................................... 75 
10.2 
Relapse-Free Survival ...................................................................................................... 75 
10.3 
Overall Survival ................................................................................................................. 75 
10.4 
Performance Status .......................................................................................................... 76 
11.0 
STATISTICAL CONSIDERATIONS ................................................................................. 76 
11.1 
Accrual goals ..................................................................................................................... 76 
11.2 
Overall survival (OS) and relapse-free survival (RFS) objectives .................................... 76 
11.3 
Overall survival (OS) and relapse-free survival (RFS) design assumptions ..................... 76 
11.4 
Alpha allocation between Overall survival (OS) and Relapse-free survival (RFS) ........... 77 
11.5 
Interim and final analysis plans ......................................................................................... 77 
11.6 
Anticipated stage distribution. ........................................................................................... 81 
11.7 
Analyses of other objectives ............................................................................................. 81 
11.8 
Quality of life (QOL data) .................................................................................................. 82 
11.9 
Data and Safety Monitoring .............................................................................................. 86 

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12.0 
DISCIPLINE REVIEW ....................................................................................................... 87 
13.0 
REGISTRATION GUIDELINES ........................................................................................ 87 
13.1 
Registration Timing ........................................................................................................... 87 
13.2 
Investigator/Site Registration ............................................................................................ 87 
13.3 
OPEN Registration Requirements .................................................................................... 93 
13.4 
Registration Procedures ................................................................................................... 94 
13.5 
Exceptions to SWOG registration policies will not be permitted. ...................................... 94 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................... 96 
14.1 
Data Submission Requirements ....................................................................................... 96 
14.2 
Master Forms .................................................................................................................... 96 
14.3 
Data Submission Procedures ........................................................................................... 96 
14.4 
Data Submission Overview and Timepoints ..................................................................... 97 
15.0 
SPECIAL INSTRUCTIONS ............................................................................................ 102 
15.1 
SWOG Specimen Tracking System (STS) ..................................................................... 102 
15.2 
Submission of slides for PD-L1 Evaluation ..................................................................... 102 
15.3 
Specimens for Banking ................................................................................................... 105 
15.4 
Pharmacokinetic (PK) and Anti Drug Antibody (ADA) testing ........................................ 106 
15.5 
Quality of life assessments: Instructions for administration ............................................ 108 
15.6 
Submission of Images for Banking (Required) ............................................................... 110 
15.7 
Mandatory Site Training .................................................................................................. 111 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................... 112 
16.1 
Adverse Event Reporting Requirements......................................................................... 114 
17.0 
BIBLIOGRAPHY ............................................................................................................. 120 
18.0 
APPENDIX ...................................................................................................................... 123 
18.1 
Surgical Management Guidelines ................................................................................... 124 
18.2 
Guidelines for Self-Administration of Interferon Alfa-2b Template ................................. 127 
18.3 
S1404 Patient Interferon Diary (for patients who self-administer Interferon) ................. 130 
18.4 
S1404 Local Pathology Review Form ............................................................................. 131 
18.5 
TNM Definitions for Pathologic Staging .......................................................................... 132 
18.6 
QA Auditing and Monitoring ............................................................................................ 137 
18.7 
Instructions for PPD Requisition Form ............................................................................ 143 
18.8 
Translational Medicine: Retrospective T-Cell Receptor Beta Chain (TCRE) Sequencing of 
Banked Samples from S1404 ......................................................................................... 145 
18.9 
Instructions for the SWOG Biospecimen Bank - Lab #201, Solid Tissue, Myeloma and 
Lymphoma Division ......................................................................................................... 149 
18.10 
Translational Medicine: Association of Circulating Tumor DNA (ctDNA) with Relapse-Free 
Survival in High-Risk, Resected Melanoma Patients ...................................................... 149 
18.11 
Translational Medicine: Optimizing Adjuvant Immunotherapy in Melanoma .............. Error! 
Bookmark not defined. 
 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the 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 by phone or email: 
1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support.  
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878), or 
CTSURegHelp@coccg.org for 
regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN)  OPEN is 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https ://OPEN.ctsu.org.  
 
Contact the CTSU Help Desk with 
any OPEN-related questions by 
phone or email : 1-888-823-5923 
or at ctsucontact@westat.com.  
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave.  Refer to 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 page located on the CTSU members’ website (https://www.ctsu.org ).  
  
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 Roster Maintenance application and in most cases  
viewable and manageable via the Roster Update Management System (RUMS) on the CTSU members’  
website.  
 
For patient eligibility or data submission questions contact the SWOG Data Operations Center by 
phone or email206/652-2267 
melanomaquestion@crab.org  
 
For treatment or toxicity related questions contact the Study Chair by phone or email:  
Sapna Pradyuman Patel, M.D.  
Phone:  713/792-2921 
 
E-mail: S1404SCquestion@swog.org  
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical 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 Website is located at https://www.ctsu.org . 
 
 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 1 
 
Physician/patient 
choice of either 
 
HDI 
Interferon Alfa-2b: IV 
 for 5 days out of 7 
every week for  
4 weeks then 
subcutaneous every 
other day  
3 times each week 
for 48 weeks 
 
OR 
 
Ipilimumab:  IV 
every 3 weeks for 4 
doses then IV every 
12 weeks for a total 
of 3 years 
Arm 2 
 
MK-3475 
(Pembrolizumab) 
IV  
every 3 weeks for 18 
doses 
Step 2 Registration/Randomization 
 
Patients with resected Stage IIIA (N2A), IIIB, IIIC,  
or IV melanoma 
Step 1 Registration  
 
Submit slides to central laboratory for PD-L1 evaluation. 
Statistical Center will notify sites when PD-L1 testing is completed. 

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1.0 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
a. 
To compare overall survival (OS) of patients with resected Stage III and 
IV melanoma treated with physician/patient choice of either high dose 
interferon alfa-2b or ipilimumab versus MK-3475 (pembrolizumab) 
 
b. 
Among patients who are PD-L1 positive, to compare OS of patients with 
resected Stage III and IV melanoma treated with physician/patient choice 
of either high dose interferon alfa-2b or ipilimumab versus MK-3475 
(pembrolizumab). 
 
c. 
To compare relapse-free survival (RFS) of patients with resected Stage III 
and IV melanoma treated with physician/patient choice of either high dose 
interferon alfa-2b or ipilimumab to MK-3475 (pembrolizumab). 
 
1.2 
Secondary Objectives 
 
a. 
To estimate OS and RFS for patients who are PD-L1 negative or PD-L1 
indeterminate in this population. 
 
b. 
To compare OS and RFS of patients between the two arms within PD-L1 
positive and negative subgroups and to look at the interaction between 
PD-L1 (positive versus negative) and treatment arm.   
 
c. 
To assess the safety and tolerability of the regimens. 
 
1.3 
Additional Objectives 
 
a. 
To bank tissue and whole blood in anticipation of future correlative studies 
in this patient population. 
 
b. 
To evaluate PD-L1 expression through immunohistochemistry assay. 
 
c. 
To evaluate the effect of treatment-related side effects that may have an 
impact on the health-related domains of quality of life (QOL) using the 
FACT-BRM, EQ-5D-3L, and FACIT-D between patients treated with 
physician/patient choice of either high-dose interferon alfa-2b or 
ipilimumab and MK-3475 (pembrolizumab). 
 
d. 
Pharmacokinetic (PK) and anti-drug antibody (ADA) testing will be 
performed on all patients receiving MK-3475 (pembrolizumab).  These 
analyses will evaluate exposure-response analyses for activity and 
efficacy, potential pharmacodynamic biomarkers, and the safety of MK-
3475 (pembrolizumab). 
 
1.4  
Other Objectives 
a. 
Translation Medicine Objective Related to T-Cell Receptor Beta Chain 
Sequencing 
 
1. To evaluate the association between TCRβ variable gene (TRBV)  
haplotype and Grade 3-4 immune-related adverse events (irAEs) among  
Stage III melanoma patients treated with adjuvant Ipilimumab or 
Pembrolizumab. 
2. To describe the TRBV haplotype distribution among this cohort of  
patients studied. 

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b. 
Translational Medicine Objective Related to Association of Circulating 
Tumor DNA (ctDNA) with Relapse-Free Survival in High-Risk, Resected 
Melanoma Patients 
c. 
To evaluate associations between pretreatment ctDNA (present versus 
absent) and relapse within 2 years of randomization in a case-control 
analysis across treatment arms. 
d. 
To evaluate associations between pretreatment ctDNA (present versus 
absent) and relapse within 2 years of randomization in a case-control 
analysis across treatment arms. 
e. 
To evaluate associations between pretreatment ctDNA and relapse within 
2 years of randomization in a case-control analysis within each treatment 
arm (after treatment arm data are unblinded to investigators). 
f. 
To evaluate associations between “early-on treatment” ctDNA levels and 
relapse within 2 years of randomization. 
g. 
To describe ctDNA levels at end of therapy and time of relapse. 
2.0 
BACKGROUND 
 
Although the long term RFS for most patients with low risk Stage I and II melanoma is 
excellent following surgery, patients who have high risk features such as tumor-involved 
lymph nodes (Stage III) have poorer outcomes with an average 5-year OS of Stage III 
patients approximating 50%. (1) Although modern therapy has significantly improved 
outcomes for patients with Stage IV melanoma such that 20% of patients achieve survival 
beyond 4 years, this still reflects a minority of patients. (2) Furthermore, relapses in this 
disease can be severely detrimental to quality of life with distant relapses accounting for 
greater than 50% of the relapse events in Stage III patients. (3)  Adjuvant therapy is 
currently considered for patients with Stage III melanoma and selected patients with 
resected Stage IV melanoma.   
 
Adjuvant treatment for Stage III melanoma – Rationale for Physician/Patient Choice 
of either High Dose Interferon alfa-2b or Ipilimumab as the Control Arm (Arm 1): 
 
Multiple studies have investigated adjuvant immunotherapy alone or in combination with 
other treatments for high-risk melanoma.  The first trial to demonstrate an OS advantage 
compared high dose interferon-alfa-2b (HDI) to observation. (4)  This study established 
HDI as the standard of care for the adjuvant treatment of melanoma, and HDI remains the 
most widely used adjuvant treatment option in the US today.  Subsequent studies involving 
differing doses, schedules, and preparations of interferon have been extensively reviewed 
and taken together have shown consistent relapse-free survival (RFS) and OS benefit in 
large meta-analyses. (5,6,7)  Pegylated interferon has also been studied by the EORTC in 
a single large Phase III trial in Stage III melanoma that showed a RFS advantage compared 
to observation, but no OS advantage was demonstrated. (8)  Based upon the RFS 
advantage of this EORTC study, the FDA granted approval for pegylated interferon for the 
adjuvant treatment of Stage III melanoma.  Biochemotherapy consisting of interferon, 
interleukin-2, dacarbazine, vinblastine, and cisplatin has also been studied in the adjuvant 
setting (S0008) and results show a RFS advantage compared to HDI but no OS difference. 
(9)  
 
Unfortunately, the toxicity of this regimen limits the use of biochemotherapy to institutions 
with sufficient expertise in its administration, and the lack of an OS advantage compared 
to HDI argues against this becoming a community-based standard for the adjuvant 
treatment of melanoma.   
 
Ipilimumab, administered intravenously, was originally approved in 2011 to treat late-stage 
melanoma that cannot be removed by surgery. Ipilimumab is a monoclonal antibody that 
blocks a molecule known as CTLA-4 (cytotoxic T-lymphocyte antigen). CTLA-4 may play 
a role in slowing down or turning off the body’s immune system, and affects its ability to 
fight off cancerous cells. Ipilimumab may work by allowing the body’s immune system to 
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In October 2015, based on preliminary results from EORTC 18071, the U.S. Food and 
Drug Administration expanded the approved use of ipilimumab to include a new use as 
adjuvant therapy for patients with stage III melanoma, to lower the risk that the melanoma 
will return following surgery. The safety and effectiveness of ipilimumab for this new use 
were studied in 951 patients who received ipilimumab or a placebo as adjuvant therapy 
following complete surgical removal of melanoma. The study measured recurrence-free 
survival and overall survival. Forty-nine percent of participants taking ipilimumab had their 
cancer return after an average of 26 months, compared to 62 percent of those receiving a 
placebo, whose cancer returned after an average of 17 months. The analysis of overall 
survival data has not yet occurred. (10) 
 
The most common side effects of ipilimumab in this study were rash, diarrhea, fatigue, 
itching, headache, weight loss and nausea. Ipilimumab can also cause autoimmune 
disease in the digestive system, liver, skin, nervous system (which would each require 
treatment with corticosteroids), as well as in the hormone-producing glands (which requires 
life-long hormone replacement therapy). Women who are pregnant should not take 
ipilimumab because it may cause harm to a developing fetus. (11) In addition, the relative 
adjuvant therapeutic impact of ipilimumab as compared to HDI is currently unknown. 
Similarly, given the toxicity profile of ipilimumab at 10 mg/kg, there is a need to better 
assess the risk-benefit ratio relative to the standard 3 mg/kg dose currently approved for 
inoperable metastatic melanoma.   
 
The benefits described above for HDI, though statistically significant, remain modest with 
the most recently published meta-analysis showing an OS advantage with a hazard ratio 
of 0.91 (95% CI 0.85 to 0.97; P value = 0.003). (12)  Additionally, the toxicity of HDI can be 
significant and prolonged over the course of one year of administration. 
 
The current landscape of other studies ongoing in high-risk melanoma:    
 
Ongoing adjuvant clinical trials in patients with melanoma include a study investigating 
ipilimumab at either 10 mg/kg or 3 mg/kg compared to HDI (U.S. Intergroup E1609).  The 
co-primary endpoints of this study are RFS and OS.  E1609 completed accrual of adult 
patients August 15, 2014 (remains open for pediatric/adolescent patients). Results of 
E1609 are not expected until after completion of accrual to the present trial, and until that 
time there is insufficient evidence to consider ipilimumab at either dose as a standard form 
of adjuvant therapy for high risk melanoma patients. 
 
Two additional ongoing adjuvant studies are industry-sponsored BRAF inhibitor-based 
studies, investigating vemurafenib or dabrafenib/trametinib compared to observation. 
Results of these studies are not expected until after completion of accrual to the present 
trial, and until that time there is insufficient evidence to consider BRAF inhibitors alone or 
in combination with MEK inhibitors as a form of adjuvant therapy for high-risk melanoma 
patients. 
 
Clinical Rationale for PD-1 blockade for the adjuvant treatment of high-risk 
melanoma: 
 
Novel therapies have been developed recently targeting the programmed cell death – 1 
(PD-1) inhibitory co-receptor on T-cells. (13)  Monoclonal antibodies directed at the PD-1 
co-receptor, or the cognate PD-L1 receptor on tumor cells, have robust activity in advanced 
melanoma. (14,15)  The drug MK-3475 (pembrolizumab) is a member of this class of 
medications and targets the PD-1 receptor.  A recently reported Phase I study in 411 
patients defined safe and effective dosing regimens (10 mg/kg IV q 2 weeks, 2 mg/kg IV q 
3 weeks, 10 mg/kg IV q 3 weeks) and showed the highest confirmed response rate yet 
observed for any single agent immunotherapy in Stage IV melanoma (41% objective 
responses across all cohorts). (16)  Furthermore, the safety and tolerability of 
pembrolizumab (12% Grade 3/4 toxicities) appears superior to both HDI (64% Grade 3/4 

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toxicities in S0008) and ipilimumab (43% Grade 3/4 toxicities in EORTC 18071), making it 
ideally suited for evaluation as adjuvant therapy. (17)  Ongoing studies, including Phase III 
studies for Stage IV patients, are confirming the high response rate and the favorable 
toxicity profile of pembrolizumab such that an adjuvant Phase III study is warranted. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to Investigator 
Brochure). Pharmacodynamic data (IL-2 release assay) suggested that peripheral target 
engagement is durable (> 21 days). This early PK and pharmacodynamic data provided 
a scientific rationale for evaluating the Q3W dosing schedule. 
 
The choice of the 200 mg Q3W as an appropriate dose for fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that 
the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally 
consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain 
individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and 3) will maintain individual patients 
exposure in the exposure range established in melanoma that is well-tolerated and safe. 
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors. A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. 
 
 
Rationale for one year of dosing with pembrolizumab 
 
Adjuvant therapy for melanoma with HDI or pembrolizumab is aimed at inducing an 
immune response that eradicates micrometastatic tumor deposits that may lead to a future 
melanoma relapse. Based on the experience with HDI it is postulated that one year of 
adjuvant therapy would be able to induce the desired antitumor effects and eradicate small 
metastatic lesions. 
 
Biological rationale for the study population based on the anticipated mechanism of 
action of pembrolizumab: 
 
PD-L1 is known to be expressed by cells in the tumor microenvironment and engages PD-
1 on T cells to subsequently trigger inhibitory signaling downstream of the T-cell receptor 
(TCR), blocking effect or functions and reducing T-cell killing capacity. PD-L1 can be 
constitutively expressed on the surface of melanoma cells through poorly characterized 
oncogenic signaling pathways or alternatively, expressed in response to the presence of T 
cells producing immune-stimulating cytokines such as interferons. (18,19,20) This process 
has been termed “adaptive immune resistance” and represents a mechanism by which 
cancer cells attempt to protect themselves from immune-cell mediated cell killing. Based 
on this conceptual framework, pre-existing tumor-infiltrating CD8+ T-cells with associated 
PD-1/PD-L1 engagement within tumors represented a key factor in determining clinical 
response to PD-1 blocking therapy. Emerging evidence from the analysis of samples from 
46 patients with metastatic melanoma  obtained before and during anti-PD-1 therapy with 
pembrolizumab 
(24 
responders 
and 
22 
non-responders) 
using 
quantitative 
immunohistochemistry, quantitative multiplex immunofluorescence, and next generation 
sequencing for T-cell receptors (TCR), supports the concept that the pre-requisite for 
responses to pembrolizumab is the presence of clonal CD8 T cells expressing PD-1 and 
closely interacting with PD-L1 expressed by melanoma cells. (21) These data indicate the 
requirement for the presence of CD8 cells interacting with adaptive immune resistance-
mediated PD-L1 expression by melanoma cells to lead to responses to PD-1 blockade.  
 
Rationale for PD-L1 status blinding  
 
Although patients will be stratified based on PD-L1 status, they and the investigator will be 
blinded to this result at randomization.  Presently there is no indication that PD-L1 status 

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predicts response to PD-L1 antibody treatment in the adjuvant setting so this will not impact 
patient care during treatment on the study.   PD-L1 expression is dynamic and PD-L1 
expression of primary or lymph node tissue is not necessarily indicative of PD-L1 status in 
other sites. Thus, at relapse we recommend that patients have the biopsy confirming 
relapse tested for PD-L1 expression with a CLIA certified test.   We recommend against 
using the S1404 baseline PD-L1 expression for subsequent treatment decisions.  Only in 
the event that tissue is limited in the relapsed setting and that there is no other reasonable 
alternative to attain PD-L1 expression for the patient, should the S1404 baseline PD-L1 
expression be used.  S1404 baseline PD-L1 expression will be provided to patients on 
study at report of relapse. 
 
FDA approval of MK-3475 (pembrolizumab) for Stage IV and unresectable Stage III 
melanoma 
 
MK-3475 (pembrolizumab) has recently received accelerated approval by the FDA for the 
treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilimumab and, if B-RAF V600 mutation positive, a B-RAF inhibitor.  This 
approval is based on the high response rate and durability of response seen in the clinical 
studies conducted so far with MK-3475 as described above.  We anticipate extensive use 
of MK-3475 among the patients who relapse on HDI, and also anticipate the use of other 
PD-1, and PD-L1 targeted antibodies in both groups.  Data regarding post-relapse therapy 
will be collected as part of this study. 
 
Rationale for collecting quality of life (QOL) data and the potential impact of the trial 
on QOL 
 
An important issue in the adjuvant treatment of patients with high-risk melanoma is the how 
patients weigh the benefits of overall survival and QOL.  Adjuvant HDI has been 
demonstrated to provide relapse-free survival and overall survival benefits for this patient 
population but it is also known to be associated with major Grade 3-4 toxicities. (22) 
Patients treated with MK-3475 (pembrolizumab) can also experience Grade 3-4 drug-
related toxicities and immune-related adverse events (irAEs). The Functional Assessment 
of Chronic Illness Therapy Diarrhea (FACIT-D) utilizes the four primary domains of the 
FACT-BRM (Physical Well-Being, Social Well-Being, Emotional Well-Being, and 
Functional Well-Being).  (23) The additional measure of the FACIT-D instrument includes 
11 questions tailored to bowel symptoms.  It is appropriate for patients with any form of 
cancer, and content was determined and validated by experts with patient input. We 
therefore plan to collect QOL data utilizing the FACT-BRM, FACIT-D and EQ-5D-3L health 
questionnaires to evaluate health-related quality-of-life outcomes between the two arms.   
 
Pharmacokinetic/Pharmacodynamic Evaluations 
 
To further evaluate pembrolizumab immunogenicity and pembrolizumab exposure in 
this indication, and also to evaluate exposure of the proposed dosing regimen, samples 
will be collected for analysis of anti-drug antibodies (ADA) and pharmacokinetics (PK). 
 
Based on PK data obtained in this study as well as PK data obtained from other studies, 
a population PK analysis will be performed to characterize pharmacokinetic parameters 
(Clearance (CL), Volume of distribution (V)) as endpoints and evaluate the effect of 
extrinsic and intrinsic factors to support the proposed dosing regimen. Pharmacokinetic 
samples will also be used to explore the exposure-response relationships for 
pembrolizumab 
antitumor  
activity/efficacy as well as safety in the proposed patient population, if feasible. The 
results of these analyses, if performed, will be reported separately from the primary results 
of this trial. 
 
 

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Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to 
measure differences of intervention effects.  To date, studies of MK-3475 (pembrolizumab) 
and similar agents have not shown evidence of significant gender or race-based 
differences in efficacy.  The anticipated accrual in the ethnicity/race and sex categories is 
shown in the table below. 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
0 
6 
0 
0 
6 
Asian 
0 
2 
0 
0 
2 
Native Hawaiian 
or Other Pacific 
Islander 
0 
4 
0 
0 
4 
Black or African 
American 
10 
3 
0 
0 
13 
White 
359 
840 
4 
10 
1213 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
369 
855 
4 
10 
1238 
 
 
INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian/ Alaska 
Native 
0 
1 
0 
0 
1 
Asian 
0 
2 
0 
0 
2 
Native 
Hawaiian or 
Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or 
African 
American 
0 
0 
0 
0 
0 
White 
41 
96 
0 
0 
137 
More Than 
One Race 
0 
0 
0 
0 
0 
Total 
41 
99 
0 
0 
140 
 
 
 

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3.0 
DRUG INFORMATION 
 
Investigator’s Brochures 
 
For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, MK-3475 (pembrolizumab) is investigational and is being provided under an 
IND held by the National Cancer Institute.  The current version of the Investigator Brochure 
(IB) will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of an 
“active” account status and a “current” password.  Questions about IB access may be 
directed via email to IBcoordinator@mail.nih.gov or by phone (240) 276-6575 Monday 
through Friday between 8:30 am and 4:30 pm (ET).  Interferon alfa-2b and ipilimumab are 
commercially available drugs.  
 
3.1 
Interferon alfa-2b (Intron® A)  
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Interferons exert their cellular activities by binding 
to specific membrane receptors on the cell surface. Once bound to the cell 
membrane, interferons initiate a complex sequence of intracellular events. 
In vitro studies demonstrated that these include the induction of certain 
enzymes, suppression of cell proliferation, immunomodulating activities 
such as enhancement of the phagocytic activity of macrophages and 
augmentation of the specific cytotoxicity of lymphocytes for target cells, 
and inhibition of virus replication in virus-infected cells. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Time to peak, serum: IM, SubQ: ~3-12 hours; IV: by 
the end of a 30-minute infusion 
 
2. 
Distribution: Volume of distribution = 31 L, but has been noted to 
be much    greater, (370-720 L) in leukemia patients receiving 
continuous infusion. Interferon alfa-2b does not penetrate the 
CSF. 
 
3. 
Metabolism: Primarily renal 
 
4. 
Elimination:  Half-life IV: ~2 hours; IM, SubQ: ~2-3 hours 
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of Interferon alfa-2b 
 
Common (>20%): infection, diarrhea, nausea, vomiting, flu-like 
symptoms including fever, chills body aches, and muscle pain, 
fatigue, loss of appetite, disorder of taste, headache, confusion, 
depression, suicidal thoughts, alopecia, rash, and/or pain. 
 
Less common (4 to ≤ 20%): cardiomyopathy, cirrhosis of liver, 
hepatotoxicity, thrombocytopenia, organ damage and/or failure, 
edema, injection site extravasation, erythema of injection site, 
generalized exfoliative dermatitis, Stevens-Johnson Syndrome, 
toxic epidermal necrolysis, transient ischemic attack (TIA), 

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cerebral infarction, cerebrovascular accident, and/or ischemic 
stroke. 
 
Rare (≤ 3%), and serious: anemia, arrhythmias, ischemic heart 
disease, myocardial infarction, NSTEMI, hypersensitivity reaction, 
anaphylaxis. 
 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse effects. 
 
2. 
Pregnancy and Lactation: Pregnancy category C. There are no 
adequate and well-controlled studies in pregnant women.  
Breastfeeding is not recommended  
 
 
3. 
Drug Interactions: Interferon alfa-2b drug interactions have not 
been fully evaluated.  Caution should be exercised when 
combining with other potentially myelosuppressive agents such 
as: aldesleukin, clozapine, dipyrone, methadone, ribavirin, 
telbivudine, theophylline derivatives, and zidovudine. Due to 
potential drug interactions, a complete patient medication list, 
including interferon alfa-2b, should be screened prior to initiation 
of and during treatment with interferon alfa-2b. See Section 8.0 
Toxicities to be Monitored and Dosage Modifications. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan  
 
e. 
DRUG SUPPLY: 
 
Interferon alfa-2b is commercially available and will not be supplied. Refer 
to the current FDA-approved package insert for the most comprehensive 
and up to date information. 
 
f. 
DOSAGE FORMS: 
 
Interferon alfa-2b is available in vials as powder for reconstitution and in 
vials containing solution for injection. 
 
NOTE:  Intron® A (interferon alfa-2b) formulation must be consistent with 
the approved product labeling for the intended route of administration. 
 
1. 
Interferon alfa-2b powder for injection 
 
a) 
Interferon alfa-2b powder for injection appears white to 
cream-colored.  The powder for injection must be 
reconstituted prior to injection using the diluent (sterile 
water for injection USP) provided with the vial.  Refer to 
the package insert for current reconstitution and infusion 
solution preparation. 
 
b) 
Available vial strengths include 10 million units, 18 million 
units or 50 million units per vial.  Refer to the package 
insert for current available formulations. 
 
c) 
Interferon alfa-2b powder for injection vials do NOT 
include a preservative.  Reconstituted vials must be 

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discarded immediately after the appropriate dose is 
withdrawn from the vial. 
 
d) 
All powder for injection vials may be used for intravenous, 
intramuscular or subcutaneous injection.  
 
Vials containing 10 million units may be used for 
intralesional injection. 
 
e) 
Ingredients in the formulation include purified sterile 
recombinant 
interferon 
product, 
glycine, 
sodium 
phosphate dibasic, sodium phosphate monobasic, and 
human albumin. 
 
2. 
Interferon alfa-2b solution for injection 
 
a) 
Interferon alfa-2b solution for injection appears clear or 
colorless and is available in 18 million units per vial or 25 
million units per vial.  Please refer to the package insert 
for current available formulations. 
 
b) 
Solution for injection vials containing 18 million units or 25 
million units may be used for subcutaneous or 
intramuscular injection. Solution for injection vials 
containing 25 million units may be used for intralesional 
injection. 
 
The Intron® A (interferon alfa-2b) formulation must be 
consistent with the approved product labeling for the 
intended route of administration. 
 
c) 
Ingredients in the formulation include purified sterile 
recombinant interferon product, sodium chloride, sodium 
phosphate dibasic, sodium phosphate monobasic, 
edetate disodium, polysorbate 80, and cresol as a 
preservative. 
 
g. 
STORAGE AND STABILITY 
 
1. 
Interferon alfa-2b powder for injection 
 
a) 
Vials should be stored in a refrigerator at 2oC - 8oC (36oF- 
46oF) until the expiration date indicated on the vial or 
packaging has been reached or until immediately prior to 
use.  Vials should be allowed to come to room 
temperature prior to use. 
 
b) 
Reconstituted vials may be stored refrigerated at 2oC - 
8oC (36oF - 46oF) for no longer than 24 hours.  However, 
the reconstituted vial must be discarded after one dose 
has been withdrawn from the vial. 
 
c) 
Interferon alfa-2b powder for injection vials do not 
contain a preservative.  Reconstituted vials containing 
leftover medication should not be re-used, as the sterility 
is not guaranteed.  Bacterial contamination may occur in 
reconstituted vials used for more than a single dose. 
 
 

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2. 
Interferon alfa-2b solution for injection 
 
a) 
Vials should be stored in a refrigerator at 2oC - 8oC (36oF 
- 46oF) until the expiration date indicated on the vial or 
packaging has been reached. 
 
Multidose solution for injection vials contain preservatives 
and can be stored refrigerated for up to one month.  
Unused doses remaining in the vial must be discarded 
after one month.   
 
b) 
Vials should not be frozen or exposed to excessive heat. 
  
3.2 
Ipilimumab (BMS-734016, MDX-010, YERVOY®) (NSC 732442) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Cytotoxic T-lymphocyte antigen-4 CTLA-4 is a 
negative regulator of T-cell activity. Ipilimumab is a full human monoclonal 
immunoglobin (lg) antibody that binds to CTLA-4 and blocks the interaction 
of CTLA-4 with its ligands, CD80/CD86.  Blockade of CTLA-4 has been 
shown to augment T-cell activation and proliferation, including the 
activation and proliferation of tumor infiltrating T-effector cells. Inhibition of 
CTLA-4 signaling can also reduce T-regulatory cell function, which may 
contribute to a general increase in T cell responsiveness, including the 
anti-tumor immune response. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: No formal pharmacokinetic drug interaction studies 
have been conducted with ipilimumab. Ipilimumab is not expected 
to have pharmacokinetic drug-drug interactions, since it is not 
metabolized by CYP450 or other drug metabolizing enzymes. 
 
2. 
Distribution: Ipilimumab is confined mainly to the extracellular 
fluid. Peak concentration (Cmax), trough concentration (Cmin), 
and area under the plasma concentration versus time curve (AUC) 
of ipilimumab increased dose proportionally within the dose range 
examined ipilimumab is confined mainly to the extracellular fluid. 
Peak concentration (Cmax), trough concentration (Cmin), and 
area under the plasma concentration versus time curve (AUC) of 
ipilimumab increased dose proportionally within the dose range 
examined. Based on population pharmacokinetic analysis, the 
mean volume of distribution (% coefficient of variation) at steady 
state was 7.47 liters (10%). 
 
3. 
Metabolism: Not applicable.  Monoclonal antibodies are usually 
degraded into amino acids and small peptides, independently 
from CYP450 or other drug-metabolizing enzymes. 
 
4. 
Elimination: Clearance increased with body weight, but no dose 
adjustment is required with dosing on a mg/kg basis. Upon 
repeated dosing every 3 weeks, the clearance (CL) of ipilimumab 
was found to be time-invariant, and systemic accumulation was 
1.5-fold or less.  The mean value (% coefficient of variation) 
generated through population pharmacokinetic analysis for the 

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terminal half-life (t1/2) was 15.4 days (34%) and for CL was 16.8 
mL/h (38%).  
 
c. 
ADVERSE EFFECTS 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by body 
system. In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset 
of AEs (SPEER) is a list of events that are protocol specific exceptions to 
expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on 
2678 patients. Below is the CAEPR for Ipilimumab (MDX-010). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
 

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Version 2.10, March 29, 20191 
 
 
 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
 
Blood and 
lymphatic system 
disorders - Other 
(acquired 
hemophilia) 
 
CARDIAC DISORDERS 
 
 
Atrial fibrillation  
 
 
 
Myocarditis2 
 
 
 
Pericardial 
effusion 
 
EAR AND LABYRINTH DISORDERS 
 
 
Hearing 
impaired 
 
 
ENDOCRINE DISORDERS 
 
 
Adrenal 
insufficiency2 
 
 
 
Hyperthyroidism
2 
 
 
 
Hypophysitis2 
 
 
 
Hypopituitarism2  
 
 
Hypothyroidism2  
 
 
Testosterone 
deficiency2 
 
 
EYE DISORDERS 
 
 
Eye disorders - 
Other 
(episcleritis)2 
 
 
 
Uveitis2 
 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain  
 
 
Colitis2 
 
Colitis2 (Gr 3) 
 
 
Colonic 
perforation3 
 
 
Constipation 
 
 
Diarrhea 
 
 
Diarrhea (Gr 3) 
 
Enterocolitis 
 
 
 
Esophagitis 
 
 
 
 
Ileus 
 
Nausea 
 
 
Nausea (Gr 3) 
 
Pancreatitis2 
 
 
 
Vomiting 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 

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 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
Chills 
 
 
Fatigue 
 
 
Fatigue (Gr 3) 
 
Fever 
 
Fever (Gr 2) 
 
 
General disorders 
and 
administration site 
conditions - Other 
(systemic 
inflammatory 
response 
syndrome [SIRS]) 
 
 
 
Multi-organ failure  
HEPATOBILIARY DISORDERS 
 
 
Hepatobiliary 
disorders - 
Other 
(hepatitis)2 
 
 
IMMUNE SYSTEM DISORDERS 
 
 
Autoimmune 
disorder2 
 
 
 
 
Immune system 
disorders - Other 
(GVHD in the 
setting of 
allotransplant)4 
 
INFECTIONS AND INFESTATIONS 
 
 
 
Infections and 
infestations - 
Other (aseptic 
meningitis)2 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
Infusion related 
reaction 
 
 
INVESTIGATIONS 
 
 
Alanine 
aminotransferas
e increased 
 
 
 
Aspartate 
aminotransferas
e increased 
 
 
 
 
Lymphocyte 
count decreased 
 
 
Neutrophil count 
decreased 
 
 
 
Weight loss 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
 
 
Dehydration 
 
 

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 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
Hyperglycemia  
 
 
 
Metabolism and 
nutrition disorders 
- Other 
(exacerbation of 
pre-existing 
diabetes mellitus) 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
Arthralgia 
 
 
 
Arthritis 
 
 
 
 
Generalized 
muscle weakness 
 
 
Musculoskeletal 
and connective 
tissue disorder - 
Other 
(polymyositis)2 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
 
 Ataxia 
 
 
Facial nerve 
disorder2 
 
 
 
Guillain-Barre 
syndrome2 
 
 
 
Headache 
 
 
 
Myasthenia 
gravis2 
 
 
 
 
Nervous system 
disorders – Other 
(immune-mediated 
encephalitis) 2 
 
 
 
Peripheral motor 
neuropathy 
 
 
 
Peripheral sensory 
neuropathy 
 
 
Trigeminal nerve 
disorder 
 
 
PSYCHIATRIC DISORDERS 
 
 
 
Psychiatric 
disorders - Other 
(mental status 
changes) 
 
RENAL AND URINARY DISORDERS 
 
 
Acute kidney 
injury 
 
 
 
Renal and 
urinary disorders 
- Other 
(granulomatous 
 
 

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 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
tubulointerstitial 
nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Pneumonitis 
 
 
 
 
 Respiratory 
failure 
 
 
 
Respiratory, 
thoracic and 
mediastinal 
disorders - Other 
(bronchiolitis 
obliterans with 
organizing 
pneumonia) 
 
 
 
Respiratory, 
thoracic and 
mediastinal 
disorders - Other 
(lung infiltration) 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
 
Erythema 
multiforme 
 
 
Pruritus 
 
Pruritus (Gr 3) 
Rash maculo-papular 
 
 
Rash maculo-
papular (Gr 3)  
 
Skin and 
subcutaneous 
disorders - 
Other (Sweet’s 
syndrome) 
 
 
 
 
Stevens-Johnson 
syndrome 
 
 
 
Toxic epidermal 
necrolysis 
 
 
Urticaria 
 
 
VASCULAR DISORDERS 
 
 
Hypotension 
 
 
 
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of 
revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
2 Ipilimumab can result in severe and fatal immune-mediated adverse 
events probably due to T-cell activation and proliferation.  These can 
include (but are not limited to) autoimmune hemolytic anemia, acquired 
anti-factor VIII immune response, autoimmune aseptic meningitis, 
autoimmune hepatitis, autoimmune thyroiditis, hepatic failure, pure red 
cell aplasia, pancreatitis, ulcerative and hemorrhagic colitis, endocrine 

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disorders 
(e.g., 
autoimmune 
thyroiditis, 
hyperthyroidism, 
hypothyroidism, autoimmune hypophysitis/hypopituitarism, and adrenal 
insufficiency), ocular manifestations (e.g., uveitis, iritis, conjunctivitis, 
blepharitis, and episcleritis), sarcoid granuloma, myasthenia gravis, 
polymyositis, and Guillain-Barre syndrome.  The majority of these 
reactions manifested early during treatment; however, a minority 
occurred weeks to months after discontinuation of ipilimumab especially 
with the initiation of additional treatments. 
3 Late bowel perforations have been noted in patients receiving MDX-010 
(ipilimumab) in association with subsequent IL-2 therapy. 
4 Complications including hyperacute graft-versus-host disease (GVHD), 
may occur in patients receving allo stem cell transplant (SCT) after 
receiving Ipilimumab (MDX-010).  These complications may occur 
despite intervening therapy between receiving Ipilimumab (MDX-010) 
and allo-SCT. 
5 In rare cases diplopia (double vision) has occurred as a result of muscle 
weakness (Myasthenia gravis). 
6 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal 
hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal 
hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal 
hemorrhage, 
Ileal 
hemorrhage, 
Intra-abdominal 
hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, 
Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage 
under the GASTROINTESTINAL DISORDERS SOC. 
7 Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC. 
 
Adverse events reported on ipilimumab (MDX-010) trials, but for 
which there is insufficient evidence to suggest that there was a 
reasonable possibility that ipilimumab (MDX-010) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and 
lymphatic system disorders - Other (pure red cell aplasia)2; Febrile 
neutropenia 
CARDIAC 
DISORDERS 
- 
Conduction 
disorder; 
Restrictive 
cardiomyopathy 
EYE DISORDERS - Extraocular muscle paresis5; Eye disorders - Other 
(retinal pigment changes) 
GASTROINTESTINAL DISORDERS - Colonic ulcer; Dyspepsia; 
Dysphagia; 
Gastrointestinal 
disorders 
- 
Other 
(gastroenteritis); 
Gastrointestinal hemorrhage6; Proctitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Flu like symptoms; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure2 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INFECTIONS AND INFESTATIONS - Infection7 
INVESTIGATIONS - Creatinine increased; Investigations - Other 
(rheumatoid factor); Lipase increased; Platelet count decreased; Serum 
amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Back pain; Joint range of motion decreased; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Ischemia 
cerebrovascular; Seizure 

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PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Allergic rhinitis; Cough; Dyspnea; Laryngospasm 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; 
Hyperhidrosis; Skin hypopigmentation 
VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders - 
Other (temporal arteritis) 
 
Note: Ipilimumab (MDX-010) in combination with other agents could cause 
an exacerbation of any adverse event currently known to be caused by the 
other agent, or the combination may result in events never previously 
associated with either agent. 
 
1. 
Pregnancy and Lactation: There are no adequate and well-
controlled studies of Ipilimumab in pregnant women. Use of 
Ipilimumab during pregnancy only if the potential benefit justifies 
the potential risk to the fetus.  Human IgG1 is known to cross the 
placental barrier and ipilimumab is an IgG1; therefore, ipilimumab 
has the potential to be transmitted from the mother to the 
developing fetus. 
 
It is not known whether ipilimumab is secreted in human milk.  
Because many drugs are secreted in human milk and because of 
the potential for serious adverse reactions in nursing infants from 
ipilimumab, a decision should be made whether to discontinue 
nursing or to discontinue ipilimumab, taking into account the 
importance of ipilimumab to the mother. 
 
2. 
Drug Interactions:  No formal pharmacokinetic drug interaction 
studies have been conducted with ipilimumab. Ipilimumab is not 
expected to have pharmacokinetic drug-drug interactions, since it 
is not metabolized by CYP450 or other drug metabolizing 
enzymes 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan. 
 
Ipilimumab injection is to be administered as an infusion with an in-line, 
sterile, nonpyrogenic, low-protein-binding filter (pore size of 0.2 
micrometer to 1.2 micrometer). Do not administer as IV push or bolus 
injection. 
 
e. 
HOW SUPPLIED 
 
Ipilimumab is a sterile, preservative-free, clear to slightly opalescent, 
colorless to pale yellow solution for intravenous infusion, which may 
contain a small amount of visible translucent-to-white, amorphous 
ipilimumab particulates.  It is supplied in single-use vials of 50 mg/10 mL 
and 200 mg/40 mL (5 mg/mL).  Each milliliter contains 5 mg of ipilimumab 
and the following inactive ingredients: diethylene triamine pentaacetic acid 
(DTPA) (0.04 mg), mannitol (10 mg), polysorbate 80 (vegetable origin) (0.1 
mg), sodium chloride (5.85 mg), tris hydrochloride (3.15 mg), and Water 
for Injection, USP at a pH of 7. 
 
Ipilimumab is commercially available and will not be supplied.  Refer to the 
current FDA-approved package insert. 

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Version Date 11/27/2023 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
1. 
Store intact vials of ipilimumab refrigerated at (2q to 8qC), protected 
from light.  Do not freeze. 
 
2. 
Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP to prepare a diluted solution with a final 
concentration ranging from 1 mg/mL to 2 mg/mL.  Mix diluted 
solution by gentle inversion.  Refer to package insert for complete 
preparation and dispensing instructions 
 
3. 
The product may be infused using a volumetric pump at the 
protocol-specific dose(s) and rate(s) through a PVC IV solution 
infusion set with an in-line, sterile, nonpyrogenic, low-protein-
binding filter (pore size of 0.2 micrometer to 1.2 micrometer). 
 
4. 
Do not administer ipilimumab as an IV push or bolus injection. 
 
5. 
Stability of prepared IV ipilimumab solution is stable up to 24 hours 
refrigerated at (2q to 8qC) or at room temperature/ room light.  
 
6. 
Partially used vials or empty vials of ipilimumab injection should 
be discarded at the site according to appropriate drug disposal 
procedures. 
 
3.3 
MK-3475 (Pembrolizumab) (NSC-776864) 
 
a. 
PHARMACOLOGY 
 
MK-3475 (Pembrolizumab) is a humanized MAb of the IgG4/kappa 
isotype.  The programmed cell death 1 (PD-1) receptor is an inhibitory 
receptor expressed by T cells.  When bound to either of its ligands, PD-L1 
or PD-L2, activated PD-1 negatively regulates T-cell activation and 
effector function.  The pathway may be engaged by tumor cells expressing 
PD-1 ligands to suppress immune control.  MK-3475 blocks the negative 
immune regulatory signaling by binding to the PD-1 receptor, inhibiting the 
interaction between PD-1 and its ligands and thereby promoting the host 
immune system to recognize tumor cells as foreign bodies to be 
eliminated.  
 
b. 
PHARMACOKINETICS 
 
The pharmacokinetic profile of MK-3475, with low clearance and limited 
volume of distribution, is typical for therapeutic antibodies.  Elimination 
half-life after IV administration was approximately 14 to 21.6 days.  Steady 
state concentration levels were achieved within 16 weeks of treatment 
when tested at 3 and 10mg/kg dosing as administered at 2 week intervals.  
During repeated dosing of 2 or 10mg/kg Q3W, steady state in trough 
concentrations appeared to have been achieved after approximately three 
months.  Furthermore, MK-3475 has a low potential of eliciting the 
formation of anti-drug antibodies.       
 
c. 
ADVERSE EFFECTS  
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for MK-
3475 (pembrolizumab, NSC 776864) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a 
uniform presentation of events by body system. In addition to the 

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comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is 
identified with bold and italicized text. This subset of AEs (SPEER) is a list 
of events that are protocol specific exceptions to expedited reporting to 
NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements'  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on 
3793 patients. Below is the CAEPR for MK-3475 (pembrolizumab). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.5, December 27, 20191 
 
 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia2 
 
 
 
Lymph node 
pain2 
 
 
 
Thrombotic 
thrombocytopeni
c purpura2 
 
 
CARDIAC DISORDERS 
 
 
 
Myocarditis2 
 
 
 
Pericarditis2 
 
ENDOCRINE DISORDERS 
 
 
Adrenal 
insufficiency2 
 
 
 
Endocrine 
disorders - Other 
(thyroiditis)2 
 
 
 
Hyperthyroidism
2 
 
 
 
Hypohysitis2 
 
 
 
Hypopituitarism2  
 
 
Hypothyroidism2  
 
EYE DISORDERS 
 
 
 
Uveitis2 
 
 
 
Eye disorders - 
Other (Vogt-
Koyanagi-
Harada 
syndrome) 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain  
 
 
Colitis2 
 
 

S1404 
 
Page 26 
Version Date 11/27/2023 
 
 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
 
Diarrhea2 
 
Diarrhea2 (Gr 2) 
 
Mucositis oral2 
 
 
 
Nausea 
 
Nausea (Gr 2) 
 
Pancreatitis2 
 
 
 
Small intestinal 
mucositis2 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
 
Chills2 
 
 
Fatigue 
 
 
Fatigue (Gr 2) 
 
Fever2 
 
 
HEPATOBILIARY DISORDERS 
 
 
Hepatobiliary 
disorders - Other 
(autoimmune 
hepatitis)2 
 
 
IMMUNE SYSTEM DISORDERS 
 
 
 
Anaphylaxis2 
 
 
 
Cytokine release 
syndrome2 
 
 
 
Immune system 
disorders - Other 
(acute graft-
versus-host-
disease)2,3 
 
 
 
Immune system 
disorders - Other 
(hemophagocyti
c 
lymphohistiocyto
sis)2 
 
 
Immune system 
disorders - Other 
(pseudoprogress
ion/tumor 
inflammation)2 
 
 
 
Immune system 
disorders - Other 
(sarcoidosis)2 
 
 
 
 
Serum sickness2  
INFECTIONS AND INFESTATIONS 
 
 
Infection4 
 
 
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS 
 
 
 
 Infusion related 
reaction 
 
INVESTIGATIONS 
 
 
Alanine 
 
 

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Page 27 
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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
aminotransferas
e increased2 
 
Alkaline 
phosphatase 
increased 
 
 
 
Aspartate 
aminotransferas
e increased2 
 
 
 
Blood bilirubin 
increased 
 
 
 
CPK increased  
 
 
 
GGT increased  
 
 
Serum amylase 
increased 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
 
 
Hyponatremia 
 
 
 
 
Metabolism and 
nutrition 
disorders - Other 
(diabetic 
ketoacidosis)2 
 
 
 
Metabolism and 
nutrition 
disorders - Other 
(type 1 diabetes 
mellitus)2 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
 
 
Arthralgia2 
 
Arthralgia2 (Gr 2) 
 
Arthritis2 
 
 
 
Avascular 
necrosis2 
 
 
 
Back pain 
 
 
 
Joint effusion2 
 
 
 
Joint range of 
motion 
decreased 
 
 
 
Musculoskeletal 
and connective 
tissue disorder - 
Other 
(tenosynovitis)2 
 
 
 
Myalgia2 
 
 
 
Myositis2 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
 
Guillain-Barre 
syndrome2 
 

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
 
 
Nervous system 
disorders - Other 
(myasthenic 
syndrome)2 
 
 
 
Nervous system 
disorders - Other 
(neuromyopathy
)2 
 
 
 
Nervous system 
disorders - Other 
(non-infectious 
encephalitis)2 
 
 
 
Nervous system 
disorders - Other 
(non-infectious 
meningitis)2 
 
 
 
Nervous system 
disorders - Other 
(non-infectious 
myelitis) 
 
 
 
Nervous system 
disorders - Other 
(polyneuropathy)
2 
 
 
 
Paresthesia 
 
 
 
Peripheral motor 
neuropathy2 
 
RENAL AND URINARY DISORDERS 
 
 
 
Renal and 
urinary disorders 
- Other 
(autoimmune 
nephritis)2 
 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
 
 
 Cough 
 
 
 
 Pleuritic pain2 
 
 
 
 Pneumonitis2 
 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Bullous 
dermatitis2 
 
 
 
 
 Erythema 
multiforme2 
 
 
Erythroderma 
 
 
 
 
Palmar-plantar 
erythrodysesthe
sia syndrome 
 
 
Pruritus2 
 
Pruritus2 (Gr 2) 

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
 
Rash acneiform2  
 
 
Rash maculo-
papular2 
 
Rash maculo-papular2 
(Gr 2) 
 
Skin and 
subcutaneous 
tissue disorders 
- Other 
(dermatitis)2 
 
 
 
Skin 
hypopigmentatio
n2 
 
 
 
 
Stevens-
Johnson 
syndrome2 
 
 
 
Toxic epidermal 
necrolysis 
 
 
Urticaria2 
 
 
VASCULAR DISORDERS 
 
 
 
Vasculitis2 
 
 
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of 
revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
2 Immune-mediated adverse reactions have been reported in patients 
receiving MK-3475 (pembrolizumab).  Adverse events potentially related 
to MK-3475 (pembrolizumab) may be manifestations of immune-
mediated adverse events. In clinical trials, most immune-mediated 
adverse reactions were reversible and managed with interruptions of 
MK-3475 (pembrolizumab), administration of corticosteroids and 
supportive care. 
3 Acute graft-versus-host disease has been observed in patients treated 
with MK-3475 (pembrolizumab) who received hematopoeitic stem cell 
transplants. 
4 Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC. 
 
Adverse events reported on MK-3475 (pembrolizumab) trials, but for 
which there is insufficient evidence to suggest that there was a 
reasonable possibility that MK-3475 (pembrolizumab) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic 
system disorders - Other (pancytopenia); Disseminated intravascular 
coagulation; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - 
cardiac; Heart failure; Myocardial infarction; Pericardial effusion; 
Pericardial tamponade; Ventricular arrhythmia 
EYE DISORDERS - Eye pain 

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GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; 
Constipation; 
Duodenal 
hemorrhage; 
Dysphagia; 
Gastritis; 
Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders 
- Other (intestinal obstruction); Gastrointestinal disorders - Other 
(intussusception); Oral pain; Rectal hemorrhage; Small intestinal 
perforation; Upper gastrointestinal hemorrhage; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Edema face; Edema limbs; Facial pain; Gait disturbance; General 
disorders and administration site conditions - Other (general physical 
health deterioration); Generalized edema; Malaise; Non-cardiac chest 
pain; Pain 
INVESTIGATIONS - Cholesterol high; Creatinine increased; Fibrinogen 
decreased; Lymphocyte count decreased; Neutrophil count decreased; 
Platelet count decreased; Weight loss; White blood cell decreased 
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Dehydration; 
Hypercalcemia; Hyperglycemia; Hyperkalemia; Hypertriglyceridemia; 
Hyperuricemia; Hypoalbuminemia; Hypokalemia; Hypophosphatemia; 
Metabolism and nutrition disorders - Other (failure to thrive); Tumor lysis 
syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Bone pain; Generalized muscle weakness; Musculoskeletal and 
connective tissue disorder - Other (groin pain); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of 
consciousness; Dysarthria; Edema cerebral; Encephalopathy; Headache; 
Hydrocephalus; Lethargy; Meningismus; Nervous system disorders - 
Other (brainstem herniation); Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Nephrotic 
syndrome; 
Proteinuria; 
Renal 
and 
urinary 
disorders 
- 
Other 
(hydronephrosis); Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Dyspnea; 
Hypoxia; 
Laryngeal 
inflammation; 
Pleural 
effusion; 
Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; 
Skin and subcutaneous tissue disorders - Other (drug eruption) 
VASCULAR 
DISORDERS 
- 
Hypertension; 
Peripheral 
ischemia; 
Thromboembolic event 
 
Note: MK-3475 (pembrolizumab) in combination with other agents could 
cause an exacerbation of any adverse event currently known to be caused 
by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
1. 
Pregnancy and Lactation: MK-3475 may have adverse effects on 
a fetus in utero.  Furthermore, it is not known if MK-3475 has 
transient adverse effects on the composition of sperm.  Patients 
are excluded from this study if pregnant or breastfeeding, or 
expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening 
visit through 120 days after the last dose of trial treatment. 
 
Men and non-pregnant, non-breast-feeding women may be 
enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive.  Highly unlikely to conceive 
is defined as 1) surgically sterilized, or 2) postmenopausal (a 
woman who is ≥45 years of age and has not had menses for 
greater than 2 years will be considered postmenopausal), or 3) 
not heterosexually active for the duration of the study. The two 

S1404 
 
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Version Date 11/27/2023 
birth control methods can be barrier method or a barrier method 
plus a hormonal method to prevent pregnancy.  Patients should 
start using birth control from study Visit 1 throughout the study 
period up to 120 days after the last dose of study therapy.  The 
following 
are 
considered 
adequate 
barrier 
methods 
of 
contraception: diaphragm, condom (by the partner), copper 
intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed 
contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, 
or intramuscular agents). 
 
Patients should be informed that taking the study medication may 
involve unknown risks to the fetus (unborn baby) if pregnancy 
were to occur during the study.  In order to participate in the study 
they must adhere to the contraception requirement (described 
above) for the duration of the study and during the follow-up 
period.  If there is any question that a patient will not reliably 
comply with the requirements for contraception, that patient 
should not be entered into the study. 
 
Pregnancy: If a patient inadvertently becomes pregnant while on 
treatment with MK-3475, the patient will immediately be removed 
from the study.  The site will contact the patient at least monthly 
and document the patient’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be 
reported without delay and within 24 hours if the outcome is a 
serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the 
mother or newborn).  The study investigator will make every effort 
to obtain permission to follow the outcome of the pregnancy and 
report the condition of the fetus or newborn.   
 
It is unknown whether MK-3475 is excreted in human milk.  Since 
many drugs are excreted in human milk, and because of the 
potential for serious adverse reactions in the nursing infant, 
patients who are breast-feeding are not eligible for enrollment. 
 
2. 
Drug Interactions: No studies on pharmacodynamic drug 
interactions have been performed.  Due to potential drug 
interactions, a complete patient medication list, including MK-
3475, should be screened prior to initiation of and during treatment 
with MK-3475. See Section 8.0 Toxicities to be Monitored and 
Dosage Modifications. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
e. 
HOW SUPPLIED 
 
MK-3475 is supplied by Merck & Co., Inc. and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as single-use 100 
mg vials containing a sterile, non-pyrogenic, clear to opalescent aqueous 
solution (25 mg/mL).  Proteinaceous particles may be present.  MK-3475 
solution for infusion is formulated in 10mM histidine buffer, pH 5.2-5.8, 
containing 7% sucrose and 0.02% polysorbate 80, supplied in Type I glass 
vials with a cap color of red, salmon, or blue. 

S1404 
 
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Version Date 11/27/2023 
 
f. 
PREPARATION  
 
MK-3475 solution for infusion must be diluted prior to administration.  Allow 
the required number of vials to equilibrate to room temperature.  Do not 
shake the vials.  Do not use if opaque or extraneous particulate matter other 
than translucent to white proteinaceous particles is observed.  Do not use if 
discolored.  To prepare the infusion solution add the dose volume of MK-
3475 to an infusion bag containing 0.9% Sodium Chloride Injection, USP 
or 5% Dextrose Injection, USP.  Gently invert the bag 10-15 times to mix 
the solution.  The final concentration must be between 1 mg/mL to 10 
mg/mL. 
 
Compatible IV bag materials: PVC plasticized with DEHP, non-PVC 
(polyolefin), EVA, or PE lined polyolefin 
 
g. 
STORAGE 
 
Store intact vials between 2°C - 8°C (36°F - 46°F).  Do not freeze.  Protect 
from light by storing in the original box.  If a storage temperature excursion 
is identified, promptly return MK-3475 to between 2-8°C and quarantine 
the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) 
to PMBAfterHours@mail.nih.gov for determination of suitability. 
 
h. 
STABILITY 
 
Stability testing of the intact vials is on-going. 
 
Administer prepared solutions immediately after preparation.  If not 
administered immediately, prepared solutions may be stored refrigerated for 
up to 20 hours.  MK-3475 solutions may be stored at room temperature for a 
cumulative time of up to 4 hours.  This includes room temperature storage of 
liquid drug product solution in vials, room temperature storage of infusion 
solution in the IV bag, and the duration of infusion. 
 
i. 
ROUTE OF ADMINISTRATION 
 
IV infusion only.  Do not administer as an IV push or bolus injection. 
 
j. 
METHOD OF ADMINISTRATION 
 
Infuse over approximately 30 minutes (range: 25 - 40 minutes) using an 
infusion set containing a low-protein binding 0.2 to 5 μm in-line filter made of 
polyethersulfone or polysulfone.  Infusion rate should not exceed 6.7 mL/min.  
A central line is not required; however if a subject has a central venous 
catheter in place, it is recommended that it be used for the infusion.  Do not 
co-administer other drugs through the same infusion line.  Following the 
infusion, flush the IV line with normal saline. 
 
Compatible infusion set materials: PVC plasticized with DEHP or DEHT, 
PVC and tri-(2-ethylhexyl) trimellitate, polyethylene lined PVC, polyurethane, 
or polybutadiene 
 
k. 
PATIENT CARE IMPLICATIONS 
 
Refer to Section 8.3a for information on evaluation and management of 
potential immune-related adverse events. 

S1404 
 
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Version Date 11/27/2023 
 
l. 
DRUG ORDERING AND ACCOUNTABILITY  
 
1. 
Drug Ordering 
 
Study specific supplies will be provided to sites once a patient has 
been randomized. Starter supplies will not be provided. NCI 
supplied agents may be requested by the Principal Investigator 
(or their authorized designee) at each participating institution. 
Pharmaceutical Management Branch (PMB) policy requires that 
drug be shipped directly to the institution where the patient is to 
be treated. PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained). The 
CTEP assigned protocol number (S1404) must be used for 
ordering all CTEP supplied investigational agents. The 
responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of 
FDA Form 1572 and a CV. If there are several participating 
investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one 
lead investigator at that institution.  Active CTEP-registered 
investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB 
Online 
Agent 
Order 
Processing 
(OAOP) 
application 
at 
https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx. Access to 
OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account (https://eapps-ctep.nci.nih.gov/iam/) 
and the maintenance of an “active” account status and a “current” 
password.  For questions about drug orders, transfers, returns, or 
accountability, call 240/276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov 
anytime. 
 
2. 
Drug Handling and Accountability (NCI logs or other) 
 
The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, 
disposition, and disposal of all drugs received from the supplier 
using the NCI Drug Accountability Record Form (DARF) available 
at http://ctep.cancer.gov.  
  
Electronic logs are allowed as long as a print version of the log 
process has the exact same appearance as the current NCI 
DARF. 
 
3. 
Drug return and/or disposition instruction  
 
b. 
Drug Disposition: All undispensed drug supplies should 
be returned to the PMB.  When it is necessary to return 
study drug (e.g., sealed bottles remaining when PMB 
sends a stock recovery letter), investigators should return 
the study drug to the PMB using the NCI Return Agent 
Form 
available 
on 
the 
NCI 
home 
page 
(http://ctep.cancer.gov). 
 
c. 
Drug Expiration:  Stability testing is ongoing. PMB will 
send a stock recovery letter when notified that the agent 
is no longer suitable for use. 
 

S1404 
 
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Version Date 11/27/2023 
4. 
Contact Information 
 
Questions about drug orders, transfers, returns or accountability 
should be addressed to the PMB by calling 240/276-6575 Monday 
through Friday between 8:30 am and 4:30 pm Eastern Time or 
email at PMBAfterHours@mail.nih.gov.  
 
 
 

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4.0 
STAGING CRITERIA (AJCC 7TH Edition, 2010) 
 
Pathologic Staging included in this trial: 
 
Stage IIIA  
T1-T4a 
N2a 
M0 
Stage IIIB 
T1-4a 
N1-N2b 
M0 
 
T1b (ulcerated) N1-N2a  
M0 
 
T2b-4b 
N1-N2a 
MO 
 
T1-4a.b 
N2c 
M0 
Stage IIIC 
T1-4b 
N1-N2b 
M0 
 
Any T 
N3 
M0 
Stage IV 
Any T 
Any N 
M1 
 
See Section 18.5 for TNM Definitions for Pathologic Staging. 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be 
considered eligible for registration.  Use the S1404 Eligibility Checklist to confirm a patient's 
eligibility.  For each criterion requiring test results and dates, please record this information 
on the Onstudy Form and submit via Medidata Rave® (see Section 14.0).  Any potential 
eligibility issues should be addressed to the Data Operations Center in Seattle at 
melanomaquestion@crab.org prior to registration. 
 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0.  Therefore, if a test is done on a Monday, the Monday 2 weeks later 
would be considered Day 14.  This allows for efficient patient scheduling without exceeding 
the guidelines.  If Day 14, 28, 42 or 90 falls on a weekend or holiday, the limit may be 
extended to the next working day. 
 
5.1 
STEP 1 REGISTRATION 
 
Disease Related Criteria 
 
a. 
Patients must have completely resected melanoma of cutaneous origin or 
of unknown primary in order to be eligible for this study.  Patients must be 
classified as Stage IIIA (N2a), IIIB, IIIC, or Stage IV melanoma. Patients 
with non-ulcerated T1b N1a disease are not eligible. Patients with 
melanoma of mucosal or other non-cutaneous origin are eligible.  Patients 
with melanoma of ocular origin are not eligible.  Patients with a history of 
brain metastases are ineligible. 
 
b. 
Patients are eligible for this trial either at initial presentation of their 
melanoma or at the time of the first detected nodal, satellite/in-transit, 
distant metastases, or recurrent disease in prior lymphadenectomy basin 
or distant site.  Nodal, satellite/in-transit metastasis, distant metastases or 
disease in a prior complete lymphadenectomy basin must have been 
confirmed histologically by H & E stained slides. 
 
c. 
Patients with multiple regional nodal basin involvement are eligible. Gross 
or microscopic extracapsular nodal extension is permitted. 
   
d. 
Patients at initial presentation of melanoma must undergo an adequate 
wide excision of the primary lesion, if present. (See Section 18.1 for 
guidelines on surgical management.)  Patients with previously diagnosed 
melanoma must have had all current disease resected with pathologically 
negative margins and must have no evidence of disease at the primary 
site or must undergo re-resection of the primary site.  A full 

S1404 
 
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Version Date 11/27/2023 
lymphadenectomy meeting the criteria outlined in Section 18.1 is required 
for all node-positive patients including those with positive sentinel nodes.  
Patients with recurrent disease who have had a prior complete 
lymphadenectomy fulfill this requirement as long as all recurrent disease 
has been resected.  For all patients, all disease must have been resected 
with negative pathological margins and no clinical, radiologic, or 
pathological evidence of any incompletely resected melanoma.  Patients 
must be registered within 98 days of the last surgery performed to 
render the patient free of disease. 
 
Specimen Submission Criteria 
 
e. 
Patients must have available and be willing to submit a minimum of five 
unstained slides from primary, lymph node, or metastatic site to determine 
PD-L1 expression as described in Section 15.2.  The tumor tissue must 
be adequate for PD-L1 testing (defined as ≥ 100 tumor cells as confirmed 
by the treating institution’s local pathologist). This must be documented by 
having a pathologist sign the S1404 Local Pathology Review form (see 
Section 18.4) prior to Step 1 registration. The specimens may come from 
an archived block but must be submitted within 20 days from cutting the 
slides. 
 
f. 
Patients must be offered the opportunity to participate in specimen 
banking as outlined in Section 15.3. 
 
g. 
Patients must be willing to have blood draws for PK/ADA analysis as 
outlined in Section 15.4, should the patient be randomized to the MK-3475 
arm. 
 
Prior/Concurrent Therapy Criteria 
 
h. 
Patients may have received prior radiation therapy, including after the 
surgical resection.  All adverse events associated with prior surgery and 
radiation therapy must have resolved to ≤ Grade 1 prior to registration. 
 
i. 
Patients must not have received neoadjuvant treatment for their 
melanoma. Patients must not have had prior immunotherapy including, but 
not limited to ipilimumab, interferon alfa-2b, high dose IL-2, PEG-IFN, anti-
PD-1, anti-PD-L1 intra-tumoral or vaccine therapies. Patients must not be 
planning to receive any of the prohibited therapies listed in Section 7.2 
during the screening or treatment phases of the study. 
 
j. 
Patients must not be planning to receive concomitant other biologic 
therapy, radiation therapy, hormonal therapy, other chemotherapy, 
surgery or other therapy after Step 2 registration. 
 
Clinical/Laboratory Criteria 
 
k. 
Patients must be ≥ 18 years of age.   
 
l. 
All patients must have disease-free status documented by a complete 
physical examination and imaging studies within 42 days prior to 
registration.  Imaging studies must include a total body PET-CT scan that 
is of diagnostic quality (with or without brain) or a CT of the chest, 
abdomen and pelvis. For patients with melanoma arising from the head 
and neck, dedicated neck imaging (CT with IV contrast or PET-CT through 
the region) is required.  If the patient has had unknown primary with 
disease in the axilla, neck imaging is required to assure region is clear of 
cancer. CT imaging should be done with intravenous contrast if there are 

S1404 
 
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Version Date 11/27/2023 
no contraindications for it.  Any other clinically-indicated imaging studies if 
performed (e.g. bone scan) must show no evidence of disease. 
 
m. 
All patients must have a CT or MRI of the brain within 90 days prior to 
registration.  The brain CT or MRI should be performed with intravenous 
contrast (unless contraindicated).   
 
n. 
Patients must have adequate bone marrow function as evidenced by all of 
the following:  ANC ≥ 1,500 microliter (mcL); platelets ≥ 100,000/mcL; 
Hemoglobin ≥ 10 g/dL.  These results must be obtained within 42 days 
prior to registration. 
 
o. 
Patients must have adequate hepatic function as evidenced by the 
following: total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) 
(except Gilbert’s Syndrome, who must have a total bilirubin < 3.0 mg/dL), 
and SGOT (AST) and SGPT (ALT) and alkaline phosphatase ≤ 2 x IULN.  
These results must be obtained within 42 days prior to registration. 
 
p. 
Patients must have adequate renal function as evidenced by ONE of the 
following: serum creatinine ≤ IULN OR measured or calculated creatinine 
clearance ≥ 60 mL/min.  This result must have been obtained within 42 
days prior to registration. 
 
Calculated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 
72 x creatinine (mg/dl) 
 
q. 
Patients must have LDH performed within 42 days prior to registration. 
 
r. 
Patients must have Zubrod Performance Status ≤ 1 (see Section 10.4). 
 
s. 
Patients must have a baseline ECG performed within 42 days of 
registration that is normal or considered not clinically significant by the site 
investigator. 
 
t. 
Patients must not have a history of (non-infectious) pneumonitis that 
required steroids or current pneumonitis. 
 
u. 
Patients must not have an active infection requiring systemic therapy. 
 
v. 
Patients must not have active autoimmune disease that has required 
systemic treatment in past 2 years (i.e., with use of disease modifying 
agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. 
 
w. 
Patients must not have received live vaccines within 42 days prior to 
registration.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, shingles, yellow fever, 
rabies, BCG, and typhoid (oral) vaccine.  Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, 
intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
 
x. 
Patients known to be HIV positive are eligible if they meet the following 
criteria within 30 days prior to registration:  stable and adequate CD4 
counts (≥ 350 mm3), and serum HIV viral load of < 25,000 IU/ml.  Patients 
may be on or off anti-viral therapy so long as they meet the CD4 count 
criteria. 

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y. 
Patients must not have known active Hepatitis B Virus (HBV) or Hepatitis 
C Virus (HCV) infection prior to registration. 
 
z. 
Patients must not have a history or current evidence of any condition, 
therapy or laboratory abnormality that might confound the trial results, 
interfere with the patient's participation for the full duration of the trial, or 
indicate that participation in the trial is not in the patient's best interests, in 
the opinion of the treating investigator. 
 
aa. 
No other prior malignancy is allowed except for the following:  adequately 
treated basal cell or squamous cell skin cancer, in situ cervical cancer, 
lobular carcinoma of the breast in situ, atypical melanocytic hyperplasia or 
melanoma in situ, adequately treated Stage I or II cancer (including 
multiple primary melanomas) from which the patient is currently in 
complete remission, or any other cancer from which the patient has been 
disease free for three years.  
 
bb. 
Women of childbearing potential must have a negative urine or serum 
pregnancy test within 28 days prior to registration.  Women/men of 
reproductive potential must have agreed to use an effective contraceptive 
method for the course of the study through 120 days after the last dose of 
study medication.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately. A woman is considered to be of 
"reproductive potential" if she has had menses at any time in the preceding 
12 consecutive months.  In addition to routine contraceptive methods, 
"effective contraception" also includes heterosexual celibacy and surgery 
intended to prevent pregnancy (or with a side-effect of pregnancy 
prevention) defined as a hysterectomy, bilateral oophorectomy, or bilateral 
tubal ligation.  However, if at any point a previously celibate patient 
chooses to become heterosexually active during the time period for use of 
contraceptive measures outlined in the protocol, he/she is responsible for 
beginning contraceptive measures.  Patients must not be pregnant or 
nursing due to unknown teratogenic side effects.   
 
cc. 
Patients who are able to complete questionnaires in English, Spanish or 
French must participate in the quality of life assessments. (Those patients 
who cannot complete the quality of life questionnaires in English, Spanish 
or French can be registered to S1404 without contributing to the quality of 
life studies.) 
 
 

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Regulatory Criteria 
 
dd. 
Patients must be informed of the investigational nature of this study and 
must sign and give written informed consent for this protocol in accordance 
with institutional and federal guidelines. 
 
ee. 
As a part of the OPEN registration process (see Section 13.4 for OPEN 
access instructions) the treating institution's identity is provided in order to 
ensure that the current (within 365 days) date of institutional review board 
approval for this study has been entered in the system. 
 
5.2 
STEP 2 REGISTRATION (Randomization) 
 
An e-mail notification from the SWOG Statistical Center should be received within 
10 business days of submitting tissue as described in Section 15.2. 
 
The following additional criteria must be met in order for a patient to be considered 
eligible for registration to the randomized trial. Any potential eligibility issues should 
be 
addressed 
to 
the 
Data 
Operations 
Center 
in 
Seattle 
at 
melanomaquestion@crab.org prior to registration. 
 
a. 
Patients must not be registered until receiving confirmation from the 
SWOG Statistical Center that the patient's tissue specimen was adequate 
for PD-L1 testing.  Patients must be registered within 7 working days of 
receiving the e-mail notification. 
 
b. 
Women of childbearing potential must plan to have a urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study 
medication.  If the urine test is positive or cannot be confirmed as negative, 
a negative serum pregnancy test will be required. 
 
c. 
No tests or exams are required to be repeated for Step 2 registration 
(Randomization).  However, patients who are known to have a change in 
eligibility status after Step 1 registration are not eligible for Step 2 
registration.  For example, ANC is not required to be repeated between 
Step 1 and Step 2 registration, but the most recent ANC performed before 
Step 2 registration is required to be ≥ 1,500 mcL. 
 
 
6.0 
STRATIFICATION FACTORS 
 
Patients will be randomized between Arm 1 – physician/patient choice of either high dose 
interferon or ipilimumab and Arm 2 – MK-3475 (pembrolizumab) in a 1:1 fashion, using a 
randomized block design. Stratification is based on:  
 
1) surgically resected AJCC stage: 
 
IIIA (N2a) versus IIIB versus IIIC versus IV  
 
2) PD-L1 status (see Section 15.2): positive versus negative versus indeterminate 
 
(NOTE:  Institutions will be blinded to the patient's PD-L1 status.) 
 
3) Planned control arm regimen *: high dose interferon versus ipilimumab. 
 
* NOTE:  The intended control arm regimen must be declared prior to randomization for 
all patients. 
 
 

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7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Sapna Patel at 713/792-
2921 (or S1404SCquestion@swog.org).  For dosing principles or questions, please consult 
the SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org 
(then click on "Policies and Procedures" under the "About" menu and choose Policy 38). 
 
7.1 
Treatment 
 
a. 
Pretreatment Labs: 
 
Blood samples collected for pretreatment laboratory tests must be 
collected and analyzed no more than 3 days prior to dosing. Albumin, 
glucose, and electrolytes (Na, K, HC03 or CO2) are required within 3 days 
prior to dosing to obtain baseline data for future toxicity assessments. 
 
 

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b. 
Arm 1: Physician/Patient Choice of Either High Dose Interferon or 
Ipilimumab 
 
1. 
High Dose Interferon 
 
Induction Therapy 
 
Agent 
Dose 
Route 
Days
 
Schedule 
 
Interferon Alfa-2b 
20 MU/m2/d* 
IV over 
1-5
 
Weeks 1 - 4 
 
 
20 min 
5 days  
 
 
 
a week 
 
 
* Dose rounding ± 10% is allowable per institutional 
standards. 
 
For the purpose of data reporting, 1 cycle = 6 weeks (4 weeks of 
HDIFN plus first 2 weeks of IFN maintenance.). 
 
If possible, on the days when patients are required to come in for 
a clinic visit, Interferon treatment should be administered after all 
questionnaires, 
procedures 
and 
assessment 
have 
been 
completed. 
 
Interferon doses must be rounded to the nearest 1 million unit.  
Interferon is given over a 20 minute infusion. Day 1 of each week 
of induction therapy should be administered at the registering 
institution.  Days 2 – 5 of interferon administration for Weeks 1 - 4 
may be administered at an institution other than the registering 
institution provided that during treatment to-date, the patient has 
not encountered any life-threatening or unusual toxicities and that 
the registering physician still retains primary responsibility for the 
patient's treatment.  Documentation concerning all drugs 
administered, side effects, and tests performed must be forwarded 
to the registering institution. Home Health Agencies (HHA) may 
be used to treat patients. The registering institution must 
document any care given at an outside institution.  
 
 

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Maintenance Therapy 
 
Agent 
Dose 
Route 
Days
 
Schedule 
 
Interferon Alfa-2b 
10 MU/m2/d* 
SC 
1, 
3, 
5
 
Weeks 5 - 52 
 
 
 
M,W,F 
 
For the purpose of data reporting, Cycle 2 (Weeks 7-12) 
is 6 weeks, and all subsequent cycles are 12 weeks. 
 
Self-Administration of Subcutaneous Doses 
 
Interferon doses must be rounded to the nearest 1 million unit.  
Patients who are deemed competent to self-administer the 
subcutaneous maintenance doses of Interferon alfa-2b may do so 
following the first 4 weeks of treatment. Patients must complete 
compliance documentation (Section 7.3) for self-administered 
doses. If patient cannot self-administer, a nurse, or qualified HHA 
staff may administer the injections. The registering institution must 
document any care given at an outside institution.   
* Dose rounding ± 10% is allowable per institutional 
standards. 
 
2. 
Ipilimumab 
 
Induction Therapy 
 
Agent 
Dose 
Route 
Days
 
Schedule 
 
Ipilimumab 
10 mg/kg* 
IV infusion 
1
 
Weeks 1-10;  
 
 
over 90 
 
Q 
3 
weeks  
 
 
minutes 
 
for a 
total of  
 
 
 
 
four 
doses 
 
For the purpose of data reporting, 1 cycle = 6 weeks. 
* Dose rounding ± 10% is allowable per institutional 
standards. 
 
If possible, on the days when patients are required to come in for 
a clinic visit, treatment should be administered after all 
questionnaires, 
procedures 
and 
assessment 
have 
been 
completed. 
 
The final concentration must be between 1-2 mg/mL. 
 
Maintenance Therapy 
 
Agent 
Dose 
Route 
Days
 
Schedule 
 

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Ipilimumab 
10 mg/kg* 
IV infusion 
1 
Weeks 
25-145;  
 
 
over 90 
 
Q 
12 
weeks  
 
 
minutes 
 
for 
11 
doses  
 
 
 
 
ending 
at  
 
 
 
 
3 years) 
 
For the purpose of data reporting, 1 cycle = 12 weeks. 
* Dose rounding ± 10% is allowable per institutional 
standards. 
 
If possible, on the days when patients are required to come in for 
a clinic visit, treatment should be administered after all 
questionnaires, 
procedures 
and 
assessment 
have 
been 
completed. 
 
The final concentration must be between 1-2 mg/mL. 
 
c. 
Arm 2: MK-3475 (Pembrolizumab) 
 
Agent 
Dose 
Route 
Schedule 
 
MK-3475 
200 mg 
IV 
Day 1, Q 3 
weeks  
(Pembrolizumab) 
 
over 30 
for 52 weeks 
 
 
minutes 
 
 
For the purpose of data reporting, Cycle 1 and Cycle 2 are 6 weeks and 
all subsequent cycles are 12 weeks. 
 
MK-3475 (pembrolizumab) treatment should be administered after all 
questionnaires, procedures and assessments have been completed.  MK-
3475 (pembrolizumab) treatment may be administered up to 3 days before 
or after the protocol-specified Q 3 weeks due to administrative reasons.   
 
MK-3475 (pembrolizumab) treatment will be administered on an outpatient 
basis. 
 
MK-3475 (pembrolizumab) will be administered as a 30 minute IV infusion. 
Infusion timing should be as close to 30 minutes as possible; however, a 
window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 
25-40 minutes).  
 
Dosing interruptions are permitted in the case of medical / surgical events 
or logistical reasons not related to study therapy (e.g., elective surgery, 
unrelated medical events, patient vacation, and/or holidays). Patients 
should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Study Chairs. The 
reason for interruption should be documented in the patient's study record. 
 
All planned doses must be administered.  Missed doses must be made up. 
 
7.2 
Prohibited and Cautionary Medications 
 
Radiation therapy must be completed at least 1 day prior to starting ipilimumab or 
MK-3475 and must be completed at least 7 days prior to starting interferon. 

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Patients are prohibited from receiving the following therapies after registration to 
Step 1 and through completion of protocol therapy: 
 
x 
Anti-cancer systemic chemotherapy or biological therapy.  
x 
Immunotherapy not specified in this protocol. 
 
Any non-study anti-cancer agent (investigational or non-investigational). 
x 
Investigational agents other than MK-3475. 
x 
Live vaccines: Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, chicken pox, shingles, yellow 
fever, rabies, BCG, and typhoid (oral) vaccine.  Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed; 
however, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
x 
Glucocorticoids for any purpose other than to modulate symptoms from an 
event of suspected immunologic etiology.  The use of physiologic doses 
of corticosteroids (defined as 10 mg prednisone) are acceptable, however 
site investigators should consult with the Study Chair for any dose higher 
than 10 mg prednisone. 
 
Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from 
protocol treatment.  Patients may receive other medications that the investigator 
deems to be medically necessary. 
 
7.3 
Drug Compliance Documentation 
 
Patients who self-administer interferon alfa-2b, may complete the S1404 Patient 
Interferon Diary which can be found in Section 18.3.  Institutional CRAs will review 
and ascertain patient adherence with protocol therapy at the end of treatment for 
each cycle.  The completed patient diary should be kept in the patient's clinic chart.  
Note that the diary is provided only as a tool for tracking patient compliance. Do 
not submit patient diaries to the SWOG Data Operations Office.  Sites may utilize 
institutional diaries or other source documentation in place of the S1404 Patient 
Interferon Diary at the discretion of the treating physician. The completed 
Interferon Diary, institutional diary, or other source documentation in place of the 
S1404 Interferon Diary must be available for upload if requested as part of the risk 
based monitoring. 
 
 

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7.4 
Criteria for Removal from Protocol Treatment 
 
a. 
Recurrence of disease (as defined in Section 10.0). 
 
b. 
Unacceptable toxicity.  
 
c. 
The patient may withdraw from the study at any time for any reason. 
 
d. 
The investigator may discontinue treatment if they determine that the 
patient’s continued treatment on the study is detrimental to their long-term 
health, or due to poor compliance with the study’s required visits and 
treatments. 
 
e. 
Positive pregnancy test. 
 
f. 
Completion of protocol treatment. 
 
g. 
Patients will be removed from protocol treatment if there is a treatment 
delay > 84 consecutive days for any reason. 
 
7.5 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off 
Treatment Notice. 
 
7.6 
Follow-Up Period, End of Study 
 
Randomized patients will be followed until death or 10 years after randomization, 
whichever occurs first. 
 
 
 

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8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) Version 5.0 for toxicity and Serious Adverse Event reporting.  A copy of 
the CTCAE Version 5.0 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov).  All appropriate treatment areas should have access to a 
copy of the CTCAE Version 5.0. 
 
8.2 
Dose Modification Considerations for Patients Receiving Interferon (Arm 1)  
 
a. 
General 
 
Induction therapy by the IV route in Weeks 1-4 shall be evaluated 
separately from Maintenance therapy in Weeks 5-52.  A patient requiring 
dose modification(s) in the first 4 weeks will therefore commence Week 5 
at full dose.  Doses missed during treatment due to toxicity, patient 
compliance, holiday, etc. should not be made up. 
 
 

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b. 
Arm 1 – IFN Dose Modification Table 
 
 
Full Dose 
Dose mod 1 
Dose mod 2 
Dose mod 3 
Induction 
(Weeks 1-4) 
20 MU/m2 
13.3 MU/m2 
6.6 MU/m2 
Remove 
from protocol 
treatment 
Maintenance 
(Weeks 5-52) 
10MU/m2 
6.6 MU/m2 
3.3 MU/m2 
Remove 
from protocol 
treatment 
 
PLEASE NOTE: If a patient experiences any of the toxicities listed below, 
the patient must have a dose modification as follows: treatment must be 
held until the toxicity returns to institution’s normal limits, patient’s 
baseline, or normal limits per CTCAE or as listed in the table under Section 
8.2c, then reduced per above.  
 
EXCEPTIONS: For Grade 3 proteinuria without creatinine or BUN 
elevation, dose should be held until return to Grade 2 toxicity. For Grade 
2 weight loss observed over a period of one month, dose should be held 
until weight gain or stabilization. 
 
Dose modifications outside of the guidelines prescribed below are allowed 
at the discretion of the treating physician if: 
 
x 
The modification is being performed due to toxicity related to HDI 
therapy; and, 
x 
After consideration of the patient’s safety and overall clinical 
status, the treating physician feels that the modification is in the 
patient’s best interest. 
 
Any modifications outside of the prescribed guidelines must be 
documented in the comment section of the S1404 Treatment Form. 
 
 

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c. 
ARM 1 (IFN) TOXICITIES TO BE MONITORED AND DOSE 
MODIFICATIONS (24) 
 
TOXICITY 
GRADE 2 
GRADE 3 
GRADE 4 
Blood/Bone Marrow 
Thrombocytopenia 
 
 
Anemia 
 
 
 
 
 
 
Neutropenia 
 
Full Dose 
 
 
 
Hold therapy* 
until return to 
Grade 1 or 
baseline; 
reduce one 
dose level 
 
Full Dose 
 
Hold therapy*; 
Reduce one 
dose level 
 
Hold therapy* 
until return to 
Grade 1 or 
baseline; 
reduce one 
dose level 
 
 
Full Dose 
 
Remove 
from protocol 
treatment 
 
Remove 
from protocol 
treatment 
 
 
 
 
Reduce one 
dose level 
Cardiovascular 
Arrhythmia 
Cardiac-Other 
 
Hold therapy 
until return to 
normal*; 
reduce one 
dose level 
after formal 
cardiologic 
evaluation and 
clearance 
 
Removal from 
protocol 
treatment 
 
Removal 
from 
protocol 
treatment 
Gastrointestinal 
Nausea, vomiting 
and/or diarrhea 
 
 
 
 
 
Weight loss 
 
Administer 
supportive 
care; if 
persistent for 
more than 2 
weeks, reduce 
one dose level 
 
Hold therapy 
for weight loss 
observed over 
a 1 month 
period until 
weight gain or 
stabilization* 
 
Hold 
therapy*; 
reduce one 
dose level 
 
Removal 
from 
protocol 
treatment 
Hepatic 
ALK PHOS. 
Bilirubin or  
SGOT(AST)/SGPT 
(ALT) 
 
Full Dose 
 
Hold therapy 
until return to 
≤ Grade 1*; 
reduce one 
dose level 
 
Removal 
from 
protocol 
treatment 
 
Neurology 
Cognitive 
disturbance 
Mood alteration 
Neuropathy – motor 
 
 
Full Dose 
 
 
Hold therapy 
*; reduce one 
dose level 
(evaluation by 
specialist) 
 
 
Removal 
from 
protocol 
treatment 

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TOXICITY 
GRADE 2 
GRADE 3 
GRADE 4 
Neuropathy - 
sensory 
 
Renal/Genitourinary 
Proteinuria 
 
 
 
Creatinine 
 
 
Full Dose 
 
 
 
 
Hold therapy*; 
reduce one 
dose level 
 
 
Hold therapy 
until return to 
≤ Grade 2*; 
reduce one 
dose level 
 
Removal from 
protocol 
treatment 
 
 
Removal 
from 
protocol 
treatment 
 
 
Removal 
from 
protocol 
treatment 
 
*PLEASE NOTE:  If a patient experiences any of the toxicities listed in the above 
table, the patient must have a dose modification as indicated (unless otherwise 
specified).  Treatment must be held until the toxicity returns to institution’s normal 
limits, patient’s baseline, or normal limits per the Common Terminology Criteria for 
Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov, then reduce as indicated 
above.  Dose re-escalation will not be attempted following resolution of toxicity that 
required dose interruption or attenuation. 
 
 

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8.3 
Dose Modification Considerations for Patients Receiving Ipilimumab (Arm 1) 
 
a. 
Dose and schedule modifications for ipilimumab 
 
There will be no dose reductions for ipilimumab. The dose of ipilimumab 
will either be given or delayed/discontinued. Patients may develop study 
drug-related toxicities that may require skipping doses or dose 
discontinuation. Some of these adverse events may be consistent with 
potentially drug-related immune-mediated phenomena; termed IRAEs. 
Details of how to dose study medication in the presence of adverse drug 
reactions that may or may not be IRAEs are addressed below.  
 
Patients will delay or discontinue treatment with ipilimumab if they 
experience at least one adverse event, specified below, considered by the 
investigator to be definitely, probably, or possibly related to ipilimumab 
treatment unless otherwise specified. The following criteria will be used to 
determine dosing delay, restarting doses, or discontinuing ipilimumab. For 
an adverse event, review the following criteria in a stepwise manner: First, 
assess the dose delay criteria and decide whether a scheduled dose 
should be delayed. Second, determine whether the permanent 
discontinuation criteria apply to the adverse event in question as well.  
 
NOTE: Due to the possible effect of treatment with ipilimumab on the 
immunologic response to infectious disease vaccines, patients must not 
have had any infectious disease vaccination (e.g., standard influenza, 
H1N1 influenza, pneumococcal, meningococcal, tetanus toxoid) 1 week 
before or after any dose of ipilimumab. 
 
b. 
Criteria to delay/skip one dose of ipilimumab  
 
**NOTE:  See also: Section 8.3e: Dose Modification and Management for 
Cardiomyophathy Myocarditis  
 
Delay ipilimumab dosing for any of the following definitely, probably, or 
possibly treatment related adverse events, unless otherwise specified:  
 
• Grade ≥ 1 diarrhea and/or colitis regardless of attribution. Grade ≥ 2 
diarrhea and/or colitis, definitely, probably, or possibly related to 
ipilimumab, requires permanent discontinuation.  
• Any other ≥ Grade 2 non-skin related adverse event (including IRAEs) 
except for laboratory abnormalities.  
• Grade ≥ 2 laboratory abnormalities that are secondary to an immune-
related adverse event or autoimmune phenomenon (e.g., Grade ≥ 2 
TSH associated with a CTCAE v.4 grade 2 thyroid dysfunction induced 
by 
ipilimumab, 
anemia, 
neutropenia, 
amylase, 
lipase, 
CPK, 
hyperglycemia, or elevated LFTs) should also lead to an ipilimumab 
dosing delay/skipping.  
• Any other ≥ Grade 3 laboratory abnormality.  
• Any ≥ Grade 3 skin-related adverse event (including IRAEs) regardless 
of attribution.  
 
c. 
Criteria to resume ipilimumab treatment  
 
**NOTE:  See also: Section 8.3e: Dose Modification and Management for 
Cardiomyophathy Myocarditis 
 

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Ipilimumab may not be restarted while the patient is being treated with 
oral or intravenous corticosteroids for the management of immune related 
adverse events except for patients on stable doses of hormone 
replacement therapy for adrenal insufficiency such as hydrocortisone. In 
addition, patients must be off and have no requirement for oral/I.V. 
corticosteroids for at least 1 week and meet the other criteria for 
retreatment as outlined below. 
 
Restart ipilimumab dosing if/when the adverse event(s) resolve(s) to ≤ 
Grade 1 severity or returns to baseline within 3 weeks of last dose 
administration:  
 
• If the adverse event has resolved (to ≤ Grade 1 severity or returns to 
baseline), restart ipilimumab dosing at the next scheduled time point per 
protocol.  
• If the adverse event has not resolved in the protocol-specified dosing 
window, the next scheduled dose will be omitted.  
• Patients with Grade 1 diarrhea and/or colitis who require steroid therapy 
must have resolution to Grade 0 (or baseline) before resuming dosing 
with ipilimumab. Patients with Grade ≥ 2 related diarrhea and/or colitis 
must have ipilimumab permanently discontinued.  
 
d. 
Criteria for permanent discontinuation of ipilimumab for Related Adverse 
Events  
 
**NOTE:  See also: Section 8.3e: Dose Modification and Management for 
Cardiomyophathy Myocarditis 
 
Ipilimumab administration must be permanently discontinued for any of the 
following definitely, probably, or possibly treatment related adverse 
events, unless otherwise specified: 
 
• Any ≥ Grade 2 eye pain or reduction of visual acuity that does not 
respond to topical therapy and does not improve to ≤ Grade 1 severity 
within 2 weeks of starting therapy, OR, requires systemic treatment.  
• Any ≥ Grade 2 diarrhea and/or colitis related to ipilimumab. Any ≥ Grade 
2 diarrhea/colitis should be considered RELATED unless immune 
related colitis is definitely ruled out (including by endoscopy and biopsy.)  
• Any ≥ Grade 2 hypophysitis, pneumonitis, nephritis, and/or sarcoid-like 
lesions.  
• Any new motor or sensory neurologic toxicity ≥ Grade 2 regardless of 
attribution (including Guillain-Barré syndrome and myasthenia gravis).  
• Any ≥ Grade 3 bronchospasm or other hypersensitivity reaction.  
• Any other ≥ Grade 3 non-skin adverse event with the exception of events 
listed under “Exceptions to Permanent Discontinuation”  
• AST or ALT > 5 x ULN.  
• Total Bilirubin > 3 x ULN.  
• Any other ≥ Grade 4 laboratory abnormalities except for specified 
exceptions  
• Any other ≥ Grade 4 adverse event.  
• Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash 
complicated by full thickness dermal ulceration or necrotic, bullous, or 
hemorrhagic manifestations.  
• Any adverse event, laboratory abnormality or intercurrent illness which, 
in the judgment of the investigator, presents a substantial clinical risk to 
the patient with continued dosing.  
• Patients who require high dose steroids, other immune suppressants or 
anti-TNF drug therapy for the management of immune related adverse 

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events as described in the Toxicity Management Guidelines/Algorithms 
should have ipilimumab permanently discontinued.  
 
 

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e. 
Dose Modification and Management for Cardiomyopathy Myocarditis 
 
• Drug will be held for Grade 2 cardiac dysfunction pending evaluation 
• Drug will be permanently discontinued for Grade 3 or 4 cardiac 
dysfunction and Grade 2 events that do not recover to baseline or that 
reoccur 
• Treatment with steroids as clinically indicated  
 
 
Cardiac *   
Management/Next Dose for BMS-936558 (Nivolumab) + Ipilimumab 
Cardiac Toxicities  
≤ Grade 1  Hold dose pending evaluation and observation.**  Evaluate for signs and 
symptoms of CHF, ischemia, arrhythmia or myositis.  Obtain history 
EKG, CK (for concomitant myositis), CK-MB.  Repeat troponin, CK and 
EKG 2-3 days.  If troponin and labs normalize may resume therapy.  If 
labs worsen or symptoms develop then treat as below.  Hold pending 
evaluation.  
Grade >2 
with 
suspected 
myocarditis 
 Hold dose.**  Admit to hospital.  Cardiology consult.  Rule out MI and 
other causes of cardiac disease.  Cardiac Monitoring.  Cardiac Echo.  
Consider cardiac MRI and cardiac biopsy.  Initiate high dose 
methylprednisolone.  If no improvement within 24 hours, add either 
infliximab, ATG or tacrolimus. Resume therapy if there is a return to 
baseline and myocarditis is excluded or considered unlikely. 
Grade >2 
with 
confirmed 
myocarditis   
Off protocol therapy.  Admit to CCU (consider transfer to nearest Cardiac 
Transplant Unit).  Treat as above.  Consider high dose 
methylprednisolone.   
Add ATG or tacrolimus if no improvement.  Off treatment. 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated according as 
“other event”   
Note:  The optimal treatment regimen for immune mediated myocarditis has not been 
established.  Since this toxicity has caused patient deaths, an aggressive approach is 
recommended.   
 
 
 

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f. 
Exceptions to permanent discontinuation of ipilimumab  
 
Ipilimumab administration may be resumed in the following cases:  
 
• Potentially reversible inflammation (< Grade 4), attributable to a local 
anti-tumor reaction and a potential therapeutic response. This includes 
inflammatory reactions at sites of tumor resections or in draining lymph 
nodes, or at sites suspicious for, but not diagnostic of metastasis.  
• Laboratory abnormalities that are rapidly reversible, not life threatening, 
do not reflect underlying organ system dysfunction, and are not related 
to the study treatment, such as transient elevations of uric acid, 
hypocalcaemia, hypophosphatemia.  
• Hospitalization for ≤ Grade 2 adverse events (not including Grade 2 
events that require permanent discontinuation) where the primary 
reason for hospitalization is to expedite the clinical work-up.  
• Patients with the following conditions where in the investigator’s opinion 
continuing study drug administration is justified:  
− Ocular toxicity that has responded to topical therapy and has improved 
to ≤ Grade 1 severity within 2 weeks of starting therapy.  
− Patients without a diagnosis of hypophysitis who have Grade 2 
hypothyroidism, Grade 2 low testosterone or Grade 2 adrenal 
insufficiency where clinical symptoms are controlled with appropriate 
hormone replacement therapy. 
 
8.4 
Dose 
Modification 
Considerations 
for 
Patients 
Receiving 
MK-3475 
(pembrolizumab) (Arm 2) 
 
a. 
General MK-3475 Dose Modifications 
 
Missed doses of MK-3475 must be made up. 
 
Adverse events (both non-serious and serious) associated with 
pembrolizumab exposure may represent an immunologic etiology.  These 
adverse events may occur shortly after the first dose or several months 
after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 1 below. 
See Section 8.4b for supportive care guidelines, including use of 
corticosteroids. 
 
NOTE:  Due to the possible effect of treatment with MK-3475 on the 
immunologic response to infectious disease vaccines, patients must not 
have had any infectious disease vaccination (e.g., standard influenza, 
H1N1 influenza, pneumococcal, meningococcal, tetanus toxoid) within 1 
week before or after any dose of MK-3475. 
 
Dose Modification 
 
Dose modification and toxicity management for immune-related AEs 
associated with pembrolizumab 
 
AEs associated with pembrolizumab exposure may represent an 
immunologic etiology. These immune-related AEs (irAEs) may occur 
shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is 
critical to reduce complications.  Based on existing clinical trial data, most 
irAEs were reversible and could be managed with interruptions of 
pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology 
or exclude other causes. Additional procedures or tests such as 

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bronchoscopy, endoscopy, skin biopsy may be included as part of the 
evaluation. 
 
 

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Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Dose modification and 
toxicity management guidelines for irAEs associated with pembrolizumab 
are provided in Table 1. 
 
 

S1404 
 
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Version Date 11/27/2023 
 
Table 1 Dose modification and toxicity management guidelines for 
immune-related AEs associated with pembrolizumab 
 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral 
steroids. Other immunosuppressive treatment should begin if the irAEs are not controlled by 
corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to 
≤ Grade 1 after corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies  
Monitoring and 
follow-up  
Pneumonitis  
Grade 2 
Withhold  
x  Administer 
corticosteroids 
(initial dose of 1 - 2 
mg/kg prednisone or 
equivalent) followed 
by taper 
x  Add prophylactic 
antibiotics for 
opportunistic 
infections 
x  Monitor 
participants for 
signs and 
symptoms of 
pneumonitis 
x  Evaluate 
participants with 
suspected 
pneumonitis with 
radiographic 
imaging and 
initiate 
corticosteroid 
treatment 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
x  Administer 
corticosteroids 
(initial dose of 1 - 2 
mg/kg prednisone or 
equivalent) followed 
by taper 
x  Monitor 
participants for 
signs and 
symptoms of 
enterocolitis (ie, 
diarrhea, 
abdominal pain, 
blood or mucus in 
stool with or 
without fever) and 
of bowel 
perforation (ie, 
peritoneal signs 
and ileus) 
x  Participants with 
≥Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing 
endoscopy to rule 
out colitis 
x  Participants with 
diarrhea/colitis 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 

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should be advised 
to drink liberal 
quantities of clear 
fluids. If sufficient 
oral fluid intake is 
not feasible, fluid 
and electrolytes 
should be 
substituted via IV 
infusion 
AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
x  Administer 
corticosteroids 
(initial dose of 
0.5 - 1 mg/kg 
prednisone or 
equivalent) followed 
by taper 
x  Monitor with liver 
function tests 
(consider weekly 
or more frequently 
until liver enzyme 
value returned to 
baseline or is 
stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
x  Administer 
corticosteroids 
(initial dose of 1 - 2 
mg/kg prednisone or 
equivalent) followed 
by taper 
Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglycemia 
New onset T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of E-cell 
failure 
Withhold d 
x  Initiate insulin 
replacement therapy 
for participants with 
T1DM 
x  Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
x  Monitor 
participants for 
hyperglycemia or 
other signs and 
symptoms of 
diabetes 
Hypophysitis 
Grade 2 
Withhold 
x  Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated 
x  Monitor for signs 
and symptoms of 
hypophysitis 
(including 
hypopituitarism 
and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroi-
dism  
Grade 2 
Continue 
x  Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate 
x  Monitor for signs 
and symptoms of 
thyroid disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroi-
dism 
Grade 2, 3, 4 
Continue 
x  Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care 
x  Monitor for signs 
and symptoms of 
thyroid disorders 

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Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold 
x  Administer 
corticosteroids 
(prednisone 
1 – 2 mg/kg or 
equivalent) followed 
by taper 
x  Monitor changes 
of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
x  Based on severity of 
AE administer 
corticosteroids 
x  Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All Other 
immune-
related AEs 
Persistent Grade 2 
Withhold 
x  Based on severity of 
AE administer 
corticosteroids 
x  Ensure adequate 
evaluation to 
confirm etiology or 
exclude other 
causes 
Grade 3 
Withhold or 
discontinue 
based on the 
event e  
Recurrent Grade 3 
or Grade 4  
Permanently 
discontinue 
a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; 
bilirubin:>3.0 - 10.0 x ULN if baseline normal; >3.0 - 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d  The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the 
investigator or treating physician. If control achieved or ≤ Grade 2, pembrolizumab may be 
resumed. 
e  Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, 
encephalitis, Stevens-Johnson Syndrome and toxic epidermal necrolysis. 
 
Other allowed dose interruption for pembrolizumab  
 
Pembrolizumab may be interrupted for situations other than treatment-
related AEs such as medical / surgical events or logistical reasons not 
related to study therapy. Participants should be placed back on study 
therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be 
documented in the patient's study record. 
 
 

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Dose modification and toxicity management of infusion-reactions 
related to pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions 
including severe hypersensitivity or anaphylaxis. Signs and symptoms 
usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Dose modification 
and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table Y. 
 
Dosing interruptions are permitted in the case of medical/surgical events 
or logistical reasons not related to study therapy (e.g., elective surgery, 
unrelated medical events, patient vacation, and/or holidays). Patients 
should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Study Chair. The reason 
for interruption should be documented in the patient's study record. 
 
b. 
Management of Infusion Reactions 
 
x 
Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of 
completion of infusion  
 
Table 2 below shows treatment guidelines for subjects who experience 
an infusion reaction associated with administration of MK-3475 
(pembrolizumab). 
 
Table 2 Pembrolizumab Infusion Reaction Dose modification and 
Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital 
signs as medically indicated 
until the participant is 
deemed medically stable in 
the opinion of the 
investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hrs 
Stop Infusion. 
Additional appropriate 
medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital 
signs as medically indicated 
until the participant is 
deemed medically stable in 
the opinion of the 
investigator. 
If symptoms resolve within 
1 hour of stopping drug 
infusion, the infusion may 
be restarted at 50% of the 
original infusion rate (e.g. 
Participant may be 
premedicated 1.5h 
(± 30 minutes) 
prior to infusion of 
_____ with: 
Diphenhydramine 
50 mg po (or 
equivalent dose of 
antihistamine). 
Acetaminophen 
500-1000 mg po 
(or equivalent dose 
of analgesic). 

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NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent 
Dosing 
from 100 mL/hr to 50 
mL/hr).  Otherwise dosing 
will be held until symptoms 
resolve and the participant 
should be premedicated for 
the next scheduled dose. 
Participants who develop 
Grade 2 toxicity despite 
adequate premedication 
should be permanently 
discontinued from further 
study drug treatment 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate 
medical therapy may 
include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital 
signs as medically indicated 
until the participant is 
deemed medically stable in 
the opinion of the 
investigator. 
Hospitalization may be 
indicated. 
**In cases of anaphylaxis, 
epinephrine should be used 
immediately. 
Participant is 
permanently discontinued 
from further study drug 
treatment. 
No subsequent 
dosing 
Appropriate resuscitation equipment should be available at the bedside and a 
physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for 
Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 
 
8.5 
Use of Transfusion and/or EPO 
 
Transfusions and/or erythropoietin may be utilized as clinically indicated for the 
treatment of anemia, but should be clearly noted as concurrent medications on the 
S1404 Concomitant Medication Form.  Transfusion of platelets may be used if 
clinically indicated. ITP should be ruled out before initiation of platelet transfusion. 
 
8.6 
Use of G-CSF 
 

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Prophylactic use of colony-stimulating factors including Granulocyte Colony-
Stimulating Factor (G-CSF), pegylated G-CSF or Granulocyte Macrophage 
Colony-Stimulating Factor GM CSF is not allowed in this study.  Therapeutic use 
of G-CSF is allowed in patients with Grade 3-4 febrile neutropenia. 
 
8.7 
Anti-infectives 
 
Patients with a documented infectious complication should receive oral or IV 
antibiotics or other anti-infective agents as considered appropriate by the treating 
Investigator for a given infectious condition, according to standard institutional 
practice. Document on the S1404 Concomitant Medication Form. 
 
8.8 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact Dr. Sapna Patel at 
713/792-2921.  For dosing principles or questions, please consult the SWOG 
Policy #38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org 
(then click on "Policies and Procedures" under the "About" menu and choose 
Policy 38). 
 
8.9 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria 
as outlined in Section 16.0 of the protocol must be reported to the Operations 
Office, Study Chair and NCI via CTEP-AERS, and to the IRB per local IRB 
requirements. 
 

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9.0 
STUDY CALENDARS 
 
9.1 
Arm 1: Interferon alfa-2b 
 
Calendar continued on next page.  Click here for footnotes. 
 
 
Induction Phasea 
Days 1-5 (M-F) of 
Weeks 1-4 
Maintenance Phasea  
Days 1, 3, 5 (M, W, F) of Weeks 5-52 
End of 
treat-
ment 
assess-
mentb 
Post 
treat-
ment 
F/U 
prior to 
relapse  
Relapse
/Recu-
rrence 
F/U post 
relapsed 
REQUIRED 
STUDIES 
Pre- 
study 
screening 
Ran-
domiza-
tion 
Cycle 1 
C2 
C3 
C4 
C5 
C6 
W
1 
W
2 
W
3 
W
4 
W
5 
W 
6 
W7-
12 
W 
13 
W
19 
W
25 
W
31 
W
37 
W
43 
W
49 
PHYSICAL 
Reg Step 
1 
Reg 
Step 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History & Physical 
(w/BSA, BP, 
Height & Weight) s 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PS & Tox Notation 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
FORMS FOR 
QOL STUDIES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cover Sheet for 
Patient-Completed 
Questionnaires 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Xp 
Xq 
 
FACT-BRM, EQ-
5D-3L and FACIT-
D Questionnaire 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Xp 
Xq 
 
LABORATORYe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANC, platelets, 
Hgb 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Total bilirubin 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
LDH f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
 
AST and ALT, 
Alkaline 
Phosphatase 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum Creatinine 
or CrCl 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Alb, Glu, Na, K, 
HCO3 (or CO2)  a 
 
 
X 
a 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Triglycerides g 
X 
 
 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
 
 
Free T3, TSH, 
Free T4 r 
X 
 
 
 
 
 
 
 
 
X r 
 
X r 
 
X r 
 
 
X r 
 
 
 
Pregnancy Test i 
X 
 
Xi 
 
 
 
 
 
Xi 
Xi 
 
Xi 
 
Xi 
 
Xi 
 
 
 
 

S1404 
 
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Version Date 11/27/2023 
9.1 
Arm 1: Interferon alfa-2b (contd. 
 
Click here for footnotes. 
NOTE:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  Form submission guidelines are found in Section 14.0. 
 
 
Induction 
Phasea 
Days 1-5 (M-F) 
of  
Weeks 1-4 
Maintenance Phasea  
Days 1, 3, 5 (M, W, F) of  
Weeks 5-52 
End of 
treat-
ment 
assess-
mentb 
Post 
treat-
ment 
F/U 
prior to 
relapse 
c 
Relapse
/Recu-
rrence 
F/U 
post 
relapsed 
REQUIRED 
STUDIES  
Pre- 
study 
screening 
Ran-
domiza-
tion 
Cycle 1 
C2 
C3 
C4 
C5 
C6 
W
1 
W
2 
W
3 
W
4 
W
5 
W
6 
W7
-12 
W
1
3 
W
19 
W
25 
W
31 
W
37 
W
43 
W
49 
X-RAYS AND 
SCANS 
Reg 
Step 1 
Reg 
Step 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole Body 
PET/CT or CT 
neck j, chest 
abdomen & pelvis 
k 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X j k 
 
 
Brain MRI or CT 
with Contrast k  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
 
Xk 
 
 
EKG h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Image Submission  
o 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
SPECIMEN 
SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Slides for PD-L1 
Expression l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E-mail 
confirmation tissue 
was adequate for 
PD-L1 analysis l 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissuem for 
banking 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serumm  for 
banking 
 
Xn 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
Plasma & Buffy 
Coatm for 
RNA/DNA  for 
banking 
 
Xn 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
TREATMENT   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interferon alfa-2b 
 
 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 

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NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for continuous treatment, 
disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined in 
https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 
Footnotes for Study Calendar 9.1: Arm 1 (Interferon alfa-2b) 
a. The following exams and labs are done weekly during induction (Weeks 1-4 of Cycle 1), the first week of maintenance (Week 5 of Cycle 1), then every first and 
seventh week of each subsequent cycle until end of protocol treatment:  physical (w BSA, BP & WT), PS, toxicity notation, ANC, platelets, Hgb, total bilirubin, AST 
and ALT, alk phos, serum creatinine or CrCl, albumin, glucose, Na, K, HCO3 (or CO2).  Adverse Event Assessments on the study will continue for all patients until 30 
days after the last study drug administration. However, patients with ongoing toxicities should be seen more often as clinically indicated.  
b. End of treatment assessment occurs at Week 53 or whenever patient comes off treatment. 
c. Post-treatment follow-up (prior to relapse):  Patients should be seen at 6 weeks (-/+ 1 week) after the last dose, then 12 weeks (-/+ 1 week) after the last dose, then 
every 3 months (+/- 2 weeks) if patient is < 2 years from study entry, every 6 months (+/- 4 weeks) if patient is 2-5 years from study entry, and every 12 months (+/- 
4 weeks) if patient is > 5 years from study entry for up to 10 years. The first two follow-up visits may be scheduled to allow follow-up visits and scans to occur on the 
same date for on-going follow-up. The following exams and labs should be performed: physical (w BSA, BP & wt), PS, ANC, platelets, Hgb, total bilirubin, AST and 
ALT, alk phos, serum creatinine or CrCl, albumin, glucose, Na, K, HCO3 (or CO2). Adverse Event Assessments on the study will continue for all patients until 30 days 
after the last study drug administration. However, patients with ongoing toxicities should be seen more often as clinically indicated.  For post-treatment follow-up 
regarding scans, see footnote k. 
d. Follow-up post relapse: Patients who develop recurrent melanoma will be followed for survival (vital status). Adverse Events Assessment on the study will continue 
for all patients until 30 days after the last study drug administration.  Patients should be followed every 6 months for up to 2 years from the  date of treatment 
discontinuation, then annually thereafter until 10 years from  date of randomization.  However, patients with ongoing toxicities should be seen more often as clinically 
indicated. 
e. While on study, blood samples collected for pretreatment laboratory tests may be collected and analyzed no more than 3 days prior to dosing. NOTE: If a visit had to 
be delayed due to major circumstances (such as a health emergency, family/personal emergency, transportation difficulties, scheduling difficulties; a visit date falls 
on a holiday), the study assessments scheduled for these dates will be delayed. 
f. LDH to be done at baseline and at relapse. 
g. Triglycerides to be done at screening, after 6 months of IFN treatment and at the end of IFN treatment. 
h. To be performed at baseline, then as clinically indicated throughout treatment. 
i. Women of child bearing potential must have a negative serum or urine pregnancy test at screening within 28 days prior to registration. Following randomization, serum 
or urine pregnancy tests are required within 72 hours prior to the first dose of study treatment, then according to institutional practice during therapy, tests should 
coincide with clinic visits for blood work and ending with the discontinuation of study treatment. At discontinuation, a negative pregnancy test within the preceding 6 
weeks is sufficient. A pregnancy test should be done at any time there are clinical concerns for possible pregnancy.    
j. Patients with primary melanoma of the head and neck or unknown primary with disease in the axilla will also require a neck CT. 
k. Disease assessments by PET-CT or CT chest/abdomen/pelvis (or MRI if CT cannot be done), and neck CT as needed will be performed every 12 weeks (-/+ 2 weeks) 
until 2 years from randomization, then every 6 months(± 4 weeks) until 5 years from randomization, then follow for survival. The same imaging modality as used at 
prestudy for disease assessment should be used throughout the trial. During treatment and follow-up, brain MRI/CT or other imaging studies must be repeated 
annually (± 4 weeks). For PET-CT imaging, iodinated contrast is recommended in addition to FDG for optimal relapse detection.  If there is a contra-indication to 
iodine, non-contrast chest CT and MRI of abdomen/pelvis with gadolinium are acceptable body imaging alternatives.  If there is a gadolinium allergy, or MRI brain 
intolerable for the patient, CT with iodinated IV contrast is adequate brain imaging. MRI of the brain is required for patients with progressive disease. 
l. Slides must be submitted as described in Section 15.2.  Patients cannot be randomized on Step 2 until e-mail confirmation has been received indicating that the 
specimen was adequate for determining PD-L1 status.  
m. If patient consents, submit specimens for banking as specified in Section 15.0. 
n. Blood needs to be drawn prior to treatment. 
o. Submit scans as outlined in Sections 14.0 and 15.0. 
p. Cover Sheet, FACT-BRM, EQ-5D-3L and FACIT-D should be completed 24 weeks (± 2 weeks) and 48 weeks(± 2 weeks) after the date of last treatment. 
 
 

S1404 
 
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q. If relapse occurs before 48 weeks after date of last treatment, Cover Sheet, FACT-BRM, EQ-5D-3L and FACIT-D should be completed at the time of relapse. 
r Thyroid function tests need to be done at screening, within 3 days prior to the start of study treatment on Week 13, Week 25 and Week 37 and at initial post-treatment 
follow-up.  Additional testing to be done as clinically indicated. 
s History prior to each treatment initiation to include a menstrual, sexual and contraceptive use history, including date of last menstrual period (for women of childbearing 
potential) which will help determine the need for pregnancy testing.  Similar questions regarding contraceptive use to be asked of men who are sexually active with 
women of childbearing potential. Height is only required at baseline. 
 
 

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9.2 
Arm 1: Ipilimumab 
REQUIRED 
STUDIES 
Pre-
screen-
ing 
Rand-
dom-
ization 
ON TREATMENT a 
 
End 
of 
treat b 
Post 
treat 
F/U 
pre-re-
lapsec 
Re-
lapse
/Rec
ur-
rence 
F/U 
post 
re-
lapsed 
PHYSICAL 
Reg 
Step 1 
Reg 
Step 2 
Induction 
C
3 
C  
4 
C
5 
C6 
C
7 
C
8 
C
9 
C
10 
C 
11 
C 
12 
C 
13 
C 
14 
Cy 1 
C 2 
* 
 
 
W 
1 
W
4 
W
7 
W 
10 
W 
13 
W 
25 
W 
37  
W 
49 
W 
61 
W 
73 
W 
85 
W 
97 
W 
109 
W 
121 
W 
133 
W 
145 
 
 
 
 
History & Physical 
(w/ BSA, BP, 
Height & Weight) t 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PS & Toxicity 
Notation 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
FORMS FOR QOL 
STUDIES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cover Sheet for 
Patient-Completed 
Questionnaires 
 
 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Xr 
Xs 
 
FACT-BRM,  
EQ-5D-3L and 
FACIT-D 
Questionnaire 
 
 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Xr 
Xs 
 
LABORATORYe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANC, platelets, 
Hgb 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Total bilirubin 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
LDH f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
 
AST and ALT, 
Alkaline 
Phosphatase 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum Creatinine 
or CrCl 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Albumin, Glucose, 
Na, K, HCO3  
(or CO2) a 
 
 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Triglyceridesg 
X 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
Xg 
 
 
 
Free T3, TSH, Free 
T4 o 
 
X 
 
 
 
 
Xo 
Xo 
Xo 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Cardiac Function u 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Pregnancy Testi 
X 
 
Xi 
 
 
 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
 
 
 
Study Calendar 9.2 continued on next page.  Click here for footnotes. 

S1404 
 
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Version Date 11/27/2023 
9.2 
Arm 1: Ipilimumab (contd.) 
 
Pre-
StudySc
reening 
Ran-
domi-
zation 
ON TREATMENT a 
End 
of 
treat 
b 
Post 
treat 
F/U pre-
re-
lapsec 
Re-
lapse
/Rec
ur-
rence 
F/U 
post re-
lapsed 
 
Reg 
Step 
1 
Reg 
Step  
2 
Induction 
C
3 
C
4 
C
5 
C6 
C
7 
C
8 
C
9 
C 
10 
C 
11 
C 
12 
C 
13 
C 
14 
Cy 1 
Cy 2 
* 
 
 
W 
1 
W 
4 
W 
7 
W 
10 
W 
13 
W 
25 
W 
37 
W 
49 
W 
61 
W 
73 
W 
85 
W 
97 
W 
109 
W 
121 
W 
133 
W 
145 
 
 
 
 
X-RAYS AND 
SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole body 
PET/CT or CT neck 
j, chest, abdomen & 
pelvis k 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X j k 
 
 
Brain MRI or CT 
with contrast k 
X 
 
 
 
 
 
 
 
 
Xk 
 
 
 
 
Xk 
 
 
 
 
X k 
 
 
EKGh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Image Submission p 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X  
 
 
SPECIMEN 
SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Slides for PD-L1 
expression l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E-mail confirmation 
tissue was 
adequate for PD-L1 
analysis  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue m for banking  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum m for banking 
 
X n 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Plasma & Buffy 
Coat m for 
RNA/DNA for 
banking 
 
X n 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ipilimumab 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Click here for footnotes. 
NOTE:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  Form submission guidelines are found in Section 14.0. 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for continuous treatment, disease assessment, 
specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined in 
https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 
 

S1404 
 
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Version Date 11/27/2023 
Footnotes for Study Calendar 9.2: Arm 1 Ipilimumab 
a. The following exams and labs are performed prior to receiving first dose and at the start of every cycle until end of protocol treatment: physical (w 
BSA, BP & WT), PS, toxicity notation, ANC, platelets, Hgb, total bilirubin, AST and ALT, alk phos, serum creatinine or CrCl, albumin, glucose, Na, 
K, HCO3 (or CO2).  Adverse Event Assessments on the study will continue for all patients until 30 days after the last study drug administration. 
However, patients with ongoing toxicities should be seen more often as clinically indicated. 
b. End of treatment assessment occurs at the 15th infusion or whenever patient comes off treatment (treatment stops at the end of Year 3, even if 
the patient has not received all 15 infusions). 
c. Post-treatment follow-up (prior to relapse): Patients should be seen at 6 weeks (-/+ 1 week) after the last dose, then 12 weeks (-/+ 1 week) after 
the last dose, then every 3 months (+/- 2 weeks) if patient is < 2 years from study entry, every 6 months (+/- 4 weeks) if patient is 2-5 years from 
study entry, and every 12 months (+/- 4 weeks) if patient is > 5 years from study entry for up to 10 years. The first 2 follow-up visits may be 
scheduled to allow follow-up visits and scans to occur on the same date for on-going follow-up. The following exams and labs should be performed:  
physical (w BSA, BP & wt), PS, ANC, platelets, Hgb, total bilirubin, AST and ALT, alk phos, serum creatinine or CrCl, albumin, glucose, Na, K, 
HCO3 (or CO2). Adverse event assessments on the study will continue for all patients until 30 days after the last study drug administration. 
However, patients with ongoing toxicities should be seen more often as clinically indicated. For post-treatment follow-up regarding scans, see 
footnote k. 
d. Follow-up post relapse: Patients who develop recurrent melanoma will be followed for survival (vital status). Adverse Events Assessment on the 
study will continue for all patients until 30 days after the last study drug administration.  Patients should be followed every 6 months for up to 2 
years from the date of treatment discontinuation date, then annually thereafter until 10 years from date of randomization.  However, patients with 
ongoing toxicities should be seen more often as clinically indicated. 
e. While on study, blood samples collected for pretreatment laboratory tests may be collected and analyzed no more than 3 days prior to dosing. 
NOTE: if ipilimumab was delayed per the dose delay/scheduling criteria or if a visit had to be delayed due to major circumstances (such as a 
health emergency, family/personal emergency, transportation difficulties, scheduling difficulties; a visit date falls on a holiday), the study 
assessments scheduled for these dates will be delayed. 
f. LDH to be done at baseline and at relapse. 
g. Triglycerides to be done at screening, after 6 months of treatment and the end of treatment. 
h. To be performed prior to Registration Step 1, then as clinically indicated.  Also see footnote “u”. 
i. Women of child bearing potential must have a negative serum or urine pregnancy test at screening within 28 days prior to registration. Following 
randomization, serum or urine pregnancy tests are required within 72 hours prior to the first dose of study treatment, then according to institutional 
practice during therapy, tests should coincide with clinic visits for blood work and ending with the discontinuation of study treatment. At 
discontinuation, a negative pregnancy test within the preceding 6 weeks is sufficient. A pregnancy test should be done at any time there are clinical 
concerns for possible pregnancy.   
j. Patients with primary melanoma of the head and neck or unknown primary with disease in the axilla will also require a neck CT. 
k. Disease assessments by PET-CT or CT chest/abdomen/pelvis (or MRI if CT cannot be done), and neck CT as needed will be performed every 
12 weeks (-/+ 2 weeks) until 2 years from randomization, then every 6 months (± 4 weeks) until 5 years from randomization, then follow for survival. 
The same imaging modality as used at prestudy for disease assessment should be used throughout the trial.  During treatment and follow-up, 
brain MRI/CT or other imaging studies must be repeated annually (± 4 weeks). For PET-CT imaging, iodinated contrast is recommended in addition 
to FDG for optimal relapse detection.  If there is a contra-indication to iodine, non-contrast chest CT and MRI of abdomen/pelvis with gadolinium 
are acceptable body imaging alternatives.  If there is a gadolinium allergy, or MRI brain intolerable for the patient, CT with iodinated IV contrast is 
adequate brain imaging. MRI of the brain is required for patients with progressive disease. Patients may still be on treatment until 3 years from 
randomization. 
l. Slides must be submitted as described in Section 15.2. Patients cannot be randomized to Step 2 until e-mail notification has been received 
indicating that the specimen was adequate for determining PD-L1 status.  
m. If patient consents, submit specimens for banking as specified in Section 15.0. 
n. Blood needs to be drawn prior to treatment. 
o. Thyroid function tests to be done at screening, within 3 days prior to the start of study treatment on Week 13, Week 25 and Week 37 and at initial 
post treatment follow-up.  Additional testing to be done as clinically indicated. 

S1404 
 
Page 70 
Version Date 11/27/2023 
p. Submit scans as outlined in Sections 14.0 and 15.0. 
r. Cover Sheet, FACT-BRM, EQ-5D-3L and FACIT-D should be completed 24 weeks (± 2 weeks) and 48 weeks (± 2 weeks) after the date of last 
treatment. 
s. If relapse occurs before 48 weeks after date of last treatment, Cover Sheet, FACT-BRM, EQ-5D-3L and FACIT-D should be completed at the time 
of relapse. 
t History prior to each treatment initiation to include a menstrual, sexual and contraceptive use history, including date of last menstrual period (for 
women of childbearing potential) which will help determine the need for pregnancy testing.  Similar questions regarding contraceptive use to be 
asked of men who are sexually active with women of childbearing potential. Height is only required at baseline. 
u Patients with history of CHF or who are deemed at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs should 
have an ECHO prior to treatment and an ECHO and EKG at the start of each cycle, as clinically indicated. Patients who have evidence at baseline 
(or subsequently) of CHF, MI, cardiomyopathy, or myositis cardiac evaluation (NYHA I/II) should have additional consult by a cardiologist, including 
review of EKG, CPK, troponin, ECHO cardiogram, as clinically indicated. 
* These are the corresponding weeks if there are no dose delays. 

S1404 
 
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Version Date 11/27/2023 
9.3 
Arm 2: MK-3475 (Pembrolizumab) 
REQUIRED STUDIES 
Pre-
study 
Screen 
Random-
ization 
 
ON TREATMENT a 
The first two cycles consist of 2 infusions,  
subsequent cycles consist of 4 infusions. 
Infusions to be given q 3 weeks for 18 total infusions (5.5 cycles). 
End of 
treat-
ment 
assess-
mentb 
Post 
treat-
ment F/U 
prior to 
relapsec 
Re-
lapse/
Recur-
rence 
F/U 
post 
relapsed 
PHYSICAL 
Reg 
Step 
1 
Reg 
Step  
2 
Cycle 1 
Cycle 2 
C3 
C4 
C5 
C6 
 
 
 
*W
1 
*W
4 
*W
7 
*W
10 
*W
13 
*W
19 
*W
25 
*W
31 
*W
37 
*W
43 
*W
49 
 
 
 
 
History & Physical (w/ 
BSA, BP, Height & 
Weight) t  
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PS & Toxicity Notation 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
FORMS FOR QOL 
STUDIES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cover Sheet for Patient-
Completed 
Questionnaires 
 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Xr 
Xs 
 
FACT-BRM,  
EQ-5D-3L, and FACIT-D 
Questionnaire 
 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Xr 
Xs 
 
LABORATORYe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANC, platelets, Hgb 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Total bilirubin 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
LDH f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
 
AST and ALT, Alkaline 
Phosphatase 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum Creatinine or CrCl 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Albumin, Glucose, Na, K, 
HCO3 (or CO2) a 
 
 
X a 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Triglycerides g 
X 
 
 
 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
 
 
Free T3, TSH, Free T4 o 
X 
 
 
 
 
 
X o 
 
X o 
 
X o 
 
 
X o 
X 
 
 
Pregnancy Testi 
X 
 
X i 
 
X i 
 
X i 
 
X i 
 
X i 
 
X i 
 
 
 
 
Cardiac Functiontv  
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Study Calendar 9.3 continued on next page.  Click here for footnotes. 

S1404 
 
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Version Date 11/27/2023 
9.3 
Arm 2: MK-3475 (Pembrolizumab) (contd.) 
 
 
Pre-
study 
Screen 
Random-
ization 
 
ON TREATMENT a 
The first two cycles consist of 2 infusions,  
subsequent cycles consist of 4 infusions. 
Infusions to be given q 3 weeks for 18 total infusions (5.5 cycles). 
End of 
treat-ment 
assess-
mentb 
Post treat-
ment F/U 
prior to 
relapsec 
Re-
lapse/R
ecur-
rence 
F/U 
post 
relapsed 
 
Reg 
Step 
1 
Reg 
Step  
2 
Cycle 1 
Cycle 2 
C3 
C4 
C5 
C6 
 
 
 
*W
1 
*W
4 
*W
7 
*W
10 
*W
13 
*W
19 
*W
25 
*W
31 
*W
37 
*W
43 
*W
49 
 
 
 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole body PET/CT or 
CT neck j, chest, 
abdomen & pelvis k 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X j k 
 
 
Brain MRI or CT with 
contrast  k 
X 
 
 
 
 
 
 
 
 
 
 
 
X k 
 
X k 
 
 
EKGh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Image Submission  p 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X  
 
 
SPECIMEN 
SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Slides for PD-L1 
expression l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for PK/ADA q 
 
 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X q 
 
 
E-mail confirmation 
tissue was adequate for 
PD-L1 analysis  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue m for banking  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum m for banking 
 
X n 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
Plasma & Buffy Coat m 
for RNA/DNA for banking 
 
X n 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MK-3475 
(Pembrolizumab) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Study Calendar 9.3 continued.   Click here for footnotes. 
 
NOTE:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  Form submission guidelines are found in Section 14.0. 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for continuous treatment, 
disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined in  
https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf.  

S1404 
 
Page 73 
Version Date 11/27/2023 
Footnotes for Study Calendar 9.3: Arm 2 MK-3475 (Pembrolizumab) 
a. Following exams & labs are performed prior to receiving first dose & prior to every other infusion until end of protocol treatment: physical (w BSA, BP & 
WT), PS, toxicity notation, ANC, platelets, Hgb, total bilirubin, AST and ALT, alk phos, serum creatinine or CrCl, albumin, glucose, Na, K, HCO3 (or 
CO2). Adverse Event Assessments on the study will continue for all patients until 30 days after the last study drug administration. However, patients 
with ongoing toxicities should be seen more often as clinically indicated. 
b. End of treatment assessment occurs at the 18th infusion or whenever patient comes off treatment. 
c. Post-treatment follow-up (prior to relapse):  Patients should be seen at 6 weeks (-/+ 1 week) after the last dose, then 12 weeks (-/+ 1 week) after 
the last dose, then every 3 months (+/- 2 weeks) if patient is < 2 years from study entry, every 6 months (+/- 4 weeks) if patient is 2-5 years from 
study entry, and every 12 months (+/- 4 weeks) if patient is > 5 years from study entry for up to 10 years. The first two follow-up visits may be 
scheduled to allow follow-up visits and scans to occur on the same date for on-going follow-up. The following exams and labs should be performed: 
physical (w BSA, BP & wt), PS, ANC, platelets, Hgb, total bilirubin, AST and ALT, alk phos, serum creatinine or CrCl, albumin, glucose, Na, K, 
HCO3 (or CO2).  Adverse Event Assessments on the study will continue for all patients until 30 days after the last study drug administration. 
However, patients with ongoing toxicities should be seen more often as clinically indicated. For post-treatment follow-up regarding scans, see 
footnote k. 
d. Follow-up post relapse: Patients who develop recurrent melanoma will be followed for survival (vital status). Adverse Events Assessment on the 
study will continue for all patients until 30 days after the last study drug administration.  Patients should be followed every 6 months for up to 2 
years from the date of treatment discontinuation, then annually thereafter until 10 years from date of randomization.  However, patients with 
ongoing toxicities should be seen more often as clinically indicated. 
e. While on study, blood samples collected for pretreatment laboratory tests may be collected and analyzed no more than 3 days prior to dosing. 
NOTE: if MK-3475 was delayed per the dose delay/scheduling criteria or if a visit had to be delayed due to major circumstances (such as a health 
emergency, family/personal emergency, transportation difficulties, scheduling difficulties; a visit date falls on a holiday), the study assessments 
scheduled for these dates will be delayed. 
f. LDH to be done at baseline and at relapse. 
g. Triglycerides to be done at screening, after 6 months of treatment and at the end of treatment. 
h. To be performed prior to Registration Step 1, then as clinically indicated.  Also see footnote “v”. 
i. Women of child bearing potential must have a negative serum or urine pregnancy test at screening within 28 days prior to registration. Following 
randomization, serum or urine pregnancy tests are required within 72 hours prior to the first dose of study treatment, then according to institutional 
practice during therapy, tests should coincide with clinic visits for blood work and ending with the discontinuation of study treatment. At 
discontinuation, a negative pregnancy test within the preceding 6 weeks is sufficient. A pregnancy test should be done at any time there are clinical 
concerns for possible pregnancy.   
j. Patients with primary melanoma of the head and neck or unknown primary with disease in the axilla will also require a neck CT. 
k. Disease assessments by PET-CT or CT chest/abdomen/pelvis (or MRI if CT cannot be done), and neck CT as needed will be performed every 12 
weeks (-/+ 2 weeks) until 2 years from randomization, then every 6 months (± 4 weeks) until 5 years from randomization, then follow for survival. 
The same imaging modality as used at prestudy for disease assessment should be used throughout the trial.  During treatment and follow-up, 
brain MRI/CT or other imaging studies must be repeated annually (± 4 weeks). For PET-CT imaging, iodinated contrast is recommended in addition 
to FDG for optimal relapse detection.  If there is a contra-indication to iodine, non-contrast chest CT and MRI of abdomen/pelvis with gadolinium 
are acceptable body imaging alternatives.  If there is a gadolinium allergy, or MRI brain intolerable for the patient, CT with iodinated IV contrast is 
adequate brain imaging. MRI of the brain is required for patients with progressive disease. 
l. Slides must be submitted as described in Section 15.2. Patients cannot be randomized to Step 2 until e-mail notification has been received 
indicating that the specimen was adequate for determining PD-L1 status.  
m. If patient consents, submit specimens for banking as specified in Section 15.0. 
Footnotes for Study Calendar 9.3: Arm 2 MK-3475 (Pembrolizumab) (contd. on next page) 
 

S1404 
 
Page 74 
Version Date 11/27/2023 
 
n. Blood needs to be drawn prior to treatment. 
o. Thyroid function tests to be done at screening, within 3 days prior to the start of study treatment on Week 13, Week 25 and Week 37 and at initial 
post treatment follow-up.  Additional testing to be done as clinically indicated. 
p. Submit scans as outlined in Sections 14.0 and 15.0. 
q. Serum for PK and anti-MK-3475 antibody testing must be submitted for all patients randomized to the MK-3475 arm as described in Section 15.4. 
Pre-dose trough PK and anti-MK-3475 samples will be collected before the first infusion Cycle 1 (Week 1), before second infusion Cycle 1 (Week 
4), before second infusion Cycle 2 (Week 10), before third infusion Cycle 3 (Week 19), before first infusion Cycle 4 (Week 25), before infusion 
Cycle 6 (Week 49) and 30 days after discontinuation of study drug (or until patient starts new anti-cancer therapy).  All pre-dose trough samples 
should be drawn within 24 hours before infusion of MK-3475.  (AS OF 12/11/2017 PK/ADA SAMPLING HAS BEEN DISCONTINUED.  
SPECIMENS ALREADY COLLECTED MUST STILL BE SHIPPED.) 
r. Cover Sheet, FACT-BRM, EQ-5D-3L and FACIT-D should be completed 24 weeks (± 2 weeks) and 48 weeks (± 2 weeks) after the date of last 
treatment. 
s. If relapse occurs before 48 weeks after date of last treatment, Cover Sheet, FACT-BRM, EQ-5D-3L and FACIT-D should be completed at the time 
of relapse. 
t History prior to each treatment initiation to include a menstrual, sexual and contraceptive use history, including date of last menstrual period (for 
women of childbearing potential) which will help determine the need for pregnancy testing.  Similar questions regarding contraceptive use to be 
asked of men who are sexually active with women of childbearing potential.  Height is only required at baseline. 
* These are the corresponding weeks if there are no dose delays. 
v Patients with history of CHF or who are deemed at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs should 
have an ECHO prior to treatment and an ECHO and EKG at the start of each cycle, as clinically indicated. Patients who have evidence at baseline 
(or subsequently) of CHF, MI, cardiomyopathy, or myositis cardiac evaluation (NYHA I/II) should have additional consult by a cardiologist, including 
review of EKG, CPK, troponin, ECHO cardiogram, as clinically indicated. 
 

S1404 
 
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Version Date 11/27/2023 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
Measurement of Effect 
 
10.1 
Progression/Relapse 
 
Appearance of any new lesion/site.  Death due to disease without prior documentation of 
progression. 
 
x 
Appearance of a new melanoma in-situ or Stage I melanoma which can be treated 
curatively by wide excision does not constitute recurrence.  If this does occur, 
upload pathology and operative reports via the Source Documentation:  Follow-Up 
Form in Rave. 
 
x 
In cases for which initial flare reaction is possible (hypercalcemia, increased bone 
pain, erythema of skin lesions), either symptoms persist beyond 4 weeks or there 
must be additional evidence of progression. 
 
x 
For bone disease documented on bone scan only, increased uptake does not 
constitute unequivocal progression.  However, increase in the soft tissue 
component of a lesion as measured by CT or MRI would constitute progression. 
 
x 
Appearance of new pleural effusions does not constitute unequivocal progression 
unless cytologically proven of neoplastic origin, since some effusions are a toxicity 
related to therapy or other medical conditions.  Increase in the size of an existing 
effusion does not constitute unequivocal progression, since the fluid status of the 
patient could alter the size of the effusion. 
 
Notes regarding new lesions: FDG-PET imaging can complement regular scans in 
identifying new lesions according to the following algorithm. 
 
1) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
progression based on a new lesion. 
 
2) No FDG-PET at baseline and a positive FDG-PET at follow-up corresponding to a 
potential new site of disease must have a confirmation by anatomical assessment 
(e.g. CT, MRI, X-ray) as new site of disease to be considered progressive disease.  
In such a case, the date of progressive disease will be the date of the initial 
abnormal FDG-PET. 
 
10.2 
Relapse-Free Survival  
 
Measured from date of randomization to date of first documentation of relapse or death 
due to any cause.  Patients last known to be alive and relapse-free are censored at date 
of last contact. 
 
10.3 
Overall Survival   
 
Measured from date of randomization to date of death due to any cause.  Patients known 
to be alive are censored at date of last contact. 
 
 

S1404 
 
Page 76 
Version Date 11/27/2023 
10.4 
Performance Status 
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light 
housework, office work. 
 
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours. 
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours. 
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Accrual goals 
 
Based on E1609, an intergroup accrual rate of at least 45 patients per month is assumed. 
 
It is assumed that up to 10% of patients will be ineligible. It is expected that 1378 registered 
patients will be required to accrue 1,240 eligible patents (see below for sample size 
calculations).  Including time to ramp up accrual, it is anticipated that it will take less than 
2.5 years to complete accrual for this trial. 
 
11.2 
Overall survival (OS) and relapse-free survival (RFS) objectives 
 
There are three primary objectives of this study: 1) to test whether OS is improved with 
pembrolizumab compared to a control arm of physician/patient choice of high-dose 
interferon (HDI) or ipilimumab in this patient population, 2) to test whether among patients 
who are PD-L1 positive OS is improved with pembrolizumab compared to this control arm 
in this patient population, 3) to test whether RFS is improved with pembrolizumab 
compared to this control arm in this patient population. 
 
11.3 
Overall survival (OS) and relapse-free survival (RFS) design assumptions 
 
OS and RFS estimates from S0008 indicate that a proportion of patients may be long-term 
survivors in the sense that they will not be observed to relapse or die during the follow-up 
period planned for the study.  It is further assumed that there are no differences in OS or 
RFS between the treatment regimens in the control arm. 
 
An exponential cure rate model fit to OS on the HDI arm of S0008 indicated that 40% of 
patients were long-term survivors and that median OS for patients who were not long-term 
survivors was 3.01 years (null hypothesis).  The null OS model is written that the OS at 
year t is equal to 0.40+0.60*exp(-0.23t).  For sample size calculations, it is assumed that 
OS with pembrolizumab will also follow an exponential cure rate model, but with 45% of 
patients long-term survivors and a median OS for non-long term survivors of 3.96 years 
(alternative hypothesis).  The alternative OS model is written that the OS at year t is equal  

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to 0.45+0.55*exp(-0.175t).  This corresponds to an average hazard ratio (HR, average of 
10,000 simulated hazard ratios from the Cox model) of 0.73 from a Cox proportional 
hazards model at 100% OS events (374 events at Study Year 5). 
 
An exponential cure rate model fit to RFS on the HDI arm of S0008 indicated that 35% of 
patients were long-term survivors and that median RFS for patients who were not long-
term survivors was 1.03 years (null hypothesis).  The null RFS model is written that the 
RFS at year t is equal to 0.35+0.65*exp(-0.67t).  For sample size calculations, it is assumed 
that RFS with pembrolizumab will also follow an exponential cure rate model, but with 41% 
of patients long-term survivors and a median RFS for non-long term survivors of 1.44 years 
(alternative hypothesis).  The alternative RFS model is written that RFS at year t is equal 
to 0.41+0.59*exp(-0.48t).  This corresponds to an average hazard ratio (HR) of 0.70 from 
a Cox proportional hazards model at 100% RFS information. 
 
We assume a total two-sided alpha of 5% (one-sided alpha of 2.5%) allocated between the 
four co-primary objectives as detailed below. We assume 1:1 randomization, 2.5 years of 
accrual, 2.5 years of follow-up after accrual completes.  We assume 48.2% of patients will 
be PD-L1 positive, (based on the lower limit of the 95% confidence interval of the 
prevalence from ClinicalTrials.gov trial NCT 01704287), 46.8% will be PD-L1 negative, and 
5% will be PD-L1 indeterminate.  All testing will be stratified by the randomization 
stratification.  Tests of the null hypothesis will be done using the log-rank test.  Futility 
analysis testing will be performed using a modified log-rank test modified for testing non-
null hypotheses (a score test of the alternative hazard ratio).   
 
11.4 
Alpha allocation between Overall survival (OS) and Relapse-free survival (RFS) 
 
Using a Bonferroni split, 4.6% (two-sided) of the alpha will be allocated to the OS endpoint 
(overall population and PD-L1+ subgroup) and 0.4% (two-sided) of the alpha will be 
allocated to the RFS endpoint (overall population).  For OS, 80% of the alpha will be 
allocated to the overall population and the remaining alpha will be allocated to the PD-L1 
positive subgroup using the method described in the next paragraph. 
 
Under the null hypothesis, the test statistics for the overall population and the PD-L1 
positive subgroups are multivariable normal with correlation equal to the proportion of 
events the PD-L1 positive subgroup relative to the whole population. (25) The residual 
alpha for the PD-L1 population can be calculated using this relationship.  For clarity in the 
exposition of the design we will assume the PD-L1 positive subgroup has 48.2% of the 
total OS events of the study (based on the lower limit of the 95% confidence interval of the 
prevalence from ClinicalTrials.gov trial NCT 01704287).  For the final analyses involving 
the PD-L1 positive subgroups, the actual alpha level will be calculated using the 
multivariate normal relationship based on the PD-L1 positive proportion observed in the 
trial 
 
Under these assumptions, the alpha allocation is expected to be as follows: the OS overall 
population with 3.7% (two-sided) and the PD-L1 + subgroup OS with 1.52% (two-sided).  
Accounting for the correlation between the subgroup and overall group, the overall alpha 
is 4.6% (two-sided) for OS and 0.4% (two-sided) for RFS. 
 
x 
OS overall population 3.7% 
x 
OS PD-L1 + subgroup 1.52%  
x 
RFS overall population 0.4%  
 
 
11.5 
Interim and final analysis plans 
 
The primary analysis will be intent-to-treat population. 
 

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All testing will be stratified by the randomization stratification factors. Tests of the null 
hypothesis will be done using the log-rank test.  Futility analysis testing will be performed 
using a modified log-rank test modified for testing non-null hypotheses (a score of the 
alternative hazard ratio). 
 
100% of expected RFS is 536 events. One formal interim analysis of the overall population 
RFS endpoint is scheduled at approximately 75% of RFS events (402 RFS events 
calculated across both arms under the alternative). At the interim analysis, an efficacy test 
will be done (test of null hypothesis HR=1) with a one-sided alpha=0.09%.  At the interim 
analysis a futility test will evaluate if the HR from a Cox regression model stratified by the 
randomization factors favors the control arm (HR>1).  If an efficacy or futility boundary is 
crossed at the interim analysis, the DSMC will consider early release of the RFS results.  
The final analysis of the overall population RFS will test of the null hypothesis (HR=1) at 
the two-sided 0.32% level (one-sided 0.16% level) in order to account for the interim 
analysis.  
 
Up to two formal interim analyses of the overall population OS will be completed at 
approximately 55% and 80% events (206 and 399 events, respectively, events calculated 
across both arms under the alternative).  At both interim analyses, an efficacy test will be 
done (test of null hypothesis HR=1) with a one-sided alpha=0.125%.  At the first interim 
analysis a futility test will evaluate if the HR from a Cox regression model stratified by the 
randomization factors favors the control arm (HR>1).  At the second interim analysis a 
futility test will be done testing the alternative hazard ratio (HR=0.73) with a one-sided alpha 
of 2.5%.  If a boundary for futility is crossed at an interim analysis, the DSMC will consider 
the toxicities on each arm.  Considering the magnitude of the survival difference between 
the two arms along with the relative toxicities, the DSMC can choose not to recommend 
reporting results early if additional data on the potential non-inferiority of pembrolizumab is 
warranted. The final analysis of the overall population OS will test of the null hypothesis 
(HR=1) at the two-sided 3.6% level (one-sided 1.8% level) in order to account for interim 
analyses. At the final analysis for the overall population OS, a two-sided test of the null 
hypothesis of OS in the PD-L1 positive subgroup will be performed at the two-sided 
alpha=1.52% level2 (one-sided 0.76% level). 
 
The final OS superiority test will be performed in a stepwise fashion following an OS non-
inferiority test using a margin of 1.045.  An upper limit of a one-sided 98.15% confidence 
interval less than 1.045 will be considered evidence of non-inferiority of pembrolizumab 
compared to the control arm. 
 
At the final analysis for OS, results for RFS with updated follow-up will be presented.  We 
note that because of the expected survival patterns with this population, the average 
hazard ratio is expected to become more null (closer to 1) over time.  Under the alternative 
hypothesis, at 3.5 years since the first patient is randomized the hazard ratio is 0.70, while 
at 5 years since the first patient is randomized the hazard ratio is 0.73. 
 
There will be no formal interim testing of RFS (overall or PD-L1 positive subgroup) or of 
OS in the PD-L1 positive subgroup. 
 
If 100% RFS or OS events has not been reached by 3.5 years after the last eligible patient 
is randomized, the final RFS and OS analyses will be performed at this time. 
 
 
1 Alpha to be calculated based on observed proportion of total OS events in the PD-L1 
positive group. 
 
The sample size of this trial was determined to ensure appropriate power to detect 
meaningful OS differences.  As such, the trial is overpowered for RFS, and may therefore 
detect small RFS differences of uncertain clinical benefit.  Hence, regardless of the 
statistical significance of the RFS results, the clinical benefit of pembrolizumab will be 

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assessed by the magnitude of the relative and absolute RFS improvement of the 
pembrolizumab arm over the control arm, and by the comparisons of overall survival and 
toxicity between the treatment arms.  
 
Under this design and assuming PD-L1 positive patients have the same OS on the control 
arm as the whole population, the alternative OS survival model for 80% power is model is 
written that OS at year t is equal to 0.44+0.56*exp(-0.13t) [44% long-term survivors and 
median OS of 5.3 years for non-long-term survivors].  This corresponds to an average HR 
of 0.58 from a Cox proportional hazards model at 100% OS events. The alternative OS 
survival model for 90% power is model is written that OS at year t is equal to 
0.45+0.55*exp(-0.13t) [45% long-term survivors and median OS of 5.3 years for non-long-
term survivors].  This corresponds to an average HR of 0.56 from a Cox proportional 
hazards model at 100% OS events. 
 
Design properties were determined via simulation with 100,000 replications.  Properties 
of the design are summarized in the tables below. 
 
Table 1 Overall population OS Interim and final analysis summary. Events calculated 
across both arms. Actual analysis timing may vary. 
 
Percent OS 
events 
Study Year 
N events 
Tests done 
55% 
3 
206 
Efficacy and futility 
80% 
4 
299 
Efficacy and futility 
100% 
5 
374 
Efficacy 
 
Table 2 Characteristics of interim and final overall population OS analyses 
 
OS Scenario 
Probability under 
alternative 
Probability 
under null 
Probability stop for futility at 1st interim analysis 
1% 
50% 
Probability stop for efficacy at 1st interim 
analysis 
28% 
<1% 
Probability stop for futility at 2nd interim analysis 
1% 
17% 
Probability stop for efficacy at 2nd interim 
analysis 
19% 
<1% 
Probability stop early for futility 
2% 
67% 
Probability stop early for efficacy 
48% 
1% 
Probability of positive result 
86% 
2.1%a 
a Ignoring futility monitoring two-sided, alpha level=3.7% 
 
 

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Table 3 Overall population RFS Interim and final analysis summary. Events calculated 
across both arms. Actual analysis timing may vary. 
 
Percent RFS 
events 
Expected 
time 
N events 
Tests done 
75% 
Mid-2018 
402 
Efficacy and futility 
100% 
Late 2018 
536 
Efficacy 
 
Table 4 Characteristics of interim and final overall population RFS analyses 
 
RFS Scenario 
Probability under 
alternative 
Probability 
under null 
Probability stop for futility at interim analysis 
<1% 
50% 
Probability stop for efficacy at interim analysis 
69% 
<1% 
Probability of positive result 
90% 
0.22%a 
a 
Ignoring futility monitoring two-sided, alpha level=0.4% 
 
Table 5 Additional characteristics of overall population OS analyses. Events calculated 
across both arms. Actual analysis timing may vary. 
 
Analysis 
Alpha level 
HR threshold 
OS Events 
Year 3 interim 
efficacy 
0.125% 
(one-sided) 
0.67 
206 
Year 3 interim 
futility 
NA 
1 
206 
Year 4 interim 
efficacy 
0.125% 
(one-sided) 
0.70 
299 
Year 4 interim 
futility 
2.5% 
0.92 
299 
Year 5 final 
efficacy 
3.6% 
(two-sided) 
0.81 
374 
HR threshold = HR that will correspond to a significant p-value based on alpha level.  For 
efficacy analyses HRs less than the threshold will be significant, for futility analyses HRs 
larger than the threshold will warrant early closure of the study. 
 
Table 6 Characteristics of overall population RFS analyses. Actual analysis timing may 
vary. 
 
Analysis 
Alpha level 
HR threshold 
RFS Events 
 
interim efficacy 
0.09% 
(one-sided) 
0.66 
402 
Interim futility 
NA 
1 
402 
 
Final efficacy 
0.32% 
(two-sided) 
0.78 
536 
 
Year 5 follow-up 
NA 
NA 
668 
HR threshold = HR that will correspond to a significant p-value based on alpha level. For 
efficacy analyses HRs less than the threshold will be significant. 
 
Table 7 PD-L1 positive subgroup analysis details, N = 596 (48.2% prevalence)* 

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Endpoint 
Time 
point 
Alpha-level 
(two sided)* 
HR 
threshold 
Design HR 
Power 
OS 
Year 5 
1.52% 
0.66 
0.57 
80% 
 
OS 
 
Year 5 
1.52% 
0.68 
0.56 
90% 
* These calculations assume a 48.2% event fraction in the PD-L1 positive subgroup. For 
the final analysis, calculations will be based on the observed fraction of events in the 
trial. HR threshold = HR that will correspond to a significant p-value based on alpha level. 
Design HR = HR that provides stated level of power. 
 
How to interpret the first line of Table 7: If 48.2% of patients are PDL1-positive (and making 
all the assumptions about survival in the protocol), at Year 5 we will have 80% power to 
detect a true hazard ratio of 0.57 for OS.  In other words, if the true hazard ratio between 
the arms is 0.57 and we ran the trial many times, 80% of the trials would have an observed 
hazard ratio of 0.62 or less or a two-sided p-value less than 0. 0152. 
 
11.6 
Anticipated stage distribution. 
 
Eligibility for SWOG trial S0008 included Stages IIIA(n2), IIIB, and IIIC.  Eligibility for ECOG 
trial E1609 included Stages IIIB, IIIC, M1a, and M1b.  Eligibility for this trial S1404 includes 
Stages IIIA(n2), IIIB, IIIC, M1a, M1b, and M1c.  Null (historical) survival estimates for S1404 
are based on S0008 data.  We note that compared to S0008, S1404 will also include M1a, 
M1b, and M1c patients.  In E1609 6% of patients were Stage M1a and 2% were M1b.  We 
expect approximately 1% of randomized patients to be Stage M1c. We expect less than 
10% of randomized patients in S1404 to be Stage M1, and because of modest differences 
in expected survival we have used S0008 survival patterns as a historical reference for this 
trial. 
 
11.7 
Analyses of other objectives 
 
a. 
Estimation of OS and RFS in PD-L1 negative subgroup: Cox regression 
models will be used to estimate hazard ratios and calculate confidence intervals to 
compare treatment arms in the PD-L1 negative subgroup.  In addition Cox 
regression models for OS and RFS will be used to estimate interaction terms 
between PD-L1 status and treatment arm.   
 
b. 
Analysis of toxicity: On the MK-3475 (pembrolizumab) arm, six hundred and 
twenty eligible patients will be sufficient to estimate toxicity rates within ± 4% (95% 
confidence interval).  Any toxicity occurring with at least a 0.8% probability is likely 
to be observed at least once (99% probability). Assuming that on the Control Arm 
310 patients receive HD-IFN and 310 patients receive ipilimumab, this will be 
sufficient to estimate toxicity rates for these regimens to within ± 6% (95% 
confidence interval).  Under this assumption any toxicity occurring on a particular 
control arm regimen with at least a 1% probability is likely to be observed at least 
once (96% probability). 
 
c. 
Analysis of post-relapse therapy:  Data on therapy after relapse will be collected 
for three years after relapse (or until 10 years after registration maximum).  
Therapies will be categorized into one of two categories:  systemic or local.  
Specific therapies after relapse will be tabulated and summarized.  Therapy after 
relapse will be analyzed as a time-dependent variable in Cox regression analyses 
for the endpoint of OS after relapse. 
 
d. 
Analysis of BRAF mutation data:  Prestudy BRAF mutation status on patients 
will be collected.  BRAF mutation status will be analyzed as a covariate in Cox 
regression analyses and exponential-logistic cure regression models. (26)  In 
addition, the interaction between BRAF mutation status and treatment arm will be 

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analyzed in Cox regression models and in exponential-logistic cure regression 
model. 
 
e. 
Analysis of long-term survivors/cured patients:  Exponential-logistic cure 
regression models will be used to examine the association between known 
prognostic factors (including stage) and long-term survivor/cure status, and 
survival for patients who are not long-term survivors/cured.  (27) 
 
f. 
Other analyses of OS and RFS: A restricted mean survival time analysis will be 
done as a supportive analysis. 
 
g. 
T-cell Receptor Beta Chain sequencing:  The statistical plan for the T-
cell receptor beta chain sequencing objectives is included in Appendix 18.8 
 
11.8 
Quality of life (QOL data) 
 
This pre-specified statistical analysis plan (SAP) is intended to describe the strategy, 
rationale, and statistical techniques that will be used to assess the patient-reported 
outcomes (PROs) data gathered in the S1404 trial. 
 
a. 
Objectives: The key objective of the PRO analysis is to evaluate overall health-
related quality of life (QOL) for patients with melanoma treated with 
physician/patient choice of either high-dose interferon alfa-2b or ipilimumab and 
MK-3475 (pembrolizumab). 
 
b. 
Instruments:  The FACT-BRM measures quality of life domains important to 
patients treated with biological response modifiers (BRMs). The domains are 
represented by six sets of response items, four of which comprise the FACT-
General (FACT-G) subscales including Physical Well-Being, Social/Family Well-
Being, Emotional Well-Being, and Functional Well-Being; and two additional 
subscales specific to the FACT-BRM instrument, the BRM Physical Subscale, and 
the BRM Cognitive/Emotional subscale. Each subscale is derived from 6-7 items 
on the questionnaire, with responses given on a five-point Likert-type scale ranging 
from 0 to 4 (0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, and 4 = very 
much). The six subscales are also combined to form a single FACT-BRM total 
score. In addition, the FACT-BRM Trial Outcome Index (TOI) is derived from a 
subset of four of the subscales (Physical Well-Being, Functional Well-Being, BRM 
Physical, and BRM Cognitive/Emotional). Each FACT BRM subscale, the FACT 
BRM total score, and the FACT BRM TOI will all be analyzed. Scoring of the scales 
will follow the standard published metrics. For the FACT BRM, the higher the 
score, the better the quality of life.  
 
The FACIT-D comprises the FACT-G and a symptom-specific subscale that 
measures quality of life specific to diarrhea.  Like the FACT-BRM, the FACIT-D 
subscales is scored on a 5-point Likert-type scale ranging from 0 to 4, with higher 
scores indicating better quality of life.  The FACIT-D subscales (distinct from the 
FACT-BRM subscales) and FACT-D total score will all be analyzed. 
 
The EQ-5D-3L has two systems. The descriptive system measures three 
functional domains (mobility, self-care, usual activities) and two symptom domains 
(pain/discomfort and anxiety/depression). Each domain has three levels (no 
problems, some problems, extreme problems). A visual analog system (VAS) 
records self-rated global health between “best imaginable health state” and “worst 
imaginable health state” and can be used as a quantitative measure of health 
outcome as judged by individual patients. The three functional and two symptom 
domains can be summarized categorically, and the VAS global health rating can 
be summarized quantitatively. The measures can then be combined into a single 
summary index. Utility scoring will follow the US and European algorithms.   

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c. 
Endpoints: PRO endpoints are measured by the FACT-BRM, FACIT-D, and EQ-
5D-3L. These endpoints are affected by both disease progression and treatment 
tolerability.  
 
The Trial Outcome Index (TOI) from FACT-BRM is the primary PRO endpoint for 
this study. The TOI combines four subscales: Physical Well-Being, Functional 
Well-Being, the BRM Physical Subscale, and the BRM Cognitive/Emotional 
Subscale. The primary TOI endpoint will be the TOI score at Cycle 3. 
 
Secondary PRO endpoints from the FACT-BRM are the six individual FACT-BRM 
subscales and the FACT-BRM total score. Secondary PRO endpoints from the 
FACIT-D are symptom-specific subscale and specific items and the FACIT-D total 
score. Secondary PRO endpoints from the EQ-5D-3L include the summary index 
as well as each of the six individual EQ-5D-3L domains. 
 
For PRO endpoints, the baseline score will be accounted for as a covariate in 
multivariable regression models. The change between the baseline and Cycle 3 
scores will also be examined as a sensitivity analysis. In addition, the changes 
over all time points in the TOI endpoint as well as all of the secondary PRO 
endpoints will be analyzed using longitudinal data analytic approaches described 
below.    
 
d. 
Schedule for PRO data collection: 
 
Table 11.8.1 PRO Data Collection Schedule 
Treatmen
t Cycle 
Baselin
e 
Cycle 
1 
Cycle 
3 
Cycle 
5 
Cycle 
7 
Cycle 
9 
Follow-
up 
Recurrenc
e 
Study 
Time* 
Before 
first day 
of 
treatme
nt 
4 
weeks 
13 
weeks 
25 
weeks 
37 
weeks 
49 
weeks 
24 and 
48 
weeks 
after 
protocol 
treatmen
t discon-
tinuation 
See below 
(a, b) 
 
* assuming no treatment delays 
a)  Once patient has disease recurrence, no subsequent PRO data will be collected. 
b)  If recurrence occurs more than 48 weeks after protocol discontinuation, then PRO data 
collection at the time of recurrence is not required. 
 
With the exception of the recurrence time point, at each time point the FACT-BRM, 
FACIT-D, and EQ-5D-3L will be administered prior to all other study procedures. 
At the time of recurrence, the FACT-BRM, FACIT-D, and EQ-5D-3L will be 
administered after the patient sees the treating investigator. At each time point, if  
 
a patient does not complete one or both PRO instruments, the site staff will record 
the reason on the PRO Coversheet from predefined choices.   
 
e. 
Analysis Populations: The primary analysis population will be based on an intent-
to-treat (ITT) approach, incorporating data from all eligible randomized patients. 
To be evaluable, patients must have completed both the baseline and the Cycle 3 
assessments.    
 
f. 
PRO instrument completion and compliance:  

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The completion rate for the primary endpoint is defined as the number of patients 
who complete a sufficient number of items to score the FACT-BRM TOI according 
to the missing data rules for the instrument, divided by the number of eligible 
randomized patients at each time point. The completion rate is expected to 
decrease over time because some patients will not complete all protocol therapy 
and some patients will have disease recurrence or die. 
 
The compliance rate for the primary endpoint is defined as the number of patients 
who complete a sufficient number of items to score the FACT BRM TOI according 
to the missing data rules for the instrument, divided by the number of patients who 
were expected to complete the PRO instrument. The denominator of the 
compliance rate will not include patients who have died, recurred, or went off 
protocol therapy prior to that time point, or could not complete an instrument due 
to language translation not being available.   
 
The completion and compliance rates of the other subscales and total scores will 
be defined in a similar fashion. Completion and compliance rates by instrument, 
visit, and treatment arm will be described.   
 
For any subscales, trial outcome indexes, or total scores, we also define the 
minimum completion rate as the number of patients who complete at least one 
item included in the subscale, TOI, or total score, respectively, in order to assess 
the extent to which sites successfully administer a form to patients, even if only 
minimal information on the form is collected and the form cannot be scored 
according to the missing data rules for the instrument.  
 
The primary reason for not completing any of the PRO assessments for any 
assessment time point will be collected on the PRO Coversheet, to be filled out by 
the personnel administering PROs at each site. The reasons will be summarized 
in table format.   
  
g. 
PRO analyses: Consistent with the design and to aid in clinical interpretation, the 
analysis of the primary endpoint of the Cycle 3 FACT BRM TOI will be conducted 
using multivariable linear regression analysis, adjusting for randomization 
stratification factors and the baseline FACT BRM TOI score as covariates. A 
window of +/- 2 weeks around the completion of cycle 3 will be allowed for inclusion 
of the FACT-BRM TOI in the final analysis. We will also conduct longitudinal 
modeling of the outcome measures over time, to assess whether the longitudinal 
results are consistent with the primary analysis.  Power for the longitudinal analysis 
will be greater since the addition of all available FACT BRM TOI scores over time 
will provide more information. For longitudinal modeling, linear mixed models will 
be used, with random effects for intercepts and slopes and using both compound 
symmetric and unstructured correlation models. Covariates for longitudinal 
modeling will include treatment arm, assessment time, their interaction, the 
baseline score, as well as the randomization stratification variables and the 
baseline FACT BRM TOI score. Additionally, a treatment by time-squared 
interaction will be evaluated.  These models are nested and so log-likelihood 
values will be compared using a Chi-squared tests with appropriate degrees of 
freedom to assess which model provides a best fit to the data.  When summarizing 
results from models with the best fit, coefficients for the intercept, treatment arm, 
time point, and baseline score will be tabulated, along with 95% confidence 
intervals and nominal p-values.  We will also plot scale and subscale means for 
groups of patients based on the number of time points that instruments were 
completed.   
 
The potential for differential dropout by arm will be mitigated by reminder 
notifications to site investigators to encourage proper assessment and submission 

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of forms at every required time point for all patients. Dropout patterns will be 
monitored on an ongoing basis. Nonetheless the potential for non-random dropout 
exists. The linear mixed models described above assume that data is missing at 
random (MAR). The MAR assumption implies that the probability of missingness 
depends only on the observed data, which can be accounted for through covariate 
adjustment in the models.  However the potential exists that missing data are a 
function of other, unobserved variables. For instance, in this study missingness 
may also depend on ill health, death, and disease recurrence, in a fashion that 
cannot be predicted by baseline factors. If the alternative hypothesis is correct and 
patients on the standard treatment arm are more likely to have worse PRO 
outcomes, they are also more likely not to report PRO outcomes due to worsening 
health or death. In this setting, differential dropout by arm will bias the results 
towards the null hypothesis of no difference between arms, in which case the 
observed result by arm is likely to be conservative, such that difference between 
the arms in favor of the experimental arm would, in truth, be even more favorable 
that what is observed. However such a pattern cannot be assumed.  
 
Additional analyses will be performed to assess the MAR assumption. To evaluate 
potential cohort biases, baseline characteristics will be compared between 
evaluable (that is, those who complete both their baseline and cycle 3 FACT BRM 
TOI) and inevaluable patients. Also, cohort plots will be prepared to examine the 
extent to which missing data are informative (i.e., scores are higher (worse) for 
patients just before their data are missing for the subsequent assessment).  If there 
is evidence of non-random dropout, pattern-mixture models will be utilized as a 
sensitivity analysis.  (28,29,30) Pattern mixture models estimate PRO trajectories 
for different patterns of attrition.  The pattern groups are defined by the last PRO 
assessment time points for patients. In this study a total of six patterns will be 
identified: 1) complete all PRO assessments; 2) die before end of PRO 
assessments; 3) disease recurrence before end of PRO assessments; 4) alive 
without disease recurrence before end of PRO assessments but do not complete 
9 cycles of protocol therapy; 5) alive, recurrence-free, and complete 9 cycles of 
protocol therapy but stopped completing PRO assessments before Cycle 3; 6) 
alive, recurrence-free, and complete 9 cycles of protocol therapy but stopped 
completing PRO assessments after Cycle 3.  If some patterns have small numbers 
of patients, patterns may be collapsed for analysis.  
 
The pattern mixture models will be fit by estimating a linear mixed model within the 
six pattern groups defined above, estimating the proportion of patients in each 
pattern group, and then averaging out the pattern-specific PRO endpoint 
trajectories using weights equal to the proportions.  The variance will be calculated 
using the delta-method.  
 
Observed mean scores for the quantitative endpoints will be plotted across 
assessment time points with fitted results from the linear mixed model analysis 
overlaid.   
 
Descriptive statistics, multivariable linear regression analyses, and longitudinal 
modeling analyses will also be conducted for the FACIT-D and EQ-5D instruments 
and all subscale scores as secondary analyses. As additional secondary analyses, 
the same analyses will be done in the subgroups of patients identified by choice of 
control arm before randomization (used a randomization stratification factor, 
choice between high-dose interferon alfa-2b or ipilimumab). 
 
Interpretation of Longitudinal Model Results: For models in which the simple 
linear model (no interaction) provides the best fit, the fitted models will have parallel 
trajectories for the treatment arms, representing a treatment effect that is constant 
over time.  Significant non-zero treatment arm coefficients will indicate that one 
arm having higher endpoint values over time compared to the other arm.  

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Significant non-zero time coefficients will indicate upward or downward endpoint 
changes over time (depending on the sign of the coefficient). 
 
Models with an interaction will indicate a differential treatment effect on PRO 
endpoints over time, so the trajectories will not be parallel.  If a square interaction 
is significant, the differential treatment effect will be modeled as quadratic (i.e., 
non-linear or curved).  With significant interactions, the main effect coefficients for 
treatment arm and time cannot be interpreted independently but must be 
considered in combination with the coefficients for the interaction terms.   
 
h. 
Power and sample size calculations:  The primary hypothesis for sample size 
calculation is that pembrolizumab is superior to IFN with respect to the cycle 3 TOI 
score. PRO will be collected and data analyzed on all patients on the trial, not a 
subset of patients. 
 
We do not have preliminary PRO data on the FACT-BRM TOI with pembrolizumab 
or IFN in this particular patient population (the trial has wider eligibility than prior 
trials).  The follow-up standard deviation for the FACT-BRM TOI was 20 in a set of 
nearly 200 patients receiving IFN for renal cell carcinoma.  (31) This is consistent 
with data from Trask et al. (2004) in a small series of patients receiving IFN for 
high risk melanoma. (32) Thus we assume a cycle 3 standard deviation of the 
FACT BRM TOI of 20, common between both arms. Using Yost (2005), the 
estimated minimally important difference for the FACT BRM TOI is 5-8 points. If 
the standard deviation is 20 points, this difference is consistent with clinically 
meaningful effect sizes of 0.25-0.33, using distribution-based methods and 
anchor-based methods, respectively, identified by Yost et al.  (33) Given the 
sample size is large, power is based on identifying a small effect size of 0.25. It is 
assumed, conservatively, that with a median OS for non-long term survivors of 
3.96 and a median RFS for non-long term survivors of 1.44 years, then by cycle 3, 
5% of patients will drop out due to death, 12% due to worsening disease, and 3% 
for other reasons, producing an overall dropout rate of 20% at cycle 3. Further, an 
additional 10% patients are assumed to be non-adherent. Patients who drop out 
or are non-adherent are considered inevaluable. Note that in power calculations, 
the 10% non-adherence rate reduces the nominal effect size by 10% (to 0.225), 
while the 20% dropout rate inflates the estimated sample size by a factor of 1/(1-
0.2) or 25%. Using a 2-sided alpha=0.05 test and a two-arm normal design, and 
accounting for dropout and non-adherence as specified, there will be 94% power 
to detect the effect size difference of 0.25 between the two arms.    
 
Power will be worse with a smaller sample size. For instance, a sample size of 260 
patients (130 per arm) will provide 83% power for a notably higher standardized 
difference (difference between means / standard deviation) of 0.4, using the same 
parameters as specified above. This effect size corresponds to a minimally 
important difference of 8 points in the FACT BRM TOI at cycle 3 if the standard 
deviation is 20%, the upper limit of the range of the minimally important difference 
as indicated in Yost et al.   
 
11.9 
Data and Safety Monitoring 
 
A Data and Safety Monitoring Committee will oversee the conduct of this study.  The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 
non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistical Center, and will meet at the Group's bi-annual 
meetings as necessary.  The Committee will be responsible for decisions regarding 
possible termination and/or early reporting of the study. 
 
In addition to the above DSMC review, toxicity and accrual monitoring are done routinely 
by the Study Chair, study Statistician, and the Disease Committee Chair.  Endpoint 

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monitoring is done by the study Statistician and Study Chair.  Accrual reports are generated 
weekly, and formal toxicity reports are generated every 6 months.  In addition, the 
Statistical Center, Adverse Event Coordinator at the Operations Office, SAE Physician 
Reviewer, and Study Chair monitor toxicities on an ongoing basis. 
 
 
12.0 
DISCIPLINE REVIEW 
 
This study will not utilize discipline review. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
a. 
STEP 1 Registration - Screening 
 
Patients must meet the eligibility criteria in the Step 1 Registration criteria in 
Section 5.0.  Patients must be registered within 7 business days prior to 
submission of specimens for PD-L1 testing. Patients must be registered within 98 
days of the last surgery performed to render the patient free of disease.   
 
b. 
STEP 2 Registration – Randomization 
 
Patients who meet the eligibility criteria as stated in the Step 2 Registration criteria 
in Section 5.0 will be registered to STEP 2 – Randomization.  Patients must register 
within 7 working days after receiving the e-mail notification confirming that their 
tissue sample was adequate for PD-L1 testing. 
 
Patients must be randomized prior to the initiation of treatment (no more than 5 
working days prior to the planned start of treatment).  
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group.  Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet to CTEP. 
 
 

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a. 
CTEP Investigator Registration Procedures 
 
Food and Drug Administration (FDA) regulations require sponsors to select qualified 
investigators. National Cancer Institute (NCI) policy requires all individuals contributing to 
NCI-sponsored trials to register with their qualifications and credentials and to renew their 
registration annually. To register, all individuals must obtain Cancer Therapy Evaluation 
Program (CTEP) credentials necessary to access secure NCI Clinical Oncology Research 
Enterprise (CORE) systems. Investigators and clinical site staff who are significant 
contributors to research must register in the Registration and Credential Repository (RCR). 
The RCR is a self-service online person registration application with electronic signature 
and document submission capability. 
RCR utilizes five-person registration types. 
x 
Investigator (IVR) — MD, DO, or international equivalent; 
x 
Non-Physician Investigator (NPIVR) — advanced practice providers (e.g., NP or PA) 
or graduate level researchers (e.g., PhD); 
x 
Associate Plus (AP) — clinical site staff (e.g., RN or CRA) with data entry access to 
CTSU applications such as the Roster Update Management System (RUMS), OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; 
x 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
x 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
X 
X 
 
 
 
Financial Disclosure Form 
X 
X 
X 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
X 
X 
X 
 
 
GCP training 
X 
X 
X 
 
 
Agent Shipment Form (if applicable) 
X 
 
 
 
 
CV (optional) 
X 
X 
X 
 
 
 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) 
covering their practice sites on the FDA Form 1572 in RCR to allow the following: 
x 
Addition to a site roster; 
x 
Selection as the treating, credit, or drug shipment investigator or consenting person in 
OPEN; 
x 
Ability to be named as the site-protocol Principal (PI) on the IRB approval; and 
x 
Assignment of the Clinical Investigator (CI) task on the Delegation of Tasks Log (DTL).     
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
 
Additional 
information 
is 
located 
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.  
 
b. 
CTEP Associate Registration Procedures 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) application is a web-based application intended for use by both 

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Investigators (i.e., all physicians involved in the conduct of NCI-sponsored clinical 
trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored 
clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration 
and annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering 
with CTEP as an Investigator, which must be completed before a CTEP-IAM 
account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU 
members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm 
 For questions, please contact the CTEP Associate Registration Help Desk by 
email at ctepreghelp@ctep.nci.nih.gov 
 
c. 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval:   
 
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central 
Institutional Review Board (NCI CIRB) in order to participate in Cancer Therapy 
Evaluation Program (CTEP) and Division of Cancer Prevention (DCP) studies 
open to the National Clinical Trials Network (NCTN) and NCI Community Oncology 
Research Program (NCORP) Research Bases. In addition, U.S.-based sites must 
accept the NCI CIRB review to activate new studies at the site after March 1, 2019. 
Local IRB review will continue to be accepted for studies that are not reviewed by 
the CIRB, or if the study was previously open at the site under the local IRB. 
International sites should continue to submit Research Ethics Board (REB) 
approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet 
(SSW) for Local Context to the CIRB using IRBManager to indicate their intent to 
open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the 
CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site 
preferences for applying NCI CIRB approvals across their Signatory Network. Site 
preferences can be set at the network or protocol level. Questions about 
establishing site preferences can be addressed to the CTSU Regulatory Office by 
email or calling 1-888-651-CTSU (2878). 
Include the following (highlighted) paragraph for trials that will include sites using 
their local IRB or REB as well as for trials with non U.S.-based NCTN and NCORP 
sites.  
Sites using their local IRB or REB, must submit their approval to the CTSU 
Regulatory Office using the Regulatory Submission Portal located in the 
Regulatory section of the CTSU website. Acceptable documentation of local 
IRB/REB approval includes: 
• Local IRB documentation; 
• IRB-signed CTSU IRB Certification Form; and/or 
• Protocol 
of 
Human 
Subjects 
Assurance 
Identification/IRB 
Certification/Declaration of Exemption Form. 

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In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on the 
IRB/REB approval) must meet the following criteria for the site to be able to have 
an Approved status following processing of the IRB/REB approval record: 
• Have an active CTEP status; 
• Have an active status at the site(s) on the IRB/REB approval (applies to US and 
Canadian sites only) on at least one participating organization’s roster; 
• If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
• Include the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile;  
• List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in 
the RCR profile; and 
• Have the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number; 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
• An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
• Compliance with all applicable protocol-specific requirements (PSRs). 
 
 
 
Downloading Site Registration Documents:   
 
Download the site registration forms from the protocol-specific page located on 
the CTSU members’ website. Permission to view and download this protocol and 
its supporting documents is restricted to institutions and their associated 
investigators and staff on a participating roster. To view/download site 
registration forms:   
x Log in to the CTSU members’ website (https://www.ctsu.org)  
x Click on Protocols in the upper left of the screen: 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select 
[Corresponding Organization], and protocol number S1404. 
x Click on Documents, Protocol Related Documents, and use the Document 
Type filter and select Site Registration to download and complete the forms 
provided. (Note: For sites under the CIRB, IRB data will load automatically to the 
CTSU.)  
 
Requirements for S1404 Site Registration: 
 
• 
CTSU Transmittal Sheet (optional)  
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of 
Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form, or combination is accepted) 
 
NOTE:  Per NCI policy all institutions that participate on protocols with a radiation 
therapy component must participate in the Image and Radiation Oncology 
Core (IROC) monitoring program.  If this form has been previously submitted 

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to CTSU it does not need to be resubmitted unless updates have occurred at 
the RT facility 
 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ 
website, go to the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately by phone or email: 1-
866-651-CTSU (2878), or CTSURegHelp@coccg.org to receive further instruction 
and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU 
website.   
 
 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 at the top of your screen 
 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 as 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. 
 
Text for Patient Enrollment 
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://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role 
on either the LPO or participating organization roster. 
 
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.  
 
Prior to accessing OPEN, site staff should verify the following: 
 
x 
All eligibility criteria have been met within the protocol stated timeframes.  
x 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
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 

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https://open.ctsu.org.  For any additional questions contact the CTSU Help Desk 
at 1-888-823-5923 or ctsucontact@westat.com.  
 
 

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d. 
Text for Data Submission / Data Reporting 
 
Data collection for this study will be done exclusively through the Medidata Rave 
clinical data management 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://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and the appropriate Rave role (Rave CRA, 
Read-Only, Site Investigator) on either the LPO or participating organization 
roster at the enrolling site. 
 
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 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.  
 
13.3 
OPEN Registration Requirements 
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org . For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com . 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet. The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
 
h. 
Country of Residence 

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i. 
ZIP Code 
 
j. 
Gender (select one): 
x 
Female Gender 
x 
Male Gender 
 
k. 
Ethnicity (select one): 
x 
Hispanic or Latino 
x 
Not Hispanic or Latino 
x 
Unknown 
 
l. 
Method of Payment (select one): 
x 
Private Insurance 
x 
Medicare 
x 
Medicare and Private Insurance 
x 
Medicaid 
x 
Medicaid and Medicare 
x 
Military or Veterans Sponsored NOS 
x 
Military Sponsored (Including Champus & Tricare) 
x 
Veterans Sponsored 
x 
Self Pay (No Insurance) 
x 
No Means of Payment (No Insurance) 
x 
Other 
x 
Unknown 
 
m. 
Race (select all that apply): 
x 
American Indian or Alaska Native 
x 
Asian 
x 
Black or African American 
x 
Native Hawaiian or other Pacific Islander 
x 
White 
x 
Unknown 
 
13.4 
Registration Procedures 
 
 
a. Patient Enrollment 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs’ registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
Requirements for OPEN access:   
• 
Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 
Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must 
hold the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 

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To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU 
members’ website. Further instructional information is in the OPEN section of the 
CTSU website at https://www.ctsu.org or https://open.ctsu.org. For any additional 
questions, contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
b. Additional Required  
 
This is a study with a radiation and/or imaging (RTI) component and the enrolling site 
must be aligned to an RTI provider. To manage provider associations or to add or 
remove associated providers, access the Provider Association page from the Regulatory 
section on the CTSU members’ website at 
https://www.ctsu.org/RSS/RTFProviderAssociation. Sites must be linked to at least one 
Imaging and Radiation Oncology Core (IROC) provider to participate on trials with an RTI 
component. Enrolling sites are responsible for ensuring that the appropriate agreements 
and IRB approvals are in place with their RTI provider. An individual with a primary role 
on a treating site roster can update the provider associations, though all individuals at a 
site may view provider associations. To find who holds primary roles at your site, view the 
Person Roster Browser under the RUMS section on the CTSU members’ website. 
 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC Houston 
to verify credentialing status or to begin a new modality credentialing process.  
 
To complete protocol-specific credentialing the RTI provider or enrolling site should follow 
instructions in the protocol to submit documentation or other materials to the designated 
IROC Quality Assurance (QA) center. Upon the IROC QA center approving the RTI 
provider for the study modality, IROC will automatically send the approval to the 
Regulatory and Roster Maintenance applications to comply with the protocol-specific 
requirement, unless otherwise noted at the bottom of the IROC Credentialing Approval 
notification. IROC will continue to copy the provider and/or enrolling site on modality 
approvals. 
 
Upon site registration approval in the Regulatory application, the enrolling site may 
access Oncology Patient Enrollment Network (OPEN) to complete enrollments. If the 
study is using the IROC integration suite, the enrolling site will select their credentialed 
provider treating the subject in the OPEN credentialing screen and may need to answer 
additional questions related to treatment in the eligibility checklist.   
 
13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 

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c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirements 
 
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
 
Data collection for this study will be done exclusively through the Medidata Rave clinical 
data management 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://eapps-ctep.nci.nih.gov/iam/index.jsp >) and the appropriate 
Rave role (Rave CRA, Read-Only, Site Investigator) on either the LPO or participating 
organization roster at the enrolling site. 
 
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 
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.   
 
 
 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol page on the CTSU website (www.ctsu.org). 
 
14.3 
Data Submission Procedures 
 
 
a. 
Medidata Rave is the clinical data management system being used for data 
collection for this trial/study. Access to the Trial in Rave is controlled through the 
CTEP-IAM system and role assignments. 
 
Requirements to access Rave via iMedidata: 
 

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• 
Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; 
and 
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave 
CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. 
 
Rave role requirements: 
 
o 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
 
o 
Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
 
o 
Rave Read Only or Rave SLA role must have at a minimum an Associates (A) 
registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm  for registration 
types and documentation required. 
 
Upon initial site registration approval for the study in the Regulatory application, all 
persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation email from iMedidata. To accept the invitation, site staff must either click 
on the link in the email or log in to iMedidata via the CTSU members’ website under 
Data Management > Rave Home and click to accept the invitation in the Tasks 
pane located in the upper right corner of the iMedidata screen. Site staff 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 eLearning link in the Tasks 
pane located in the upper right corner of the iMedidata screen. If an eLearning is 
required for a study and has not yet been taken, the link to the eLearning will 
appear under the study name in the Studies pane located in the center of the 
iMedidata screen; once the successful completion of the eLearning has been 
recorded, access to the study in Rave will be granted, and a Rave EDC link will 
replace the eLearning link under the study name.  
 
Site staff who have not previously activated their iMedidata/Rave account at the 
time of initial site registration approval for the study in the Regulatory application 
will receive a separate invitation from iMedidata to activate their account. Account 
activation instructions are located on the CTSU website in the Data Management 
section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is 
available on the CTSU members’ website in the Data Management > Rave section 
or by contacting the CTSU Help Desk at 1-888-823-5923 or by email at 
ctsucontact@westat.com .   
 
 
b. 
You may also access Rave® via the SWOG CRA Workbench.  Go to the SWOG 
web site (https://swog.org )). 
 
For difficulties with the CRA Workbench, please email  
technicalquestion@crab.org.  
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU), please 
refer to the CTSU Participation Table. 
 
d. 
Data Quality Portal  

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The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms, DQP 
Form Status and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, forms with current status, and 
timeliness reports. Site staff should review the DQP modules on a regular basis 
to manage specified queries and delinquent forms. 
The DQP is accessible by site staff who are rostered to a site and have access to 
the CTSU website. Staff who have Rave study access can access the Rave 
study data via direct links available in the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice 
a month. These notifications serve as alerts that queries and/or delinquent forms 
require site review, providing a summary count of queries and delinquent forms 
for each Rave study that a site is participating in. Additional site staff can 
subscribe and unsubscribe to these notifications using the CTSU Report and 
Information Subscription Portal on the CTSU members’ website. 
To learn more about DQP use and access, click on the Help Topics button 
displayed on the Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form 
Status, and DQP Reports modules. 
 
14.4 
Data Submission Overview and Timepoints  
 
a. 
WITHIN 7 DAYS OF REGISTRATION TO STEP 1: 
 
Submit the following: 
 
S1404 Eligibility Checklist, confirmed a patient’s eligibility (NOTE:  This must be 
uploaded into Rave® via Source Documentation Baseline Form) 
 
S1404 Onstudy Form 
 
S1404 Medical History Form 
 
Submit slides for PD-L1 evaluation as specified in Section 15.2. 
 
*S1404 Local Pathology Review Form (Section 18.4) 
 
*Radiology reports from all scans performed to assess disease at baseline 
 
*Pathology reports documenting histologic confirmation and complete resection of 
all disease.  
 
*NOTE:  Upload reports via the Source Documentation: Baseline form in Rave®. 
 
b. 
IF PATIENT WILL NOT BE REGISTERED TO STEP 2 (RANDOMIZATION), 
SUBMIT WITHIN 7 DAYS OF DECISION NOT TO RANDOMIZE PATIENT: 
 
S1404 Pre-Randomization Off Study Form 
 
NOTE:  For patients who do not register to Step 2 (Randomization), no additional 
follow-up is required other than the items listed in Sections 14.4a and 14.4b. 

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c. 
WITHIN 28 DAYS OF REGISTRATION TO STEP 2 (RANDOMIZATION): 
 
If patient consents to banking, submit specimens as specified in Section 15.3. 
 
d. 
WITHIN 14 DAYS OF REGISTRATION TO STEP 2 (RANDOMIZATION): 
 
Submit S1404 Baseline Laboratory Values Form 
 
Submit to IROC via TRIAD for Image Banking. Images from scans performed to 
assess disease as specified in Section 15.6. 
 
 
e. 
PATIENTS RANDOMIZED TO ARM 2, MK-3475 (PEMBROLIZUMAB), THEREBY 
PARTICPATING IN PHARMACOKINETIC (PK) AND ANTI-DRUG ANTIBODY 
(ADA) TESTING: 
 
Submit specimens as specified in Section 15.4. 
 
f. 
WITHIN 14 DAYS AFTER EACH CYCLE OF TREATMENT (CYCLE 1 AND 
CYCLE 2 = 6 WEEKS EACH; ALL SUBSEQUENT CYCLES = 12 WEEKS): 
 
Submit the following: 
 
S1404 Treatment Form 
 
S1404 Adverse Event Form 
 
S1404 Laboratory Values Form 
 
S1404 Concomitant Medications Form 
 
g. 
AFTER RANDOMIZATION, WITHIN 14 DAYS AFTER EACH DISEASE 
ASSESSMENT, INCLUDING ANNUAL BRAIN IMAGING (SEE STUDY 
CALENDAR FOR SCHEDULE) UNTIL RECURRENCE (AS DEFINED IN 
SECTION 10.0) OR 5 YEARS AFTER RANDOMIZATION (WHICHEVER 
OCCURS FIRST): 
 
Submit the following: 
 
S1404 Disease Assessment Form 
 
Radiology reports from all scans performed to assess disease (uploaded via the 
Source Documentation: Follow-Up Form in Rave®) 
 
Submit to IROC via TRIAD for image banking. Images from scans performed to 
assess disease as specified in Section 15.6. 
 
If patient is no longer on protocol treatment, also submit the Adjuvant Melanoma 
Follow-up Form 
 
h. 
AFTER 
RANDOMIZATION, 
WITHIN 
14 
DAYS 
AFTER 
EVERY 
QOL 
ASSESSMENT (SEE STUDY CALENDAR FOR SCHEDULE): 
 
Submit the following: 
 
S1404 Cover Sheet for Patient-Completed Questionnaires 
 
S1404 FACT-BRM - FACIT-D 
 

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S1404 EQ-5D-3L 
 
For the first two patients enrolled at each site, in addition, upload copies of the 
patient completed paper forms via Source Documentation:  Other form in Rave®. 
NOTE:  Some sites, identified by Risk-Based Monitoring, may be required to 
submit for additional patients. 
 
 

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i. 
WITHIN 7 DAYS OF DISCONTINUATION OF PROTOCOL TREATMENT: 
 
Submit the following: 
 
Off Treatment Notice documenting reasons for off treatment 
 
S1404 Treatment Form 
 
S1404 Adverse Event Form  
 
S1404 Laboratory Values Form 
 
S1404 Concomitant Medications Form 
 
j. 
ONCE OFF ALL PROTOCOL TREATMENT, SUBMIT EVERY 6 MONTHS FOR 
THE FIRST 2 YEARS, THEN YEARLY THROUGH YEAR 10: 
 
Adjuvant Melanoma Follow-Up Form 
 
Late Effects Form (if prior to treatment for progression or relapse or a second 
primary, and prior to non-protocol treatment, the patient experiences any severe 
[Grade ≥ 3] long term toxicity that has not been previously reported). 
 
k. 
WITHIN 14 DAYS OF PROGRESSION OR RELAPSE: 
 
Submit the following: 
 
S1404 Disease assessment form 
 
S1404 Cover Sheet for Patient-Completed Questionnaires 
 
S1404 FACT-BRM-FACIT-D 
 
S1404 EQ-5D-3L 
 
Site(s) of progression/relapse Form 
 
Radiology reports from all scans performed to assess disease (uploaded via the 
Source Documentation: Follow-Up Form in Rave®). 
 
Submit to IROC via TRIAD for image banking. Images from scans performed to 
assess disease as specified in Section 15.6. 
 
If patient is no longer on protocol treatment, also submit the Adjuvant Melanoma 
Follow-Up Form. 
 
l. 
WITHIN 28 DAYS OF KNOWLEDGE OF DEATH: 
 
Notice of Death and all of the items listed in Section 14.4e or 14.4f (if the patient 
was still on protocol treatment) or the Adjuvant Melanoma Follow-Up Form (if the 
patient was off protocol treatment) documenting death information. 
 
 
 

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15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
SWOG Specimen Tracking System (STS) 
 
a. 
All specimen submissions for this study must be entered and tracked using the 
SWOG online Specimen Tracking system. SWOG members may log on the online 
system via the CRA Workbench. To access the CRA Workbench, go to the SWOG 
Web site (https://swog.org) and logon using your CTEP ID and password. After 
you have logged on, click on the “Member Resources” tab, and then from this page 
click on “CRA Workbench”. . Non- SWOG users may log into SpecTrack using 
their CTSU User ID and password on the SpecTrack login page located at 
https://crawb.crab.org/SpecTrack/Logon.aspx (select the option “SWOG – SWOG 
– CTSU”).  SpecTrack start-up instructions (both written and demo) are available 
after signing in to SpecTrack. For non-SWOG members, please visit 
https://crawb.crab.org/TXWB/Logon.aspx.  
 
A copy of the Shipment Packing List produced by the online Specimen Tracking 
system should be printed and placed in the pocket of the specimen bag if it has 
one, or in a separate resealable bag.  
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE NO 
EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database errors or 
connectivity issues, please send an email to technicalquestion@crab.org. For 
procedural help with logging and shipping specimens, there is an introduction to 
the system on the Specimen Tracking main page 
(http://dnet.crab.org/SpecTrack/Documents/Instructions.pdf); or contact the Data 
Operations Center at 206/652-2267 to be routed to the Data Coordinator for further 
assistance. 
 
In the online specimen tracking system, the appropriate SWOG laboratory for 
submission of tissue and blood samples for SWOG Biospecimen Bank  
Submission is identified as follows: 
 
Lab #201: 
SWOG Specimen Biospecimen Bank   
 
Solid Tissue, Myeloma, and Lymphoma Division 
Phone: 
614-722-2865 
FAX: 
614-722-2897 
E-mail: 
bpcbank@nationwidechildrens.org 
 
b. 
Federal guidelines for the shipment of blood products: 
 
1. 
The tube must be wrapped in an absorbent material. 
 
2. 
The tube must then be placed in an AIRTIGHT container (like a resealable 
bag). 
 
3. 
Pack the resealable bag and tube in a Styrofoam shipping container. 
 
4. 
Pack the Styrofoam shipping container in a cardboard box. 
 
5. 
Mark the box "Biohazard". 
 
15.2 
Submission of slides for PD-L1 Evaluation 
 

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At time of tissue selection, quality control measures of tumor tissue should be performed 
to ensure sufficient viable tumor tissue, which should contain ≥ 100 viable tumor cells. 
Tumor material must be reviewed by a local pathologist to ensure sufficient tumor cells are 
present in the sample. This must be documented by having the pathologist sign the S1404 
Local Pathology Review form (see Section 18.4).  If slides do not contain a sufficient 
number of cells for analysis the site will be asked to resubmit and/or the patient may be 
deemed ineligible. 
 
Specimens for PD-L1 evaluation (submitted to the designated central laboratory, Lab #218) 
(required for patient): 
 
a. 
Five unstained slides from the primary, lymph node, or metastatic site, and the 
Pathology Report must be submitted at the following times: 
 
x 
Within 7 days after Registration to Step 1. 
 
b. 
Specimen submissions must be entered and tracked using the SWOG Online 
Specimen Tracking System (SpecTrack). See Section 15.1 for instructions. 
 
The following will be provided to sites by the Central Laboratory: 
 
x 
Plastic slide holders (each can hold up to 5 slides) 
x 
Positively charged microscope slides  
o 
Please use only positively charged slides provided by CENTRAL LAB 
which are standard sized positively charged microscope slides (75 mm 
x 25 mm x 1 mm). 
x 
Bubble wrap pouch 
x 
CENTRAL LAB Labels (NOTE:  Labels may use an alternate study ID 
number:  “MK3475-053”.  This is how the lab is identifying S1404). 
x 
Amber Bag 
x 
Biohazard Bag (also labeled as Specimen Transport Bag) 
x 
Shipping container 
x 
Gel packs  
 
NOTE:  Expiry dates will be clearly marked on the label that is placed on the 
outside of the collection kit box.  The expiry date is always reflective of the tube 
that expires the earliest.  The expiry date displayed on the label is good to the 
last day of the month displayed unless otherwise noted. 
 
c. 
Kit Ordering  
 
1. 
To order initial specimen kits log onto the SWOG Specimen Tracking 
System (https://crawb.crab.org/SpecTrack/Logon.aspx) and click on the 
link “Specimen kits for S1404” at the bottom of the page.  When placing 
this initial order, sites must provide laboratory contact information. For 
SWOG institutions the fields will be pre-populated based on the current 
data in the SWOG roster. Please note, the initial order will contain four PD-
L1 kits and three PK/ADA kits and may take up to 15 days to be filled by 
PPD. Once PPD CL receives site information, a site username will be 
assigned and faxed to the site on the fax verification form. This username 
will be used for sites to access  
http://preclaruslabdata.ppdi.com to reorder supplies. 
 
If your site does not receive the fax verification form within 3 days of 
registration, please call SWOG Data Operations at 206/652-2267. 
 

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2. 
For 
subsequent 
orders 
only, 
sites 
may 
reorder 
supplies 
at 
http://preclaruslabdata.ppdi.com.  After reordering, a confirmation email 
will be sent automatically to the site email address. 
 
d. 
Sample Preparation and Collection Procedures  
 
1. 
A fine needle aspirate, frozen sample, plastic embedded sample, cell 
block, bone, bone marrow, clot, or cytologic specimen will not be 
acceptable for IHC analysis. 
 
2. 
Obtain a plastic slide holder container from kit.  Each slide holder can hold 
a maximum of 5 slides (placing additional slides in the holder above 5 will 
result in slide breakage during shipping). 
 
3. 
Prepare freshly cut serial sections at 4 micron thickness onto the provided 
positively charged microscope slides (4-5 micron thickness is acceptable) 
as close to the day of shipping as possible (no more than 20 days).   Other 
non-standard sized slides cannot be accepted for testing. 
 
4. 
Standard sized positively charged slides are required for samples; slide 
measurements are 75 mm x 25 mm x 1 mm.  Other sized slides cannot be 
accommodated.   
 
5. 
DO NOT BAKE SLIDES – only air dry at room temperature12-24 hours 
prior to shipment. 
 
6. 
Five slides are required to be submitted. 
 
7. 
Label each slide with SWOG Patient ID Number and serially in the 
order they were sectioned with indelible ink.  
 
8. 
Place slides in slots of the plastic slide holder in order of sectioning, with 
a maximum of 5 slides per plastic slide holder.  Place the provided label 
on one side of the plastic slide holder to allow the barcode to be scanned.  
Do not wrap the label. 
 
9. 
Once plastic slide holder is closed, tape shut with some standard masking 
or general purpose tape prior to shipment.  
 
10. 
Place sample within amber bag to ensure sample will be in the dark. 
 
11. 
Store in the dark at 2-8 ºC until ready to ship.  
 
12. 
Bubble wrap the slide holders to help prevent breakage.  
 
13. 
Place bubble wrapped slide holders in the biohazard bag (Specimen 
Transport Bag). 
 
14. 
If needed, secure the slide box in the shipping container with packing 
paper. 
 
15. 
Using the appropriate provided shipper from kits, ship cold (2-8ºC) 
by using the frozen gel packs/wraps.  
 
16. 
In the shipping container along with the Specimen Transport Bag and 
frozen gel packs/wraps, place copies of 1) the Pathology Report, and 2) 
the SWOG Specimen Tracking System Packing List. 
 

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17. 
A minimum of 5 slides need to be shipped for PD-L1 testing and 
slides need to be shipped within 20 days of cutting the slides. 
 
18. 
PD-L1 testing may need to be repeated if first set of slides were not 
adequate for testing.  A minimum of 5 slides would need to be shipped for 
PD-L1 re-testing. 
 
e. 
Shipping instructions 
 
When submitting tissue to LabCorp for PD-L1 testing, be prepared to provide 
answers to the following questions in the SWOG specimen Tracking System: 
  
x 
Tissue collection method (surgical resection, biopsy) 
x 
Anatomic location of tumor tissue collection (Liver, Lung, Lymph node, Oral, 
Skin/subcutaneous tissue, Other) 
x 
Month and year of patient's birth 
x 
Date unstained slides were cut 
x 
Method used to prepare paraffin embedded tissue (unknown, 10% neutral 
buffered formalin, Other) 
x 
Time from tissue excision to immersion in fixative (unknown, >= 60 min, >30 
- < 60 min, <= 30 min) 
Shipping: 
x 
Airway bills will be provided by PPD for shipping directly to LabCorp 
x 
Shipments to LabCorp should be on Mondays through Thursdays. 
x 
Forms to be included in shipping: 
o 
A copy of SWOG Specimen Tracking System Packing List  
o 
A copy of the pathology report 
x 
FFPE sectioned slides should be shipped refrigerated (2ºC-8ºC) and in the 
dark (amber bag to be used). GEL packs used must be FROZEN. 
 
x 
Ship the container overnight Monday through Thursday, along with a copy of 
SWOG Specimen Tracking System Packing List, the same day to the 
address below: 
 
Lab #218: LabCorp Clinical Trials  
 
Note: LabCorp identifies S1404 using an alternate study ID number: 
“MK3475-053”. 
 
x 
Refer to PPD Laboratory Manual for additional shipping instructions. 
 
f. 
Within 10 business days after specimen submission, institutions will be notified via 
e-mail whether or not the tissue specimen was adequate for PD-L1 testing. If the 
result comes back as “adequate”, register the patient to Step 2 “Randomization” 
with 7 working days of receiving the email. If the result comes back as 
“inadequate”, a second tissue specimen may be submitted if sufficient tissue 
remains. NOTE: The email will not include the patient’s PD-L1 status.  
 
If there are any questions, please contact the SWOG Data Operations Center at 
206/652-2267. 
 
15.3 
Specimens for Banking 
 
Specimens for banking (submitted to the SWOG Specimen Biospecimen Bank   – Solid 
Tissue, Myeloma and Lymphoma Division, Lab #201) (optional for patient): 
 
a. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies.  Please do not use tubes provided by PPD. Do NOT submit 
specimens for banking to LabCorp. 

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b. 
With patient’s consent, the following specimens must be submitted at the following 
times: 
 
1. 
Entire block of paraffin embedded tissue (from primary, lymph node, and 
metastasis if present) or 10 unstained slides may be submitted if the 
institution cannot release a pathology paraffin embedded block, and one 
H&E (Hematoxylin and Eosin) stained slide at the following times: 
x 
Baseline 
x 
Relapse 
 
Submit tissue according to guidelines provided by SWOG  
Biospecimen Bank: 
https://www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures.  
 
Collect three tubes of whole blood in 10 mL red/black marble top (SST) 
vacutainer tubes with no anticoagulant.  Process whole blood to serum 
according to guidelines provided by SWOG  
Biospecimen Bank: 
https://www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures.  
 
Collect at the following times: 
x 
Baseline (prior to the start of study treatment) 
x 
Start of Cycle 3 (Week 13, if there are no dose delays) 
x 
Start of Cycle 4 (Week 25 if there are no dose delays)  
x 
When patient is removed from protocol therapy for any reason 
x 
Relapse   
 
Collect three tubes of whole blood in 10 mL pink/lavender top vacutainer 
tubes with EDTA. Process whole blood to plasma and buffy coat 
according to guidelines provided by SWOG  
Biospecimen Bank: 
https://www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures.  
 
Collect at the following times: 
x 
Baseline (prior to the start of study treatment) 
x 
Start of Cycle 3 (Week 13 if there are no dose delays) 
x 
Start of Cycle 4 (Week 25 if there are no dose delays) 
x 
When patient is removed from protocol therapy for any reason 
x 
Relapse 
 
c. 
If a patient has a treatment delay or interruption due to an adverse event, the blood 
sample for banking should be drawn even if the patient did not receive study 
treatment.  The goal is to collect the sample as close to the week designated by 
the protocol. 
 
d. 
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage 
(https://www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures). 
 
15.4 
Pharmacokinetic (PK) and Anti Drug Antibody (ADA) testing 
 
NOTE:  AS OF 12/11/2017 PK/ADA SAMPLING HAS BEEN DISCONTINUED. 
 
a. 
Requirements 
 

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All patients randomized to the MK-3475 (pembrolizumab arm) will have blood 
draws for PK and ADA analysis. 
 
b. 
PK/ADA Sampling for the trial 
 
PK/ADA sampling may be discontinued upon confirmation that results are 
consistent with the current PK/ADA profile of MK-3475 (pembrolizumab) as 
determined by the Merck Pharmacokinetics and Pharmacodynamics Drug 
Metabolism Quantitative Pharmacology and Pharmacometrics group. 
 
c. 
Specimen Tracking 
 
Specimen submissions must be entered and tracked using the SWOG Online 
Specimen Tracking System (SpecTrack). See Section 15.1 for instructions. 
 
d. 
Kit ordering  
 
1. 
To order initial specimen kits log onto the SWOG Specimen Tracking 
System (https://crawb.crab.org/SpecTrack/Logon.aspx) and click on the 
link “Specimen kits for S1404” at the bottom of the page.  When placing 
this initial order, sites must provide laboratory contact information. For 
SWOG institutions the fields will be pre-populated based on the current 
data in the SWOG roster. Please note, the initial order will contain three 
(3) PK/ADA kits and four (4) PD-L1 kits and may take up to 15 days to be 
filled by PPD.  Once PPD receives site information, a site username will 
be assigned and faxed to the site on the fax verification form. This 
username will be used for sites to access the PPD portal to reorder 
supplies: http://preclaruslabdata.ppdi.com.  
 
If your site does not receive the fax verification form within 3 days or 
registration, please call SWOG Data Operations at 206/652-2267. 
 
2. 
For 
subsequent 
orders 
only, 
sites 
may 
reorder 
supplies 
at 
http://preclaruslabdata.ppdi.com. After placing the order, a confirmation 
email will be sent automatically to the site email address. 
 
e. 
Frequency 
 
PK and ADA samples will be collected before first infusion Cycle 1 (Week 1), before 
second infusion Cycle 1 (Week 4), before second infusion Cycle 2 (Week 10), 
before third infusion Cycle 3 (Week 19), before first infusion Cycle 4 (Week 25), 
before infusion Cycle 6 (Week 49) and 30 days after discontinuation of study drug 
(as long as patient has not started new anti-cancer therapy).  Samples should be 
drawn within 24 hours before infusion of MK-3475 (pembrolizumab).  
 
f. 
Sample collection and preparation procedures 
 
1. 
SST and corning tubes will be pre-labeled with study/protocol number. 
Note that the study number on the pre-printed labels appear as MK3475-
053 instead of S1404.  That is how the lab is identifying the study. Site 
should write the 6-digit SWOG Patient ID and collection date/time on the 
label and the PPD Requisition Form. Please ensure to mark the 
corresponding visit name on the PPD Requisition Form. 
 
Each pre-labeled tube is linked to a pre-labeled Requisition Form in each 
kit.  
 

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2. 
At each time point, collect 3 mL whole blood PK sample in one properly 
labeled 3.5 mL SST tube and collect 6 mL whole blood ADA sample into 
one properly labeled 8.5 mL SST tube.   
 
Record the time and cycle number (or week since off protocol therapy) 
each sample is collected as you will need to enter these data into the 
SWOG Specimen Tracking System. Record the date and time of 
administration of MK-3475 (pembrolizumab) as you will need to enter 
these data on the S1404 Treatment Form (see Section 14.4d) and on audit 
the times will need to confirm that the PK/ADA samples were drawn before 
infusion of MK-3475 (pembrolizumab). NOTE: If a sample needs to be 
drawn post-dose in error, the sample collection must be from the opposite 
arm to that used for study drug infusion. If drug was administered via a 
central venous catheter, the sample collection should be from a different 
site. 
 
3. 
Invert each tube 5 times and let stand for 30 minutes (but no longer than 
60 minutes). The blood samples should remain at room temperature prior 
to centrifugation.   
 
4. 
Centrifuge each sample 1100-1300 g for 15 minutes (speed/time may vary 
according to make and model of centrifuge). 
 
5. 
Immediately transfer the PK serum evenly to two labeled 2mL Corning 
cryovials (PK Aliquot 1 and 2).  Transfer the ADA serum evenly to three 
labeled 2 mL Corning cryovials (ADA Aliquot 1, 2, and 3) (each containing 
approximately 1 mL of serum).   Serum samples must be frozen within 30 
min of separation after the centrifuge at  -20ºC for storage up to 1 month) 
and maintained in the frozen state until assayed. 
 
g. 
Shipping instructions 
 
1. 
Batch ship monthly to PPD Central Lab 
o 
Place PK Aliquot 1 and ADA Aliquot 1 in one box. 
o 
Place PK Aliquot 2 and ADA Aliquot 2, 3 in a separate box. 
 
NOTE:  Samples from multiple patients may be sent in the same box. 
 
2. 
Complete the PPD Requisition Form (2-part form) that is included in each 
kit. Include the original form (white form) in the sample shipment box and 
keep the copy (yellow form) on site for your records. The visit and patient 
information on the Requisition form is critical to accession of samples. 
Incomplete or missing requisition forms will delay testing and put the site 
lab report on hold.  Refer to PPD Laboratory Manual for additional shipping 
instructions and PPD requisition forms. Instructions for filling out the PPD 
Requisition Form are also provided in Appendix 18.7. 
 
3. 
All shipments should be made in freezer boxes containing at least 20 kg 
DRY ICE, and labeled as HUMAN SAMPLES: NONINFECTIOUS. 
Samples should not be shipped on a holiday. It is recommended to send 
batched dry ice shipments monthly on Monday through Wednesday to 
ensure arrival before the weekend. PK and ADA samples should be 
shipped frozen on dry ice (-20°C): 
 
Lab #219: PPD Central Lab for PK and Anti-pembrolizumab Antibodies 
 
15.5 
Quality of life assessments: Instructions for administration 
 
a. 
Administration of questionnaires 

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1. 
All questionnaires should be completed prior to the visit with the physician.  
The time the questionnaire is completed and the time of the physician visit 
should be documented. 
 
2. 
The first time the patient completes the questionnaires: Please read to the 
patient the instructions attached to each patient questionnaire. Explain the 
specific administration times for this protocol. Patients should be directed 
to report all symptoms and limitations whether or not they are related to 
the cancer or its treatment. 
 
3. 
It is permissible to assist patients with completing the questionnaires being 
careful not to influence the patient's response. Note on the S1404 Cover 
Sheet for Patient-Completed Questionnaires what assistance was 
required and indicate reason (e.g., elderly, too sick, etc.). Discourage 
family members from: 1) being present while the patient completes the 
questionnaire and/or 2) influencing patient responses to the questions. 
 
4. 
It is very important to review the questionnaires after the patient has 
completed them to be sure all of the questions have been answered and 
that only one answer is marked. If the patient has marked more than one 
answer per question, ask the patient which answer reflects how she is 
feeling. If the patient has skipped a question, tell the patient that a question 
was not answered and ask if she would like to answer the question. Always 
give the patient the option to refuse. Indicate on the form by the question 
that the patient did not want to answer this question. 
 
5. 
If a patient refuses or cannot complete the questionnaire for some reason, 
this must be documented on the S1404 Cover Sheet for Patient 
Completed Questionnaires and submitted (see Section 14.4h). 
 
6. 
Questionnaires must be completed by the patient at disease 
recurrence.  On-treatment questionnaires may be submitted in place of 
recurrence questionnaires if: 
- 
The patient has already completed the on-treatment questionnaires, 
AND 
- 
The patient was aware of recurrence prior to completing the on-
treatment questionnaires, AND 
- 
The patient did not receive any treatment after completing the on-
treatment questionnaires.   
 
Otherwise, separate recurrence questionnaires must be completed by the 
patient and submitted by the study site. 
 
b. 
Additional quality control procedures: 
 
When a patient is registered on S1404, a calendar should be made with dates of 
upcoming patient-completed questionnaires noted. A copy of this calendar can be 
given to the patient with the notation that the questionnaires should be completed. 
You may wish to photocopy the Study Calendar, Section 9.0, and include the 
patient's name and specific dates. A copy of this should be kept in the patient file.  
 
If a patient refuses or cannot complete the patient questionnaires at one time 
point, he or she should be asked to do so at the next scheduled assessment 
time. Submit the S1404 Cover Sheet for Patient-Completed Questionnaires 
documenting the reason why the questionnaires were not done. 
 
Anyone involved in the collection of quality of life data in SWOG trials should review 
the training program available on the SWOG website accessible from three 

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locations. On the SWOG Home Page (prior to member login), in the QUICKLINKS 
section on the bottom right corner of the page, there is a link to the Patient 
Reported Outcomes Training. The other two locations that the training is available 
are after SWOG member login on the CRA Workbench. The Training section and 
the New CRAs! section both contain access to the Patient Reported Outcomes 
(PROs) training module. The training program is a narrated set of slides designed 
to standardize the way quality of life data is collected from patients. Questions 
regarding the quality of life assessments can be addressed to the SWOG Data 
Operations Office (206/652-2267). 
 
c. 
S1404 Cover Sheet for Patient-Completed Questionnaires 
 
For each time point that the FACT-BRM, EQ-5D-3L, and FACIT-D are 
administered, the nurse or CRA completes the S1404 Cover Sheet for Patient-
Completed Questionnaires. The Cover Sheet is submitted with the set of patient-
completed forms at each scheduled assessment. The Cover Sheet is very 
important for tracking how and when the patient forms were completed. When a 
patient-completed form is not administered at a scheduled time point, it is important 
to know why the assessment did not occur; the form includes potential reasons for 
a patient not completing a form. See Section 14.4g for data submission guidelines. 
 
d. 
QOL Questionnaire Administration Schedule 
 
The FACT-BRM, EQ-5D-3L, and FACIT-D are scheduled to be administered at the 
following time points: 
 
x 
Prior to Cycle 1 
x 
Week 4 of the first cycle of treatment 
x 
Prior to Cycles 3, 4, 5 and 6  
x 
Week 24 after the date of last treatment 
x 
Week 48 after the date of last treatment 
x 
Relapse 
 
Patients who relapse before 48 weeks after date of last treatment will complete a 
questionnaire at relapse.  Patients do not need to complete any further 
questionnaires after relapse.  Patients who go off protocol therapy before Week 49 
(Cycle 6) without recurrence will complete the two post-treatment questionnaires 
(at 24 and 48 weeks from the date of last treatment). 
 
15.6 
Submission of Images for Banking (Required) 
 
All participants will undergo PET-CT, CT or MRI imaging at baseline/pre-treatment and 
every 12 weeks until 2 years from randomization, then every 6 months until 5 years from 
randomization.  Imaging exams must then be submitted to the Imaging and Radiation 
Oncology Core (IROC) at Ohio via TRIAD Imaging Submission procedures for quality 
control and image banking. Any imaging that is used for relapse detection must be 
submitted; this would include ultrasound imaging if that is used by your institution for nodal 
basin surveillance.  In addition, if imaging done for other reasons detects a relapse (i.e., 
chest-x-ray done for pulmonary symptoms that subsequently detects a metastasis) it must 
also be submitted. 
 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s 
(ACR) image exchange application. TRIAD provides sites participating in clinical 
trials a secure method to transmit images. TRIAD anonymizes and validates the 
images as they are transferred. 
 
TRIAD Access Requirements: 
•Active CTEP registration with the credentials necessary to access 
secure NCI/CTSU IT systems; 
 

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•Registration type of: Associate (A), Associate Plus (AP), Non-Physician 
Investigator (NPIVR), or Investigator (IVR). Refer to the CTEP 
Registration Procedures section for instructions on how to request a 
CTEP-IAM account and complete registration in RCR; and 
 
•TRIAD Site User role on an NCTN, ETCTN, or other relevant roster. 
All individuals on the Imaging and Radiation Oncology Core provider 
roster have access to TRIAD and may submit images for credentialing 
purposes, or for enrollments to which the provider is linked in OPEN. 
 
TRIAD Installations: 
To submit images, the individual holding the TRIAD Site User role will need to 
install the TRIAD application on their workstation. TRIAD installation 
documentation is available at https://triadinstall.acr.org/triadclient/. 
 
This process can be done in parallel to obtaining your CTEP-IAM account and 
RCR registration. 
 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org  or 1-703-390-9858. 
 
 
15.7 
Mandatory Site Training 
 
Prior to registering patients, at least one person involved with the study at each institution 
is required to view the S1404 training module. To obtain credit for completing the training, 
after viewing the presentation sites must complete the short form at the bottom of the 
training page. The form is automatically forwarded to CTSU Regulatory Support System 
for processing and may take up to 3 days to be included in the system.  
 
The training is available at:  
https://www.swog.org/member-resources/training-forms/required-s1404-training  
 
 
 

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16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the 
Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312.  
 
Publication and Industry Contact 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between Merck (hereinafter referred to as 
"Collaborator(s)") and the NCI Division of Cancer Treatment and Diagnosis.  Therefore, the 
following obligations/guidelines in addition to the provisions in the "Intellectual Property Option to 
Collaborator"  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award apply to the use of the Agent in this study: 
 
a. 
Agent(s) may not be used outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study.  Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained 
as such by the investigators.  The protocol documents for studies utilizing Agents contain 
confidential information and should not be shared or distributed without the permission of 
the NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
 
1. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different Collaborative 
Agreements, the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as "Multi-
Party Data"): 
 
2. 
NCI will provide all Collaborators with written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations which would 
tend to restrict NCI's participation in the proposed combination protocol. 
 
3. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 

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Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
 
4. 
Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-
Party Data solely for development, regulatory approval, and commercialization of 
its own Agent. 
 
b. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order as described in the IP 
Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  Additionally, all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent 
with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
 
c. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
d. 
Any data provided to the Collaborator(s) for Phase III studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there 
is a DMC for this clinical trial. 
 
e. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential 
and proprietary data, in addition to the Collaborator(s)'s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) 
for courtesy review as soon as possible and preferably at least three (3) days prior to 
submission, but in any case, prior to presentation at the meeting or publication in the 
proceedings.  Press releases and other media presentations must also be forwarded to 
CTEP prior to release.  Copies of any manuscript, abstract and/or press release/media 
presentation should be sent to: 
 
E-mail:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to the Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information. 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports 
are due January 31, April 30, July 31 and October 31.  This study will have abbreviated 
CDUS monitoring. 

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Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and 
should not be used or shared beyond the purposes of completing protocol requirements 
until or unless additional permission is obtained. 
 
16.1 
Adverse Event Reporting Requirements 
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well 
as those who will enroll in future studies using similar agents.  Adverse events are 
reported in a routine manner at scheduled times during a trial. (Directions for 
routine reporting are provided in Section 14.0.) Additionally, certain adverse events 
must be reported in an expedited manner to allow for more timely monitoring of 
patient safety and care.  The following guidelines prescribe expedited adverse 
event reporting for this protocol.  
 
b. 
Reporting method 
 
This study requires that expedited adverse events be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS).  
CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted to the SWOG Operations Office 
electronically via the CTEP-AERS Web-based application located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm. 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP-
AERS.  
 
When the adverse event requires expedited reporting, submit the report within the 
number of calendar days of learning of the event, as specified in Table 16.1. 
 
In the rare event when internet connectivity is disrupted a 24-hour notification is 
made to NCI by telephone at 301/897-7497.  An electronic report MUST be 
submitted immediately upon re-establishment of internet connection. 
 
Any supporting documentation requested by CTEP should be submitted in 
accordance with instructions provided by the CTEP-AERS system.  
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures. 
 
 

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e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agents as part of the trial.  Reporting requirements are provided in 
Table 16.1.  The investigational agent used in this study is MK-3475 
(pembrolizumab).  If there is any question about the reportability of an adverse 
event or if on-line CTEP-AERS cannot be used, please telephone or email the SAE 
Specialist at the Operations Office, 210/614-8808 or adr@swog.org, before 
preparing the report. 
 
 

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Table 16.1: 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under a CTEP IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1   MK-3475 (Pembrolizumab). 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR or [Section 
16.1f.] 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 
24-hour report. 
 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
x Grade 3 adverse events 
 
May 5, 2011 
 
 
 

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f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Late Phase 2 and Phase 3 Studies Utilizing an Agent under 
a CTEP IND: 
 
1. 
Group-specific instructions 
 
Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements.  In 
addition, you may be asked to submit supporting clinical data to the 
Operations Offices in order to complete the evaluation of the event.  If 
requested, the supporting data should be sent within 5 calendar days 
by fax to 210-614-0006.  Supporting clinical data submitted should 
include: 
x 
Printed copy of the first page of the CTEP-AERS Report. 
x 
Copies of clinical sourced documentation of the event. 
x 
If applicable, and they have not yet been submitted to the 
SWOG Data Operations Center copies of Off Treatment 
Notice and/or Notice of Death. 
 
g. 
Expedited reporting for commercial agents 
 
Commercial reporting requirements are provided in Table 16.2. The commercial 
agent(s) used this study are interferon alfa 2b and ipilimumab. If there is any 
question about the reportability of an adverse event or if on-line CTEP-AERS 
cannot be used, please telephone or email the SAE Program at the Operations 
Office, 210/614-8808 or adr@swog.org, before preparing the report. 
 
Table 16.2. Expedited reporting requirements for adverse events 
experienced by patients on interferon alfa-2b or ipilimumab who have 
received the commercial drug(s) listed in Section 16.1g within 30 days of the 
last administration of the commercial agent(s). 
 
ATTRIBUTIO
N 
 
Grade 4 
 
Grade 5a 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated or 
Unlikely 
 
 
CTEP-AERS 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
CTEP-AERS 
CTEP-AERS:  Indicates an expedited report is to be submitted via CTEP-AERS within 
10 calendar days of learning of the eventb. 
a This includes all deaths within 30 days of the last dose of treatment with a commercial 
agent(s), regardless of attribution.  Any death that occurs more than 30 days after the 
last dose of treatment with a commercial agent(s) and is attributed (possibly, probably, 
or definitely) to the agent(s) and is not due to cancer recurrence must be reported 
according to the instructions above. 
 
b Submission of the on-line CTEP-AERS report plus any necessary amendments 
generally completes the reporting requirements. You may, however, be asked to 
submit supporting clinical data to the Operations Office in order to complete the 
evaluation of the event. If requested, the specified data should be sent within 5 
calendar days by fax to 210-614-0006.  
 
 
 
 

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h. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
 
CTEP requires all secondary malignancies that occur following treatment 
with an agent under an NCI IND to be reported via CTEP-AERS.  Three 
options are available to describe the event. 
 
x 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
x 
Myelodysplastic syndrome (MDS) 
x 
Treatment-related secondary malignancy 
 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in 
each protocol. 
 
Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the initial 
malignancy).  Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified. 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf. 
   
2. 
Any supporting documentation should be submitted to CTEP per NCI 
guidelines for AE reporting located at:   
http://ctep.cancer.gov/protocoldevelopment/electronic_applications/aegui
delines.pdf.   
 
A copy of the report and the following supporting documentation must also 
be submitted to SWOG Operations Office within 30 days by fax to 210-
614-0006 or mail to the address below: 
 
x 
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis 
x 
(if available) a copy of the cytogenetics report   
 
SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 
 
i. 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
 
1. 
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.  
 

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2. 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
3. 
Fetal Death Fetal Death defined in CTCAE as “A disorder characterized 
by death in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation” should be 
reported expeditiously as Grade 4 “pregnancy, puerperium and 
perinatal conditions – Other (pregnancy loss)” under the Pregnancy, 
puerperium and perinatal conditions SOC.   
 
4. 
Death Neonatal Neonatal death, defined in CTCAE as “A disorder 
characterized by cessation of life occurring during the first 28 days 
of life” that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention should be reported expeditiously.   
 
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration – Other (neonatal loss)” under the 
General disorders and administration SOC. 
 
Fetal death and neonatal death should NOT be reported as a Grade 5 event.  If 
reported as such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed and 
faxed with any additional medical information to 301-230-0159.  The potential risk 
of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS 
report. 
 
The Pregnancy Information Form is available at  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm.  
 
 

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17.0 
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Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, 
Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-
Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, 
Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N 
Engl J Med, 369(2): p. 134-44, 2013. 
 
17  
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, 
Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-
Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, 
Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N 
Engl J Med, 369(2): p. 134-44, 2013. 
 
18  
Atefi, M, et al. Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma. Clin Cancer 
Res, 20(13): p. 3446-57, 2014. 
 
19  
Pardoll DM. Immunology beats cancer: a blueprint for successful translation. Nat Immunol, 13(12): 
p. 1129-32, 2012. 
 
20  
Taube J., et al. Colocalization of inflammatory response with B7-h1 expression in human 
melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl 
Med, 4(127): p. 127ra37, 2012. 
 
21  
Tumeh PC, et al.  PD-1 blockade induces responses by inhibiting adaptive immune resistance.  
Nature, 27 November, 515:568-571, 2014. 
 
22  
Kilbridge, et al. Patient preferences for adjuvant interferon alfa-2b treatment.  JCO, Vol:19 no. 
3:812-823, 2001. 
 
23  
Webster K, Odom L, Peterman A, Lent L, Cella D. The Functional Assessment of Chronic Illness 
Therapy (FACIT) measurement system: Validation of version 4 of the core questionnaire. Qual Life 
Res. 8:604, 1999. 
 
24  
Hauschild A, Gogas H, Tarhini A, Middleton MR, Testori A, Dreno B, Kirkwood JM.  Practical 
guidelines for the management of interferon-alpha-2b side effects in patients receiving adjuvant 
treatment for melanoma: expert opinion. Cancer, Mar 1;112(5):982-94. doi: 10.1002/cncr.23251, 
2008. 
 
25  
Spiessens B, Debois M.  Adjusted significance levels for subgroup analyses in clinical trials.  
Contempoary Clinical Trials 31.6:647-656, 2010. 
 
26  
Sy JP, Taylor JMG. Estimation in a Cox proportional hazards cure model. Biometrics 56(1): 227-
236, 2000. 
 
27  
Sy JP, Taylor JMG. Estimation in a Cox proportional hazards cure model. Biometrics 56(1): 227-
236, 2000. 
 
28  
Little RJA.  A class of pattern-mixture models for normal incomplete data. Biometrika, 81, 471-483, 
1994. 
 

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29  
Pauler DK, McCoy S, Moinpour C. Pattern mixture models for longitudinal quality of life studies in 
advanced stage disease. Stat Med, 22(5), 795-809, 2003. 
 
30  
Fairclough DL. Design and analysis of quality of life studies in clinical trials, Second Edition (2nd 
ed.). Boca Raton, FL: Chapman & Hall/CRC, Taylor & Francis Group, LLC, 2010. 
 
31  
Bacik J, Mazumdar M, Murphy BA, Fairclough DL, Eremenco S, Mariani T, Motzer RJ, Cella D. 
The functional assessment of cancer therapy-BRM (FACT-BRM): a new tool for the assessment of 
quality of life in patients treated with biologic response modifiers. Qual Life Res. 2004 
Feb;13(1):137-54. 
 
32  
Trask, Peter C., et al. "Longitudinal course of depression, fatigue, and quality of life in patients with 
high risk melanoma receiving adjuvant interferon." Psycho-Oncology 13.8 (2004): 526-536. 
 
33  
Yost KJ, Sorensen MV, Hahn EA, Glendenning GA, Gnanasakthy A, Cella D. Using multiple 
anchor- and distribution-based estimates to evaluate clinically meaningful change on the Functional 
Assessment of Cancer Therapy-Biologic Response Modifiers (FACT-BRM) instrument. Value 
Health. 2005 Mar-Apr;8(2):117-27 
 
 
 
 

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18.0 
APPENDIX 
 
18.1 
Surgical Management Guidelines 
 
18.2 
Guidelines for Self Administration of Interferon Alfa-2b Template 
 
18.3 
S1404 Patient Interferon Diary (for patients who self-administer Interferon) 
 
18.4 
S1404 Local Pathology Review Form 
 
18.5 
TNM Definitions for Pathologic Staging  
 
18.6 
QA Auditing and Monitoring 
 
18.7 
Instructions for PPD Requisition Form 
 
18.8 
Translational Medicine: Retrospective T-Cell Receptor Beta Chain (TCRE) Sequencing of 
Banked Samples from S1404 
 
18.9 
Instructions for the SWOG Biospecimen Bank - Lab #201, Solid Tissue, Myeloma and 
Lymphoma Division  
 
18.10 
Translational Medicine: Association of Circulating Tumor DNA (ctDNA) with Relapse-Free 
Survival in High-Risk, Resected Melanoma Patients  
 
 
 
 
 
 
 

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18.1 
Surgical Management Guidelines 
 
All patients must be free of disease at the time of registration.  All surgery is to be completed 
prior to registration and meet the criteria outlined in Section 5.0, Eligibility Criteria. Patients 
must be registered within 98 days of the last surgery performed to render the patient free 
of disease. 
 
a. 
Excision of the Primary Site 
 
These guidelines apply to patients presenting with an intact primary and 
undergoing sentinel lymph node biopsy or regional lymph node dissection to 
establish eligibility.  All such patients must undergo adequate wide excision of the 
primary tumor meeting the suggested criteria outlined below.  In most cases, this 
must be a wide excision with 1 cm minimum margins.  In all cases, the margins of 
excision must be histologically free of melanoma (including melanoma in-situ or 
atypical junctional melanocytic hyperplasia).  For all sites except head & neck and 
extremities distal to the wrist or ankle, the primary melanoma must be excised with 
at least 1 cm margins of normal skin in all directions, measured either from the 
edge of the primary tumor or from the edge of the biopsy scar if prior excisional 
biopsy has been done.  The excision should go down to the fascia; including the 
fascia in the resection is optional.  Measurements of margins should ideally be 
done by the surgeon at the time of wide excision using a ruler; if the measurement 
is done by the pathologist, allowance of 33% for shrinkage will be made.  In 
addition to the gross margin, a histologically negative margin (including histologic 
freedom from atypical junctional melanocytic hyperplasia) must be obtained.   
 
For primary melanomas on the head & neck or extremities distal to the wrist or 
ankle, the primary melanoma must be excised and a histologically negative margin 
(including histologic freedom from atypical junctional melanocytic hyperplasia) 
must be obtained.  Measured margins of at least 1 cm are desirable, but not 
mandatory.  Acral-lentiginous melanomas (including subungual primaries) may be 
resected by any procedure that yields a histologically negative margin, including 
amputation and digit-conserving surgery.   
 
b. 
Excision of Recurrent Disease 
 
All patients enrolled with regional disease, including recurrence after initial 
presentation, must have no evidence of active disease at the primary site or have 
undergone a re-excision of the primary site that meets the criteria outlined in 
Section 18.1a above (including histologically negative margins of excision) prior to 
registration.  Patients presenting with satellite metastases (within 2 cm of the 
primary) or in transit metastases (beyond 2 cm from the primary but proximal to 
the regional lymph nodes) are eligible provided that all tumor has been excised 
with negative margins, they have undergone complete lymph node dissection 
meeting the criteria outlined below (if any histologic or clinical evidence of lymph 
node involvement), and they have NOT undergone prohibited systemic therapy for 
their satellite/in transit metastases (see Section 5.1b).   
 
c. 
Regional Lymph Nodes 
 
Regional lymph node dissection is mandatory for all patients with histologic or 
clinical evidence of regional lymph node involvement enrolled on this trial.  
(Patients with satellite/in transit disease and no evidence of nodal involvement may 
be enrolled without having undergone lymph node dissection.)  The node 
dissection must be done in accord with the following guidelines; lymph node 
sampling is not acceptable.  Sentinel lymph node biopsy alone, without completion 
lymph node dissection, is not acceptable. 

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The number of tumor-involved nodes must be documented for all cases.  Either 
H&E or immunohistochemical evidence of involvement is acceptable for 
determining the number of involved nodes, but RT-PCR or other molecular 
techniques are not.  Patients with confluent nodal involvement that makes 
determination of the exact number of involved nodes difficult are eligible, and are 
considered to have "matted nodes" and classified as N3. 
 
Micrometastasis versus macrometastasis - As outlined in Section 4.0 Staging 
Criteria, the status of regional lymph node involvement will be determined by 
histopathologic assessment and by the clinical presentation of those nodes. By 
definition, micrometastases are diagnosed by sentinel node biopsy or elective 
lymph node dissection.  Macrometastases are defined as clinically detectable 
nodal metastases confirmed pathologically.  Note:  Patients with extranodal 
extension are eligible for the trial, and for the purposes of this protocol are 
considered to have macrometastatic involvement (i.e., eligible even if only one 
tumor-involved node). 
 
1. 
Cervical Lymph Node Dissection 
 
A classic radical neck dissection is not required and is discouraged.  In 
cases with clinically negative nodes, less than a full neck dissection is 
permissible, including modified dissections such as supraomohyoid or 
posterior triangle dissections.  In such cases, the entire triangle should be 
dissected.  Preservation of the internal jugular vein, sternocleidomastoid 
muscle, and eleventh cranial nerve ("functional neck dissection") should 
be performed whenever possible.  Radionuclide lymphatic drainage scans 
may be helpful in delineating lymph node groups at risk for tumor 
involvement.  Consideration should be given to the parotid gland nodes, 
particularly for melanomas of the face, anterior ear and temporal region, 
which should be removed by superficial or if necessary total parotidectomy 
if there is evidence of involvement by tumor.  The facial nerve (seventh 
cranial nerve) should be spared unless invaded by tumor. 
 
2. 
Axillary Lymph Node Dissection 
 
Removal of at least the level I and II axillary lymph nodes is the minimum 
acceptable operation.  Level III nodes must be removed if clinically 
suspicious.  The minimum borders of the dissection are the latissimus 
dorsi muscle laterally, the axillary vein superiorly, and the medial border of 
the pectoralis minor muscle medially.  The nerves to the serratus anterior 
(long thoracic nerve) and latissimus dorsi (thoracodorsal nerve) should be 
identified and preserved if possible.  If the primary tumor is on the trunk, 
consideration should be given to remove the low axillary nodes (at or 
below the level of the nipple) by following the latissimus dorsi muscle down 
to its origin on the chest wall and dissecting the node-bearing tissue 
between it and the serratus anterior muscle. 
 
3. 
Inguinal or Ilioinguinal Lymph Node Dissection 
 
The minimum operation for groin node dissections is a superficial inguinal 
lymph node dissection (inguinal or inguinofemoral lymphadenectomy).  A 
pelvic (iliac and obturator) node dissection is also necessary (ilioinguinal 
lymphadenectomy) if these nodes are felt to be involved by imaging 
studies or intraoperative palpation.  The borders of a superficial inguinal 
lymph node dissection are the adductor muscles medially, the sartorius 
laterally, the junction of these two muscles caudally, the femoral vessels 
posteriorly, and a line connecting the pubic tubercle and the anterior 

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superior iliac spine superiorly.  The node-bearing tissue superficial to the 
external oblique fascia and superior to the inguinal ligament should be 
included with the specimen, up to the level of this line.  Removal of the 
pelvic nodes, if required, may be accomplished through the same or a 
separate incision; "sampling" of the deep nodes rather than a radical 
dissection is adequate.  Minimally invasive surgical approaches, such as 
robotic-assisted pelvic lymphadenectomy, are acceptable provided the 
operation otherwise conforms to the standards described. 
 
d. 
Other Sites of Nodal Involvement 
 
Lymph node dissections at sites other than those mentioned (e.g., popliteal or 
epitrochlear) should be carried out only if involvement of the nodes with melanoma 
is documented or if the primary site lies directly over the node group and node 
dissection is necessary to allow adequate wide excision.  Patients with nodal 
involvement in these sites, as well as those with recurrent disease in the regional 
nodal basin after a previous complete lymphadenectomy, are eligible for this trial 
provided that all evidence of disease has been resected with histologically negative 
margins.  Failure to document the margin status may lead to the patient being 
declared ineligible. 
 
e. 
Resection of Distant Metastatic Disease 
 
Patients with Stage IV melanoma metastatic to skin, subcutaneous sites, distant 
lymph nodes or lung or other visceral sites are allowed provided all sites are 
resected with histologically negative margins, they have NOT undergone 
prohibited systemic therapy for their metastatic disease (see Section 7.2) and the 
patient otherwise meets the eligibility criteria outlined in Section 5.0.  Patients with 
resected brain metastases are not eligible. Minimally invasive surgical 
approaches, such as video-assisted thoracotomy, are acceptable.  Failure to 
document the margin status may lead to the patient being declared ineligible.  
Stereotactic radiosurgery or ablative techniques that do not involve resection of 
the tumor to negative margins are not acceptable. 
 

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18.2 
Guidelines for Self-Administration of Interferon Alfa-2b Template 
 
For emergency contact: 
 
Insert Site Contact Information. 
 
Instructions for Self-Administering Medication 
 
1. 
Preparation 
 
a. 
Wash hands well.  Take acetaminophen (Tylenol®) as premedication if 
directed by your doctor. 
 
2. 
Assemble necessary supplies.  The Interferon should be kept refrigerated until 
several minutes before each treatment.  You also need a syringe with a needle, at 
least 3 alcohol prep pads, and a container* for used materials. 
_____________________________________ 
*An unbreakable, leak-proof, reclosable container - milk carton, coffee 
can. 
 
3. 
Reconstituting the Interferon Powder 
 
a. 
If this is the first dose that will be coming from a vial, the Interferon powder 
must be dissolved, using the diluent provided.  Snap the plastic cap off 
both vials, and cleanse both rubber stoppers with an alcohol pad and allow 
to air dry. 
 
b. 
There may be a different syringe/needle provided that you will use to 
reconstitute the Interferon.  Open the package containing one of these 
syringes and attach (or tighten) the appropriate needle to it.  Pull back the 
plunger of the syringe so that the top of it rests right on the line 
representing the volume of diluent that you are to add to the Interferon 
powder. 
 
c. 
Insert the needle through the stopper of the diluent vial, and invert the 
vial/syringe in front of you at eye level, holding the syringe in your dominant 
hand and the vial in the other. 
 
d. 
Inject the air from the syringe into the vial slowly.  If you feel like you are 
forcing it, pull back the plunger to allow some solution into the syringe, 
then push the remaining air into the vial.  Ultimately, your syringe should 
be filled with diluent solution up to the correct line and no air will be left in 
the syringe.  If you have bubbles, tap the syringe with your finger until they 
rise to the top, push them up into the vial and recheck the plunger to insure 
that it is still at the correct volume mark. 
 
e. 
Withdraw the needle from the diluent vial and insert it into the vial 
containing the Interferon powder.  This time keep the vial on the surface 
and push the plunger down to inject the diluent into the powder vial.  If you 
meet resistance, allow some air to rise into the syringe before pushing 
down and expelling the remaining solution into the vial. 
 
Eventually, all the solution will be in the vial.  Pull back the plunger to return 
it to the line that is the same as the volume of solution that you injected.  
This will prevent pressure build-up in the Interferon vial.  Remove the 
needle and discard it appropriately. 
 

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f. 
To help dissolve the Interferon powder, you may need to roll the vial 
between your palms or swirl the solution around.  DO NOT shake the vial.  
Be sure that all the powder is dissolved before proceeding to #3. 
 
4. 
Withdrawing Your Dose From the Vial 
 
a. 
Cleanse the rubber stopper of the vial containing the Interferon solution 
with an alcohol pad and allow to air dry. 
 
b. 
Open syringe package and needle package (if separate) and attach or 
tighten needle by twisting until tight.  Pull back the plunger to the mark that 
represents your dose (i.e., 3 MU/0.5 ml, top of plunger should rest at the 
0.5 ml mark).  This fills the syringe with air in a volume equal to the volume 
of your dose. 
 
c. 
Uncap the needle and push it through the stopper, at least half-way into 
the vial.  Now pick up the vial (with syringe/needle in it) with your left hand 
and turn it upside down, holding it at eye-level, about 12 inches from your 
face.  You should now have the vial in one hand and your other hand free 
to manipulate the syringe.  (Note:  Left-handed persons should have the 
vial in their right hand, so that they can manipulate the syringe with their 
left hand.) 
 
d. 
Inject air from the syringe into the vial slowly, and then withdraw the 
plunger.  The syringe will gradually fill with drug solution.  Repeat this 
procedure until only solution is in the syringe, solidly, to the mark that 
indicates your dose.  Withdraw needle and recap it. 
 
5. 
Administration 
 
a. 
Thoroughly clean the area to be injected with an alcohol pad.  Areas 
appropriate for this type of injection have been shown to you.  A new site 
should be used for each injection whenever possible. 
 
b. 
As demonstrated, pinch 1 1/2 to 2 inches of loose skin from the site to be 
injected. 
 
c. 
Uncap the needle, and insert the needle approximately 1/4 inch into the 
skin and push the syringe plunger in all the way, thereby giving the dose 
of Interferon. 
 
d. 
Remove needle and wipe injection site with a new alcohol pad, but do not 
massage the area to any great extent. 
 
e. 
Carefully recap needle and return needle and syringe to the clinic 
pharmacy for disposal.   
 
If the interferon vial is a multidose vial (eg., solution for injection vial) and 
contains more than one dose, write the date on the label.  It is usable for 
30 days.  Unused doses in a multidose vial must be discarded after one 
month. 
 
Reconstituted vials (eg., powder for injection vials) must be discarded after 
one dose has been withdrawn from the vial.  Do not re-use reconstituted 
vials, as bacterial contamination may occur. 
 
f. 
If a drug administration diary has been provided, remember to complete it 
after each dose.  Enter the date and time of day given, along with any 

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notable side effects that you may have experienced since the previous 
dose was given. 
 

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18.3 
S1404 Patient Interferon Diary (for patients who self-administer Interferon)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Signature:  
 
 
 
 
SWOG Patient ID________  Patient Initials (L, F, M) ________ SWOG Study #__________
 
 
 
Institution/Affiliate _______________________  Physician _____________________________ 
Instructions for the participant: 
This is a monthly calendar on which you are to record the number of injections you self-
administer.  Be sure you have enough calendars to last until your next appointment.  If you 
develop any side effects from interferon alfa-2b, mark this on the calendar on the day you note 
the effect.  Bring your calendars with you each time you have an appointment. 
 
If you have questions contact: ____________________ Telephone: _____________________ 
Your next appointment is: _______________________ 
Special instructions:  The dose of interferon alfa-2b for maintenance is 10 MU/m2/d. 
Month: _______________________ 
Year: ___________________ 

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18.4 
S1404 Local Pathology Review Form 
 
 

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18.5 
TNM Definitions for Pathologic Staging 
 
Table 1 TNM Definitions for Stage III Melanoma: Pathologic Stagingb  
Stage  
TNM  
Description  
IIIA 
T1–4a 
T1a = Melanomas ≤1.0 mm in thickness without ulceration; mitosis 
<1/mm2 
T1b = Melanomas ≤1.0 mm in thickness with ulceration or mitoses 
≥1/mm2 
T2a = Melanomas 1.01–2.0 mm in thickness without ulceration 
T2b = Melanomas 1.01–2.0 mm in thickness with ulceration 
T3a = Melanomas 2.01–4.0 mm in thickness without ulceration 
T3b = Melanomas 2.01–4.0 mm in thickness with ulceration 
T4a = Melanomas >4.0 mm in thickness without ulceration 
N1a 
1 regional lymph node metastasis with micrometastasisc 
N2a 
2–3 regional lymph node metastases with micrometastasisc 
M0 
No detectable evidence of distant metastases 
IIIB 
T1–4b 
T1a = Melanomas ≤1.0 mm in thickness without ulceration; mitosis 
<1/mm2 
T1b = Melanomas ≤1.0 mm in thickness with ulceration or mitoses 
≥1/mm2 
T2a = Melanomas 1.01–2.0 mm in thickness without ulceration 
T2b = Melanomas 1.01–2.0 mm in thickness with ulceration 
T3a = Melanomas 2.01–4.0 mm in thickness without ulceration 
T3b = Melanomas 2.01–4.0 mm in thickness with ulceration 
T4a = Melanomas >4.0 mm in thickness without ulceration 
T4b = Melanomas >4.0 mm in thickness with ulceration 
N1a 
1 regional lymph node metastasis with micrometastasisc 
N2a 
2–3 regional lymph node metastases with micrometastasisc 
M0 
No detectable evidence of distant metastases 
IIIB 
T1–4a 
T1a = Melanomas ≤1.0 mm in thickness without ulceration; mitosis 
<1/mm2 
T1b = Melanomas ≤1.0 mm in thickness with ulceration or mitoses 
≥1/mm2 
T2a = Melanomas 1.01–2.0 mm in thickness without ulceration 
T2b = Melanomas 1.01–2.0 mm in thickness with ulceration 
T3a = Melanomas 2.01–4.0 mm in thickness without ulceration 

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Stage  
TNM  
Description  
T3b = Melanomas 2.01–4.0 mm in thickness with ulceration 
T4a = Melanomas >4.0 mm in thickness without ulceration 
N1b 
N1b = 1 regional lymph node metastasis with macrometastasisd 
N2b 
N2b = 2–3 regional lymph node metastases with macrometastasisd 
N2c 
N2c = In transit met(s)/satellite(s) without metastatic lymph nodes 
M0 
No detectable evidence of distant metastases 
IIIC 
T1–4b 
T1a = Melanomas ≤1.0 mm in thickness without ulceration; mitosis 
<1/mm2 
T1b = Melanomas ≤1.0 mm in thickness with ulceration or mitoses 
≥1/mm2 
T2a = Melanomas 1.01–2.0 mm in thickness without ulceration 
T2b = Melanomas 1.01–2.0 mm in thickness with ulceration 
T3a = Melanomas 2.01–4.0 mm in thickness without ulceration 
T3b = Melanomas 2.01–4.0 mm in thickness with ulceration 
T4a = Melanomas >4.0 mm in thickness without ulceration 
T4b = Melanomas >4.0 mm in thickness with ulceration 
N1b 
N1b = 1 regional lymph node metastasis with macrometastasisd 
N2b 
N2b = 2–3 regional lymph node metastases with macrometastasisd 
N2c 
N2c = In transit met(s)/satellite(s) without metastatic lymph nodes 
M0 
No detectable evidence of distant metastases 
IIIC 
Any T 
TX = Primary tumor cannot be assessed (e.g., curettaged or severely 
regressed melanoma) 
T0 = No evidence of primary tumor 
Tis = Melanoma in situ 
T1a = Melanomas ≤1.0 mm in thickness without ulceration; mitosis 
<1/mm2 
T1b = Melanomas ≤1.0 mm in thickness with ulceration or mitoses 
≥1/mm2 
T2a = Melanomas 1.01–2.0 mm in thickness without ulceration. 
T2b = Melanomas 1.01–2.0 mm in thickness with ulceration 
T3a = Melanomas 2.01–4.0 mm in thickness without ulceration 
T3b = Melanomas 2.01–4.0 mm in thickness with ulceration 
T4a = Melanomas >4.0 mm in thickness without ulceration 

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Stage  
TNM  
Description  
T4b = Melanomas >4.0 mm in thickness with ulceration 
N3 
≥4 regional lymph node metastases; or matted nodes; or in transit 
met(s)/satellite(s) with metastatic lymph node(s) 
M0 
No detectable evidence of distant metastases 
T = primary tumor; N = regional lymph nodes; M = distant metastasis. 
Adapted with permission from AJCC: Melanoma of the skin. In: Edge SB, Byrd DR, Compton 
CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-
44. 
The explanations for superscripts b–d are at the end of Table 2. 
 

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Table 2 TNM Definitions for Stage IV Melanoma  
Stage  
TNM  
Description  
Clinicala  Pathologicalb  
 
 
IV 
IV 
Any T 
TX = Primary tumor cannot be assessed (e.g., curettaged or 
severely regressed melanoma) 
T0 = No evidence of primary tumor 
Tis = Melanoma in situ 
T1a = Melanomas ≤1.0 mm in thickness without ulceration; 
mitosis <1/mm2 
T1b = Melanomas ≤1.0 mm in thickness with ulceration or 
mitoses ≥1/mm2 
T2a = Melanomas 1.01–2.0 mm in thickness without 
ulceration 
T2b = Melanomas 1.01–2.0 mm in thickness with ulceration 
T3a = Melanomas 2.01–4.0 mm in thickness without 
ulceration 
T3b = Melanomas 2.01–4.0 mm in thickness with ulceration 
T4a = Melanomas >4.0 mm in thickness without ulceration 
T4b = Melanomas >4.0 mm in thickness with ulceration 
Any N 
NX = Regional lymph nodes cannot be assessed (e.g., 
previously removed for another reason) 
N1a = 1 regional lymph node metastasis with 
micrometastasisc 
N1b = 1 regional lymph node metastasis with 
macrometastasisd 
N2a = 2–3 regional lymph node metastases with 
micrometastasisc 
N2b = 2–3 regional lymph node metastases with 
macrometastasisd 
N2c = In transit met(s)/satellite(s) without metastatic lymph 
nodes 
N3 = ≥4 regional lymph node metastases; or matted nodes; 
or in transit met(s)/satellite(s) with metastatic lymph node(s) 
M1 
M1a = Metastases to skin, subcutaneous, or distant lymph 
nodes and normal serum LDH 
M1b = Metastases to lung and normal serum LDH 
M1c = Metastases to all other visceral sites and normal 
serum LDH; or distant metastases to any site and elevated 
serum LDH 

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Stage  
TNM  
Description  
Stage  
TNM  
Description  
Clinicala  Pathologicalb  
 
 
LDH = Lactate dehydrogenase; T = primary tumor; N = regional lymph nodes; M = distant 
metastasis. 
Adapted with permission from AJCC: Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, 
et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44. 
aClinical staging includes microstaging of the primary melanoma and clinical and/or radiologic 
evaluation for metastases. By convention, it should be used after complete excision of the 
primary melanoma with clinical assessment for regional and distant metastases. 
bPathologic staging includes microstaging of the primary melanoma and pathologic information 
about the regional lymph nodes after partial or complete lymphadenectomy. Pathologic Stage 0 
or Stage IA patients are the exception; they do not require pathologic evaluation of their lymph 
nodes. 
cMicrometastases are diagnosed after sentinel lymph node biopsy and complete 
lymphadenectomy (if performed). 
dMacrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic 
lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension. 
 

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18.6 
QA Auditing and Monitoring 
 
The Quality Assurance Program of the Groups participating in the NCTN was developed 
to enhance the reliability and validity of clinical trials data through the use of routine 
monitoring procedures which includes auditing as one component. The purpose of an audit 
is to document the accuracy of data submitted to the Data Operations Center and to verify 
compliance with protocol and regulatory requirements. The program also surveys data 
management practices at each institution in order to provide educational support to the 
sites regarding issues related to data quality, data management, and other aspects of 
quality assurance. 
 
Audits are conducted according to FDA regulations and NCI guidelines for Auditing Clinical 
Trials for the National Clinical Trials Network (NCTN) Program, NCI Community Oncology 
Research Program (NCORP) and Research Bases:  
http://ctep.cancer.gov/branches/ctmb/clinicalTrials/docs/ctmbauditguidelines.pdf. 
 
Each institution is audited at least once every three years, but remains at annual risk of an 
audit. Routine monitoring of Institutional Performance Review reports and timeliness of 
reporting of Serious Adverse Events (SAEs) is conducted to identify institutions that may 
require more frequent audits. 
 
The audit team consists of qualified individuals capable of providing a medical assessment 
of the patient cases (Quality Assurance, physician, nurse or experienced clinical research 
associate [CRA]). A number of patients equal to 10% of the accrual since the last audit 
with a minimum of three are randomly selected for review at each institution.  In addition, 
a limited review of eligibility and consent only is conducted for at least one unannounced 
case at each on site audit. 
 
The major objective of the audit process is to verify study data that could affect the 
interpretation of primary study endpoints. This is done through independent verification of 
study data against the source documents. Primary source documentation reviewed during 
an audit includes the following: research records, hospital charts, clinic charts, lab reports, 
x-rays, scans, radiotherapy reports, operative reports, pathology reports and other special 
studies required by protocol. 
 
By comparing the data collection forms submitted to the Data Operations Center with the 
primary records and referring to the protocol, the audit team reviews the records to 
determine compliance with protocol requirements for eligibility, treatment administration, 
response assessment, toxicity reporting and general data quality. Auditors verify that the 
current IRB-approved version of the consent form was signed prior to registration and that 
subjects were informed of new findings that could affect their willingness to participate in 
the study. NCTN investigators and institutions are expected to follow the protocol and 
lead Group policies in treating patients registered on Group protocols. Among other 
requirements, investigators/institutions must follow SWOG's policies for dosing principles, 
reporting of SAEs, and follow-up of all patients. 
 
The audit team also verifies that the protocol and its amendments received initial and 
continuing IRB review and approval and that safety reports and serious adverse events 
were submitted to the IRB. Investigational drug accountability record forms (DARFs) are 
reviewed and random patients are cross referenced against the medical record. A tour of 
the pharmacy is conducted to verify security and storage conditions as well as the physical 
inventory. 
 
The audit report is comprised of three components: 1) conformance to IRB and informed 
consent requirements, 2) the pharmacy and use of NCI DARFs, and 3) patient case review. 
An acceptable rating requires no deficiencies, few lesser deficiencies, or major deficiencies 
that were addressed prior to the audit.  Institutions found to be “unacceptable” or 
“acceptable, needs follow-up” on any component are required to 
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response and/or corrective and preventative (CAPA) action plan. Failure to submit a 
written response including a corrective and preventative action plan within the required 
timeframe will result in suspension of registration privileges. A re-audit of any 
component rated as unacceptable will be conducted within one year after the unacceptable 
audit. An unacceptable rating for the same audit component on two consecutive audits will 
result in probation. Accrual will be suspended pending submission of a site improvement 
plan that addresses key infrastructural issues contributing to poor performance. An 
unacceptable rating at the second re-audit may result in termination from the group. If 
systematic misrepresentation of data is identified, an immediate repeat audit is scheduled 
by the representatives from the Group with the NCI and/or the FDA present. 
 
In some cases, non-compliance for issues such as timeliness of data submission, SAE 
reporting and submission of specimens is monitored off site rather than scheduling a re- 
audit. Failure to show improvement may result in scheduling of a re-audit or other 
disciplinary action. 
 
Results of all Quality Assurance Audits are reported to the NCI, the Principal Investigator 
of the institution that was audited, and representatives of the Group. Protocol specific audit 
results are also sent to the Statistical Center to inform the statisticians, data chairs and 
study chairs of any significant discrepancies involving eligibility, treatment, toxicity or 
response assessment. 
 
The Quality Assurance Program performs their educational role through several 
mechanisms including presentations during the Group Meetings, online Clinical Trials 
Training Courses, collaboration with others such as the Pharmacy Committee and 
Statistical Center to develop training tools, and memos and newsletter articles that are 
distributed to all Group institutions to educate research staff about changes in regulatory 
and quality assurance issues and audit procedures. 
 
Additional Monitoring 
 
In addition to the standard auditing process outlined above, the following additional 
requirements will be implemented for this study: 
x 
Routine monitoring by Data Coordinators at the Statistics and Data Management 
Center.   
x 
Risk-based monitoring by Monitors at the Statistics and Data Management Center.   
x 
Additional on-site monitoring visits by Quality Assurance Auditors at the Operations 
Office.  
 
Routine Monitoring at the SWOG Statistics and Data Management Center 
 
Data Coordinators at the SWOG Statistics and Data Management Center (SDMC) will 
perform routine monitoring with the following actions: 
x 
Monitor data quality through routine review of submitted data such as on-study, 
baseline and follow up tumor assessment, lab, treatment, off treatment, and follow up 
case report forms to identify and follow-up on missing data, inconsistent data, data 
outliers, and potential protocol deviations that may be indicative of systemic or 
significant errors in data collection and reporting at a site. 
 
x 
Analyze site characteristics, performance metrics and clinical data to identify trial sites 
with characteristics correlated with poor performance or noncompliance through the 
SWOG Institutional Performance Reporting mechanism and other available reports. 
 
x 
Verify critical source data remotely via the collection and review of pathology, radiology 
and applicable lab reports.  This includes the review and confirmation of appropriate 
disease classification as determined by the pathology report, and assessment of 
response to treatment utilizing RECIST 1.1 based on scan reports uploaded to the 

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Electronic Data Capture (EDC) system and submitted follow-up tumor assessment 
forms. 
 
x 
To assure data are as consistent, complete and accurate as possible, all subject data 
must undergo careful review by Data Coordinators (DCs).  After verifying that all data 
forms required to determine eligibility have been received or at a time point designated 
when all the required forms should have been received, the DC reviews the data and 
completes an initial evaluation. 
 
The initial review includes the following: 
x 
Determine that all required data fields on each form were completed and are consistent 
with other data. 
x 
Determine if all prestudy tests and exams were performed within protocol specified 
time limits. 
x 
Determine if each eligibility criterion was met and properly documented. 
x 
Review and confirm pathology based on the pathology report uploaded to the EDC 
system. 
x 
Verify that stratification and/or descriptive factors (if applicable) were correctly 
identified at registration. 
x 
Verify that the subject received the assigned study treatment and correct dose(s). 
x 
Verify that the treatment was started within the time limit indicated in the protocol (if 
applicable). 
x 
Determine if adverse events reported are consistent with other data and entered as 
required by study specifications. 
x 
Post internal notes to add additional information which may be useful to the study 
sponsor, monitors, or statisticians, but which do not require action by site personnel. 
x 
Use the query tool to request additional data classifications and corrections of the CRA. 
 
The DC will perform subsequent review of data when new data become available or 
queries are answered.  Regular review will also occur while patients are still on-study, at 
the time of progression, once they are removed from study and at the time of death. 
Subsequent reviews include the following: 
x 
Determine if all required data fields on each newly submitted form were completed and 
consistent with other data. 
x 
Evaluate all new treatment documentation for correct treatment and dose. 
x 
Conduct assessment of response to treatment utilizing RECIST 1.1 based on scan 
reports uploaded to the EDC and submitted follow-up tumor assessment forms. 
x 
Review and code any new concomitant medications as required by study 
specifications. 
x 
Evaluate if the subject is or should be off protocol treatment per protocol criteria. 
x 
Review and evaluate death if death of subject is reported. 
x 
Use the query tool to request additional data classifications and corrections. 
x 
Post internal query notes to add additional information that may be useful to the study 
sponsor, monitor, or statisticians but which do not require action by site personnel. 
x 
Review site responses to the queries and the corrected or amended eCRF pages.  
When corrections and responses are considered satisfactory, queries are closed by 
the data coordinators.  Unsatisfactory responses are re-queried and tracked. 
x 
Perform re-evaluations promptly after responses to queries are received 
 
Centralized Risk-based Monitoring at the Statistics and Data Management Center (SDMC)  
Monitors at the Statistics and Data Management Center (SDMC) will support the risk based 
monitoring approach for this trial through off-site monitoring to include auditable elements 
through administration of eight weeks of treatment for the first two patients randomized at 
each site. Within 10 weeks of randomization, the Head CRA (or Data Manager) at the study 
site will be contacted by a SDMC monitor via email with instructions for uploading the 
auditable elements including: 
 
x 
Copy of the signature page of the patient informed consent signed prior to registration. 

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x 
Documentation to support all eligibility criteria including: 
o 
Copy of the signed and dated eligibility checklist (unless previously uploaded into 
RAVE) 
o 
Operative and pathology reports to support histology and stage of disease 
o 
An H & P including vital signs, height and weight, review of symptoms, 
performance status and past medical history. The medical history should include 
details of the malignancy, prior surgical procedures, prior chemotherapy and/or 
radiotherapy, history of relevant medical disorders and concomitant medications 
o 
Lab reports to support all required prestudy tests. Lab reports must include 
institutional normal limits. 
o 
Reports of baseline scans, brain CT/MRI, and EKG 
o 
Documentation of baseline toxicities 
 
x 
Documentation for the first eight weeks of treatment including: 
o 
An H & P including weight, BP, performance status, concomitant  medications and 
toxicity notation 
o 
Lab reports prior to each cycle 
o 
Drug orders and documentation of drug administration through chemo flowsheets, 
progress notes, etc. 
o 
Documentation to support  dose modifications or treatment delays 
 
Onsite Monitoring by the Quality Assurance Program 
x 
Additional on-site monitoring visits will be conducted with the first site visit within 6 
months of first patient randomization. 
x 
Monitoring visits will be combined with other routine audits whenever possible. The 
initial monitoring visit may be postponed up to 3 months to coincide with a routine 
audit or to coincide with a routine audit of another institution in the same geographic 
area. Monitoring visits may also be postponed if no accrual or activity has occurred 
beyond the timeframe covered by the off-site central monitoring. 
x 
Subsequent monitoring visits will be conducted according the following criteria: 
- 
If > 10 patients per year (~ 10% of sites) – annually 
- 
5 – 10 patients per year (~ 20% of sites) – every 2 years 
- 
< 5 patients per year – every 3 years or as part of routine audit cycle 
x 
More frequent monitoring visits to a site may be scheduled in response to several 
factors – high rate of accrual, unacceptable monitoring visit results, centralized 
electronic monitoring outcome, turnover in staff, etc.   
x 
All sites that receive and dispense investigational agents must be monitored on site to 
allow at least one visit to the pharmacy with the following exceptions: 
o 
Sites that use a centralized pharmacy may be monitored at this central 
location. 
o 
After an initial onsite visit, NCORP sites and LAPS/Main Member Affiliates may be 
monitored at a central location. 
o 
Pharmacies monitored during SWOG site visits for other studies will suffice for the 
on site monitoring requirement. 
o 
The need for subsequent onsite visits will be determined on a case by case 
basis including past audit results, number of patients on the investigational 
agent, etc. 
 
 
 
 

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Communication of Monitoring Results 
 
The monitoring team will meet routinely to share all aspects of monitoring (on site, 
centralized, safety, for-cause).  When needed, the SWOG Executive Officer for Quality 
Assurance will be consulted. 
 
All monitoring visits results will be reported according to NCI-CTMB requirements via the 
CTMB-AIS data base and regularly reviewed by SWOG monitoring staff. 
 
Summarized results of all monitoring visits will be provided semi-annually to the SWOG 
Board of Governors and the study team. Any problems or issues of concern will be reported 
to the Data and Safety Monitoring Committee on an as-needed basis. 
 
Safety Specific Centralized Monitoring 
Each Serious Adverse Event (SAE) report submitted (via CTEP-AERS) will be reviewed by 
the SWOG SAE Coordinator at the Operations Office.  Supporting documentation for any 
deaths on study will be requested and compiled with the report and sent to the Physician 
Reviewer.  As mentioned below all sites will undergo mandatory training and this will 
include training regarding SAE reporting.  SWOG regularly monitors timeliness of SAE 
reporting and addresses any issues of poor performance with individual sites. 
 
The study will be monitored for under reporting/missed Serious Adverse Events:  
The SWOG SAE Coordinator receives a weekly report from the data base that includes all 
adverse events that are submitted through routine submission that potentially also meet 
expedited reporting criteria but for which no CTEP-AERS report is found.  The Coordinator 
is responsible for following up with the responsible site to ensure that SAEs are not 
missed/under-reported. 
 
The study will be monitored for trends in Serious Adverse Events:  A “new SAE on 
study” report is generated each time a new Serious Adverse Event is entered into the 
SWOG data base.  It is a cumulative report that lists all SAEs reported for the protocol.  
This allows those who review the report to identify concerning trends in reported events; 
events that may be occurring at greater intensity (higher toxicity grade) or frequency than 
expected.  The SAE Coordinator, Physician Reviewer, Study Chair, and assigned 
Statisticians are responsible for regularly monitoring this report. 
 
Additional Approaches to be Used 
x 
Mandatory training of key site personnel prior to first patient registration. 
x 
Timely review of all monitoring reports to identify sites that require additional training, 
monitoring, disciplinary action, etc. 
x 
Mentoring visits and additional communication between monitor and site staff to 
assess potential problem areas, provide feedback on data submission quality and 
timeliness, identify staff turnover, etc. 
x 
Additional mandatory centralized training to be provided to all sites if major changes to 
the protocol occur or common problem areas are identified. 
 
Management of Noncompliance 
 
Issues of particular concern related to patient safety and questions of site fraud will be 
managed according to SWOG standard policies and the policies of the NCI CTMB for 
auditing of clinical trials under the NCI National Clinical Trials Network (NCTN) Program. 
Where important deviations are discovered, additional site training components will be 
developed and implemented. 
 
As with standard NCTN procedures, sites will be required to develop and implement 
corrective action plans in response to any major deficiencies identified at a monitoring visit 

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Ensuring Quality Monitoring 
 
All staff involved in monitoring are required to undergo training in the principles of clinical 
investigations and human subjects protection.  They are also required to complete the 
same protocol specific training required of the site staff. 
All monitoring and auditing processes for the study will be reviewed by study leadership 
twice per year to ensure conformance to the monitoring plan. 
 
Monitoring Plan Amendments 
 
At each formal review of the monitoring plan and conformance to it, the study leadership 
will make a recommendation regarding the need for amendments to the monitoring plan.  
These amendments will be reviewed and approved by the NCI and provided in this 
protocol section and will be submitted to the FDA. 
 

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18.7 
Instructions for PPD Requisition Form 
 
Instructions for filling out the PPD Requisition Form. 
Every PPD/ADA specimen submission must include a copy of the PPD Requisition Form. 
This form is supplied along with the kit. In addition, PPD will send you a copy of their 
Laboratory Manual. 
 
Subject Information Section 
Site 
Number: 
Fill in the NCI code for your institution. In addition, PPD requires that you 
add leading zeros so that all 10 spaces are filled. Do not leave any blank 
spaces or it will delay processing of your specimen. For example, if your 
NCI code is CA006, then you would enter “00000CA006” in this field. 
Patient 
ID: 
Enter the 6-digit SWOG patient identification number assigned at 
registration.  
Year of 
Birth: 
Enter all 4 digits of the patient’s year of birth. For example, “1976”. 
Gender: 
Place a mark in the appropriate box. 
 
Below is an example of how this would look: 
 
 
 
 
 
 

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Visit Information Section 
PK and ADA sampling should be done based on the treatment cycles for pembrolizumab, 
not on calendar weeks. However, PPD has created visit labels assuming that there will 
be no treatment delays or variation in schedule. The following table is intended to help 
you pick the most appropriate visit label for your PK/ADA specimen submission: 
Visit Label 
Specimen to be submitted 
Week 1 
Sample collected prior to the first 
infusion on Cycle 1 
Week 4 
Sample collected prior to the 
second infusion during Cycle 1. 
Week 10 
Sample collected prior to the 
second infusion during Cycle 2 
Week 19 
Sample collected prior to the third 
infusion on Cycle 3 
Week 25 
Sample collected prior to the first 
infusion on Cycle 4 
Week 49 
Sample collected prior to the 
infusion on Cycle 6 
Post 
Treatment FU 
30 Days 
Sample collected 30 days after 
discontinuation of pembrolizumab 
(provided patient has not started a new 
anti-cancer therapy prior to this time) 
Unscheduled 
PPD has provided 10 “unscheduled 
visit” labels. These should be used 
sparingly if at all. Using the guide 
provided above, you should be able to 
identify the correct visit label for your 
submission. 
 
 
 

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18.8 
Translational Medicine: Retrospective T-Cell Receptor Beta Chain (TCRE) Sequencing of 
Banked Samples from S1404 
 
a. 
Objectives 
 
1. 
Primary: To evaluate the association between TCRE variable gene (TRBV) 
haplotype and Grade 3-4 immune-related adverse events (irAEs) among 
Stage III melanoma patients treated with adjuvant Ipilimumab or 
Pembrolizumab.    
 
2.      Secondary: To describe the TRBV haplotype distribution among this 
cohort of patients studied.   
 
3.      
Secondary: 
To 
assess 
associations 
between 
baseline 
patient 
demographics and TRB haplotype.   
 
b. 
Background 
 
Checkpoint blockade immunotherapy (CPI) can elicit anti-cancer T cell responses 
mediating durable progression free survival but may also promote T cell 
destruction of healthy tissue to elicit irAEs. Efforts to identify germline variants 
associated with irAEs using whole genome sequencing (WGS) or microarrays 
have yet to reveal markers predictive of adverse events following immunotherapy. 
Identifying such biomarkers could allow for personalized drug selection and dosing 
to ultimately enable safer and more effective immunotherapy, particularly in light 
of the increasing use of combination CPI regimens having a significant incidence 
of severe adverse events. (1)  
 
Despite previous efforts, three lines of reasoning support the notion that germline 
encoded TRBV polymorphism could be a key determinant of adverse events 
during CPI. First, the TCR locus is repetitive and structurally complex, impeding 
the measurement of variation by traditional short read WGS or microarray-based 
methods. (2) Second, single amino acid substitutions within the framework or 
complementarity-determining region (CDR) 1 and 2 regions of the rearranged 
TCRE chain are known to significantly alter TCR affinity for human leukocyte 
antigen (HLA). (3) Third, adverse events during immunotherapy may manifest as 
acute versions of chronic autoimmune diseases (i.e. fulminant type 1 diabetes) that 
have been separately linked to TRBV polymorphism. (4)  To circumvent the 
challenge in measuring TRBV polymorphism by WGS, Thermo Fisher has 
developed a cost-efficient and rapid method for detection of TRBV polymorphism 
by next-generation sequencing (NGS) of rearranged TCRE chains from peripheral 
blood leukocytes. (5) Based on current knowledge, this represents the first NGS-
based method to permit haplotype-level resolution of the TRB locus. 
 
A pilot study involving haplotype analysis of the TRB locus by TCRE sequencing 
was previously conducted at the University of Texas MD Anderson Cancer Center 
(MDACC) under the PI, Aung Naing, MD, using the peripheral blood of 81 
Caucasians who had graded adverse events following immunotherapy. The results 
of this analysis revealed the presence of 6 major haplotype groups within the study 
cohort. Strikingly, members of one haplotype group, accounting for 33% of 
patients, appear to be protected against severe (Grade 3-5) adverse events (0% 
frequency) while 14% to 44% of patients in other haplotype groups had severe 
adverse events (p=7.1E-4, Fisher’s 2x2 exact test). Should this finding be 
confirmed in the larger SWOG cohort, this would indicate that TRBV allele profiling 
may serve as a predictive biomarker for adverse events to enable personalized 
checkpoint blockade drug selection and dosing. 
 

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c. 
Experimental Research Technique 
 
Baseline banked blood samples from Caucasian patients on S1404 
Preferred source of sample: buffy coat 
 
Total RNA extracted from PBL or whole blood will be used as input for TCRE 
sequencing using the Thermo Fisher Scientific product Oncomine TCRB-LR (SKU 
A35386). This assay utilizes a long-amplicon approach (up to 400 bp) to capture 
the sequences of all 3 CDR regions of the TCR Beta chain. Sequencing assays 
for up to 240 patients (details of patient selection provided in the statistical section) 
will be performed at Thermo Fisher.  Results from the haplotype analyses will be 
provided to the PI, Aung Naing, MD and the SWOG Statistical Center. This 
protocol will allow for extraction of both DNA and RNA from the cryopreserved cell 
pellets. Total RNA will then be used for TCRB-LR library preparation at Thermo 
Fisher. 
 
d. 
Statistical Plan 
 
Sample selection: the pilot haplotype work has been in Caucasian patients, so we 
will use baseline blood samples from Caucasian patients enrolled on S1404. We 
note that melanoma incidence is higher among Caucasian patients than other 
races, and 95% of patients enrolled on S1404 were Caucasian. In addition, we will 
restrict analyses to the subset of patients who planned to receive Ipilimumab as 
their control arm regimen prior to randomization.  First, we will analyze 120 patients 
who were randomized to the control arm and treated with Ipilimumab on S1404; 
we will select 60 patients with Grade 0-2 irAEs and 60 patients with Grade 3-4 
irAEs (selection will be random among all patients with appropriate consent who 
have baseline samples meeting these criteria [>150 patients available for each 
irAE cohort]). We note that the Grade 3-4 irAE rate is 35% among patients treated 
with Ipilimumab on the control arm.  We chose to over-sample Grade 3-4 irAE 
because the incidence of haplotype 2 among this subset is expected to be small, 
and we want adequate power to evaluate the incidence (further details of expected 
incidence below in the primary analysis section).  If the pilot data results are 
validated among these Ipilimumab patients (details of primary analysis below), we 
will select 120 patients randomized and treated with pembrolizumab; we will select 
60 patients with Grade 0-2 irAEs and 60 patients with Grade 3-4 irAEs (selection 
will be random among all patients with appropriate consent who have baseline 
samples meeting these criteria [>150 patients available for each irAE cohort]).  We 
note that the Grade 3-4 irAE rate is 15% on the pembro arm.  
 
Primary analysis: TRBV haplotype analysis will be performed as described in 
Looney et al. (at Thermo Fisher) and the results of the analysis will be provided to 
Dr. Naing and the SWOG statistical center. The association between haplotype 
Group 2 and the incidence of severe Grade 3-4) adverse events will be assessed 
using Fisher’s exact test; haplotypes 1, 3, 4, 5, 6 will be grouped together for this 
analysis (i.e., we will compare haplotype 2 versus all other haplotypes). (6) In the 
pilot data, the haplotype 2 incidence was 33%. We assume the Grade 3-4 irAE to 
be 12% among haplotype 2 patients (was 0% in the pilot data) and to be 46% 
among other haplotype patients. Given these incidence assumptions, we expect 
that 11% (0.33*0.12/ (0.33*0.12+0.67*0.46)) of patients with a Grade 3-4 irAE in 
the Ipilimumab cohort of S1404 will be haplotype 2, and that 89% will have another 
haplotype. Similarly, we expect that 43% (0.33*0.88/ (0.33*0.88+0.67*0.54)) of 
patients with a Grade 0-2 irAE in the Ipilimumab cohort of S1404 will be haplotype 
2, and that 92% will have another haplotype. With 60 patients with Grade 3-4 irAE 
and 60 patients with Grade 0-2 irAE, under these assumptions Fisher’s exact test 
has 92% power with a two-sided alpha of 5%.  
 

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If a significant association between haplotype 2 and Grade 3-4 irAE is observed in 
the Ipilimumab cohort, we will process samples on the 120 Pembro patients and 
perform the same analysis (Fisher’s exact test with two-sided alpha = 5%). If we 
assume the same incidence of haplotype 2 (33%), and that 2% of of the Grade 3-
4 AE cohort will be haplotype 2, this test has 86% power.  
 
Secondary analysis: Associations between haplotype and baseline patient 
characteristics (age, performance status, stage, primary tumor characteristics, 
LDH) will be evaluated using Fisher’s exact test and Wilcoxon-rank sum tests. 
 
Analyses and interpretation of data output will be completed within 1 year of the 
receipt of specimens. 
 
e. 
Data Analysis 
 
The data will be analyzed by the SWOG Statistics and Data Management Center 
(Megan Othus, Ph.D.). The Haplotype Analysis will be performed by Thermo 
Fisher (Tim Looney). 
 
f. 
Specimen Information 
 
Laboratory Performing Analysis:  
 
The University of Texas MD Anderson Cancer Center 
Aung Naing, MD (c/o Mohamed Derbala) 
The University of Texas MD Anderson Cancer Center 
Investigational Cancer Therapeutics 
1515 Holcombe Blvd., Room Y3.5623, Box 387 
Houston, Texas 77030 
713-745-9805 
 
 
Thermo Fisher Scientific: 
Loni Pickle 
Thermo Fisher Scientific  
5781 Van Allen Way | Carlsbad, CA 92008 U.S.A.  
Phone +1 (760) 268-8334   
Loni.Pickle@thermofisher.com  | thermofisher.com  
 
 Specimens used: 
Preserved frozen pelleted peripheral blood leukocytes (PBL), peripheral blood 
mononuclear cells (PBM) are highly preferred, though whole peripheral blood is 
also acceptable. 
 
2 ml of whole peripheral blood, from which peripheral blood leukocyte (PBL) total 
RNA will be extracted in the laboratory of Thermo Fisher. 50 ng of PBL RNA will 
be used for library preparation and sequencing via the Oncomine TCRB-LR 
assay. 
Baseline (pretreatment) samples are highly preferred, though any timepoint is 
acceptable. 
 
g. 
References
 
 
1  
Larkin, J et al. Combined Nivolumab and Ipilimumab or monotherapy in 
untreated melanoma. NEJM  373:23-34, 2015. 
 
 

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2  
Watson, C et al. Comment on ‘A database of human immune receptor 
alleles recovered from population sequencing data’. J Immunol  198:3371-
3373, 2017. 
 
3  
Robbins, P et al. Single and dual amino acid substitutions in TCR CDRs 
can enhance antigen-specific T cell functions. J Immunol 180:6116-6131, 
2008. 
 
4  
Pierce, B et al. The missing heritability in T1D and potential new targets 
for prevention. J Diabetes Res 737485, 2013. 
 
5  
Looney, T et al. Haplotype analysis of the TRB locus by TCRB repertoire 
sequencing. bioRxiv 406157, 2018. 
 
6  
Looney, T et al. Haplotype analysis of the TRB locus by TCRB repertoire 
sequencing. bioRxiv 406157, 2018. 

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18.9 
Instructions for the SWOG Biospecimen Bank - Lab #201, Solid Tissue, Myeloma and 
Lymphoma Division  
 
a. 
General Banking Instructions 
 
The SWOG Biospecimen Bank will store formalin-fixed paraffin-embedded (FFPE) 
tissue blocks or slides at room temperature.  
 
Aliquots of frozen, processed plasma, buffy coat, and serum are banked in -80°C 
freezers for long-term storage.  
 
b. 
Instructions Related to RNA Extraction and T-Cell Receptor Beta Chain 
(TCRE)  Sequencing (Appendix 18.8) 
 
The SWOG SDMC will provide a list of patients and time points to the Bank for 
distribution to Thermo Fisher. For each patient, the Bank will ship 1 vial of frozen 
buffy coat (from Baseline time point, if possible) on dry ice for RNA extraction and 
T-Cell Receptor Beta Chain (TCRE) Sequencing.  
 
c. 
Instructions Related to circulating tumor DNA (ctDNA) (Appendix 18.10) 
 
The SWOG SDMC will provide a list of patients and time points to the Bank for 
distribution to the Natera laboratory. For each patient, an H&E slide from the 
primary tumor or lymph node metastasis will be scanned to a 40X digital image for 
digital pathology review by Dr. Allie Grossmann, who will provide specimen quality 
data (e.g., %tumor vs. necrosis, %tumor vs. normal, confirmation of concordance 
with institutional diagnosis, and comments when applicable) and will digitally 
annotate slides, as needed, for specimens that will require macrodissection to 
enrich tumor content. Following pathology QA review, the Bank will either scrape 
unstained slides (macrodissected as needed), or section FFPE blocks. All tissue 
will undergo co-extraction for DNA and RNA.  
 
DNA will be extracted from buffy coat from one time point for each patient.   
 
All nucleic acids will undergo quantitation and QC before storage in a -80°C 
freezer.  
 
For each patient, the Bank will ship the following specimens to Natera on dry ice 
for overnight delivery: 
x 
At least 500 ng DNA from primary tumor or lymph node metastasis and 
DNA from buffy coat 
x 
A minimum of 4 ml of frozen plasma from Baseline  
x 
A minimum of 4 ml of frozen plasma at start of cycle 3 
x 
A minimum of 4 ml of frozen plasma at start of cycle 4 
x 
A minimum of 4 ml of frozen plasma at removal from protocol therapy or 
relapse 
 
18.10 
Translational Medicine: Association of Circulating Tumor DNA (ctDNA) with Relapse-Free 
Survival in High-Risk, Resected Melanoma Patients 
 
a. 
Objectives 
 
1. 
Primary (integrated): To evaluate associations between pretreatment 
ctDNA (present versus absent) and relapse within 2 years of 
randomization in a case-control analysis across treatment arms 
2. 
Secondary (integrated): To evaluate associations between pretreatment 
ctDNA and relapse within 2 years of randomization in a case-control 

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analysis within each treatment arm (after treatment arm data are unblinded 
to investigators). 
3. 
Secondary (integrated): To evaluate associations between “early-on 
treatment” ctDNA levels and relapse within 2 years of randomization 
4. 
Secondary (integrated): To describe ctDNA levels at end of therapy and 
time of relapse 
 
b. 
Background 
 
From a double-blind, randomized, placebo-controlled trial, Eggermont, AMM et al. 
reported improved relapse free survival with adjuvant pembrolizumab in high risk, 
resected, Stage III melanoma patients compared to placebo. Specifically, 
pembrolizumab therapy was associated with a one-year rate of recurrence-free 
survival of 75.4% [95% confidence interval CI, 71.3 to 78.9] vs. 61.0% [95% CI, 
56.5 to 65.1] in the placebo cohort. Thus, while anti-PD-1 therapy reduces the risk 
of disease progression of Stage III melanoma, 25% of patients are predicted to 
relapse within 1-year. For those untreated, up to 39% will relapse. At present, there 
are no biomarkers available to predict which of these patients are most likely to 
relapse. Improving outcomes for these patients in the future will require significant 
advancements in risk stratification tools. 
 
The Signatera test, offered by Natera, is an emerging biomarker that has shown 
promising clinical utility for the detection of minimal residual disease and early 
detection of relapse. (1, 2, 3, 4) The assay quantifies cell free, circulating tumor 
DNA (ctDNA) present in plasma, down to a 0.1% mutant allele fraction. In patients 
with non-small cell lung cancer, colorectal cancer, muscle-invasive bladder cancer 
and breast cancer, studies with Signatera have shown an unprecedented positive 
predictive value (PPV) for relapse ranging from 93%-100%with an average lead 
time of 2.8-9.5 months compared to radiographic detection. (5, 6,. 7, 8) 
 
The S1404 Stage III melanoma cohort includes post-operative plasma samples 
collected prior to the initiation of immunotherapy. With these samples, we may be 
able to discern if baseline ctDNA levels can risk stratify patients. The overall goal 
is to determine if highly sensitive, tumor-guided ctDNA testing can distinguish 
S1404 patients who remain disease free from those who have relapsed. We 
hypothesize that the Signatera test results will be associated with relapse 
outcomes in the trial (and within each treatment arm) and that nondetectable 
ctDNA levels will be associated with lack of relapse within 2 years. For patients 
who have detectable ctDNA at time zero, we hypothesize that reduction in ctDNA 
levels will be associated with a lack of relapse within 2 years. 
 
c. 
Experimental Research Technique 
 
The Natera Signatera assay is a personalized medicine approach for cancer 
patients that allows for serial testing of peripheral blood for monitoring of minimal 
residual disease and molecular relapse. Sixteen patient tumor-specific, somatic, 
non-driver mutations are selected based on exome sequencing comparisons of 
germline (buffy coat) to tumor (FFPE tissue). Through a proprietary algorithm, 
Natera chooses truncal, founder mutations that persist throughout the clonal 
phylogeny of the heterogeneous tumor population. Each patient plasma sample is 
then tested with a custom-designed assay that quantifies the 16 unique somatic 
mutations. For this study, germline and tumor exome data files will be provided to 
SWOG for future studies. 
 
Dr. Allie Grossmann (PI) is board certified in both Anatomic Pathology and 
Molecular Genetic Pathology. She is a Medical Director of Molecular Oncology at 
ARUP Laboratories, a national reference laboratory owned by the University of 
Utah, where she oversees the design, validation and routine clinical testing of a 

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variety of molecular, genomic and immunohistochemical clinical assays, including 
ctDNA assays. She is an independent investigator at the Huntsman Cancer 
Institute (Department of Pathology, University of Utah), with an NCI and American 
Cancer Society-funded melanoma research laboratory. She is Co-Director of the 
Biospecimen Pathology Core for the HCI Melanoma SPORE initiative. She is a 
quality control anatomic pathologist for HCI Biorepository – providing 
histomorphologic review of melanoma and sarcoma tumor banking. Dr. 
Grossmann is ideally suited to lead this study. 
 
d. 
Statistical Plan 
 
The case-control pairs will be selected randomly among eligible patients with all 
required samples. Cases will be patients who relapsed within 2 years of 
randomization.  Controls will be patients who were alive without relapse for at least 
2 years after randomization.  To the degree possible with the sample sizes 
available, case-control patients will be matched based on the randomization 
stratification factors stratification factors stage (stage IIIA and IIIB versus IIIC and 
IV) and PD-L1 status (positive versus negative versus indeterminate).  Also, to the 
degree possible with the sample sizes available, we will restrict to patients who 
received ipilimumab on the control arm, and restrict to patients on the 
pembrolizumab arm who declared before randomization that they would have 
received ipilimumab if randomized to the control arm.   
 
With 100 total patients, 50 cases and 50 controls, and assuming 24% of control 
patients (no relapse or death within first two years) have detectable baseline 
ctDNA levels, we will have 90% power with a two-sided alpha of 5% to detect an 
odds ratio (OR) of 5.3 or more extreme if the correlation between cases and 
controls is 0.5. If the correlation is lower than 0.5, we have additional power. For 
example, if the correlation is 0.2, we have 90% power to detect an OR of 4.26 or 
more extreme.    
 
For secondary analyses we will: 
x 
evaluate baseline ctDNA as a quantitative covariate in a conditional logistic 
regression model, 
x 
evaluate associations between presence/absence of ctDNA and quantitative 
ctDNA levels at the third and fifth cycles and relapse within 2 years using 
conditional logistic regression and landmark analyses,   
x 
descriptively summarize changes in ctDNA levels over time using descriptive 
statistics including means, medians, and inter-quartile ranges and spaghetti 
plots 
x 
perform all the above analyses within each treatment arm, and fit regression 
models with a treatment arm interaction covariate (to be performed after 
results by treatment arm from the trial are released by the DSMC). 
 
No information on arm label will be provided during the processing, labeling, or 
analyses of this project until the DSMC releases results of the trial.   
 
Analyses and interpretation of data are planned to be completed within 1 year of 
the receipt of specimens. 
 
e. 
Data Analysis 
 
Natera will report ctDNA levels to SWOG Statisticians. SWOG statisticians will 
perform all analyses linking ctDNA results with patient-level data. 
 
f. 
Specimen Information 
 

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Exome sequencing and ctDNA detection will be performed by Natera and 
statistical testing will be performed by SWOG statisticians ctDNA and outcome 
correlation data will be reported to Dr. Allie Grossmann (PI). 
 
 
The SWOG Biospecimen Bank - Lab #201 will ship the following specimens to 
Natera on dry ice for overnight delivery as outlined in Section 18.9.c: 
 
1) 
DNA from FFPE tumor 
2) 
DNA from germline (buffy coat) 
3) 
frozen plasma aliquots 
 
Natera 
201 Industrial Road, Suite 420San Carlos, CA 94070 
 
Natera study contact: 
Alexey Aleshin, MD, MBA (Medical Director, Oncology)  
aaleshin@natera.com   
858-335-6526 
 
Specimens used: 
 
Eligible patients who received ipilimumbab or pembolizumab on S1404. This 
proposal requires: 
x 
primary tumor or lymph node metastasis AND plasma AND buffy coat from 
baseline,  
x 
plasma at start of cycle 3 (if relapsed after start of cycle 3),  
x 
plasma at start of cycle 4 (if relapsed after start of cycle 4),  
x 
plasma at removal from protocol therapy or relapse.   
 
50 patients from each arm will be selected with a 1:1 case control design as 
follows: 
x 
control arm (patients who received IFN) 
 
n=25 patients who relapsed within 2 years 
 
n=25 patients who were alive without relapse at 2 years 
x 
pembrolizumab arm 
 
n=25 patients who relapsed within 2 years 
 
n=25 patients who were alive without relapse at 2 years 
 
We note that treatment arm information will not be released until the DSMC 
releases the treatment arm results of the trial.  
 
 
g. Reference 
 
 
1  
Reinert T, Henriksen TV, Christensen E, et al. Analysis of plasma cell-free DNA by 
ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol. 
2019. doi:10.1001/jamaoncol.2019.05282. 
 
2  
Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. Early detection of 
metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing 
of plasma cell-free DNA in patients with urothelial bladder carcinoma [published 
online ahead of print May 6, 2019]. J Clin Oncol. 2019. doi:10.1200/JCO.18.02052. 
 
3  
Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts 
early-stage lung cancer evolution. Nature. 2017;545(7655):446-451. 
 
 

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4  
Coombes RC, Page K, Salari R, et al. Personalized detection of circulating tumor 
DNA antedates breast cancer metastatic recurrence [published online ahead of 
print April 16, 2019]. Clin Cancer Res. 2019. doi:10.1158/1078-0432.CCR-18-
3663. 
 
5  
Reinert T, Henriksen TV, Christensen E, et al. Analysis of plasma cell-free DNA by 
ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol. 
2019. doi:10.1001/jamaoncol.2019.05282. 
 
6  
Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. Early detection of 
metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing 
of plasma cell-free DNA in patients with urothelial bladder carcinoma [published 
online ahead of print May 6, 2019]. J Clin Oncol. 2019. doi:10.1200/JCO.18.02052. 
 
7  
Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts 
early-stage lung cancer evolution. Nature. 2017;545(7655):446-451. 
 
8  
Coombes RC, Page K, Salari R, et al. Personalized detection of circulating tumor 
DNA antedates breast cancer metastatic recurrence [published online ahead of 
print April 16, 2019]. Clin Cancer Res. 2019. doi:10.1158/1078-0432.CCR-18-
3663.