A Phase II Randomized Study of Adjuvant Versus NeoAdjuvant Pembrolizumab (MK-3475) for Clinically Detectable Stage III-IV High-Risk Melanoma
Phase: PHASE2
Conditions: Acral Lentiginous Melanoma, Clinical Stage III Cutaneous Melanoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Mucosal Melanoma
Sponsor: National Cancer Institute (NCI)

 
 
Version Date: February 15, 2023 
 
 
TO:  
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS; CTSU  
 
 
FROM: 
SWOG Operations Office (protocols@swog.org) 
 
RE: 
S1801,  “A   Phase   II   Randomized   Study   of   Adjuvant   Versus   Neoadjuvant 
Pembrolizumab (MK-3475) for Clinically Detectable Stage III-IV High Risk Melanoma”. 
Study Chairs: Dr. S. Patel 
  
REVISION #11 
 
Study Chair: Sapna Patel, M.D.  
Phone number: 713/792-2921 
E-mail: S1801SCquestion@swog.org 
 
Action Codes 
(✓) 
Patients Must be Informed*  
(✓) 
Consent Must Be Amended*  
* 
See “Patient Notification and Use of Consent Addendum” and “Regulatory 
Considerations” instructions below.  
 
Key Updates   
(✓)  
Dose modification updates 
(✓)  
Informed Consent changes 
(✓)  
Other: Other: Pembrolizumab (MK-3475, NSC 776864) CAEPR update 
 
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 
distribution of this notice through the CTSU Bi-Monthly Broadcast email. 
 
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 through the CTSU Bi-Monthly Broadcast email.  
 
REVISION #11 
S1801 has been revised with the following changes in response to the Request for Rapid Amendment 
(RRA) received on February 3, 2023 from Dr. Elad Sharon (sharone@mail.nih.gov). The associated 
Action Letter is attached. 
 
Protocol Changes 
 
1. 
The version date has been updated. 
 
2. 
The Table of Contents has been updated.  
 
3. 
Throughout the protocol, formatting, typographical errors, pagination, and cross-references have 
been corrected as needed. 
 
4. 
Section 3.1.c: Instances of “MK-3475 (pembrolizumab)” have been updated to “pembrolizumab 
(MK-3475)”. The Pembrolizumab (MK-3475) CAEPR has been updated to Version 2.7, December 
13, 2022 as follows: 
 
a. Added New Risk: 
• 
Rare but Serious: Endocrine disorders - Other (hypoparathyroidism); Nervous system 
disorders -Other (optic neuritis)  
 

S1801 
Revision #11 (contd.) 
Page 2 
b. Decrease in Risk Attribution:  
• 
Changed to Also Reported on Pembrolizumab (MK-3475) Trials But With Insufficient 
Evidence for Attribution from Less Likely: CPK increased; Joint effusion; Pleuritic pain 
 
c. Deleted: 
• 
Less Likely: Immune system disorders - Other (pseudoprogression/tumor inflammation); 
Infection; Musculoskeletal and connective tissue disorder – Avascular Necrosis; 
Musculoskeletal and connective tissue disorder - Other (tenosynovitis) 
• 
Footnote #4 “Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC.” is deleted. 
 
5. 
Section 7.1: A section regarding supportive care for pembrolizumab has been added. Subsequent 
sections have been renumbered. 
 
6. 
Section 8.2: A new section for “General Considerations” has been added. Information regarding 
missed doses and dose delays has been moved to this section. A statement regarding supportive 
care information has been added to cross reference Sections 7.1 and 8.3a. Subsequent sections 
have been renumbered. 
 
7. 
Section 8.3: The Dose Modification Guidelines for Pembrolizumab have been updated in this 
section to reflect the Jan.10, 2023 NCI modifications to pembrolizumab dose modification 
guidelines. The changes are as follows: 
  
a. Section 8.3a: The section title has been updated to “Dose Modification and Toxicity 
Management for Immune-related Adverse Events Associated with Pembrolizumab”. 
Additional information has been added regarding identification and management of 
immune-related AEs (irAEs), infusion-reactions, and non-irAEs. 
 
b. Section 8.3a, Table 1 has been updated as follows: 
 
General instructions  
• Instruction 1 has been changed to include non-endocrine-related severe and life-
threatening irAEs. A statement has been added to highlight that some non-endocrine irAEs 
do not require steroids.  
• Instruction 2 has been revised to specifically mention non-endocrine-related toxicities. 
• Instruction 3 has been reworded for clarity. 
• Instruction 4 has been revised to clarify instructions for non-endocrine irAE. 
 
irAEs Toxicity Management Guidelines 
• 
Diarrhea / Colitis: 
o 
In the "Corticosteroid and/or other therapy" section, a sentence has been added to 
clarify that a gastroenterologist should examine patients who do not respond to 
corticosteroids in order to confirm the diagnosis and assess secondary immune 
suppression.  
o 
The section "Monitoring and Follow-up" has been updated to include a statement 
that participants should specifically be evaluated for celiac disease serologically 
and rule out Clostridium difficile infections. Additionally, wording has been added for 
assessing mucosal severity for participants with ≥Grade 2.  
 
• 
Type 1 diabetes mellitus (T1DM) or Hyperglycemia: 
o 
New guidelines for “Grade 1 or 2” have been added.  
o 
“New Onset T1DM or Grade 3 or 4 hyperglycemia associated with evidence of Β-
cell failure” has been updated to “New onset T1DM (evidence of Β-cell failure) or 
Grade 3 or 4 hyperglycemia” and the following have been added: a clarification for 
resuming pembrolizumab and updates to management, monitoring, and follow-up. 
 
 
 

S1801 
Revision #11 (contd.) 
Page 3 
• 
Hypophysitis: 
o 
Under the column "Monitoring and follow-up," a statement has been added to 
instruct patients are to be provided with adrenal insufficiency precautions, including 
indications for stress dosage steroids and medical alert jewelry, and that they 
should consider referral to an endocrinologist. 
 
• 
Hyperthyroidism: 
o 
For Grade 2, in the column "Action with pembrolizumab", “continue" have been 
updated to "Consider withholding. Resume pembrolizumab once symptoms have 
subsided and thyroid function has improved".  
o 
A sentence has been added under the column "Corticosteroid and/or other 
medications" to initiate treatment with an anti-thyroid medicine such as 
methimazole or carbimazole as needed.  
o 
A sentence has been inserted under the column "Monitoring and follow-up" stating 
that patients should strongly consider referral to an endocrinologist.  
 
• 
Nephritis:  
o 
In the "Monitoring and Follow-up" section, a statement has been added advising 
patients to strongly consider referral to a nephrologist.  
 
• 
The “Myocarditis” section have been updated to “Cardiac Events (including myocarditis, 
pericarditis, arrhythmias, impaired ventricular function, vasculitis)” 
o 
Grade 1 has been clarified as “Asymptomatic cardiac enzyme elevation with clinical 
suspicion of myocarditis (previously CTCAE v4.0 Grade 1), or Grade 1” and now 
has separate guidelines for management, monitoring, and follow-up.  Additional 
guidelines have been added for Grade 1. 
o 
The guidelines for Grade 2 have been combined with Grades 3-4.  Additional 
guidelines for management, monitoring, and follow-up have been added. 
 
• 
Guidelines for “Exfoliative Dermatologic Conditions” have been added.  
 
• 
The footnotes have been updated as follows: 
o 
Added definitions for acronyms used within the table. 
o 
Added a note about managing non-irAEs following clinical practice 
recommendations. 
o 
The sentence referring to resuscitation equipment and physician availability has 
also been included here. 
 
c. Section 8.3b, Table 2: The table title was revised to “Pembrolizumab (MK-3475) Infusion 
Reaction Treatment Guidelines”. The table has been updated as follows: 
o 
An additional column has been added for “Infusion Reactions” description as it 
applies to each NCI CTCAE Grade. 
o 
Under grade 3 treatment, corticosteroids was clarified to include the following 
additional information “ (e.g. methylprednisolone 2 mg/kg/day or dexamethasone 10 
mg every 6 hours)” 
o 
"Grade 4" guidelines have been separated from “Grade 3”.  Instructions have been 
added to admit participants to the intensive care unit (ICU) with monitoring and 
additional treatment and, as appropriate, follow Grade 3 recommendations. 
 
d. Section 8.3, Table 3: A section has been added for Management of Neurological toxicities 
and The Neurological Toxcities table has been added to this section. Subsequent sections 
have been renumbered. 
 
Model Consent Form Changes 
 
1. 
The version date has been updated. 
 

S1801 
Revision #11 (contd.) 
Page 4 
2. 
The Pembrolizumab (MK-3475) risk profile date has been updated to CAEPR Version 2.7, 
December 13, 2022. 
 
3. 
Possible Side effects of Pembrolizumab (MK-3475) updates: 
 
 Deleted Risk Attribution: 
• 
Occasional: Infection 
 
Decreased in Risk Attribution:  
• 
Changed to Also Reported on Pembrolizumab (MK-3475) Trials But With Insufficient 
Evidence for Attribution from Occasional (i.e., removed from the Risk Profile): Fluid in the 
joints; Pain in chest 
• 
Provided Further Clarification: Rare: Changed from “Swelling and redness of the eye” to 
“Swelling and redness of the eye which may cause blurred vision with a chance of blindness” 
 
PLEASE NOTE: The potential risks listed in the CAEPR whose relationship to pembrolizumab is 
still undetermined are not required by CTEP to be described in the ICD; however, they may be 
communicated to patients according to local IRB requirements. 
 
Patient Notification and use of Consent Addendum: 
 
Please note that the information provided below regarding patient notification and amendments to local 
consent forms reflects SWOG’s minimum requirements.  Sites should refer to the policies/procedures of 
the IRB of record to determine whether they have any more stringent requirements 
 
SWOG has determined that the changes above that are bolded may affect a patient’s willingness to 
participate in the study; therefore, SWOG requires that patients be notified of these changes.  
 
Who must be informed?   
• 
All patients currently on study treatment with Pembrolizumab (MK-3475). 
 
How must patients be notified? 
• 
For patients currently receiving Pembrolizumab (MK-3475):  Notification must take place either 
via the attached Consent Addendum or via amended consent form by next study visit.  After the 
change has been discussed with the patient, the patient must sign and date either the Consent 
Addendum or the 2/15/2023 version of the consent form. 
 
What is the notification deadline and process? 
• 
For patients currently receiving treatment with Pembrolizumab (MK-3475):  Patients must be 
notified by their next scheduled visit or within 90 days after CTSU distribution of this revision, 
whichever is sooner. 
• 
Sites using the NCI CIRB as their IRB of record:  CIRB has approved the attached Consent 
Addendum; therefore, the Consent Addendum may be utilized immediately to notify patients of 
these changes.  
• 
Sites not using the NCI CIRB as their IRB of record:  If local IRB approval of the Consent 
Addendum is required before sites may utilize it, the site must still notify patients verbally prior to 
the notification deadline and notification must be documented in the patient chart.  The site must 
then obtain patient signature on the Consent Addendum or updated consent form once the 
addendum and/or revised consent is locally approved. Important: Any changes to eligibility 
criterion are effective 30 days after distribution of this notice. If local IRB approval is not granted 
within 30 days, new registrations must meet any revised eligibility criteria included in the revision 
or accrual must be suspended until approval is obtained. 
 
Regulatory Considerations: 
 
Do local consent forms need to be updated? 

S1801 
Revision #11 (contd.) 
Page 5 
• 
It depends.  If your site will utilize the updated consent form for notification and formal reconsent 
then local consent forms must be updated.  If your site will not utilize updated consent form for 
notification and formal reconsent then local consent forms need not be updated. 
 
Can accrual continue until local implementation of the 2/15/2023 version of the consent form? 
• 
Unless otherwise noted in the Action Letter, accrual may continue; however: 
o 
Patients enrolled after the notification deadline must be enrolled under the 2/15/2023 version 
of the consent form. 
o 
Sites using the NCI CIRB as their IRB of record:  Patients enrolled prior to the notification 
deadline but before the 1/30/2023 version is implemented locally may be consented by 
signing the previous version of the consent form 3/21/2022 together with signing the attached 
Consent Addendum. 
o 
Sites not using the NCI CIRB as their IRB of record:  Patients enrolled prior to the notification 
deadline but before the 1/30/2023 version is implemented locally may be consented by 
signing the previous version of the consent form 3/21/2022 together with being notified of the 
updated information verbally at the time of consent.  The site must then obtain patient 
signature on the Consent Addendum or updated consent form once the addendum and/or 
revised consent is locally approved. Important: Any changes to eligibility criterion are effective 
30 days after distribution of this notice. If local IRB approval is not granted within 30 days, 
new registrations must meet any revised eligibility criteria included in the revision or accrual 
must be suspended until approval is obtained. 
o 
Patients enrolled prior to the notification deadline but before the 2/15/2023 version is 
implemented locally may be consented by signing the previous version of the consent form 
3/21/2022 together with signing the attached Consent Addendum. 
 
PLEASE NOTE: If the Action Letter requires suspension of accrual until the updated 
consent is implemented locally, the Action Letter instructions supersede this memo. 
 
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. 
 
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 

S1801 
 
Consent Addendum (Revision #11) 
 
Page 1 
 
Version Date 2/15/2023 
 
 
 
 
Informed Consent Addendum Model for S1801 
 
S1801, “S1801 A Phase II Randomized Study of Adjuvant vs. 
Neoadjuvant Pembrolizumab (MK-3475) for Clinically Detectable 
Stage III-IV High-Risk Melanoma” 
 
The following information should be read as an update to the original Consent form that you read 
and signed at the beginning of the study. Unless specifically stated below, all information 
contained in that original Consent Form is still true and remains in effect. Your participation 
continues to be voluntary. You may refuse to participate, or may withdraw your consent to 
participate at any time, and for any reason, without jeopardizing your future care at this institution 
or your relationship with your study doctor. 
 
New or additional information 
 
The following risk has been identified with the to Pembrolizumab (MK-3475) updates: 
 
• Rare: Changed from “Swelling and redness of the eye” to “Swelling and redness of the 
eye which may cause blurred vision with a chance of blindness” 
 
Patient Signature and Date  
 
By signing this form, I acknowledge that I have read the information above or had it read to me. I 
have discussed it with a member of the study team and my questions have been answered. I 
understand that I will be given a copy of this form.  
 
Participant’s signature 
 
 
Date of signature_____________________________________ 
 
 
Signature of person(s) conducting the informed consent discussion________________________ 
 
Date of signature_____________________________________ 
 

 
S1801 
 
Page 1 
 
Version Date 2/15/2023 
 
 
 
PRIVILEGED COMMUNICATION 
FOR INVESTIGATIONAL USE ONLY 
 
 
SWOG 
TITLE 
A PHASE II RANDOMIZED STUDY OF ADJUVANT VERSUS NEOADJUVANT PEMBROLIZUMAB 
(MK-3475) FOR CLINICALLY DETECTABLE STAGE III-IV HIGH RISK MELANOMA  
 
NCT# 03698019 
 
STUDY CHAIRS: 
AGENTS: 
 
Sapna Pradyuman Patel, M.D. (Medical Oncology)  
NCI Supplied Investigational Agents 
MD Anderson Cancer Center 
Melanoma Medical Oncology  
(DCTD-sponsored): 
1515 Holcombe Blvd., Unit 0430 
Pembrolizumab (MK-3475) (NSC 776864) 
 
Houston, TX 77030 
Phone: 713/792-2921 
 
  
 
E-mail: S1801SCquestion@swog.org  
ECOG-ACRIN STUDY CHAIR: 
 
 
 
Victor G. Prieto, M.D., Ph.D. (Pathology) 
Elizabeth Buchbinder, M.D. (Medical Oncology) 
The University of Texas – M.D. Anderson Cancer 
Dana-Farber Cancer Institute 
Center 
450 Brookline Avenue 
1515 Holcombe Blvd, Unit 85 – G1.3457 
Boston, MA  02215 
Houston, TX 77030 
Phone: 617-632-5055 
Phone: 713/792-3187 
Email:Elizabeth_Buchbinder@dfci.harvard.edu  
E-mail: vprieto@mdanderson.org 
 
 
BIOSTATISTICIANS: 
 
 
Vernon K. Sondak, M.D.  (Surgery) 
Megan Othus, Ph.D. 
H. Lee Moffitt CC 
 
 
 
 
James Moon, M.S. 
MKC-CutProg    
SWOG Statistical Center 
10920 N. McKinley Dr 
1100 Fairview Ave N, M3-C102 
Tampa, FL 33612 
P.O. Box 19024  
Phone:  813/745-8788 
Seattle, WA 98109-1024 
FAX:  813/745-7211 
Phone:  206/667-4623 
E-mail:  vernon.sondak@moffitt.org 
FAX:  206/667-4408 
 
E-mail:  mothus@fredhutch.org  
Michael C. Lowe, M.D. (Surgery)  
E-mail: jmoon@fredhutch.org 
Emory Univ Hosp/Winship Ca Inst 
1365-C Clifton Rd NE 
Clinic C, Ste 3012 
Atlanta GA 30322  
Phone: 404-778-3738 
E-Mail: mlowe3@emory.edu  
 

 
S1801 
 
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PARTICIPANTS 
 
SWOG/SWOG 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research 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 ....................... 6 
SCHEMA ....................................................................................................................................................... 7 
1.0 
OBJECTIVES .................................................................................................................................. 7 
1.1 
Primary Objective(s) ......................................................................................................................... 8 
1.2 
Secondary Objective(s) .................................................................................................................... 8 
1.3 
Additional Objective(s) ..................................................................................................................... 8 
2.0 
BACKGROUND ............................................................................................................................... 8 
2.1 
Inclusion of Women and Minorities and Planned Enrollment Report ............................................ 10 
3.0 
DRUG INFORMATION .................................................................................................................. 10 
3.1 
Pembrolizumab (MK-3475) (NSC-776864) .................................................................................... 10 
4.0 
STAGING CRITERIA ..................................................................................................................... 20 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 21 
5.1 
STEP 1 REGISTRATION (Randomization) ................................................................................... 21 
5.2 
STEP 2 REGISTRATION (Surgery) ............................................................................................... 24 
5.3 
STEP 3 REGISTRATION (Adjuvant Therapy) ............................................................................... 24 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 25 
7.0 
TREATMENT PLAN ...................................................................................................................... 25 
7.1 
Supportive Care ............................................................................................................................. 25 
7.2 
Treatment ....................................................................................................................................... 26 
7.3 
Prohibited and Cautionary Medications ......................................................................................... 29 
7.4 
Follow-Up Disease Assessment Schedule .................................................................................... 30 
7.5 
Criteria for Removal from Protocol Treatment ............................................................................... 30 
7.6 
Full CDUS Reporting Requirement ................................................................................................ 31 
7.7 
Discontinuation of Treatment ......................................................................................................... 31 
7.8 
Follow-Up Period, End of Study ..................................................................................................... 31 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 31 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 31 
8.2 
General Considerations                                                                                                                 31 
8.3 
Dose Modification Considerations for Participants Receiving pembrolizumab (MK-3475) ........... 32 
8.4 
Anti-infectives ................................................................................................................................. 45 
8.5 
Dose Modification Contacts ........................................................................................................... 45 
8.6 
Adverse Event Reporting ............................................................................................................... 45 
9.0 
STUDY CALENDAR ...................................................................................................................... 46 
9.1  
Pembrolizumab (MK-3475) Adjuvant Arm ..................................................................................... 46 
9.2  
Pembrolizumab (MK-3475) Neoadjuvant Arm ............................................................................... 48 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 52 
10.1 
Measurability of lesions .................................................................................................................. 52 
10.2 
RECIST Objective status at each disease evaluation: ............................................................. 53 
10.3 
RECIST Best Response.  This is calculated from the sequence of objective statuses. .............. 54 
10.4 
Progression before surgery ............................................................................................................ 55 
10.5 
Relapse after surgery ..................................................................................................................... 55 
10.6 
Pathologic Response ..................................................................................................................... 56 
10.7 
iRECIST Objective status at each disease evaluation: ............................................................ 56 
10.8 
Objective status notes .................................................................................................................... 58 
10.9 
iRECIST Best Response ................................................................................................................ 58 
10.10 
Event-Free Survival ........................................................................................................................ 59 
10.11 
Length of disease control ............................................................................................................... 60 
10.12 
Length of loco-regional control ....................................................................................................... 60 
10.13 
Overall Survival .............................................................................................................................. 60 
10.14 
Performance Status ....................................................................................................................... 60 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 61 
11.1  
Accrual goals .................................................................................................................................. 61 
11.2  
Analysis plan and sample size justification for primary objective .................................................. 61 

 
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11.3  
Sample size re-design .................................................................................................................... 61 
11.4  
Secondary endpoints and analyses ............................................................................................... 61 
11.5  
Data and Safety Monitoring ........................................................................................................... 63 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 63 
12.1 
Surgical Review and Quality Assurance ........................................................................................ 63 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 64 
13.1 
Registration Timing ........................................................................................................................ 64 
13.2 
Investigator/Site Registration ......................................................................................................... 64 
13.3 
CTEP Registration Procedures ...................................................................................................... 64 
13.4 
CTSU Registration Procedures ...................................................................................................... 65 
13.5 
Oncology Patient Enrollment Network (OPEN) Registration Requirements .................................. 67 
13.6 
Exceptions to SWOG registration policies will not be permitted. ................................................... 68 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 68 
14.1 
Data Submission Requirement ...................................................................................................... 68 
14.2 
Data Submission Procedures ........................................................................................................ 68 
14.3 
Data Submission Overview and Timepoints .................................................................................. 69 
14.4 
Master Forms ................................................................................................................................. 72 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 72 
15.1 
Submission of surgical tissue for pathologic response assessment (Required for all participants 
on the Neoadjuvant arm). .............................................................................................................. 72 
15.2 
Specimens for Banking (Optional) ................................................................................................. 73 
15.3 
SHIPPING SAMPLES .................................................................................................................... 75 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 76 
16.1 
ADVERSE EVENT REPORTING REQUIREMENTS .................................................................... 78 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 83 
18.0 
APPENDIX ..................................................................................................................................... 85 
18.1 
Surgical Management Guidelines .................................................................................................. 86 
18.2 
AJCC 8th Edition TNM Definitions for Pathologic Staging .............................................................. 89 
18.3 
Translational Medicine: Pathological Response ............................................................................ 92 
18.4 
Specimen Banking Instructions for the SWOG Biospecimen Bank ............................................... 94 
 
 
 

 
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PROTOCOL CONTACT INFORMATION 
 
 
Eligibility, RAVE, Data Submission: 
 
SWOG Statistics and Data Management Center  
E-mail: melanomaquestion@crab.org or Phone: 
206/652-2267 
 
Regulatory, Protocol, Informed Consent: 
 
SWOG Operations Office 
E-mail: protocols@swog.org or Phone: 210/614-8808 
 
 
Medical Queries (treatment or toxicity related 
questions): 
Email: S1801SCquestion@swog.org or call: 
Dr. Sapna P. Patel, M.D. at Phone: 713/792-2921 
Investigational Drug questions: 
Requests for Investigator’s Brochures: 
 
Access issues for the PMB Online Agent 
Ordering Processing (OAOP) application: 
See Protocol Section 3.0 or 
PMBAfterHours@mail.nih.gov 
See Protocol Section 3.0 or 
http://ctep.cancer.gov/branches/pmb/agent_order_proc
essing.htm 
IBCoordinator@mail.nih.gov 
 
Specimen Tracking System (STS) 
Amendments, Errors, Connectivity Issues 
and Technical issues with the SWOG CRA 
Workbench: 
 
technicalquestion@crab.org 
 
Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-
IAM) 
 
To review CTEP-IAM account (new requests, reset 
passwords): 
 
https://ctepcore.nci.nih.gov/iam/index.jsp 
Access to iMedidata Rave or Delegation of 
Task Log (DTL) 
See Protocol Section 14.2 or contact  
CTSU Help Desk:  
Phone: 1-888-823-5923 or Email: 
ctsucontact@westat.com 
Questions related to: 
Oncology Patient Enrollment Network 
(OPEN) 
See Protocol Section 13.3 or contact  
CTSU Help Desk:  
Phone: 1-888-823-5923 or Email: 
ctsucontact@westat.com 
TRIAD installations: 
https://triadinstall.acr.org/triadclient/  
Questions: TRIAD-Support@acr.org  
Participant Transfers: 
patienttransfer@crab.org 
Serious Adverse Event Reporting questions:  
See Protocol Section 8.5  
Email: adr@swog.org  
 
Source Documentation Portal – Central 
Monitoring 
 
centralmonitorquestion@crab.org 
 
 
 
 

 
S1801 
 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory requirements: 
For participant 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 participants 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 866-651-2878 to 
receive further information and 
support.   
 
Contact the CTSU Regulatory 
Help Desk at 866-651-2878 for 
regulatory assistance. 
 
Please refer to the participant 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com. 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions.  
 
Other Tools and Reports: 
Institutions participating through 
the CTSU continue to have 
access to other tools and reports 
available on the SWOG 
Workbench. Access this by 
using your active CTEP-IAM 
userid and password at the 
following url: 
 
https://crawb.crab.org/TXWB/cts
ulogon.aspx  
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS.   
For participant eligibility or data submission questions contact the SWOG Data Operations Center 
by phone or email: 
206/652-2267 
melanomaquestion@crab.org  
 
For treatment or toxicity related questions contact the Study Chair by phone or email:  
Sapna P. Patel, M.D. 
Phone:  713/792-2921 
 
E-mail: S1801SCquestion@swog.org  
 
For non-clinical questions (i.e. unrelated to participant 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*  Participants on Adjuvant arm must be registered to Step 2 (Surgery) within 17 days (preferably 
within 14 days) after randomization and must undergo surgical resection within 17 days 
(preferably within 14 days) after Step 2 registration. 
** See Section 7.1 for dosage and timing.  Participants must start adjuvant therapy within 84 days 
of surgery.  
1.0 
OBJECTIVES 
 
Adjuvant Pembrolizumab (MK-3475) 
200 mg IV flat dosing every 3 weeks 
for 18 doses 
Pembrolizumab (MK-3475) 200 mg IV 
flat dosing every 3 weeks x 3 doses 
Surgical Resection  
Step1: Registration and Randomization  
Arm 1 
Adjuvant Arm* 
Arm 2 
Neoadjuvant Arm 
Adjuvant Pembrolizumab (MK-
3475) 200 mg IV flat dosing every 3 
weeks x 15 doses (18 doses total 
pre-operative doses + post-
operative doses) 
Surgical Resection  
Step 2:  Surgery 
Step 3: Adjuvant Pembrolizumab ** 

 
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1.1 
Primary Objective(s)  
 
a. 
To compare event-free survival (EFS) in participants with high-risk resectable 
melanoma randomized to neoadjuvant pembrolizumab (MK-3475) with 
participants randomized to adjuvant pembrolizumab (MK-3475). 
 
1.2 
Secondary Objective(s) 
 
a. 
To assess the frequency and severity of toxicities on each of the arms. 
 
b. 
To compare between arms overall survival (OS), disease control at 24 weeks, 
locoregional control in the surgical site(s), and total number of pembrolizumab 
(MK-3475) doses received. 
 
c. 
On the neoadjuvant arm, to estimate the pathologic response rate, the RECIST 
1.1 response rate (confirmed and unconfirmed CR and PR), and the iRECIST 
response rate (confirmed and unconfirmed CR and PR), before surgical resection; 
to compare definitions of pathologic partial response; and to evaluate the 
association between pathologic response and EFS and OS. 
 
d. 
To describe the proportion of participants on each arm who received the surgery 
planned at randomization. 
 
1.3 
Additional Objective(s) 
 
a. 
To bank tumor tissue and whole blood in anticipation of future correlative studies 
in this participant population. Such proposed analysis includes deep immune 
profiling, with evaluation of CD3, CD8, PD-L1, CD20, whole exome sequencing 
studies, and RNA analysis. 
 
 
2.0 
BACKGROUND 
 
Although the long-term relapse-free survival (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 in Stage III 
patients of approximately 50%. (1) Modern therapy has significantly improved outcomes for patients 
with Stage IV melanoma such that 20% of patients are alive beyond 4 years or longer after 
diagnosis, but 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.   
 
Treatment with anti-programmed death-1 (PD-1) antibody induces significant response rates and 
durable survival in patients with metastatic melanoma. (4,5,6) Historically, adjuvant therapy for 
melanoma typically involves treatment with either high-dose interferon or high-dose ipilimumab. 
(7,8) But the role of PD-1 has moved to the forefront of adjuvant therapy with the results of 
CheckMate-238. (9) At this time, we are not able to predict which patients will derive benefit from 
adjuvant therapy and be long-term survivors (or cured). However, there is a need to identify patient 
or tumor characteristics that can distinguish those who will benefit from the cost, side effects, and 
time commitment of adjuvant treatment from those who will not.  
 
While adequate and effective surgery is the goal of early treatment of primary melanoma, some 
cases with bulky nodal involvement are at high risk of local or distant recurrence despite upfront 
surgical resection. Neoadjuvant treatment offers the benefit of an early on-treatment pathological 
sample that can be profiled for additional biomarkers and correlated with survival. Additionally, 
treating with anti-PD1 antibody while tumor transiently remains in the body may generate a stronger 

 
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immune response against in vivo tumor antigens compared to the traditional adjuvant setting where 
tumor antigen is presented by microscopic residual tumor burden. 
 
Patients with bulky resectable disease have been treated in pilot studies using a neoadjuvant 
approach with chemotherapy, targeted therapy, and more recently, checkpoint blockade. 
Multidisciplinary coordination in these cases is paramount as is timing of surgical resection. In these 
pilot studies investigating neoadjuvant targeted therapy for melanoma, an improvement in relapse-
free survival and overall survival has been observed; additionally, pathologic response rates to 
neoadjuvant therapy have been estimated in small studies. An unpublished Phase II clinical trial of 
adjuvant versus neoadjuvant targeted therapy in melanoma patients at MD Anderson had a 
RECIST 1.1 response rate after neoadjuvant targeted therapy of 85% and a pathologic complete 
response rate of 58%. Compared to patients randomized to surgery followed by adjuvant targeted 
therapy, there was a statistically significant difference in 12-month EFS favoring the neoadjuvant 
arm. 
 
Among S1404 enrollment, 43% of patients had clinically detectable and resectable nodal disease, 
the ideal population for a neoadjuvant cohort. This study, S1801, will answer two pressing 
questions in the field of melanoma: 1) Is there evidence that neoadjuvant treatment with a PD-1 
inhibitor can improve relapse-free and overall survival in patients with clinically detectable 
resectable node-positive melanoma compared to adjuvant PD-1 inhibitor treatment; and 2) Can a 
multi-center multidisciplinary high-quality neoadjuvant melanoma trial be executed within the 
cooperative group system. 
 
The current landscape of other immunotherapy studies in high-risk melanoma:    
 
The current standard of care has been set by the recently reported CheckMate-238 study, and the 
FDA has approved the use of nivolumab for completely resected node-positive or metastatic 
melanoma. (10)  Nivolumab and pembrolizumab (MK-3475) have never been tested head-to-head 
but results from clinical trials in metastatic melanoma demonstrate equitable outcomes with these 
two agents. Ongoing adjuvant clinical trials in patients with melanoma include S1404 
(pembrolizumab (MK-3475) versus choice of standard of care), KEYNOTE-054 (pembrolizumab 
(MK-3475) versus placebo), and CheckMate-915, a randomized, Phase III, double-blind study of 
nivolumab versus the combination of nivolumab plus ipilimumab in patients with resected, Stage III 
melanoma). As of May 2018, KEYNOTE-054 data demonstrated that adjuvant pembrolizumab is 
associated with an improved 1-year and 18-month recurrence-free survival (RFS) compared to 
placebo.  (11) The data have not yet matured to produce distant metastasis-free survival and overall 
survival results. 
 
Biological rationale for the study population based on the anticipated mechanism of action 
of pembrolizumab (MK-3475): 
Patients with bulky resectable melanoma have been treated using a neoadjuvant approach with 
chemotherapy, targeted therapy, and more recently, checkpoint blockade at multidisciplinary 
academic medical centers. Studying systemic treatment in this resectable population offers insight 
into biologic and pathologic response to treatment. It also provides an intact tumor-infiltrating 
lymphocyte population upon which checkpoint blockade often has its greatest effects in antigen 
presentation and generation of an anti-tumor immune response. While adequate and effective 
surgery is the goal of early treatment of primary melanoma, some cases with bulky nodal 
involvement are at high risk of local or distant recurrence despite upfront surgical resection. 
Neoadjuvant treatment further offers the benefit of an early on-treatment pathological sample that 
can be profiled for additional biomarkers and correlated with survival. 
 
 

 
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Inclusion of Women and Minorities 
 
2.1 
Inclusion of Women and Minorities and Planned Enrollment Report 
 
This study was designed to include women and minorities but was not designed to measure 
differences of intervention effects.  To date, studies of pembrolizumab (MK-3475) 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 
2 
0 
0 
2 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian 
or Other Pacific 
Islander 
0 
1 
0 
0 
1 
Black or African 
American 
4 
4 
0 
0 
8 
White 
145 
337 
2 
4 
488 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
149 
345 
2 
4 
500 
 
3.0 
DRUG INFORMATION 
 
Investigator’s Brochures 
 
For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, pembrolizumab (MK-3475) 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).   
 
3.1 
Pembrolizumab (MK-3475) (NSC-776864) 
 
a. 
PHARMACOLOGY 
 
Pembrolizumab (MK-3475) 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.  
PEMBROLIZUMAB (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 
 

 
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The pharmacokinetic profile of pembrolizumab (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, pembrolizumab 
(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) 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/aeguide
lines.pdf for further clarification. Frequency is provided based on 3793 participants. 
Below is the CAEPR for pembrolizumab (MK-3475). 
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 2.7, December 13, 20221 
 
 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475 ) 
 (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 
 
 
 
 
Blood and lymphatic system
disorders - Other (immune 
thrombocytopenic purpura)
 
 
Lymph node pain2  
 
CARDIAC DISORDERS 
 
 
 
Myocarditis2 
 
 
 
Pericarditis2 
 
ENDOCRINE DISORDERS 
 
 
Adrenal insufficiency 
 
 
 
Endocrine disorders - Othe
(hypoparathyroidism) 
 
 
Endocrine disorders 
Other (thyroiditis)2 
 
 
 
Hyperthyroidism2 
 
 
 
Hypophysitis2 
 
 
 
Hypopituitarism2 
 
 
 
Hypothyroidism2 
 
 
EYE DISORDERS 
 
 
 
Uveitis2 
 
 
 
Eye disorders - Other (Vogt
Koyanagi-Harada syndrome
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
 
 
Colitis2 
 
 
 
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 
 
 
 
 
Hepatobiliary disorders - 
Other (sclerosing 
cholangitis) 
 
IMMUNE SYSTEM DISORDERS 
 
 
 
Anaphylaxis2 
 
 
 
Cytokine release syndrome 

 
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 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475 ) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 Specific 
Protocol 
Exceptions to
Expedited 
Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20% Rare but Serious (<3%)
 
 
 
Immune system disorders -
Other (acute graft-versus-
host-disease)2,3 
 
 
 
Immune system disorders -
Other (hemophagocytic 
lymphohistiocytosis)2 
 
 
Immune system 
disorders - Other 
(sarcoidosis)2 
 
 
 
 
Serum sickness2 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
 
 Infusion related reaction  
INVESTIGATIONS 
 
 
Alanine 
aminotransferase 
increased2 
 
 
 
Alkaline phosphatas
increased 
 
 
 
Aspartate 
aminotransferase 
increased2 
 
 
 
Blood bilirubin 
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 
 
 
 
Back pain 
 
 
 
Joint range of motion
decreased 
 
 
 
Myalgia2 
 
 
 
Myositis2 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
 
Guillain-Barre syndrome2  
 
 
Nervous system disorders -
Other (myasthenic 
syndrome)2 
 
 
 
Nervous system disorders -
Other (neuromyopathy)2 
 

 
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 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475 ) 
 (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 (non-infectious 
encephalitis)2 
 
 
 
Nervous system disorders -
Other (non-infectious 
meningitis)2 
 
 
 
Nervous system disorders -
Other (non-infectious 
myelitis) 
 
 
 
Nervous system disorders -
Other (optic neuritis) 
 
 
 
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 
 
 
 
 Pneumonitis2 
 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Bullous dermatitis2  
 
 
 
 Erythema multiforme2 
 
 
Erythroderma 
 
 
 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
 
Pruritus2 
 
Pruritus2 (Gr 2)
 
Rash acneiform2 
 
 
 
Rash maculo-papula 
Rash maculo-
papular2 (Gr 2) 
 
Skin and 
subcutaneous tissue
disorders - Other 
(dermatitis)2 
 
 
 
Skin 
hypopigmentation2 
 
 
 
 
Stevens-Johnson syndrome 
 
 
Toxic epidermal necrolysis  
 
Urticaria2 
 
 
VASCULAR DISORDERS 
 
 
 
Vasculitis2 
 
 
 
 
 
 
1This 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 

 
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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. 
 
2Immune-mediated adverse reactions have been reported in patients receiving 
pembrolizumab (MK-3475).  Adverse events potentially related to pembrolizumab 
(MK-3475 ) may be manifestations of immune-mediated adverse events. In clinical 
trials, most immune-mediated adverse reactions were reversible and managed 
with interruptions of pembrolizumab (MK-3475), administration of corticosteroids 
and supportive care. 
 
3Acute graft-versus-host disease has been observed in patients treated with 
pembrolizumab (MK-3475) who received hematopoeitic stem cell transplants. 
 Adverse events reported on pembrolizumab (MK-3475) trials, but for which there 
is insufficient evidence to suggest that there was a reasonable possibility that 
pembrolizumab (MK-3475) 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 
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 – CPK increased; 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; Joint effusion2; 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 

 
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incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS – Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS – Dyspnea; 
Hypoxia; Laryngeal inflammation; Pleural effusion; Pleuritic pain2; 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: Pembrolizumab (MK-3475) 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:  pembrolizumab (MK-3475) may have adverse 
effects on a fetus in utero.  Furthermore, it is not known if pembrolizumab 
(MK-3475) has transient adverse effects on the composition of sperm.  
Participants 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 birth control methods can be barrier method or a barrier 
method plus a hormonal method to prevent pregnancy.  Participants 
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). 
 
Participants 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 participant will not reliably comply with the requirements 
for contraception, that participant should not be entered into the study. 
 
Pregnancy: If a participant inadvertently becomes pregnant while on 
treatment with pembrolizumab (MK-3475), the participant will immediately 
be removed from the study.  The site will contact the participant at least 
monthly and document the participant’s status until the pregnancy has 
been completed or terminated.  The outcome of the pregnancy will be 

 
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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 pembrolizumab (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, participants 
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 participant 
medication list, including pembrolizumab (MK-3475), should be screened 
prior to initiation of and during treatment with pembrolizumab (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 
 
Pembrolizumab (MK-3475) is supplied by Merck & Co., Inc. and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI.  Pembrolizumab (MK-
3475) injection is a sterile, preservative-free, clear to slightly opalescent, colorless 
to slightly yellow solution for intravenous use. Each vile contains 100 mg of 
pembrolizumab (MK-3475) and is formulated in: L-histidine (1.55 mg), polysorbate 
80 (0.2 mg), sucrose (70 mg), and Water for injection, USP. 
 
f. 
PREPARATION  
 
Pembrolizumab (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 pembrolizumab 
(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 pembrolizumab (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 
 
Refer to the package label for expiration. 
 

 
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Administer prepared solutions immediately after preparation.  If not administered 
immediately, prepared solutions may be stored refrigerated for up to 24 hours.  
Pembrolizumab (MK-3475) solutions may be stored at room temperature for a 
cumulative time of up to 6 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. 
 
 

 
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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. 
PARTICIPANT CARE IMPLICATIONS 
 
Refer to Section 8.3a for information on evaluation and management of potential 
immune-related adverse events. 
 
l. 
DRUG ORDERING AND ACCOUNTABILITY  
 
1. 
Drug Ordering 
 
Sites may order initial agent supplies when a subject has been 
randomized.  Starter supplies will not be provided.  NCI-supplied agents 
may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational 
agents.  The eligible participating investigators at each participating 
institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, 
Agent Shipment Form, and Financial Disclosure Form (FDF).  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 participating investigator at that institution. 
 
Submit agent requests 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, a “current” password, and 
active person registration status.  For questions about drug orders, 
transfers, returns, or accountability, call or email PMB any time.  Refer to 
the PMB’s website for specific policies and guidelines related to agent 
management. 
 
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, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page.  Store and maintain separate NCI Investigational 
Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
 
 

 
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3. 
Drug return and/or disposition instruction  
 
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). 
 
Drug Expiration:  Stability testing is ongoing. PMB will send a stock 
recovery letter when notified that the agent is no longer suitable for use. 
 
4. 
Contact Information 
 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov  
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP  
• 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• 
CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• 
IB Coordinator:  IBCoordinator@mail.nih.gov  
• 
PMB email:  PMBAfterHours@mail.nih.gov  
PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
 
4.0 
STAGING CRITERIA 
 
All participants will be staged using the AJCC 8th edition, 2017. Below are the study specific staging 
criteria for eligibility purposes. For a full list of staging criteria, see Section 18.2 
 
Clinically detectable Stage III or Stage IV 
  
T Stage 
  
Nodal Disease 
Satellite / 
In-Transit 
Metastases 
  
M stage 
IIIB 
T0,T1,T2,T3a 
  
One clinically detected node 
No 
  
M0 
  
T0,T1,T2,T3a 
  
none 
Yes 
  
M0 
  
  
IIIC 
T3b, T4 
  
One clinically detected node 
No 
  
M0 
  
T3b, T4 
0-1 clinically detected nodes 
Yes 
M0 
  
T0,T1,T2,T3,T4a 
2+ clinically detected nodes or matted nodes 
No 
M0 
  
T0,T1,T2,T3,T4a 
  
2+ clinically detected nodes or matted nodes 
Yes 
  
M0 
  
  
IIID 
T4b 
  
2+ clinically detected nodes or matted nodes 
No 
  
M0 
  
T4b 
  
2+ clinically detected nodes or matted nodes 
Yes 
  
M0 
  
  
IV 
any T 
  
any N 
yes/no 
  
M1 
 

 
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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 
randomization. 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 
randomization. NCI policy does not allow for waiver of any eligibility criterion  
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
 
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 28, 30, 42 or 84 falls on a 
weekend or holiday, the limit may be extended to the next working day. 
 
5.1 
STEP 1 REGISTRATION (Randomization) 
 
a. 
Disease Related Criteria 
 
1. 
Patients must have clinically detectable Stage III (clinically detectable 
N1b, N1c, N2b, N2c, N3b and N3c) or Stage IV resectable melanoma. 
Patients with melanoma of mucosal or acral origin are eligible.  Patients 
with melanoma of uveal origin are not eligible.  Patients with a history of 
brain metastases are not eligible.  
 
Clinically detectable is defined as disease that is apparent and measurable 
via physical examination or radiographic imaging (Section 10.1). 
 
Note: Planned surgery must be documented on the S1801 Planned Surgery Form. 
 
2. 
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. 
 
3. 
Patients with multiple regional nodal basin involvement are eligible. Gross 
or microscopic extracapsular nodal extension is permitted. 
 
4. 
Patients must have histologically proven Stage IIIB or higher. This would 
entail pathologic confirmation beyond the primary or initial diagnosis of 
melanoma involving fine needle aspiration cytology or biopsy confirmation 
of any N-category or M-category resectable site. 
   
b. 
Prior/Concurrent Therapy Criteria 
 
1. 
Patients must not have received previous neoadjuvant treatment for their 
melanoma.  Patients may have received prior non-immunotherapy 
adjuvant therapy.  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 treatment phases on the study. 
 
2. 
Patients must not be planning to receive concomitant other biologic 
therapy, hormonal therapy, other chemotherapy, surgery, while on 
protocol therapy. 

 
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3. 
Patients may have received prior radiation therapy, including after prior 
surgical resection.  All adverse events associated with prior surgery and 
radiation therapy must have resolved to ≤ Grade 1 prior to randomization. 
 
c. 
Clinical/Laboratory Criteria 
 
1. 
Patients must be ≥ 18 years of age.   
 
2. 
All patients must have disease status documented by a complete physical 
examination 
and 
imaging 
studies 
within 
42 
days 
prior 
to 
randomization.  Imaging studies must include a CT of the chest, abdomen, 
and pelvis with intravenous contrast (unless contraindicated). For patients 
with melanoma arising from the head and neck, dedicated neck imaging 
(CT with intravenous contrast) is required.  If the patient has unknown 
primary with disease in the axilla, neck imaging is required. CT imaging 
must be done with intravenous contrast if there are no contraindications 
for it. Extremity melanomas must be imaged using CT with intravenous 
contrast or MRI with and without gadolinium. 
 
Note: PET-CT scans are NOT acceptable to establish eligibility. Non-
iodinated CT scans that are part of common PET-CT imaging protocols do 
not provide contrast for difficult to ascertain areas such as the neck and 
liver, and do not provide enough CT detail to perform appropriate RECIST 
1.1 measurements. As such, a PET-CT with non-contrast CT or non-
diagnostic quality CT images is considered insufficient for the detection of 
melanoma. 
 
3. 
All patients must have a CT or MRI of the brain within 42 days prior to 
randomization.  The brain CT or MRI should be performed with 
intravenous contrast (unless contraindicated).   
 
4. 
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 randomization. 
 
5. 
Patients must have adequate hepatic function as evidenced by the 
following: total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) 
(except patients with 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 randomization. 
 
6. 
Patients must have LDH performed within 42 days prior to randomization. 
 
7. 
Patients must have adequate renal function as evidenced by calculated 
creatine clearance > 30 mL/min. The creatinine level (mg/dL) used in the 
calculation must be obtained within 42 days prior to randomization. 
 
Calculate creatinine clearance = (140-age) x wt (Kg) x 0.85 (if female) 
 
72 x creatinine (mg/dL 
 
8. 
Patients must have Zubrod Performance Status ≤ 2 (see Section 10.14). 
 
9. 
Patients must not have a history of (non-infectious) pneumonitis that 
required steroids or current pneumonitis. 
 

 
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10. 
Patients must not have an active infection requiring systemic therapy. 
 
11. 
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. 
 
12. 
Patients must not have received live vaccines within 42 days prior to 
randomization.  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. NOTE: The COVID-19 vaccines 
(currently available and those in the pipeline for FDA emergency use 
authorization or FDA approval) do not contain live virus, and therefore, 
COVID-19 vaccination does not affect or preclude eligibility for the S1801 
trial. For patients who have undergone lymphadenectomy, vaccines 
should be delivered to a limb with an intact lymph node basin (Sentinel 
lymph node biopsy in a limb is acceptable). The vaccine should not be 
administered in a limb that has undergone lymphadenectomy. 
 
13. 
Patients known to be HIV positive are eligible if they meet the following 
criteria within 30 days prior to randomization:  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. 
 
14. 
Patients must not have known active Hepatitis B Virus (HBV) or Hepatitis 
C Virus (HCV) infection prior to randomization. Note: No testing for 
Hepatitis B and Hepatitis C is required unless mandated by local health 
authority. 
 
15. 
Prior malignancy is allowed providing it does not require concurrent 
therapy. 
 
16. 
Women of childbearing potential must have a negative urine or serum 
pregnancy test within 28 days prior to randomization.  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.   
 
17. 
Patients must be deemed medically fit to undergo surgery by the treating 
medical/surgical team. 

 
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d. 
Specimen Submission Criteria 
 
1. 
Patients must be willing to submit the following surgical specimens: either 
all tissue blocks from the surgical specimen or two slides per block [(1) 
H&E slide and (1) unstained slide OR (2) unstained slides if H&E stained 
slides cannot be provided) 
 
2. 
Patients must be offered the opportunity to participate in specimen 
banking as outlined in Section 15.2. 
 
e. 
Regulatory Criteria 
 
1. 
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. 
 
2. 
As a part of the OPEN randomization 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 (Surgery) 
 
a. 
Patients randomized to Arm 2 (Neoadjuvant arm) must be willing to submit tissue 
to determine pathologic response as described in Section 15.1 regardless of 
number of pre-operative doses of pembrolizumab (MK-3475) received.  
Determination of pathologic response cannot be done on less than the full surgical 
specimen. 
 
b. 
Patients must have disease assessments by CT chest/abdomen/pelvis with IV 
contrast, and neck CT with IV contrast if primary head and neck melanoma, 
performed within 42 days (and no more than 49 days) before the planned date of 
surgery. MRI combined with non-contrast CT is an acceptable alternative for 
patients with CT contrast allergy, but imaging must encompass total body. 
 
c. 
Patients must register to Step 2 within 17 days prior to planned date of surgery. 
 
5.3 
STEP 3 REGISTRATION (Adjuvant Therapy) 
 
a. 
Patients must have undergone surgery prior to Step 3 registration.  The Step 2 
surgery must have completely resected their melanoma.   
• 
Patients with gross positive residual disease following surgery do not 
qualify as having disease-free status, and, therefore, such patients are not 
eligible to register for adjuvant therapy.  
• 
Patients with microscopic residual disease (i.e., positive margins) can be 
treated with re-excision or radiation, per site discretion, to render the 
patient disease-free prior to registration of adjuvant therapy. 
• 
Disease-free status must be documented by a complete physical 
examination and radiographic imaging studies within 42 days prior to Step 
3 registration.  Imaging studies must include a CT of the chest, abdomen, 
and pelvis (unless contraindicated).  Extremity melanomas must be 
imaged using CT with intravenous contrast or MRI with and without 
gadolinium. CT imaging must be done with intravenous contrast if there 
are no contraindications for it.   
• 
For patients with melanoma arising from the head and neck, dedicated 
neck imaging (CT with IV contrast, unless contraindicated) is required.   

 
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• 
If the patient has had unknown primary with disease in the axilla, neck 
imaging is required to assure the region is clear of cancer.   
• 
Any other clinically indicated imaging studies if performed (e.g., bone 
scan) must show no evidence of disease.  
 
b. 
Patients must be registered to Step 3 no more than 84 days after date of Surgery. 
 
c. 
Patients with R0 or R1 resections must have disease-free status documented by 
a complete physical examination and imaging studies within 42 days prior to Step 
3 Registration. These patients must have disease assessment by CT 
chest/abdomen/pelvis with IV contrast, and neck CT with IV contrast if primary 
head and neck melanoma. MRI combined with non-contrast CT is an acceptable 
alternative for patients with CT contrast allergy. 
 
d. 
Patients with R2 resections are not eligible for Step 3 and must be removed from 
study treatment per Section 7.4. 
 
 
6.0 
STRATIFICATION FACTORS 
 
Participants will be randomized between the Adjuvant arm and the Neoadjuvant arm in a 1:1 
fashion, using dynamic balancing. Stratification will be based on:  
 
1. 
Baseline LDH: Low/Normal ( institutional upper limit of normal) versus High (> institutional 
upper limit of normal) and  
 
2. 
Stage of disease at randomization:  IIIB* versus IIIC* versus IIID*/IV 
 
*Note: Based on clinical staging as outlined in Section 4.0. Participants who have only clinically 
occult lymph nodes, i.e. N1a-N3a, are not eligible. 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Sapna Patel at 713/792-2921 or 
Dr. Kenneth Grossmann at 801/213-8435 (or S1801SCquestion@swog.org).  For dosing principles 
or questions, please consult the SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" 
at https://www.swog.org/about/policies-procedures.  
 
7.1 
Supportive Care 
 
Patients should receive appropriate supportive care measures as deemed necessary by 
the treating investigator.  Suggested supportive care measures for the management of 
AEs with potential immunologic etiology are also outlined in the table in Section 8.2b.  
Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve 
with administration of corticosteroids.  Note that several courses of steroid tapering may 
be necessary as symptoms may worsen when the steroid dose is decreased.  For each 
disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab. 
 
NOTE:  If after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined below). 
 

 
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It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of the evaluation of the event. 
 
7.2 
Treatment 
 
a. 
Pre- pembrolizumab (MK-3475) Labs 
 
Blood collected for pretreatment laboratory tests must be collected and analyzed 
no more than 3 days prior to dosing. 
 
b. 
Surgery 
 
Participants must undergo surgical resection (lymphadenectomy or resection of in-
transit or distant metastasis +/- wide local excision, if applicable) of clinically 
detectable melanoma. Timing of surgery is dependent on treatment arm.  
 
For all participants, the S1801 Planned Surgery Form must be filled out prior to 
randomization and the S1801 Post-Surgery Form filled out post-surgery. Submit 
forms as indicated in Section 14.0.  
 
Pembrolizumab (MK-3475) timing after surgery is up to the discretion of the local 
investigator. Interval between surgery and start of adjuvant therapy should not 
exceed 84 days. 
 
c. 
Arm 1: Pembrolizumab (MK-3475) Adjuvant Arm 
 
Step 1: RANDOMIZATION 
 
Participants will be randomized. 
 
Step 2: SURGERY 
 
Participants on Adjuvant arm must be registered to Step 2 (Surgery) within 
17 days (preferably within 14 days) after randomization and must undergo 
surgical resection within 17 days (preferably within 14 days) after Step 2 
registration.  Radiation is allowed after surgery.  However, interval between 
Surgery and the start of Adjuvant therapy must not exceed 84 days. 
 
Step 3: ADJUVANT THERAPY 
 
It is recommended that participants be registered to and initiate treatment 
on Step 3 (Adjuvant therapy) within 17 days (preferably within 14 days) after 
surgery.  Radiation is allowed after surgery. However, interval between Surgery 
and start of Adjuvant therapy must not exceed 84 days. 
 
Agent 
Dose  
Schedule 
Route  
 
MK-3475 
200 mg 
IV 
 
Day 1, Q 3 weeks  
(pembrolizumab) 
 
over 30  
for 18 doses 
 
 
 
 
minutes  
 
 
Pembrolizumab (MK-3475) treatment should be administered after all procedures 
and assessments have been completed.  Pembrolizumab (MK-3475) treatment 
may be administered up to 3 days before or after the protocol-specified Q 3 weeks 
due to administrative reasons.   
 
Pembrolizumab (MK-3475) treatment will be administered on an outpatient basis. 

 
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Pembrolizumab (MK-3475) 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, participant vacation, and/or holidays). Participants 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 participant’s study record. 
 
All planned doses must be administered.  Missed doses must be made up. 
 
 

 
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d. 
Arm 2:  Pembrolizumab (MK-3475) Neoadjuvant Arm 
 
Step 1: RANDOMIZATION AND NEOADJUVANT THERAPY 
 
Agent 
Dose 
Route 
Schedule 
 
 
200 mg 
IV 
Day 1, Q 3 weeks  
MK-3475 
 over 30 
for 3 doses  
followed  
(pembrolizumab) 
 
minutes 
by surgical resection. 
 
 
Participants will receive 3 doses of pre-operative (MK-3475) pembrolizumab 
Administration of less than 3 doses of pre-operative pembrolizumab (MK-3475) 
may be allowed in cases of progressive disease requiring surgery or due to toxicity. 
This must be discussed with the Study Chair for approval. No additional doses of 
pre-operative pembrolizumab (MK-3475) treatment beyond 3 doses may be given.  
 
Pembrolizumab (MK-3475) treatment should be administered after all procedures 
and assessments have been completed.  Pembrolizumab (MK-3475) treatment 
may be administered up to 3 days before or after the protocol-specified Q 3 weeks 
due to administrative reasons.   
 
Pembrolizumab (MK-3475) treatment will be administered on an outpatient basis. 
 
Pembrolizumab (MK-3475) 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, participant vacation, and/or holidays). Participants 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 participant's study record. 
 
All planned doses must be administered.  Missed doses must be made up. 
 
Step 2: SURGERY: 
 
Surgery should be arranged prior to Step 2 registration.  It is recommended that 
participants undergo Surgery within 3 weeks after the last dose of pembrolizumab 
(MK-3475). 
 
Note: participants must be registered to Step 2 (Surgery) before surgery is 
performed. 
 
If participants are unable to undergo Surgery by Week 12 due to development of 
irAE or an unrelated event such as intercurrent medical illness or life event, 
additional doses of pre-operative pembrolizumab (MK-3475) must be discussed 
with the Study Chair for approval with a plan to reschedule Surgery at the safest 
and earliest time point. Inability to coordinate Surgery by Week 12 with the 
local surgeon is not an acceptable reason to administer additional doses of 
pembrolizumab (MK-3475). 
 
 

 
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Step 3: ADJUVANT THERAPY 
 
It is recommended that participants be registered to and initiate treatment 
on Step 3 (Adjuvant therapy) within 17 days (preferably within 14 days) after 
surgery.  Radiation is allowed after surgery. However, interval between Surgery 
and start of Adjuvant therapy must not exceed 84 days. 
 
Agent 
Dose 
Route 
Schedule 
 
MK-3475 
200 mg 
IV 
Q 3 weeks 
(pembrolizumab) 
 
over 30 
for 18 doses total 
 
minutes  
(pre-operative 
doses 
+ 
post-operative doses) 
 
 
Pembrolizumab (MK-3475) is to be resumed after surgery and continued every 3 
weeks x 15 doses for a total of 18 doses (neoadjuvant + adjuvant). 
 
Pembrolizumab (MK-3475) treatment should be administered after all procedures 
and assessments have been completed.  Pembrolizumab (MK-3475) treatment 
may be administered up to 3 days before or after the protocol-specified Q 3 weeks 
due to administrative reasons.   
 
Pembrolizumab (MK-3475) treatment will be administered on an outpatient basis. 
 
Pembrolizumab (MK-3475) 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, participant vacation, and/or holidays). Participants 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 participant's study record. 
 
All planned doses must be administered.  Missed doses must be made up. 
 
7.3 
Prohibited and Cautionary Medications 
 
• 
Anti-cancer systemic chemotherapy or biological therapy.  
• 
Immunotherapy not specified in this protocol. 
• 
Any non-study anti-cancer agent (investigational or non-investigational). 
• 
Investigational agents other than pembrolizumab (MK-3475). 
• 
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. 
• 
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. 
 
 

 
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Participants 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.  Participants may receive other medications that the investigator deems to be 
medically necessary. 
 
7.4 
Follow-Up Disease Assessment Schedule 
 
The same imaging modality as used at prestudy for disease assessment (see Section 
5.1.c) must be used throughout the study.  
 
For 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. Extremity 
melanomas must be imaged using CT with intravenous contrast or MRI with and without 
gadolinium. 
 
Neoadjuvant participants must undergo disease assessments after the 3rd pre-operative 
dose/before surgery (Weeks 7-12, timing per site discretion). Disease assessments then 
occur every 12 weeks thereafter until participant receives surgery or has progression of 
disease before surgery such that the participant cannot receive the planned surgery. 
 
Following surgery, disease-free status must be documented within 42 days prior to step 3 
registration, using the same modalities as prestudy. If the interval between scans and 
Adjuvant therapy exceeds 42 days, repeat imaging must be obtained.  
 
Disease assessments will then continue every 12 weeks (+/- 2 weeks) until relapse or 2 
years from randomization and timed from prior imaging. Participants who are still relapse-
free will then have disease assessments performed every 6 months (± 4 weeks) until 
relapse or 5 years from randomization.  
 
In the case of a variation in scan schedule due to early or missed or delayed scans, the 
subsequent scan is to be scheduled at the appropriate interval from the date of prior total 
body scan.  
 
During treatment and follow-up (through year 5), brain MRI/CT must be repeated annually 
(± 4 weeks); for years 6 through 10, brain MRI/CT to be performed annually as clinically 
indicated.  If there is a gadolinium allergy, or MRI brain intolerable for the participant, CT 
with iodinated IV contrast is adequate brain imaging. Brain imaging is required for 
participants with progressive disease. 
 
7.5 
Criteria for Removal from Protocol Treatment 
 
a. 
Progression of disease per RECIST 1.1 or requires additional surgery (as defined 
in Section 10.0). Progression of disease that maintains the ability to undergo the 
planned surgery is not a criterion for removal from treatment. 
 
b. 
Relapse of disease after surgery (as defined in Section 10.0). 
 
c. 
Unacceptable toxicity.  
 
d. 
The investigator may discontinue treatment if they determine that the participant’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. 
 
 

 
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e. 
Participant’s surgical margins note R2 resection. 
 
f. 
Positive pregnancy test in a female participant 
 
g. 
Completion of protocol treatment. 
 
h. 
Participants will be removed from protocol treatment if there is a treatment delay > 
84 consecutive days for any reason. 
 
i. 
The participant may withdraw from the study at any time for any reason. 
 
7.6 
Full CDUS Reporting Requirement 
 
Because this study contains an investigational drug for which CTEP holds the IND, it falls 
under CTEP requirements for full reporting.  This involves required submission of cycle-
specific toxicity and dose information (see Section 14.4, the S1801 Treatment Form, and 
the S1801 Adverse Event Form).  A cycle is defined as 21 days. 
 
7.7 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice. 
 
7.8 
Follow-Up Period, End of Study 
 
Randomized participants will be followed until death or 10 years after randomization, 
whichever occurs first. 
 
 
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 
General Considerations 
a. 
Missed doses of MK-3475 should be made up. 
 
b. 
Refer to Section 7.1 and 8.3a for supportive care information for pembrolizumab.  
 
c. 
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. 
 
 

 
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8.3 
Dose Modification Considerations for Participants Receiving pembrolizumab (MK-3475)  
 
Pembrolizumab must be withheld for drug-related toxicities and severe or life-threatening 
AEs as described in the tables below. 
 
Adverse events (both nonserious and serious) 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 
study 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 bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids.   
 
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 for irAEs and infusion 
reactions associated with pembrolizumab are provided in the table below. 
 
NOTE that non-irAEs will be managed as appropriate, following clinical practice 
recommendations. 
 
 
 

 
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a. 
Dose Modification and Toxicity Management for Immune-related Adverse Events Associated with Pembrolizumab   
 
Table 1 Dose Modification and Toxicity Management Guidelines for Immune-related AEs and Infusion Reactions Associated 
with Pembrolizumab  
General instructions: 
1. For non-endocrine-related severe and life-threatening irAEs, investigators should consider the use of IV 
corticosteroids followed by oral steroids.  Other immunosuppressive treatment should begin if the irAEs are not 
controlled by corticosteroids.  Some non-endocrine irAEs do not require steroids.  For example, celiac disease 
induced by pembrolizumab can be controlled by diet alone. 
2. For non-endocrine-related toxicities, 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. Generally, when corticosteroids are used, investigators should begin a taper when the irAE is ≤Grade 1 and continue 
at least 4 weeks. 
4. If pembrolizumab has been withheld due to a non-endocrine irAE, pembrolizumab may generally resume after the 
irAE has decreased to ≤Grade 1 after a corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab  
Corticosteroid and/or other 
therapies  
Monitoring and follow-
up  
Pneumonitis  
Grade 2 
Withhold  
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg prednisone or 
equivalent) followed by 
taper 
Add prophylactic antibiotics 
for opportunistic infections 
 
Monitor participants for 
signs and symptoms 
of pneumonitis 
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 
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg prednisone or 
equivalent) followed by 
taper 
Monitor participants for 
signs and symptoms 
of enterocolitis (i.e., 
diarrhea, abdominal 
pain, blood or mucus 
in stool with or 

 
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Recurrent Grade 
3 or Grade 4 
Permanently 
discontinue 
Patients who do not respond 
to corticosteroids should 
be seen by a 
gastroenterologist for 
confirmation of the 
diagnosis and 
consideration of 
secondary immune 
suppression 
 
 
without fever) and of 
bowel perforation 
(i.e. peritoneal signs 
and ileus) 
Specifically assess for 
celiac disease 
serologically, and 
exclude Clostridium 
difficile infection 
Participants with ≥Grade 
2 diarrhea 
suspecting 
enterocolitis should 
consider GI 
consultation and 
performing 
endoscopy to rule 
out enterocolitis and 
assess mucosal 
severity 
Participants with 
diarrhea/colitis 
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 
Administer corticosteroids 
(initial dose of 0.5 to 1 
mg/kg prednisone or 
equivalent) followed by 
taper 
Monitor with liver 
function tests 
(consider weekly or 
more frequently until 
liver enzyme value 

 
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Grade 3 b or 4 c 
Permanently 
discontinue 
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg prednisone or 
equivalent) followed by 
taper 
returned to baseline 
or is stable) 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
Grade 1 or 2 
Continue 
 
Investigate for 
diabetes.  In the 
absence of 
corticosteroids or 
diabetes medication 
non-adherence, any 
grade hyperglycemia 
may be an indication 
of beta-cell 
destruction and 
pembrolizumab-
induced diabetes 
akin to type 1 
diabetes.  This 
should be treated as 
a Grade 3 event.  
Given this risk, 
exercise caution in 
utilizing non-insulin 
hypoglycemic agents 
in this setting.  After 
a thorough 
investigation of other 
potential causes, 
which may involve a 
referral to an 
endocrinologist, 
follow institutional 
guidelines. 
 

 
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New onset T1DM 
(evidence of -cell 
failure) or  
Grade 3 or 4 
hyperglycemia 
Withhold d 
Resume 
pembrolizumab 
when symptoms 
resolve and glucose 
levels are stable 
Initiate treatment with insulin 
If patient is found to have 
diabetic ketoacidosis or 
hyperglycemic 
hyperosmolar syndrome, 
treat as per institutional 
guidelines with 
appropriate management 
and laboratory values 
(e.g. anion gap, ketones, 
blood pH, etc.) reported 
 
Monitor for glucose 
control 
Strongly consider 
referral to 
endocrinologist 
Obtain C-peptide 
level paired with 
glucose, 
autoantibody levels 
(e.g. GAD65, islet 
cell autoantibodies), 
and hemoglobin A1C 
level 
 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids and 
initiate hormonal 
replacements as clinically 
indicated 
Monitor for signs and 
symptoms of 
hypophysitis 
(including 
hypopituitarism and 
adrenal insufficiency) 
Provide adrenal 
insufficiency 
precautions including 
indications for stress 
dose steroids and 
medical alert jewelry 
Strongly consider referral 
to endocrinologist 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Consider 
withholding. 
Resume 
pembrolizumab 
when symptoms are 
controlled, and 
thyroid function is 
improving 
Treat with nonselective beta-
blockers (e.g., 
propranolol) or 
thionamides as 
appropriate 
Initiate treatment with anti-
thyroid drug such as 
Monitor for signs and 
symptoms of thyroid 
disorders 
Strongly consider referral 
to endocrinologist 
 

 
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Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
methimazole or 
carbimazole as needed 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
Initiate thyroid replacement 
hormones (e.g., 
levothyroxine or 
liothyronine) per standard 
of care 
Monitor for signs and 
symptoms of thyroid 
disorders 
Nephritis: 
grading according to 
increased creatinine 
or acute kidney 
injury 
Grade 2 
Withhold 
Administer corticosteroids 
(prednisone 1 to 2 mg/kg 
or equivalent) followed by 
taper 
Monitor changes of renal 
function 
Strongly consider referral 
to nephrologist 
Grade 3 or 4 
Permanently 
discontinue 
Cardiac Events 
(including 
myocarditis, 
pericarditis, 
arrhythmias, 
impaired ventricular 
function, vasculitis) 
Asymptomatic 
cardiac enzyme 
elevation with 
clinical suspicion 
of myocarditis 
(previously 
CTCAE v4.0 
Grade 1), or 
Grade 1 
Withhold 
Based on severity of AE 
administer corticosteroids 
 
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other 
causes 
Strongly consider referral 
to cardiologist and 
cardiac MRI 
Consider 
endomyocardial 
biopsy 
If event resolves to 
Grade 1 or better, 
taper corticosteroids 
over ≥1 month 

 
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Grade 2, 3 or 4 
Permanently 
discontinue 
Initiate treatment with 
corticosteroids equivalent 
to 1-2 mg/kg/day IV 
methylprednisolone and 
convert to 1-2 mg/kg/day 
oral prednisone or 
equivalent upon 
improvement 
If event does not improve 
within 48 hours after 
initiating corticosteroids, 
consider adding an 
immunosuppressive agent 
Initiate treatment per 
institutional guidelines 
and consider 
antiarrhythmic drugs, 
temporary pacemaker, 
extracorporeal membrane 
oxygenation (ECMO), 
ventricular assist device 
(VAD), or 
pericardiocentesis as 
appropriate 
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other 
causes 
Strongly consider referral 
to cardiologist and 
cardiac MRI 
Consider 
endomyocardial 
biopsy 
If event resolves to 
Grade 1 or better, 
taper corticosteroids 
over ≥1 month 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
Based on severity of AE 
administer corticosteroids 
Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes 
Strongly consider referral 
to dermatologist 
Consider skin biopsy for 
evaluation of etiology 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All Other irAEs 
Persistent Grade 
2 
Withhold 
Based on severity of AE 
administer corticosteroids 
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 

 
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AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology 
Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; ECMO=extracorporeal membrane 
oxygenation; GI=gastrointestinal; ICU=intensive care unit; IO=immuno-oncology; ir=immune related; IV=intravenous; 
MRI=magnetic resonance imaging; PO=per os; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; 
TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal; VAD=ventricular assist device. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN 
if baseline normal; >3.0 to 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: encephalitis and other clinically important irAEs (e.g. 
vasculitis and sclerosing cholangitis). 
____________________________________________________________________________________________________ 
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. 
 
 
 
b. 
Management of Infusion Reactions  
 
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 patients who experience an infusion reaction associated with administration of 
pembrolizumab (MK-3475) 
 
 

 
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Table 2 Pembrolizumab (MK-3475) Infusion Reaction Treatment Guidelines 
 
Infusion Reactions 
NCI CTCAE 
Grade 
Treatment  
Premedication at 
subsequent dosing 
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated 
  
Grade 1 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
Requires therapy or 
infusion interruption 
but responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, 
IV fluids); 
prophylactic 
medications 
indicated for ≤24 
hrs. 
Grade 2 
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. 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 
Participant 
may 
be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
study intervention with: 
Diphenhydramine 50 mg PO 
(or 
equivalent 
dose 
of 
antihistamine). 
Acetaminophen 500-1000 
mg PO (or equivalent dose 
of analgesic). 

 
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Infusion Reactions 
NCI CTCAE 
Grade 
Treatment  
Premedication at 
subsequent dosing 
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 3 
Stop Infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids (e.g. methylprednisolone 2 
mg/kg/day or dexamethasone 10 mg every 6 
hours) 
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. 
 

 
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Infusion Reactions 
NCI CTCAE 
Grade 
Treatment  
Premedication at 
subsequent dosing 
Life-threatening; 
pressor or ventilator 
support indicated 
 
Grade 4 
Admit participant to intensive care unit (ICU) and 
initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as 
needed. Monitor other organ function closely. 
Manage constitutional symptoms and organ 
toxicities as per institutional practice. 
Follow Grade 3 recommendations as applicable. 
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. 
 
 
 

 
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c. 
Management of Neurological Toxicities  
 
Table 3 Neurological Toxicities 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
• 
Continue pembrolizumab. 
• 
Investigate etiology. 
• 
Any cranial nerve disorder (including facial paresis) should be managed as per Grade 2 
management guidelines below. 
Immune-mediated 
neuropathy, including 
facial paresis, Grade 2 
• 
Withhold pembrolizumab for up to 12 weeks after event onset. a 
• 
Investigate etiology and refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
For general immune-mediated neuropathy: 
o 
If event resolves to Grade 1 or better, resume pembrolizumab. b 
o 
If event does not resolve to Grade 1 or better while withholding pembrolizumab, 
permanently discontinue pembrolizumab. c 
• 
For facial paresis: 
o 
If event resolves fully, resume pembrolizumab. b 
o 
If event does not resolve fully while withholding pembrolizumab, permanently 
discontinue pembrolizumab. c 
Immune-mediated 
neuropathy, including 
facial paresis, Grade 3 
or 4 
• 
Permanently discontinue pembrolizumab. c  
• 
Refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
Myasthenia gravis and 
Guillain-Barré 
syndrome (any grade) 
• 
Permanently discontinue pembrolizumab. c 
• 
Refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
Consider initiation of corticosteroids equivalent to 1−2 mg/kg/day oral or IV prednisone. 
 
a Pembrolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on an assessment of benefit−risk by the investigator and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone 
before pembrolizumab can be resumed. 
c Resumption of pembrolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event.  The decision to re-challenge patients with pembrolizumab should be based on investigator's 
assessment of benefit−risk and documented by the investigator (or an appropriate delegate). 
 

 
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Event 
Management 
Immune-mediated 
myelitis, Grade 1 
• 
Continue pembrolizumab unless symptoms worsen or do not improve. 
• 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated 
myelitis, Grade 2 
• 
Permanently discontinue pembrolizumab.  
• 
Investigate etiology and refer patient to a neurologist. 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral prednisone. 
Immune-mediated 
myelitis, Grade 3 or 4 
• 
Permanently discontinue pembrolizumab. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 
Event 
Management 
Immune-mediated 
meningoencephalitis, all 
grades 
• 
Permanently discontinue pembrolizumab. a 
• 
Refer patient to neurologist. 
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• 
If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 1 month. 
a Resumption of pembrolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event.  The decision to re-challenge patients with pembrolizumab should be based on investigator's 
assessment of benefit−risk and documented by the investigator (or an appropriate delegate). 
 

 
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8.4 
Anti-infectives 
 
Participants 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.  
 
8.5 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact Dr. Sapna Patel at 713/792-
2921 or S1801SCquestion@swog.org or if Dr. Patel is not available, please contact Dr.  
Grossmann at 813/745-3437.  For dosing principles or questions, please consult the 
SWOG 
Policy 
#38 
"Dosing 
Principles 
for 
Patients 
on 
Clinical 
Trials" 
at 
https://www.swog.org/about/policies-procedures 
 
8.6 
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 CALENDAR 
 
9.1  
Pembrolizumab (MK-3475) Adjuvant Arm 
REQUIRED STUDIES 
Pre-Study 
STEP 1: 
Random-
ization 
STEP 2: 
Surgery * 
STEP 3: ADJUVANT PEMBROLIZUMAB 
(MK-3475)  
ON TREATMENT 
Infusions to be given q 3 weeks (+/- 3 days) 
for 18 total infusions  
End of 
Treatment 
Assessment 
Off 
treatment 
F/U prior to 
progression/ 
relapsec 
F/U post 
relapsed 
PHYSICAL 
 
 
 
C1 
C2 
C3 
C4 
C5 
C6g 
C18 
 
 
History, PS & Physical a 
(w/BP, Height & Weight) t  
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Toxicity Notation h 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY e 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Diff, 
Comprehensive 
Metabolic Panel a 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
LDH 
X 
 
 
 
 
 
 
 
 
 
 
X 
TSH, Free T4 o 
X  
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testi 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Cardiac Functionv  
 
 
 
 
 
 
 
 
 
 
 
 
X-RAYS AND SCANS 
Please refer to footnotes j and k for details on the timing of scans. 
CT neck j, chest, 
abdomen & pelvis k 
X 
 
 
 
 
 
 
 
 
 
 
 
Brain MRI or CT with 
contrast l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study Calendar 9.1 continued on next page. Click here for footnotes. 
 
 

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REQUIRED STUDIES 
Pre-Study 
STEP 1: 
Randomi-
zation 
STEP 2: 
Surgery * 
STEP 3: ADJUVANT PEMBROLIZUMAB (MK-
3475)  
ON TREATMENT 
Infusions to be given q 3 weeks (+/- 3 days) 
for 18 total infusions  
End of 
Treatment 
Assessment 
Off 
treatment 
F/U prior to 
progressio
n /  
relapsec 
F/U post 
relapsed 
 
 
 
 
C1 
C2 
C3 
C4 
C5 
C6g 
C18 
 
 
SPECIMEN 
SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue m,n for banking  
 
 
 
X 
 
 
 
 
 
 
 
X 
Whole Blood for banking 
m,n 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
Surgical Resection 
 
 
X 
 
 
 
 
 
 
 
 
 
 pembrolizumab (MK-
3475)  
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Click here for footnotes. 
 
NOTE: Forms are found on www.ctsu.gov. 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/2019-06/Best%20Practices_6.19.pdf.  
 
 
 

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9.2  
Pembrolizumab (MK-3475) Neoadjuvant Arm 
 
REQUIRED STUDIES 
Pre- 
Study 
ON TREATMENT a 
Infusions to be given q 3 weeks (+/- 3 days) for 18 total infusions  
End of 
treatment 
assessment 
Off 
 treatment F/U 
prior to 
progression/ 
relapsec 
F/U post 
progression/ 
relapsed 
                    
 
STEP 1: 
NEOADJUVANT 
pembrolizumab 
(MK-3475)  
STEP 2: 
SURGERY ** 
STEP 3: 
ADJUVANT MK-3475 
(PEMBROLIZUMAB 
 
 
 
PHYSICAL 
 
C1 
C2 
C3 
Surgery 
C
4 
C
5 
C
6 
C
7 
C8 
C18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History, PS, & Physical a 
(w/BP, Height & Weight) t  
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X  
 
Toxicity Notation h 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X  
LABORATORY e 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Diff, 
Comprehensive Metabolic 
Panel a 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
LDH 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
TSH, Free T4 o 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testi 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
Cardiac Functionv  
 
 
 
 
 
 
 
 
 
 
 
 
 
X-RAYS AND SCANS 
Please refer to footnotes j and k for details on the timing of scans. 
CT neck j, chest, 
abdomen & pelvis q  
X 
 
 
 
Xq 
 
 
 
 
 
 
 
 
Brain MRI or CT with 
contrast  q, l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Calendar 9.2 continued on next page.  Click here for footnotes. 
9.2 
Pembrolizumab (MK-3475) Neoadjuvant Arm (contd.) 
 
REQUIRED STUDIES 
Pre-
Study 
 
ON TREATMENT 
Infusions to be given q 3 weeks (+/- 3 days) for 18 total infusions w 
End of 
treatment 
assessment 
Off 
treatment F/U 
prior to 
progression/ 
relapsec 
F/U post 
progression/ 
relapsed 
 
 
STEP 1: 
NEOADJUVANT 
pembrolizumab 
(MK-3475)  
STEP 2: 
SURGERY ** 
STEP 3: 
ADJUVANT PEMBROLIZUMAB (MK-
3475)  
 
 
 
 
 
C1 
C2 
C3  
Surgery 
C4 
C5 
C6g 
C7 
C8 
C18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPECIMEN 
SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue for assessing 
Pathologic Response 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Tissue m,n for banking  
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole Blood  for 
banking m,n  
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
MK-3475 w  
(pembrolizumab) 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Surgical Resection 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Click here for footnotes. 
 
NOTE:  :  Forms are found on www.ctsu.gov.  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/2019-06/Best%20Practices_6.19.pdf.   

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Footnotes for Study Calendars 
* Participants on Adjuvant arm must be registered to Step 2 (Surgery) within 17 days (preferably within 14 days) after randomization and must undergo 
surgical resection within 17 days (preferably within 14 days) after Step 2 registration.  Interval between surgery and start of adjuvant therapy must not 
exceed 84 days. 
** Participants on Neoadjuvant arm should: receive 3 doses of neoadjuvant (pre-operative) pembrolizumab (MK-3475) prior to registration to Step 2; arrange 
surgery before registration to Step 2; and register to Step 2 within 4 weeks after the last neoadjuvant dose of pembrolizumab (MK-3475).  Administration of 
less than 3 doses of pre-operative pembrolizumab (MK-3475) must be discussed with the Study Chair for approval.    
 
a. Following exams & labs are performed prior to receiving first dose and prior to every cycle until end of protocol treatment: physical (including BP & WT), PS, toxicity 
notation, CBC with differential (including ANC) and Comprehensive Metabolic Panel (Na, K, HC03 or CO2, Serum creatinine or CrCl, non-fasting glucose, 
albumin, total bilirubin, AST, ALT, alkaline phosphatase).  
c. Post-treatment follow-up (prior to relapse):  Participants should be seen at 3 weeks (-/+ 1 week) after the last dose, then 12 weeks (-/+ 1 week) after the last 
dose, then every 3 months (+/- 2 weeks) if participant is < 2 years from study entry, every 6 months (+/- 4 weeks) if participant is 2-5 years from study entry, 
and every 12 months (+/- 4 weeks) if participant 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 (including BP & wt), and 
PS. For post-treatment follow-up regarding scans, see footnote k. 
d. Follow-up post progression/relapse: Participants who develop recurrent melanoma or who have progression of disease such that the participant cannot 
receive their planned surgery or require additional surgery will be followed for survival (vital status). Participants should be followed every 6 months for up to 
2 years from the date of progression/relapse, then annually thereafter until 10 years from treatment randomization. 
e. While on study, blood collected for pretreatment laboratory tests must be collected and analyzed no more than 3 days prior to dosing. NOTE: if pembrolizumab 
(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. 
g. Treatment and visits should continue at these intervals through Cycle 18. 
h Adverse Event Assessments on the study will continue for all participants until 30 days after the last study drug administration. However, participants with 
ongoing toxicities should be seen more often as clinically indicated. 
i. Women of child bearing potential must have a negative serum or urine pregnancy test at screening within 28 days prior to randomization. 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.  A pregnancy test should be 
done at any time there are clinical concerns for possible pregnancy.   
j. Participants 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 CT chest/abdomen/pelvis (or MRI if CT cannot be done), and neck CT as needed will be performed within 42 days (+/- 1 week) 
before surgery, and every 12 weeks (+/- 2 weeks) from the start of Adjuvant therapy until 2 years from randomization, then every 6 months (± 4 weeks) until 
5 years from randomization, then follow for survival. In the case of a variation in scan schedule due to early or missed or delayed scans, the following scan is 
to be scheduled at the appropriate interval from the date of prior scan. If the interval between scans and Adjuvant therapy exceeds 42 days, repeat imaging 
must be obtained.  The same imaging modality as used at prestudy for disease assessment should be used throughout the trial.  If there is a contra-indication 
to iodine, non-contrast chest CT and MRI of abdomen/pelvis with gadolinium are acceptable body imaging alternatives. Extremity melanomas must be imaged 
using CT with intravenous contrast or MRI with and without gadolinium. 
Note: PET-CT scans are NOT acceptable to establish eligibility. 
 
 

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(k. continued) 
NOTE: If the disease assessment was completed within the last 42 days between the post-cycle 3 scan and registration for Step 3 (Adjuvant therapy), scans do 
not need to be repeated. If more than 42 days have elapsed between the post-cycle 3 scan and registration for Step 3 (Adjuvant therapy), scans must be 
repeated.  
 
l  During treatment and follow-up (through year 5), brain MRI/CT must be repeated annually (± 4 weeks); for years 6 through 10, brain MRI/CT to be performed 
annually as clinically indicated.  If there is a gadolinium allergy, or MRI brain intolerable for the participant, CT with iodinated IV contrast is adequate brain 
imaging. Brain imaging is required for participants with progressive disease. 
 
m If participant consents, submit specimens for banking as specified in Section 15.2.  
n. Blood needs to be drawn prior to treatment. 
o. TSH (with a reflex to free T4) to be done at baseline on the same day of treatment (but prior to administration) and then as clinically indicated while on protocol 
treatment. 
q. Neoadjuvant participants must undergo disease assessments and tumor measurements via RECIST 1.1 at baseline and after the 3rd pre-operative dose/before 
Surgery (Weeks 7-12, timing per site discretion). Disease assessments then occur every 12 weeks thereafter until 2 years from randomization, then every 6 
months ( 4 weeks) until 5 years from randomization, then follow for survival. In the case of a variation in scan schedule due to early or missed or delayed 
scans, the following scan is to be scheduled at the appropriate interval from the date of prior total body scan. If the interval between scans and the start of 
Adjuvant therapy exceeds 42 days, repeat imaging must be obtained.  The same imaging modality as used at prestudy for disease assessment should be 
used throughout the trial.  If there is a contra-indication to iodine, non-contrast chest CT and MRI of abdomen/pelvis with gadolinium are acceptable body 
imaging alternatives. Extremity melanomas must be imaged using CT with intravenous contrast or MRI with and without gadolinium. 
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. 
v. Participants 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. Participants 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. 
w. Neoadjuvant Arm:  pembrolizumab (MK-3475) 200 mg flat dosing IV every 3 weeks for 3 doses followed by surgical resection. Post-operative dosing every 3 
weeks x 15 doses (18 doses total). 
 
 

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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
10.1 
Measurability of lesions 
 
a. 
Measurable disease: Measurable disease is defined differently for lymph nodes 
compared with other disease and will be addressed in a separate section below. 
 
1. 
Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 2.0 cm by chest x-ray, by ≥ 1.0 cm 
with CT or MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All tumor 
measurements must be recorded in decimal fractions of centimeters (or 
millimeters). 
 
The defined measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 0.5 cm or less.  If CT scans have 
slice thickness greater than 0.5 cm, the minimum size for a measurable 
lesion should be twice the slice thickness.   
 
2. 
Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by scan 
(CT scan slice recommended being no greater than 0.5 cm). 
 
b. 
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to < 
1.5 cm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered non-measurable as are previously radiated 
lesions that have not progressed. 
 
c. 
Notes on measurability 
 
1. 
For CT and MRIs, the same type of scanner should be used, and the 
image acquisition protocol should be followed as closely as possible to 
prior scans.  Body scans should by performed with breath-hold scanning 
techniques, if possible.  
 
2. 
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  Therefore, PET-CT is not allowed as an imaging 
modality for S1801. Extremity melanomas must be imaged using CT with 
intravenous contrast or MRI with and without gadolinium. 
 
3. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
 
4. 
Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable 
nor non-measurable) since they are, by definition simple cysts. 
 
5. 
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure.  If the lesion is actually still present, a default 
measurement of 0.5 cm should be applied.  If the radiologist believes the 
lesion has gone, a default measurement of 0.0cm should be recorded. 
 
 

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10.2 
RECIST Objective status at each disease evaluation:   
 
Objective Status is to be recorded at each evaluation. All measurable lesions up to a 
maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline. All other lesions (or sites of disease) 
including any measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions.  Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-measurable 
disease. 
 
For studies that use disease progression as an endpoint, whole body scanning at specific 
intervals is necessary to determine that progression is NOT present outside of the “target” 
areas. Therefore, in these studies it is not acceptable to image only the “target” areas of 
the body in follow-up scans. For study-specific imaging requirements, see the Study 
Calendar in Section 9.0.   
 
a. 
Complete Response (CR):  Complete disappearance of all target and non-target 
lesions (with the exception of lymph nodes mentioned below).  No new lesions.  
No disease related symptoms.   Any lymph nodes (whether target or non-target) 
must have reduction in short axis to < 1.0 cm.  All disease must be assessed using 
the same technique as baseline. 
 
b. 
Partial Response (PR): Applies only to participants with at least one measurable 
lesion. Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target measurable 
lesions must be assessed using the same techniques as baseline. 
 
c. 
Stable: Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline. 
 
d. 
Progression: One or more of the following must occur:  20% increase in the sum 
of appropriate diameters of target measurable lesions over smallest sum observed 
(over baseline if no decrease during therapy) using the same techniques as 
baseline, as well as an absolute increase of at least 0.5 cm.  Unequivocal 
progression of non-measurable disease in the opinion of the treating physician (an 
explanation must be provided).   Appearance of any new lesion/site.  Death due to 
disease without prior documentation of progression and without symptomatic 
deterioration (see Section 10.2e). 
 
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.   
 
e. 
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation. 
 

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f. 
Assessment inadequate, objective status unknown.  Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment methods 
were used. 
 
g. 
Objective status notes 
 
1. 
Non-measurable and non-target measurable disease do not affect 
Objective Status in determination of CR (must be absent--a participant 
who otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR). However, non-measurable and non-target lesions are included in 
determination of progression (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician).  
 
2. 
An objective status of PR or stable cannot follow one of CR.  Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds. 
 
3. 
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression.   
 
4. 
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed.  
 
5. 
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. 
 
6. 
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 participant could alter the size of 
the effusion.  
 
7. 
If CR determination depends on a lesion for which the status is unclear by 
the required tests, it is recommended the residual lesion be investigated 
with biopsy or fine needle aspirate. 
 
10.3 
RECIST Best Response.  This is calculated from the sequence of objective statuses. 
 
a. 
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration. 
 
b. 
PR: Two or more objective statuses of PR or better a minimum of four weeks apart 
documented before progression or symptomatic deterioration, but not qualifying as 
CR. 
 
c. 
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
 

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d. 
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
 
e. 
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above. 
 
f. 
Increasing disease:  Objective status of progression within 12 weeks of 
registration, not qualifying as anything else above.   
 
g. 
Symptomatic deterioration: Objective status of symptomatic deterioration within 12 
weeks of registration, not qualifying as anything else above.   
 
h. 
Inadequate assessment, response unknown:  Progression or symptomatic 
deterioration greater than 12 weeks after registration and no other response 
category applies. 
 
10.4 
Progression before surgery 
 
a. 
Progression of disease per RECIST 1.1 before surgery such that the participant 
cannot receive the planned surgery or requires additional surgery. 
 
Note:  Progression of disease that maintains the ability to undergo the planned 
surgery is not criteria for removal from treatment. 
 
10.5 
Relapse after surgery 
 
Appearance of any new metastatic lesion/site.   
 
a. 
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. 
 
b. 
Any enlargement in lymph nodes >1 cm in short axis and >50% from baseline must 
be biopsied to rule out relapse of disease. 
 
c. 
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 
participant 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. 
 
 

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10.6 
Pathologic Response 
 
In prior studies using neoadjuvant targeted (BRAF/MEK inhibitor) and neoadjuvant immune 
checkpoint blockade therapy, previously agreed upon standard definitions of pathologic 
response are: 
 
• 
Complete pathologic response (path CR): the complete absence of viable tumor 
cells in the surgically resected post-treatment specimen. 
 
• 
Partial pathologic response (path PR): admixture of viable tumor cells but these 
comprise less than 50% of the treated tumor bed surface area together with 
evidence of treatment effect, including necrosis, fibrosis, and a lymphohistiocytic 
inflammatory infiltrate including aggregates of pigmented macrophages (tumoral 
melanosis). 
 
• 
Pathologic non-response (path NR): admixture of viable tumor cells and these 
comprise greater than 50% of the treated tumor bed surface area together with 
evidence of treatment effect, including necrosis, fibrosis, and a lymphohistiocytic 
inflammatory infiltrate including aggregates of pigmented macrophages (tumoral 
melanosis). 
 
10.7 
iRECIST Objective status at each disease evaluation: 
 
Objective Status is to be recorded at each evaluation. All measurable lesions up to a 
maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline All other lesions (or sites of disease) 
including any measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions. Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-measurable 
disease.  
 
New lesions: All measurable lesions not present at baseline up to a maximum of 2 lesions 
per organ 5 lesions in total, representative of all involved organs, should be identified as 
new target lesions (NTL). All other new lesions (not present at baseline) including any 
measurable new lesions over and above the 5 new target lesions should be identified as 
new lesions, non-target (NLNT). Measurements must be provided for NTL, while presence 
or absence must be noted for NLNT.  
 
a. 
Complete Response (CR):  Complete disappearance of all target and non-target 
lesions (with the exception of lymph nodes mentioned below).  No new lesions.  
No disease related symptoms.   Any lymph nodes (whether target or non-target) 
must have reduction in short axis to < 1.0 cm.  All disease must be assessed using 
the same technique as baseline. 
 
b. 
Partial Response (PR): Applies only to participants with at least one measurable 
lesion. Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target measurable 
lesions must be assessed using the same techniques as baseline. 
 
c. 
Stable: Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline. 
 
 

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d. 
Immune-related Unconfirmed Progression (iUPD): One or more of the following 
must occur:  20% increase in the sum of appropriate diameters of target lesions 
over smallest sum observed (over baseline or nadir) using the same techniques 
as baseline, as well as an absolute increase of at least 0.5 cm. Do not include the 
sum of diameters of NTL.  Unequivocal progression of non-measurable disease in 
the opinion of the treating physician (an explanation must be provided).   
Appearance of any new lesion/site.  Death due to disease without prior 
documentation of progression and without symptomatic deterioration. 
 
Notes regarding new lesions:  FDG-PET imaging can complement regular scans 
in identifying new lesions according to the following algorithm.  
 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
progression based on a new lesion. 
 
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.   
 
e. 
Immune-related Confirmed Progression (iCPD): Can only be reported in the 
assessment immediately following iUPD. One or more of the following must occur: 
 
• 
An absolute increase of at least 0.5 cm in the sum of target lesions over 
the sum observed at iUPD. Do not include the sum of diameters of NTL  
• 
An absolute increase of at least 0.5 cm in the sum of NTL over the sum 
observed at iUPD. Do not include the sum of diameters of target lesions. 
• 
Clear worsening of unequivocal progression of non-measurable disease 
in the opinion of the treating physician as documented at iUPD (an 
explanation must be provided). 
• 
Unequivocal progression, in the opinion of the treating investigator, of new 
non-target lesions (NNTL) initially documented at iUPD 
• 
Any additional cause of progression, as defined in 10.7a, that was not 
present at iUPD.  
 
f. 
Immune-related Complete Response (iCR): Can only occur after an assessment 
of iUPD, but not necessarily in the assessment immediately following iUPD. 
Cannot occur after iCPD. Complete disappearance of all lesions (with the 
exception of lymph nodes mentioned below). No new lesions. No disease related 
symptoms. Any lymph nodes (whether target, non-target, NTL, or NLNT) must 
have reduction in short axis to < 1.0 cm. All disease must be assessed using the 
same technique as baseline.   
 
g. 
Immune-related Partial Response (iPR): Can only occur after an assessment of 
iUPD, but not necessarily in the assessment immediately following iUPD. Cannot 
occur after iCPD. Applies only to participants with at least one measurable lesion 
at baseline. Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target lesions present at baseline. Do not include the 
sum of diameters of NTL.  No unequivocal progression of non-measurable 
disease.  No new lesions other than those documented at iUPD. No increase in 
the sum of diameters of NTL, or an increase of less than 0.5 cm.   All target lesions 
must be assessed using the same techniques as baseline. 
 
 

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h. 
Immune-related Stable Disease (iSD): Can only occur after an assessment of 
iUPD, but not necessarily in the assessment immediately following iUPD. Cannot 
occur after iCPD. Does not qualify for iCR, iPR, iUPD or Symptomatic 
Deterioration. All target measurable lesions must be assessed using the same 
techniques as baseline. 
  
i. 
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation. 
 
j. 
Assessment inadequate, objective status unknown.  Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment methods 
were used. 
 
10.8 
Objective status notes  
 
Non-measurable disease does not affect objective Status in determination of iCR (must be 
absent--a participant who otherwise has a iCR, but who has non-measurable disease 
present or not assessed, will be classified as having an iPR). However, non-measurable 
lesions are included in determination of iPD (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician). 
 
a. 
An objective status of iPR or irD cannot follow one of iCR. iSD can follow iPR only 
in the rare case that tumor increases too little to qualify as iPD, but enough that a 
previously documented 30% decrease no longer holds. 
 
b. 
In cases for which initial flare reaction is possible (hypercalcemia, increased bone 
pain, erythema of skin lesions), objective status is not iPD unless either symptoms 
persist beyond 4 weeks or there is additional evidence of progression. 
 
c. 
Lesions that appear to increase in size due to presence of necrotic tissue will not 
be considered to have progressed. 
 
d. 
For bone disease documented on bone scan only, increased uptake does not 
constitute unequivocal iPD. However, increase in the soft tissue component of a 
lesion as measured by CT or MRI would constitute ir-progression. 
 
e. 
Appearance of new pleural effusions does not constitute unequivocal iPD 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 iPD, since the fluid status of the participant could 
alter the size of the effusion.   
 
f. 
If iCR determination depends on a lesion for which the status is unclear by the 
required tests, it is recommended the residual lesion be investigated with biopsy 
or fine needle aspirate. 
 
10.9 
iRECIST Best Response 
 
This is calculated from the sequence of iRECIST objective statuses. (12)  
 
a. 
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before iUPD or symptomatic deterioration. 
 

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b. 
PR: Two or more objective statuses of PR or better a minimum of four weeks apart 
documented before iUPD or symptomatic deterioration, but not qualifying as CR. 
 
c. 
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
 
d. 
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
 
e. 
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before iUPD or symptomatic 
deterioration, but not qualifying as anything else above. 
 
f. 
iCR: Two or more objective statuses of iCR a minimum of four weeks apart 
documented before iCPD or symptomatic deterioration, but not qualifying as CR. 
 
g. 
iPR: Two or more objective statuses of iPR or better a minimum of four weeks 
apart documented before iCPD or symptomatic deterioration, but not qualifying as 
iCR, CR or PR. 
 
h. 
Unconfirmed iCR: One objective status of iCR documented before iCPD or 
symptomatic deterioration but not qualifying as CR, PR, unconfirmed CR, iCR or 
iPR. 
 
i. 
Unconfirmed iPR: One objective status of iPR documented before iCPD or 
symptomatic deterioration but not qualifying as CR, PR, unconfirmed CR, 
unconfirmed PR, iCR, iPR or unconfirmed iCR. 
 
j. 
iSD: At least one objective status of iSD before iCPD or symptomatic deterioration, 
but not qualifying as anything else above. 
 
k. 
iUPD:  Objective status of iUPD within 12 weeks of registration, before 
symptomatic deterioration or iCPD and not qualifying anything else above.  There 
can be multiple IUPD assessments with no iCPD when the original cause of iUPD 
persists and no new causes of progression appear. 
 
l. 
iCPD:  An objective status of iCPD, which must be documented a minimum of four 
weeks apart from and immediately follow an objective status of iUPD and must be 
documented before symptomatic deterioration.  
 
m. 
Symptomatic deterioration: Objective status of symptomatic deterioration within 12 
weeks of registration, not qualifying as anything else above. 
 
n. 
Inadequate assessment, response unknown: Progression or symptomatic 
deterioration greater than 12 weeks after registration and no other response 
category applies 
 
10.10 
Event-Free Survival  
 
Measured from date of randomization to date of first: documentation of progression that 
renders participant unable to receive planned protocol surgery, off protocol therapy for any 
reason without subsequent protocol surgery (with one exception noted below), failure to 
begin adjuvant therapy within 84 days after surgery, relapse after surgery or death due to 
any cause.  Participants last known to be alive and event-free are censored at date of last 
contact.  On both arms, all participants who do not register for adjuvant therapy (for 
whatever reason) will be assigned the event time of 84 days.   
 

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Patients treated on the neo-adjuvant arm who achieve an unconfirmed PR or CR (per 
RECIST 1.1) at the first protocol disease assessment and choose not to undergo protocol 
surgery will not be counted as an event if the PR or CR is confirmed prior to starting any 
non-protocol therapy other than pembrolizumab.  Such patients will not have an event 
when not receiving protocol surgery, and their EFS will be measured from the date of 
randomization to the first of relapse or death due to any causes with patients last known to 
be alive without relapse censored at the date of last contact.  All other patients who do not 
receive protocol surgery will be assigned the EFS event time of 84 days.  
 
10.11 
Length of disease control 
 
Measured from date of randomization to date of the first of the following events: 
progression such that the participant cannot receive protocol surgery, protocol surgery that 
does not render the participant disease-free, relapse after surgery that did render a 
participant disease-free, death due to any cause; participants last known to be alive without 
any of these events will be censored at the date of last contact. 
 
 
10.12 
Length of loco-regional control  
 
Measured from date of randomization to date of the first of the following events: 
progression such that the participant cannot receive protocol surgery, protocol surgery that 
does not render the participant disease-free, relapse at the primary site and pre-
randomization defined regional nodal basins after surgery that did render a participant 
disease-free; participants last known to be without any of these events will be censored at 
the date of death or date of recurrence outside of the primary site or pre-randomization 
defined nodal basin, whichever comes first. 
 
10.13 
Overall Survival   
 
Measured from date of randomization to date of death due to any cause.  Participants 
known to be alive are censored at date of last contact. 
 
10.14 
Performance Status 
 
Participants 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 
 
 
 

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11.0 
STATISTICAL CONSIDERATIONS 
 
11.1  
Accrual goals 
 
Based on S1404 accrual, 43% of S1404 participants would have been eligible for this 
neoadjuvant protocol.  S1404 has enrolled an average 80 participants/month.  Not all sites 
participating in S1404 will necessarily participate in this trial, so we anticipate that 
approximately 24 participants/month would enroll in this trial. 
 
11.2  
Analysis plan and sample size justification for primary objective 
 
Based on EFS trends in this participant population, we will use exponential-mixture cure 
models to describe EFS patterns in the arms.  Based on Weber 2017, we assume that on 
the adjuvant pembrolizumab (MK-3475) arm (null hypothesis) 60% participants will be long-
term survivors (or cured or not observed to have an event during the finite follow-up of the 
trial) and that median EFS for participants who are not long-term survivors will be 2 years.  
We power this study to detect an alternative EFS in the neoadjuvant arm with 70% of 
participants being long-term survivors and median EFS among those who are not long-
term survivors of 2.5 years.  We note that these survival patterns do not follow a 
proportional hazards assumption and that average hazard ratios from Cox models are 
expected to become more null with additional follow-up.   
 
We assume 1:1 randomization, accrual over 2 years, and up to10 years of follow-up after 
randomization. Under these assumptions the average hazard ratio under the alternative is 
0.64.  Under the alternative, with a sample size of 500 eligible participants (250/arm), 100% 
of expected events is 104 events across both arms.  At 50% of expected events (51 events, 
expected approximately when accrual completes), we will perform a futility test testing the 
alternative hazard ratio from a Cox regression model at the one-sided 2.5% level.  No 
formal interim test of efficacy will be performed.  Under the null hypothesis the probability 
of stopping early for futility is 45% and under the alternative is 2%.  The final analysis will 
consist of a log-rank test of the null hypothesis at the two-sided 15% level (expected 1.5 
years after accrual completes).  The power of this design is 81%.   
 
11.3  
Sample size re-design 
 
Because accrual to the study has been slower than anticipated, it is expected that 100% 
of events may be reached before accrual to the study completes, and so the total sample 
size of the study will be adjusted as follows. 
 
To account for the slower than anticipated accrual rate, a total of 336 eligible, randomized 
patients will be accrued.  If up to 1.5% of patients are not eligible, up to 342 patients will 
be registered.  With the same assumptions for EFS as in the original design, this design 
should have the same power as the original design using the same alpha.  We expect to 
reach full events within 6 months of completing accrual. 
 
11.4  
Secondary endpoints and analyses 
 
OS, local/regional control, and disease control will be estimated using the Kaplan-Meier 
method and compared between arms using log-rank tests and Cox regression models. 
Fisher’s exact test will be used to compare the number of pembrolizumab (MK-3475) doses 
received by participants on each treatment arm.  Pathologic response, RECIST 1.1 

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response rates, iRECIST response rates will be tabulated for the neoadjuvant arm and 
exact 95% confidence intervals will be constructed.  For each arm, 250 participants will be 
sufficient to estimate toxicity to within ± 6%.  Any toxicity occurring with at least 1% 
probability is likely to be seen at least once (99% probability).   
 
Primary analyses will all be intent-to-treat.  We will perform additional analyses per 
protocol, to understand how variation in treatment in the neoadjuvant arm can impact the 
analyses.   
 
 

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11.5  
Data and Safety Monitoring 
 
A Data and Safety Monitoring Committee will oversee the conduct of the 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 
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.  
 
After 20, 40, and 60 eligible participants are randomized to the neoadjuvant arm, the 
following proportions will be tabulated and provided to the DSMC: 1) proportion of 
participants who develop a higher disease stage (i.e., are upstaged) between 
randomization and surgery, 2) proportion of participants who become unresectable prior to 
surgery, and 3) proportion of participants who become ineligible for surgery due to toxicity. 
At each analysis, we will evaluate whether any of the proportions crosses one of the 
following thresholds: 1) proportion of participants who develop a higher disease stage (i.e., 
are upstaged) between randomization and surgery is greater than 25%, 2) proportion of 
participants who become unresectable prior to surgery is greater than 16%, or 3) proportion 
of participants who become ineligible for surgery due to toxicity is greater than 5%.  If any 
proportion crosses the corresponding threshold, accrual to the study will be suspended 
while the study team reviews and evaluates the data from the neoadjuvant arm.  Accrual 
will only re-open after the DSMC reviews the study team evaluation and approves any 
protocol modifications if proposed.   
 
 
12.0 
DISCIPLINE REVIEW 
 
12.1 
Surgical Review and Quality Assurance 
 
All surgeries performed as part of this study will undergo a pathologic response 
assessment. Refer to Section 15 for specimen submission and labeling instructions. The 
goal of this review is to verify that the resection was done according to the criteria specified 
in the protocol (Section 18.1).  The central surgery review will evaluate whether the planned 
surgical intervention does not change in response to systemic therapy or randomization. 
This minimizes variables influencing relapse or disease progression by avoiding 
incomplete or lesser surgery in participants receiving upfront systemic treatment 
(Neoadjuvant Arm).  
 
Surgical management should follow principles outlined in Section 18.1. 
 
The surgical note originating before study entry describing the planned surgical intervention 
and the operative report performed on study as part of S1801 should be submitted to S1801 
Surgical Chair for review.  The surgical quality monitoring will be completed by the Surgical 
Study Chair (Dr. Vernon Sondak). Surgical data including operative notes and pathology 
reports will be reviewed. Any deviations in surgical quality that are identified will be 
addressed by the study chairs, Drs. Patel and Grossmann. 
 
 
 

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13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Participants must be registered prior to initiation of treatment (no more than 14 calendar 
days prior to planned start of treatment.   
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a participant 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. 
 
13.3 
CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
https://ctepcore.nci.nih.gov/iam.  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository 
(RCR) at https://ctepcore.nci.nih.gov/rcr. 
 
RCR utilizes five-person registration types. 
• 
IVR — MD, DO, or international equivalent. 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
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. 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• 
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 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
 
 
GCP training 
 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and Cancer Trials Support Unit (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: 
 
• 
Addition to a site roster 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol Principle (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     

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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.  
 
13.4 
CTSU Registration Procedures 
 
Permission to view and download this protocol and its supporting documents is restricted 
and is based on person and site roster assignment housed in the CTSU Regulatory 
Support System (RSS). 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
a. 
IRB Approval:   
 
For 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 after March 1, 2019, all U.S.-based sites must be 
members of the NCI Central Institutional Review Board (NCI CIRB). 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 for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open 
the study locally. In order for the SSW approval to be processed, the Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. 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). 
 
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. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of 
the IRB/REB approval record to be completed: 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian 
sites only) and on at least one participating roster; 

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• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled 
all regulatory criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
 
b. 
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 based on person and site roster assignment. 
To participate, the institution and its associated investigators and staff must be 
associated with the LPO or a Protocol Organization (PO) on the protocol. One way 
to search for a protocol is listed below.  
• 
Log in to the CTSU members’ website (https://www.ctsu.org) using your 
CTEP-IAM username and password; 
• 
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 S1801. 
• 
Click on Documents, select Site Registration, and download and complete 
the forms provided. (Note: For sites under the CIRB, IRB data will load 
automatically to the CTSU.) 
 
c. 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU 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 participants waiting that are unable to use the Regulatory 
Submission Portal should alert the CTSU Regulatory Office immediately at 1-866-
651-2878 in order to receive further instruction and support. 
 
d. 
Checking Your Site’s Registration Status: 
 
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go. 
o 
Additional filters are available to sort by Protocol, Registration 
Status, Protocol Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol or the enrolling 

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investigator’s status with NCI or their affiliated networks. 
 
13.5 
Oncology Patient Enrollment Network (OPEN) Registration Requirements 
 
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 participant registration/randomization 
assignment. OPEN will populate the participant enrollment data in NCI’s clinical data 
management system, Medidata Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
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 participant 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 participant 
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: 
• 
Participant has met all eligibility criteria within the protocol stated timeframes; and 
the affirmation of eligibility on the Registration Worksheet has been signed by the 
registering investigator or another investigator designate. Site staff should refer to 
Section 5.0 to verify eligibility. 
• 
All participants 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. 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. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the participant must be prepared to provide answers 
to the following questions: 
 
• 
Institution CTEP ID 
• 
Protocol Number 
• 
Registration Step 
• 
Treating Investigator 
• 
Credit Investigator 
• 
Participant Initials 
• 
Participant’s Date of Birth 
• 
Participant SSN (SSN is desired, but optional.  Do not enter invalid 
numbers.) 
• 
Country of Residence 
• 
ZIP Code 
• 
Gender (select one): 

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o 
Female Gender 
o 
Male Gender 
• 
Ethnicity (select one): 
o 
Hispanic or Latino 
o 
Not Hispanic or Latino 
o 
Unknown 
• 
Method of Payment (select one): 
o 
Private Insurance 
o 
Medicare 
o 
Medicare and Private Insurance 
o 
Medicaid 
o 
Medicaid and Medicare 
o 
Military or Veterans Sponsored NOS 
o 
Military Sponsored (Including Champus & Tricare) 
o 
Veterans Sponsored 
o 
Self Pay (No Insurance) 
o 
No Means of Payment (No Insurance) 
o 
Other 
o 
Unknown 
• 
Race (select all that apply): 
o 
American Indian or Alaska Native 
o 
Asian 
o 
Black or African American 
o 
Native Hawaiian or other Pacific Islander 
o 
White 
o 
Unknown 
 
13.6 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Participants must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
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 Requirement 
 
Data must be submitted according to the protocol requirements for ALL participants 
registered, whether or not assigned treatment is administered, including participants 
deemed to be ineligible.  Participants for whom documentation is inadequate to determine 
eligibility will generally be deemed ineligible 
 
14.2 
Data Submission Procedures 
 
a. 
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://ctepcore.nci.nih.gov/iam) 
and the appropriate Rave role (Rave CRA, Read-Only, CRA, Lab Admin, SLA, or 
Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must 

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hold a minimum of an AP registration type.  To hold the Rave Site Investigator role, 
the individual must be registered as an NPIVR or IVR.  Associates can hold read-
only roles in Rave.  If the study has a DTL, individuals requiring write access to 
Rave must also be assigned the appropriate Rave tasks on the DTL.    
 
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 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 
888/823-5923 or by e-mail at ctsucontact@westat.com  
 
b. 
You may also access Rave® via the SWOG CRA Workbench via the SWOG 
website (www.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. 
 
14.3 
Data Submission Overview and Timepoints 
 
Please reference the ORP Manual on the CRA Workbench (www.swog.org) for detailed 
General Forms and Guidelines, as well as some disease-specific and study-specific 
forms.  There are also many other chapters available in the manual to be used for regular 
reference of SWOG processes and procedures. 
 
a. 
STEP 1 REGISTRATION 
 
1. 
WITHIN 15 DAYS AFTER RANDOMIZATION: 
 
Submit the following: 
 
S1801 Onstudy Form 
 
S1801 Baseline Tumor Assessment Form  
 
S1801 Planned Surgery Form  
 
S1801 Baseline Abnormalities Form 
 
*Radiology reports from all scans performed to assess disease at baseline 
 

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*Pathology reports documenting histologic confirmation (must include 
confirmation of any N-category or M-category resectable site). 
 
*NOTE: Upload reports via the Source Documentation: Baseline form in 
Rave®. 
 
2. 
NEOADJUVANT ARM: WITHIN 15 DAYS AFTER EACH CYCLE OF 
TREATMENT (1 CYCLE = 3 WEEKS): 
 
Submit the following: 
 
S1801 Treatment Form 
 
S1801 Adverse Event Form 
 
3. 
NEOADJUVANT ARM: AFTER RANDOMIZATION, WITHIN 15 DAYS 
AFTER EACH DISEASE ASSESSMENT UNTIL SURGERY OR 
RECURRENCE (AS DEFINED IN SECTION 10.0) OR 5 YEARS AFTER 
RANDOMIZATION (WHICHEVER OCCURS FIRST): 
 
Submit the following: 
 
Follow Up Tumor Assessment Form (iRECIST) 
 
Radiology reports from all scans performed to assess disease (uploaded 
via the Source Documentation: Follow-Up Form in Rave®). 
 
4. 
WITHIN 15 DAYS OF DISCONTINUATION OF STEP 1 PROTOCOL 
TREATMENT (INCLUDES PARTICIPANTS RANDOMIZED TO THE 
ADJUVANT ARM WHO DO NOT REGISTER TO STEP 2): 
 
Submit the following: 
 
If participant will not receive surgery on protocol, submit the Notice that 
Participant Will Not Receive Protocol Surgery 
 
NEOADJUVANT ARM: 
 
Off Treatment Notice documenting reasons for off treatment 
 
S1801 Treatment Form 
 
S1801 Adverse Event Form 
 
b. 
STEP 2 REGISTRATION: SURGERY 
 
1. 
WITHIN 84 DAYS AFTER SURGERY: 
 
Submit the following: 
 
S1801 Post-Surgery Form 
 
S1801 Adverse Event Form 
 
*Operative and Pathology Reports 
 
If participant received radiation therapy: 

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*Anonymized Radiation Treatment Record including the date, fraction #, 
daily dose for each treatment fraction, reason for any missed days of RT, 
and the Treatment Prescription page which has the Radiation Oncologist’s 
treatment prescription for the case PRIOR to the start of RT 
 
 
 
*NOTE: Upload reports via the Source Documentation: Surgery form in 
Rave®. 
 
S1801 Post-Surgery Disease Assessment Form 
 
 
Radiology reports from all scans performed to assess disease (uploaded 
via the Source Documentation:  Follow-Up Form in Rave®). 
 
Off Treatment Notice documenting reasons for off treatment 
 
If participant will not receive surgery on protocol, submit the Notice that 
Participant Will Not Receive Protocol Surgery 
 
c. 
STEP 3 REGISTRATION: PEMBROLIZUMAB (MK-3475)  
 
1. 
WITHIN 15 DAYS AFTER EACH CYCLE OF TREATMENT (1 CYCLE = 
3 WEEKS): 
 
Submit the following: 
 
S1801 Treatment Form 
 
S1801 Adverse Event Form 
 
2. 
WITHIN 15 DAYS AFTER EACH DISEASE ASSESSMENT (SEE STUDY 
CALENDAR FOR SCHEDULE) UNTIL RECURRENCE (AS DEFINED IN 
SECTION 10.0) OR 5 YEARS AFTER RANDOMIZATION (WHICHEVER 
OCCURS FIRST): 
 
Submit the following: 
 
S1801 Post-Surgery Disease Assessment Form 
 
Radiology reports from all scans performed to assess disease (uploaded 
via the Source Documentation: Follow-Up Form in Rave®). 
 
3. 
WITHIN 15 DAYS OF DISCONTINUATION STEP 2 OF PROTOCOL 
TREATMENT: 
 
Submit the following: 
 
Off Treatment Notice documenting reasons for off treatment 
 
S1801 Treatment Form 
 
S1801 Adverse Event Form 
 
d. 
FOR ALL REGISTRATION STEPS: 
 

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1. 
ONCE OFF ALL PROTOCOL TREATMENT, SUBMIT EVERY 6 
MONTHS FOR 2 YEARS (SEE STUDY CALENDAR FOR SCHEDULE), 
THEN YEARLY THROUGH YEAR 10: 
 
S1801 Follow-Up Form 
 
S1801 Late Adverse Events Form 
 
2. 
WITHIN 15 DAYS AFTER PROGRESSION OR RELAPSE: 
 
Submit the following: 
 
S1801 Follow-Up Form 
 
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®). 
 
3. 
WITHIN 30 DAYS AFTER KNOWLEDGE OF DEATH: 
Submit the Notice of Death, and all of the items listed in Section 14.3d.1 
(if the participant was still on protocol treatment) or the Follow-Up Form (if 
the participant was off protocol treatment) documenting death information. 
 
14.4 
Master Forms 
 
Master forms can be found on the protocol page on the CTSU website (www.ctsu.org) and 
(with the exception of the sample consent form and the Registration Worksheet) must be 
submitted on-line via the Web; see above for details. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Submission of surgical tissue for pathologic response assessment (Required for all 
participants on the Neoadjuvant arm). 
 
Note:  all specimens are to be shipped to Lab #201 (see Section 15.3). 
 
a. 
The submission of surgical tissue for pathologic response assessment is required 
for all participants on the Neoadjuvant arm.  Submit the following from the 
surgically resected specimen:     
 
• 
all tissue blocks, OR 
• 
two (2) representative unstained FFPE slides per block, OR 
• 
one (1) representative H&E slide and one (1) representative 
unstained slide per block. 
 
Note: 
A three-dimensional macroscopic measurement of the largest grossly 
positive identified lymph node should be provided in the gross description 
accompanying the specimen.  Any grossly positive lymph node 
measuring < 5 cm in greatest dimension should be entirely submitted for 
histopathologic assessment at 2 mm serially sectioned intervals.  For any 
grossly positive lymph node measuring > 5 cm in greatest dimension, 
representative sections of the largest lymph nodes may be utilized to 
avoid oversampling as follows:  following serial sectioning of each lymph 
node, for those nodes > 5 cm, sections representing a complete cross 
section of the entire surface area should be submitted per 1 cm of each 

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grossly positive lymph node.  Sections submitted should include grossly 
obvious tumor. All grossly positive lymph nodes < 5cm in specimens (in 
specimens where the largest node(s) exceeds 5 cm) should be submitted 
entirely as described above. 
 
Note:  
For additional training guidance on the collection of this tissue, please 
visit ctsu.org or contact vprieto@mdanderson.org.    
 
b. 
Ship within 3 months after surgery.  Ship on cool packs. 
 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
Refer to the general labeling, packaging, and shipping instructions at 
https://www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures 
and 
ship 
to 
Lab 
#201 
(SWOG 
Biospecimen Bank – Solid Tissue, Myeloma and Lymphoma Division). 
 
15.2 
Specimens for Banking (Optional) 
 
a. 
Participants must be offered the opportunity to participate in specimen banking. If 
participant consents, the following specimens must be submitted:  
 
1. 
Entire block of formalin-fixed paraffin-embedded (FFPE) tissue (from 
primary, lymph node, and metastasis if present) submitted at the following 
times: 
• 
Baseline 
• 
Relapse 
 
Note: If the institution cannot release a pathology paraffin embedded 
block, then 10 unstained slides (5 um each), and one H&E (Hematoxylin 
and Eosin) stained slide may be instead.  
 
Submit tissue according to guidelines provided by SWOG Biospecimen 
Bank: 
https://www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures. 
 
2. 
Collect 30 mL whole blood in red/black marble top (SST) vacutainer tubes 
without anticoagulant or in red top tubes without anticoagulant. Collect at 
the following times: 
• 
Cycle 1 
• 
Cycle 5  
• 
Cycle 9 
• 
End of Treatment (Cycle 18)   
• 
When participant is removed from protocol therapy for any reason 
• 
Relapse, after starting adjuvant therapy. 
 
3. 
Process whole blood to serum and ship with dry ice according to 
guidelines provided by SWOG Biospecimen Bank:  
https://www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures 
 
4. 
Collect 30 mL whole blood in pink/lavender top vacutainer tubes with 
EDTA. Collect at the following times: 
• 
Cycle 1 
• 
Cycle 5, 

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• 
Cycle 9,  
• 
End of Treatment (Cycle 18)   
• 
When participant is removed from protocol therapy for any reason 
• 
Relapse, after starting adjuvant therapy. 
 
5. 
Do not process. Ship at ambient temperature according to guidelines 
provided by SWOG Biospecimen Bank:  
• 
https://www.swog.org/clinical-trials/biospecimen-
resources/biospecimen-processing-and-submission-procedures 
 
 

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b. 
If a participant has a treatment delay or interruption due to an adverse event, the 
blood sample for banking should not be drawn even if the participant did not 
receive study treatment.  The goal is to collect the sample as close to the cycle or 
timepoint designated by the protocol. 
 
15.3 
SHIPPING SAMPLES 
 
a. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
b. 
Specimen Labeling  
 
1. 
FFPE tissue specimens must be labeled with the following:  
• 
SWOG participant number 
• 
Redacted Pathology Report that includes pathology ID# or SWOG 
participant number 
• 
Participant initials 
• 
Collection date (date the specimen was collected from the 
participant) 
• 
Specify whether the tissue is from primary (P), metastatic (M), or 
normal/uninvolved (N)  
• 
For lymph nodes, indicate it positive (+) or negative (-) for tumor 
involvement 
• 
Surgical Pathology ID # (Accession#) and block number (e.g., A2, 
3E, 2-1, B, etc.) must be on both the specimen label and the 
pathology report in order for the Bank to adequately match the 
specimen with any findings in the pathology report 
 
2. 
Liquid specimens must be labeled with the following: 
• 
SWOG participant number 
• 
Participant initials 
• 
Collection date (date the specimen was collected from the 
participant) 
• 
Specimen type (e.g. blood, serum, etc.) 
 
c. 
Whole blood specimens should be shipped on same day as collection and shipped 
overnight Monday - Friday, for Tuesday - Saturday delivery. If shipping for 
Saturday delivery, please mark for Saturday delivery and notify the Bank. 
 
d. 
For additional information about labeling and shipping instructions for fresh blood 
or bone marrow, refer to the SWOG Specimen Submission webpage 
(https://www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures).  
 
e. 
SWOG Specimen Tracking System (STS) 
 
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 (http://swog.org) Non- SWOG users may log into SpecTrack using their 
CTSU UserID and password on the SpecTrack login page located at  
https://spectrack.crab.org (select the option “SWOG – SWOG – CTSU”).  
SpecTrack start-up instructions (both written and demo) are available after signing 
in to SpecTrack.  
 

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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. The Specimen Submission Form is NOT 
required when the online system is used. 
 
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 
(https://spectrack.crab.org/Instructions); 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 Biospecimen Bank 
Solid Tissue, Myeloma, and Lymphoma Division 
Phone: 614-722-2865 
FAX: 614-722-2897 
E-mail: bpcbank@nationwidechildrens.org 
 
 
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 the Pharmaceutical Company(ies) 
(hereinafter referred to as "Collaborator(s)") and the NCI Division of Cancer Treatment and 

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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: 
 
1. 
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 participant or participant’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.  
 
2. 
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"): 
 
a. 
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. 
 
b. 
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 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
 
c. 
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. 
 
3. 
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. 
 
4. 
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. 
 
5. 
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. 
 
6. 
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 

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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. 
 
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 participants 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 
participant 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.  

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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 should be submitted to CTEP per NCI guideline s 
for AE reporting located at:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf. 
 
d. 
Other recipients of adverse event reports 
 
The DCTD/NCI will forward reports and documentation to the FDA and drug 
companies as required 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the participant must be reported according to local 
policy and procedures. 
 
e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the participant 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 pembrolizumab (MK-
3475).  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 pembrolizumab (MK-3475). 
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 participant 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, 
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: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 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 310-897-7404 and 210-614-0006.  Supporting clinical data 
submitted should include: 
• 
Printed copy of the first page of the CTEP-AERS Report. 
• 
Copies of clinical sourced documentation of the event. 
• 
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. 
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. 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
• 
Myelodysplastic syndrome (MDS) 
• 
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: 
 

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• 
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis 
• 
(if available) a copy of the cytogenetics report   
 
SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
NOTE: If a participant has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 
 
h. 
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.  
 
Additionally, the pregnancy outcome for participants 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. 
 
2. 
Pregnancy Loss Pregnancy loss is defined in CTCAE as “Death in utero.” 
Pregnancy loss should be reported expeditiously as Grade 4 “Pregnancy 
loss” under the Pregnancy, puerperium and perinatal conditions 
SOC.   
 
A Pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-
AERS recognizes this event as a participant death. 
 
3. 
Death Neonatal “Death neonatal is defined in CTCAE as “Newborn death 
occurring during the first 28 days after birth” 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, “Death neonatal” 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 participant 
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 301-897-7404.  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 
BIBLIOGRAPHY
 
1  
Balch CM, Gershenwald JE, Soong SJ, et al. Final Version of 2009 AJCC Melanoma Staging and 
Classification. J Clin Oncol 27 (36): 6199-206, 2009. 
 
2  
Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, Lazar AJ, Faries MB, 
Kirkwood JM, McArthur GA, Haydu LE, Eggermont AMM, Flaherty KT, Balch CM, Thompson JF; 
for members of the American Joint Committee on Cancer Melanoma Expert Panel and the 
International Melanoma Database and Discovery Platform. Melanoma staging: Evidence-based 
changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA 
Cancer J Clin. 2017 Nov;67(6):472-492. doi: 10.3322/caac.21409. Epub 2017 Oct 13. PMID: 
29028110 Free Article 
 
3  
Romano E, et al. Site and timing of first relapse in stage III melanoma patients: implications for 
follow-up guidelines. J Clin Oncol, 28(18): p. 3042-7, 2010. 
 
4  
Balch CM, Gershenwald JE, Soong SJ, et al. Final Version of 2009 AJCC Melanoma Staging and 
Classification. J Clin Oncol 27 (36): 6199-206, 2009. 
 
5  
Gershenwald JE et al Melanoma Staging 8th edition. CA Cancer J Clin 2017 (insert full citation 
from pubmed). 
 
6  
Romano E, et al. Site and timing of first relapse in stage III melanoma patients: implications for 
follow-up guidelines. J Clin Oncol, 28(18): p. 3042-7, 2010. 
 
7  
Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, 
Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, 
Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, 
Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, 
Larkin J, Ascierto PA; CheckMate 238 Collaborators. N Engl J Med. 2017 Nov 9;377(19):1824-
1835. doi: 10.1056/NEJMoa1709030. Epub 2017 Sep 10. 
 
8  
Seymour, L., Bogaerts, J., Perrone, A., Ford, R., Schwartz, L. H., Mandrekar, S., ... & Hodi, F. S. 
(2017). iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. The 
Lancet Oncology, 18(3), e143-e152. 
 
9  
Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, 
Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, 
Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, 
Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, 
Larkin J, Ascierto PA; CheckMate 238 Collaborators. N Engl J Med. 2017 Nov 9;377(19):1824-
1835. doi: 10.1056/NEJMoa1709030. Epub 2017 Sep 10. 
 
10  
Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, 
Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, 
Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, 
Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, 
Larkin J, Ascierto PA; CheckMate 238 Collaborators. N Engl J Med. 2017 Nov 9;377(19):1824-
1835. doi: 10.1056/NEJMoa1709030. Epub 2017 Sep 10. 
 
 
 
 

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11  
Eggermont AMM1, Blank 
CU1, Mandala 
M1, Long 
GV1, Atkinson 
V1, Dalle 
S1, Haydon 
A1, Lichinitser 
M1, Khattak 
A1, Carlino 
MS1, Sandhu 
S1, Larkin 
J1, Puig 
S1, Ascierto 
PA1, Rutkowski P1, Schadendorf D1, Koornstra R1, Hernandez-Aya L1, Maio M1, van den 
Eertwegh AJM1, Grob JJ1, Gutzmer R1, Jamal R1, Lorigan P1, Ibrahim N1, Marreaud S1, van 
Akkooi ACJ1, Suciu S1, Robert C1. N Engl J Med. 2018 May 10;378(19):1789-1801. doi: 
10.1056/NEJMoa1802357. Epub 2018 Apr 15. 
 
12  
Gershenwald JE et al Melanoma Staging 8th edition. CA Cancer J Clin 2017 (insert full citation 
from pubmed). 
 
 

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18.0 
APPENDIX 
 
18.1 
Surgical Management Guidelines 
 
18.2 
AJCC 8th Edition TNM Definitions for Pathologic Staging  
 
18.3 
Translational Medicine: Pathological Response  
 
18.4 
Specimen Banking Instructions for the SWOG Biospecimen Bank 
 
 
 
 

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18.1 
Surgical Management Guidelines 
 
a. 
Excision of the Primary Site 
 
These guidelines apply to participants presenting with an intact primary and 
planning for a lymph node dissection as their surgical procedure. 
 
Primary Tumor:  All such participants must undergo adequate wide excision of the 
primary tumor meeting the suggested criteria outlined below, if not already 
completed.  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 participants enrolled with regional disease, including recurrence after initial 
presentation, must have clinically detectable, surgically resectable disease 
(regional or distant disease). Participants 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 they have been 
deemed surgically resectable by a surgeon, 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 participants with histologic or 
clinical evidence of regional lymph node involvement enrolled on this trial.  
(Participants with satellite/in transit disease and no evidence of nodal involvement 
may be enrolled without 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.  Participants 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. 
 
1. 
Cervical Lymph Node Dissection 
 
A classic radical neck dissection is not required and is discouraged. 
Preservation of the internal jugular vein, sternocleidomastoid muscle, and 
eleventh cranial nerve ("functional neck dissection") should be performed 
whenever possible.  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 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 
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.  Minimally invasive surgical approaches, such as 
robotic-assisted pelvic lymphadenectomy, are acceptable provided the 
operation otherwise conforms to the standards described. 
 
 

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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.  Participants 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. 
 
e. 
Resection of Distant Metastatic Disease 
 
Participants with Stage IV melanoma metastatic to skin, subcutaneous sites, 
distant lymph nodes or lung or other visceral sites are allowed provided  sites are 
resectable per surgical note source document and they have NOT undergone 
prohibited systemic therapy for their metastatic disease (see Section 7.2) and the 
participant otherwise meets the eligibility criteria outlined in Section 5.0.  
Participants 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 participant 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 
AJCC 8th Edition TNM Definitions for Pathologic Staging 
 
a. 
Table 1 TNM Definitions for Stage III Melanoma: Pathologic Staging 
 
Stage 
TNM 
Description 
IIIB 
T0 
No evidence of primary tumor (e.g., unknown primary or completely 
regressed melanoma 
N1b 
One clinically detected node without micrometastasis 
N1c 
No regional lymph node disease with in-transit, satellite, and/or 
microsatellite metastases 
M0 
No evidence of distant disease 
IIIC 
T0 
No evidence of primary tumor (e.g., unknown primary or completely 
regressed melanoma 
N2b 
2-3 regional lymph nodes, at least one of which was clinically detected 
without in-transit, satellite, and/or microsatellite metastases 
N2c 
One clinically occult or clinically detected regional lymph node with in-
transit, satellite, and/or microsatellite metastases 
N3b 
4 or more regional lymph nodes, at least one of which was clinically 
detected, or presence of any number of matted nodes without in-transit, 
satellite, and/or microsatellite metastases 
N3c 
2 or more clinically occult or clinically detected regional lymph nodes and/or 
presence of any number of matted nodes with in-transit, satellite, and/or 
microsatellite metastases 
M0 
No evidence of distant disease 
IIIA 
T1a/b-
T2a 
T1a= Melanomas < 0.8 mm in thickness without ulceration  
T1b = Melanomas <0.8 mm in thickness with ulceration; 
 Melanomas 0.8-1.0 mm in thickness with or without ulceration 
T2a = Melanomas >1.0-2.0 mm in thickness without ulceration 
N1a 
One clinically occult regional lymph node (i.e., detected by SLN biopsy) 
without in-transit, satellite, and/or microsatellite metastases 
N2a 
2 or 3 clinically occult regional lymph node (i.e., detected by SLN biopsy) 
without in-transit, satellite, and/or microsatellite metastases 
M0 
No evidence of distant disease 
IIIB 
T1a/b-
T2a 
T1a= Melanomas < 0.8 mm in thickness without ulceration  
T1b = Melanomas <0.8 mm in thickness with ulceration; 
 Melanomas 0.8-1.0 mm in thickness with or without ulceration 
T2a = Melanomas >1.0-2.0 mm in thickness without ulceration 
N1 b/c 
or N2b 
N1b = One clinically detected regional lymph node without in-transit, 
satellite, and/or microsatellite metastases 
N1c = No regional lymph node disease with in-transit, satellite, and/or 
microsatellite metastases 
N2b = 2-3 regional lymph nodes, at least one of which was clinically 
detected without in-transit, satellite, and/or microsatellite metastases 
M0 
No evidence of distant disease 
IIIB 
T2b/T3a T2b = Melanomas > 1.0-2.0 mm in thickness with ulceration 
T3a = Melanomas > 2.0-4.0 mm in thickness without ulceration 
N1a -
N2b 
N1a= One clinically occult regional lymph node (i.e., detected by SLN 
biopsy) without in-transit, satellite, and/or microsatellite metastases 
N1b= One clinically detected regional lymph node without in-transit, 
satellite, and/or microsatellite metastases 
N1c= No regional lymph node disease with in-transit, satellite, and/or 
microsatellite metastases 

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Stage 
TNM 
Description 
N2a= 2 or 3 clinically occult regional lymph node (i.e., detected by SLN 
biopsy) without in-transit, satellite, and/or microsatellite metastases 
M0 
No evidence of distant disease 
IIIC 
T1a-
T3a 
T1a = Melanomas < 0.8 mm in thickness without ulceration 
T1b= Melanomas <0.8 mm in thickness with ulceration; 
 Melanomas 0.8-1.0 mm in thickness with or without ulceration 
T2a= Melanomas >1.0-2.0 mm in thickness without ulceration 
T2b= Melanomas > 1.0-2.0 mm in thickness with ulceration 
T3a= Melanomas > 2.0-4.0 mm in thickness without ulceration 
N2c or 
N3a/b/c 
N2c= One clinically occult or clinically detected regional lymph node with in-
transit, satellite, and/or microsatellite metastases 
N3a= 4 or more clinically occult regional lymph nodes (i.e., detected by 
SLN biopsy) without in-transit, satellite, and/or microsatellite metastases 
N3c= 2 or more clinically occult or clinically detected regional lymph nodes 
and/or presence of any number of matted nodes with in-transit, satellite, 
and/or microsatellite metastases 
M0 
No evidence of distant disease 
IIIC 
T3b/T4a T3b= Melanomas > 2.0-4.0 mm in thickness with ulceration 
T4a= Melanomas > 4.0 mm in thickness without ulceration 
Any N 
≥N1 
N1a= One clinically occult regional lymph node (i.e., detected by SLN 
biopsy) without in-transit, satellite, and/or microsatellite metastases 
N1b = One clinically detected regional lymph node without in-transit, 
satellite, and/or microsatellite metastases 
N1c= No regional lymph node disease with in-transit, satellite, and/or 
microsatellite metastases 
N2a = 2 or 3 clinically occult regional lymph node (i.e., detected by SLN 
biopsy) without in-transit, satellite, and/or microsatellite metastases 
N2b = 2-3 regional lymph nodes, at least one of which was clinically 
detected without in-transit, satellite, and/or microsatellite metastases 
N2c = One clinically occult or clinically detected regional lymph node with 
in-transit, satellite, and/or microsatellite metastases 
N3a= 4 or more clinically occult regional lymph nodes (i.e., detected by 
SLN biopsy) without in-transit, satellite, and/or microsatellite metastases 
N3b= 4 or more regional lymph nodes, at least one of which was clinically 
detected, or presence of any number of matted nodes without in-transit, 
satellite, and/or microsatellite metastases 
N3c = 2 or more clinically occult or clinically detected regional lymph nodes 
and/or presence of any number of matted nodes with in-transit, satellite, 
and/or microsatellite metastases 
M0 
No evidence of distant disease 
IIIC 
T4b 
T4b= Melanomas > 4.0 mm in thickness with ulceration 
N1a-
N2c 
N1a= One clinically occult regional lymph node (i.e., detected by SLN 
biopsy) without in-transit, satellite, and/or microsatellite metastases 
N1b = One clinically detected regional lymph node without in-transit, 
satellite, and/or microsatellite metastases 
N1c= No regional lymph node disease with in-transit, satellite, and/or 
microsatellite metastases 
N2a = 2 or 3 clinically occult regional lymph node (i.e., detected by SLN 
biopsy) without in-transit, satellite, and/or microsatellite metastases 
N2b = 2-3 regional lymph nodes, at least one of which was clinically 
detected without in-transit, satellite, and/or microsatellite metastases 

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Stage 
TNM 
Description 
N2c = One clinically occult or clinically detected regional lymph node with 
in-transit, satellite, and/or microsatellite metastases 
M0 
No evidence of distant disease 
IIID 
T4b 
T4b= Melanomas > 4.0 mm in thickness with ulceration 
N3a/b/c 
N3a= 4 or more clinically occult regional lymph nodes (i.e., detected by 
SLN biopsy) without in-transit, satellite, and/or microsatellite metastases 
N3b= 4 or more regional lymph nodes, at least one of which was clinically 
detected, or presence of any number of matted nodes without in-transit, 
satellite, and/or microsatellite metastases 
N3c = 2 or more clinically occult or clinically detected regional lymph nodes 
and/or presence of any number of matted nodes with in-transit, satellite, 
and/or microsatellite metastases 
M0 
No evidence of distant disease 
 
b. 
Table 2 TNM Definitions for Stage IV Melanoma: Pathologic Staging 
 
IV 
 
 
Any T, 
Tis 
TX= Primary tumor thickness cannot be assessed (e.g., diagnosis by 
curettage) 
T0= No evidence of primary tumor (e.g., unknown primary or completely 
regressed melanoma) 
Tis= Melanoma in situ 
T1a= Melanomas < 0.8 mm in thickness without ulceration  
T1b = Melanomas <0.8 mm in thickness with ulceration. 
 Melanomas 0.8-1.0 mm in thickness with or without ulceration 
T2a = Melanomas >1.0-2.0 mm in thickness without ulceration 
T2b= Melanomas > 1.0-2.0 mm in thickness with ulceration 
T3a= Melanomas > 2.0-4.0 mm in thickness without ulceration 
T3b= Melanomas > 2.0-4.0 mm in thickness with ulceration 
T4a= Melanomas > 4.0 mm in thickness without ulceration 
T4b= Melanomas > 4.0 mm in thickness with ulceration 
M1 
Evidence of distant metastasis with LDH elevated 
T – primary tumor; N – regional lymph nodes; M – distant metastasis 
Adapted with permission from AJCC: Melanoma of the Skin. AJCC Cancer Staging Manual. 8th 
ed. Chicago, IL: Springer 2017, pp. 577-78. 
 
 

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18.3 
Translational Medicine: Pathological Response  
 
Translational medicine study objective(s):  
 
1)  
On the neoadjuvant arm, to estimate the complete pathologic response rate and 
compare different definitions of partial pathologic response. 
 
2)  
To evaluate associations between pathologic responses and the endpoints of 
event-free survival and overall survival.  
 
Background: 
 
Pathologic response after neoadjuvant therapy as a surrogate for survival has been studied 
in breast cancer. However, the reliability of pathologic evaluation is controversial due to 
differing evaluation methods and definitions, as well as applicability to different subtypes 
of breast cancer. In melanoma, neoadjuvant therapy has been studied at only a few 
academic centers; however, collaborative efforts to standardize pathologic evaluation are 
underway. S1801 affords an even greater opportunity for this effort and in addition, the 
opportunity to review a large cohort of neoadjuvant cases and establish guidelines and 
standardization for pathologic response evaluation.  
 
1. Santa-Maria CA et al. Neoadjuvant Therapy for Early-Stage Breast Cancer: Current 
Practice, Controversies, and Future Directions Oncology 2015.   
 
Statistical Plan:  
 
The feasibility of specimen submission for this aim will be monitored as follows: the 
feasibility of obtaining full surgical specimens will first be evaluated after the first 10 
participants are enrolled on the neoadjuvant arm. If difficulty exists at the site level 
releasing complete surgical specimens, SWOG will work with the local PIs to determine 
barriers and facilitate tissue release.  The study team will continue to review and potentially 
modify the central path review specimen submission procedures until at least 85% of 
specimens are submitted.  If this rate is not achieved in 20 consecutive participants (so 
17/20 participants providing specimens) by the time 120 participants have undergone 
surgery on the neoadjuvant arm, the study team will re-visit the use a sub-study at a limited 
number of institutions for this objective. 
 
The pathologic complete response (pCR) rate will be estimated on the neoadjuvant arm 
and exact 95% confidence intervals will be calculated. There is no current consensus 
definition of pathologic partial response (pPR). Some authors have proposed < 50% viable 
tumor, though others have argued that 40% necrosis should be considered a partial 
response. We will use the minimum p-value approach (Mazumdar and Glassman, Statistics 
in Medicine, 2000) to evaluate potential cut-points in percent viable tumor with respect to 
the outcome EFS for definitions of partial response. In addition, we will use Cox regression 
models to evaluate the association between the quantitative value of percent viable tumor 
and overall and event-free survival. We will use C-statistics to estimate the predictive ability 
of the quantitative and categorical versions of the data. In addition, associations between 
pCR and pPR (using the definition derived using EFS) and the outcome of overall survival 
will be assessed with log-rank tests and Cox regression models,  
 
Laboratory conducting the testing: 
The University of Texas MD Anderson  
Department of Pathology, Immunohistochemistry Laboratory  
Contact for this trial: Victor Prieto, M.D., Ph.D. 
1515 Holcombe Blvd Unit 0085 – G1.3547 
Houston, TX 77030  
713/792-3187  
 

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Central review is essential to determine the extent of pathologic response in the post-
treatment surgical excision specimens.   
 
For this, the following are required from the surgical specimens for central review: 
• 
all tissue blocks, OR 
• 
two (2) unstained FFPE slides per block, OR 
• 
one (1) H&E slide and one (1) unstained slide per block  
 
To the extent that a consistent determination of pathologic response also correlates with 
pathologic response in other cancer types (notably breast), an accurate and consistent 
determination of pathologic response is critical. 
 
 
A critical variable to a consistent pathologic review is consistent pathologic submission 
guidelines to ensure that the post-treatment surgically resected tumor bed has been 
adequately sampled when determining pathologic response.    
 
Gross evaluation of the surgical specimen  
 
 
For the most part, neoadjuvant trials in melanoma have been directed towards surgically 
resectable nodal disease.  As such, the surgical specimen typically consists of regional 
lymphadenectomy specimens; however, for other specimen types, the same rules as below 
would apply.  Gross examination of the excised regional lymph node basin should seek to 
identify all possible lymph nodes (including both grossly positive and negative nodes). 
Three dimensional measurements of all of the grossly positive nodes should be recorded, 
as the dimensions of the largest involved lymph node will direct subsequent tissue 
processing.   
 
Histologic assessment by Dr. Victor Prieto: 
 
(1) 
The largest contiguous viable deposit of metastatic melanoma (if there is viable 
tumor) will be recorded in two dimensions.  This will be limited to contiguous viable 
tumor cells and will not include tumoral melanosis. 
 
(2) 
The percentage of the entire apparent tumor bed surface area occupied by viable 
tumor will be designated as % Viable tumor.   
 
(3) 
Viable extracapsular extension of melanoma tumor cells will be recorded as 
present or absent.  If there is evidence of completely regressed extracapsular 
extension, then the extracapsular extension will be noted as “Present” (completely 
regressed)   
 
(4) 
In addition, evidence of treatment effect will be recorded, including any of the 
following features and the relative percentages of each:  
(a) tumor necrosis (% of tumor bed) 
(b) tumoral melanosis and/or (% of tumor bed) 
(c) fibrosis (% of tumor bed) 
 
Results of the testing will not be provided to the treating physicians or the participants. 
 
 
 

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18.4 
Specimen Banking Instructions for the SWOG Biospecimen Bank 
 
The SWOG Bank will receive formalin-fixed, paraffin-embedded (FFPE) tumor tissue as 
either blocks or unstained slides. Upon receipt, the Bank will accession, barcode, and bank 
all FFPE tissues at room temperature until distribution.  
 
For each case, one H&E stained slide and one unstained slide will be sent to Dr. Victor 
Prieto for pathology review. These will be shipped with a redacted pathology report to Dr. 
Prieto in batches throughout the study.  
 
The SWOG Bank will receive fresh whole blood in EDTA tubes at ambient temperature 
from up to 5 time points. Upon receipt, blood in EDTA tubes will be processed for plasma. 
After plasma processing, one tube (up to 10 mL blood) will be processed for buffy coat, 
and the remaining tubes (up to 20 mL) of blood will be processed for peripheral blood 
mononuclear cells (PBMCs) using a ficoll-hypaque gradient.  Plasma will be divided into 1-
mL aliquots, both buffy coat and plasma will be stored in a -80°C freezer for future studies.  
 
The SWOG Bank will receive frozen serum aliquots from up to 5 time points. Upon receipt 
the Bank will accession, barcode and bank all serum aliquots in a -80°C freezer for future 
studies.