A Phase II and Pilot Trial of PD-1 Blockade With Pembrolizumab (MK-3475) in Patients With Resectable or Unresectable Desmoplastic Melanoma (DM)
Phase: PHASE2
Conditions: Desmoplastic Melanoma
Sponsor: National Cancer Institute (NCI)

 
 
Version Date: January 30, 2023  
 
TO:  
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS; CTSU  
 
 
 
FROM: 
SWOG Operations Office (protocols@swog.org) 
 
RE: 
 
S1512, “A Phase II and Pilot Trial of PD-1 Blockade with Pembrolizumab (MK-3475) 
in Patients with Resectable or Unresectable Desmoplastic Melanoma (DM)”. Study 
 
Chairs: Drs. K. Kendra, S. Hu-Lieskovan, W. E. Carson III 
  
REVISION #10 
 
Study Chair:  Kari Kendra, M.D., Ph.D. 
Phone number: : 614/293-4320 
E-mail: kari.kendra@osumc.edu 
 
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 
( √ )  
Other: CAEPR Update for Pembrolizumab 
( √ ) 
Informed Consent Changes 
 
Sites using the CIRB as their IRB of record:  The protocol and/or informed consent 
form changes have been approved by the CIRB and must be activated within 30 days of 
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 #10 
S1512 has been revised with the following changes in response to the Request for Rapid Amendment 
(RRA) received on February 03, 2023 from Dr. Elad Sharon (sharone@mail.nih.gov). The associated 
Action Letter is attached. 
 
1. 
Throughout the protocol and consent, formatting has been updated as needed. 
 
Protocol Changes: 
 
1. 
The version date has been updated. 
 
2. 
The table of contents has been updated. 
 
3. 
Section 3.1.c: The pembrolizumab (MK-3475) CAEPR has been updated to Version 2.7, 
December 13, 2022 as follows: 
 
 
 
Added New Risk: 

S1512 
Revision #10 (contd.) 
Page 2 
a. 
Rare but Serious: Endocrine disorders - Other (hypoparathyroidism); Nervous system 
disorders - Other (optic neuritis)  
 
Decrease in Risk Attribution: 
a. 
Changed to Also Reported on pembrolizumab (MK-3475) Trials But With Insufficient 
Evidence for Attribution from Less Likely: CPK increased; Joint effusion; Pleuritic pain 
 
Deleted: 
b. 
Less Likely: Immune system disorders - Other (pseudoprogression/tumor inflammation); 
Infection; Musculoskeletal and connective tissue disorder – Avascular Necrosis; 
Musculoskeletal and connective tissue disorder - Other (tenosynovitis) 
c. 
Footnote #4 “Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC.” is deleted. 
 
4. 
Section 7.1: A section regarding supportive care for pembrolizumab has been added. 
Subsequent sections have been renumbered. 
 
5. 
Section 8.1: This section has been updated to reference CTCAE Criteria version 5.0 for 
consistency with the updated pembrolizumab dose modification guidelines provided by the NCI. 
 
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 section title has been updated.  Additional information has been added 
regarding identification and management of immune-related AEs (irAEs), infusion-reactions, and 
non-irAEs. 
 
8. 
Section 8.3a: The section title has been updated.  
 
9. 
Section 8.3a, Table 1: The table has been revised in the following ways:  
 
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.  

S1512 
Revision #10 (contd.) 
Page 3 
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. Additionally, 
wording has been added for assessing mucosal severity for participants with ≥Grade 
2. 
 
• 
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" has 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 has 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. 
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. 
 
10. 
Section 8.3b, Table 2: The table title has been revised to “Pembrolizumab (MK-3475) Infusion 
Reaction Treatment Guidelines”  
• 
An additional column has been added for “Infusion Reactions” description as it applies to 
each NCI CTCAE Grade. 
• 
Throughout the table “patient(s)” has been updated to “participant(s)” 
• 
The description for "Infusion Reactions" and "Treatment" for Grade 2 has been reworded 
for clarity.  
 
• 
Under grade 3 treatment: 

S1512 
Revision #10 (contd.) 
Page 4 
o 
Corticosteroids has been clarified to include the following additional information “ 
(e.g. methylprednisolone 2 mg/kg/day or dexamethasone 10 mg every 6 hours)” 
o 
A statement has been added that epinephrine should be used immediately in 
situations of anaphylaxis.  
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. 
 
11. 
 Section 8.3c, Table 3: The “Management of Neurological Toxicities” section and “Neurological 
Toxcities” table have been added.  
 
Model Consent Form Changes 
 
1. 
The version date has been updated. 
 
2. 
The pembrolizumab (MK-3475) risk profile date has been updated to CAEPR Version 2.7, 
December 13, 2022.  Instances of MK-3475 (pembrolizumab) have been updated to 
pembrolizumab (MK-3475). 
 
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 1/30/2023 version of the consent form. 
 
 
 
 

S1512 
Revision #10 (contd.) 
Page 5 
What is the notification deadline and process? 
• 
For patients currently receiving treatment with MK-3475 (pembrolizumab):  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? 
• 
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 1/30/2023 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 1/30/2023 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 
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

 
S1512 
Consent Addendum (Revision #10) 
 
Page 1 
 
Version Date 1/30/2023 
 
 
 
 
 
 
Informed Consent Addendum Model for S1512 
 
S1512, “A Phase II and Pilot Trial of PD-1 Blockade with Pembrolizumab 
(MK-3475) in Patients with Resectable or Unresectable Desmoplastic 
Melanoma (DM)” 
  
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 risks have been identified with the 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 (or legally authorized representative) _____________________________ 
 
 
Date of signature_________________________ 
 
 
Signature of person(s) conducting the informed consent discussion________________________ 
 
 
Date of signature  
 

 
S1512 
 
Page 1 
 
Version Date 1/30/2023   
 
 
 
 
 
 
PRIVILEGED COMMUNICATION 
Activation date October 20, 2016 
FOR INVESTIGATIONAL USE ONLY 
 
 
SWOG 
TITLE 
A PHASE II AND PILOT TRIAL OF PD-1 BLOCKADE WITH PEMBROLIZUMAB (MK-3475) IN 
PATIENTS WITH RESECTABLE OR UNRESECTABLE DESMOPLASTIC MELANOMA (DM) 
 
NCT#02775851 
 
STUDY CHAIRS: 
AGENTS: 
 
Kari Kendra, M.D., Ph.D. (Medical Oncology) 
NCI Supplied Investigational Agents  
Ohio State University 
B415 Starling Loving Hall, 320 W. 10th Ave. 
Pembrolizumab (MK-3475) (NSC-776864) 
Columbus, OH 43210 
 
(DCTD, NCI) 
Phone:  614/293-4320 
 
FAX: 614/293-2584 
E-mail: kari.kendra@osumc.edu  
 
 
STUDY CHAIRS (contd.): 
Siwen Hu-Lieskovan, M.D., Ph.D. (Translational Med) 
 
University of Utah Medical Center 
 
 
David Wada, M.D. (Pathology) 
Huntsman Cancer Institute  
University of Utah, Dept. of Dermatology 
2000 Circle of Hope, Suite 2100 
30N 1900E 4A330SOM 
Salt Lake City, UT 84112 
Salt Lake City, UT  84132 
Phone: 801/585-1659 
Phone: 801-585-0221/ 801-213-2098 
E-mail: siwen.hu-lieskovan@hci.utah.edu  
E-mail: David.Wada@hsc.utah.edu 
 
 
William E. Carson III, M.D., FACS (Surgery) 
Jose A. Plaza, M.D. (Pathology) 
The Ohio State University 
 
 
 
The Ohio State University 
410 W 10th Ave, N924 Doan Hall 
930 Martha Morehouse Tower, 2050 Kenny Rd 
Columbus, OH 43210-1228 
Columbus, OH 43221 
Phone: 614/293-6306 
Phone: 614/293-9887 
Fax: 614/293-3465 
Fax: 614/293-7634 
Email: william.carson@osumc.edu    
Email: JoseAPlaza@osumc.edu    
 
  
 
 
BIOSTATISTICIANS: 
 
Michael Wu, Ph.D. 
James Moon, M.S. 
SWOG Statistical Center 
1100 Fairview Ave N, M3-C102 
P.O. Box 190204 
Seattle, WA 98109-1024 
Phone: 206/667-4623 
FAX: 206/667-4408 
E-mail: mcwu@fredhutch.org  
E-mail: jmoon@fredhutch.org 
 
 

 
S1512 
 
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Version Date 1/30/2023   
 
 
 
 
 
PARTICIPANTS 
 
 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
SWOG/SWOG 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
 
 
 

 
S1512 
 
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Version Date 1/30/2023   
 
 
 
 
 
TABLE OF CONTENTS 
 
TITLE  ......................................................................................................................................................... 1 
PARTICIPANTS ............................................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................................... 3 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 5 
SCHEMA ....................................................................................................................................................... 6 
1.0 
OBJECTIVES .................................................................................................................................. 7 
1.1 
Primary Objective ............................................................................................................................. 7 
1.2 
Secondary Objectives ...................................................................................................................... 7 
1.3 
Other objectives (all patients) .......................................................................................................... 7 
2.0 
BACKGROUND ............................................................................................................................... 8 
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 
Disease Related Criteria ................................................................................................................ 21 
5.2 
Prior/Concurrent Therapy Criteria .................................................................................................. 22 
5.3 
Clinical/Laboratory Criteria ............................................................................................................. 22 
5.4 
Specimen Criteria ........................................................................................................................... 23 
5.5 
Regulatory Criteria ......................................................................................................................... 23 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 23 
7.0 
TREATMENT PLAN ...................................................................................................................... 24 
7.1 
Supportive Care Guidelines ........................................................................................................... 24 
7.2 
Treatment ....................................................................................................................................... 24 
7.3 
Surgical guidelines ...................................................................................................................... 27 
7.4 
Prohibited and Cautionary Medications ......................................................................................... 27 
7.5 
Criteria for Removal from Protocol Treatment – Cohort A ............................................................. 28 
7.6 
Criteria for Removal from Protocol Treatment – Cohort B ............................................................. 28 
7.7 
Full CDUS Reporting Requirement ................................................................................................ 28 
7.8 
Discontinuation of Treatment ......................................................................................................... 28 
7.9 
Follow-Up Period ............................................................................................................................ 28 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 29 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 29 
8.2 
General Considerations ................................................................................................................. 29 
8.3 
Pembrolizumab Dose Modification Guidelines for Drug-Related Adverse Events ........................ 29 
8.4 
Use of Transfusion and/or EPO ..................................................................................................... 43 
8.5 
Use of G-CSF ................................................................................................................................. 43 
8.6 
Anti-Infectives ................................................................................................................................. 43 
8.7 
Dose Modification Contacts ........................................................................................................... 43 
8.8 
Adverse Event Reporting ............................................................................................................... 43 
9.0 
STUDY CALENDAR ...................................................................................................................... 44 
9.1 
Pembrolizumab (MK-3475)-Cohort A ............................................................................................. 44 
9.2 
Pembrolizumab (MK-3475)-Cohort B ............................................................................................. 48 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 51 
10.1 
Measurability of Lesions................................................................................................................. 51 
10.2 
Objective Status at Each Disease Evaluation ................................................................................ 52 
10.3 
Best Response ............................................................................................................................... 53 
10.4 
Performance Status ....................................................................................................................... 54 
10.5 
Progression-Free Survival ............................................................................................................. 54 
10.6 
Time to Death ................................................................................................................................. 55 
10.7 
Pathologic Complete Response ..................................................................................................... 55 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 55 
11.1 
Cohort A ......................................................................................................................................... 55 
11.2 
Cohort B ......................................................................................................................................... 57 

 
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11.3 
Data and Safety Monitoring ........................................................................................................... 59 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 59 
12.1 
Pathology Review .......................................................................................................................... 59 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 59 
13.1 
Registration Timing ........................................................................................................................ 59 
13.2 
Investigator/Site Registration ......................................................................................................... 60 
13.3 
OPEN Registration Requirements ................................................................................................. 62 
13.4 
Registration Procedures................................................................................................................. 64 
13.5 
Exceptions to SWOG registration policies will not be permitted. ................................................... 64 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 64 
14.1 
Data Submission Requirement ...................................................................................................... 64 
14.2 
Master Forms ................................................................................................................................. 64 
14.3 
Data Submission Procedures ........................................................................................................ 64 
14.4 
Data Submission Overview and Timepoints .................................................................................. 65 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 68 
15.1 
Specimen Submission for Translational Medicine ......................................................................... 68 
15.2 
Specimen Submission for Central Confirmatory Quality Review ................................................... 72 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 74 
16.1 
Adverse Event Reporting Requirements ........................................................................................ 76 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 82 
18.0 
APPENDIX ..................................................................................................................................... 83 
18.1 
Translational Medicine Details ....................................................................................................... 84 
18.2 
Specimen Banking Instructions for the UCLA Lab #224: The Ribas Laboratory ........................... 87 
18.3 
Specimen Banking Instructions for the SWOG Biospecimen Bank ............................................... 88 
 
 
 

 
S1512 
 
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Version Date 1/30/2023   
 
 
 
 
 
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal: 
 
(Sign in at www.ctsu.org, and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately 
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 patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_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 patient 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:  
Kari Kendra, M.D., Ph.D. 
Phone: 614-293-4320 
E-mail: kari.kendra@osumc.edu  
 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org.  
 

 
S1512 
 
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Version Date 1/30/2023   
 
 
 
 
 
SCHEMA 
 
COHORT A 
 
Registration 
 
 
Treatment with pembrolizumab (MK-3475) 
3 cycles 
 
 
Disease Assessment 
 
 
Progression and 
Resectable 
Unresectable 
 
 
 
 
Surgery (required) 
 
1 cycle 
 
of treatment 
 
 
Disease Assessment 
Off Treatment 
 
 
Progression 
Resectable 
and Unresectable 
 
 
 
Surgery (required) 
 
 
Off Treatment 
Off Treatment 
 
COHORT B 
 
Registration 
 
 
Continuous treatment with pembrolizumab (MK-3475) 
 
 
Disease Assessment 
      Progression 
 
 
 
 
 
 Resectable 
 
 
 
 
 
Patient/Physician Choice 
1 cycle of treatment 
 
 
Surgery 
Continued treatment  
 
for up to 2 years 
Disease Assessment 
 
 
 
Progression 
No Progression            Off Treatment 
 
 
 
 
Off Treatment 
Continue protocol treatment for up to 2 years 
 

 
S1512 
 
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Version Date 1/30/2023   
 
 
 
 
 
1.0 
OBJECTIVES 
 
This study will enroll two separate cohorts to assess the efficacy of pembrolizumab (MK-3475) in 
desmoplastic melanoma (DM).  Cohort A will evaluate pembrolizumab (MK-3475) as neoadjuvant 
therapy for patients with DM that is deemed resectable by the treating investigator; including 
primary DM, locally advanced DM, and locally recurrent DM.  Cohort B will be a pilot study to 
evaluate the use of pembrolizumab (MK-3475) for patients with DM that is deemed unresectable 
by the treating investigator, including metastatic DM. 
 
1.1 
Primary Objective 
 
a. 
Cohort A - To evaluate the pathologic complete response rate (pCR as defined in 
Section 10.0) in patients with resectable desmoplastic melanoma treated with 
neoadjuvant pembrolizumab (MK-3475) 
 
b. 
Cohort B - To evaluate the complete response rate (confirmed and unconfirmed 
in patients with unresectable desmoplastic melanoma treated with pembrolizumab 
(MK-3475). 
 
1.2 
Secondary Objectives 
 
Cohort A  
 
a. 
To estimate the 9 week response rate (RR) (unconfirmed complete and partial 
responses) among patients with measurable disease. 
 
b. 
To estimate the median overall survival (OS). 
 
c. 
To evaluate safety and tolerability of pembrolizumab (MK-3475) in the neoadjuvant 
setting. 
 
Cohort B 
 
a. 
To estimate the median progression-free survival (PFS). 
 
b. 
To estimate the median overall survival (OS). 
 
c. 
To evaluate safety and tolerability of pembrolizumab (MK-3475) in this setting. 
 
1.3 
Other objectives (all patients) 
 
a. 
To evaluate the hypothesis that higher mutational load in the patient derived 
baseline tumor biopsy samples is associated with higher pathologic complete 
response (pCR). 
 
b. 
To evaluate T cell infiltration into the tumors and circulating tumor DNA profile from 
blood samples in DM patients and correlate with response to PD-1 blockade. 
 
c. 
To evaluate the clonality of tumor infiltrating T cells in DM patients and correlate 
with response to PD-1 blockade. 
 
d. 
To evaluate adaptive immune resistant mechanism in DM tumors. 
 
 
 

 
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2.0 
BACKGROUND 
 
Rationale for selected approach and trial design.  
 
Emerging evidence is being generated that a high mutational load may be one of the requisites for 
a melanoma to be immunogenic and detected by T cells, which are then turned off by PD-1/PD-L1 
engagements. (1,2) Desmoplastic melanoma is one of the subtypes of melanoma with a known 
relationship to chronic skin sun damage and high mutational load. Anecdotal experience with 
pembrolizumab (MK-3475) suggests that desmoplastic melanoma may be uniquely sensitive to 
PD-1 blockade. 
 
The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint, which may 
be hijacked by tumor cells to overcome active T-cell immune surveillance. (3,4,5) The ligands for 
PD-1 (PD-L1 and PD-L2) can be constitutively expressed or can be induced in various tumors. (6) 
Preclinical in vitro and in vivo experiments have shown that PD-1 and/or PD-L1 blockade using 
monoclonal antibodies (mAb) enhances tumor-specific T-cell activation, T cell infiltration into the 
tumors, cytokine production, anti-tumor effector function, and clearance of tumor cells by the 
immune system. Pembrolizumab (MK-3475) strongly enhances T lymphocyte immune responses 
in cultured blood cells from healthy human donors, cancer patients, and primates. Pembrolizumab 
(MK-3475) also modulates the level of interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), 
interferon gamma (IFNγ), and other cytokines in the tumor microenvironment. The antibody 
potentiates existing immune responses only in the presence of antigen and does not nonspecifically 
activate T-cells. 
 
Pembrolizumab (MK-3475) has recently been FDA approved under accelerated approval for the 
treatment of patients with unresectable or metastatic melanoma and disease progression following 
ipilimumab, and, if BRAF V600 mutation positive, treatment with a BRAF inhibitor. The indication 
is based on an overall response rate (ORR) of 24% and durability of response with 18 of the 21 
responders demonstrating ongoing response with durations ranging from 1.4+ - 8.5+ months, 
including 8 patients with ongoing responses of 6 months or longer. 
 
After analyzing biopsies from 46 patients with metastatic melanoma obtained before and during 
anti-PD1 therapy with pembrolizumab (MK-3475) using quantitative immunohistochemistry, 
quantitative multiplex immunofluorescence, and next generation sequencing for T-cell receptors 
(TCR), it became evident that responding patients showed proliferation of intratumoral CD8+ T-cells 
that directly correlated with radiographic reduction in tumor size. (7) Pre-treatment samples 
obtained from responding patients showed higher numbers of CD8, PD1, and PD-L1 expressing 
cells at the invasive tumor margin and inside tumors, with close proximity between PD-1 and PD-
L1, and a more clonal TCR repertoire. Using multivariate analysis, the authors established a 
predictive model based on CD8 expression at the invasive margin and validated the model in an 
independent cohort of 15 patients. These findings indicate that tumor regression following 
therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-
1/PD-L1 mediated adaptive immune resistance. 
 
It is currently unknown which antigens are being recognized by T cells attacking tumors after 
release of PD-1 blockade. But evidence from studies with other immunotherapies suggests that 
most of these antigens are neoepitopes resultant from somatic mutations. In a recent experience, 
whole exome sequencing was performed on tumors and matching blood of patients treated with 
CTLA4 blockade with ipilimumab or tremelimumab. (8) Somatic mutations and candidate 
neoantigens generated from these mutations were characterized.  Neoantigen peptides were 
tested for the ability to activate lymphocytes from ipilimumab-treated patients.  A discovery set 
(n=25) consisted of 11 patients who derived long-term clinical benefit and 14 who derived minimal 
or no benefit.  Mutational load was associated with clinical benefit (p=0.01), but alone was not 

 
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sufficient to predict benefit.  Using genome-wide somatic neoepitope analysis and patient-specific 
HLA typing, the authors identified candidate tumor neoantigens for each patient.  This work 
elucidated a neoantigen landscape that is specifically present in tumors with strong benefit from 
CTLA-4 blockade.  This signature was validated in a second set of ipilimumab–treated melanoma 
patients (n=39).  Predicted neoantigens activated T cells from the patients treated with ipilimumab.  
 
Desmoplastic melanoma (DM) is a difficult tumor to remove surgically. (9) Frequently there is 
extensive perineural spread and surgery ends up being quite extensive with poor local control. 
Many times, these lesions present as small primaries only to find intraoperatively that they extend 
well beyond what is seen clinically or in imaging. (10,11) Patients are left with significant surgical 
deficits in the face of locally progressive disease. Due to the difficulty in gaining local control 
surgically, this study will offer patients with measurable desmoplastic melanoma treatment with 
pembrolizumab (MK-3475).  
 
Patients with desmoplastic melanoma, locally advanced or metastatic, will be eligible to receive 
therapy on the trial. This will enhance the accrual rate. The primary end point of ORR after 3 cycles 
will normalize the data between the two groups while allowing for subsequent clinical intervention 
(ie surgery in those with locally advanced disease, or continued treatment in those with metastatic 
disease). The secondary endpoints of PFS and OS will also be collected for both groups. For 
individuals undergoing resection, this study will obtain data on the pCR and the ability to obtain 
clean margins. This study will evaluate tissue samples for mutational load and determine if the 
higher mutational load is associated with the ORR, in search of potential markers predictive of 
response. Tissue will also be evaluated for T cell infiltration, the clonality of tumor infiltrating T cells, 
and adaptive immune resistant mechanisms. 
 
This trial hypothesizes that immune responses after administering pembrolizumab (MK-3475) will 
be also focused on neoepitopes resultant from somatic mutations, and that melanoma subsets with 
the highest mutational loads should have higher response rates than unselected melanomas. 
Among all melanomas, desmoplastic melanoma is a subset with a strong link to chronic UV 
exposure and high mutational load. 
 
There are no prospective studies evaluating the response of desmoplastic melanoma to biologic 
therapies. This study has the potential to change the course of therapy for those with locally 
advanced disease, to improve overall survival in individuals with desmoplastic melanoma, and to 
obtain data that, if favorable, can be used further to determine predictive value of PD1 blockade 
with pembrolizumab (MK-3475). 
 
Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex categories 
is shown in the table below. 
 
This study will be open to U.S. sites only. 
 
 

 
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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 
1 
0 
0 
1 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian 
or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
0 
1 
0 
0 
1 
White 
16 
37 
0 
1 
54 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
16 
39 
0 
1 
56 
 
 
3.0 
DRUG INFORMATION 
 
For information regarding Investigator’s 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-77686)  
 
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.  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.  
 
 

 
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b. 
PHARMACOKINETICS 
 
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 10 mg/kg dosing as administered at 2 week intervals.  During repeated dosing 
of 2 or 10mg/kg Q3W, steady state in trough concentrations appeared to have 
been achieved after approximately three months.  Furthermore, MK-3475 has a 
low potential of eliciting the formation of anti-drug antibodies.        
 
c. 
ADVERSE EFFECTS  
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements'  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 3793 patients. 
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. 
       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)2 
 
 
 
Lymph node 
pain2 
 
 
 
CARDIAC DISORDERS 
 
 
 
 
Myocarditis2 
 
 
 
 
Pericarditis2 
 
 

 
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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%) 
 
 
ENDOCRINE DISORDERS 
  
 
Adrenal 
insufficiency2 
 
  
 
 
Endocrine disorders 
- Other 
(hypoparathyroidism
) 
  
 
Endocrine 
disorders - 
Other 
(thyroiditis)2 
 
  
 
Hyperthyroidi
sm2 
 
  
 
Hypophysitis2  
  
 
Hypopituitaris
m2 
 
  
 
Hypothyroidis
m2 
 
  
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 
  

 
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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%) 
 
 
 
Hepatobiliary 
disorders - 
Other 
(autoimmune 
hepatitis)2 
 
  
 
 
Hepatobiliary 
disorders - Other 
(sclerosing 
cholangitis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis2 
  
 
 
Cytokine release 
syndrome2 
  
 
 
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 
aminotransfer
ase 
increased2 
 
  
 
Alkaline 
phosphatase 
increased 
 
  
 
Aspartate 
aminotransfer
ase 
increased2 
 
  

 
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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%) 
 
 
 
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 
  
 
 
Nervous system 
disorders - Other 
(non-infectious 
encephalitis)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 
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-
papular2 
 
 Rash maculo-papular2 (Gr 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%) 
 
 
 
Skin and 
subcutaneous 
tissue 
disorders - 
Other 
(dermatitis)2 
 
  
 
Skin 
hypopigmenta
tion2 
 
  
 
 
Stevens-Johnson 
syndrome2 
  
 
 
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 
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. 
 
 
 
 

 
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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 
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. 
 

 
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1. 
Pregnancy and Lactation: The central function of the PD-1/PD-L1 pathway 
is to maintain immune tolerance to the fetal allograft, and its important role 
in maintaining pregnancy has been recently emphasized in literature [4-6, 
4-7] The PD-L1 molecule expressed at the uteroplacental interface 
effectively protects the concepti from maternal T cell-mediated immunity. 
Blockade of PD-L1 signaling has been shown in murine models of 
allogeneic pregnancy [4-6, 4-7] to abrogate fetomaternal tolerance to the 
concepti and to result in an increase in fetal resorption. The evidence from 
these experimental results indicates that there is a theoretical risk 
associated with the administration of MK-3475 to women of child-bearing 
potential (WOCBP). It is therefore anticipated that the inhibition of PD-1 by 
treatment with anti-PD-1 monoclonal antibody (i.e., MK-3475) during 
pregnancy would have detrimental effects that might include increased 
rates of abortion and stillbirth. Women/men of reproductive potential 
should use an effective contraceptive method while on treatment and 
through 120 days after the last dose of MK-3475. 
 
It is not known whether MK-3475 is excreted in human milk.  Because of 
the potential for drugs to be excreted in human milk, the risk to the nursing 
infant cannot be excluded and therefore MK-3475 should not be 
administered to nursing mothers. 
 
Drug Interactions: No studies on pharmacodynamic drug interactions have 
been performed.  Due to potential drug interactions, a complete patient 
medication list, including MK-3475, should be screened prior to initiation 
of and during treatment with MK-3475. See Section 8.0 Toxicities to be 
Monitored and Dosage Modifications 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
e. 
HOW SUPPLIED 
 
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 vial contains 100 mg of 
pembrolizumab (MK-3475) in 4 mL of solution. Each 1 mL of solution contains 25 
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. 
STORAGE, PREPARATION & STABILITY 
 
1. 
Preparation: MK-3475 solution for infusion must be diluted prior to 
administration.  Allow the required number of vials to equilibrate to room 
temperature.  Do not shake the vials.  Do not use if opaque or extraneous 
particulate matter other than translucent to white proteinaceous particles 
is observed.  Do not use if discolored.  To prepare the infusion solution 
add the dose volume of MK-3475 to an infusion bag containing 0.9% 
Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.  Gently 
invert the bag 10-15 times to mix the solution.  The final concentration 
must be between 1 mg/mL to 10 mg/mL. 
 

 
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Compatible IV bag materials: PVC plasticized with DEHP, non-PVC 
(polyolefin), EVA, or PE lined polyolefin 
 
2. 
Storage: Store intact vials between 2°C - 8°C (36°F - 46°F).  Do not 
freeze.  Protect from light by storing in the original box.   
 
If a storage temperature excursion is identified, promptly return MK-3475 
to between 2-8°C and quarantine the supplies.  Provide a detailed report 
of the excursion (including documentation of temperature monitoring and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov 
for 
determination of suitability. 
 
3. 
Stability: Refer to the package label for expiration. 
 
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. 
 
4. 
Route of Administration: IV infusion only.  Do not administer as an IV 
push or bolus injection. 
 
5. 
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 
patient 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 
 
 
g. 
DRUG ORDERING & ACCOUNTABILITY 
 
1. 
Drug Ordering  
 
Starter supplies will not be provided. NCI supplied agents may be 
requested by the Principal Investigator (or their authorized designee) at 
each participating institution. Pharmaceutical Management Branch (PMB) 
policy requires that drug be shipped directly to the institution where the 
patient is to be treated. PMB does not permit the transfer of agents 
between institutions (unless prior approval from PMB is obtained). The 
CTEP assigned protocol number (S1512) must be used for ordering all 
CTEP supplied investigational agents. The responsible investigator at 
each participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA Form 1572 and a CV. If there are several 
participating investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one lead 
investigator at that institution.  Active CTEP-registered investigators and 

 
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investigator-designated shipping designees and ordering designees can 
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 and a “current” password.  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. In general, sites may order initial 
agent supplies when a patient is being screened for enrollment onto the 
study. 
 
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. 
 
3. 
Drug return and/or disposition instruction  
 
Drug disposition: PMB will send a stock recovery letter when the agent is 
no longer suitable for use. All undispensed drug supplies should be 
returned to the PMB. When it is necessary to return study drug, 
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). 
 
4. 
Drug Expiration:  Stability testing is ongoing. PMB will send a stock 
recovery letter when notified that the agent is no longer suitable for use. 
 
5. 
Contact Information 
 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/  
 
NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov  
 
PMB policies and guidelines:  
http://ctep.cancer.gov/branches/pmb/agent_management.htm   
 
PMB Online Agent Order Processing (OAOP) application:  
https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx    
 
CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/  
 
CTEP 
Associate 
Registration 
and 
IAM 
account 
help:  
ctepreghelp@ctep.nci.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 
 

 
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Staging criteria are not required for eligibility.  Please refer to Section 18.1 (Appendix) for staging 
definitions. Staging must be documented.  Clinical staging may be used where appropriate. 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered 
eligible for registration.  Use the spaces provided to confirm a patient's eligibility.  For each criterion 
requiring test results and dates, please record this information on the Onstudy Form and submit 
via MediData Rave ® (see Section 14.0).  Any potential eligibility issues should be addressed to 
the Data Operations Center in Seattle at 206/652-2267 or melanomaquestion@crab.org prior to 
registration. 
 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0.  Therefore, if a test is done on a Monday, the Monday 1 week later would be 
considered Day 7.  This allows for efficient patient scheduling without exceeding the guidelines.  If 
Day 7, 14, 28 or 42 falls on a weekend or holiday, the limit may be extended to the next 
working day. 
 
5.1 
Disease Related Criteria 
 
a. 
Cohort A:  Patients must have histologically or cytologically confirmed primary 
desmoplastic melanoma (see Section 12.1 for definition) that is deemed 
resectable. The decision to perform surgery on patients must be based on good 
clinical judgment.  Eligible patients for surgical resection must have disease that, 
in the judgment of the surgeon, is deemed completely resectable resulting in free 
surgical margins. Patients must have residual disease after initial biopsy which can 
be measurable or non-measurable disease per RECIST 1.1 (see Section 10.1).  
Residual disease can either be confirmed with FNA or if measurable disease is 
present, no FNA needs to be obtained. 
 
OR 
 
b. 
Cohort B:  Patients must have histologically or cytologically confirmed primary 
desmoplastic melanoma (see Section 12.1 for definition) that is unresectable. 
Patients in Cohort B must have measurable disease per RECIST 1.1 (see Section 
10.1). 
 
c. 
Contrast-enhanced CT scans of the chest, abdomen and pelvis are required. A 
whole-body PET/CT scan with diagnostic quality images and intravenous iodinated 
contrast may be used in lieu of a contrast enhanced CT of the chest, abdomen and 
pelvis. Imaging of the head and neck is required only if the patient has a head/neck 
primary. Contrast may be omitted if the treating investigator believes that exposure 
to contrast poses an excessive risk to the patient. If skin lesions are being followed 
as measurable disease, photograph with a ruler included and physician 
measurements, must be kept in the patient’s chart as source documentation. All 
measurable lesions must be assessed within 28 days prior to registration.  Tests 
to assess non-measurable disease must be performed within 42 days prior to 
registration.  All disease must be assessed and documented on the Baseline 
Tumor Assessment Form (RECIST 1.1). 
 
 

 
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d. 
Patients must not have known brain metastases unless brain metastases have 
been treated and patient is asymptomatic with no residual neurological dysfunction 
and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at 
least 14 days prior to registration. 
 
5.2 
Prior/Concurrent Therapy Criteria 
 
a. 
Patients must not have received prior systemic treatment for this melanoma. 
 
b. 
Patients must not be planning to receive concomitant other biologic therapy, 
hormonal therapy, other chemotherapy, anti-cancer surgery or other anti-cancer 
therapy while on this protocol. 
 
c. 
Patients must not have received radiation therapy, non-cytotoxic agents or 
investigational agents or systemic corticosteroids within 14 days prior to 
registration. 
 
d. 
Patients may have received prior surgery.  All adverse events associated with prior 
surgery must have resolved to ≤ Grade 1 (per CTCAE 4.0) prior to registration 
 
5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must be ≥ 18 years of age. 
 
b. 
Patients must have adequate bone marrow function as evidenced by all of the 
following:  ANC ≥ 1,500/mcl; platelets ≥ 50,000/mcl; and hemoglobin ≥ 8 g/dL. 
These results must be obtained within 28 days prior to registration. 
 
c. 
Patients must have adequate liver function as evidenced by the following: total 
bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (or ≤ 3.0 x IULN with 
Gilbert’s Syndrome), and AST and ALT ≤ 2.5 x IULN (or < 5 x IULN for patients 
with known liver metastases).  These results must be obtained within 28 days prior 
to registration. 
 
d. 
Patients must have LDH performed within 28 days prior to registration. 
 
e. 
Patients must have Zubrod Performance Status ≤ 2 (see Section 10.4). 
 
f. 
Patients must not have history of (non-infectious) pneumonitis that required 
steroids or current pneumonitis. 
 
g. 
Patients must not have an active infection requiring systemic therapy. 
 
h. 
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. 
 
i. 
Patients must not have received live vaccines within 42 days prior to registration.  
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox, shingles, yellow fever, rabies, BCG, and typhoid 
(oral) vaccine.  Seasonal influenza vaccines for injection are generally killed virus 

 
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vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) 
are live attenuated vaccines, and are not allowed. 
 
j. 
Patients known to be HIV positive prior to registration are eligible if they meet the 
following criteria within 30 days prior to registration:  stable and adequate CD4 
counts (≥ 350 mm3), and serum HIV viral load of < 25,000 IU/ml.  Patients must be 
on a stable anti-viral therapy. 
 
k. 
No other prior malignancy is allowed except for the following:  adequately treated 
basal cell or squamous cell skin cancer, adequately treated in situ cancer, 
adequately treated Stage I or II cancer (including multiple primary melanomas) 
from which the patient is currently in complete remission, or any other cancer from 
which the patient has been disease free for three years. 
 
l. 
Women of childbearing potential must have a negative urine or serum pregnancy 
test within 28 days prior to registration.  Women/men of reproductive potential must 
have agreed to use an effective contraceptive method for the course of the study 
through 120 days after the last dose of study medication.  Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this 
study, she should inform her treating physician immediately. A woman is 
considered to be of "reproductive potential" if she has had menses at any time in 
the preceding 12 consecutive months.  In addition to routine contraceptive 
methods, "effective contraception" also includes heterosexual celibacy and 
surgery intended to prevent pregnancy (or with a side-effect of pregnancy 
prevention) defined as a hysterectomy, bilateral oophorectomy, or bilateral tubal 
ligation.  However, if at any point a previously celibate patient chooses to become 
heterosexually active during the time period for use of contraceptive measures 
outlined in the protocol, he/she is responsible for beginning contraceptive 
measures.  Patients must not be pregnant or nursing due to unknown teratogenic 
side effects. 
 
5.4 
Specimen Criteria 
 
a. 
Patients must have specimens available and institutions must be planning to 
submit for centralized pathology review as outlined in Section 12.0 and for 
integrated translational medicine objectives as outlined in Section 15.1. 
 
5.5 
Regulatory Criteria 
 
a. 
Patients must be informed of the investigational nature of this study and must sign 
and give written informed consent in accordance with institutional and federal 
guidelines. 
 
b. 
As a part of the OPEN registration process (see Section 13.4 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study 
has been entered in the system. 
 
 
6.0 
STRATIFICATION FACTORS 
 
Patients will be stratified by the following factors: Cohort A (resectable) vs Cohort B (unresectable) 
 
 
 

 
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7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Kendra at 614/293-4320 or 
kari.kendra@osumc.edu or Dr. Hu-Lieskovan at 310/794-4955 or  
siwen.hu-lieskovan@hci.utah.edu.  For dosing principles or questions, please consult the SWOG 
Policy #38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org ("Policies and 
Manuals" under the "Visitors" menu and choose Policy 38). 
 
7.1 
Supportive Care Guidelines 
 
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 8.3a. 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). 
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. 
Pretreatment Labs: 
 
Blood samples collected for pretreatment laboratory tests may be collected and 
analyzed no more than 3 days prior to dosing at each cycle. Albumin, glucose, 
electrolytes (Na, K, HC03 or CO2), and thyroid function tests (T3, TSH and T4) are 
required to obtain baseline data for future toxicity assessments. 
 
b. 
Cohort A: Pembrolizumab (MK-3475) for resectable disease 
 
Agent 
Dose 
Route 
Schedule 
 
MK-3475 
200 mg 
IV 
Day 1, Q 3 weeks  
(pembrolizumab) 
 
over 30 minutes 
for 3 cycles * 
 
1 cycle = 21 days. 
* One additional cycle may be given for patients whose disease is unresectable 
after 3 cycles.  See below. 
 
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.   
 
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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).   
 
• 
Disease assessment, using the same technique as baseline, will be 
performed every 9 weeks until discontinuation of protocol treatment.  
Patients with treatment delays may have additional disease assessments.  
• 
After discontinuation of treatment, if the tumor is potentially resectable, the 
patients will proceed with surgical resection (see surgical guidelines below 
in Section 7.2). Pathology will be evaluated for evidence of pCR. If 
potentially resectable, surgery is required. This includes patients who have 
a complete response per RECIST 1.1 with no macroscopic evidence of 
disease. 
• 
If at any time after the first disease assessment the patient’s disease is 
deemed to be unresectable, treatment will continue for 1 more cycle and 
a repeat disease assessment, using the same techniques as baseline, 
must be obtained 4 weeks (Day 28 +/- 7 days) later. If, after this second 
disease assessment the patient’s disease is deemed to be resectable the 
patient must continue with resection as previously planned. Patients who 
do not undergo a second disease assessment following an initial 
documentation of progression will be considered failures. [Note: Most 
responses to pembrolizumab (MK-3475) will occur within 3 cycles, but a 
delayed response is also possible.  If the patient has become unresectable 
after 3 cycles, one more cycle is given to capture those who might have a 
delayed response to therapy. If the delayed response is present, 
unresectable disease may become resectable]. 
 
c. 
Cohort B: Pembrolizumab (MK-3475) for unresectable disease 
 
Patients in Cohort B will receive the following treatment for a maximum of 34 cycles 
or until the patient has met any of the criteria in Section 7.5, whichever is first.  
 
 
Agent 
Dose 
Route 
Schedule 
 
MK-3475 
200 mg 
IV over 30 
Day 1, Q 3 weeks  
(pembrolizumab) 
 
minutes 
 
 
1 cycle = 21 days. 
 
 
Pembrolizumab (MK-3475) treatment should be administered after all procedures 
and assessments have been completed and the patient is deemed eligible.  
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).   
 
• Disease assessments, using the same technique as baseline, must be 
performed every 3 cycles (9 weeks) for the first 6 months. Scans should then 
be obtained every 4 months. Tumor measurements are determined with 

 
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scans or if the only site of measurable disease is cutaneous, with 
photographically measurable disease. 
• Patients whose disease becomes resectable in the opinion of the treating 
investigator, may have surgery which must be performed as described below 
in Section 7.2. Patient may choose to continue protocol therapy instead of 
surgical resection. 
• Patients may remain on protocol treatment after progression if they continue 
to derive clinical benefit in the opinion of the treating investigator. 
 
 

 
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7.3 
Surgical guidelines 
 
Definitive Surgical Procedure  
The surgical procedure necessary to resect the tumor with negative margins should be 
used. A marker can be placed prior to initiating treatment or in early treatment at the 
surgeon’s discretion to identify the site of disease if a complete response is noted.  The 
approach used will be at the discretion of the surgeon performing the procedure using best 
clinical judgment and institutional guidelines. Repeat surgeries are allowed. Intent is for all 
sites of disease to be completely resected. Pathology from all of the resection(s) will need 
to be submitted for histologic review. For potentially resectable tumors, surgery is required. 
 
Sentinel lymph node evaluation 
Sentinel lymph nodes will be obtained per NCCN guidelines. If sentinel lymph nodes are 
positive, further nodal dissection will be performed per institutional guidelines. 
 
Histological tumor assessment of the surgical specimens. Surgical specimens will be 
assessed for presence of tumor and tumor margin status. 
- 
Tumor free margins (negative margins, resections defined by pathologist as absence 
of ink on the tumor), R0. All other resections of viable tumor are described as tumor 
positive margins resections, and are defined as 
o 
R1 resection – complete resection with no grossly visible tumor left behind as 
defined by the surgeon, or 
o 
R2 resection – partial resection with grossly visible tumor left behind as defined 
by the surgeon. 
 
See Section 10.7 for definition of pathologic complete response. 
 
7.4 
Prohibited and Cautionary Medications 
 
Patients are prohibited from receiving the following therapies before discontinuing protocol 
treatment during this trial: 
 
• 
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 MK-3475. 
• 
Radiation therapy 
• 
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. 
 
Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from protocol 
treatment.  Patients may receive other medications that the investigator deems to be 
medically necessary. 
 
 

 
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7.5 
Criteria for Removal from Protocol Treatment – Cohort A 
 
a. 
Progression of disease (as defined in Section 10.0) that renders the patient unable 
to have disease resected. 
 
b. 
Patient chooses to proceed with surgical resection rather than continue on 
pembrolizumab. 
 
c. 
Unacceptable toxicity. 
 
d. 
The patient may withdraw from the study at any time for any reason. 
 
e. 
The investigator may discontinue treatment if they determine that the patient’s 
continued treatment on the study is detrimental to their long-term health, or due to 
poor compliance with the study’s required visits and treatments. 
 
f. 
Positive pregnancy test. 
 
g. 
Completion of protocol treatment (after resection). 
 
7.6 
Criteria for Removal from Protocol Treatment – Cohort B 
 
a. 
Progression of disease (as defined in Section 10.0). However, patients may remain 
on protocol treatment after progression if they continue to derive clinical benefit in 
the opinion of the treating investigator.  
 
b. 
Disease becomes resectable and patient chooses to have surgical resection. 
 
c. 
Unacceptable toxicity. 
 
d. 
The patient may withdraw from the study at any time for any reason. 
 
e. 
The investigator may discontinue treatment if they determine that the patient’s 
continued treatment on the study is detrimental to their long-term health, or due to 
poor compliance with the study’s required visits and treatments. 
 
f. 
Positive pregnancy test. 
 
g. 
Completion of protocol treatment (either resection or 34 cycles of pembrolizumab).  
 
7.7 
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 14.4c, the S1512 Treatment Form, and 
the S1512 Adverse Event Form).  A cycle is defined as 21 days. 
 
7.8 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice. 
 
7.9 
Follow-Up Period 
All patients will be followed until death or 5 years after initial registration, whichever occurs 
first. 
 
 

 
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8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE Version 
5.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov).  All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0. 
 
8.2 
General Considerations 
a. 
Missed doses of pembrolizumab 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. 
 
8.3 
Pembrolizumab Dose Modification Guidelines for Drug-Related Adverse Events 
 
Pembrolizumab must be withheld for drug-related toxicities and severe or life-threatening 
AEs as described 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.  See Section 8.3a, Table 1, 
below. 
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 Section 8.3b, Table 2, 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. 
irA
Es 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizuma
b  
Corticosteroid and/or 
other therapies  
Monitoring and follow-up  
Pne
um
onit
is  
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 

 
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Dia
rrhe
a / 
Coli
tis  
Grade 2 or 3 
Withhold 
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg prednisone or 
equivalent) followed 
by taper 
Patients who do not 
respond to 
corticosteroids should 
be seen by a 
gastroenterologist for 
confirmation of the 
diagnosis and 
consideration of 
secondary immune 
suppression 
 
 
Monitor participants for signs and 
symptoms of enterocolitis (i.e., 
diarrhea, abdominal pain, blood 
or mucus in stool with or 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 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 
AS
T or 
AL
T 
ele
vati
on 
or 
Incr
eas
ed 
Bilir
ubi
n 
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 returned to baseline or is 
stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg prednisone or 
equivalent) followed 
by taper 

 
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Typ
e 1 
dia
bet
es 
mel
litus 
(T1
DM
) or 
Hyp
ergl
yce
mia 
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. 
 
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 
 

 
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Hyp
oph
ysiti
s 
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 
Hyp
erth
yroi
dis
m 
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 
methimazole or 
carbimazole as 
needed 
Monitor for signs and symptoms of 
thyroid disorders 
Strongly consider referral to 
endocrinologist 
 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyp
oth
yroi
dis
m 
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 

 
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Ne
phri
tis: 
gra
din
g 
acc
ordi
ng 
to 
incr
eas
ed 
cre
atin
ine 
or 
acu
te 
kid
ney 
inju
ry 
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 
 
 
Car
dia
c 
Eve
nts 
(inc
ludi
ng 
my
oca
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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rditi
s, 
peri
car
ditis
, 
arrh
yth
mia
s, 
imp
aire
d 
ven
tric
ular 
fun
ctio
n, 
vas
culit
is) 
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 
Exf
olia
Suspected SJS, 
TEN, or DRESS 
Withhold 

 
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tive 
Der
mat
olo
gic 
Co
ndit
ion
s 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
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 
All 
Oth
er 
irA
Es 
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 
 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). 

 
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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 
protocol treatment 
Participant 
may 
be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab 
(MK-
3475)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 
Use of Transfusion and/or EPO 
 
Transfusions and/or erythropoietin may be utilized as clinically indicated for the treatment 
of anemia, but should be clearly noted as concurrent medications.  Transfusion of platelets 
may be used if clinically indicated. ITP should be ruled out before initiation of platelet 
transfusion. 
 
8.5 
Use of G-CSF 
 
Prophylactic use of colony-stimulating factors including Granulocyte Colony-Stimulating 
Factor (G-CSF), pegylated G-CSF or Granulocyte Macrophage Colony-Stimulating Factor 
GM CSF is not allowed in this study.  Therapeutic use of G-CSF is allowed in patients with 
Grade 3-4 febrile neutropenia. 
 
8.6 
Anti-Infectives 
 
Patients with a documented infectious complication should receive oral or IV antibiotics or 
other anti-infective agents as considered appropriate by the treating Investigator for a given 
infectious condition, according to standard institutional practice. 
 
8.7 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact Dr. Kendra at 614/293-4320 
or kari.kendra@osumc.edu or Dr. Hu-Lieskovan at 310/794-4955 or siwen.hu-
lieskovan@hci.utah.edu.  For dosing principles or questions, please consult the SWOG 
Policy #38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org (then click 
on "Policies and Manuals" under the "Visitors" menu and choose Policy 38). 
 
8.8 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.1 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)-Cohort A 
 
REQUIRED STUDIES 
Pre-study 
(screening) t 
 
 
ON TREATMENT  
Each cycle consists of 1 infusion. 
Infusions to be given q 3 weeks. aq   
 
End of 
Treatment 
assessment u 
Surgical 
Resection s 
Post 
treatment 
F/U prior to 
progression/ 
relapsec 
Post 
treatment 
F/U post-
progression/ 
relapsed 
Cycle 1 
 
Week 1* 
Cycle 2 
 
Week 4* 
Cycle 3 
 
Week 7* 
Possible 
Cycle 4 
 
Week 10* 
PHYSICAL  
 
 
 
 
 
 
 
 
 
History & Physical, PS 
(w/BP &Weight) r 
X 
X 
X 
X 
X 
X 
 
X 
X 
Adverse Event 
Notation 
 
 
X 
X 
X 
X b 
 
X b 
X b 
Baseline Abnormalities 
X 
X 
 
 
 
 
 
 
 
Skin exam p  
X 
X 
X 
X 
X  
X q 
 
X 
 
LABORATORYe 
 
 
 
 
 
 
 
 
 
ANC, platelets, Hgb 
X 
X 
X 
X 
X 
X 
 
X 
 
Total bilirubin 
X 
X 
X 
X 
X 
X 
 
X 
 
LDH f 
X 
 
 
 
 
 
 
 
X 
AST and ALT, Alkaline 
Phosphatase 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum Creatinine or 
CrCl 
X 
X 
X 
X 
X 
X 
 
X 
 
Albumin, Glucose, Na, 
K,  
HCO3/CO2  
 
X 
X 
X 
X 
X 
 
X 
 
Thyroid function test o 
 
X 
 
X 
 
 
 
X 
X 
Pregnancy test i 
X 
X 
X 
X 
X 
X 
 
 
 
 
Study Calendar 9.1 continued on next page. Click here for footnotes. 
 
 
 

 
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REQUIRED STUDIES 
Pre-study t 
(screening) 
 
ON TREATMENT  
Each cycle consists of 1 infusion. 
Infusions to be given q 3 weeks. a  q 
 
 
End of 
treatment 
assessmentu 
Surgical 
resection s 
Post 
treatment 
F/U prior to 
progression/ 
relapsec 
Post 
treatment 
F/U post 
progression/ 
relapsed 
Cycle 1 
 
Week 1 * 
Cycle 2 
 
Week 4 * 
Cycle 3 
 
Week 7 * 
Possible 
Cycle 4 
 
Week 10 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
 
 
CT j, chest, abdomen 
& pelvis or whole body 
PET/CT  
X 
 
 
 
X q 
X k,q 
 
X  k 
X v 
EKGh 
X 
 
 
 
 
 
 
 
 
Brain MRI or CT with 
contrast h 
X 
 
 
 
 
 
 
 
 
SPECIMEN 
SUBMISSION 
 
 
 
 
 
 
 
 
 
Tissue X 
X 
 
X 
 
 
 
X 
 
X (optional) 
Whole Blood w 
X 
 
 
 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
Pembrolizumab (MK-
3475) a 
 
X 
X 
X 
Xq 
 
 
 
 
Click here for footnotes. 
 
NOTE:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  Form submission guidelines are found in 
Section 14.0. 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for continuous 
treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined in  
https://swog.org/Visitors/Download/QA/Best%20Practices%20upddate.pdf.  
 

 
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Footnotes for Study Calendar 9.1: Pembrolizumab (MK-3475) 
 
a. Treatment will continue every 3 weeks, with scans after 3 cycles (9 weeks). 
b. Adverse Event Assessments on the study will continue for all patients until 30 days after the last study drug administration. However, patients with 
ongoing toxicities should be seen more often as clinically indicated. 
c. Post-treatment (after receiving the final dose of pembrolizumab on study) follow-up (prior to progression/relapse):  Patients should be seen at 6 
weeks (-/+ 1 week) after the last dose, then every 12 weeks (+/- 2 weeks) to the end of the first year after registration, then every 6 months (+/- 4 
weeks) to the end of the fifth year after registration.  
d. After progression patients should be followed every 6 months for up to 2 years from the date of treatment registration, then annually thereafter 
until 5 years from treatment registration.   
e. While on study, blood samples collected for pretreatment laboratory tests may be collected and analyzed no more than 3 days prior to dosing. 
NOTE: if MK-3475 was delayed per the dose delay/scheduling criteria or if a visit had to be delayed due to major circumstances (such as a health 
emergency, family/personal emergency, transportation difficulties, scheduling difficulties; a visit date falls on a holiday), the study assessments 
scheduled for these dates will be delayed. 
f. LDH to be done at screening and at progression/relapse. If patient has a subsequent scan 4 weeks later that does not document progression, 
following an initial progression while on protocol therapy do not need to have LDH done at this time. 
h. ECG to be performed at baseline, then as clinically indicated. 
i. Women of childbearing potential must have a negative serum or urine pregnancy test within 28 days prior to registration. Following randomization, 
serum or urine pregnancy tests are required within 72 hours prior to the first dose of study treatment, then according to institutional practice during 
therapy, tests should coincide with clinic visits for blood work and ending with the discontinuation of study treatment. At discontinuation, a negative 
pregnancy test within the preceding 6 weeks is sufficient. A pregnancy test should be done at any time there are clinical concerns for possible 
pregnancy.   
j. Patients with primary melanoma of the head and neck will also require a neck CT. 
k. For patients who have not progressed/relapsed, disease assessments by CT (or MRI if CT cannot be done) chest/abdomen/pelvis or whole body 
PET-CT will be performed at Week 9 (at end of neoadjuvant therapy) and then imaging studies may be done as clinically indicated at the discretion 
of the treating investigator. 
o. Thyroid function tests to include TSH, Free T3, and Free T4 must be performed prior to initiating treatment (within 3 days prior to initial dose on 
Cycle 1) as a reference, should hypothyroidism symptoms arise during treatment. TSH is to be performed prior to dose at week 7, and at initial 
post treatment follow-up. Additional testing of Free T3 and Free T4 should be performed as clinically indicated if TSH is abnormal or if symptoms 
are suggestive of thyroid dysfunction. 
p. If a skin lesion is a site of disease, photographs (with a ruler in the photo if the lesion is measurable per RECIST 1.1) must be taken as 
documentation. Physician’s report and photograph must be stored in the patient’s chart as source documentation.  In addition, the physician’s 
report must be uploaded into Medidata Rave (see Section 14.0). In addition, abnormal lesions concerning for basal cell or squamous cell should 
be documented in the physician’s report and, if biopsy obtained, the pathology report should be included in the patient’s chart as source 
documentation. 
q. See the third bullet under Section 7.1b. If after the first disease assessment, the tumor is unresectable, treatment will continue for 1 more cycle 
and a repeat disease assessment using the same technique as baseline will be obtained 4 weeks later. If at this time the patient’s disease is 
deemed resectable, the patient must continue with resection as previously planned.  
r. 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 should 
be asked of men who are sexually active with women of childbearing potential. Height is only required at baseline. 

 
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Footnotes for Study Calendar 9.1 (contd.): Pembrolizumab (MK-3475) 
 
s. As the primary endpoint of the study is pCR and the goal of the surgery is to remove visible and microscopic disease, surgery is required for all 
potentially resectable tumors. If the tumor is deemed unresectable at 9 weeks, a biopsy should be obtained. 
t.  Pre-study labs, MRI brain, and ECG should be obtained within 28 days prior to registration.  
u. End of treatment assessment is defined as the first clinical assessment after completion of all pembrolizumab treatments (treatment stopped in 
preparation for surgical resection). If treatment stopped due to progression, the F/U post progression column would apply. If treatment stopped 
due to toxicity, the F/U prior to progression would apply. 
v. Survival data are to be collected. Scans obtained in post-treatment F/U post progression, are at the clinical discretion of the treating physician and 
do not need to be submitted into the EDC system. 
w. Whole blood must be collected prior to protocol treatment (mandatory), but after protocol registration. 
x. Please see Section 15.1 for FFPE submission for translational medicine and Section 15.2 for submission of slides for pathology review. 
* These are the corresponding weeks if there are no dose delays. 

 
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9.2 
Pembrolizumab (MK-3475)-Cohort B 
 
REQUIRED STUDIES 
Pre-study 
(screening s) 
 
ON TREATMENT  
Each cycle consists of 1 infusion.  Infusions to be 
given q 3 weeks. a q 
 
 
Post 
treatment 
F/U prior to 
progression c 
Post 
treatment  
F/U post 
progression d 
Cycle 1 
Week 1 * 
Cycle 2 
W4 * 
 
Cycle 3 
W7* 
 
Cycle 
4+ 
 
 
 
PHYSICAL 
 
 
 
 
 
 
 
History & Physical, PS (w/BP, 
Weight)r 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Notation b 
 
X 
X 
X 
X  
X  
X  
Skin exam  p 
X 
X 
X 
X 
X q 
X q 
 
Baseline Abnormalities 
X 
X 
 
 
 
 
 
LABORATORYe 
 
 
 
 
 
 
 
ANC, platelets, Hgb 
X 
X 
X 
X 
X 
X 
 
Total bilirubin 
X 
X 
X 
X 
X 
X 
 
LDH f 
X 
 
 
 
 
 
X 
AST, ALT, and Alkaline 
Phosphatase 
X 
X 
X 
X 
X 
X 
 
Serum Creatinine or CrCl 
X 
X 
X 
X 
X 
X 
 
Albumin, Glucose, Na, K, 
HCO3/CO2 
 
X 
X 
X 
X 
X 
 
Thyroid function tests o 
 
X 
 
X 
Xo 
Xo 
X  
Pregnancy Testi 
X 
X  
X 
X 
X 
 
X 
Click here for footnotes. 
 
Study Calendar 9.2 continued on next page. 
 
 
 

 
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REQUIRED STUDIES 
 
Pre-study s 
(Screening) 
ON TREATMENT  
 Each cycle consists of 1 infusion.  Infusions to 
be given q 3 weeks. a q 
Post treatment  
F/U prior to 
progression c 
Post treatment  
F/U post 
progression d 
 Cycle 1 
W 1 * 
Cycle 2 
W 4 * 
 
Cycle 3 
W 7 * 
Cycle 
4+ a 
 
 
PHYSICAL 
 
 
 
 
 
 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
CT j, chest, abdomen & pelvis or whole 
body PET/CT k 
X 
 
 
 
Xy  
X k 
X t 
Brain MRI or CT with contrast k h 
X 
 
 
 
 
 
 
EKG h 
X 
 
 
 
 
 
 
SPECIMEN SUBMISSION 
 
 
 
 
 
 
 
Tissue w 
X 
 
X 
 
 
 
X (optional) 
Whole Blood u 
X 
 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
Pembrolizumab (MK-3475)  
 
X 
X 
X 
X  
 
 
Click here for footnotes. 
 
NOTE:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  Form submission guidelines are found in 
Section 14.0. 
 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment 
for continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines 
as outlined in  
https://swog.org/Visitors/Download/QA/Best%20Practices%20upddate.pdf.  
 
  
 

 
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Footnotes for Study Calendar 9.2: Pembrolizumab (MK-3475) 
a.  Treatment will continue every 3 weeks, with scans after each 3 cycles (9 weeks).  Protocol treatment and parameters will continue on the same schedule until 
patient has met any of the criteria in Section 7.5.  If disease becomes resectable, see surgical guidelines under Section 7.2 and also 14.4h.  
b. Adverse Event Assessments on the study will continue for all patients until 30 days after the last study drug administration. However, patients with ongoing toxicities 
should be seen more often as clinically indicated.  
c. Post-treatment follow-up (prior to progression/relapse):  Patients should be seen at 6 weeks (-/+ 1 week) after the last dose, then every 12 weeks (+/- 2 weeks) to 
the end of the year after registration, then every 6 months (+/- 4 weeks) to the end of the fifth year after registration.   
d. After progression patients should be followed every 6 months for up to 2 years from the date of treatment registration, then annually thereafter until 5 years from 
treatment registration.   
e. While on study, blood samples collected for pretreatment laboratory tests may be collected and analyzed no more than 3 days prior to dosing. NOTE: if MK-3475 
was delayed per the dose delay/scheduling criteria or if a visit had to be delayed due to major circumstances (such as a health emergency, family/personal 
emergency, transportation difficulties, scheduling difficulties; a visit date falls on a holiday), the study assessments scheduled for these dates will be delayed. 
f. LDH to be done at screening and at progression/relapse. If patient has a subsequent scan 4 weeks later that does not document progression, following an initial 
progression while on protocol therapy, they do not need to have LDH done at this time. 
h. To be performed at baseline, then as clinically indicated throughout treatment. 
i. Women of child bearing potential must have a negative serum or urine pregnancy test within 28 days prior to registration. Following randomization, serum or urine 
pregnancy tests are required within 72 hours prior to the first dose of study treatment, then according to institutional practice during therapy, tests should coincide 
with clinic visits for blood work and ending with the discontinuation of study treatment. At discontinuation, a negative pregnancy test within the preceding 6 weeks 
is sufficient. A pregnancy test should be done at any time there are clinical concerns for possible pregnancy.   
j. Patients with primary melanoma of the head and neck will also require a neck CT. 
k. Disease assessments by CT (or MRI if CT cannot be done) chest/abdomen/pelvis or whole body PET/CT will be performed every 9 weeks until disease progression. 
During treatment and follow-up, brain MRI/CT or other imaging studies may be done as clinically indicated but are not required in the absence of clinical indications. 
o. Thyroid function tests to include TSH, Free T3, and Free T4 must be performed prior to initiating treatment (within 3 days prior to initial dose on Cycle 1) as a 
reference, should hypothyroidism symptoms arise during treatment. TSH is to be performed prior to dose at week 7, and at initial post treatment follow-up. 
Additional testing of Free T3 and Free T4 should be performed as clinically indicated if TSH is abnormal or if symptoms are suggestive of thyroid dysfunction. 
p. If a skin lesion is a site of measurable disease, photographs (with a ruler in the photo if the lesion is measurable per RECIST 1.1) must be taken as 
documentation. Physician’s report and photograph must be stored in the patient’s chart as source documentation.  In addition, the physician’s 
report must be uploaded into Medidata Rave (see Section 14.0). In addition, abnormal lesions concerning for basal cell or squamous cell should be 
documented in the physician’s report and, if biopsy obtained, the pathology report should be included in the patient’s chart as source documentation. If the skin 
lesion is the site of measurable disease, measurements should be taken after 3 cycles (9 week intervals). 
q Patients may continue protocol treatment following progression if they are still deriving clinical benefit in the opinion of the treating investigator.  
r. 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 should be asked of men who are 
sexually active with women of childbearing potential. Height is only required at baseline. 
s.  Pre-study labs, MRI brain, and ECG should be obtained within 28 days prior to registration.  
t. Survival data are to be collected. Scans obtained in post-treatment F/U post progression, are at the clinical discretion of the treating physician and do not need to 
be submitted into the EDC system. 
u. Whole blood must be collected prior to protocol treatment (mandatory). 
w. Please see Section 15.1 for FFPE submission for translational medicine and Section 15.2 for additional submission of slides for pathology review. 
y.   Scans will be obtained every 9 weeks for the first 6 months, then every 4 months. 
* 
These are the corresponding weeks if there are no dose delays. 

 
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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.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT, then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT. 
 
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 

 
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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. 
 
10.2 
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 patients 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. 
 

 
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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. 
 
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 patient 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 patient 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 
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. 

 
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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. 
 
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. 
 
Inadequate assessment, response unknown:  Progression or symptomatic deterioration 
greater than 12 weeks after registration and no other response category applies. 
 
10.4 
Performance Status 
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light 
housework, office work. 
 
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours. 
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours. 
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair. 
 
 
 
 
 
10.5 
Progression-Free Survival 
 
From date of registration to date of first documentation of progression or symptomatic 
deterioration (see Section 10.2e), or death due to any cause.  Patients last known to be 
alive without report of progression are censored at date of last contact. 
 

 
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10.6 
Time to Death 
 
From date of registration to date of death due to any cause.  Patients last known to be alive 
are censored at date of last contact. 
 
10.7 
Pathologic Complete Response 
 
No evidence of viable tumor cells on complete pathological evaluation of the surgical 
specimen per institutional standard of care. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Cohort A 
 
a. 
Cohort A will use a single stage design with an accrual goal of 25 eligible patients 
in total.  The anticipated accrual rate for Cohort A is 2 patients per 
month.  Assuming an ineligibility rate of 20%, we will accrue 30 total patients to 
enroll 25 eligible patients. 
 
b. 
Primary Endpoint:  
 
The primary endpoint for Cohort A is pathologic complete response rate (pCR) as 
defined in Section 10.7. All patients who begin neoadjuvant therapy with 
pembrolizumab will be included in the analysis. Patients who are unable to have 
all sites of disease completely resected and patients who do not undergo surgery 
on protocol (for any reason) will be counted as non-responders. 
 
This is a single stage design with the assumption that a true pCR of 25% or higher 
indicates that the treatment is of considerable interest for patients with resectable 
DM whereas a true pCR of 5% or lower indicates that the treatment will not be of 
further interest. Specifically, we will enroll 25 eligible patients with resectable 
DM.  Four or more pathologic complete responses out of 25 would be considered 
evidence that the treatment warrants further study, provided other factors such as 
toxicity and overall survival also appear favorable. This design has an alpha of 
3.4% (i.e. probability of declaring the regimen warrants further study when the true 
CR is 5%) and a power of 90% (probability of declaring the regimen warrants 
further study when the true pCR is 25%). 
 
c. 
Secondary Endpoints  
 
For the secondary endpoints, 25 eligible patients with measurable disease will be 
sufficient to estimate the overall response rate (ORR) at 9 weeks within ±19.6% 
(95% confidence interval). If only half of patients have measurable disease (13), 
then ORR can be estimated to within 27.2% (95% confidence Interval). Twenty-
five eligible patients will also be sufficient to estimate the OS rate at a particular 
time point (e.g. 9 weeks) to within ±19.6% (95% confidence interval). 
 
 

 
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d. 
Other Objectives:  
 
Toxicity will be assessed across all patients receiving pembrolizumab.  With 25 
patients, any toxicity with at least 5% chance of occurring has 72.3% chance of 
being observed at least once.  For any toxicities, the study will estimate the rate of 
occurrence to within 19.6% (95% confidence interval).   
 
To assess the hypothesis that higher mutational load is associated with pCR rate, 
the study will assess the association between overall mutational load and pCR 
rate.  We will first calculate the per megabase mutation rate for each 
individual.  Then we will use logistic regression to regress pCR status on the 
mutation rates and use a 1-degree freedom likelihood ratio test to obtain a p-value 
for the association between response and mutation rate.  We will control the type 
I error at the two-sided alpha=0.05 level.  We estimated the minimal detectable 
odds-ratio under the assumption that we will collect exome sequencing data on 25 
patients and that we will control the type I error rate at the two-sided alpha=0.05 
level.  In prior data, the median number of mutations per megabase in 
desmoplastic melanoma was found to be 62 and the 25th and 75th percentiles were 
33 and 101, respectively (private communication, Boris Bastian to Antoni Ribas, 
11/18/2014).  Therefore, by matching the quantiles, we approximate the 
distribution of the per megabase mutation rate across patients as a Weibull with 
shape parameter 1.4 and scale parameter 80.  Assuming a baseline response rate 
of 5%, we anticipate over 80% power to detect a log odds-ratio of 0.31 
(corresponding to an odds-ratio of 1.36) for each 10 mutation increase in the per 
megabase mutation rate.  If logistic regression is unstable or behaves poorly, e.g. 
due to low response rates, we will also consider robust and flexible alternatives 
such as the Wilcoxon test to compare mutation rates between responders and non-
responders.  
 
The study will examine whether change in T-cell infiltration following treatment is 
higher in the DM patients who respond.  Specifically, we will compute the change 
in CD8 expression from baseline to resection and then compare the change 
between responders and non-responders using a two-sample t-test.  We will 
control type I error at the alpha=0.05 level.  Assuming that 25% of patients 
respond, then we anticipate 80% power to detect a difference in mean CD8 
expression change 1.35 standard deviations. We will repeat the analysis 
comparing the change in CD8 expression from baseline to week 4 to determine 
whether T-cell infiltration in the on-treatment biopsy is associated with response at 
resection.  
 
To assess the hypothesis that ctDNA fraction at baseline and week 4 are 
associated with response in DM patients, we will assess the association between 
response and ctDNA fraction using a two-sample t-test at the two-sided α=0.05 
level.   Assuming that 25% of patients respond, then we anticipate 80% power to 
detect a difference in mean ctDNA fraction of 1.35 standard deviations.  
To assess the hypothesis that TCR clonality is higher in DM patients who respond, 
suggesting that the T-cells are targeting the tumor, we will compute the clonality 
metric as the normalized Shannon entropy for all patients at baseline, Week 4, and 
resection.  We will then compute the change in clonality metric from baseline to 
resection.  The change in clonality will be compared between responders and non-
responders using a two-sample t-test with significance determined at the two-sided 
alpha=0.05 level.  Assuming that 25% of patients respond, then we anticipate 80% 
power to detect a difference in clonality change of 1.35 standard deviations. We 
will repeat the analysis comparing the change in clonality from baseline to week 4 
to determine whether T-cell clonality in the on-treatment biopsy is associated with 
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The study will examine adaptive immune resistance by first evaluating whether 
PD-L1 expression is increased at Week 4 and resection as compared to baseline 
using paired t-tests and controlling the type I error at the two-sided alpha=0.05 
level.  With 25 patients, we anticipate 80% power at each time point to detect a 
mean difference in expression of 0.58 standard deviations. We will further evaluate 
whether increased PD-L1 expression at Week 4 or at resection is associated with 
response.  Specifically, we will compute the change in expression from baseline to 
resection and then compare the change between responders and non-responders 
using a two-sample t-test.  We will control type I error at the two-sided alpha=0.05 
level. Assuming that 25% of patients respond then at each time point we anticipate 
80% power to detect a difference in mean PD-L1 expression change of 1.35 
standard deviations. We will repeat the analysis comparing the change in PD-L1 
expression from baseline to week 4 to determine whether T-cell infiltration in the 
on-treatment biopsy is associated with response at resection. In addition to our 
assessment of overall mutational load, we will further conduct a neoantigen 
analysis.  Specifically, we will predict the immunogenicity of each nonsynonymous 
somatic mutation using NetMHC.  We will then use logistic regression to regress 
pCR status on the number of predicted immunogenic mutations, computing a p-
value using a 1-df test and controlling type I error at the two-sided alpha=0.05 level. 
 
11.2 
Cohort B  
 
a. 
As a pilot study, Cohort B will use a single stage design with an accrual goal of 21 
eligible patients.  The anticipated accrual rate for Cohort B is 1 patient per 
month.  Assuming an ineligibility rate of 20%, the study will accrue 26 total patients 
to enroll 21 eligible patients. 
 
b. 
Primary Endpoint 
 
The primary endpoint for Cohort B is complete response rate (CR).  Given that 
Cohort B is intended as a pilot trial, we propose single stage design with the 
assumption that a true CR of 20% or higher indicates that the treatment is of 
considerable interest for patients with unresectable/metastatic DM whereas a true 
CR of 5% or lower indicates that the treatment will not be of further interest. 
Specifically, we will enroll 21 eligible patients with unresectable/metastatic 
DM.  Three or more complete responses out of 21 would be considered evidence 
that the treatment warrants further study, provided other factors such as toxicity 
and overall survival also appear favorable. This design has an alpha of 8.5% (i.e. 
probability of declaring the regimen warrants further study when the true CR is 5%) 
and a power of 82% (probability of declaring the regimen warrants further study 
when the true CR is 20%).  The higher alpha and lower power used in this design 
reflect the intention to use this as a pilot trial. 
 
c. 
Secondary Endpoints  
 
For the secondary endpoints, 21 eligible patients will be sufficient to estimate the 
PFS and OS at a particular time point (e.g. 9 weeks) to within ±21.4% (95% 
confidence interval). However, since PFS is estimated only among patients who 
do not undergo resection, we will only be able to estimate the PFS to within 
±21.9%, ±22.5%, or ±23.9% (95% confidence intervals) if the percentage of 
patients who undergo resection is 5%, 10%, or 20%, respectively.   
 
d. 
Translational Medicine Objectives: The statistical analysis of the translational 
medicine objectives for Cohort B will be the same as for Cohort A except we will 
use CR as the endpoint instead of pCR.  

 
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To assess the hypothesis that higher mutational load is associated with CR rate, 
the study will assess the association between overall mutational load and CR rate.  
We will first calculate the per megabase mutation rate for each individual.  Then 
we will use logistic regression to regress CR status on the mutation rates and use 
a 1-degree freedom likelihood ratio test to obtain a p-value for the association 
between response and mutation rate.  We will control the type I error at the two-
sided alpha=0.05 level.  We estimated the minimal detectable odds-ratio under the 
assumption that we will collect exome sequencing data on 21 patients and that we 
will control the type I error rate at the two-sided alpha=0.05 level.  In prior data, the 
median number of mutations per megabase in desmoplastic melanoma was found 
to be 62 and the 25th and 75th percentiles were 33 and 101, respectively (private 
communication, Boris Bastian to Antoni Ribas, 11/18/2014).  Therefore, by 
matching the quantiles, we approximate the distribution of the per megabase 
mutation rate across patients as a Weibull with shape parameter 1.4 and scale 
parameter 80.  Assuming a baseline response rate of 5%, we anticipate over 70% 
power to detect a log odds-ratio of 0.45 (corresponding to an odds-ratio of 1.57) 
for each 10 mutation increase in the per megabase mutation rate.  If logistic 
regression is unstable or behaves poorly, e.g. due to low response rates, we will 
also consider robust and flexible alternatives such as the Wilcoxon test to compare 
mutation rates between responders and non-responders.  
 
The study will examine whether change in T-cell infiltration following treatment is 
higher in the DM patients who respond.  Specifically, we will compute the change 
in CD8 expression from baseline to progression and then compare the change 
between responders and non-responders using a two-sample t-test.  We will 
control type I error at the alpha=0.05 level.  Assuming that 20% of patients 
respond, then we anticipate 80% power to detect a difference in mean CD8 
expression change 1.61 standard deviations. We will repeat the analysis 
comparing the change in CD8 expression from baseline to week 4 to determine 
whether T-cell infiltration in the on-treatment biopsy is associated with response at 
progression.  
 
To assess the hypothesis that ctDNA fraction at baseline and week 4 are 
associated with response in DM patients, we will assess the association between 
response and ctDNA fraction using a two-sample t-test at the two-sided α=0.05 
level.   Assuming that 20% of patients respond, then we anticipate 80% power to 
detect a difference in mean ctDNA fraction of 1.61 standard deviations.  
To assess the hypothesis that TCR clonality is higher in DM patients who respond, 
suggesting that the T-cells are targeting the tumor, we will compute the clonality 
metric as the normalized Shannon entropy for all patients at baseline, Week 4, and 
progression.  We will then compute the change in clonality metric from baseline to 
progression.  The change in clonality will be compared between responders and 
non-responders using a two-sample t-test with significance determined at the two-
sided alpha=0.05 level.  Assuming that 20% of patients respond, then we anticipate 
80% power to detect a difference in clonality change of 1.61 standard deviations. 
We will repeat the analysis comparing the change in clonality from baseline to 
Week 4 to determine whether T-cell clonality in the on-treatment biopsy is 
associated with response at progression.  
 
The study will examine adaptive immune resistance by first evaluating whether 
PD-L1 expression is increased at Week 4 and progression as compared to 
baseline using paired t-tests and controlling the type I error at the two-sided 
alpha=0.05 level.  With 21 patients, we anticipate 80% power at each time point to 
detect a mean difference in expression of 0.64 standard deviations. We will further 
evaluate whether increased PD-L1 expression at Week 4 or at progression is 

 
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associated with response.  Specifically, we will compute the change in expression 
from baseline to progression and then compare the change between responders 
and non-responders using a two-sample t-test.  We will control type I error at the 
two-sided alpha=0.05 level. Assuming that 20% of patients respond, then at each 
time point we anticipate 80% power to detect a difference in mean PD-L1 
expression change of 1.61 standard deviations. We will repeat the analysis 
comparing the change in PD-L1 expression from baseline to Week 4 to determine 
whether T-cell infiltration in the on-treatment biopsy is associated with response at 
progression. In addition to our assessment of overall mutational load, we will 
further conduct a neoantigen analysis.  Specifically, we will predict the 
immunogenicity of each nonsynonymous somatic mutation using NetMHC.  We 
will then use logistic regression to regress CR status on the number of predicted 
immunogenic mutations, computing a p-value using a 1-df test and controlling type 
I error at the two-sided alpha=0.05 level. 
 
11.3 
Data and Safety Monitoring 
 
While the SWOG DSMC does not monitor non-randomized studies, SWOG has policies 
and procedures in place to monitor single arm studies. Accrual reports are generated 
weekly and study-specific accrual monitoring is done by the Study Chair, Study Statistician 
and the Disease Committee Chair. Reports summarizing adverse events, serious adverse 
events (SAEs) and treatment administration are provided monthly to the Study Chair and 
Study Statistician for monitoring. In addition all SAEs, which by definition require 
expeditious reporting, are reviewed and processed by the Adverse Event Coordinator at 
the SWOG Operations Office and a physician reviewer based on data provided via the NCI 
CTEP-AERS system. Cumulative study-specific SAE reports are provided to the Study 
Chair and Study Statistician upon occurrence of an event. Formal reports summarizing the 
study are prepared for all SWOG members every 6 months. 
 
 
12.0 
DISCIPLINE REVIEW 
 
12.1 
Pathology Review 
  
Desmoplastic melanoma will be defined as: a proliferation of spindle cells in the 
background of stromal fibrosis. Lesional cells may resemble fibroblasts, but there are 
scattered cells with hyperchromatic atypical nuclei. These would be S100+ and/or SOX-
10+ and negative for HMB45, gp100, tyrosinase, and often negative for Melan-A. After 
completion of the study, tissues will be reviewed centrally to standardize the pathologic 
eligibility. (12,13,14)  
 
The slides used for the primary diagnosis of desmoplastic melanoma must be submitted 
for confirmatory review if available. These include the H&E slides and any immunostains 
completed to diagnose desmoplastic melanoma and to rule out other diagnoses. All 
possible attempts should be made to obtain these slides. 
 
These specimens will be submitted as outlined in Section 15.2. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than nine calendar days 
prior to planned start of treatment). 
 

 
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13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group.  Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet to CTEP. 
 
a. 
CTEP Investigator Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all investigators participating in any NCI-sponsored clinical trial 
to register and to renew their registration annually. 
 
Registration requires the submission of: 
 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an 
original signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website 
at http://ctep.cancer.gov/investigatorResources/investigator_registration.htm.  
 
For questions, please contact the CTEP Investigator Registration Help Desk by 
email at pmbregpend@ctep.nci.nih.gov.  
 
b. 
CTEP Associate Registration Procedures 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) application is a web-based application intended for use by both 
Investigators (i.e., all physicians involved in the conduct of NCI-sponsored clinical 
trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored 
clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration 
and annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering 
with CTEP as an Investigator, which must be completed before a CTEP-IAM 
account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU 
members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
ctepreghelp@ctep.nci.nih.gov.  
 
c. 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 

 
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IRB Approval:   
 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients.  
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: an active Federal Wide Assurance 
(FWA) number, an active roster affiliation with the Lead Network or a participating 
organization, a valid IRB approval, and compliance with all protocol specific 
requirements. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this 
study are not required to submit IRB approval documentation to the CTSU 
Regulatory Office. For sites using the CIRB, IRB approval information is received 
from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to 
the CIRB via IRBManager to indicate their intent to open the study locally.  The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  
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. 
 
Downloading Site Registration Documents:   
 
Site registration forms may be downloaded from the S1512 protocol page located 
on the CTSU members’ website.  Permission to view and download this protocol 
and its supporting documents is restricted and is based on person and site roster 
assignment housed in the CTSU RSS. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol 
S1512 tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the SWOG link to expand, then select trial protocol S1512 
• 
Click on LPO Documents, select the Site Registration documents link, 
and download and complete the forms provided.   
 
Requirements For S1512 Site Registration: 
 
• 
CTSU Transmittal Sheet (optional)  
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol 
of 
Human 
Subjects 
Assurance 
Identification/IRB 
Certification/Declaration of Exemption Form, or combination is 
accepted) 
 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office via 
the Regulatory Submission Portal, where they will be entered and tracked 
in the CTSU RSS.  
 
Regulatory Submission Portal:  www.ctsu.org (members’ area) → 
Regulatory Tab → Regulatory Submission 

 
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When applicable, original documents should be mailed to: 
 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should 
alert the CTSU Regulatory Office immediately at 866-651-2878 in order to 
receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the 
CTSU website.   
 
• Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
 
 

 
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OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
 

 
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13.4 
Registration Procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is integrated with 
the CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient in the Rave database.  OPEN can be accessed at 
https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on the 
SWOG CRA Workbench. 
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met 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 patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
c. 
The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.  Please print this confirmation for your records. 
 
d. 
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org.  
For any additional questions contact the CTSU Help Desk at 888/823-5923 or 
ctsucontact@westat.com. 
 
13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
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 patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see below for details. 
 
14.3 
Data Submission Procedures 
 

 
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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, you must have 
an 
active 
CTEP-IAM 
account 
(check 
at 
https://eapps-
ctep.nci.nih.gov/iam/index.jsp) and the appropriate Rave role (Rave CRA, Read-
Only, Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata. To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on 
the link in the upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time 
of initial 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.  Go to the SWOG 
web site (http://swog.org) and logon to the Members Area using your SWOG 
Roster ID Number and password. After you have logged on, click on Workbenches, 
then CRA Workbench to access the home page for the CRA Workbench and follow 
the link to Rave® provided in the left-hand navigation panel. 
 
To access the CRA Workbench the following must be done (in order): 
 
1. 
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
2. 
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, 
3. 
Your Web User Administrator has added you as a web user and has given 
you the appropriate system permissions to view data for that institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  For 
point 3, contact your local Web User Administrator (refer to the "Who is my Web 
User Administrator?" function on the swog.org Members logon page). 
 
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. 
 
14.4 
Data Submission Overview and Timepoints  
 
a. 
WITHIN 7 DAYS OF INITIAL REGISTRATION, SUBMIT: 

 
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S1512 Onstudy Form 
 
S1512 Baseline Abnormalities Form 
 
Baseline Tumor Assessment Form (RECIST 1.1) 
 
Radiology reports from all scans performed to assess disease at baseline** 
 
Physician report documenting any measurement of skin lesions made during a 
physical examination** 
 
Pathology report documenting histologic confirmation of desmoplastic melanoma** 
 
**NOTE: Upload reports via the Source Documentation: Baseline form in Rave®. 
 
Whole blood specimens must be collected prior to starting protocol 
treatment and MUST BE SUBMITTED THE SAME DAY AS COLLECTED. 
 
b. 
WITHIN 28 DAYS OF REGISTRATION: 
 
See Section 15.0 for specimen submission requirements. 
 
c. 
WITHIN 7 DAYS AFTER EACH CYCLE OF TREATMENT  (1 CYCLE = 21 DAYS) 
SUBMIT: 
 
S1512 Treatment Form  
 
S1512 Adverse Event Form 
 
 
d. 
FOR COHORT A, WITHIN 7 DAYS AFTER THE END OF TREATMENT DISEASE 
ASSESSMENT: 
 
Follow-Up Tumor Assessment Form (RECIST 1.1) 
 
Radiology reports from all scans performed to assess disease*.  Physician must 
note tumor measurement in patient records. 
 
Physician report documenting any measurements of skin lesions made during a 
physical examination.* 
 
*NOTE: Upload reports via the Source Documentation: Follow-Up form in Rave® 
 
e. 
FOR COHORT B, WITHIN 7 DAYS AFTER EACH DISEASE ASSESSMENT (SEE 
STUDY CALENDAR FOR SCHEDULE) UNTIL PROGRESSION* (AS DEFINED 
IN SECTION 10.2d), SUBMIT: 
 
Follow-Up Tumor Assessment Form (RECIST 1.1) 
 
Radiology reports from all scans performed to assess disease.* Physician must 
note tumor measurement in patient records. 
 
Physician report documenting any measurements of skin lesions made during a 
physical examination.* 
 
*NOTE: Upload reports via the Source Documentation: Follow-Up form in Rave®. 
 

 
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f. 
WITHIN 7 DAYS OF DISCONTINUATION OF PROTOCOL TREATMENT, 
SUBMIT: 
 
Off Treatment Notice 
 
S1512 Treatment Form 
 
S1512 Adverse Event Form. 
 
g. 
WITHIN 14 DAYS OF PROGRESSION OR RELAPSE, SUBMIT: 
 
Follow-Up Tumor Assessment Form (RECIST 1.1) OR Follow-Up Form (if patient 
underwent surgery to resect disease after starting protocol therapy). 
 
Radiology reports from all scans performed to assess disease*. Physician must 
note tumor measurement in patient records. 
 
Physician report documenting any measurements of skin lesions made during a 
physical examination.* 
 
If patient was on protocol treatment at the time of progression, also submit the 
materials specified in Section 14.4f. 
 
See Section 15.0 for specimen submission requirements. 
 
*NOTE: Upload reports via the Source Documentation: Follow-Up form in Rave®. 
 
h. 
WITHIN 14 DAYS OF SURGERY TO RESECT DISEASE, SUBMIT: 
 
S1512 Pathologic Response Form 
 
All operative and pathology reports from the procedure*. 
 
Submit surgical specimen and specimen from biopsy between Weeks 3-5. See 
Section 15.0 for specimen submission requirements. 
 
*NOTE: Upload reports via the Source Documentation: Follow-Up form in Rave®. 
 
i. 
ONCE OFF ALL PROTOCOL TREATMENT SUBMIT EVERY 6 MONTHS FOR 
THE FIRST 2 YEARS, THEN YEARLY FOR A TOTAL OF 5 YEARS FROM 
INITIAL REGISTRATION: 
 
Follow-Up Form 
 
Late Effects Form (if prior to treatment for progression or relapse or a second 
primary, and prior to non-protocol treatment, the patient experiences any severe 
[Grade ≥ 3] long term toxicity that has not been previously reported). 
 
j. 
WITHIN 28 DAYS OF KNOWLEDGE OF DEATH: 
 
Notice of Death and all of the items listed in Section 14.4e (if the patient was 
still on protocol treatment) or Follow-Up Form (if the patient was off protocol 
treatment) documenting death information. 
 
 
 

 
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15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Specimen Submission for Translational Medicine  
 
Specimens for Translational Medicine studies outlined in Section 18.1 are required for 
participation in this study.  
 
a. 
Specimens must be submitted at the timepoints listed below.  Collection 
instructions are outlined in Section 15.1c and submission instructions are outlined 
in Section 15.1e. NOTE:  With patient consent, leftover specimens will be banked 
for future unknown use. 
 
b. 
Specimens must be submitted at the following times (see Section 9.0): 
 
1. 
Three cores (at least 18 gauge needle) to be obtained from primary 
(preferred) or metastatic lesions (avoid lymph node biopsy if possible) and 
made into three different FFPE blocks (one core per block). Sending all 
three blocks is preferred. Thirty slides (minimum 5um thick) per block from 
each of the blocks may be submitted if the institution cannot release 
pathology paraffin embedded blocks, at the following times: 
• 
Baseline (required) – prior to the start of study treatment. 
Initial/Archival biopsy may be used if 4 cm x 30 slides can be 
provided). Submit tissue within 30 days after registration. 
• 
Biopsy between 3 and 5 weeks after initiation of treatment 
(required for all patients with residual disease to biopsy). Submit 
tissue within 30 days of collection. 
• 
Surgical specimen from each site of surgical resection (required if 
surgical resection is performed). Submit tissue within 30 days of 
collection. 
• 
Progression/relapse (optional). Submit tissue within 30 days of 
collection. 
 
Submit formalin fixed paraffin embedded (FFPE) tissue according to 
guidelines below. 
 
2. 
Twenty mL whole blood in vacutainer tubes with EDTA coating.  Collect at 
the following times: 
• 
Baseline (mandatory prior to the start of study treatment) 
 
c. 
Specimen Collection Instructions 
 
1. 
Standard collection of Paraffin Embedded Tissue Block. 
• 
Place the fresh tissue in formalin. Do Not Exceed 24 hours fixation 
time. 
• 
Fixed tissue must be paraffin embedded within 24 hours. 
• 
Send H & E (Hematoxylin and Eosin) stained section if it is routine 
practice for the site.  Otherwise, sending the block without the 
H&E slide is adequate. 

 
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2. 
Standard collection of Slides. 
• 
Slides may be processed according to local pathology guidelines. 
 
3. 
Standard Instructions for Shipping Paraffin Embedded Tissues and Slides: 
• 
Include in shipment: 
i. 
Tissue as outlined above 
ii. 
A pathology report (indicating the morphological 
diagnosis). 
iii. 
A copy of the packing/shipping list produced by the 
SWOG Online Specimen Tracking System. 
• 
Ship paraffin embedded tissue according to the shipping 
guidelines for ambient specimens in the General Specimen 
Submission Instructions below. 
 
NOTE: FFPE tissue blocks will NOT be returned to the submitting institution unless 
it is required for patient care. If the block is needed for patient care, a written 
request must be submitted to the Ribas Laboratory with a rationale for the return. 
If a site will have an issue with this requirement, the option to submit cores in place 
of the block should be considered. 
 
4. 
Standard Instructions for Collecting and Shipping Fresh Whole Blood 
Specimens. 
• 
Use 10 ml vacutainer tubes with EDTA to collect whole blood. 
o 
If your site does not have the recommended size of 
vacutainer tubes required by the treatment protocol, other 
sized tubes may be used to collect the required/requested 
amount of blood. 
o 
Avoid using < 3mL collection tubes. 
o 
Pre-label vacutainer tube(s) according to specimen 
labeling requirements indicated in the General Specimen 
Submission Instructions. 
• 
Use aseptic techniques and draw blood from the patient into the 
vacutainer tube(s). The amount of blood required will vary per 
protocol. 
• 
Immediately after the blood is drawn, thoroughly mix the blood 
with the anticoagulant by gently inverting the vacutainer tube(s) 
multiple times. 
• 
Store whole blood prior to shipping at room temperature. Do not 
freeze the whole blood. Storage time longer than 24 hours should 
be noted on the specimen shipping form. 

 
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• 
Whole blood should be shipped the same day (day of collection) 
preferably using Federal Express, Priority Overnight service. Use 
of other courier services may delay package receipt. 
 
o 
Specimens may be shipped Monday through 
Thursday using only overnight delivery to arrive 
Monday through Friday. No blood should be collected 
or shipped on Friday or right before a holiday.  For 
questions about shipping specimens around a 
holiday, please reference the Bank’s holiday hours 
memo distributed by the SWOG Operations Office, or 
call the Ribas Lab directly at 310-825-2676. 
 
o 
During the months of April-September, ship fresh 
specimens on a cold pack. During the months of October-
March, insulate fresh specimens to keep from freezing 
due to weather (ex. wrap specimen in bubble wrap). 
 
For packaging instructions, refer to the shipping guidelines for ambient 
specimens in the General Specimen Submission Instructions outlined below. 
 
d. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
e. 
SHIPPING SAMPLES 
 
1. 
All submitted specimens must be labeled with the treatment protocol 
number, SWOG patient number, patient initials, time point, and date of 
specimen collection, specimen number and/or specimen type, Surgical 
Pathology ID (Accession # from pathology report), and block number (as 
applicable). 
 
a. 
Instructions for Labels 
i. 
Large Labels: 
▪ 
Use Avery 5160 labels* 
▪ 
Use for all specimens submitted 
▪ 
Type or write information 
▪ 
Place on outside bag or container, depending on 
specimen type 
 
ii. 
Small Labels: 
• 
Use Avery 5160 labels* 
• 
Use for all specimens submitted 
• 
Type or write information on right side of line 
• 
Cut the label on the line 
• 
Place only the right side of the label on each 
specimen 
• 
For blood products, place on each vial submitted 
• 
For paraffin specimens, place on slides or blocks 
*If Avery 5160 labels are not available, the label may be 
printed on regular paper and taped to the specimen 
container.  
 
2. 
Include a specimen shipping form in every shipment, ensuring the 
information on the form exactly matches the specimens in the shipment. 
 

 
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3. 
Ship specimens according to IATA shipping regulations. 
 
a. 
Shipping guidelines for ambient specimens: 
i. 
The specimen must be wrapped in absorbable material. 
ii. 
Place the specimen in an AIRTIGHT container (must have a 
primary and secondary container, ex a Saf-T-Pak). 
iii. 
Place packaged specimen in an appropriate shipping 
container (ex. FedEx box or clinical pack). 
 
Mark the outside shipping container with an "Exempt Human 
Specimen" label. 
 
4. 
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) and logon to the 
Members Area. After you have logged on using your SWOG roster ID 
number and password, click on the CRA Workbench link to access the 
home page for CRA Workbench website. Non- SWOG users may log into 
SpecTrack using their CTSU UserID and password on the SpecTrack login 
page located at  
https://crawb.crab.org/SpecTrack/Logon.aspx (select the option “SWOG – 
SWOG – CTSU”).  SpecTrack start-up instructions (both written and 
demo) are available after signing in to SpecTrack.  
 
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 
(http://dnet.crab.org/SpecTrack/Documents/Instructions.pdf); or contact 
the Data Operations Center at 206/652-2267 to be routed to the Data 
Coordinator for further assistance. 
 
 

 
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In the online specimen tracking system, the appropriate SWOG laboratory 
for submission is identified as follows: 
 
Lab #224: 
The Ribas Laboratory   
Attn: Agustin Vega-Crespo 
Medical Receiving – Study S1512 
CHS 54-200 
650 Charles E Young Drive S 
UCLA Medical Center 
Los Angeles, CA 90095 
Phone: 310-825-2676 
FAX: 310-825-2493  
 
Contact:  Agustin Vega-Crespo 
E-mail: avegacrespo@mednet.ucla.edu     
 
ATTENTION:  DO NOT SHIP SPECIMENS FROM SECTION 15.1 TO 
THE SWOG BIOSPECIMEN BANK  
 
5. 
Federal guidelines for the shipment of blood products: 
 
a.     
The tube must be wrapped in an absorbent material. 
 
b.   
The tube must then be placed in an AIRTIGHT container (like 
a resealable bag). 
 
c.    
Pack the resealable bag and tube in a Styrofoam shipping 
container. 
 
d.    
Pack the Styrofoam shipping container in a cardboard box. 
 
e.     
Mark the box "Biohazard" 
 
 
15.2 
Specimen Submission for Central Confirmatory Quality Review  
 
Specimens for central review as outlined in Section 12.1 are required (if available) for 
participation in this study.  
 
Specimen instructions are outlined in Section 15.2a and submission instructions are 
outlined in Section 15.2b. NOTE:  With patient consent, leftover specimens will be 
banked for future unknown use. 
 
a. 
Within 120 days after CTSU’s distribution of Revision #7, archival slides from the 
primary diagnosis of desmoplastic melanoma must be submitted for central 
confirmatory quality review, if available: 
 
1. 
Slides 
• 
At least one (1) H&E slide representative of the diagnosis 
• 
If available, at least one (1) immunostain, such as gp100, Sox 10, 
Melan-A, HMB-45, completed from the initial diagnosis of 
desmoplastic melanoma (the slides that were used to rule out other 
diagnoses), though all immunostains are preferred. All possible 
attempts should be made to obtain these slides 
 

 
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2. 
The corresponding anatomic pathology report that includes the diagnosis 
is required. Label the report with the patient ID# and surgical pathology 
identification number. 
 
b. 
SHIPPING CENTRAL CONFIRMATORY QUALITY REVIEW SAMPLES 
 
1. 
Specimen Labeling 
 
Slides must be labeled with the following:  
• 
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. 
For additional information about labeling and shipping instructions 
(including address) for slides, refer to the SWOG Specimen Submission 
webpage  
(https://www.swog.org/clinical-trials/biospecimen-
resources/biospecimen-processing-and-submission-procedures).    
 
3. 
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.  
 
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 patient ID 
must be included on any source documentation included with the 
shipment. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE 
NO EXCEPTIONS. 
 
Note: If limited or no tissue is available, then the site must document 
reason for incomplete specimen submission (insufficient tissue available) 
in the participant’s medical record and in the SWOG Specimen Tracking 
System. If limited tissue is available, this must be documented in the 
Specimen Tracking System under “Comments” at the time of specimen 
submission.  If no tissue available, this must be documented in the 

 
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Specimen Tracking System by choosing “Notify that Specimen Cannot be 
Submitted”. 
 
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 SWOG Statistics 
and Data Management 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 central confirmatory pathology review tissue samples for 
SWOG Repository 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 Patients (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 Patients (Code of Federal 
Regulations 45 CFR 46). 
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312.  
 
Publication and Industry Contact 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between Merck (hereinafter referred to as 
"Collaborator(s)") and the NCI Division of Cancer Treatment and Diagnosis.  Therefore, the 
following obligations/guidelines in addition to the provisions in the "Intellectual Property Option to 
Collaborator"  

 
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(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 for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators.  The protocol documents for studies 
utilizing Agents contain confidential information and should not be shared or distributed 
without the permission of the NCI.  If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov.  
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the patient 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 prior 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 
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 patients, 
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:  ncicteppubbs@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 patients enrolled in the studies as well 
as those who will enroll in future studies using similar agents.  Adverse events are 
reported in a routine manner at scheduled times during a trial. (Directions for 
routine reporting are provided in Section 14.0.) Additionally, certain adverse events 
must be reported in an expedited manner to allow for more timely monitoring of 
patient safety and care.  The following guidelines prescribe expedited adverse 
event reporting for this protocol. See also Appendix 18.1 for general and 
background information about expedited reporting. 
 
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.  
 
 

 
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c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP-
AERS.  
 
When the adverse event requires expedited reporting, submit the report within the 
number of calendar days of learning of the event, as specified in Table 16.1. 
 
In the rare event when internet connectivity is disrupted a 24-hour notification is 
made to NCI by telephone at 301/897-7497.  An electronic report MUST be 
submitted immediately upon re-establishment of internet connection.   
 
Any supporting documentation requested by CTEP should be submitted in 
accordance with instructions provided by the CTEP-AERS system. 
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures. 
 
e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agents as part of the trial.  Reporting requirements are provided in 
Table 16.1.  The investigational agent used in this study is 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 patient or patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR or [Section 
16.1f.] 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 
24-hour report. 
 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 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 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. 
 
2. 
The adverse events listed below also require expedited monitoring for 
this trial:   
• 
Fever ≥ Grade 1 per CTCAE 4.0 accompanied by hypotension, 
dehydration requiring IV fluids 
• 
Renal insufficiency (≥ Grade 2) 
• 
≥ Grade 3 chills in the absence of an obvious infectious cause 
 
3. 
For both study arms, the adverse events listed below do not require 
expedited reporting via CTEP-AERS:  none. 
 
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. 
 
 

 
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For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applicatio2.  
 
2. 
Supporting documentation should be submitted to CTEP in accordance 
with instructions provided by the CTEP-AERS system.  A copy of the 
report and the following supporting documentation must also be submitted 
to SWOG Operations Office within 30 days: 
 
• 
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 patient 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 
 
• 
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 patients on study should be reported 
via CTEP-AERS at the time the outcome becomes known, accompanied by 
the same Pregnancy Report Form used for the initial report. 
 
• 
Fetal Death Fetal Death defined in CTCAE as “A disorder characterized by 
death in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation” should be 
reported expeditiously as Grade 4 “pregnancy, puerperium and perinatal 
conditions – Other (pregnancy loss)” under the Pregnancy, puerperium 
and perinatal conditions SOC.   
 
• 
Death Neonatal  Neonatal death, defined in CTCAE as “A disorder 
characterized by cessation of life occurring during the first 28 days of life” that 
is felt by the investigator to be at least possibly due to the investigational 
agent/intervention should be reported expeditiously.   
 
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration – Other (neonatal loss)” under the General 
disorders and administration SOC. 
 
Fetal death and neonatal death should NOT be reported as a Grade 5 event.  If 
reported as such, the CTEP-AERS interprets this as a death of the patient 
being treated. 
 
 

 
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NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, or 
“Neonatal loss”, the Pregnancy Information Form should also be completed and faxed with 
any additional medical information to 301-230-0159.  The potential risk of exposure of the 
fetus to the investigational agent(s) or chemotherapy agent(s) should be documented in 
the “Description of Event” section of the CTEP-AERS report. 
 
The Pregnancy Information Form is available at  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htmns/docs/aeguidelines.pdf 
. 
 
 

 
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17.0 
BIBLIOGRAPHY 
 
1  
Champiat S, Ferte C, Lebel-Binay S, Eggermont A, Soria J. Exomics and immunogenics: Bridging 
mutational load and immune checkpoints efficacy. OncoImmunology 3(1):e27817, 2014. 
 
2  
Mar VJ, Wong SQ, Li J,Scolyer RA, McLean C, Papenfuss AT, Tothill RW, Kakavand H, Mann GJ, 
Thompson JF, Behren A, Cebon JS, Wokfe R, Kelly JW, Dobrovic A, McArthur GA. BRAF/NRAS 
wild-type melanomas have a high mutation load correlating with histologic and molecular signatures 
of UV damage. Clinical Cancer Research 19(17):4589-98, 2013. 
 
3  
Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T, A rheostat for immune responses: the unique 
properties of PD-1 and their advantages for clinical application. Nat Immunol 14:1212-1218, 2013. 
 
4  
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu 
Rev Immunol 26:677-704, 2008. 
 
5  
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 
12:252-64, 2012. 
 
6  
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu 
Rev Immunol 26:677-704, 2008. 
 
7  
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, 
Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, 
Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, 
Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance.  Nature 
27;515(7528):568-71, 2014. 
 
8  
Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, 
Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, 
Wang L, Ribas A, Wolchok JD, Chan TA. Genetic basis for clinical response to CTLA-4 blockade 
in melanoma. N Engl J Med (4);371(23):2189-99, 2014. 
 
9  
Margaritescu I, Chirita AD. Desmoplastic melanoma-challenges in the diagnosis and management 
of a rare cutaneous tumor. Rom J Morphol Embryol 55 (3):947-952, 2014. 
 
10  
Margaritescu I, Chirita AD. Desmoplastic melanoma-challenges in the diagnosis and management 
of a rare cutaneous tumor. Rom J Morphol Embryol 55 (3):947-952, 2014. 
 
11  
Chen LL, Jaines N, Barker CA, Busam KJ, Marghoob AA. Desmoplastic melanoma: a review. J Am 
Acad Dermato 68(5):825-33, 2013. 
 
12  
Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T, A rheostat for immune responses: the unique 
properties of PD-1 and their advantages for clinical application. Nat Immunol 14:1212-1218, 2013. 
 
13  
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu 
Rev Immunol 26:677-704, 2008. 
 
14  
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 
12:252-64, 2012. 
 
 
 
 
 

 
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18.0 
APPENDIX 
 
18.1 
Translational Medicine Details 
 
18.2  
Specimen Banking Instructions for the UCLA Lab #224: The Ribas Laboratory   
 
18.3  
Specimen Banking Instructions for the SWOG Biospecimen Bank 
 
 

 
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18.1 
Translational Medicine Details  
 
Data storage and computational infrastructure: To optimally perform computational 
analysis on the large amount of genomic and imaging data to be generated from this study, 
it is expected that appropriate cloud computing infrastructure with the necessary analysis 
pipeline is required for the storage and computation of these data. One such computational 
infrastructure and resource available for this study is through the collaboration with the 
Parker Institute for Cancer Immunotherapy. 
 
Whole exome sequencing to analyze mutational load: To test whether there is a 
correlation of tumor mutational load and response to PD-1 antibody therapy, DNA will be 
isolated from thick slides of FFPE tissues and *PBMC via commercial kit (i.e. Qiagen 
AllPrep DNA/RNA FFPE kit, cat 80234). Whole exome sequencing (WES), including probe-
based exon capture, library preparation, and high throughput 100bp paired-end 
sequencing on the Illumina HiSeq2500 platform will be performed at the UCLA 
Immunogenetics core laboratory (CLIA approved lab). DNA from the same patient’s PBMC 
(preferably) or other non-cancerous tissue will be isolated and sequenced for baseline 
comparison and differentiation of germline SNPs from true somatic mutations. Read 
mapping and data preprocessing will be performed according to the Broad Institute Best 
Practices Guidelines for the Genome Analysis Toolkit (version 3), and mutation detection 
will require a consensus call among several published programs (Varscan2, MuTect, GATK 
HaplotypeCaller). Mutational load will be quantified as the number of nonsynonymous 
somatic mutations per MB.    
 
Quantitative analysis of T cell infiltration and circulating tumor DNA (ctDNA) profile: 
To analyze whether baseline CD8+ cell infiltration and ctDNA profile are correlated with 
response to anti-PD1 therapy, and whether PD-1 blockade can increase CD8+ cell 
infiltration in DM patients, slides taken from standard formalin-fixed paraffin-embedded 
(FFPE) tissue blocks obtained from baseline, 4 week (on treatment), and 9 week biopsies 
will be stained by quantitative multiplexed immunohistochemistry (IHC) for, at the minimum, 
S100 and CD8 to determine the presence of CD8+ T cells inside tumors and in the invasive 
margin. ctDNA profiling will be performed on plasma processed from patient baseline blood 
sample to determine the amount or fraction of ctDNA corresponding to the genetic profile 
of the patient tumor biopsies. Slides will be analyzed using quantitative digital pathology 
following published methods, such as described by Tumeh et al. and Angelo et al.. (1, 2)  
This analysis will provide a predictive score for response or lack of response to 
pembrolizumab based on the baseline CD8+ T cell infiltration or ctDNA profile. 
 
Method: Slides will be stained with, at the minimum, S100 and CD8 (one slide per stain, or 
multiple stain per slide as appropriate for chosen quantitative multiplexed IHC technique) 
at a core facility with the instrumentation, such as the UCLA Anatomic Pathology IHC 
Laboratory (CLIA approved lab). Immunostaining will be performed using staining 
procedures appropriate for the specific quantitative multiplexed IHC technique and 
validated by the Translational Medicine team, for example, Leica Bond III autostainers 
using Leica Bond ancillary reagents and REFINE polymer DAB detection system (Leica 
DS9800). Antibodies used will include rabbit polyclonal S100 (DAKO, 1/1,000 dilution, low 
pH retrieval), mouse anti-CD8 clone C8/144B (DAKO, 1/100, low PH retrieval), and all 
staining will be performed on Dako autostainers, and visualized with DAB. Slides will be 
baked for 60 minutes at 60C.  Procedure involves dewaxing, heat-retrieved in Bond 
ER1(pH6) buffer for 20 minutes, and sequential incubations with primary antibody, post-
primary reagent, and polymer for 15 minutes, 8 minutes, and 8 minutes, respectively, and 
subsequent DAB chromogen application and Hematoxylin counterstaining. All stained 
slides will be evaluated in a blinded fashion by one dermatopathologist and one investigator 
trained to identify the features of melanoma, and the presence of CD8 within the tumor 
parenchyma (tumor) and the connective tissue surrounding the tumor (invasive margin) will 
be examined. 

 
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All slides will be scanned at an absolute magnification of X200 (resolution of 0.5 mm/pixel). 
An algorithm was designed based on pattern recognition that quantified immune cells 
within S100-positive areas (tumor) and S100-negative areas (invasive margin). Image 
analysis based on RGB (red, green, blue) spectra will be used to detect all cells by 
counterstaining with haemotoxylin (blue), and DAB or fast red. The algorithm calculated 
the density (cells mm-2) and percentage cellularity (% positive cells/all nucleated cells) 
using Indica Labs Halo platform. 
 
Analysis of TCR clonality in tumors: To answer the question whether the T cell response 
is targeting specific tumor antigen (mono-clonal) or a non-specific process (poly-clonal) in 
the tumors, we will analyze TCR clonality by deep sequencing the TCR Vβ CDR region 
using the ImmunoSeq assay from Adaptive Biotech as described.  (3) From thick slides of 
FFPE tissues taken at baseline, 4 weeks, and 9 weeks, we will isolate DNA and submit it 
for TCR Vβ sequencing. This analysis will provide information about the clonality or 
diversity of T cells infiltrating tumors in DM samples. DNA analysis will be performed by the 
UCLA Immunogenetics core laboratory (CLIA approved lab). 
 
DNA will be isolated from FFPE thick cuts followed by extraction using a DNeasy kit 
(Qiagen). Melanin will be removed from visibly pigmented melanoma samples using a PCR 
Inhibitor Removal kit (ZymoResearch). TCR Vβ CDR3 regions will be amplified and 
sequenced using the survey ImmunoSeq assay in a multiplexed PCR method using 45 
forward primers specific to TCR Vβ gene segments and 13 reverse primers specific to TCR 
Vβ gene segments (Adaptive Biotechnologies). Reads of length 87bp will be obtained 
using the Illumina HiSeq System. For each sample, Shannon entropy will be calculated on 
the clonal abundance of all productive TCR sequences in the data set. Shannon entropy 
will be normalized to the range by dividing Shannon entropy by the logarithm of the number 
of unique productive TCR sequences in the data set. This normalized entropy value will be 
then inverted (12 normalized entropy) to produce our clonality metric. 
 
Analysis of adaptive immune resistance mechanism in tumors: Slides taken from 
standard FFPE tissue blocks obtained from baseline, the on treatment biopsy (week 4) and 
the 
week 
9 
biopsy/resection 
will 
be 
stained 
by 
quantitative 
multiplexed 
immunohistochemistry (IHC) for a set of multiple immune-relevant biomarkers, including 
PD-L1 (SP142, Spring Bioscience), to evaluate whether PD-L1 can be induced by PD-1 
blockade, the patient’s immune response, and which is correlated with response. Slides 
will be analyzed using quantitative digital pathology following the methods described for 
Quantitative analysis of T cell infiltration.  Analysis will be performed at core facilities with 
the relevant instrumentations and infrastructures, such as the UCLA Anatomic Pathology 
IHC Laboratory (CLIA approved lab).  
 
Method: 
 
1. 
Bake slides for 1 hour at 65°C. 
 
2. 
Deparaffinize slides in xylene (3 changes) and rehydrate through graded ethanol 
to deonized-H2O. 
 
3. 
Perform antigen retrieval in pressure cooker for 5 minutes with Tris-EDTA pH9 
buffer (Leica ER2).  Cool for 15 minutes at room temperature and rinse in DI-water. 
 
Perform IHC  of samples using staining procedures appropriate for the specific quantitative 
multiplexed IHC technique and validated by the Translational Medicine team, for example,  
Leica Bond III autostainer with Refine Polymer Detection (Leica DS9800); autostainer  
programmed for primary antibody at 1/200 dilution in daVinci Green Diluent (Biocare 
Medical) for 60 minutes,  Polymer  for 15 minutes, Peroxidase block for 5 minutes, DAB for 

 
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10 minutes, and offline manual steps 0.5% cupric sulfate for 10 minutes and Hematoxylin 
for  5 minutes.  Usual Bond washes between steps.  Use Bond Refine Polymer Detection 
kit (DS9800), which includes reagents for all steps after primary antibody, except for cupric 
sulfate and hematoxylin counterstain. 
 
References for 18.1
 
1  
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, 
Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, 
Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, 
Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance.  Nature 
27;515(7528):568-71, 2014 
 
2  
Angelo M, Bendall SC, Finck R, Hale MB, Hitzman C, Borowsky AD, Levenson RM, Lowe JB, Liu 
SD, Zhao S, Natkunam Y, Nolan GP. Multiplexed ion beam imaging of human breast tumors. Nat 
Med. 2014 Apr;20(4):436-42. doi: 10.1038/nm.3488. Epub 2014 Mar 2. PMID: 24584119; PMCID: 
PMC4110905. 
 
3  
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, 
Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, 
Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, 
Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance.  Nature 
27;515(7528):568-71, 2014 

 
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18.2 
Specimen Banking Instructions for the UCLA Lab #224: The Ribas Laboratory   
 
The UCLA Lab #224, The Ribas Laboratory, will receive formalin-fixed, paraffin-embedded 
(FFPE) tumor tissue as either blocks or unstained slides as noted in Section 15.1.  
 
Upon receipt, the Ribas Laboratory will accession, barcode, and bank all FFPE specimens 
at room temperature until ready for translational medicine as detailed in Section 18.1. 
 
The UCLA lab #224 will also receive twenty mL fresh whole blood in vacutainer tubes with 
EDTA coating at ambient temperature approximately as noted in Section 15.1.  Upon 
receipt, blood will be processed per translational medicine details in Section 18.1.  

 
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18.3 
Specimen Banking Instructions for the SWOG Biospecimen Bank 
 
The SWOG Bank will receive stained slides from formalin-fixed, paraffin-embedded (FFPE) 
tumor tissue as noted in Section 15.2. Upon receipt, the Bank will accession, barcode, and 
bank all FFPE tissue slides at room temperature. 
 
For each case, one H&E stained slide and all immunostained slides will be scanned at 40X 
magnification to Dr. Wada and Dr. Plaza for digital pathology review in batches throughout 
the study. A redacted pathology report will accompany the digital whole slide images.