appendix b. foundationone™️ heme sample
a p p e n

St u d y Titl e: A P h a s e I/II st u d y of bli n at u m o m a b i n c o m bi n ati o n wit h p e m br oli z u m a b ( M K 3 4 7 5) f or a d ult s wit h r el a p s e d or r efr a ct or y B li n e a g e a c ut e l y m p h o bl a sti c l e u k e mi a wit h hi g h b o n e m arr o w l y m p h o bl a st p er c e nt a g e:  
U ni v er sit y of C alif or ni a H e m at ol o gi c M ali g n a n ci e s C o n s orti u m St u d y \# 1 5 0 4 ( U C H M C 1 5 0 4)"  
P ati e nt I niti al s: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ SI D: 1 5 0 4 D O B: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
  
| All o g e n ei c H S C T wit hi n 5 y e ar s of st u d y dr u g a d mi ni str ati o n  C urr e nt or a nti ci p at e d u s e of ot h er i n v e sti g ati o n al a g e nt s d uri n g t h e st u d y  G M C S F or G C S F u s e wit hi n 2 w e e k s of st u d y tr e at m e nt a n d t hr o u g h o ut t h e st u d y Cli ni c al E vi d e n c e of a cti v e C N S or t e sti c ul ar i n v ol v e m e nt b y l e u k e mi a A cti v e s e c o n d m ali g n a n c y e x cl u di n g n o n m el a n o m a s ki n c a n c er B ur kitt L y m p h o m a/ L e u k e mi a  Di a g n o si s of c o n g e nit al i m m u n o d efi ci e n c y  K n o w n hi st or y of a cti v e T B K n o w n HI V i nf e cti o n   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |         |                                                                                           |                             |            |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|-------------------------------------------------------------------------------------------|-----------------------------|------------|
| 1 0                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | A cti v e H e p atiti s B or H e p atiti s C i nf e cti o n                                                                                                                                                                                                                                                                                                                                                                                                                                               |         |                                                                                           |                             |            |
| 1 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | A n y u n c o ntr oll e d i nf e cti o n                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |         |                                                                                           |                             |            |
| 1 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | H a s r e c ei v e d a li v e v a c ci n e wit hi n 3 0 d a y s pri or t o fir st d o s e                                                                                                                                                                                                                                                                                                                                                                                                                 |         |                                                                                           |                             |            |
| 1 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Pri or c h e c k p oi nt i n hi bit or t h er a p y i n cl u di n g a nti                                                                                                                                                                                                                                                                                                                                                                                                                                 | P D     | 1, a nti P D                                                                              | L 1, a nti C T L A 4, a nti | C D 3 7 or |
| a nti P D                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | L 2 t h er a p y                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |         |                                                                                           |                             |            |
| 1 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Pri or tr e at m e nt wit h a n                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | C D 1 9 | dir e ct e d t h er a p y ( e. g. bli n at u m o m a b, C D 1 9 dir e ct e d c hi m eri c |                             |            |
| a nti g e n r e c e pt or T c ell t h er a p y, a nti C D 1 9 a nti b o di e s).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |         |                                                                                           |                             |            |
| 1 5                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Pr e g n a nt or br e a stf e e di n g                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |         |                                                                                           |                             |            |
| 1 6                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Hi st or y of a ut oi m m u n e di s e a s e                                                                                                                                                                                                                                                                                                                                                                                                                                                              |         |                                                                                           |                             |            |
| 1 7                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | K n o w n i nt er stiti al l u n g di s e a s e                                                                                                                                                                                                                                                                                                                                                                                                                                                           |         |                                                                                           |                             |            |
| 1 8                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | A cti v e, n o n i nf e cti o u s p n e u m o niti s or h a s a hi st or y of ( n o n i nf e cti o u s) p n e u m o niti s t h at  r e q uir e d st er oi d s or c urr e nt p n e u m o niti s                                                                                                                                                                                                                                                                                                            |         |                                                                                           |                             |            |
| 1 9                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | P ati e nt s w h o h a v e r e c ei v e d c h e m ot h er a p y or r a di ot h er a p y wit hi n 2 w e e k s pri or t o e nt eri n g t h e  st u d y or h a s n ot r e c o v er e d fr o m a d v er s e e v e nt s d u e t o a g e nt s a d mi ni st er e d m or e t h a n 2  w e e k s e arli er.                                                                                                                                                                                                        |         |                                                                                           |                             |            |
| 2 0                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | P ati e nt s w h o ar e l e s s t h a n 4 w e e k s fr o m s ur g er y or h a v e i n s uffi ci e nt r e c o v er y fr o m s ur gi c al r el at e d tr a u m a or w o u n d h e ali n g                                                                                                                                                                                                                                                                                                                   |         |                                                                                           |                             |            |
| 2 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Hi st or y of all er gi c r e a cti o n s attri b ut e d t o c o m p o u n d s of si mil ar c h e mi c al or bi ol o gi c  c o m p o siti o n t o bli n at u m o m a b or p e m br oli z u m a b or ot h er a g e nt s u s e d i n st u d y                                                                                                                                                                                                                                                               |         |                                                                                           |                             |            |
| 2 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | I m p air e d c ar di a c f u n cti o n a s s p e cifi e d i n t h e pr ot o c ol                                                                                                                                                                                                                                                                                                                                                                                                                         |         |                                                                                           |                             |            |
| 2 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | A n y c o n diti o n t h at r e q uir e s t h e u s e of c orti c o st er oi d s o ut si d e of c orti c o st er oi d s d efi n e d i n t h e  pr ot o c ol aft er D a y 1 of t h er a p y wit h t h e e x c e pti o n of t o pi c al or i n h al e d st er oi d s .                                                                                                                                                                                                                                      |         |                                                                                           |                             |            |
| 2 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | S e v er e or u n c o ntr oll e d m e di c al di s or d er t h at w o ul d, i n t h e i n v e sti g at or' s o pi ni o n, i m p air a bilit y  t o r e c ei v e st u d y tr e at m e nt (i. e., u n c o ntr oll e d di a b et e s, c hr o ni c r e n al di s e a s e, c hr o ni c  p ul m o n ar y di s e a s e or a cti v e, u n c o ntr oll e d i nf e cti o n, p s y c hi atri c ill n e s s/ s o ci al sit u ati o n s t h at  w o ul d li mit c o m pli a n c e wit h st u d y r e q uir e m e nt s) |         |                                                                                           |                             |            |  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
appendix b. foundationone™️ heme sample
i n v e sti

Wit h eli gi bilit y c h e c kli st pl e a s e pr o vi d e t h e b el o w it e m s i n or d er t o c o nfir m eli gi bilit y 1. Si g n e d I nf or m e d C o n s e nt 2. All s o ur c e (r e d a ct e d wit h p ati e nt i niti al s a n d D O B) r e q uir e d t o c o nfir m eli gi bilit y, i n cl u di n g b ut n ot  
```
li mit e d t o

a. B o n e M arr o w bi o p s y

b. P h y si c al e x a m wit h vit al s, E C O G, a n d m e di c al hi st or y

c. L a b r e s ult s

d. C o nfir m ati o n of f o u n d ati o n o n e s u b mi s si o n

Pl e a s e e m ail vi a s e c ur e e m ail t o J R ei n er @ u c s d. e d u a n d M Wi e d u wilt @ u c s d. e d u

U p o n c o nfir m ati o n of eli gi bilit y b y i niti ati n g sit e wit hi n 2 4 4 8 h o ur s of r e c ei vi n g, p ati e nt st u d y I D will b e

pr o vi d e d a n d p ati e nt m a y i niti at e tr e at m e nt

```
appendix b. foundationone™️ heme sample
a p p e n

St u d y Titl e: A P h a s e I/II st u d y of bli n at u m o m a b i n c o m bi n ati o n wit h p e m br oli z u m a b ( M K 3 4 7 5) f or a d ult s wit h r el a p s e d or r efr a ct or y B li n e a g e a c ut e l y m p h o bl a sti c l e u k e mi a wit h hi g h b o n e m arr o w l y m p h o bl a st p er c e nt a g e: U ni v er sit y of C alif or ni a H e m at ol o gi c M ali g n a n ci e s C o n s orti u m St u d y \# 1 5 0 4  
( U C H M C 1 5 0 4)"  
P ati e nt I niti al s: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ SI D: 1 5 0 4 D O B: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
At t hi s ti m e, t h er e i s n o i nt e nt f or t h e p ati e nt t o ulti m at el y r e c ei v e all o g e n ei c tr a n s pl a nt.  
At t hi s ti m e, t h e i nt e nt i s f or t h e p ati e nt t o ulti m at el y r e c ei v e a n all o g e n ei c tr a n s pl a nt.  
I n v e sti g at or/ S u b I n v e sti g at or Si g n at ur e D at e Pl e a s e f a x t o J e si k a R ei n er at 8 5 8 8 2 2 1 4 7 3 or e m ail vi a s e c ur e e m ail t o J R ei n er @ u c s d. e d u u p o n c o m pl eti o n al o n g wit h eli gi bilit y c h e c kli st a n d si g n e d i nf or m e d c o n s e nt.
appendix b. foundationone™️ heme sample
appendix f. correlative research sample

UNIVERSITY of CALIFORNIA, SAN DIEGO
medical center moores Cancer Center  
| Clinical Trials Office            |
|-----------------------------------|
| 3855 Health Sciences Drive, #0698 |
| La Jolla, CA 92093-0698           |
| Phone (858) 822-5367              |
| Fax (858) 822-5380                |
appendix b. foundationone™️ heme sample
sample collection case report form

Page 1 of 1 UNIVERSITY of CALIFORNIA, SAN DIEGO
MEDICAL CENTER MIJORES CANCER CENTER
Clinical Trials Office 3855 Health Sciences Drive, \#0698 La Jolla, CA 92093-0698 Phone (858) 822-5367 Fax (858) 822-5380  
T-cell subsets, PD-1 and PD-L1 expression studies by Flow Cytometry  
  
Email the completed sample collection form prior to shipment
to: JReiner@ucsd.edu Make a copy of the form to include with the sample(s) Retain the original at the site for your records Email a de-identified (redacted) pathology report(s) if available. Write the Study ID on the top of each page of the pathology report.  
  
UNIVERSITY of CALIFORNIA, SAN DIEGO  
  
MEDICAL CENTER MIJORES CANCER CENTER  
|  Clinical Trials Office           |
|-----------------------------------|
| 3855 Health Sciences Drive, #0698 |
| La Jolla, CA 92093-0698           |
| Phone (858) 822-5367              |
| Fax (858) 822-5380                |
appendix b. foundationone™️ heme sample
sample collection case report form

| Serum cytokine assays                                                                           |                                                                                                            |                   |                            |
|-------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------|-------------------|----------------------------|
| UCHMC#                                                                                          | UCHMC1504                                                                                                  | UCSD Investigator | Matthew Wieduwilt, MD, PhD |
| Name:                                                                                           |                                                                                                            |                   |                            |
| Site:                                                                                           | Site #:                                                                                                    |                   |                            |
| Protocol Title:                                                                                 | A Phase I/II study of blinatumomab in combination with pembrolizumab (MK-3475) for adults with relapsed or |                   |                            |
| refractory B-lineage acute lymphoblastic leukemia with high bone marrow lymphoblast percentage: |                                                                                                            |                   |                            |
| University of California Hematologic Malignancies Consortium Study #1504 (UCHMC1504)            |                                                                                                            |                   |                            |
| Study ID                                                                                        | Time                                                                                                       |                   |                            |
| Collected                                                                                       |                                                                                                            |                   |                            |
| DOB                                                                                             | Study Day                                                                                                  |                   |                            |
| Date                                                                                            |                                                                                                            |                   |                            |
| Collected                                                                                       |                                                                                                            |                   |                            |  
Email the completed sample collection form prior to shipment to: JReiner@ucsd.edu Make a copy of the form to include with the sample(s) Retain the original at the site for your records.  
Peripheral blood to be collected in 1-10ml. EDTA tube.  
Sample to be processed at 1200g for 10min and the plasma stored at -70C.  
Samples to be batched and shipped overnight on dry ice:  
  
Study Coordinator, BMT Clinical Trials  
  
UCSD Moores Cancer Center 3855 Health Sciences Drive, Room 2037  
  
La Jolla, CA 92093 Tel: 858-822-5364/6396/6397 Appendix G. Pembrolizumab Program: Events of Clinical Interest Pembrolizumab Event of Clinical Interest Guidance Document PEMBROLIZUMAB PROGRAM
(MK-3475)
EVENT OF CLINICAL INTEREST
GUIDANCE DOCUMENT
Version 5.0 Final 18-Dec-2014 Version 5.0  
  
i  
| REVISION HISTORY LOG                                       |                                                          |                                                     |
|------------------------------------------------------------|----------------------------------------------------------|-----------------------------------------------------|
| Effective                                                  |                                                          |                                                     |
| Version                                                    | Revision                                                 | Action                                              |
| Date "                                                     | Author                                                   |                                                     |
| 08-Aug-2012                                                | Initial Release of guidance document for MK-3475         |                                                     |
| i                                                          | Kevin Gergich                                            | Revised title, formerly was "MK-3475 Immune-Related |
| 07-June-2013                                               | Marty Huber,                                             |                                                     |
| Kevin Gergich,                                             | Adverse Event Identification, Evaluation and Management  |                                                     |
| Holly Brown                                                | Guidance Document for Investigators"                     |                                                     |
| Revised the format of irAE Guidance document, including    |                                                          |                                                     |
| lyout, font, sectioning, etc. for consistency with Sponsor |                                                          |                                                     |
| Events of Clinical Interest guidance documents.            |                                                          |                                                     |
| Modified Categories for irAEs:                             |                                                          |                                                     |
| Replaced GI with Colitis category.                         |                                                          |                                                     |
| -                                                          | Removed Neurologic category.                             |                                                     |
| Added Renal category.                                      |                                                          |                                                     |
| Removed detail in the irAE Guidance document that can      |                                                          |                                                     |
| be located in the Investigator's Brochure for MK-3475.     |                                                          |                                                     |
| Removed details regarding non-MK-3475 compounds.           |                                                          |                                                     |
| Added ECI reporting guidelines.                            |                                                          |                                                     |
| Included a Table Events of Clinical Interest: Immune¬      |                                                          |                                                     |
| Related Adverse Events that includes the key terms.        |                                                          |                                                     |
| Also placed a pull-out quick-review sheet in the           |                                                          |                                                     |
| Appendix.                                                  |                                                          |                                                     |
| Updated background, diagnosis and course of treatment      |                                                          |                                                     |
| details for irAEs.                                         |                                                          |                                                     |
| 10-Sep-2014                                                | Marty Huber,                                             | Renamed the document: "Pembrolizumab Program (MK-   |
| Kevin Gergich,                                             | 3475) - Events of Clinical Interest Guidance Document ". |                                                     |
| Holly Brown                                                | Introduced generic name: pembrolizumab (MK-3475) and     |                                                     |
| inserted throughout the document.                          |                                                          |                                                     |
| Updated Overview - Section 1                               |                                                          |                                                     |
| - Clarified the scope of the document and the reporting    |                                                          |                                                     |
| window for ECIs                                            |                                                          |                                                     |
| - Updated Table 1 with medDRA Preferred Terms for          |                                                          |                                                     |
| adverse events to correspond with reporting of terms to    |                                                          |                                                     |
| clinical database, rearranged the order, and updated the   |                                                          |                                                     |
| reporting criteria.                                        |                                                          |                                                     |
| - Updated the dose modification/discontinuation section to |                                                          |                                                     |
| clarify discontinuation and hold term inology.             |                                                          |                                                     |
| Updated Section 2 - ECI Reporting Guidelines               |                                                          |                                                     |
| Final 18-Dec-2014                                          | 2                                                        |                                                     |
| Version 5.0                                                |                                                          |                                                     |
appendix b. foundationone™️ heme sample
revision history log

C. Confidential etiology. CONSIDER  
  
-
.  
.  
. .  
.  
Final 18-Dec-2014 Version 5.0  
  
Updated Section 3 Grade 1 events.  
- Section 3.3 Endocrine:
- Section 3.5: Hepatic: - Section 3.6 Neurologic:
- Section 3.7 Ocular:
- Section 3.8 Renal:
- Section 3.9 Skin:
- Section 3,10 Other:
3
C Confidential Pembrolizumab Event of Clinical Interest Guidance Document  
| - Section 3.11 Infusion Reactions:                                    |                                                    |                         |
|-----------------------------------------------------------------------|----------------------------------------------------|-------------------------|
| - New section added.                                                  |                                                    |                         |
| - Section 3.12: Follow-up to Resolution:                              |                                                    |                         |
| : New section added.                                                  |                                                    |                         |
| - Section 4:                                                          |                                                    |                         |
| References updated                                                    |                                                    |                         |
| '                                                                     |                                                    |                         |
| - Section 5:                                                          |                                                    |                         |
| ECI table updated for consistency with Table 1.                       |                                                    |                         |
| .                                                                     |                                                    |                         |
| - Section 6: Appendix 2 - Past Medical History Related to             |                                                    |                         |
| Dermatologic Event: New section added.                                |                                                    |                         |
| - Section 7: Appendix 3 - Presentation of the                         |                                                    |                         |
| Dermatologic Event: New section added.                                |                                                    |                         |
| - Section 8: Appendix 4 - Focused Skin Examination:                   |                                                    |                         |
| New section added.                                                    |                                                    |                         |
| Scot Ebbinghaus,                                                      |                                                    |                         |
| i                                                                     | 04-Dec-2014a                                       | - Table 1               |
| Oswaldo Bracco,                                                       | Updated Endocrine (reported as ECI if > Grade 3    |                         |
| .                                                                     |                                                    |                         |
| Holly Brown,                                                          | or > Grade 2 and resulting in dose modification or |                         |
| Kevin Gergich                                                         | use of systemic steroids to treat the AE) Section  |                         |
| to include:                                                           |                                                    |                         |
| Hyperglycemia, if >Grade 3 and associated                             |                                                    |                         |
|                                                                       | with ketosis or metabolic acidosis (DKA)           |                         |
| Created new section in Table 1 - Endocrine                            |                                                    |                         |
| .                                                                     | (reported as ECI) and added.                       |                         |
| Type Indiabetes mellitus (if new onset)                               |                                                    |                         |
| Hepatic: Clarified Transaminase elevations as:                        |                                                    |                         |
| -                                                                     | Transaminase elevations (ALT and/or AST)           |                         |
| - Section 3.2 Colitis                                                 |                                                    |                         |
| - Updated the duration of diarrhea requirments                        |                                                    |                         |
| under the Course of Action for Grade 2 and Grade                      |                                                    |                         |
| - Section 3.3 Endocrine                                               |                                                    |                         |
| Clarified Course of Action for hyperthyroidism                        |                                                    |                         |
| and hypothyroidism                                                    |                                                    |                         |
| Added Course of Action section for Type 1                             |                                                    |                         |
| .                                                                     | diabetes mellitus (if new onset) and > Grade 3     |                         |
| hyperglycemia                                                         |                                                    |                         |
| - Section 5                                                           |                                                    |                         |
| Updated Reference Table in Appendix 1                                 |                                                    |                         |
| 18-Dec-2014                                                           | Holly Brown                                        | - Section 3.3 Endocrine |
| Updated the Course of Action for Hypophysitis                         |                                                    |                         |
| Kevin Gergich                                                         | Merged Grades 2-4 into one course of action        |                         |
| 'Ensure that you are using the most current version of this document. |                                                    |                         |  
Final 18-Dec-2014 Version 5.0  
C. Confidential  
  
4 Pembrolizumab Event of Clinical Interest Guidance Document
appendix b. foundationone™️ heme sample
table of contents

| 1. OVERVIEW                                                                                                         |
|---------------------------------------------------------------------------------------------------------------------|
| 2. ECI REPORTING GUIDELINES                                                                                         |
| 3. ECI CATEGORIES AND TERMS                                                                                         |
| 3.1 Pneumonitis                                                                                                     |
| 3.2 Colitis                                                                                                         |
| 3 Endocrine                                                                                                         |
| 3.4 Hematologic                                                                                                     |
| 3.5 Hepatic                                                                                                         |
| 3.6 Neurologic .                                                                                                    |
| 3.7 Ocular                                                                                                          |
| 3.8 Renal                                                                                                           |
| 3.9 Skin .                                                                                                          |
| 3.9.1. Immediate Evaluation for Potential Skin ECIs                                                                 |
| 3.10 Other .                                                                                                        |
| 3.11 Infusion Reactions                                                                                             |
| 3.12 Follow-up to Resolution .                                                                                      |
| 4. REFERENCES                                                                                                       |
| 5. APPENDIX 1 –Events of Clinical Interest (ECI) - Reference Table .......................................... 28    |
| 6. APPENDIX 2 - Past Medical History Related to Dermatologic Event ............................................. 29 |
| 7. APPENDIX 3 - Fresentation of the Dermatologic Event .                                                            |
| 8. APPENDIX 4 - Focused Skin Examination .                                                                          |  
Final 18-Dec-2014 Version 5.0 S  
Concentration
appendix b. foundationone™️ heme sample
1. overview

The purpose of this document is to provide study sites with guidance on the identification and management of Events of Clinical Interest for the MK-3475 (also known as pembrolizumab) program.  
Based on the literature review [1-11], and consideration of mechanism of action of pembrolizumab, potential immune-related adverse events (irAEs) are the primary Event of Clinical Interest (ECI). Immune-related AEs are adverse events associated with the treatment of patients with immunotherapy treatments that appear to be associated with the immune therapy's mechanism of action. Based on these potential irAEs, the sponsor has defined a list of specific adverse event terms (ECIs) that are selected adverse experiences that must be reported to Merck within 24 hours from the time the Investigator/physician is aware of such an occurrence, regardless of whether or not the investigator/physician considers the event to be related to study drug(s). In addition, these ECIs require additional detailed information to be collected and entered in the study database.  
ECIs may be identified through spontaneous patient report and / or upon review of subject data. Table 1 provides the list of terms and reporting requirements for AEs that must be reported as ECIs for MK-3475 protocols. Of note, the requirement for reporting of ECIs applies to all arms, including comparators, of MK-
3475 clinical trials Given that our current list of events of clinical interest is not comprehensive for all potential immune-related events, it is possible that AEs other than those listed in this document may be observed in patients receiving pembrolizumab. Therefore any Grade 3 or higher event that the investigator/physician considers to be immune-related should be reported as an ECI regardless of whether the specific event term is in Table 1 and reported to Merck within 24 hours from the time the Investigator/physician is aware of such an occurrence.  
Adverse events that are both an SAE and an ECI should be reported one time as an SAE only, however the event must be appropriately identified as an ECI as well in in the database.  
Final 18-Dec-2014 Version 5.0  
  
6 Pembrolizumab Event of Clinical Interest Guidance Document  
| Table 1: Events of Clinical Interest                                                                                            |                                                                                    |                                          |
|---------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|------------------------------------------|
| Pneumonitis (reported as ECI if ≥ Grade 2)                                                                                      |                                                                                    |                                          |
| Acute interstitial pneumonitis                                                                                                  | Interstitial lung disease                                                          | Pneumonitis                              |
| Colitic (reported as ECI if 2 Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE)  |                                                                                    |                                          |
| Intestinal Obstruction                                                                                                          | Colitis                                                                            | Colitis microscopic                      |
| Enterocolitis                                                                                                                   | Enterocolitis hemorrhagic                                                          | Gastrointestinal perforation             |
| Necrotizing colitis                                                                                                             | Dianhea                                                                            |                                          |
| Endocrine (reported as ECI if > Grade 3 or > Grade 2 and resulting in dose modification or use of systemic steroids to treat    |                                                                                    |                                          |
| the AE)                                                                                                                         |                                                                                    |                                          |
| Adrenal Insufficiency                                                                                                           | Hyperthyroidism                                                                    | Hypophysitis                             |
| Hypopituitarism                                                                                                                 | Hypothyroidism                                                                     | Thyroid disorder                         |
| Thyroiditis                                                                                                                     | Hyperglycemia, if 2Grade 3 and associated with ketosis or metabolic acidosis (DKA) |                                          |
| Endocrine (reported as ECI)                                                                                                     |                                                                                    |                                          |
| Type 1 diabetes mellitus (if new onsel)                                                                                         |                                                                                    |                                          |
| Hematologic (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat the  |                                                                                    |                                          |
| AE)                                                                                                                             | Thrombotic Thrombocytopenic Purpura                                                |                                          |
| Autoimmune hemolytic anemia                                                                                                     | Aplastic ancmia                                                                    | (TTP)                                    |
| Idiopathic (or immune) Thrombocytopenia                                                                                         | Disseminated Intravascular Coagulation                                             | Haemolytic Uraemic Syndrome (HUS)        |
| Purpurat (ITF)                                                                                                                  | (DIC)                                                                              |                                          |
| Any Grade 4 anemia regardless of underlying mechanism                                                                           |                                                                                    |                                          |
| Hepatic (reported as ECI if ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the AE) |                                                                                    |                                          |
| Hepatitis                                                                                                                       | Autoimmune hepatitis                                                               | Transaminase elevations (ALT and/or AST) |
| Infusion Reactions (reported as ECI for any grade)                                                                              |                                                                                    |                                          |
| Allergie reaction                                                                                                               | Anaphylaxis                                                                        | Cytokine release syndrome                |
| Serum sickness                                                                                                                  | Infusion reactions                                                                 | Infusion-like reactions                  |
| Neurologic (reported as ECI for any grade)                                                                                      |                                                                                    |                                          |
| Autoimmune neuropathy                                                                                                           | Guillain Barre syndrome                                                            | Domyclinating polyncuropathy             |
| Myasthenic syndrome                                                                                                             |                                                                                    |                                          |
| Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE)     |                                                                                    |                                          |
| Iritis                                                                                                                          |                                                                                    |                                          |
| Uveilis                                                                                                                         |                                                                                    |                                          |
| Renal (reported as ECI if 2 Grade 2)                                                                                            |                                                                                    |                                          |
| Nephritis                                                                                                                       | Nephritis autoimmune                                                               | Rnal Failure                             |
| Creatimic elevations (report as ECI if >Grade 3 or any grade resulting in dose                                                  |                                                                                    |                                          |
| Renal failure acute                                                                                                             | modification or use of systemic steroids to treat the AE)                          |                                          |
| Skin (reported as ECI for any grade)                                                                                            |                                                                                    |                                          |
| Dermatitis exfoliative                                                                                                          | Stevens-Johnson syndrome                                                           |                                          |
| Erythema multiforme                                                                                                             |                                                                                    |                                          |
| Toxic epidermal neerolysis                                                                                                      |                                                                                    |                                          |
| Skin (reported as ECI if ≥ Grade 3)                                                                                             |                                                                                    |                                          |
| Pruritus                                                                                                                        | Rash                                                                               | Rash generalized                         |
| Rash maculo-papular                                                                                                             |                                                                                    |                                          |
| Any rash considered clinically significant in the physician's judgment                                                          |                                                                                    |                                          |
| Other (reported as ECI for any grade)                                                                                           |                                                                                    |                                          |
| Myocarditis                                                                                                                     | Pancreatitis                                                                       | Pcricarditis                             |
| Any other Grade 3 event which is considered immune-related by the physician                                                     |                                                                                    |                                          |  
Final 18-Dec-2014 Version 5.0 Confidential s Pembrolizumab Event of Clinical Interest Guidance Document Each of the events above is described within this guidance document, along with site requirements for reporting these events to the Sponsor. The information collected should be entered into the narrative field(s)
of the Adverse Event module in the database (please note, if narrative entry into the database is not available, please use the narrative text box on the 1727/AER Form). If additional Medical History or Concomitant Medications are reported, the Medical History and Concomitant Medication modules in the database must be updated.  
In addition, the guidelines include recommendations on the management of these ECIs. These guidelines are intended to be applied when the physician determines the events to be related to pembrolizumab. Note: if after tlie evaluation the event is determined not to be related, the physician is instructed to follow the ECI reporting guidance but does not need to follow the treatment guidance (below). Therefore, these recommendations should be seen as guidelines and the treating physician should exercise individual clinical judgment based on tlie patient. For any question of dose modification or other treatment options, the specific language in the protocol should be followed. Any questions pertaining to the collection of this information or management of ECIs should be directed to your local Sponsor contact.  
Dose Modification/Discontinuation The treatment guidance provides specific direction when to hold and/or discontinue pembrolizumab for each immune related adverse event. 'Of note, when the guidance states to "discontinue" pembrolizumab this is the permanent discontinuation of treatment with pembrolizumab. "Hold's means to stop treating with pembrolizumab but resumption of treatment may be considered assuming the patient meets the criteria for resumption of treatment.
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2. eci reporting guidelines

ECIs are selected non-serious and serious adverse experiences that must be reported to Merck within 24 hours.  
regardless of attribution to study treatment. The AEs listed in this document and any event that meets the ECI
criteria (as noted) in Table 1 or in the respective protocol (event term and Grade) must be reported regardless of physician-determined causality with study medication and whether or not considered immune-related by the physician (unless otherwise specified). Physicians/study coordinators/designated site personnel are required to record these experiences as ECIs on the Adverse Experience electronic Case Report Forms (eCRFs) (or on per) and to provide supplemental information (such as medical history, concomitant medications, investigations, etc.) about the event.  
Please refer to the Data Entry Guidelines (DEGs) for your protocol.  
s Please refer to protocol for details on reporting timelines and reporting of Overdose and Drug Induced
=
Liva Injury (DILI).  
8
3. ECI CATEGORIES AND TERMS
This section describes the ECI categories and outlines subject management guidelines when an ECI is reported.
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3.1 pneumonitis

The following AE terms, if considered 2 Grade 2, are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
-
Pneumonitis
-  
Interstitial lung disease Acute interstitial pneumonitis
If symptoms indicate possible new or worsening cardiac abnormalities additional testing and/or a cardiology consultation should be considered.  
All attempts should be made to rule out other causes such as metastatic disease, bacterial or viral infection. It Is important that patients with a suspected diagnosis of pneumonitis be managed as per the guidance below until treatment-related pneumonitis is excluded. Treatment of both a potential infectious ellology and pneumonitis in parallel may be warranted. Management of the treatment of suspected pneumonitis with steroid treatment should not be delayed for a therapeutic trial of antibiotics. If an alternative diagnosis is established, the patient does not require management as below; however the AE should be reported regardless of etiology.
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course of action

Grade 2 events:
l l Report as ECI
Hold pembrolizumab.  
Consider pulmonary consultation with bronchoscopy and biopsy/BAL
Consider ID consult.  
Conduct an in person evaluation approximately twice per weeks Consider frequent Chest X-ray as part of monitoring Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 wcks.  
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
Second episode of pneumonitis - discontinue pembrolizumab if upon re-challenge the patient develops a second episode of Grade 2 or higher pneumonitis.  
l
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grade 3 and 4 events

-
l Report as ECI
Discontinue pembrolizumab.  
Hospitalize patient Bronchoscopy with biopsy and/or BAL is recommended.  
Immediately treat with intravenous steroids (methylprednisolone 125 mg IV). When symptoms improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours) taper should be started and continued over no less than 4 weeks.  
I IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 to 72 hours, treat with additional anti-inflammatory measures. Discontinue additional anti-inflammatory measures upon symptom relief and initiate a prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, initiate a relapering of steroids starting at a higher dose of 80 or 100. mg followed by a more prolonged taper and administer additional anti-inflammatory measures, as neded Add prophylactic antibiotics for opportunistic infections.  
9 Final 18-Dec-2014 Version 5.0 C Confidential
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3.2 colitis

The following AE terms, if considered > Grade 2 or resulting in dose modification or use of systemic steroids to treat the AE, are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
Colitis 1 i l e Colitis microscopic Enterocolitis Enterocolitis hemorrhagic Gastrointestinal perforation Intestinal obstruction Necrotizing colitis Diarrhea All attempts should be made to rule out other causes such as metastatic disease, bacterial or parasitic infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel disease by examination for stool leukocytes, stool cultures, a Clostridium difficile tite and endoscopy. However the AE should be reported regardless of etiology.
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course of action

Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 24 hours, abdominal pain, mucus or blood in stool):
Report as ECI
Hold pembrolizumab.  
Symptomatic Treatment For Grade 2 diarrhea that persists for greater than 3 days, and for diarrhea with blood and/or mucus, y Consider GI consultation and endoscopy to confirm or rule out colitis o Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent)
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less
-
than 4 weeks.  
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
If symptoms worsen or persist > 3 days treat as Grade 3 Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persists for > 1 week):
Report as ECI
Hold pembrolizumab.  
Rule out bowel perforation. Imaging with plain films or CT can be useful.  
=
Recommend consultation with Gastroenterologist and confirmation biopsy with endoscopy.  
Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose oral steroids  
(prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours) When symptoms improve to Grade I or less, steroid taper should be started and continued over no less than 4 weeks.  
Taper over 6 to 8 weeks in patients with diffuse and severe ulceration and/or bleeding Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 to 72 l hours, consider treatment with additional anti-inflammatory measures as described in the literature [5].  
Discontinue additional anti-inflammatory measures upon symptom relief and initiate a prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, initiate a retapering of steroids starting at a higher dose of 80 or 100 mg followed by a more prolonged taper and administer additional anti-inflammatory measures as needed.  
Final 18-Dec-2014 Version 5.0 10 C Confidential Pembrolizumab Event of Clinical Interest Guidance Document Grade 4 events:
Report as ECI
l Permanently discontinue pembrolizumab.  
.  
Manage as per Grade 3.  
-
Final 18-Dec-2014 Version 5.0  
  
11 Protocol Amendment 9
Protocol Date 3/17/2021 Pembrolizumab Event of Clinical Interest Guidance Document
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3.3 endocrine

The following AE terms, if considered >Grade 3 or if >Grade 2 and require holding/discontinuation/
modification of pembrolizumab dosing, are considered ECIs and should be reported to the Spensor within 24 hours of the event:
-
Adrenal insufficiency 1 Hyperthyroidism  
i
Hypophysitis t Hypopituitarism l Hypothyroidism
-
Thyroid disorder Thyroiditis All attempts should be made to rule out other causes such as brain metastases, sepsis and/or infection.  
However the AE should be reported regardless of etiology.
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hypophysitis or other symptomatic endocrinopathy

Orade 2-4 events:
Report as ECI if appropriate Hold pembrolizumable Rule out infection and sepsis with appropriate cultures and imaging.  
1 Monitor thyroid function or other hormonal level tests and serum chemistries more frequently until  
returned to baseline values.  
Pituitary gland imaging should be considered (MRIs with gadolinium and selective cuts of the l pituitary can show enlargement or heterogeneity and confirm the diagnosis).  
Treat with prednisone 40 mg p.o. or equivalent per day. When symptoms improve to Grade 1 or less,
-
steroid taper should be started and continued over no less than 4 weeks. Replacement of appropriate hermones may be required as the steroid dose is tapered.  
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or
-
equivalent per day within 12 weeks.  
Hypophysitis with clinically significant adrenal insufficiency and hypotension, dehydration, and l electrolyte abnormalities (such as hyponatremia and hyperkalemia) constitutes adrenal crisis.  
Consultation with an endocrinologist may be considered.  
Final 18-Dec-2014 Version 5.0  
  
12 Pembrolizumab Event of Clinical Interest Guidance Document
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hyperthyroidism and hypothyroidism

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid, function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Grade 2 hyperthyroidism, Grade 2-4 hypothyroidism events:
Report as ECI if appropriate (see Table 1)
Monitor thyroid function or other hormonal level tests and serum chemistries more frequently until r returned to baseline values.  
Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency.  
Therapy with pembrolizumab can be continued while treatment for the thyroid disorder is instituted.  
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial therapy.  
(
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or liothyroinine, is I
indicated per standard of care.  
Consultation with an endocrinologist may be considered.  
Grade 3 hyperthyroidism events:
Report as ECI
i i i Hold pembrolizumab.  
Rule out infection and sepsis with appropriate cultures and imaging.  
Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed by oral prednisone 1 to 2 mg/kg per day. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered.  
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
Grade 4 hyperthyroidism events:
Report as ECI
-
Discontinue pembrolizumab.  
l Manage as per Grade 3
'
Final 18-Dec-2014 Version 5.0 C Confidential 13 Pembrolizumab Event of Clinical Interest Guidance Document Type 1 diabetes mellitus (if new onset) and > Grade 3 Hyperglycemia The following AE terms are considered ECIs and should be reported to the Spensor within 24 hours of the event:  
Type I diabetes mellitus (T1DM), if new onset, including diabetic ketoacidosis (DKA)
Grade 3 or higher hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA).  
Immune-mediated diabetes may present as new onset of Type 1 diabetes or an abrupt worsening of preexisting diabetes associated with laboratorial evidence of beta cell failure. All attempts should be made to rule out other causes such as type 2 diabetes mellitus (T2DM), T2DM decompensation, steroid-induced diabetes, physiologic stress-induced diabetes, or poorly controlled pre-existing diabetes (either TIDM or T2DM), but events meeting the above criteria should be reported as ECIs regardless of etiology. The patients may present with hyperglycemia (abrupt onset or abrupt decompensation) with clinical evidence of diabetic ketoacidosis or laboratory evidence of insulin deficiency, such as ketonuria, laboratory evidence of metabolic acidosis, or low or undetected c-peptide.
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course of action

TIDM should be immediately treated with insulin.  
T1DM or Grade 3-4 Hyperglycemia events:
Report as ECI if appropriate (see Table 1)
Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 3-4 hyperglycemia associated n with evidence of beta cell failure, and resume pembrolizumab when patients are clinically and mctabolically stable.  
Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4
-
hyperglycemia associated with metabolic acidosis or ketonuria.  
Evaluate patients with scrum glucose and a metabolic panel, urine ketones, glycosylated hemoglobin, e and C-peptide.  
Consultation with an Endocrinologist is recommended.  
t t Consider local testing for islet cell antibodies and antibodies to GAD, IA-2, ZnT8, and insulin may be obtained.  
Final 18-Dec-2014 Version 5.0  
  
14 Pembrolizumab Event of Clinical Interest Guidance Document
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3.4 hematologic

The following AE term, if considered Grade >3 or requiring dose modification or use of systemic steroids to treat the AE, are considered an ECI and should be reported to the Sponsor within 24 hours of the event:
l Autoimmune hemolytic anemia l Aplastic anemia i r Disseminated Intravascular Coagulation (DIC) Haemolytic Uraemic Syndrome (HUS)
e Idiopathic (or immune) Thrombocytopenia Purpura (ITP)
Thrombotic Thrombocytopenic Purpura (TTP)
Any Grade 4 anemia regardless of underlying mechanism All attempts should be made to rule out other causes such as metastases, sepsis and/or infection. Relevant dagnostic studies such as peripheral blood smear, reticulocyte count, LDH, haptoglobin, bone marrow biopsy or Coomb's test, etc., should be considered to confirm the diagnosis. However the AE should be reported regardless of ctiology. Course of Action Grade 2 events:
-  
r Grade 3 cycnts:  
i l Report as ECI
Hematology consultation.  
Hold pembrolizumab Discontinuation should be considered as per specific protocol guidance.  
Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as appropriate Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
-
Grade 4 events:
ti Report as ECI
Hematology consultation 1 Discontinue pembrolizumab for all solid tumor indications, refer to protocol for hematologic malignancies.  
Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as appropriate
Final 18-Dec-2014 Version 5.0 15 C Confidential Report as ECI
Hold pembrolizumable Prednisone 1-2 mg/kg daily may be indicated Consider Hematology consultation. Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.
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3.5 hepatic

The following AE terms, if considered > Grade 2 or greater (or any grade with dose modification or use of systemic steroids to treat the AE), are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
l  
Autoimmune hepatitis
i Hepatitis Transaminase elevations All attempts should be made to rule out other causes such as metastatic disease, infection or other hepatic diseases. However the AE should be reported regardless of etiology.
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drug induced liver injury (dili)

In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the patient meets the laboratory criteria for potential DILI defined as:
An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is greater than 1.0 or equal to three times (3X) the upper limit of normal (ULN) and An elevated total bilirubin lab value that is greater than or equal to two times (2X) ULN and
.  
At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN,
.  
As a result of within-protocol-specific testing or unscheduled testing.  
Note that any hepatic immune ECI meeting DILI criteria should culy be reported once as a DILI event.
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course of action

Grade 2 events:
Report as ECI
Hold pembrolizumab when AST or ALT >3.0 to 5.0 times ULN and/or total bilirubin >1.5 to 3.0 times ULN.  
Monitor liver function tests more frequently until returned to baseline values (consider weekly).  
Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT returns to CO
grade 1 or baseline, taper steroids over at least 1 month, consider prophylactic antibiotics for oppertunistic infections, and resume pembrolizumab per protocol Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
Permanently discontinue pembrolizumab for patients with liver metastasis who begin treatment with Grade 2 elevation of AST or ALT, and AST or ALT increases ≥ 50% relative to baseline and lasts ≥ 1 week.  
Orade 3 events:
Report as ECI
Discontinue pembrolizumab when AST or ALT >5.0 times ULN and/or total bilirubin >3.0 times ULN.  
Consider appropriate consultation and liver biopsy to establish etiology of hepatic injury, if necessary l Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours. When symptoms improve to l Grade 1 or less, a steroid taper with dexamethasone 4 mg every 4 hours or prednisone at 1 to 2 mg/kg should be started and continued over no less than 4 weeks.  
If serum transaminase levels do not decrease 48 hours after initiation of systemic steroids, oral mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab is not recommended due to its potential for hepatotoxicity.  
Final 18-Dec-2014 16 Version 5.0 C Confidential Pembrolizumab Event of Clinical Interest Guidance Document i Several courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  
r  
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.
Grade 4 events:
- Report as ECI
Permanently discontinue pembrolizumab l
- Manage patient as per Grade 3 above Final 18-Dec-2014 Version 5.0  
  
17 Pembrolizumab Event of Clinical Interest Guidance Document
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3.6 neurologic

The following AE terms, regardless of grade, are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
i y Autoimmune neuropathy Demyelinating polyneuropathy Guillain-Barre syndrome Myasthenic syndrome l All attempts should be made to rule out other causes such as metastatic disease, other medications or infectious causes. However the AE should be reported regardless of etiology. Course of Action Grade 2 events:  
l l l l Report as ECI
Moderate (Grade 2) - consider withholding pembrolizumab.  
Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate Consider Neurology consultation. Consider biopsy for confirmation of diagnosis.  
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
Grade 3 and 4 events:
Report as ECI
Discontinue pembrolizumab l Obtain neurology consultation. Consider biopsy for confirmation of diagnosis s Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day. If condition worsens consider IVIG or other immunosuppressive therapies as per local guidelines When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.  
Final 18-Dec-2014 Version 5.0 18 C Confidential Pembrolizumab Event of Clinical Interest Guidance Document
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3.7 ocular

The following AE terms, if considered Grade 22 or requiring dose modification or use of systemic stereids to treat the AE, is considered an ECI and should be reported to the Sponsor within 24 hours of the event:
- Uveitis
- Iritis All attempts should be made to rule out other causes such as metastatic disease, infection or other ocular disease (e.g. glaucoma or cataracts). However the AE should be reported regardless of etiology.  
Course of Action Grade 2 events:
a  
-
Evaluation by an ophthalmologist is strongly recommended.  
Treat with topical steroids such as 1% prednisolone acetate suspension and iridocyclitics.  
immunosuppressive therapy.  
Discontinue pembrolizumab as per protocol if symptoms persist despite treatment with topical
Grade 3 events:
Evaluation by an ophthalmologist is strongly recommended Hold pembrolizumab and consider permanent discontinuation as per specific protocol guidance.  
1 Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per day. When l symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 wcks.  
=  
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.
Grade 4 events:
l
,
Evaluation by an ophthalmologist is strongly recommended Permanently discontinue pembrolizumab.  
Treat with corticosteroids as per Grade 3 above 1 Final 18-Dec-2014 Version 5.0  
  
19 Pembrolizumab Event of Clinical Interest Guidance Document
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3.8 renal

The following AEs if > Grade 2 are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
Nephritis l l  
Nephritis autoimmune
l  
Rnal failure
i Rnal failure acute Creatinine elevations > Grade 3 or any grade with dose modification or use of systemic steroids to treat the AE.  
All attempts should be made to rule out other causes such as obstructive uropathy, progression of disease, or injury due to other chemotherapy agents. A renal consultation is recommended. However the AE should be reported regardless of etiology.  
Course of Action Grade 2 events:
l Hold pembrolizumable 1 i  
Treatment with prednisone 1-2 mg/kg p.o. daily.  
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.
Grade 3-4 events:
-
Discontinue pembrolizumab l  
Renal consultation with consideration of ultrasound and/or biopsy as appropriate Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or equivalent once per day.  
1
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4.  
www Final 18-Dec-2014 Version 5.0 20  
  
Pembrolizumab Event of Clinical Interest Guidance Document
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3.9 skin

Rash and Pruritus The following AEs should be considered as ECIs, if > Grade 3 and should be reported to the Sponsor within 24 hours of the event:
l Pruritus Rash i r s
-
Rash generalized Rsh maculo-papular In addition to CTCAE Grade 3 rash, any rash that is considered clinically significant, in the physician's judgment, should be treated as an ECI. Clinical significance is left to the physician to determine, and could possibly include rashes such as the following:
o rash with a duration >2 weeks; OR o rash that is >10% body surface area; OR
or rash that causes significant discomfort not relieved by topical medication or temporary cessation of study drug.
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other skin ecis

The following AEs should always be reported as ECIs, regardless of grade, and should be reported to the Sponsor within 24 hours of the event:
Dermatitis exfoliative l Erythema multiforme a Steven's Johnson syndrome Toxic epidermal necrolysis Please note, the AE should be reported regardless of etiology. Course of Action Grade 2 events:
l Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing creams in combination with oral anti-prurities
(e.g., diphenhydramine HCI or hydroxyzine HCI).  
Treatment with oral steroids is at physician's discretion for Grade 2 events.  
Grade 3 events:
l Hold pembrolizumab. Consider Dermatology Consultation and biopsy for confirmation of diagnosis.  
l Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or equivalent once per day or dexamethasone 4 mg four times orally daily. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.  
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
Grade 4 events:  
Permanently discontinue pembrolizumab Dermatology consultation and consideration of biopsy and clinical dermatology photograph.  
Initiate steroids at 1 to 2 mg/kg prednisone or equivalent. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.  
Final 18-Dec-2014 Version 5.0 C Confidential 21 Pembrolizumab Event of Clinical Interest Guidance Document 3.9.1. Immediate Evaluation for Potential Skin ECIs A. Photographs : Every attempt should be made to get a photograph of the actual ECI skin lesion or rash as soon as possible.  
Obtain appropriate consent for subject photographs if a consent form addendum is required by your IRB/ERC.  
Take digital photographs of:
the head (to assess mucosal or eye involvement),
o the trunk and extremities, and o  
o a close-up of the skin lesion/rash.
If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed marker of  
distance.
l  
The time/date stamp should be set in the 'ON' position for documentation purposes.  
Photographs should be stored with the subject's study records.  
The Sponsor may request copies of photographs. The local study contact (e.g., CRA) will provide guidance to the site, if needed.  
l
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b. past medical history

Collect past medical history relevant to the event, using the questions in Appendix 2 (Past Medical History Related to Dermatologic Event) as a guide. Any preexisting conditions not previously reported (e.g., dug allergy) should be entered into the Medical History eCRF.
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c. presentation of the event

Collect information on clinical presentation and potential contributing factors using the questions in Appendix 3 (Presentation of the Dermatologic Event) as a guide. This information should be summarized and entered in narrative format in the AE eCRF. Please use the available free-text fields, such as Signs and Symptoms. Note pertinent negatives where applicable to reflect that the information was collected. Any treatments administered should be entered on the Concomitant Medication eCRF.
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d. vitals signs and standard

Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record on the Vital Signs eCRF. Perform standard laboratory tests (CBC with manual differential and scrum chemistry panel, including LFTs).  
E. Focused Skin Examination:
Perform a focused skin examination using the questions in Appendix 4 (Focused Skin Examination) as a guide. Information should be summarized and entered on the Adverse Experience eCRF as part of the narrative.
appendix b. foundationone™️ heme sample
f. dermatology consult

Refer the subject to a dermatologist as soon as possible.  
For a "severe rash", the subject must be seen within 1-2 days of reporting the event.  
For clinically significant rash, the subject should be seen within 3-5 days.  
The dermatologist should submit a biopsy sample to a certified dermatopathology laboratory or to a pathologist experienced in reviewing skin specimens.  
The site should provide the dermatologist with all relevant case history, including copies of clinical photographs and laboratory test results.  
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3.10 other

The following AEs, regardless of grade, are considered ECIs and should be reported to the Sponsor within 24 hours of the event:  
Myocarditis  
l
Pericarditis  
r  
Pancreatitis Any additional Grade 3 or higher event which the physician considers to be immune related
All attempts should be made to rule out other causes. Therapeutic specialists should be consulted as appropriate. However the AE should be reported regardless of etiology.  
Course of Action Grade 2 events or Grade 1 events that do not improve with symptomatic treatment:
Withhold pembrolizumab.  
Systemic corticosteroids may be indicated.  
l Consider biopsy for confirmation of diagnosis.  
1 If pembrolizumab held and corticosteroid required, manage as per grade 3 below.  
i Grade 3 events:  
l  
l i
Hold pembrolizumab Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day.  
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.  
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks. Otherwise, pembrolizumab treatment may be restarted and the dose modified as specified in the protocol Grade 4 events:
l Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day.  
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3.11 infusion reactions

The following AE terms, regardless of grade, are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
- Allergic reaction
- Anaphylaxis
- Cytokine release syndrome Senim sickness 1 Infusion reactions r
- Infusion-like reactions Please note, the AE should be reported regardless of etiology. Course of Action Refer to infusion reaction table in the protocol and below.  
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| Infusion Reactions                                                                                               |                                          |                              |
|------------------------------------------------------------------------------------------------------------------|------------------------------------------|------------------------------|
| NCICICAE Grade                                                                                                   | Treatment                                | Premedication at subsequent  |
| dosing                                                                                                           |                                          |                              |
| Mld reaction; infusion                                                                                           | Incrense monitoring of vital signs as    | None                         |
| medically indicated until the subject is                                                                         |                                          |                              |
| deemed medically stable in the opinion of                                                                        |                                          |                              |
| interruption not indicated;                                                                                      |                                          |                              |
| intervention not indicated                                                                                       | the investigator.                        |                              |
| Grade 2                                                                                                          | Stop Infusion.                           | Subject may be premedicated  |
| Requires infusion interruption                                                                                   | Additional appropriate medical therapy   | 1.5h (± 30 minutes) prior to |
| but respends promptly to                                                                                         | may include but is not limited to:       | infusion of pembrolizumab    |
| symptomatic treatment (e.g.,                                                                                     | IV fluids                                | with:                        |
| antihistamines, NSAIDS,                                                                                          | Antihistamines                           |                              |
| nrcotics. IV fluids);                                                                                            | NSAIDS                                   | Diphenhydramine 50 mg p.e.   |
| prophylactic medications                                                                                         | Acctaminophen                            | (or equivalent dose of       |
| indicated for < -24 hrs                                                                                          | Narcotics                                | autibistannine).             |
| Increase monitoring of vital signs as                                                                            |                                          |                              |
| medically indicated until the subject is                                                                         | Acetaminophen 300-1000 mg                |                              |
| decmed medically stable in the coinion of                                                                        | p.o. (or equivalent dose of              |                              |
| the investigator.                                                                                                | antipyretic).                            |                              |
| If symptoms resolve within one hour of                                                                           |                                          |                              |
| stopping drug infusion, the infusion may                                                                         |                                          |                              |
| be restarted at 30% of the original infusion.                                                                    |                                          |                              |
| rate (e.g. from 100 mL/br to 50 mL/br).                                                                          |                                          |                              |
| Otherwise dosing will be held until                                                                              |                                          |                              |
| symptoms resolve and the subject should                                                                          |                                          |                              |
| be premedicated for the next scheduled                                                                           |                                          |                              |
| dose.                                                                                                            |                                          |                              |
| Subjects who develop Grade 2 texicity                                                                            |                                          |                              |
| despite adequate premedication should                                                                            |                                          |                              |
| be permanently discontinued from                                                                                 |                                          |                              |
| further trial treatment administration.                                                                          |                                          |                              |
| Cirades Gror 4                                                                                                   | Stop Infusion.                           | No subsequent dosing         |
| Grade 3:                                                                                                         | Additional appropriate medical therapy   |                              |
| Prolonged (i.e., not rapidly                                                                                     | may include but is not limited to:       |                              |
| responsive to symptomatic                                                                                        | IV fluids                                |                              |
| modication and/or brief                                                                                          | Antihistamines                           |                              |
| interruption of infusion);                                                                                       | NSAIDS                                   |                              |
| recurrence of symptoms                                                                                           | Acetaminophen                            |                              |
| following initial improvement;                                                                                   | Narcotics                                |                              |
| hospitalization indicated for                                                                                    | Oxygen                                   |                              |
| other clinical sequelae (e.g.,                                                                                   | Pressors                                 |                              |
| renal impairment, pulmonary                                                                                      | Corticosteroids                          |                              |
| infiltrates)                                                                                                     | Epinephnine                              |                              |
| Grade 4:                                                                                                         |                                          |                              |
| Life-threatening; pressor or                                                                                     | Incrense monitoring of vital signs as    |                              |
| ventilatory support indicated                                                                                    | medically indicated until the subject is |                              |
| deemed medically stable in the opinion of                                                                        |                                          |                              |
| the investigator.                                                                                                |                                          |                              |
| Hospitalization may be indicated.                                                                                |                                          |                              |
| Subject is permanently discontinued                                                                              |                                          |                              |
| from further trial treatment                                                                                     |                                          |                              |
| Appropriate resuscitation equipment should be available in the room and a physician readily available during the |                                          |                              |
| period of drug administration.                                                                                   |                                          |                              |
| For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at      |                                          |                              |
| http://stee.cancer.gov.                                                                                          |                                          |                              |  
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3.12 follow-up to resolution

Subjects should be followed to resolution. The Adverse Experience eCRF should be updated with information regarding duration and clinical course of the event. Information obtained from the consulting specialist, including diagnosis, should be recorded in the appropriate AE fields. Free-text fields should be used to record narrative information:
- Clinical course of the event  
Course of treatment
-
Evidence supporting recovery Follow-up to the clinical course  
Any treatments administered for the event should also be entered in the Concomitant Medication eCRF.  
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4. references

1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer 2012; 12:252-264.  
Weber JS Practical Management of Immune-Related Adverse Events from Immune Checkpoint Protein 2 Antibodies for the Oncologist. American Society of Clinical Oncology 2012; 1092-9118/10/1-10.  
3. Weber JS, Kathler KC, and Hauschild A. Management of Immune-Related Adverse Events and Kinetics Responses With Ipilimumab.  
of Clin Oncol 30.  
2012.  
.  
http://co.ascopubs.org/cgi/doi/10.1200/JCO.2012.41.6750.  
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, et al. Improved Survival with Ipilimumab in 4 Patients with Metastatic Melanoma. N Engl J Med 363:711-723, 2010.  
5 Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med 2012; 366:2443-2454.  
Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, et al. Safety and Activity of Anti-PD-L1 Antibody in 6.  
Patients with Advanced Cancer. N Engl J Med 2012; 366:2455-2465.  
7 Weber J, Thompson JA, Hamid O, et al: A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 15:5591-5598, 2009.  
8. Lemech C and Arkenau HT. Novel Treatments for Metastatic Cutaneous Metanoma and the Management of Emergent Toxicities. Clinical Medicine Insights: Oncology 2012:6 53-66.  
Phan GQ, Weber JS, and Sondak VK. CTLA-4 Blockade with Monoclonal Antibodies in Patients with 9.  
Mctastatic Cancer: Surgical Issues. Annals of Surgical Oncology 15(11):3014-3021.  
10. Bristol-Myers Squibb: YERVOY (ipilimumab): Serious and fatal immune-mediated adverse reactions-
YERVOY Risk Evaluation and Mitigation Strategy (REMS). http://www.yorvoy.com/hcp/rems.aspx 1. Bristol-Myers Squibb: YERVOY (ipilimumab) prescribing information revised March 2011.  
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| 5. APPENDIX 1 –Events of Clinical Interest (ECI) - Reference Table                                                              |                                                                                    |                                          |
|---------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|------------------------------------------|
| Pneumonitis (reported as ECI if > Grade 2)                                                                                      |                                                                                    |                                          |
| Acute interstitial pacumonitis                                                                                                  | Interstitial lung disease                                                          | Pneumonitis                              |
| Colitis (reported as ECI if> Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE)   |                                                                                    |                                          |
| Intestinal Obstruction                                                                                                          | Colitis                                                                            | Colitis microscopic                      |
| Enterocolitis                                                                                                                   | Enterocolitis hemorrhagic                                                          | Gastrointestinal perforation             |
| Necrotizing colitis                                                                                                             | Diarrhea                                                                           |                                          |
| Endocrine (reported as ECI if > Grade 3 or > Grade 2 and resulting in dose modification or use of systemic steroids to treat    |                                                                                    |                                          |
| the AE)                                                                                                                         |                                                                                    |                                          |
| Adrenal Insufficiency                                                                                                           | Hyperthyroidism                                                                    | Hypophysitis                             |
| Hypopituritarism                                                                                                                | Hypothyroidism                                                                     | Thyroid disorder                         |
| Thyroiditis                                                                                                                     | Hyperglycemia, if >Grade 3 and associated with ketosis or metabolic acidosis (DKA) |                                          |
| Endocrine (reported as ECT)                                                                                                     |                                                                                    |                                          |
| Type 1 diabetes mellitus (if new onset)                                                                                         |                                                                                    |                                          |
| Hematologic (reported as ECI if  ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat the |                                                                                    |                                          |
| AE)                                                                                                                             | Thrombotic Thrombocytopenic Purpura                                                |                                          |
| Autoimmune hemolytic anemia                                                                                                     | Aplastic anemia                                                                    | (LTF)                                    |
| Idiopathic (or immune) Thrombocytopenia                                                                                         | Disseminated Intravascular Coagulation                                             | Haemolytic Uraemic Syndrome (HUS)        |
| Purpura (ITP)                                                                                                                   | (DIC)                                                                              |                                          |
| Any Grade 4 anemia regardless of underlying mechanism                                                                           |                                                                                    |                                          |
| Hepatic (reported as ECI if 2 Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the AE) |                                                                                    |                                          |
| Hep2titis                                                                                                                       | Autoimmune hepatitis                                                               | Transaminase elevations (ALT and/or AST) |
| Infusion Reactions (reported as ECI for any grade)                                                                              |                                                                                    |                                          |
| Allergie reaction                                                                                                               | Anaphylaxis                                                                        | Cytokine release syndrome                |
| Serum sickness                                                                                                                  | Infusion reactions                                                                 | Infusion-like reactions                  |
| Neurologic (reported as ECI for any grade)                                                                                      |                                                                                    |                                          |
| Autoimmune neuropathy                                                                                                           | Quillain Barre syndrome                                                            | Demyelinating polyneuropathy             |
| Myasthenic syndrome                                                                                                             |                                                                                    |                                          |
| Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE)     |                                                                                    |                                          |
| Uveilis                                                                                                                         | Intis                                                                              |                                          |
| Renal (reported as ECI if ≥ Grade 2)                                                                                            |                                                                                    |                                          |
| Nephntis                                                                                                                        | Neplantis autoinmum                                                                | Rnal Failure                             |
| Creatinine elevations (report as ECI if 2Grade 3 or any grade resulting in dose                                                 |                                                                                    |                                          |
| Renal failure acute                                                                                                             | modification or use of systemic steroids to treat the AE)                          |                                          |
| Skin (reported as ECI for any grade)                                                                                            |                                                                                    |                                          |
| Dermatitis exfoliative                                                                                                          | Erythema multiformor                                                               | Stevens-Johnson syndrome                 |
| Toxic epidermal necrolysis                                                                                                      |                                                                                    |                                          |
| Skin (reported as ECI if > Grade 3)                                                                                             |                                                                                    |                                          |
| Prunitus                                                                                                                        | Rsh                                                                                | Rash generalized                         |
| Rsh maculo-papular                                                                                                              |                                                                                    |                                          |
| Any rash considered clinically significant in the physician's judgment                                                          |                                                                                    |                                          |
| Other (reported as ECI for any grade)                                                                                           | Pericarditis                                                                       |                                          |
| Myocarditis                                                                                                                     | Pancreatitis                                                                       |                                          |
| Any other Grade 3 event which is considered immune-related by the physician                                                     |                                                                                    |                                          |  
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6. appendix 2 - past

Past Medical History:
Any preexisting conditions not previously reported (e.g., drug allergy) should be entered into the Medical History cCRF.  
1. Does the subject have any allergies? 0 Yes 0 No If yes, please obtain the following information:
a. Any allergy to drugs (including topical or ophthalmic drugs)? 0 Yes 0 No List the drug name(s) and describe the type of allergic response (e.g. rash, anaphylaxis, etc):
b. Any allergy to external agents, such as laundry detergents, soaps, poison ivy, nickel, etc.? :: Yes ::
No Describe the agent and type of allergic response:
c. Any allergy to food? □ Yes □ No Describe the food and type of allergic response: d. Any allergy to animals, insects? □ Yes □ No Describe the allergen and type of allergic response:
c. Any other allergy? □ Yes □ No Describe the allergen and type of allergic respense:
2. Does the subject have any other history of skin reactions, skin eruptions, or rastes? 0 Yes 0 No If so what kind?  
3. Has the subject ever been treated for a skin condition? 0 Yes 0 No If so what kind?  
4. Is the current finding similar to a past experience?  
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7. appendix 3 - presentation

Presentation of the event:
Collect information on clinical presentation and potential contributing factors. Key information should be summarized and entered on the Adverse Experience eCRF. Any treatments administered should be entered on the Concomitant Medication eCRF.  
1. What is the onset time of the skin reaction, skin cruption, or rash relative to dose of study drug? 2. Has the subject contacted any known allergens? 0 Yes a No If so what kind? If so what kind?  
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry detergents, soap, personal care product, poison ivy, etc.)? □ Yes □ No If so what kind?  
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and supplement)? ם Ycs □ No If so what kind?  
5. Has the subject consumed unaccustomed, special or unusual foods? 0 Yes 0 No If so what kind?  
6. Does the subject have or had in the last few days any illness? D Yes D No If so what kind?  
7. Has the subject come into contact with any family or house members who are ill? 0 Yes 0 No If so who and what?  
8. Has the subject recently been near children who have a skin reaction, skin cruption, or rash (e.g. Molluscum Contaglosum)?  
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30 Pembrolizumab Event of Clinical Interest Guidance Document 9. Has the subject had recent sun exposure? □ Yes □ No 10. For the current rash, have there been any systemic clinical signs? ::: Yes ::: No If so what kind? i. Anaphylaxis? □ Yes □ No i. Signs of hypotension? □ Yes □ No iii. Signs of dyspnea? □ Yes □ No iv. Fever, night sweals, chills? □ Yes □ No 1. For the current rash, has the subject needed subcutaneous epinephrine or other systemic catecholamine therapy? □ Yes □ No If so what kind?  
12. For the current rash, has the subject used any other medication, such as inhaled bronchodilators, antihistaminic medication, topical corticosteroid, and/or systemic corticosteroid? D Yes D No List medication(s) and dose(s):
13. Is the rash pruritic (itchy)? c Yes c No Final 18-Dec-2014 Version 5.0 CCCConfidential 31