6.0 trial flow chart 6.1
8.1.2 analysis of primary endpoint

The secondary endpoint (dose expansion cohort) is the response rate to intralesional pembrolizumab as measured by an increase in intralesional CD8+ T cells. For this study, we will define a responder to pembrolizumab as demonstrating a >= 50% increase (baseline to surgical sample) of intralesional CD8+ T cells. In a recent study in melanoma, 44% of patients treated with pembrolizumab demonstrated a >=50% increase in intratumoral CD8+ T cells (Tumeh et al., 2014). Point estimate of the response rate and its 95% confidence interval will be obtained by arm, and two-sample proportion test will be used to test if the response rate is different between the two arms. For the expansion cohort, a sample size of 30 patients (2:1 - treatment:control) will have 80% power, with an alpha of 0.05, to detect a 44% or greater response rate in the treatment arm compared to the control arm.
6.0 trial flow chart 6.1
8.2 accrual objectives

A 3x3 dose escalation design will be followed, so sample size will be between 12 and 18 for this phase. The expansion cohort will consist of 30 additional patients with DCIS. We anticipate accruing 2-3 patients per month and estimate that it will require approximately 16-20 months to complete the study.
6.0 trial flow chart 6.1
8.3 stratification factors

Page 53 of 102 There are no planned patient stratification factors.
6.0 trial flow chart 6.1
9.0 labeling packaging storage and

The investigator shall take responsibility for and shall take all steps to maintain appropriate records and ensure appropriate supply, storage, handling, distribution and usage of investigational product in accordance with the protocol and any applicable laws and regulations. Clinical Supplies will be provided by Merck as summarized in Table 8.  
Table 8. Product Descriptions  
| Product Name & Potency    | Dosage Form                      |
|---------------------------|----------------------------------|
| Pembrolizumab 50 mg       | Lyophilized Powder for Injection |
| Pembrolizumab 100 mg/ 4mL | Solution for Injection           |
6.0 trial flow chart 6.1
9.2 packaging and labeling information

This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; random code/disclosure envelopes or lists are not provided.
6.0 trial flow chart 6.1
9.4 storage and handling requirements

Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified on the label. Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. Clinical supplies may not be used for any purpose other than that stated in the protocol.
6.0 trial flow chart 6.1
9.5 returns and reconciliation

The investigator is responsible for keeping accurate records of the clinical supplies received from Merck or designee, the amount dispensed to and returned by the subjects and the amount remaining at the conclusion of the trial. Upon completion or termination of the study, all unused and/or partially used investigational product will be destroyed at the site per institutional policy. It is the Investigator's responsibility to arrange for disposal of all empty containers, provided that procedures for proper disposal have been established according to applicable federal, state, local and institutional guidelines and procedures, and provided that appropriate records of disposal are kept.
6.0 trial flow chart 6.1
10.0 administrative and regulatory details

This study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable regulatory requirements. Before initiating this trial, the Investigator will have written and dated approval from the Institutional Review Board for the protocol, written informed consent form, subject recruitment materials, and any other written information to be provided to subjects before any protocol related procedures are performed on any subjects. The clinical investigation will not begin until either FDA has determined that the study under the Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a letter from FDA stating that the study is exempt from IND requirements. The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable regulatory requirements.
6.0 trial flow chart 6.1
10.2 institutional review board approval

The protocol, the proposed informed consent form, and all forms of participant information related to the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the UCSF Institutional Review Board (IRB). Prior to obtaining IRB approval, the protocol must be approved by the Helen Diller Family Comprehensive Cancer Center Site Committee and by the Protocol Review Committee (PRC). The initial protocol and all protocol amendments must be approved by the IRB prior to implementation.
6.0 trial flow chart 6.1
10.3 informed consent

All participants must be provided a consent form describing the study with sufficient information for each participant to make an informed decision regarding their participation. Participants must sign the IRB -approved informed consent form prior to participation in any study specific procedure. The participant must receive a copy of the signed and dated consent document. The original signed copy of the consent document must be retained in the medical record or research file.
6.0 trial flow chart 6.1
10.4 changes in the protocol

Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be documented in the form of an amendment. The amendment must be signed by the Investigator and approved by PRC and the IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an amendment may be implemented prior to IRB approval. In this circumstance, however, the Investigator must then notify the IRB in writing within five (5) working days after implementation. The Study Chair and the UCSF study team will be responsible for updating any participating sites.
6.0 trial flow chart 6.1
10.5 handling and documentation of

The UCSF Principal Investigator and each participating site will maintain complete records showing the receipt, dispensation, return, or other disposition of all investigational drugs. The date, quantity and batch or code number of the drug, and the identification of patients to whom study drug has been dispensed by patient number and initials will be included. The sponsor-investigator will maintain written records of any disposition of the study drug. The Principal Investigator shall not make the investigational drug available to any individuals other than to qualified study patients. Furthermore, the Principal Investigator will not allow the investigational drug to be used in any manner other than that specified in this protocol.
6.0 trial flow chart 6.1
10.6 case report forms (crfs)

The Principal Investigator and/or his/her designee will prepare and maintain adequate and accurate participant case histories with observations and data pertinent to the study. Study specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety monitoring and data analysis. All study data will be entered into OnCore® via standardized CRFs in accordance with the CTMS study calendar, using single data entry with a secure access account. The Clinical Research Coordinator (CRC) will complete the CRFs as soon as possible upon completion of the study visit; the Investigator will review and approve the completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source documents. Source documents will be found in the patient's medical records maintained by UCSF personnel. All source documentation should be kept in separate research folders for each patient.  
In accordance with federal regulations, the Investigator is responsible for the accuracy and authenticity of all clinical and laboratory data entered onto CRFs. The PI will approve all completed CRFs to attest that the information contained on the CRFs is true and accurate. All source documentation and CTMS data will be available for review/monitoring by the UCSF DSMC and regulatory agencies. The Principal Investigator will be responsible for ensuring the accurate capture of study data. At study completion, when the CRFs have been declared to be complete and accurate, the database will be locked. Any changes to the data entered into the CRFs after that time can only be made by joint written agreement among the Study Chair, the Trial Statistician, and the Protocol Project Manager.
6.0 trial flow chart 6.1
10.7 oversight and monitoring plan

The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring entity for this study. The UCSF DSMC will monitor the study in accordance with the NCI-approved Data and Safety Monitoring Plan (DSMP). The DSMC will routinely review all adverse events and suspected adverse reactions considered "serious". The DSMC will audit study-related activities to ensure that the study is conducted in accordance with the protocol, local standard operating procedures, FDA regulations, and Good Clinical Practice (GCP). Significant results of the DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as applicable. See Appendix 12.4 Data and Safety Monitoring Plan for a Phase 1/2 Institutional Study, for additional information.
6.0 trial flow chart 6.1
10.8 regulatory documentation

Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, HIPAA authorization and any other information pertaining to participants must be approved by the UCSF Institutional Review Board (IRB). Prior to implementing this protocol at the participating sites, approval for the UCSF IRB approved protocol must be obtained from the participating site's IRB. The following documents must be provided to UCSF HDFCCC before the participating site can be initiated and begin enrolling participants:  
Participating Site IRB approval(s) for the protocol, appendices, informed consent form and HIPAA authorization Participating Site IRB approved consent form Participating Site IRB membership list
Page 57 of 102  
Participating Site IRB membership list form ce number and OHRP Registration number Curriculum vitae and medical license for each investigator and consenting professional Documentation of Human Subject Research Certification training for investigators and key staff members at the Participating Site Participating site laboratory certifications and normals Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant permission to proceed with enrollment.
6.0 trial flow chart 6.1
10.9 protection of human subjects

Each clinical site is responsible for protecting all subjects involved in human experimentation. This is accomplished through the IRB mechanism and the process of informed consent. The IRB reviews all proposed studies involving human experimentation and ensures that the subject's rights and welfare are protected and that the potential benefits and/or the importance of the knowledge to be gained outweigh the risks to the individual. The IRB also reviews the informed consent document associated with each study in order to ensure that the consent document accurately and clearly communicates the nature of the research to be done and its associated risks and benefits.
6.0 trial flow chart 6.1
10.9.2 protection of privacy

Patients will be informed of the extent to which their confidential health information generated from this study may be used for research purposes. Following this discussion, they will be asked to sign the HIPAA form and informed consent documents. The original signed document will become part of the patient's medical records, and each patient will receive a copy of the signed document. The use and disclosure of protected health information will be limited to the individuals described in the informed consent document.
6.0 trial flow chart 6.1
11.0 references

1. Silverstein, M. J. The University of Southern California/Van Nuys prognostic index for ductal carcinoma in situ of the breast. Am J Surg. 2003; 186(4): 337-343.  
2. Wai, E. S., Lesperance, M. L., Alexander, C. S., Truong, P. T., Moccia, P., Culp, M., . . . Olivotto, I. A. Predictors of local recurrence in a population-based cohort of women with ductal carcinoma in situ treated with breast conserving surgery alone. Ann Surg Oncol. 2011; 18(1): 119-124. doi: 10.1245/s10434-010-1214-x 3. Wang, S. Y., Shamliyan, T., Virnig, B. A., & Kane, R. Tumor characteristics as predictors of local recurrence after treatment of ductal carcinoma in situ: a meta-analysis. Breast Cancer Res Treat. 2011; 127(1): 1-14. doi: 10.1007/s10549-011-1387-4 4. Campbell MJ, Tonlaar NY, Garwood ER, Huo D, Moore DH, Khramtsov AI, Au A, Baehner F, Chen Y, Malaka DO, Lin A, Adeyanju OO, Li S, Gong C, McGrath M, Olopade OI, Esserman LJ. Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Res Treat. 2011 Aug;128(3):703-11.  
5. Mukhtar RA, Moore AP, Tandon VJ, Nseyo O, Twomey P, Adisa CA, Eleweke N, Au A, Baehner FL, Moore DH,
McGrath MS, Olopade OI, Gray JW, Campbell MJ, Esserman LJ. Elevated levels of proliferating and recently migrated tumor-associated macrophages confer increased aggressiveness and worse outcomes in breast cancer. Ann Surg Oncol. 2012 Nov;19(12):3979-86.  
6. Obeid E, Nanda R, Fu YX, Olopade OI. The role of tumor-associated macrophages in breast cancer progression
(review). Int J Oncol. 2013 Jul;43(1):5-12.  
7. de la Cruz-Merino L, Barco-Sánchez A, Henao Carrasco F, Nogales Fernández E, Vallejo Benítez A, Brugal Molina J, Martínez Peinado A, Grueso López A, Ruiz Borrego M, Codes Manuel de Villena M, Sánchez-Margalet V, Nieto-García A, Alba Conejo E, Casares Lagar N, Ibáñez Martínez J. New insights into the role of the immune microenvironment in breast carcinoma. Clin Dev Immunol. 2013; Epub 2013 Jun 3.  
8. Campbell MJ, Wolf D, Mukhtar RA, Tandon V, Yau C, Au A, Baehner F, van't Veer L, Berry D, Esserman LJ. The prognostic implications of macrophages expressing proliferating cell nuclear antigen in breast cancer depend on immune context. PLoS One. 2013 Oct 29;8(10):e79114.  
9. Hussein MR, Hassan HI. Analysis of the mononuclear inflammatory cell infiltrate in the normal breast, benign proliferative breast disease, in situ and infiltrating ductal breast carcinomas: preliminary observations. J Clin Pathol. 2006 Sep;59(9):972-7.  
10. Esserman LJ, Kumar AS, Herrera AF, Leung J, Au A, Chen YY, Moore DH, Chen DF, Hellawell J, Wolverton D,
Hwang ES, Hylton NM. Magnetic resonance imaging captures the biology of ductal carcinoma in situ. J Clin Oncol. 2006 Oct 1;24(28):4603 11. Sharma M, Beck AH, Webster JA, Espinosa I, Montgomery K, Varma S, van de Rijn M, Jensen KC, West RB.  
Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ. Breast Cancer Res Treat. 2010 Sep;123(2):397-404.  
12. Marabelle A, Kohrt H, Sagiv-Barfi I, Ajami B, Axtell RC, Zhou G, Rajapaksa R, Green MR, Torchia J, Brody J,
Luong R, Rosenblum MD, Steinman L, Levitsky HI, Tse V, Levy R. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest. 2013 Jun;123(6):2447-63.  
13. Asís Palazón, Iván Martínez-Forero, Alvaro Teijeira, et al. The HIF-1α Hypoxia Response in Tumor-Infiltrating T
Lymphocytes Induces Functional CD137 (4-1BB) for Immunotherapy. Cancer Discovery 2012;2:608-623.  
14. Van De Voort TJ, Felder MA, Yang RK, Sondel PM, Rakhmilevich AL. Intratumoral delivery of low doses of anti-CD40 mAb combined with monophosphoryl lipid a induces local and systemic antitumor effects in immunocompetent and T cell-deficient mice. J Immunother. 2013; 36(1):29-40.  
15. Sandin LC, Eriksson F, Ellmark P, Loskog AS, Tötterman TH, Mangsbo SM. Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo. Oncoimmunology. 2014;3(1):e27614.  
16. Dai M, Yip YY, Hellstrom I, Hellstrom KE. Curing mice with large tumors by locally delivering combinations of immunomodulatory antibodies. Clin Cancer Res. 2015;21(5):1127-38.  
17. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G,
Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C,
Page 59 of 102  
Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568-71.
6.0 trial flow chart 6.1
12.0 appendices 12.1 ecog performance

| Grade                                                                                                                                                                                                              | Description                                                                                                                                                                           |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0                                                                                                                                                                                                                  | Normal activity. Fully active, able to carry on all pre-disease performance  without restriction. Symptoms, but ambulatory. Restricted in physically strenuous activity,              |
| 1                                                                                                                                                                                                                  | but ambulatory and able to carry out work of a light or sedentary nature  (e.g., light housework, office work). In bed <50% of the time. Ambulatory and capable of all self-care, but |
| 2                                                                                                                                                                                                                  | unable to carry out any work activities. Up and about more than 50% of  waking hours.                                                                                                 |
| 3                                                                                                                                                                                                                  | In bed >50% of the time. Capable of only limited self-care, confined to  bed or chair more than 50% of waking hours.                                                                  |
| 4                                                                                                                                                                                                                  | 100% bedridden. Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair.                                                                                |
| 5                                                                                                                                                                                                                  | Dead.                                                                                                                                                                                 |
| * As published in Am. J. Clin. Oncol.:                                                                                                                                                                             | Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E.,                                                                                                                      |
| McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group.  Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. |                                                                                                                                                                                       |
6.0 trial flow chart 6.1
12.1.1 contraceptive guidance and pregnancy

Woman of Childbearing Potential (WOCBP) A woman is considered fertile following menarche and until becoming post-menopausal unless permanently sterile (see below) Women in the following categories are not considered WOCBP: - Premenarchal - Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy Note: Documentation can come from the site personnel's review of the participant's medical records, medical examination, or medical history interview.  
- Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. - A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with two FSH measurements in the postmenopausal range is required.  
- Females on HRT and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment.
6.0 trial flow chart 6.1
contraception requirements female participants

Female participants of childbearing potential are eligible to participate if they agree to use a highly effective method of contraception consistently and correctly as described in Table 9 during the protocol-defined time frame in Section 5.1.2.
6.0 trial flow chart 6.1
male participants

Male participants with female partners of childbearing potential are eligible to participate if they agree to one of the following during the protocol defined time frame in section 5.1.2:
- Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
- Use a male condom plus partner use of a contraceptive method with a failure rate of <1% per year as described in Table 9 when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant.  
- Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration.
6.0 trial flow chart 6.1
pregnancy testing

WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test and in accordance with local requirements. This test should be repeated a maximum of 72-hours before each dose.  
Table 9. Highly Effective Contraception Methods Highly Effective Contraceptive Methods That Are User Dependent a Failure rate of <1% per year when used consistently and correctly.  
- Combined (estrogen- and progestogen- containing ) hormonal contraception b, c
- Oral - Intravaginal - Transdermal - Injectable
- Progestogen-only hormonal contraception b, c
- Oral - Injectable Highly Effective Methods That Have Low User Dependency Failure rate of <1% per year when used consistently and correctly.  
- Progestogen- only contraceptive implant b, c
- Intrauterine hormone-releasing system (IUS) b
- Intrauterine device (IUD) - Bilateral tubal occlusion
6.0 trial flow chart 6.1
- vasectomized partner

A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.  
- **Sexual abstinence**
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.)
Notes: Use should be consistent with local regulations regarding the use of contraceptive methods for participants of clinical studies.  
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and correctly).  
b) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable hormonal contraceptives are limited to those which inhibit ovulation.
6.0 trial flow chart 6.1
12.2 common terminology criteria for

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. (http://ctep.cancer.gov/reporting/ctc.html) 12.3 UCSF Policy/Procedure for required regulatory documents for single site and multicenter investigator-initiated oncology clinical trials
6.0 trial flow chart 6.1
purpose

This policy defines the required Regulatory Documents for Single Site and Multicenter Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer Center (HDFCCC) for both IND and IND-exempt trials.
6.0 trial flow chart 6.1
background

The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines define Essential Regulatory Documents as those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of data produced. These documents serve to demonstrate compliance with standards of GCP and with all applicable regulatory requirements. Filing essential documents in a timely manner can greatly assist in the successful management of a clinical trial.  
The Regulatory Documents will consist of electronic files in both iRIS and OnCore®, as well as paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
6.0 trial flow chart 6.1
procedures 1. single site (hdfccc)

Current and prior versions of the Informed Consent Form(s) (ICFs). IRB approvals for initial submission of application, all modifications, and continuing annual renewals.  
Current and prior approved protocol versions.  
IRB roster Current and prior versions of the Investigator Brochure (IB).  
Serious Adverse Event (SAE) Reports.  
Subject diary and handouts (if applicable).  
Single Patient Exception (SPE) Report(s) to IRB with Approval Letter(s) from IRB.  
Protocol Violation (PV) Reports with acknowledgement from the IRB.
6.0 trial flow chart 6.1
documents filed in oncore

Package Insert (if the study drug is commercial).  
Protocol signature page(s) with Pl signature(s) for all protocol versions.  
Protocol Review Committee (PRC) approved protocols, protocol amendments and Summary of Changes (SOC) document.  
Screening/enrollment log.  
Data and Safety Monitoring Committee (DSMC) monitoring reports. DSMC dose escalation approvals with study status summary forms.  
Case Report Form (CRF) completion manual.  
Drug Destruction Standard Operating Procedure (SOP).  
Completed Food and Drug Administration (FDA) 1572 document with Principal Investigator's signature.  
For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need Financial Disclosure Forms, CVs, MD Licenses, and Staff Training Documents (i.e., Collaborative Institute Training Initiative (CITI), etc.).  
As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center.  
Serious Adverse Event (SAE) reports to IRB and sponsor.  
MedWatch reporting to FDA and sponsor. Drug Destruction Standard Operating Procedure (SOP).  
For all laboratories listed on the FDA 1572, will need CUA certifications, CAP
certifications, lab licenses, CV(s) and Medical License(s) of Lab Director(s), and laboratory reference ranges.
6.0 trial flow chart 6.1
documents filed in regulatory binder

Delegation of Authority Log with signatures (to be scanned in OnCore once the trial is complete).
6.0 trial flow chart 6.1
2. additional essential documents for

- Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent Form
(ICF), and Health Insurance Portability and Accountability Act {HIPAA) Consent Form for the Participating Site(s).  
- For all Principal Investigators and Sub-Investigators listed on the 1572 at the Participating Site(s), will need Financial Disclosure Forms, CVs, MD Licenses, and Staff Training documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) (for investigational New Drug Application).  
- Site Initiation Visit (SIV) minutes and correspondence with the Participating Site(s).  
- As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center for the Participating Site(s).  
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- Protocol Violations (PV) Reports to IRB with acknowledgement from IRB for Participating Site(s).  
- Single Patient Exception (SPE) Reports to IRB with IRB Approval Letters for Participating Site(s).  
- Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s).  
- Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating Site(s).  
- For all laboratories listed on FDA 1572, will need CUA certifications, CAP certifications, lab licenses, CVs and Medical License(s) of Lab Director(s), and laboratory reference ranges for the Participating Site(s).  
- Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all participating site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan (if an outside CRO is used for the study).  
- Serious Adverse Event (SAE) forms submitted to the IRB for the Participating Site(s).
6.0 trial flow chart 6.1
4. required essential regulatory documents

- For IND Exempt studies, the Essential Regulatory Documents for UCSF would include all documents in Section \#1 of this policy. The Essential Regulatory Documents from the participating site(s) for Multicenter Trials when UCSF is the Coordinating Center would only include the signed protocol signature page, CV of the Pl, and the IRB approval letters. All other documents in Section \#2 of this policy would be the responsibility of the Participating Site(s).
6.0 trial flow chart 6.1
5. required essential regulatory documents

- For Single Site non-therapeutic trials, all Regulatory Documents in Section \#1 of this policy are required except for: current and prior versions of the Investigator Brochure (IB), package insert (if the study drug is commercial), DSMC dose escalation approvals with study status summary forms, approvals for Biosafety Committee, Radiation Committee, and Infusion Center, and drug destruction SOPs.
6.0 trial flow chart 6.1
6. required essential regulatory documents

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- For Multicenter non-therapeutic trials with UCSF as the Coordinating Site, all required Regulatory Documents listed above in Section \#5 for Single Site non-therapeutic trials are required for the Coordinating Site. The only required Regulatory Documents from the Participating Site(s) will be: IRB approval letters, IRB roster, and ICF and HIPAA consent forms, the Delegation of Authority Log (with NIH or CITI human subject protection training certificates or GCP training certification), Protocol Violations and Single Patient Exception (SPE) reports to the IRB with supporting fax documentation (if applicable), Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor, and the Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating Site(s). If applicable, a copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all participating site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan (if an outside CRO is used for the study) will be required.
6.0 trial flow chart 6.1
alternate procedures

There are no alternate procedures to the HDFCCC policy for requirements for Essential Regulatory Documents for Multicenter Investigator-Initiated Oncology Clinical Trials.
6.0 trial flow chart 6.1
references

- ICH Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance (current version).  
- International Conference on Harmonization: Good Clinical Practice: Consolidated Guideline (current version).  
- International Conference on Harmonization: Essential Documents for the Conduct of a Clinical Trial (current version).  
- 21CFR50
- 21 CFR56.11
- 45CFR46
- 21 CFR312 Required Regulatory Documents for Sub-sites Participating in Therapeutic UCSF Investigator Initiated Multicenter trial Directions: Scan the documents in a zip drive and upload to OnCore.  
PI and Sub investigators:
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CV and Medical license Financial disclosure form NIH or CITI human subject protection training certification Laboratories:
CLIA &CAP and Lab Licenses CV and Medical License of Lab Director Laboratory reference ranges
6.0 trial flow chart 6.1
local institutional review board

IRB Approval letter Reviewed/Approved documents Protocol version date: ___________ Informed consent version date: ___________ Investigator Brochure version date: ___________ HIPAA
Current IRB Roster Other Delegation of Authority Log Include NIH or CITI human subject protection training certificates or GCP training certification Pharmacy Drug destruction SOP and Policy Protocol signature page Executed sub contract
6.0 trial flow chart 6.1
12.4 data and safety monitoring

The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for all HDFCCC institutional clinical studies. A summary of DSMC activities for this study includes:  
- Review of subject data in each cohort for the Phase 1 portion of trial - Review of suspected adverse reactions considered "serious" - During the Phase 1 portion of trial, approval of dose escalation by DSMC Chair (or qualified alternate)
- Monthly monitoring (depending on study accrual) for the Phase 1 portion of trial and biannual monitoring for the Phase 2 portion of trial.  
- Minimum of a yearly regulatory audit
Monitoring and Reporting Guidelines Investigators will conduct continuous review of data and subject safety and discuss each subject's treatment at weekly Site Committee meetings. The discussions are documented in the Site Committee meeting minutes. For each dose level, the discussion will include the number of subjects, significant toxicities in accordance with the protocol, doses adjustments, and observed responses.  
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All institutional Phase 1/2 therapeutic studies are designated with moderate to high-risk assessment; therefore, during the Phase 1 portion of trial, the data is monitored once per month, as subjects are enrolled, through the DLT period and, during the Phase 2 portion of the trial, the data is monitored twice per year, with twenty percent of the subjects monitored (or at least three subjects if the calculated value is less than three). Adverse Event Review and Monitoring
6.0 trial flow chart 6.1
during phase 1

All clinically significant adverse events, whether or not unexpected, and whether or not considered to be associated with the use of the study drug, will be entered into OnCore®,
UCSF's Clinical Trial Management System.  
All clinically significant adverse events entered into OnCore® will be reviewed on a weekly basis at the Site Committee meetings. The Site Committee will review and discuss the selected toxicity, t h e toxicity grade, and the attribution of relationship of the adverse event to the administration of the study drug(s). In addition, all suspected adverse reactions considered "serious" are entered into OnCore® and will be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and discussed at the DSMC meetings, which take place every six (6) weeks. If a death occurs during the treatment phase of the study or within 30 days after the last administration of the study drug(s) and is determined to be related either to the study drug(s) or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair or his qualified alternate within **1 business day** of knowledge of this event. The contact may be by phone or e-mail. Dose Escalations (During Phase 1) At the time of dose escalation, a written report will be submitted to the DSMC Chair (or qualified alternate) describing the cohorts, dose levels, adverse events, safety reports, and any Dose Limiting Toxicities observed, in accordance with the protocol. The report will be reviewed by the DSMC Chair (or qualified alternate) and written authorization to proceed or a request for more information will be issued within **2 business days** of the request. Approval for dose escalation by the DSMC (or qualified alternate) must be obtained prior to implementation.
6.0 trial flow chart 6.1
increase in adverse event rates

If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the Investigator Brochure or package insert) is noted in the study, a report should be submitted to the DSMC at the time the increased rate is identified. The report will indicate if the incidence of adverse events observed in the study is above the range stated in the Investigator Brochure or package insert.  
Page 72 of 102 If at any time the Investigator stops enrollment or stops the study due to safety issues, the DSMC
Chair and DSMC Manager must be notified within **1 business day** via e-mail.  
  
* DSMP approved by NCI 09/February2012
12.5 event of clinical interest
increase in adverse event rates

REVISION HISTORY LOG  
| Version   | Effective   | Revision Author   | Action                                           |
|-----------|-------------|-------------------|--------------------------------------------------|
| Date*     |             |                   |                                                  |
| 1         | 08-Aug-2012 | Kevin Gergich     | Initial Release of guidance document for MK-3475 |  
| Version date: 23OCT2018    | CC# 16704    |                                          |    |
|----------------------------|--------------|------------------------------------------|----|
| 2                          | 07-June-2013 | Marty Huber, Kevin Gergich,  Holly Brown | Revised title, formerly was "MK-3475 Immune-Related Adverse Event Identification, Evaluation and Management Guidance Document for Investigators" Revised the format of irAE Guidance document, including  layout, 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: ImmuneRelated 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.    |
| 3                          | Marty        | Huber,                                   |    |
| Kevin Gergich, Holly Brown | Renamed the document: "Pembrolizumab Program (MK3475) - Events of Clinical Interest Guidance Document". 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 terminology. Updated Section 2 - ECI Reporting Guidelines              |                                          |    |  
| Version date: 23OCT2018                      | CC# 16704 - Clarified that ECIs must be reported to Merck within 24 hours regardless of attribution to study treatment or  etiology. Updated Section 3 - For All Sections, removed the Course of Action for Grade 1 events. - Section 3.1 Pneumonitis - Moved Pneumonitis to beginning of ECI Section - Updated management guidelines for Grade 2 and Grade 3-4 events - Section 3.2 Colitis: - Updated AE terms and ECI criteria, updated  course of action language for clarity - Section 3.3 Endocrine: - Updated ECI criteria and updated course of action  language for clarity. - Added subsections for hypophysitis,  hyperthyroidism and hypothyroidism to clarify  management guidelines. - Section 3.4 Hematologic: - New section added. - Section 3.5: Hepatic: - Updated terms and added additional guidance for  reporting of DILI ECI; updated course of action  for clarity - Section 3.6 Neurologic: - New section added. - Section 3.7 Ocular: - Changed the name of this section from Eye to Ocular - Added the term "iritis", updated ECI guidance,  and updated course of action language for clarity - Section 3.8 Renal: - Updated section for clarity. - Section 3.9 Skin: - Updated list of terms and added terms for  reporting of other skin ECIs; added section 3.9.1:  Immediate Evaluation for Potential Skin ECIs - Section 3.10 Other: - Updated list of terms for clarity; revised course of  action for clarity.   |
|----------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Pilot: Intralesional Injection Pembrolizumab | Page 75 of 102                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |  
| - 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.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| *Ensure that you are using the most current version of this document.                                                                                                                                                                                                                                                                                                                                                                                                                   |
12.5 event of clinical interest
table of contents

| 1. OVERVIEW                                                                                                                                                           |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 2. ECI REPORTING GUIDELINES                                                                                                                                           |
| 3. ECI CATEGORIES AND TERMS ....................................................................................................................................... 8 |
| 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 ..................................................................................... 2                           |
| 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 .......................................... 29                                                      |
| 6. APPENDIX 2 - Past Medical History Related to Dermatologic Event ......................................... 30                                                       |
| 7. APPENDIX 3 - Presentation of the Dermatologic Event .                                                                                                              |
| 8. APPENDIX 4 - Focused Skin Examination                                                                                                                              |
12.5 event of clinical interest
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 immunerelated 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.  
| Table 1: Events of Clinical Interest                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|
| Pneumonitis (reported as ECI if ≥ Grade 2) Acute interstitial pneumonitis 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 Hypopituitarism Hypothyroidism Thyroid disorder Thyroiditis Hematologic (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat the AE) Autoimmune hemolytic anemia Aplastic anemia Thrombotic Thrombocytopenic Purpura (TTP) Idiopathic (or immune) Thrombocytopenia Disseminated Intravascular Coagulation (DIC) Haemolytic Uraemic Syndrome (HUS) Purpura (ITP) 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 Infusion Reactions (reported as ECI for any grade) Allergic reaction Anaphylaxis Cytokine release syndrome Serum sickness Infusion reactions Infusion-like reactions Neurologic (reported as ECI for any grade) Autoimmune neuropathy Guillain-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) Uveitis Iritis Renal (reported as ECI if ≥ Grade 2) Nephritis Nephritis autoimmune Renal Failure Renal failure acute Creatinine elevations (report as ECI if ≥Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat the AE) Skin (reported as ECI for any grade) Dermatitis exfoliative Erythema multiforme Stevens-Johnson syndrome Toxic epidermal necrolysis Skin (reported as ECI if ≥ Grade 3) Pruritus Rash Rash generalized Rash maculo-papular Any rash considered clinically significant in the physician's judgment |                |
| Pilot: Intralesional Injection Pembrolizumab                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Page 80 of 102 |  
| Other (reported as ECI for any grade) Myocarditis                           | Pancreatitis   | Pericarditis   |
|-----------------------------------------------------------------------------|----------------|----------------|
| Any other Grade 3 event which is considered immune-related by the physician |                |                |  
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 the 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 the 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.
12.5 event of clinical interest
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" means to stop treating with pembrolizumab but resumption of treatment may be considered assuming the patient meets the criteria for resumption of treatment.
12.5 event of clinical interest
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 paper) 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. - Please refer to protocol for details on reporting timelines and reporting of Overdose and Drug Induced Liver Injury (DILI).
12.5 event of clinical interest
3. eci categories and terms

This section describes the ECI categories and outlines subject management guidelines when an ECI is reported Page 82 of 102
12.5 event of clinical interest
3.1 pneumonitis

The following AE terms, if considered ≥ 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 etiology 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.
12.5 event of clinical interest
course of action grade 2

- Report as ECI - Hold pembrolizumab. - Consider pulmonary consultation with bronchoscopy and biopsy/BAL. - Consider ID consult - Conduct an in person evaluation approximately twice per week - 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 weeks.  
- 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.
12.5 event of clinical interest
grade 3 and 4 events

- 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 Page 83 of 102  
per day or dexamethasone 4 mg every 4 hours) taper should be started and continued over no less than 4 weeks.  
- If 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 antiinflammatory 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
- Add prophylactic antibiotics for opportunistic infections.
12.5 event of clinical interest
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 - 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 titer and endoscopy. However the AE should be reported regardless of etiology.
12.5 event of clinical interest
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 >1 week, and for diarrhea with blood and/or mucus, o Consider GI consultation and endoscopy to confirm or rule out colitis o Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent)
- When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.  
Page 84 of 102  
- 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 persist for greater than 3 days):
- 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 1 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 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.  
Grade 4 events:
- Report as ECI - Permanently discontinue pembrolizumab. - Manage as per Grade 3.
12.5 event of clinical interest
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 Sponsor within 24 hours of the event:
- Adrenal insufficiency - Hyperthyroidism - Hypophysitis - Hypopituitarism - 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.
12.5 event of clinical interest
hypophysitis or other symptomatic endocrinopathy

Grade 2 events:
- Report as ECI if appropriate - Hold pembrolizumab - 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 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 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.  
- Consultation with an endocrinologist may be considered.  
Grade 3 events:
- Report as ECI - Hold pembrolizumab. - Endocrine consultation is recommended. - 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.  
- Hypophysitis with clinically significant adrenal insufficiency and hypotension, dehydration, and electrolyte abnormalities (such as hyponatremia and hyperkalemia) constitutes adrenal crisis.  
- Hospitalization and endocrine consultation should be considered.  
Grade 4 events:
- Report as ECI - Discontinue pembrolizumab. - Manage as per Grade 3
12.5 event of clinical interest
hyperthyroidism and hypothyroidism

Page 86 of 102  
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 events (and Grade 3-4 hypothyroidism):
- Report as ECI if appropriate (see Table 1) - Monitor thyroid function or other hormonal level tests and serum chemistries more frequently until 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 indicated per standard of care.  
- Consultation with an endocrinologist may be considered.  
Grade 3 hyperthyroidism events:
- Report as ECI - 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 events:
- Report as ECI
- Discontinue pembrolizumab - Manage as per Grade 3
12.5 event of clinical interest
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:
- Autoimmune hemolytic anemia - Aplastic anemia - Disseminated Intravascular Coagulation (DIC) - Haemolytic Uraemic Syndrome (HUS) - 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 diagnostic 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 etiology.
12.5 event of clinical interest
course of action

Grade 2 events:
- Report as ECI - Hold pembrolizumab - 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.
12.5 event of clinical interest
grade 3 events

- 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:
- Report as ECI - Hematology consultation Page 88 of 102  
- 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
12.5 event of clinical interest
3. 5 he p atic

T he f oll o wi n g A E ter ms, if c o nsi dere d ≥ Gra de 2 or greater ( or a n y gra de wit h d ose m o dificati o n or use of s yste mic ster oi ds t o treat t he A E), are c o nsi dere d E CIs a n d s h o ul d be re p orte d t o t he S p o ns or wit hi n 2 4 h o urs of t he e ve nt:  
- A ut oi m m u ne he patitis  
- He patitis  
- Tra nsa mi nase ele vati o ns All atte m pts s h o ul d be ma de t o r ule o ut ot her ca uses s uc h as metastati c disease, i nfecti o n or ot her he patic diseases. H o we ver t he A E s h o ul d be re p orte d re gar dless of eti ol o g y.  
Dr u g I n d uce d Li ver I nj ur y
12.5 event of clinical interest
( di li)

```
I n a d diti o n, t he e ve nt m ust be re p orte d as a Dr u g I n d uce d Li ver I nj ur y ( DI LI) E CI, if t he patie nt

meets t he la b orat or y criteria f or p ote ntial DI LI defi ne d as:

A n ele vate d ala ni ne tra nsa mi nase ( A L T) or as partate tra nsa mi nase ( A S T) la b val ue t hat is

greater t ha n or e q ual t o t hree ti mes ( 3 X) t he u p per li mit of n or mal ( U L N) a n d

A n ele vate d t otal bilir u bi n la b val ue t hat is greater t ha n or e q ual t o t w o ti mes ( 2 X) U L N a n d

At t he sa me ti me, a n al kali ne p h os p hatase ( A L P) la b val ue t hat is less t ha n 2 X U L N,

As a res ult of wit hi n- pr ot oc ol-s pecific testi n g or u nsc he d ule d testi n g.


```  
N ote t hat a n y he patic i m m u ne E CI meeti n g DI LI criteria s h o ul d o nl y be re p orte d o nce as a DI LI  
e ve nt.
12.5 event of clinical interest
c o urse of acti

```
Gra de 2 e ve nts:

- Re p ort as E CI

- H ol d pe m br oliz u ma b w he n A S T or A L T > 3. 0 t o 5. 0 ti mes U L N a n d/ or t otal bilir u bi n > 1. 5 t o 3. 0

ti mes

U L N.

- M o nit or li ver f u ncti o n tests m ore fre q ue ntl y u ntil ret ur ne d t o baseli ne val ues (c o nsi der wee kl y).

o Treat wit h 0. 5- 1 m g/ k g/ da y met h yl pre d nis ol o ne or oral e q ui vale nt a n d w he n L F T

ret ur ns t o gra de 1 or baseli ne, ta per ster oi ds o ver at least 1 m o nt h, c o nsi der pr o p h ylactic

a nti bi otics f or o p p ort u nistic i nfecti o ns, a n d res u me pe m br oliz u ma b per pr ot oc ol

- Per ma ne ntl y disc o nti n ue f or i na bilit y t o re d uce c ortic oster oi d d ose t o 1 0 m g or less of

pre d nis o ne or e q ui vale nt per da y wit hi n 1 2 wee ks.

- Per ma ne ntl y disc o nti n ue pe m br oliz u ma b f or patie nts wit h li ver metastasis w h o be gi n treat me nt

wit h Gra de 2 ele v ati o n of A S T or A L T, a n d A S T or A L T i ncreases ≥ 5 0 % relati ve t o baseli ne

a n d lasts ≥ 1 wee k.

```  
Pil ot: I ntr alesi o n al I njecti o n Pe m br oliz u m a b Pa ge 9 0 of 1 0 2 Grade 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
- Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours. When symptoms improve to 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.  
- Several courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  
- Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.
12.5 event of clinical interest
grade 4 events

- Report as ECI - Permanently discontinue pembrolizumab - Manage patient as per Grade 3 above
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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:
- Autoimmune neuropathy
- Demyelinating polyneuropathy
- Guillain-Barre syndrome - Myasthenic syndrome 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.
12.5 event of clinical interest
course of action

Grade 2 events:
- Report as ECI - Moderate (Grade 2) - consider withholding pembrolizumab. - Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate Page 91 of 102  
- 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.
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grade 3 and 4 events

- Report as ECI - Discontinue pembrolizumab - Obtain neurology consultation. Consider biopsy for confirmation of diagnosis - 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.
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3.7 ocular

The following AE terms, if considered Grade ≥2 or requiring dose modification or use of systemic steroids to treat the AE, is considered an ECI and should be reported to the Sponsor within 24 hours of the event:
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- 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.
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course of action

Grade 2 events:
- Evaluation by an ophthalmologist is strongly recommended. - Treat with topical steroids such as 1% prednisolone acetate suspension and iridocyclitics. - Discontinue pembrolizumab as per protocol if symptoms persist despite treatment with topical immunosuppressive therapy.
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grade 3 events

- Evaluation by an ophthalmologist is strongly recommended - Hold pembrolizumab and consider permanent discontinuation as per specific protocol guidance. - Treat with systemic corticosteroids such as prednisone at a dose of 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.  
- 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:
- Evaluation by an ophthalmologist is strongly recommended - Permanently discontinue pembrolizumab. - Treat with corticosteroids as per Grade 3 above
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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 - Nephritis autoimmune - Renal failure - Renal 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.
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course of action

Grade 2 events:
- Hold pembrolizumab - 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 - 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.
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.
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3.9 skin other skin ecis

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:
- Pruritus - Rash - Rash generalized - Rash 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 o rash that causes significant discomfort not relieved by topical medication or temporary cessation of study drug.  
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 - Erythema multiforme - Steven's Johnson syndrome - Toxic epidermal necrolysis Please note, the AE should be reported regardless of etiology. Grade 2 events:
- 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-pruritics (e.g., diphenhydramine HCl or hydroxyzine HCl).  
- Treatment with oral steroids is at physician's discretion for Grade 2 events.  
Grade 3 events:
- Hold pembrolizumab. - Consider Dermatology Consultation and biopsy for confirmation of diagnosis.  
Page 95 of 102  
- 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.
12.5 event of clinical interest
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:
o the head (to assess mucosal or eye involvement), o the trunk and extremities, and 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.  
- 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.
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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., drug 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.  
Page 96 of 102
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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 serum chemistry panel, including LFTs).
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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.
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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 - Pericarditis - 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.
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course of action

Grade 2 events or Grade 1 events that do not improve with symptomatic treatment:
- Withhold pembrolizumab. - Systemic corticosteroids may be indicated. - Consider biopsy for confirmation of diagnosis.  
Page 97 of 102  
- If pembrolizumab held and corticosteroid required, manage as per grade 3 below.  
Grade 3 events:
- 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:
- Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day.  
- Discontinue pembrolizumab
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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 - Serum sickness - Infusion reactions - Infusion-like reactions Please note, the AE should be reported regardless of etiology.
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course of action

Refer to infusion reaction table in the protocol and below.  
| Infusion Reactions                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                      |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| NCI CTCAE Grade                                                                                                                                                                                                                                                                                                                                                          | Treatment                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Premedication at subsequent  dosing                                                                                                                                                                                                  |
| Grade 1 Mild reaction;                                                                                                                                                                                                                                                                                                                                                   | infusion                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                      |
| interruption not indicated; intervention not indicated                                                                                                                                                                                                                                                                                                                   | Increase monitoring of vital signs as medically indicated until the subject is  deemed medically stable in the opinion of the investigator.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | None                                                                                                                                                                                                                                 |
| Grade 2 Requires infusion interruption  but responds promptly to  symptomatic treatment (e.g.,  antihistamines, NSAIDS,  narcotics, IV fluids);  prophylactic medications  indicated for < =24 hrs                                                                                                                                                                       | Stop Infusion. Additional appropriate medical therapy  may include but is not limited to: IV fluids Antihistamines NSAIDS  Acetaminophen  Narcotics Increase monitoring of vital signs as  medically indicated until the subject is deemed medically stable in the opinion of the investigator. If symptoms resolve within one hour of  stopping drug infusion, the infusion may be restarted at 50% of the original infusion  rate (e.g. from 100 mL/hr to 50 mL/hr). Otherwise dosing will be held until  symptoms resolve and the subject should be premedicated for the next scheduled  dose. Subjects who develop Grade 2 toxicity  despite adequate premedication should  be permanently discontinued from  further trial treatment administration. | Subject may be premedicated 1.5h (± 30 minutes) prior to  infusion of pembrolizumab  with: Diphenhydramine 50 mg p.o.  (or equivalent dose of  antihistamine). Acetaminophen 500-1000 mg  p.o. (or equivalent dose of  antipyretic). |
| Grades 3 or 4 Grade 3: Prolonged (i.e., not rapidly  responsive to symptomatic medication and/or brief interruption of infusion);  recurrence of symptoms  following initial improvement;  hospitalization indicated for  other clinical sequelae (e.g.,  renal impairment, pulmonary  infiltrates) Grade 4: Life-threatening; pressor or  ventilatory support indicated | Stop Infusion. Additional appropriate medical therapy  may include but is not limited to: IV fluids Antihistamines NSAIDS  Acetaminophen  Narcotics  Oxygen Pressors  Corticosteroids  Epinephrine                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | No subsequent dosing                                                                                                                                                                                                                 |
| Increase monitoring of vital signs as  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  administration.                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                      |
| Pilot: Intralesional Injection Pembrolizumab                                                                                                                                                                                                                                                                                                                             | Page 100 of 102                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                      |  
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://ctep.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.