Phase II Single Arm Study of Gemcitabine and Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Prior to Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer
Phase: PHASE2
Conditions: Bladder Cancer
Sponsor: UNC Lineberger Comprehensive Cancer Center

LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC 1520: Phase II Single Arm Study of Gemcitabine and Cisplatin plus 
Pembrolizumab as Neoadjuvant Therapy Prior to Radical Cystectomy in Patients 
with Muscle-Invasive Bladder Cancer 
 
Principal Investigator  
Matthew I. Milowsky, MD  
170 Manning Drive,  
Campus Box 7305 
Chapel Hill, NC 27599  
919-843-7942 (phone); 919-966-6735 (fax) 
matt_milowsky@med.unc.edu  
 
Co-Principal Investigator  
Tracy L. Rose, MD MPH  
919-962-8561 (phone); 919-966-6735 (fax) 
tracy_rose@med.unc.edu  
 
 
Biostatistician  
Allison Deal, MS 
Lineberger Comprehensive Cancer Center 
University of North Carolina at Chapel Hill 
Chapel Hill, NC 27599-7295  
Email: allison_deal@med.unc.edu 
 
Clinical Protocol Office: Lineberger Comprehensive Cancer Center 
The University of North Carolina at Chapel Hill 
450 West Drive, 3rd Floor, CB# 7295; Chapel Hill, NC 27599-7295 
 
UNC Multicenter Project Manager: 
Phone: 919-966-7359 
Fax: 919-966-4300 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
Funding Source: Merck, Inc.  
Merck Reference # IND 122,753  
 
Version:  September 25, 2018 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
PROTOCOL AMENDMENT #11 
 
AMENDMENT INCORPORATES:  
[X] Editorial, administrative changes 
[    ] Scientific changes (IRB approval) 
[__] Therapy changes (IRB approval) 
[__] Eligibility changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
 
• Minor editorial and formatting changes were made.  
• T3 analysis was clarified to state “total or free T3” throughout the protocol.  
• Dose modification for kidney dysfunction has been updated to state that both 
gemcitabine and cisplatin administration can proceed if creatinine clearance 
improves to ≥ 50ml/min within 1 week of scheduled day 1. 
• The guidance for dose modifications for grade 3 and above, non-hematological 
toxicities was updated to note that treatment can also be resumed at the same dose 
level under the discretion of the treating physician.  
• The number of ACD tubes have been updated to seven from three. 
• Pembrolizumab language was updated per the new IB version 16.   
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED September 25, 2018 INCORPORATES THE ABOVE 
REVISIONS 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
PROTOCOL AMENDMENT #10 
 
AMENDMENT INCORPORATES:  
[X] Editorial, administrative changes 
[X] Scientific changes (IRB approval) 
[__] Therapy changes (IRB approval) 
[__] Eligibility changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
The LCCC1520 protocol is updated to clarify that sequential boundaries to suspend the 
trial will be used for subjects enrolled after the approval of Amendment 9. The protocol 
was updated in Amendments #8 and #9 to address a higher number than expected grade 
3-4 acute kidney injury and myelosuppression adverse events. In these amendments, the 
lead-in dose of pembrolizumab was removed, administration of cisplatin was changed to 
split dosing rather than administration of one dose, a safety lab draw on cycle 1 day 15 
was added and clarification in reference to day 8 dose modifications was made. These 
changes alter the risk profile of the study and thus the sequential boundaries for 
suspending the trial have been updated to be dependent on the enactment of these 2 
amendments.  
Additionally, the protocol was amended include updated language from Merck and 
incorporate minor editorial changes to maintain consistency throughout the protocol. 
 
Editorial, administrative changes 
• Section 4.2: added clarification of the dosing order to state that on Day 1 
of each cycle pembrolizumab will be administered first, followed by 
gemcitabine and cisplatin. Each site must follow their institutional 
guidelines for administration of each drug and hydration. 
• Section 4.4.3: updated to include correction that subjects should be placed 
back on study therapy within 2 weeks of the scheduled interruption, to 
maintain consistency throughout the protocol.  
• Section 5.1: updated to include detailed pharmacy instructions on 
pembrolizumab. 
• Section 7.2: updated to add a requirement that any grade 4 or 5 adverse 
events must be reported to the UNC Multicenter Project 
Manager immediately as they occur. 
Scientific changes 
• Section 4.4.3: updated Dose Modifications for Pembrolizumab for Events 
other than Infusion Reactions to reflect changes in the current 
Investigator’s Brochure. 
• Section 1.4.1: updated pembrolizumab clinical safety information to 
reflect changes in the current Investigator’s Brochure. 

LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
• Section 8.3: updated to include the statement that sequential boundaries 
will be used to suspend the trial if unacceptable toxicity is seen in subjects 
enrolled after the approval of Amendment 9 of this protocol. 
• Several portions of the protocol were updated to reflect that Merck no 
longer considers immune related adverse events, other than transaminitis, 
and pregnancy to be events of clinical interest.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED June 12, 2018 INCORPORATES THE ABOVE 
REVISIONS 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
PROTOCOL AMENDMENT #9 
 
AMENDMENT INCORPORATES:  
[_x_] Editorial, administrative changes 
[__] Scientific changes (IRB approval) 
[_x_] Therapy changes (IRB approval) 
[__] Eligibility changes (IRB approval) 
[_x_] Other 
 
AMENDMENT RATIONALE AND SUMMARY: 
The LCCC1520 protocol is updated to add a safety lab draw on cycle 1 day 15 and to 
clarify exact protocol instructions for calculation of GFR, day 8 dose modifications, and 
timing of study imaging requirements if patients come off treatment early. 
This amendment clarifies regulatory requirements pertaining to data management and 
monitoring, and FDA expedited reporting requirements per recent guidelines and 
policies.  
The protocol is also updated in section 9.5.2 in accordance with Lineberger 
Comprehensive Cancer Center’s policy on single subject exceptions to indicate that 
eligibility single subject exceptions are not permitted for this study and other types of 
single subject exceptions require proper regulatory review.  
 
• Clarifications were made throughout the protocol that all use of a time 
“window” means +/- the duration of said time window. 
• Section 3.1.10: The full CKD Epi equation was added to clarify use of 
non-BSA-adjusted equation.  
• Section 4.2: Table changed to include that the duration of gemcitabine and 
cisplatin may be altered per institutional protocol.  
• Section 4.4.1: Day 8 dose modifications were made adjusted to hold day 8 
treatment for ANC <1000 (instead of 500) and platelets <75,000 (instead 
of 50,000) in order to decrease risk of severe neutropenia and febrile 
neutropenia. 
• Section 4.4.2: Clarifications were made in multiple places to the dose 
modification table, particularly to include wording in multiple places that 
day 8 dosing should not be made up if held. 
• Section 4.9:  Details study withdrawal procedures and proper 
documentation were revised. 
• Section 5.1.6: Updated to describe additional adverse events like Stevens-
Johnson Syndrome, toxic epidermal necrolysis, myocarditis, sarcoidosis, 
and encephalitis reported by Merck associated to pembrolizumab.  
• Section 6.1: The time and events table was updated to add Cycle 1 Day 15 
lab draw with a +/- 1 day window as an additional safety lab for 
monitoring subjects and added windows to the long-term follow-up plan.  
Also the time and events table now notes that the imaging scans for pre-
surgery should be 30 days with a +/- 14 day window after last dose of 

LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
pembrolizumab and not required to be repeated if come off treatment early 
and have had scans within 30 days.  
• Clarified need to use CKD Epi throughout study in Section 6.3.1 and 
Section 6.3.2. 
• Section 6.3.3: Added to describe the labs done on Day 15 of Cycle 1. 
• Section 7.3.3 Updated IRB submission language to be consistent with the 
UNC IRB’s standard operating procedures. Revised to remove language 
that states that UNC will submit an aggregate list of SAEs.  
• Section 7.3.4: Updated to describe the FDA expedited reporting 
requirements.  
• Section 9.2: Included financial disclosures as required documentation 
before site initiation.  
• Section 9.4: Amended to detail data monitoring and management of the 
study.  
• Section 9.5.2: Altered to summarize that the eligibility single subject 
exceptions are not permitted in this clinical trial.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED January 18, 2018 INCORPORATES THE ABOVE 
REVISIONS 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT #8 
 
AMENDMENT INCORPORATES:  
_X__Editorial, administrative changes 
___ Scientific changes (IRB approval) 
_X_ Therapy changes (IRB approval) 
___ Eligibility changes (IRB approval) 
 __ Other 
 
AMENDMENT RATIONALE AND SUMMARY: 
The LCCC1520 protocol is updated to remove the lead-in dose of pembrolizumab and to 
administer the cisplatin in a split dose rather than one dose. These changes were made to 
address a higher number than expected of grade 3-4 acute kidney injury and 
myelosuppression adverse events which were noted in the first cohort of enrolled 
patients. 
 
• Section 1.0 Background and rationale: updated to include new information related 
to the rationale for the study as it has changed. 
• Section 2.1 The primary and secondary objectives has changed with the 
elimination of reference to the lead in dose of pembrolizumab 
• Eligibility Criteria: Item 3.1.15 has been changed to add whole blood collection 
on cycle 2, day 1 
• Section 4.1 The schema was updated to reflect the deletion of the pembrolizumab 
lead-in dose and split dose cisplatin.  
• Section 4.2 This section was updated with the new treatment plan. 
• Section 6.3 the description of the lead-in dose related procedures was removed. 
• Section 6.7.2 the 3 ACD tubes will now be collected pre-study, at Cycle 2 day 1, 
and at the time of cystectomy. 
 
 
 
 
 
 
THE ATTACHED VERSION DATED May 9, 2017 INCORPORATES THE ABOVE 
REVISIONS 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT #7 
 
AMENDMENT INCORPORATES:  
_X__Editorial, administrative changes 
_X_ Scientific changes (IRB approval) 
__ Therapy changes (IRB approval) 
__ Eligibility changes (IRB approval) 
 __ Other 
 
AMENDMENT RATIONALE AND SUMMARY: 
The LCCC1520 protocol is updated to include the latest safety language required for 
Pembrolizumab IIT Study Protocols and includes revisions to management guidelines for 
infusion reactions (Section 4.2.3) dose modification requirements for adverse events 
(Section 4.4.3 and 4.4.4), changes in procedures required for reporting events of clinical 
interests and revisions (Sections 7.1.3, 7.3.2 and 7.3.3) to eligibility criteria (3.1.11 and 
3.1.12). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED DECEMBER 7, 2016 INCORPORATES THE ABOVE 
REVISIONS 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT #6 
 
AMENDMENT INCORPORATES:  
___Editorial, administrative changes 
__ Scientific changes (IRB approval) 
_X Therapy changes (IRB approval) 
__ Eligibility changes (IRB approval) 
 __ Other 
 
AMENDMENT RATIONALE AND SUMMARY: 
4.4 Toxicities and Dosing Delays/Dose Modifications: Text was added to this section to 
note that once an individual is put on a split dose of cisplatin, they will remain on a split-
dose. 
 
4.4.2 Dose Modifications for GC for Non-Hematologic Toxicity: Text was added to 
the table to note that once an individual is put on a split-dose of cisplatin, they will 
remain on a split-dose for all subsequent cycles. 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED September 13, 2016 INCORPORATES THE ABOVE 
REVISIONS 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
PROTOCOL AMENDMENT #5 
 
AMENDMENT INCORPORATES:  
X Editorial, administrative changes 
__ Scientific changes (IRB approval) 
__ Therapy changes (IRB approval) 
 X Eligibility changes (IRB approval) 
 X Other 
 
AMENDMENT RATIONALE AND SUMMARY: 
3.1.10 Inclusion Criteria: in the table of laboratory values, renal function should be measured 
either by serum creatinine or by estimated GFR per CKD-EPI equation 
 
3.2.9 Exclusion Criteria: the exclusion criterion regarding pneumonitis was changed to include a 
history of (non-infectious) pneumonitis. 
4.2 Language was added noting that the Day 8 visit has a window of 1 day, as opposed to 
the other visits that have a 3 day window. 
4.2.2 “PO” was added as an alternative to IV dexamethasone treatment. 
6.1 Time and Events Table: “x”s were removed from the “tumor samples” item that were 
inadvertently placed in the table. 
10.0 References: A new reference was added regarding the CKD-EPI equation 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED July 7, 2016 INCORPORATES THE ABOVE 
REVISIONS 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
PROTOCOL AMENDMENT #4 
 
AMENDMENT INCORPORATES:  
X Editorial, administrative changes 
__ Scientific changes (IRB approval) 
__ Therapy changes (IRB approval) 
__ Eligibility changes (IRB approval) 
 X Other 
 
AMENDMENT RATIONALE AND SUMMARY: 
3.1.9 Inclusion Criteria: The wording was changed to state that patients “must agree to 
submission” of tumor tissue rather than stating that the patient must have sufficient tumor 
tissue. 
4.1 Schema: The schema has been updated to reflect that patients must agree to 
submission of tissue for correlative studies, but adequate tissue is not required to enroll. 
6.1 Time and Events Table: “cystectomy” was added as one of the study-related events 
6.1 Time and events Table: the 10-day period for laboratory assessments was amendment 
to include “and other assessments”. 
6.1 Time and Events Table: superscript “2” was added to the pembrolizumab lead-in visit 
to give a 3 day window to that visit. 
7.3 and throughout the protocol: Language related to a separate guidance document for 
Events of Clinical Interest was removed since the Guidance Document is no longer being 
updated by Merck. 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED May 25, 2016 INCORPORATES THE ABOVE 
REVISIONS 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
PROTOCOL AMENDMENT #3 
 
AMENDMENT INCORPORATES:  
X Editorial, administrative changes 
__ Scientific changes (IRB approval) 
__ Therapy changes (IRB approval) 
__ Eligibility changes (IRB approval) 
 X Other 
 
AMENDMENT RATIONALE AND SUMMARY: 
 
Changes in this amendment were largely clarifying ones. Specific changes are: 
3.1.13 A description of adequate contraception was added. 
Schema: the schema was updated with the removal of “green top” for what ACD tubes 
would be used. This change was also made throughout the protocol. 
4.3 The timing of the cystectomy was changed from within 70 days to within 4-8 weeks 
if possible. This was also changed in other relevant parts of the protocol. 
4.4 Information on treatment in the circumstance of dose delay was clarified. 
6.2 Pre-study laboratory assessments were updated to match the Time and Events Table. 
6.4 Laboratory assessments for the pre-surgical visit were updated to match the Time and 
Events Table. 
11.2 The PRO-CTCAE Questionnaire was added to the protocol. 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED March 29, 2016 INCORPORATES THE ABOVE 
REVISIONS 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT #2 
 
AMENDMENT INCORPORATES:  
X Editorial, administrative changes 
__ Scientific changes (IRB approval) 
__ Therapy changes (IRB approval) 
__ Eligibility changes (IRB approval) 
_X Other 
 
AMENDMENT RATIONALE AND SUMMARY: 
Section 1.8: Language was added to explain the biospecimen handling procedures and the 
storage process, including storage for unspecified future research. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED February 9, 2016 INCORPORATES THE ABOVE 
REVISIONS 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT #1 
 
AMENDMENT INCORPORATES:  
X Editorial, administrative changes 
X Scientific changes (IRB approval) 
X  Therapy changes (IRB approval) 
X  Eligibility changes (IRB approval) 
__Other 
 
AMENDMENT RATIONALE AND SUMMARY: 
1.4.1 Updated clinical information was added to the section on “Pembrolizumab 
Clinical Safety”. 
1.5 
Pembrolizumab will be administered as a single dose alone at the start of the 
study 
1.6 
The use of the PRO-CTCAE and PROMIS was added. 
1.7.2  The Claudin-low molecular subtype has been added to the planned biomarker 
studies. 
2.2.4 A new secondary objective has been added that the study will estimate the 
proportion of patients who are alive at 3 years 
3.1.9  The inclusion criterion regarding archived tissue was expanded and clarified. 
3.2.15 An exclusion criterion was added that prohibits prior radiation therapy to the 
bladder for the purpose of treating urothelial carcinoma 
4.1 and 4.2 The dosing of the monotherapy with pembrolizumab was clarified 
5.1.6 Details from study results of other disease groups were added for the immune 
related adverse events. 
5.1.8 Information on the use of contraception was added. 
5.1.9 Information on fetal toxicity was added 
5.1.11 toxicity related to presence in breast milk was added. 
9.3 
Affiliate site registration procedures were corrected. 
 
 
THE ATTACHED VERSION DATED January 20, 2016 INCORPORATES THE ABOVE 
REVISIONS 
 
  
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LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC1520 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
Version: September 25, 2018 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
LCCC  1520:  Phase II Single Arm Study of Gemcitabine and Cisplatin plus 
Pembrolizumab as Neoadjuvant Therapy Prior to Radical Cystectomy in Patients with 
Muscle-Invasive Bladder Cancer 
 
 
Principal Investigator 
Matthew I. Milowsky, MD  
170 Manning Drive, 3rd Floor Physician’s Office Building  
Campus Box 7305 
Chapel Hill, NC 27599  
919-843-7942  (Phone) 
919-966-6735  (Fax) 
matt_milowsky@med.unc.edu  
 
 
 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal regulations 
and ICH guidelines. 
 
Principal Investigator (PI) Name: Matthew Milowsky, MD 
 
PI Signature: ___________________ 
 
Date: ____________________ 
 
Version date: September 25, 2018 
 
Version: Amendment 11 
 
 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
i 
TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE .................................................................4 
1.1 
Study Synopsis .....................................................................................................4 
1.2 
Bladder Cancer and Chemotherapy .....................................................................4 
1.3 
The PD-L1/PD-1 Pathway in Cancer ...................................................................7 
1.4 
Pembrolizumab ....................................................................................................8 
1.5 
Rationale for Inclusion of Pembrolizumab as NAC for MIBC .........................11 
1.6 
Inclusion of Patient-Reported Outcomes version of the Common Terminology 
Criteria for Adverse Events (PRO-CTCAE) ..................................................................12 
1.7 
Correlative Studies .............................................................................................12 
2.0 
STUDY OBJECTIVES ........................................................................................14 
2.1 
Primary Objective ..............................................................................................14 
2.2 
Secondary Objectives .........................................................................................14 
2.3 
Exploratory Objectives ......................................................................................15 
2.4 
Endpoints ...........................................................................................................15 
3.0 
PATIENT ELIGIBILITY ...................................................................................16 
3.1 
Inclusion Criteria ...............................................................................................16 
3.2 
Exclusion Criteria ..............................................................................................18 
4.0 
TREATMENT PLAN ..........................................................................................20 
4.1 
Schema ...............................................................................................................20 
4.2 
Treatment Dosage and Administration ..............................................................21 
4.3 
Timing of Cystectomy after Chemotherapy ......................................................23 
4.4 
Toxicities and Dosing Delays/Dose Modifications ...........................................24 
4.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ......................33 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
ii 
4.6 
Duration of Therapy ...........................................................................................35 
4.7 
Duration of Follow Up .......................................................................................35 
4.8 
Removal of Patients from Protocol Therapy .....................................................36 
4.9 
Study Withdrawal ..............................................................................................36 
4.10 
Clinical Criteria for Early Trial Termination .....................................................36 
5.0 
DRUG INFORMATION .....................................................................................38 
5.1 
Pembrolizumab ..................................................................................................38 
5.2 
Gemcitabine Hydrochloride ...............................................................................47 
5.3 
Cisplatin (CDDP) ...............................................................................................49 
6.0 
EVALUATIONS AND ASSESSMENTS ...........................................................52 
6.1 
Time and Events Table ......................................................................................52 
6.2 
Pre-Study Assessments ......................................................................................57 
6.3 
On-Study Treatment Assessments .....................................................................57 
6.4 
Pre-Surgical Visit (post-pembrolizumab) ..........................................................58 
6.5 
Cystectomy ........................................................................................................59 
6.6 
Long Term Follow-Up Assessments .................................................................60 
6.7 
Correlative Studies Procedures ..........................................................................60 
6.8 
Assessment of Safety .........................................................................................62 
6.9 
Assessment of Efficacy ......................................................................................62 
7.0 
ADVERSE EVENTS ...........................................................................................64 
7.1 
Definitions..........................................................................................................64 
7.2 
Documentation of non-serious AEs or SARs ....................................................66 
7.3 
SAEs or Serious SARs and Events of Clinical Interest .....................................66 
7.4 
Data and Safety Monitoring Plan .......................................................................72 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
iii 
8.0 
STATISTICAL CONSIDERATIONS ...............................................................73 
8.1 
Study Design/Study Endpoints ..........................................................................73 
8.2 
Sample Size and Accrual ...................................................................................73 
8.3 
Continuous Monitoring for Toxicity ..................................................................73 
8.4 
Data Analysis Plans ...........................................................................................74 
9.0 
STUDY MANAGEMENT ...................................................................................75 
9.1 
Institutional Review Board (IRB) Approval and Consent .................................75 
9.2 
Required Documentation ...................................................................................75 
9.3 
Registration Procedures .....................................................................................75 
9.4 
Data Management and Monitoring/Auditing .....................................................76 
9.5 
Adherence to the Protocol ..................................................................................76 
9.6 
Amendments to the Protocol ..............................................................................78 
9.7 
Record Retention ...............................................................................................79 
9.8 
Compliance with Trial Registration and Results Posting Requirements ...........79 
9.9 
Obligations of Investigators ...............................................................................79 
10.0 
REFERENCES .....................................................................................................81 
11.0 
APPENDICES ......................................................................................................85 
11.1 
Appendix A:  ECOG Performance Status ..........................................................85 
11.2 
Appendix B: Patient-Reported Symptom Assessment ......................................86 
11.3 
Appendix C: The CKD-EPI Creatinine Equation ..............................................91 
 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
4 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
This multicenter single-arm phase II trial will evaluate the humanized monoclonal 
antibody targeted against cell surface receptor programmed cell death-1 (PD-1), 
pembrolizumab in combination with gemcitabine and cisplatin in patients with 
muscle-invasive bladder cancer (MIBC) as neoadjuvant therapy prior to radical 
cystectomy. The study will enroll 39 patients, using a Simon’s two-stage design, 
with a primary endpoint of pathological downstaging to <pT2. Secondary 
objectives include toxicity assessment, rate of complete pathologic response 
(pT0), event free survival (EFS), and overall survival (OS).  
 
Exploratory objectives include an evaluation of the predictive capacity of PD-L 
(ligand) 1 expression, immune gene signatures, and RNA subtypes of bladder 
cancer for pathological downstaging, and a characterization of the change in 
phenotype in tumor-infiltrating lymphocytes (TILs) before and after neoadjuvant 
therapy. We hypothesize that neoadjuvant treatment with pembrolizumab in 
combination with gemcitabine and cisplatin in MIBC will result in an 
improvement in the rate of pathological downstaging to <pT2 compared to 
historical controls. We hypothesize that each of the following (a) tumors of the 
basal and claudin-low subtypes, (b) increased PD-L1 mRNA expression, (c) 
effector immune infiltrate, (d) clonality in TILs and (e) decreased regulatory cell 
populations will be associated with a higher rate of pathological downstaging.   
1.2 
Bladder Cancer and Chemotherapy 
Bladder cancer is the 6th most common cancer in the United States, with an 
estimated 74,690 new cases and 15,580 deaths for 2014.[1] Although most cases 
are non-invasive at initial diagnosis, nearly 25% of these cases will progress to 
MIBC. Further, 20-30% of patients have MIBC at the time of diagnosis.[2] Current 
guidelines for MIBC recommend neoadjuvant cisplatin-based chemotherapy 
followed by cystectomy based on randomized clinical trials and meta-analyses.[3-5] 
Despite this aggressive management, more than 50% of patients develop 
recurrent/metastatic disease within two years and ultimately die of complications 
related to bladder cancer.[6] The development of more effective treatment for 
MIBC is clearly warranted. 
1.2.1 Neoadjuvant Chemotherapy as Standard of Care in MIBC 
The mainstay of neoadjuvant chemotherapy (NAC) in MIBC has been cytotoxic 
cisplatin-based combination chemotherapy. The MVAC regimen (methotrexate, 
vinblastine, doxorubicin, and cisplatin) was introduced in the 1980’s and was 
found to have more activity than single drug regimens for advanced bladder 
cancer.[7, 8] A randomized clinical trial later demonstrated an improvement in rate 
of pT0 and an improvement in OS after MVAC plus cystectomy compared to 
cystectomy alone (OS 77 vs 46 months, respectively, p=0.06) in patients with 

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MIBC.[3] Another randomized trial showed similar results with neoadjuvant CMV 
(cisplatin, methotrexate, vinblastine) plus cystectomy conferring a 5.5% 
improvement in OS at 3 years compared to cystectomy alone (p=0.075).[4] A 
meta-analysis published in 2005 demonstrated a significant survival benefit of 5% 
at 5 years with platinum-based combination NAC compared to cystectomy alone 
and NAC was thus adopted as standard of care.[5] 
 
MVAC has been associated with substantial toxicity, most notably hematologic 
and gastrointestinal complications.[3] The combination of gemcitabine and 
cisplatin (GC) was compared with MVAC in a phase III randomized trial of 
subjects with metastatic urothelial carcinoma of the bladder. GC was found to 
have similar efficacy to MVAC (OS 14 vs 15.2 months, respectively, p=0.66) but 
with substantially less toxicity (febrile neutropenia 1% in GC group and 12% in 
MVAC group).[9] This study used a 28-day cycle of GC with cisplatin dosed on 
day 1 and gemcitabine dosed on days 1, 8, and 15, but subsequent studies have 
shown preserved efficacy and improved tolerability with a 21-day cycle with 
gemcitabine dosed on days 1 and 8 only.[10, 11] In addition, several studies have 
evaluated split-dose cisplatin (where cisplatin is dosed on days 1 and 8) of a 21-
day cycle and found response rates similar to conventional dosing.[12, 13] 
 
GC has also been used in the neoadjuvant setting. Memorial Sloan-Kettering 
Cancer Center has reported their experience of treating 42 patients with 
neoadjuvant GC demonstrating similar rates of pathological downstaging 
compared to historical controls (<pT2 rates of 36% in GC patients and 35% in 
MVAC patients).[14] In addition, rates of pT0 were also similar (26% in GC 
patients and 28% of MVAC patients). Given the improved tolerability and similar 
efficacy compared with MVAC, GC has become the most widely used 
neoadjuvant chemotherapy regimen for MIBC. 
1.2.2 The Neoadjuvant Paradigm for Drug Development: An Ideal Model 
in Bladder Cancer 
MIBC has been promoted as a model for drug development given the ease of pre- 
and post-treatment tissue collection without the need for research-directed 
biopsies.[15] Similar to the neoadjuvant trials in breast cancer, pT0 at the time of 
cystectomy in patients with MIBC treated with neoadjuvant cisplatin-based 
chemotherapy is associated with improved outcomes and predicts OS.[3, 16] A 
separate analysis has confirmed the prognostic significance of both pT0 and <pT2 
at the time of cystectomy.[17] Assessment of pathological downstaging and 
complete pathologic response allows early feedback of drug efficacy with results 
in months rather than years.  
1.2.3 Gemcitabine Cisplatin (GC) Regimen 
Gemcitabine 
Gemcitabine is a nucleoside analog of deoxycytidine that is transported into a 
cell, phosphorylated by deoxycytidine kinase to an active form, and incorporated 
into DNA causing an inhibition of replication and cell death. Gemcitabine has 

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been shown to attenuate immune tolerance achieved by many tumors by depleting 
myeloid-derived suppressor cells (MDSC) and regulatory T cells while preserving 
the number of CD4+ and CD8+ T cells in mice.[18-21] It has been suggested as 
useful in chemo-immunotherapy protocols due to its selective effects on the 
humoral immune response while not impairing antitumor cellular immunity.[2] 
The most common (≥20%) adverse reactions for gemcitabine when used as a 
single agent are nausea/vomiting, anemia, transaminitis, neutropenia, increased 
alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, 
dyspnea, and peripheral edema.   
 
Cisplatin 
Cisplatin is a bifunctional alkylating agent that inhibits DNA synthesis and is cell 
cycle nonspecific. There is some preclinical data suggesting that cisplatin can also 
induce anti-tumor immunomodulation via recruitment and upregulation of 
effector T cells and downregulation of the immunosuppressive tumor 
microenvironment.[22] 
 
Adverse effects reported in 10% or more of patients receiving cisplatin include 
peripheral neuropathy, nausea, vomiting, diarrhea, myelosuppression, liver 
enzymes elevation, nephrotoxicity (acute renal failure and chronic renal 
insufficiency), alopecia, tissue irritation, and ototoxicity. The nausea and 
vomiting associated with cisplatin are now much better tolerated due to the 
widespread availability and use of effective prophylactic anti-emetic regimens. 
 
Rationale for the GC Regimen 
As summarized in the individual drug sections, the GC regimen in combination 
with an immunotherapy agent, such as an immune checkpoint inhibitor, may 
enhance the modulatory effect of immunotherapy and assist in immune-mediated 
tumor destruction. The MVAC regimen incorporates methotrexate, which has 
known immunosuppressive effects and may theoretically deplete the effector T 
cell population causing an interference with the positive immunostimulatory 
effects of an immune checkpoint inhibitor. GC was chosen in this study due to its 
widespread use in the neoadjuvant setting, its safety profile, and potential 
synergistic effect with immunotherapy.  
 
There are several effective dosing regimens of GC chemotherapy (see section 
1.2.1). This protocol was initially implemented with cisplatin dosed as 70mg/m2 
on day 1 of a 21-day cycle. However, a higher number than expected of grade 3-4 
acute kidney injury and myelosuppression adverse events were noted in the first 
cohort of enrolled patients, and the protocol is therefore amended to dose cisplatin 
at 35mg/m2 on days 1 and 8 to minimize toxicity. In addition, the earlier cohort 
was treated with a single dose of pembrolizumab two weeks prior to concurrent 
GC and pembrolizumab treatment. This lead-in dose has also been omitted. 
 

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1.3 
The PD-L1/PD-1 Pathway in Cancer 
The PD-1 pathway is a major immune control switch which may be engaged by 
tumor cells to overcome active T-cell immune surveillance. The importance of 
intact immune surveillance in controlling outgrowth of neoplastic transformation 
has been known for decades.[23] Accumulating evidence shows a correlation 
between TILs in cancer tissue and favorable prognosis in various malignancies. 
[24-28] In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis 
and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to 
suppress immune control.  The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate 
unwanted or excessive immune responses, including autoimmune reactions.  PD-1 
(encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and 
CTLA-4 which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2).[29, 30]   
The structure of murine PD-1 has been resolved.[31] PD-1 and family members are 
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) 
domain responsible for ligand binding and a cytoplasmic tail which is responsible 
for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition 
motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which 
are involved in the CD3 T-cell signaling cascade.[29, 32-34] The mechanism by which 
PD-1 down modulates T-cell responses is similar to, but distinct from that of 
CTLA-4 as both molecules regulate an overlapping set of signaling proteins.[35, 36]   
PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, Tregs and Natural Killer cells.[37, 38]  Expression 
has also been shown during thymic development on CD4-CD8- (double negative) 
T-cells as well as subsets of macrophages and dendritic cells.[39] The ligands for 
PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various 
tumors.[35, 40-42] Both ligands are type I transmembrane receptors containing both 
IgV- and IgC-like domains in the extracellular region and contain short 
cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  
PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably 
expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments.  PD-L2 is thought to control immune T-cell 
activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-

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cell function in peripheral tissues.[35] Although healthy organs express little (if 
any) PD-L1, a variety of cancers were demonstrated to express abundant levels of 
this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in subjects with melanoma.[43] This suggests that the PD-1/PD-L1 
pathway plays a critical role in tumor immune evasion and should be considered 
as an attractive target for therapeutic intervention. 
1.3.1 Bladder Cancer and Immunotherapy 
Bladder cancer was the first malignancy with an FDA-approved immunotherapy 
when Bacillus Calmette-Guérin (BCG), a live but attenuated strain of 
mycobacterium, was approved for localized disease in 1990.  Advanced bladder 
cancer is associated with a high mutational complexity and the potential for 
foreign antigen detection by the immune system represents a unique opportunity 
for development of immunotherapeutics.[44, 45] 
1.3.2 Immune Checkpoint Inhibitors in Bladder Cancer 
Anti-PD-1 and PD-L1 agents have demonstrated exciting activity in several 
human cancers (most notably lung, renal cell, and melanoma) with an overall 
response rate of 21% in human cancers.[46, 47] Initial data from studies in the 
metastatic setting of PD-1 and PD-L1 inhibition show activity of these agents in 
bladder cancer as well. [48, 49] Recently, several immune checkpoint inhibitors 
have been approved for the treatment of metastatic urothelial cancer that has 
progressed after first-line platinum-based chemotherapy. Atezolizumab (anti-PD-
L1) was first approved in May 2016 after a large phase II trial showed an overall 
response rate (ORR) of 15%.[50] It has since been approved in the first-line 
metastatic setting for cisplatin-ineligible patients.[51] Nivolumab, durvalumab, and 
avelumab were also approved in early 2017 based on data from several phase II 
trials demonstrating ORR of 19.6%. [52, 53] 
 
Initial data from a phase Ib study of pembrolizumab in patients with metastatic 
bladder cancer showed an ORR of 24% with a median time to response of only 8 
weeks with several durable responses noted (median duration of response not yet 
reached).(NCT01848834)[49] Subsequently, the Keynote-045 trial randomized 
patients with metastatic UC that had progressed after platinum-based 
chemotherapy to pembrolizumab or investigator’s choice chemotherapy 
(paclitaxel, docetaxel, or vinflunine).[54] Treatment with pembrolizumab was 
associated with an improvement in overall survival compared with chemotherapy. 
Therefore, immune checkpoint inhibition is a new standard of care for second-line 
treatment of metastatic UC and is approved for use in the first-line setting in 
cisplatin-ineligible patients. 
1.4 
Pembrolizumab 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) 

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has recently been approved in the United Stated for the treatment of patients with 
unresectable or metastatic melanoma, non-small cell lung cancer with high PD-L1 
expression, head and neck squamous cell carcinoma, and classical Hodgkin 
lymphoma. 
 
A detailed summary of preclinical and clinical data for pembrolizumab is 
provided in the Investigator’s Brochure. Relevant clinical safety and 
pharmacokinetic data supporting this proposed study are briefly summarized in 
subsequent sections. 
 
1.4.1 Pembrolizumab Clinical Findings 
Rationale for Pembrolizumab Clinical Dose (200 mg IV Q3W):  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the 
safety and clinical activity of single agent MK-3475.  The dose escalation portion 
of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, 
administered every 2 weeks (Q2W) in subjects with advanced solid tumors.  All 
three dose levels were well tolerated and no dose-limiting toxicities were 
observed.  This first in human study of MK-3475 showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 
mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 
mg/kg Q2W, the highest dose tested in PN001, will be the dose and schedule 
utilized in Cohorts A, B, C and D of this protocol to test for initial tumor activity.  
Recent data from other clinical studies within the MK-3475 program has shown 
that a lower dose of MK-3475 and a less frequent schedule may be sufficient for 
target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow 
systemic clearance, limited volume of distribution, and a long half-life (refer to 
IB).  Pharmacodynamic data (IL-2 release assay) suggested that peripheral target 
engagement is durable (>21 days).  This early PK and pharmacodynamic data 
provides scientific rationale for testing a Q2W and Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum 
concentration time data from 476 patients. Within the resulting population PK 
model, clearance and volume parameters of MK-3475 were found to be dependent 
on body weight. The relationship between clearance and body weight, with an 
allometric exponent of 0.59, is within the range observed for other antibodies and 
would support both body weight normalized dosing or a fixed dose across all 
body weights.  MK-3475 has been found to have a wide therapeutic range based 
on the melanoma indication. The differences in exposure for a 200 mg fixed dose 
regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in 
the melanoma indication. The exposure margins are based on the notion of similar 

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efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen 
of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK 
evaluation revealed that there was no significant impact of tumor burden on 
exposure. In addition, exposure was similar between the NSCLC and melanoma 
indications. Therefore, there are no anticipated changes in exposure between 
different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of 
pembrolizumab in solid tumors is based on: 1) similar efficacy and safety of 
pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W in melanoma 
patients, 2) the flat exposure-response relationships of pembrolizumab for both 
efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the 
lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption 
that the dynamics of pembrolizumab target engagement will not vary meaningfully 
with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing 
is based on simulations performed using the population PK model of 
pembrolizumab showing that the fixed dose of 200 mg every 3 weeks will provide 
exposures that 1) are optimally consistent with those obtained with the 2 mg/kg 
dose every 3 weeks, 2) will maintain individual patient exposures in the exposure 
range established in melanoma as associated with maximal efficacy response and 
3) will maintain individual patients exposure in the exposure range established in 
melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors. A fixed dosing scheme will 
also reduce complexity in the logistical chain at treatment facilities and reduce 
wastage. 
Pembrolizumab Clinical Safety: 
As of Mar 2018 pembrolizumab monotherapy and combination therapy have been 
administered to 25,519  subjects, with hematologic malignancies and solid 
tumors. Safety data are available for a total of 2799 subjects in 4 Merck-
sponsored clinical trials. The majority of participants, 2727 or 97.4%, experienced 
1 or more AEs, and 2062(73.7%) experienced 1 or more AEs reported as drug-
related by the investigator. The most commonly reported AEs reported in 
monotherapy trials were fatigue (37.3%), nausea (24.5%), decreased appetite 
(22.5%), diarrhea (22.3%), and cough (22.0%).[55] 
 
 
Safety of Combinations of Pembrolizumab and Chemotherapy: 
There are nine Merck-sponsored pembrolizumab + chemotherapy trials that are 
ongoing based on recent information provided in the IB [48]. For example, 5 Phase 
I/II studies are ongoing evaluating the combination of pembrolizumab with 

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chemotherapy, including a study combining pembrolizumab with either cisplatin 
and pemetrexed or carboplatin and paclitaxel in non-small cell lung cancer 
(NCT01840579). A phase III trial of pembrolizumab vs pembrolizumab plus 5-
FU plus cisplatin or carboplatin vs cetuximab plus 5-FU plus cisplatin or 
carboplatin in recurrent or metastatic head and neck cancer is actively recruiting 
subjects (NCT02358031). Another phase Ib/II study of neoadjuvant 
pembrolizumab in combination with either cisplatin and gemcitabine or 
gemcitabine alone is also currently recruiting patients with muscle-invasive 
bladder cancer (NCT02365766). Another study is ongoing evaluating nivolumab, 
a PD-L1 antibody with similar theoretical toxicity to pembrolizumab, in 
combination with gemcitabine and cisplatin in patients with non-small cell lung 
cancer (NCT 01454102). 
 
Safety data encompassing all subjects from these trials is pending. However, the 
major toxicities of pembrolizumab including fatigue, constipation, nausea, 
decreased appetite, and diarrhea, should not overlap with the major toxicities of 
gemcitabine and cisplatin as outlined above, and the mechanisms of action are 
distinct.  Therefore, no serious safety issues are anticipated as a result of this 
combination given the low likelihood of overlapping toxicities. Any unexpected 
toxicities from the chemotherapy combination trials just summarized and 
sponsored by Merck will be shared with the PI of LCCC1520 and can be used to 
supplement toxicity monitoring if needed. The optimal timing of the 
administration of pembrolizumab, gemcitabine, and cisplatin in combination is 
not entirely clear.  
1.5 
Rationale for Inclusion of Pembrolizumab as NAC for MIBC  
Despite a proven survival benefit with NAC in MIBC, utilization remains low and 
more than half of patients develop recurrent or metastatic disease and die within 2 
years.[56] More effective and tolerable perioperative regimens are desperately 
needed. 
 
The inhibition of antitumor cytotoxic T cell activity via PD-1/PD-L1 interaction is 
a major immunosuppressant mechanism of many cancers and inhibition of this 
blockade leads to an anticancer immune response.  Pembrolizumab has shown 
promising results in metastatic bladder cancer as well as several other solid tumor 
cancers. This study expands the application of pembrolizumab immunotherapy to 
the neoadjuvant setting, potentially adding efficacy without substantial toxicity to 
the treatment of MIBC. Inhibition of immune evasion by tumor cells, and 
therefore activation of cytotoxic T-cells, may have an additive effect to the 
gemcitabine and cisplatin combination chemotherapy in the neoadjuvant setting. 
Further, the anti-PD-1 activated T cells may progress toward a memory 
phenotype, which is more refractory to tolerance, longer living, and has greater 
anti-cancer activity. These memory cells may continue to expand, recognize, and 
kill micrometastases, which account for relapses despite the neoadjuvant 
chemotherapy and surgical extirpation. 
 

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Study Endpoints: Pathologic downstaging after NAC can be defined as absence of 
any residual muscle-invasive disease at the time of cystectomy (<pT2) and 
includes pT1, pTcis, pTa, and T0 disease. Due to the multifocal nature of this 
disease, it is very common at both pre-chemotherapy and post-chemotherapy 
evaluations to see pre-existing and/or residual superficial transitional cell 
carcinoma such as Tcis, Ta, or T1 disease (frequently collectively defined as 
<pT2). The likelihood of residual superficial disease is also directly related to the 
extent of the TURBT prior to NAC. Superficial disease, and in particular Tcis, is 
typically unresponsive to chemotherapy, non-life threatening, and frequently 
included within the definition of major chemotherapy response.  
 
The prognostic value of defining response to NAC as <pT2 as opposed to 
complete pathologic response (pT0) was initially shown in an analysis by Splinter 
et al of 147 patients with MIBC treated at eight different centers.[57] This study 
demonstrated that patients who achieved <pT2 after NAC achieved 75% 5-year 
survival in contrast to 20% 5-year survival in those whose tumors were still 
muscle-invasive (≥pT2 residual disease). 
 
pT0 at the time of radical cystectomy is also associated with long-term survival 
outcomes in MIBC as demonstrated in the SWOG 8710 trial.[3] An independent 
study at MSKCC has validated comparable survival rates of patients achieving 
<pT2 and pT0.[58] A subsequent analysis confirmed both pT0 and <pT2 were 
associated with survival. Those with pT0 had a median OS of 13.6 years, those 
with <pT2 (but not pT0) had a median OS of 10.6 years, and those with pT2 or 
greater disease had a median OS of 3.7 years.[17] The use of pathological 
downstaging and pathologic complete response rate as study endpoints allows for 
initial efficacy data to be collected shortly after completion of neoadjuvant 
chemotherapy, allowing for earlier data interpretation than traditional time to 
event endpoints such as recurrence-free survival and overall survival. 
 
1.6 
Inclusion of Patient-Reported Outcomes version of the Common 
Terminology Criteria for Adverse Events (PRO-CTCAE) 
Adverse event reporting has historically been collected during clinical trials using 
the provider-reported common terminology criteria for adverse events (CTCAE). 
The National Cancer Institute (NCI) has been developing a system for patient 
self-reporting of symptom adverse events (AE) listed in the CTCAE in an effort 
to improve the accuracy and precision of grading this class of AEs. The PRO-
CTCAE is incorporated in this trial along with the CTCAE to improve the 
accuracy of symptom toxicity monitoring. In addition, several questions from the 
Patient Reported Outcomes Measurement Information System (PROMIS) are 
utilized as a general measure of the patients’ state of wellbeing. 
1.7 
Correlative Studies 
1.7.1 Predictive and Prognostic Biomarkers in Bladder Cancer 

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There are many recent examples of predictive and prognostic biomarkers in other 
types of cancer (HER2/neu overexpression and trastuzumab response in breast 
cancer, for example). However, no current molecular markers are widely used for 
targeted therapy in bladder cancer. 
 
MIBC is, with rare exceptions, classified as high-grade (versus low-grade) via 
pathological review, using the consensus system developed by The World Health 
Organization and the International Society of Urologic Pathologists.[59] RNA 
subtypes of high grade bladder cancer have been recently described including a 
unique gene expression pattern using a 47-gene signature (BASE47) recently 
described by investigators at the University of North Carolina (UNC) (Kim – co-
PI). These subtypes have been named “basal” and “luminal” subtypes due to 
similarities with the intrinsic subtypes of breast cancer.[60] The basal subtype has 
been associated with more aggressive disease (i.e., may be prognostic), although 
has also recently been reported to have a prolonged OS after neoadjuvant 
chemotherapy in MIBC (i.e., may also be predictive).[61] A subset of basal and 
claudin-low subtypes of MIBCs express biomarkers reflective of high immune 
cellular content, and T cell modulators may be more active in this subset (claudin-
low subtype data unpublished).[62] It is therefore theorized that subtypes of high-
grade bladder cancer may predict response to anti-PD-1 and anti-PD-L1 therapies.  
1.7.2 Planned Biomarker Studies for LCCC1520 
All patients will have pre- and post-treatment tumor tissue submitted for 
correlative studies.  Tissue from primary tumor samples (pre-treatment and tumor 
tissue at cystectomy) and lymph nodes removed at cystectomy will be processed 
for RNA extraction and generation of formalin-fixed paraffin embedded (FFPE) 
blocks/slides. See section 6.7 and the accompanying laboratory manual for 
details.   
 
Through our planned correlative studies, we hope to gather preliminary data on 1) 
potential determinants of response to pembrolizumab and 2) changes in the 
immune microenvironment driven by pembrolizumab therapy.  
 
The basal and claudin-low molecular subtypes of bladder cancer are enriched in 
tumor-infiltrating immune cells with a gene-expression signature consistent with 
active immunosuppression.[63]  This study will explore the hypothesis that the 
basal subtype classification will be associated with response to pembrolizumab 
via correlation with the presence of substantial tumor immune infiltrate.     
 
In addition to the basal and claudin-low molecular subtype, other pre-treatment 
tumor features we hypothesize will be associated with response include:  
1) Increased mRNA expression of PD-L1,  
2) Increased expression of general immune gene signatures and signatures 
associated with immune regulation,  
3) Clonal restriction in T-cell receptor (TCR) and B-cell receptor (BCR) 
repertoires,  

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4) Increased tumor infiltration with effector cells of multiple lineages localized 
intratumorally or peritumorally in regions staining heavily for PD-L1, and  
5) Decreased tumor infiltration by regulatory cells of multiple lineages.  Patients 
who respond to therapy that have lymph nodes assayable at the time of 
cystectomy will show similar findings. We also hypothesize that certain TCR and 
BCR repertoire characteristics will be associated with response and will be 
enriched in the basal vs. luminal subtypes. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To estimate the proportion of patients with pathological downstaging to <pT2 after 
neoadjuvant therapy with pembrolizumab in combination with gemcitabine and cisplatin 
in patients with MIBC. 
 
Hypothesis: The rate of pathologic downstaging to <pT2 will improve compared to 
historical controls 
2.2 
Secondary Objectives  
2.2.1 To estimate the proportion of patients with pT0 after neoadjuvant 
therapy with pembrolizumab when administered in combination with 
gemcitabine and cisplatin in patients with MIBC 
 
Hypothesis: The rate of pathologic downstaging to pT0 will improve compared to 
historical controls 
2.2.2 To estimate event free survival (EFS) 
 
Hypothesis: EFS will be improved compared to historical controls 
 
2.2.3 To estimate overall survival (OS) 
 
Hypothesis: OS will be improved compared to historical controls 
 
2.2.4 To estimate the proportion of patients who are alive at 3 years (OS at 3 
years) 
 
Hypothesis: OS at 3 years will be improved compared to historical controls 
2.2.5 To characterize the toxicity profile for the combination of 
pembrolizumab, gemcitabine, and cisplatin  
 

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Hypothesis: Pembrolizumab, gemcitabine, and cisplatin will be a safe combination with 
acceptable toxicity rates 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.4 
Endpoints 
2.4.1 Primary Endpoint 
Pathological downstaging to <pT2 is defined as pT0-T1N0M0 at the time of 
cystectomy  
2.4.2 Secondary Endpoints 
• Complete pathologic response rate (pT0) is defined as pT0N0M0 at the time 
of cystectomy  
• EFS is defined from D1 of neoadjuvant treatment until progression (in those 
who progress prior to surgery) or until recurrence (post-surgery) or until death 
as a result of any cause. Recurrence of disease includes second primary 
urothelial carcinoma malignancies. 
• OS is defined as the time from D1 of treatment until death as a result of any 
cause 
• OS at 3 years is defined from D1 of treatment until 3 years or death as a result 
of any cause 
• Safety and toxicity will be characterized according to the reported adverse 
event (AE) profile using NCI Common Terminology Criteria for Adverse 
Events (CTCAE) v4.03, as well as a patient questionnaire derived from the 
Patient Reported Outcomes (PRO)-CTCAE and Patient Reported Outcomes 
Measurement Information System (PROMIS). 
 

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3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
The subject must meet all of the inclusion criteria to participate in this study: 
3.1.1 Be able to give written IRB approved informed consent and be able to 
follow protocol requirements. 
3.1.2 Be ≥ 18 years of age on day of signing informed consent. 
3.1.3 Has a performance status of 0 or 1 on the ECOG Performance Scale (see 
section 11.1, Appendix A). 
3.1.4 Has histologically confirmed urothelial carcinoma of the bladder; those 
with mixed histology, including a component of urothelial carcinoma, 
are eligible. Pure small cell carcinoma, pure adenocarcinoma, and pure 
squamous cell carcinoma are excluded. 
3.1.5 Has clinical stage T2-T4a N0/X M0 urothelial carcinoma. Clinical T 
stage is based on the pre-study standard of care transurethral resection of 
the bladder tumor (TURBT) sample and imaging studies. 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count 
(ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO 
dependency (within 7 days of assessment) 
Renal 
Serum creatinine 
OR 
Estimated GFR per CKD-
EPI equationa 
≤1.5 X upper limit of normal (ULN)  
OR 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN (≤ 3 X ULN if Gilbert’s Syndrome) OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels 
> 1.5 ULN 
AST (SGOT) and ALT 
(SGPT) 
≤ 2.5 X ULN  
Coagulation 
International Normalized 
Ratio (INR) or Prothrombin 
Time (PT) 
Activated Partial 
Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy. 
If subject receiving anticoagulants, PT or PTT should be 
within therapeutic range of intended use of anticoagulants 
 
 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
17 
3.1.6 Has staging scans with abdominal/pelvic CT or MRI scan and CT scan 
or X-ray of the chest within 4 weeks prior to treatment initiation 
3.1.7 Be a medically appropriate candidate for radical cystectomy as 
determined by an attending urologist and be planning to receive 
cystectomy. 
3.1.8 Has had no prior systemic cytotoxic chemotherapy for urothelial 
carcinoma (prior intravesicular chemotherapies are permitted) 
3.1.9 Patients must agree to submission of tumor tissue from transurethral 
resection of the bladder tumor (TURBT) including a paraffin block or 20 
formalin-fixed paraffin embedded (FFPE) slides of 5-10 microns in 
thickness. Patients must also agree to submission of tissue from 
cystectomy. 
3.1.10 Demonstrate adequate organ function as defined in the table below; all 
screening labs should be performed within 10 days of treatment 
initiation. 
3.1.11 Female subjects of childbearing potential should have a negative urine 
or serum pregnancy within 72 hours prior to receiving the first dose of 
pembrolizumab.   If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.   
3.1.12 Female subjects of childbearing potential must be willing to adequate 
method of contraception as outlined in Section 5.1.11 – Contraception, 
for the course of the study through 120 days after the last dose of study 
medication.  
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
3.1.13 Male subjects of childbearing potential must agree to use an adequate 
method of contraception as outlined in Section 5.1.11 - Contraception, 
starting with the first dose of study therapy through 120 days after the 
last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
3.1.14 Life expectancy greater than 3 months 
3.1.15 Consents to whole blood collection prior to initiating therapy, on cycle 2 
day 1, and at cystectomy for support of correlative research studies 
aCreatinine clearance should be calculated per CKD-EPI equation[64] 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
18 
3.2 
Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject meets 
any of the following: 
3.2.1 Is currently participating in or has participated in a study of an 
investigational agent or using an investigational device within 4 weeks 
of the first dose of pembrolizumab. 
3.2.2 Has a diagnosis of immunodeficiency or is receiving systemic steroid 
therapy or any other form of immunosuppressive therapy within 7 days 
prior to the first dose of trial treatment. NOTE: see exception to use of 
systemic steroid as prophylactic anti-emetic prior to cisplatin in section 
4.2.2. Inhaled and topical steroids are allowed. 
3.2.3 Has a known history of active TB (Bacillus Tuberculosis) 
3.2.4 Hypersensitivity to pembrolizumab or any of its excipients. 
3.2.5 Has had a prior monoclonal antibody within 4 weeks prior to study Day 
1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to agents administered more than 4 weeks earlier. 
3.2.6 Has had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day 1 or who has not 
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a 
previously administered agent.  
• Note:  If subject received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention 
prior to starting therapy. 
3.2.7 Has a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, or in situ cervical cancer that has 
undergone potentially curative therapy.   
3.2.8 Has active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e. with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs). Replacement therapy (eg., 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for 
adrenal or pituitary insufficiency, etc.) is not considered a form of 
systemic treatment.  
3.2.9 Has a history of (non-infectious) pneumonitis that required steroids or 
current pneumonitis. 
3.2.10 Has an active infection requiring systemic therapy 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
19 
3.2.11 Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with 
the subject’s participation for the full duration of the trial, or is not in the 
best interest of the subject to participate, in the opinion of the treating 
investigator.   
3.2.12 Has known psychiatric or substance abuse disorders that would interfere 
with cooperation with the requirements of the trial 
3.2.13 Is pregnant or breastfeeding or expecting to conceive or father children 
within the projected duration of the trial, starting with the pre-screening 
or screening visit through 120 days after the last dose of trial treatment. 
3.2.14 Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 
(CTLA-4) antibody (including ipilimumab or any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathways). 
3.2.15 Has received prior radiation therapy to the bladder for the purpose of 
treating urothelial carcinoma. 
3.2.16 Has a known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies). 
3.2.17 Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C 
(e.g., HCV RNA [qualitative] is detected). 
3.2.18 Has clinically relevant hearing impairment > Grade 2 
3.2.19 Has received a live vaccine within 30 days prior to the first dose of trial 
treatment 
 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
20 
4.0 
TREATMENT PLAN 
4.1 
Schema 
 
 
This is a phase II, open-label, single arm study evaluating pembrolizumab 
administered in combination with gemcitabine and cisplatin in the neoadjuvant 
setting prior to radical cystectomy in patients with MIBC.  Toxicity will be 
assessed during treatment using NCI CTCAE v4.03, PRO-CTCAE and PROMIS. 
A tumor specimen (fresh frozen specimen or FFPE or both) from a pre-study 
transurethral resection of bladder tumor (TURBT; performed as per routine 
clinical care) and post-treatment surgical specimen (fresh frozen tissue if possible, 
although FFPE acceptable, or both) will be collected for correlative studies.  
 
Pembrolizumab 200mg IV is administered IV on day 1 in combination with 
cisplatin 35mg/m2 and gemcitabine 1000mg/m2 on day 1 and day 8 every 3 weeks 
for 4 cycles over 12 weeks. 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
21 
4.2 
Treatment Dosage and Administration 
A window of +/- 3 days will apply to each study visit (see Time and Events table), 
except Day 8 visits each cycle will have a window of +/- 1 day. 
 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Time and Events 
table (Section 6.1).  Trial treatment may be administered up to 3 days before or 
after the scheduled Day 1 of each cycle due to administrative reasons. Day 8 visits 
will have a window of +/- 1 day. 
 
All trial treatments will be administered on an outpatient basis. 
 
After screening and enrollment, patients will receive: (see section 4.2.1, 
Pembrolizumab Administration below, for details on administration of 
pembrolizumab): 
Pembrolizumab 200mg IV on Day 1 every 3 weeks for 4 cycles  
Gemcitabine 1000mg/m2 IV on Day 1 and Day 8 every 3 weeks for 4 cycles  
 
Cisplatin 35mg/m2 IV on Day 1 and Day 8 every 3 weeks for 4 cycles. 
 
 
This will total 12 weeks of neoadjuvant therapy. 
On Day 1 of each cycle pembrolizumab will be administered first, followed by 
gemcitabine and cisplatin. Each site must follow their institutional guidelines for 
administration of each drug and hydration. 
 
Concomitant GC + Pembrolizumab Therapy 
 
Drug 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length 
& 
Number 
 
Use 
Pembrolizumab 
200 mg 
IV over 30 
minutes 
Day 1 
Every 21 
days x 4 
cycles 
Experimental 
Gemcitabine 
1000 mg/m2* IV over 1 
hour***  
Days 1,8 
Standard 
Cisplatin 
35 mg/m2* 
IV over 1 
hour***  
Day 1, 8 
Standard 
In select 
patients**: 
Pegfilgrastim 
 
Alternative 
to 
pegfilgrastim: 
Filgrastim 
6 mg 
 
 
 
5mcg/day 
SC 
 
 
 
SC 
Day 9 
 
 
 
Days 9-13 
 
*Dose on total body weight 
** Use of growth factor support (pegfilgrastim or filgrastim) should be based on age (notable age 65 and 
older), preexisting conditions (neutropenia at baseline, etc), and other patient risk factors for the 
development of neutropenic fever. Pegfilgrastim may be included with the first cycle of this regimen at 
the treating physician’s discretion and institutional practice. Additionally, according to institutional 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
22 
practice, filgrastim may be used as an alternative to pegfilgrastim in accordance with local practice. 
Duration of filgrastim administration may be altered based on patient response or institutional practice. 
*** Duration of gemcitabine and cisplatin may be altered per institutional practice 
4.2.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 
1.4.1. 
4.2.2 Anti-Emetics and Hydration Prior to and Post Cisplatin 
Appropriate pre- and post-hydration for cisplatin chemotherapy will be included 
according to institutional guidelines. Furosemide, mannitol, and electrolyte 
supplementation may be included according to local practices as well. Anti-
emetic prophylaxis should be administered with cisplatin according to the 
following table and are recommended to include a corticosteroid and a 5-HT3 
antagonist. Corticosteroids should only be used as pre- and post-medication for 
antiemetic prophylaxis for cisplatin therapy and should be dosed as delineated 
below. 
 
Chemotherapy 
Premed Day 
Premeds 
Suggested Home Regimen 
 
Cisplatin and 
Gemcitabine 
 
Day 1 and 8 
Dexamethasone 8mg IV or 
po 
and 
5-HT3 antagonist 
and/or 
Lorazepam 
Dexamethasone 8mg po days 
2,3 9, and 10 
AND 
5-HT3 antagonist prn 
and/or 
Lorazepam prn 
 
4.2.3 Pembrolizumab Administration 
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion. Sites 
should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a 
window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 
minutes: -5 min/+10 min).  
 
Management of Infusion Reactions: Signs and symptoms usually develop 
during or shortly after drug infusion and generally resolve completely within 24 
hours of completion of infusion.  Refer to the table below for infusion reaction 
treatment guidelines: 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
23 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 
hrs 
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. 
infusion of 
pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 
 
Acetaminophen 500-
1000 mg po (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 
 
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. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration. 
 
 
4.3 
Timing of Cystectomy after Chemotherapy 
Enrollment into LCCC1520 should not impact this standard of care procedure. 
This procedure should be performed 4-8 weeks, if possible, from the last dose of 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
24 
neoadjuvant chemotherapy with recovery from all associated toxicities to grade 1 
or less at the time of surgery. At minimum, a standard lymph node dissection 
must be performed at the time of radical cystectomy, as per standard of care. 
4.4 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. 
Each patient will be assessed periodically for the development of any toxicity 
according to the Time and Events table (Section 6.1). Toxicity will be assessed 
according to the NCI CTCAE, version 4.0, the PRO-CTCAE, and PROMIS for 30 
days after dosing is completed. Serious adverse events (SAEs) and Events of 
Clinical Interest (ECI) will be followed for 90 days after dosing is completed. 
Dose adjustments should be made according to the system showing the greatest 
degree of toxicity according to the NCI CTCAE, version 4.0. The patient-reported 
adverse events (collected via the PRO-CTCAE and PROMIS) will be assessed 
concurrently with the CTCAE, and dose modification or delay can be considered 
by the treating physician according to the highest patient-reported grade of 
toxicity. 
 
Per the dose modification tables below, if administration of either cisplatin or 
gemcitabine on Day 1 is delayed, the other chemotherapy agent will also be held, 
and a new Day 1 will be scheduled. When that occurs, pembrolizumab should 
also be held until the new Day 1 based on gemcitabine/cisplatin is scheduled. 
Unless otherwise noted in the tables, treatment may be delayed for ≤ 2 weeks for 
any reason.  If Day 1 treatment is delayed ≤ 2 weeks, subjects will proceed with 
the current cycle of treatment at the dose level recommended according to the 
tables below. The reason for interruption should be documented in the medical 
record and treatment form. If >2 week delay is required, or if cumulative delays of 
>4 weeks are required, discontinue the subject from protocol-mandated treatment 
but maintain follow-up per protocol. 
 
On any given cycle, day 8 treatment is given only if day 1 treatment has been 
administered. Per the tables below, day 8 treatment should be held due to toxicity 
as outlined and held day 8 doses will not be made up. 
 
On day 1 of each cycle, if pembrolizumab is held due to toxicity but the patient is 
eligible to receive cisplatin and gemcitabine based on the tables below, ONLY 
pembrolizumab should be held and patients should receive gemcitabine and 
cisplatin as scheduled. Pembrolizumab should be held for the duration of that 
cycle and restarted (if applicable) on day 1 of the subsequent cycle. If 
pembrolizumab is permanently discontinued, the subject should be discontinued 
from protocol-mandated treatment but maintain follow-up per protocol. 
 
For the purposes of required dose reductions with gemcitabine, refer to the dose 
levels below. If more than 2 dose reductions of gemcitabine and/or more than 1 
dose reduction of cisplatin are required, discontinue patient from protocol directed 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
25 
treatment and follow-up per protocol. Note that once a drug dose is reduced, there 
is no re-escalation to a previous dosing level. 
 
 
 
Cisplatin Dose Levels 
Dose Level 
Cisplatin Dose 
Level 0 
35mg/m2 on Day 1 and Day 8 
Level -1 
25mg/m2 on Day 1 and Day 8 
 
Gemcitabine Dose Levels 
Dose Level 
Gemcitabine Dose 
Level 0 
1000 mg/m2 on Day 1 and Day 8 
Level -1 
750 mg/m2 on Day 1 and Day 8 
Level -2 
500 mg/m2 on Day 1 and Day 8 
 
No doses lower than cisplatin 25mg/m2 or gemcitabine 500mg/m2 will be 
permitted. 
4.4.1 Dose Modifications for GC for Hematologic Toxicity 
 
Hematological Toxicity Dose Reductions for Cisplatin 
Labs 
Action 
ANC ≥ 1,500/µL 
on Day 1 
None 
 
ANC <1500/µL 
on Day 1 
For ANC <1500/µL on day 1, delay cisplatin until the ANC ≥ 1500/µL. If the 
delay is one week or less, continue cisplatin at the same dose and consider 
pegfilgrastim with subsequent cycles, if not receiving. If the delay is for more 
than a week* but ≤14 days and pegfilgrastim has not been used, include 
pegfilgrastim in all subsequent cycles. If there is a dose delay for more than a 
week* due to neutropenia despite pegfilgrastim use but ≤14 days, reduce 
cisplatin by one dose level for this and all subsequent cycles and continue 
pegfilgrastim  
Platelets ≥ 100,000/µL 
on Day 1 
None 
Platelets < 100,000/µL  
on Day 1 
For platelets <100,000 on day 1, delay cisplatin* until platelets ≥ 100,000, 
then continue cisplatin at the same dose  
Platelets ≥ 75,000/µL 
on Day 8 
None 
Platelets < 75,000/µL 
but ≥ 50,000/µL 
on Day 8 
For platelets <75,000 on day 8, hold cisplatin and do not make up dose. 
Platelets < 50,000/µL  
on Day 8 
For platelets <50,000 on day 8, hold cisplatin and do not make up dose and 
reduce cisplatin by one dose level for all subsequent cycles. 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
26 
ANC ≥ 1000/µL on Day 
8 
None 
ANC < 1000/µL but ≥ 
500/µL on Day 8 
For ANC <1000 but >=500/µL on day 8, hold cisplatin and do not make up 
dose. 
ANC < 500/µL 
on Day 8 
For ANC <500 on day 8, hold cisplatin and do not make up dose and reduce 
cisplatin by one dose level for all subsequent cycles. 
* If >2 week delay is required at any time, discontinue the subject from protocol-mandated treatment and follow-up 
per protocol. 
 
 
Hematological Toxicity Dose Reductions for Gemcitabine 
Labs 
Action 
ANC ≥ 1,500/µL 
on Day 1 
None 
 
ANC <1500/µL 
on Day 1 
For ANC <1500/µL on day 1, delay gemcitabine until the ANC ≥ 1500/µL. If the 
delay is one week or less, continue gemcitabine at the same dose and consider 
pegfilgrastim with subsequent cycles, if not receiving. If the delay is for more than 
a week* but ≤14 days and pegfilgrastim has not been used, include pegfilgrastim in 
all subsequent cycles. If there is a dose delay for more than a week due to 
neutropenia despite pegfilgrastim use, reduce gemcitabine by one dose level for 
this and all subsequent cycles and continue pegfilgrastim 
ANC ≥ 1000/µL 
on Day 8 
None 
ANC < 1000/µL 
but  
≥500/µL on Day 
8 
For ANC <1000 but >=500 on day 8, hold gemcitabine and do not make up dose.  
ANC < 500/µL 
on Day 8 
For ANC <500/µL on day 8, hold gemcitabine (do not make up dose) and reduce 
gemcitabine by one dose level for all subsequent cycles. 
Platelets 
≥100,000/µL 
on Day 1 
None 
Platelets 
< 
100,000/µL  
on Day 1 
For platelets <100,000/µL on day 1, delay gemcitabine until platelets ≥ 
100,000/µL. If the delay is one week or less, continue gemcitabine at the same 
dose. If there is a dose delay for more than a week* but ≤14 days, reduce 
gemcitabine by one dose level for this and all subsequent cycles.  
Platelets 
≥ 
75,000/µL 
on Day 8 
None 
Platelets 
< 
75,000/µL but ≥ 
50,000/µL  
on Day 8 
For platelets < 75,000/µL but ≥ 50,000/µL on day 8, hold gemcitabine (do not 
make up dose). 
Platelets 
< 
50,000/µL  
on Day 8 
For platelets <50,000 on day 8, hold gemcitabine (do not make up dose) and 
reduce gemcitabine by one dose level for all subsequent cycles. 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
27 
*If >2 week delay is required, discontinue the subject from protocol-mandated treatment and follow-up per 
protocol. 
 
 
 
 
4.4.2 Dose Modifications for GC for Non-Hematologic Toxicity 
 
Non-Hematological Toxicity Dose Reductions for Gemcitabine and Cisplatin 
Event 
Action 
Grade 4 Febrile Neutropenia 
(defined as ANC <500/µL and 
temperature ≥ 38.3° C orally or a 
temperature of ≥ 38.0° C for 
more than 1 hour) 
Add pegfilgrastim if not previously included, continuing GC at the 
same dose level. If pegfilgrastim had been used, then dose reduce 
cisplatin by one dose level for all subsequent cycles and continue 
pegfilgrastim. 
Kidney Dysfunction (calculate CrCl on Day 1 and 8 of each cycle using CKD-Epi equation) 
CrCl ≥ 50ml/min 
None. 
CrCl < 50ml/min 
Hold gemcitabine and cisplatin for up to 1 week if occurs on day 1. 
If the CrCl does not improve to ≥ 50ml/min in 1 week despite 
hydration and other supportive measures, discontinue the 
chemotherapy (all agents) and proceed to surgery. If it improves to ≥ 
50ml/min within 1 week of scheduled day 1, proceed with 
gemcitabine and cisplatin administration. Hold gemcitabine and 
cisplatin and do not make up dose if occurs on day 8. 
Liver Dysfunction 
Total bilirubin ≥ Grade 2 normal 
(or Grade 4  in patients with 
Gilbert’s syndrome) 
Hold gemcitabine and cisplatin until bilirubin is < Grade 2 (≤1.5 x 
ULN) (or <Grade 4 in patients with Gilbert’s syndrome), then restart 
with a one dose level reduction in gemcitabine for this and all 
remaining cycles.  
Neurologic Toxicity: Neuropathy 
Grade 1-2 
None 
Grade 3 
Hold gemcitabine and cisplatin until resolves to Grade 1 or 2, then 
resume with a one dose level reduction in cisplatin. If occurs on day 
8, hold gemcitabine and cisplatin and do not make up dose. 
Grade 4 
Remove from protocol directed treatment, and follow-up per 
protocol 
Gastrointestinal Toxicity: Vomiting  
Grade 1-2 
None 
Grade 3 or 4 (despite maximal 
antiemetic medical intervention 
with aprepitant, corticosteroids, 
and 5HT-3 antagonists (e.g. 
ondansestron)) 
Proceed with one dose level reduction for next cycle in both 
cisplatin and gemcitabine. If grade 3 or 4 vomiting occurs despite 
dose reduction and maximal antiemetic therapy, remove from 
protocol directed treatment, and follow-up per protocol 
Other Non-specified Treatment-related Toxicity 
Grade 2 
None 
Grade 3 or 4 (excluding alopecia 
and skin pigment changes) 
Hold gemcitabine and cisplatin and monitor patient at least weekly. 
If toxicity resolves to grade 1 or completely resolves in ≤ 2 weeks, 
treatment can be resumed in the next cycle at the same dose levels 
for cisplatin and gemcitabine at the discretion of the treating 
provider and in consultation with the medical monitor. Any single 
delay in chemotherapy of more than 2 weeks or cumulative delays 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
28 
of more than 4 weeks will lead to removal from the protocol 
directed treatment and follow-up per protocol. If occurs on day 8, 
hold gemcitabine and cisplatin and do not make up dose.  
 
 
4.4.3 Dose Modifications for Pembrolizumab for Events other than 
Infusion Reactions 
Adverse events (both non-serious and serious) associated with pembrolizumab 
exposure may represent an immunologic etiology.  These adverse events may 
occur shortly after the first dose or several months after the last dose of treatment. 
Pembrolizumab must be withheld for drug-related toxicities and severe or life-
threatening AEs as per Table below. See Sections 7.1.4 and 7.3.   
 
Dosing interruptions are permitted in the case of medical / surgical events or 
logistical reasons not related to study therapy (e.g., elective surgery, unrelated 
medical events, patient vacation, and/or holidays). Subjects should be placed back 
on study therapy within 2 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in 
the patient's study record. 
 
Of note: Per the dose modification tables above, if administration of either 
cisplatin or gemcitabine on Day 1 is delayed, the other chemotherapy agent will 
also be held, and a new Day 1 will be scheduled. When that occurs, 
pembrolizumab should also be held until the new Day 1 based on 
gemcitabine/cisplatin is scheduled. 
 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to 
taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after 
AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab 
should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by 
oral steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be 
controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE 
management with 
corticosteroid 
and/or other 
therapies  
Monitor and follow-
up  
Pneumonitis  
Grade 2 
Withhold  
• Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
• 
Monitor 
participants for 
signs and 
symptoms of 
pneumonitis 
• 
Evaluate 
participants with 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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followed by 
taper 
 
suspected 
pneumonitis with 
radiographic 
imaging and 
initiate 
corticosteroid 
treatment 
• 
Add prophylactic 
antibiotics for 
opportunistic 
infections 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
 
• 
Monitor 
participants for 
signs and 
symptoms of 
enterocolitis (ie, 
diarrhea, 
abdominal pain, 
blood or mucus in 
stool with or 
without fever) and 
of bowel 
perforation 
(ie, peritoneal 
signs and ileus). 
• 
Participants with 
≥ Grade 2 
diarrhea 
suspecting colitis 
should consider 
GI consultation 
and performing 
endoscopy to rule 
out colitis.  
• 
Participants with 
diarrhea/colitis 
should be advised 
to drink liberal 
quantities of clear 
fluids.  If 
sufficient oral 
fluid intake is not 
feasible, fluid and 
electrolytes 
should be 
substituted via IV 
infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
0.5- 1 mg/kg 
prednisone or 
equivalent) 
• 
Monitor with liver 
function tests 
(consider weekly 
or more 
frequently until 
liver enzyme 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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followed by 
taper 
value returned to 
baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure 
Withhold 
• Initiate insulin 
replacement 
therapy for 
participants 
with T1DM  
• Administer 
anti-
hyperglycemic 
in participants 
with 
hyperglycemia  
 
• 
Monitor 
participants for 
hyperglycemia or 
other signs and 
symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated.   
 
• 
Monitor for signs 
and symptoms of 
hypophysitis 
(including 
hypopituitarism 
and adrenal 
insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  Grade 2 
Continue  
• Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate  
• 
Monitor for signs 
and symptoms of 
thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine 
or 
liothyroinine) 
per standard of 
care 
• 
Monitor for signs 
and symptoms of 
thyroid disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
equivalent) 
followed by 
taper. 
• 
Monitor changes 
of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on 
severity of AE 
• 
Ensure adequate 
evaluation to 

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September 25, 2018 
 
 
 
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Grade 3 or 4 
Permanently 
discontinue 
administer 
corticosteroids 
confirm etiology 
and/or exclude 
other causes 
 
All other 
immune-related 
AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
• Based on type 
and severity of 
AE administer 
corticosteroids  
• 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or 
treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of 
pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is 
controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
Dosing interruptions are permitted in the case of medical / surgical events or 
logistical reasons not related to study therapy (e.g., elective surgery, unrelated 
medical events, patient vacation, and/or holidays). Subjects should be placed back 
on study therapy within 2 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in 
the patient's study record. 
4.4.4 Rescue Medications and Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed 
necessary by the treating investigator.  Suggested supportive care measures for the 
management of adverse events with potential immunologic etiology are outlined 
below. Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that 
several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased. For each disorder, attempts should be made to 
rule out other causes such as metastatic disease or bacterial or viral infection, 
which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab.  
 

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September 25, 2018 
 
 
 
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Note: if after the evaluation the event is determined not to be related, the 
investigator does not need to follow the treatment guidance (as outlined below).  
 
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event.  
 
 
 
Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis 
(such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) 
and of bowel perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be substituted via IV infusion.  For 
Grade 2 or higher diarrhea, consider GI consultation and endoscopy to 
confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed 
by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
 
Type 1 diabetes mellitus: (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with 
metabolic acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
Hypophysitis: 

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o For Grade 2 events, treat with corticosteroids. 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. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids 
followed by oral corticosteroids. 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. 
 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical signs and 
symptoms of thyroid disorders 
 
o Grade 2 hyperthyroidism events (and Grade 3-4 hypothyroidism): 
 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. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. 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. 
 
Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks. 
 
Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
4.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are 
not allowed during the ongoing trial.  If there is a clinical indication for one of 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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these or other medications or vaccinations specifically prohibited during the trial, 
discontinuation from trial therapy or vaccination may be required.  The 
investigator should discuss any questions regarding this with the Merck Clinical 
team.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician. An exception to this is 
corticosteroids that are allowed to be administered as antiemetic prophylaxis. In 
addition, topical and inhaled corticosteroids are allowed. Vaccinations for flu that 
are not live vaccines are allowed. 
4.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may 
be administered at the discretion of the investigator in keeping with the community 
standards of medical care. All concomitant medication will be recorded on the case 
report form (CRF) including all prescription, over-the-counter (OTC), herbal 
supplements, and IV medications and fluids.  If changes occur during the trial 
period, documentation of drug dosage, frequency, route, and date may also be 
included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial 
treatment and 30 days after the last dose of trial treatment should be recorded.  
Concomitant medications administered after 30 days after the last dose of trial 
treatment should be recorded for SAEs and ECIs as defined in Section 7.3.3. 
4.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening 
and Treatment Phase of this trial: 
• Anti-neoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab  
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited 
to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, 
BCG, typhoid (oral) vaccine and FluMist®.  
• Glucocorticoids for any purpose other than to modulate symptoms from an 
event of suspected immunologic etiology or for antiemetic prophylaxis.  The 
use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.  
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the 
trial and followed up per protocol.  Subjects may receive other medications that the 
investigator deems to be medically necessary. 

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September 25, 2018 
 
 
 
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The Exclusion Criteria describes other medications which are prohibited in this 
trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
4.5.3 Diet 
Subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea or vomiting. 
4.6 
Duration of Therapy 
In the absence of treatment delays due to AEs, treatment may continue until the 
end of 4 cycles or until: 
• Inter-current illness that prevents further administration of treatment 
• Unacceptable toxicity  
• Pregnancy 
• Patient decides to withdraw from study treatment, OR 
• General or specific changes in the patient’s condition render the 
patient unacceptable for further treatment in the judgment of the 
investigator. 
• Inability to complete protocol chemotherapy due to the following 
reasons: 
• A continuous treatment delay for any reason >14 days at any time 
after starting chemotherapy, a cumulative delay in chemotherapy 
of 28 days total, or if CrCl<50mL/min persists for one week 
despite best supportive care and holding the chemotherapy 
• The need for more than one dose level reduction for cisplatin or 
more than two dose level reductions for gemcitabine 
• Patient is no longer a candidate for cystectomy in the opinion of 
the physician 
 
A subject must be discontinued from the study treatment for any of the following 
reasons: 
• Evidence of radiographic disease progression 
• Unacceptable adverse experiences as described in Section 7.0 
• Investigator’s decision to withdraw the subject 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Administrative reasons 
. 
4.7 
Duration of Follow Up 
After the end of treatment, each subject will be followed for 30 days for adverse 
event monitoring (serious adverse events and Events of Clinical Interest will be 
collected for 90 days after the end of treatment as described in section 7.3). 
 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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Patients will otherwise be followed from enrollment for up to 5 years or until 
death, whichever comes first. 
4.8 
Removal of Patients from Protocol Therapy 
Patients will be removed from protocol therapy and the site PI notified when any 
of the criteria listed in section 4.6 apply. The reason for discontinuation of 
protocol therapy will be documented on the eCRF.   
 
In case a patient decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the patient should be asked if she or he may still be contacted for 
further scheduled study assessments. The outcome of that discussion should be 
documented in both the medical records and in the eCRF. 
 
Excessive patient withdrawals from protocol therapy or from the study can render 
the study un-interpretable; therefore, unnecessary withdrawal of patients should 
be avoided.  
4.9 
Study Withdrawal 
If a patient decides to withdraw from the study (and not just from protocol 
therapy) an effort should be made to complete and report study assessments as 
thoroughly as possible.  At the time of withdrawal, the investigator should attempt 
to establish as completely as possible the reason for the study withdrawal.  
• 
The patient should be asked if they are willing to allow for the abstraction 
of relevant information from their medical record in order to meet the long 
term follow up (e.g., survival) objectives outlined in the protocol.   
• 
A complete final evaluation at the time of the patient’s study withdrawal 
should be obtained with an explanation of why the patient is withdrawing 
from the study.   
• 
If the patient is noncompliant and does not return for an end of study 
follow up assessment, this should be documented in the eCRF.  
• 
If the reason for removal of a patient from the study is an adverse event, 
the principal specific event will be recorded on the eCRF.  
 
Excessive patient withdrawals from protocol therapy or from the study can render 
the study un-interpretable; therefore, unnecessary withdrawal of patients should 
be avoided. 
4.10 
Clinical Criteria for Early Trial Termination 
 
Early trial termination will be the result of the criteria specified below: 
1. 
Quality or quantity of data recording is inaccurate or incomplete. 
2. 
Poor adherence to protocol and regulatory requirements. 
3. 
Incidence or severity of adverse drug reaction in this or other studies 
indicates a potential health hazard to subjects. 

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4. 
Plans to modify or discontinue the development of the study drug. 
In the event of Merck decision to no longer supply study drug, ample notification will 
be provided so that appropriate adjustments to subject treatment can be made. 
 
 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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5.0 
DRUG INFORMATION 
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. 
5.1 
Pembrolizumab 
 
5.1.1 Description 
Pembrolizumab (MK-3475) solution for infusion is a sterile, non-pyrogenic 
aqueous solution supplied in single-use type I glass vial containing 100 mg/4 mL 
of pembrolizumab (manufactured using the fully formulated drug substance with 
L-histidine as a buffering agent, polysorbate 80 as a surfactant, and sucrose as a 
stabilizer/tonicity modifier). The product is preservative-free solution which is 
essentially free of extraneous particulates.  
5.1.2 Supplier/How Supplied/Packaging and Labeling Information 
Pembrolizumab will be provided at no cost to the study patient by Merck, the 
manufacturer of the drug. Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements. 
 
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. 
5.1.3 Storage and Handling Requirements and Dispensing 
Clinical supplies must be stored in a secure, limited-access location under 
refrigerated conditions (2°C to 8°C). 
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. 
5.1.4 Preparation of Infusion Solution 
Aseptic technique must be strictly observed throughout the preparation procedure 
preferably in a biologic safety cabinet or hood since no anti-microbial 
preservative is present in the solutions.  
Equilibrate required number of pembrolizumab (MK-3475) vials to room 
temperature. 
The preferred method of dose preparation is the volumetric method, gravimetric 
method is not permitted.  
Choose a suitable infusion bag size so that the following conditions are met: 

LCCC 1520 
 
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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
39 
o Concentration of pembrolizumab MK-3475 is between 1 mg/mL and 10 
mg/mL 
o The infusion volume to bag capacity ratio should not be less than 0.3.  In 
other words, the bag must be filled to at least 30% of its capacity.   
Choose a suitable infusion bag material. The bag may be empty, or it may contain 
normal saline. The following infusion bag materials are compatible with 
pembrolizumab:  
 PVC plasticized with DEHP 
 Non-PVC (polyolefin) 
 EVA 
 PE lined polyolefin 
      *Contact Sponsor for materials not listed above 
 
Calculate the volume of pembrolizumab and normal saline required to prepare the 
infusion (admixture) bag 
 
Volume of pembrolizumab (mL) = required dose amount (mg) / 25 (mg/mL) 
 
Volume of normal saline = total infusion volume – volume of pembrolizumab 
from above 
 
If a bag pre-filled with normal saline is being used, remove the excess volume of 
normal saline using a sterile syringe (Polypropylene, latex-free) attached to a 
suitable needle. Keep in consideration the excess bag fill volume as well as the 
volume of reconstituted pembrolizumab to be added to the bag to prepare the 
infusion solution. 
If an empty bag is being used, withdraw the necessary volume of normal saline 
from another appropriate bag and inject into the empty bag. Keep in consideration 
the volume of reconstituted pembrolizumab to be added to the bag to prepare the 
infusion solution. 
 
Withdraw the required volume of pembrolizumab from the vial(s) (up to 4 mL 
from each vial) using a sterile syringe attached to a suitable needle. The vial(s) 
may need to be inverted to remove solution. 
 
Volume of pembrolizumab (mL) = required dose amount (mg) / 25 (mg/mL) 
 
Note: If it is necessary to use several vials, it is advisable to withdraw from 
several vials into a suitable size single use syringe using a new needle for each 
vial.  
 
Add the required pembrolizumab into the infusion IV bag containing normal 
saline and gently invert the bag 10-15 times to mix the solution. 
 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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40 
Pembrolizumab solutions may be stored at room temperature for a cumulative 
time of up to 4 hours. This includes room temperature storage of admixture 
solutions in the IV bags and the duration of infusion.  
 
In addition, IV bags may be stored under refrigeration at 2 °C to 8 °C (36 °F to 46 
°F) for up to 20 hours. If refrigerated, allow the IV bags to come to room 
temperature prior to use.   
Do not freeze the pembrolizumab infusion solution. 
Discard any unused portion left in the vial as the product contains no preservative. 
5.1.5 Method of Administration 
Pembrolizumab (MK-3475) infusions should be administered in 30 minutes, with 
a window of -5 and +10 minutes, using an infusion pump. A central catheter is not 
required for infusion; however, if a subject has a central venous catheter in place, 
it is recommended that it be used for the infusion. The following infusion set 
materials are compatible with (pembrolizumab) MK-3475: 
 
o PVC and tri-(2-ethylhexyl) trimellitate (TOTM) infusion set 
o Polyethylene lined PVC infusion set 
o PVC Infusion set that is plasticized using Di-2-ethylhexyl Terephthalate 
(DEHT) 
o Polyurethane set 
 
A sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line filter made of 
polyethersulfone (PES) must be used during administration to remove any 
adventitious particles.  If the infusion set does not contain 0.2 to 5 µm in-line 
filter, it is recommended to use 0.2 to 5 µm add-on filter which may contain an 
extension line (Note: the materials of the extension line and filter should be as 
mentioned above). 
Attach the infusion line to the pump and prime the line, either with normal saline 
(at least 25 mL) or with infusion solution as per local SOP, before starting the 
infusion. 
Infuse pembrolizumab (MK-3475) over approximately 30 minutes, with a 
window of -5 and +10 minutes, through a peripheral line or indwelling catheter.  
Ensure the entire contents of the bag are dosed and all remaining drug solution in 
the line is administered according to institutional guidelines for saline flushing.  
Document volume administered according to data entry guidelines. 
 
In case of infusion reactions, infusion rate may differ; refer to protocol for 
specific instructions.  
Whenever possible, the lowest infusion rate should be used that will allow 
completion of the infusion within the 30 minutes. Maximum rate of infusion 
should not exceed 6.7 mL/min. through a peripheral line or indwelling 
catheter. However, when it is necessary to infuse a larger volume (i.e. 250 
mL), the flow rate may go as high as 10 mL/min (maximum) in order to keep 
the infusion within the window as defined above.  

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September 25, 2018 
 
 
 
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Do not co-administer other drugs through the same infusion line. 
 
Unused infusion solution for injection should not be used for another infusion of 
the same subject or different subject. 
5.1.6 Storage and Stability 
Pembrolizumab (MK-3475) Solution for Infusion, 100 mg/ 4 mL vial:  
pembrolizumab (MK-3475) Solution for Infusion vials should be stored at 
refrigerated conditions (2 – 8 °C) and protected from light. 
 
Note: Vials should be stored in the original box to ensure the drug product is 
protected from light. 
 
Pembrolizumab (MK-3475) infusion solutions should be prepared in 0.9% 
Sodium Chloride Injection, USP (normal saline) or regional equivalent or 5% 
Dextrose Injection, USP (5% dextrose) or regional equivalent and the final 
concentration of pembrolizumab (MK-3475) in the infusion solutions should be 
between 1 mg/mL and 10 mg/mL. 
Please note, the preferred diluent is 0.9% sodium chloride and 5% dextrose is 
only permissible if normal saline is not available. 
Pembrolizumab (MK-3475) should not be mixed with other diluents.  
Pembrolizumab (MK-3475) solutions may be stored at room temperature for a 
cumulative time of up to 4 hours. This includes room temperature storage of 
admixture solutions in the IV bags and the duration of infusion 
In addition, IV bags may be stored under refrigeration at 2°C to 8°C (36°F to 
46°F) for up to a cumulative time of 20 hours. If refrigerated, allow the IV bags to 
come to room temperature prior to use. 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration. Discard the drug product vial if extraneous 
particulate matter other than translucent to white proteinaceous particles is 
observed. 
Sites should follow their SOPs for drug transport and delivery, with all possible   
effort to minimize agitation of the drug product between the pharmacy and the 
clinic. 
Do not use pembrolizumab (MK-3475) if discoloration is observed. 
Do not shake or freeze the vial(s). 
Do not administer the product as an intravenous (IV) push or bolus. 
Do not combine, dilute or administer it as an infusion with other medicinal 
products. 
Any deviation from this guidance must be discussed with sponsor. 
5.1.7 Return and Retention 
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.  

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per UNC IDS drug destruction 
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. 
5.1.8 Drug Ordering and Accountability 
Pembrolizumab should be ordered from Merck by completing and emailing Drug 
Request Form provided to each site. 
5.1.9 Adverse Events Associated with Pembrolizumab 
The most common adverse reactions (reported in ≥20% of subjects in clinical 
trials of pembrolizumab) included fatigue, cough, nausea, pruritus, rash, 
decreased appetite, constipation, arthralgia, and diarrhea. The following warnings 
are associated with the use of pembrolizumab:  
 
 
 
Immune-Mediated Pneumonitis 
Pneumonitis occurred in ~3% of melanoma patients treated in clinical trials of 
pembrolizumab. The median time to development of pneumonitis was 5 months 
with a median duration of 4.9 months. The one patient with Grade 3 pneumonitis 
required initial treatment with high-dose systemic corticosteroids (greater than or 
equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid 
taper. Pneumonitis completely resolved in seven of the nine patients with Grade 
2-3 pneumonitis. 
 
Immune-Mediated Colitis 
Colitis (including microscopic colitis) occurred 1% of melanoma patients treated 
in clinical trials of pembrolizumab. The median time to onset of was 6.5 months 
with a median duration of 2.6 months. All three patients with Grade 2 or 3 colitis 
were treated with high-dose corticosteroids (greater than or equal to 40 mg 
prednisone or equivalent per day). 
 
Immune-Mediated Hepatitis  
Hepatitis (including autoimmune hepatitis) occurred in 0.5% of melanoma 
patients treated in clinical trials of pembrolizumab. The time to onset was 22 days 
for the case of Grade 4 hepatitis, which lasted 1.1 months. The patient with Grade 
4 hepatitis permanently discontinued pembrolizumab and was treated with high-
dose (greater than or equal to 40 mg prednisone or equivalent per day) systemic 
corticosteroids followed by a corticosteroid taper. Both patients with hepatitis 
experienced complete resolution of the event.  
 
Immune-Mediated Hypophysitis  
Hypophysitis occurred in 0.5% of melanoma patients treated in clinical trials of 
pembrolizumab. The time to onset was 1.7 months for the patient with Grade 4 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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hypophysitis and 1.3 months for the patient with Grade 2 hypophysitis. Both 
patients were treated with high-dose (greater than or equal to 40 mg prednisone or 
equivalent per day) corticosteroids followed by a corticosteroid taper and 
remained on a physiologic replacement dose.  
 
Renal Failure and Immune-Mediated Nephritis  
Nephritis occurred in 3 (0.7%) patients of melanoma patients treated in clinical 
trials of pembrolizumab, consisting of one case of Grade 2 autoimmune nephritis 
(0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 
3 and one Grade 4. The time to onset of autoimmune nephritis was 11.6 months 
after the first dose of pembrolizumab (5 months after the last dose) and lasted 3.2 
months; this patient did not have a biopsy. Acute interstitial nephritis was 
confirmed by renal biopsy in two patients with Grades 3-4 renal failure. All three 
patients fully recovered their renal function with treatment with high-dose 
corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) 
followed by a corticosteroid taper. 
 
Immune-Mediated Hyperthyroidism  
Hyperthyroidism occurred in 5 (1.2%) of 411 melanoma patients treated in 
clinical trials of pembrolizumab. The median time to onset was 1.5 months and 
the median duration was 2.8 months (range 0.9 to 6.1). One of two patients with 
Grade 2 and the one patient with Grade 3 hyperthyroidism required initial 
treatment with high-dose corticosteroids (greater than or equal to 40 mg 
prednisone or equivalent per day) followed by a corticosteroid taper. One patient 
(0.2%) required permanent discontinuation of pembrolizumab due to 
hyperthyroidism. All five patients with hyperthyroidism experienced complete 
resolution of the event. 
 
Immune-Mediated Hypothyroidism  
Hypothyroidism occurred in 34 (8.3%) of 411 melanoma patients treated in 
clinical trials of pembrolizumab. The median time to onset of hypothyroidism was 
3.5 months. All but two of the patients with hypothyroidism were treated with 
long-term thyroid hormone replacement therapy. The other two patients only 
required short-term thyroid hormone replacement therapy. No patient received 
corticosteroids or discontinued pembrolizumab for management of 
hypothyroidism. Thyroid disorders can occur at any time during treatment.  
 
Other Immune-Mediated Adverse Reactions 
Other clinically important immune-mediated adverse reactions can occur. The 
following clinically significant, immune-mediated adverse reactions occurred in 
less than 1% of patients treated with pembrolizumab, including exfoliative 
dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial 
seizures arising in a patient with inflammatory foci in brain parenchyma, and 
adrenal insufficiency. 
 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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Across clinical studies with pembrolizumab in approximately 2,000 patients, the 
following additional clinically significant, immune-mediated adverse reactions 
were reported in less than 1% of patients: myasthenic syndrome, optic neuritis, 
and rhabdomyolysis. 
 
Embryofetal Toxicity 
Based on its mechanism of action, pembrolizumab may cause fetal harm when 
administered to a pregnant woman. Animal models link the PD-1/PD-L1 
signaling pathway with maintenance of pregnancy through induction of maternal 
immune tolerance to fetal tissue.  
 
Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) 
The risk of SJS and TEN is reported at approximately 0.4 – 7 cases per million 
patient years in the general adult population. Independent risk factors include 
certain medications such as anticonvulsants, sulfonamides, aminopenicillins, 
allopurinol, and NSAIDs. Non-medication triggers include infection, contrast 
media, and vaccinations. Malignancy is associated with an increased mortality 
rate in patients with SJS and TEN. 
 
Myocarditis 
A total of 6 cases of myocarditis have been reported in patients treated with 
pembrolizumab in clinical trials in an expanded access program. There was one 
fatal case reported in a clinical trial. Immune-mediated myocarditis should be 
suspected if other causes of myocarditis such as infection or prior radiation 
therapy have been excluded. Risk factors include certain medications and 
treatment modalities such as radiation, anthracycline, alkylating agents and most 
recently checkpoint inhibitors. 
 
5.1.10 Contraindications 
There are no reported contraindications associated with the use of 
pembrolizumab. 
 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if pembrolizumab has transient adverse effects on the composition of 
sperm.   
5.1.11 Contraception 
 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if pembrolizumab has transient adverse effects on the composition of 
sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential 
if they have azoospermia (whether due to having had a vasectomy or due to an 
underlying medical condition).   

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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Female subjects will be considered of non-reproductive potential if they are 
either:  
(1) postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to 
screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving study drug and 
for 120 days after the last dose of study drug by complying with one of the 
following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual 
activity.   
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with 
cervical cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin 
pill or progestin-only pill), contraceptive skin patch, vaginal 
contraceptive ring, or subcutaneous contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and 
ERCs/IRBs.  Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-
ovulation methods, etc.) and withdrawal are not acceptable methods of 
contraception.  
‡If a contraceptive method listed above is restricted by local 
regulations/guidelines, then it does not qualify as an acceptable method of 
contraception for subjects participating at sites in this country/region. 
Subjects should be informed that taking the study medication may involve 
unknown risks to the fetus (unborn baby) if pregnancy were to occur during the 
study.  In order to participate in the study subjects of childbearing potential must 
adhere to the contraception requirement (described above) from the day of study 
medication initiation (or 14 days prior to the initiation of study medication for 
oral contraception) throughout the study period up to 120 days after the last dose 
of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject 
should not be entered into the study. 
5.1.12 Use in Pregnancy 
 
Risk Summary 
Based on its mechanism of action, pembrolizumab can cause fetal harm when 
administered to a pregnant woman. In animal models, the PD-1/PD-L1 signaling 
pathway is important in the maintenance of pregnancy through induction of 
maternal immune tolerance to fetal tissue. Human IgG4 (immunoglobulins) are 
known to cross the placenta; therefore, pembrolizumab has the potential to be 
transmitted from the mother to the developing fetus. There are no available 
human data informing the risk of embryo-fetal toxicity. Apprise pregnant women 
of the potential risk to a fetus. 
 
In the U.S. general population, the estimated background risk of major birth 
defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 
respectively. 
 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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If a subject inadvertently becomes pregnant while on treatment with 
pembrolizumab, the subject will immediately be removed from the study.  The 
site will contact the subject at least monthly and document the subject’s status 
until the pregnancy has been completed or terminated.  The outcome of the 
pregnancy will be reported to the Sponsor and to Merck without delay and within 
24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).   
 
The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. If a male subject impregnates his female partner the study personnel at 
the site must be informed immediately and the pregnancy reported to the Sponsor 
and to Merck and followed as described above and in Section 7.3.3. 
5.1.13 Use in Nursing Women 
It is not known whether pembrolizumab is excreted in human milk. No studies 
have been conducted to assess the impact of pembrolizumab on milk production 
or its presence in breast milk. Because many drugs are excreted in human milk, 
instruct women to discontinue nursing during treatment with pembrolizumab and 
for 4 months after the final dose.  
5.1.14 Overdose 
For purposes of this trial, an overdose of pembrolizumab will be defined as any 
dose of 1,000 mg or greater (≥5 times the indicated dose).  No specific 
information is available on the treatment of overdose of pembrolizumab. 
Appropriate supportive treatment should be provided if clinically indicated. In the 
event of overdose, the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck 
product, the adverse event(s) is reported as a serious adverse event, even if no 
other seriousness criteria are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the 
overdose is reported as a non-serious Event of Clinical Interest (ECI), using the 
terminology “accidental or intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 
24 hours to the Sponsor and within 2 working days hours to Merck Global Safety. 
(Attn: Worldwide Product Safety; Fax: 215 993-1220).  
5.2 
Gemcitabine Hydrochloride 
Mechanism of Action: Gemcitabine (2'-Deoxy-2', 2'-difluorocytidine 
monohydrochloride) is a nucleoside analog of deoxycytidine. This antimetabolite, 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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a pyrimidine analog inhibiting both DNA and RNA viruses, is cell-cycle-specific 
in blocking the cells at the G1/S and is retained in human tumor cells for long 
periods. Studies suggest that gemcitabine is activated by deoxycytidine kinase. 
Deoxycytidine has been shown to reverse the growth inhibitory activity of 
gemcitabine.  
 
Metabolism and Elimination: Gemcitabine is metabolized by the liver to form the 
inactive uracil derivative, 2'-deoxy-2',2'-difluorouridine (dFdU). The inactive 
metabolite does not appear to accumulate with weekly dosing; however, it is 
excreted by the kidneys and may accumulate in patients with decreased renal 
function.  
 
Dosing, Administration, Preparation, Storage, and Stability: See Section 4.2 for 
dosing information. Refer to the current FDA-approved package insert for drug 
administration, preparation, storage, stability and special handling information.  
 
How Supplied: Gemcitabine is commercially available and will not be supplied 
free of charge to the patient. Refer to the current FDA-approved package insert. 
 
Adverse Events: Adverse effects reported in 10% or more of patients receiving 
gemcitabine monotherapy include myelosuppression (i.e., anemia, leukopenia, 
neutropenia, thrombocytopenia), proteinuria, hematuria, increased BUN, nausea, 
vomiting, pain, fever, rash, pruritus, dyspnea, constipation, diarrhea, hemorrhage, 
peripheral edema, edema, flu-like symptoms, infection, alopecia, stomatitis, 
somnolence, paresthesias, and increased serum AST, ALT, alkaline phosphatase, 
and bilirubin concentrations.  
 
Dose limiting toxicity is bone marrow suppression with mild to moderate 
granulocytopenia, anemia and thrombocytopenia. There has been no evidence of 
cumulative WBC or platelet toxicity. Gastrointestinal toxicities include nausea, 
vomiting, and diarrhea. Gemcitabine should be used with caution in patients with 
impaired liver function since abnormalities of liver transaminase enzymes have 
been reported. Mild proteinuria and hematuria have been reported but were not 
clinically significant and usually not associated with any change in serum 
creatinine or BUN. A few cases of renal failure of uncertain etiology have been 
reported. Gemcitabine should be used with caution in patients with impaired renal 
function. Toxicities associated with allergic reaction include rash, pruritus, 
desquamation, vesiculation, ulceration, and dyspnea. Bronchospasm has been 
reported in less than 1% of patients. Twenty percent of patients have also 
experienced flu-like symptoms such as fever, headache, back pain, chills, 
myalgia, asthenia, anorexia, cough, rhinitis, malaise, sweating, and insomnia. 
Other toxicities include edema or peripheral edema in 30% of patients, alopecia, 
somnolence, diarrhea, constipation, and oral toxicity (soreness and erythema). 
Pulmonary edema has been a rare occurrence (less than 1%). A few cases of 
hypotension have been reported, as well as myocardial infarction, congestive 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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heart failure and arrhythmia. However, there is no clear evidence that gemcitabine 
causes cardiac toxicity.  
 
Refer to the current FDA-approved package insert for the most comprehensive 
and up to date information on adverse reactions.  
 
Pregnancy and Lactation: Category D. Gemcitabine may cause fetal harm when 
administered to a pregnant woman. This agent has produced teratogenic effects in 
mice and rabbits when administered at a dose of < 2 mg/m2. Adverse effects 
included decreased fetal viability, weight and morphologic defects. There is no 
data on gemcitabine administration during human pregnancy, and it is not 
currently known if metabolites are excreted in human milk. However, many drugs 
are excreted in human milk, and there is a potential for adverse effects in nursing 
infants. Therefore, the use of gemcitabine should be avoided in pregnant or 
nursing women because of the potential hazard to the fetus or infant.  
 
Drug Interactions: Per gemcitabine package insert, no formal drug interaction 
studies have been performed to date. When gemcitabine was administered with 
carboplatin or paclitaxel there was minimal or no effect on the pharmacokinetics 
of the studied drugs. 
5.3 
Cisplatin (CDDP) 
Mechanism of Action: Cisplatin (cis-diamminedichloroplatinum) is a heavy metal 
complex containing a central platinum atom surrounded by two chloride atoms 
and two ammonia molecules in the cis position. It is water soluble and acts as a 
bifunctional alkylating agent with cell cycle nonspecific characteristics. The intra-
strand cross-links, in particular with guanine and cytosine, change DNA 
conformation and inhibit DNA synthesis leading to the cytotoxic and anti-tumor 
effects of cisplatin. Although cisplatin seems to act as an alkylating agent, there 
are data to indicate that its mode and sites of action are different from those of 
nitrogen mustard and the standard alkylating agents and that cisplatin does not 
exhibit cross-resistance with other alkylating agents or nitrosoureas.  
 
 
Metabolism and Elimination: Cisplatin is non-enzymatically transformed to one 
or more metabolites that are extensively protein bound and have minimal 
cytotoxic activity. The non-protein bound (unchanged) fraction is cytotoxic. 
Following bolus injection or infusion over a dose range of 40-140 mg/m2 varying 
in length from 1-24 hours, from 10 to about 40% of the administered platinum is 
excreted in the urine in 24 hours. Renal clearance of free platinum exceeds the 
glomerular filtration rate, indicating that cisplatin or other platinum-containing 
molecules are actively secreted by the kidneys. Renal clearance of free platinum 
is nonlinear and variable, and is dependent on dose, urine flow rate, and 
individual variability in the extent of active secretion and possible tubular 
reabsorption.  
 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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Dosing, Administration, Preparation, Storage, and Stability: See Section 4.2 for 
dosing information. Refer to the current FDA-approved package insert for drug 
administration, preparation, storage, stability and special handling information.  
 
How Supplied: Cisplatin is commercially available and will not be supplied free 
of charge to the patient. Refer to the current FDA-approved package insert. 
 
Adverse Events: Adverse effects reported in 10% or more of patients receiving 
cisplatin include peripheral neuropathy, nausea, vomiting, diarrhea, 
myelosuppression, liver enzymes elevation, nephrotoxicity (acute renal failure 
and chronic renal insufficiency), alopecia, tissue irritation, and ototoxicity.  
 
Human toxicity includes anorexia, nausea, vomiting, renal toxicity (with an 
elevation of BUN, creatinine, serum uric acid and impairment of endogenous 
creatinine clearance, as well as renal tubular damage), ototoxicity (with hearing 
loss which initially is in the high-frequency range, as well as tinnitus), peripheral 
neuropathy and hyperuricemia. Much more severe and prolonged toxicity has 
been observed in patients with abnormal or obstructed urinary excretory tracts. 
Raynaud’s phenomena and digital ischemia has been described. Anaphylactic-like 
reactions including facial edema, bronchoconstriction, tachycardia and 
hypotension may occur within minutes of administration.  
 
Myelosuppression, often with delayed erythrosuppression, is expected. In the 
high-dose treatment regimen with osmotic diuresis, the nadir of white cells and 
platelets occurred regularly at about two weeks with recovery generally at about 
three weeks after the initiation of therapy. Alopecia, malaise and asthenia have 
been reported. Rare complications are alopecia, seizures, loss of taste and allergic 
reactions. Tetany may occur due to hypomagnesemia and/or hypocalcemia. Other 
electrolyte disturbances may occur. At high doses patients have experienced optic 
neuritis, papilledema, cerebral blindness, blurred vision, and altered color 
perception. Patients have also experienced cardiac abnormalities, elevated 
aspartate aminotransferase and rash. Subsequent courses should not be given until 
serum creatinine returns to normal if elevated. Audiometric analyses should be 
monitored, and courses withheld until auditory acuity is within normal limits. The 
occurrence of acute leukemia has been reported rarely in patients treated with 
anthracycline/alkylator combination chemotherapy.  
 
Refer to the current FDA-approved package insert for the most comprehensive 
and up to date information on adverse reactions.  
 
Pregnancy and Lactation: Category D. Cisplatin can cause fetal harm when 
administered to a pregnant woman. In mice, cisplatin is teratogenic and 
embryotoxic. This drug has been found to be excreted in human milk and because 
of the potential for serious adverse reactions in nursing infants, patients receiving 
cisplatin should not breast feed.  
 

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Drug Interactions: During cisplatin therapy, plasma levels of anticonvulsant 
agents may become sub-therapeutic and should be monitored. For complete 
information refer to the current FDA-approved package insert.  
 

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6.0 
EVALUATIONS AND ASSESSMENTS 
6.1 
Time and Events Table 
The Time and Events Table below summarizes the trial procedures to be 
performed at each visit.  Individual trial procedures are described in detail below.  
It may be necessary to perform these procedures at unscheduled time points if 
deemed clinically necessary by the investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the 
Sponsor and/or Merck for reasons related to subject safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis C, 
etc.), and thus local regulations may require that additional informed consent be 
obtained from the subject.  In these cases, such evaluations/testing will be 
performed in accordance with those regulations. 

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September 25, 2018  
 
 
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Assessm
ent 
 
 
Neoadjuvant Chemotherapy plus Pembrolizumab 
Pre- 
Surgery
3 
Surgery
4 
 
 
Post-
Surgery 
Visit5 
Long-
term 
Follow-
up6 
Pre-
study1 
 
D12 
Cycle 1 
D82 
Cycle 1 
D152  
Cycle 1 
D12 
Cycle 2 
D82 
Cycle 2 
D12 
Cycle 3 
D82 
Cycle 3 
D12 
Cycle 4 
D82 
Cycle 4 
Informe
d 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
History7 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Physical 
exam7 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Vital 
signs7 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Perform
ance 
Status 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
CT chest  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI 
of 
Ab/Pelvi
s 
X 
 
 
 
 
 
 
 
 
 
X 8 
 
 
 
Bone 
scan 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnan
cy test 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
with 
different
ial 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Serum 
chemistr
ies11 
X 
X 
X11 
X 
X 
X11 
X 
X11 
X 
X11 
X 
 
 
 
Liver 
function 
tests12 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Thyroid 
panel13 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Uric 
acid, 
PTT 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 

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PT/INR 
X 
X14 
 
 
X14 
 
X14 
 
X14 
 
X 
 
 
 
Urinalys
is15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concom
itant 
Meds 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Toxicity 
Assessm
ent  
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X5 
X 
Sympto
m 
Assessm
ent16 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pembrol
izumab  
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Gemcita
bine 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Cisplati
n 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Tumor 
Samples 
X17 
 
 
 
 
 
 
 
 
 
 
X17 
 
 
Blood 
sample 
(require
d) 
X18 
 
 
 
X18 
 
 
 
 
 
 
X18 
 
 
Survival 
analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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UNIVERSITY OF NORTH CAROLINA 
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Key to Time and Events Table Footnotes 
1Unless otherwise noted, laboratory evaluations may be performed up to 10 days prior to first dose of protocol 
treatment. Laboratory assessments on cycle 1 day 1 do not need to be repeated if screening labs performed less 
than 72 hours prior to the scheduled visit.  Imaging studies may be performed up to 30 days prior to first dose of 
protocol treatment. 
 
2A window of +/-3 days will be applied to all study visits, except Day 8 visits each cycle will have a window of 
+/-1 day and Cycle 1 D15 labs will have a window of +/-1 day 
 
3 Pre-Surgery visit to take place approximately 30 days after last dose of pembrolizumab given. Also serves as 
standard pre-op assessment, and mandatory ~30-day post pembrolizumab safety visit. Patients who continue to 
experience ≥ Grade 2 treatment-related adverse event will be contacted every 2 weeks until the event is resolved 
to Grade 0 or 1, determined to be irreversible by the investigator, or until the patient begins an alternate form of 
drug treatment.  This visit should occur in patients when treatment stops for any reason (toxicity, progression, or 
at discretion of the investigator) even if surgery no longer planned. 
 
4Cystectomy should occur between 4-8 weeks, if possible, from the last dose of neoadjuvant chemotherapy.  
 
5The post-surgery visit should be scheduled 4-8 weeks after surgery. Serious adverse events (SAEs) or any grade 
of Events of Clinical Interest (see section 7.3 that occur within 90 days of the end of pembrolizumab (or prior to 
start of new anti-cancer therapy) must be recorded.  NOTE: Patients who do not complete neoadjuvant 
chemotherapy + pembrolizumab for whatever reason other than withdrawal from the study (see section 4.9), but 
still undergo surgery, will be requested to participate in correlative studies of excess surgical specimen (optional) 
 
6Long-term follow-up will take place every 3 months (with window of +/-2 weeks) after surgery for the first 12 
months, every 6 months (with window of +/-2 weeks) for the next 24 months, then annually (with window of +/- 
one month) until 5 years from enrollment.  For study purposes, data gathered will be limited to history of any 
subsequent cancer treatments, any disease assessments performed as per standard of care, an assessment of any 
SAE’s considered to be possibly or probably related to study treatment until resolution, and survival status.   
 
7Complete history at baseline only, thereafter focused history on symptoms/toxicity.  Physical exam (PE) to 
include height (baseline only), and weight; PE to be comprehensive at screening and pre-surgery; other 
scheduled PE to be directed based on symptoms; vital signs to include systolic and diastolic blood pressure, pulse 
rate and temperature. 
 
8Repeat imaging must be done prior to surgery (30 days after last dose of pembrolizumab with a +/-14 day 
window). Imaging does not need to be repeated if patient is removed from protocol-directed therapy and imaging 
has been done within 30 days. 
 
9Obtain at baseline in patients with any clinical or laboratory suspicion of metastatic bone involvement 
 
10Serum or urine B-HCG within 72 hours prior to first dose of pembrolizumab and only if clinically appropriate 
(e.g. women of childbearing potential); if the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.   
 
11Serum chemistries include Na, K, Cl, creatinine, BUN, calcium, magnesium, bicarbonate, phosphorus, and 
glucose. All serum chemistries should be drawn on day 1 and day 8 of each cycle. 

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September 25, 2018 
 
 
 
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12 Liver function tests (LFTs) include bilirubin, alkaline phosphatase, ALT, AST, albumin, LDH, and total 
protein. 
 
13 Thyroid panel includes TSH, total or free T3 and free T4 
 
14 PT/INR for all subjects pre-study and pre-surgery. Patients on anticoagulation with warfarin should also have 
PT/INR checked each cycle on day 1.  
 
15Urinalysis includes blood, glucose, protein, specific gravity, and microscopic exam if abnormal results are 
noted 
 
16Patient-reported symptom assessment is a patient questionnaire derived from the Patient Reported Outcomes 
(PRO)-CTCAE and Patient Reported Outcomes Measurement Information System (PROMIS) (Appendix B) 
 
17Pre-study archival tumor tissue will be requested from all patients; post-chemotherapy tissue to be obtained at 
cystectomy. Sample collection, storage, and shipment instructions for tumor tissue samples will be provided in 
the Laboratory Manual. See section 6.7 for additional information. 
 
18Blood sample (7 x 8.5 mL ACD tubes) to be obtained for correlative studies prior to first dose of 
pembrolizumab, on cycle 2 day 1, and at time of cystectomy; sample collection, storage, and shipment 
instructions for serum samples will be provided in the Laboratory Manual. 
 
 
 

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6.2 
Pre-Study Assessments 
The assessments required as part of screening can be completed in one or more 
visits, as long as the assessments are completed within the time frames listed in 
the Key to the Time and Events table. 
 
Clinical evaluation: complete history (including disease details with all prior 
treatments, all active medical conditions and any condition diagnosed within the 
prior 10 years that are considered to be clinically significant by the Investigator), 
comprehensive physical examination (to also include vital signs, height, and 
weight), ECOG performance status, QOL questionnaire 
Laboratory studies: 
• Pregnancy test: serum or urine pregnancy test is required for all 
women of childbearing potential within 72 hours prior to start of 
study treatment 
• Hematology: CBC with differential 
• Serum chemistries: Na, K, Cl, creatinine, BUN, calcium, 
magnesium, bicarbonate, phosphorus, glucose 
• LFTs: AST, ALT, total bilirubin, alkaline phosphatase, albumin, 
LDH, total protein 
• Coagulation and thyroid panel, and uric acid: PT/INR, PTT, TSH, 
total or free T3, free T4, uric acid 
• Urinalysis 
• Blood sample (required) for correlative studies: 7 x 8.5 mL ACD 
tubes  
Staging: CT chest and CT abdomen/pelvis or MRI abdomen/pelvis. Imaging 
studies may be performed up to 4 weeks prior to first dose of study treatment. 
Bone scan: Bone scan should be obtained at baseline in patients with any clinical 
or laboratory suspicion of metastatic bone involvement 
Prior and concomitant medication review: Documentation of all medications 
taken by the subject within 28 days before starting the trial; documentation of all 
concomitant medications, and in particular any immunosuppressive medications. 
Tissue acquisition: Primary tumor formalin-fixed, paraffin-embedded blocks will 
be collected. See section 6.5 and the laboratory manual for additional details. 
Toxicity/QOL: Toxicity will be assessed according to the NCI CTCAE v 4.03, 
PRO-CTCAE, and PROMIS for notation of any baseline toxicity. 
 
 
6.3 
On-Study Treatment Assessments 
6.3.1 Day 1 of Each Cycle of Pembrolizumab, Gemcitabine, and Cisplatin 
Clinical evaluation: focused history, directed physical examination (to also 
include vital signs and weight), ECOG performance status 
Laboratory studies: 
• Hematology: CBC with differential 

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• Serum chemistries: Na, K, Cl, creatinine (calculate CrCl on day 1 
of each cycle per CKD-Epi equation), BUN, calcium, magnesium, 
bicarbonate, phosphorus, glucose 
• LFTs: AST, ALT, total bilirubin, alkaline phosphatase, albumin, 
LDH, total protein 
• Thyroid function tests: TSH, total or free T3 and free T4 should 
also be drawn on cycle 3 day 1 
• PT/INR: Should be drawn only if anticoagulated with warfarin 
• Blood sample (required) for correlative studies: 7 x 8.5 mL ACD 
tubes on cycle 2 day 1 only 
 
Concomitant medications: Documentation of any changes in concomitant 
medications 
Toxicity/QOL: Toxicity will be assessed according to the NCI CTCAE v 4.03, 
PRO-CTCAE, and PROMIS. 
6.3.2 Day 8 of Each Cycle 
Clinical evaluation: Vital signs 
Laboratory studies: 
• Hematology: CBC with differential 
• Serum chemistries: Na, K, Cl, creatinine (calculate CrCl per CKD-
Epi equation), BUN, calcium, magnesium, bicarbonate, 
phosphorus, glucose  
Toxicity/QOL: Toxicity will be assessed according to the NCI CTCAE v 4.03, 
PRO-CTCAE, and PROMIS. 
 
6.3.3 Day 15 of Cycle 1 
Laboratory studies: 
• Hematology: CBC with differential 
• Serum chemistries: Na, K, Cl, creatinine, BUN, calcium, 
magnesium, bicarbonate, phosphorus, glucose  
 
6.4 
Pre-Surgical Visit (post-pembrolizumab) 
This visit should occur approximately 30 days after completion of last dose of 
pembrolizumab. This visit should serve as standard pre-operative visit prior to 
cystectomy. 
 
Clinical evaluation: focused history on symptoms/toxicity, comprehensive 
physical examination (to include vital signs and weight), ECOG performance 
status 
Laboratory studies: 
• Hematology: CBC with differential 

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• Serum chemistries: Na, K, Cl, creatinine, BUN, calcium, 
magnesium, bicarbonate, phosphorus, glucose  
• LFTs: AST, ALT, total bilirubin, alkaline phosphatase, albumin, 
LDH, total protein 
• Coagulation and thyroid panel, and uric acid: PT/INR, PTT, TSH, 
total or free T3, free T4, uric acid 
Tumor assessment: CT abdomen/pelvis or MRI abdomen/pelvis 
Concomitant medications: Documentation of any changes in concomitant 
medications 
Toxicity/QOL: Toxicity will be assessed according to the NCI CTCAE v 4.03. 
Patients who experience ≥ Grade 2 treatment related adverse event will be 
contacted every 2 weeks until the event is resolved to Grade 0 or 1, determined to 
be irreversible by the investigator, or until the patient begins an alternate form of 
drug treatment.  Toxicity will also be assessed according to PRO-CTCAE and 
PROMIS with need for continued assessment until resolution as determined by 
the investigator. 
6.5 
Cystectomy 
This should occur within 4-8 weeks, if possible, of the last dose of neoadjuvant 
chemotherapy. The surgery with curative intent will occur as per routine clinical 
standard of care and will be performed at the discretion of the surgeon.  
Enrollment into LCCC1520 should not impact this standard of care procedure. 
Tissue acquisition: A sample of tumor tissue from the cystectomy will be 
preserved for correlative studies in those who do not achieve pT0. A sample of 
lymph node tissue from the lymph node biopsy and normal tissue from the 
cystectomy specimen will be preserved for correlative studies from all patients, 
including those who achieve pT0. These tissues will be preserved in consultation 
with surgical pathology, and tissue released for correlative studies post 
pathological review. NOTE: Patients who do not complete neoadjuvant 
chemotherapy + pembrolizumab for whatever reason other than withdrawal from 
the study (see section 4.9), but still undergo surgery, will be requested to 
participate in correlative studies of excess surgical specimen (optional). 
Blood sample for correlative studies: 7 x 8.5 mL ACD tubes (see laboratory 
manual for details)  
 
6.5.1 Post-Surgery Visit 
This visit should be scheduled 4-8 weeks after cystectomy. Serious adverse events 
(SAEs) or any grade of Events of Clinical Interest (see section 7.3) that occur 
within 90 days of the end of pembrolizumab (or prior to start of new anti-cancer 
therapy) must be recorded.  NOTE: Patients who do not complete neoadjuvant 
chemotherapy + pembrolizumab for whatever reason other than withdrawal from 
the study (see section 4.9), but still undergo surgery, will be requested to 
participate in correlative studies of excess surgical specimen (optional). 

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6.6 
Long Term Follow-Up Assessments 
After cystectomy, follow-up will take place every 3 months for the first 12 
months (with +/-2 week window), every 6 months for the next 24 months (with 
+/- 2 week window), and then annually (with a +/- one month window) until 5 
years from enrollment. For study purposes, data gathered will be limited to history 
of any subsequent cancer treatments, any disease assessments performed as per 
standard of care, an assessment of any SAE’s considered to be possibly or 
probably related to study treatment until resolution, and survival status. 
 
6.7 
Correlative Studies Procedures 
6.7.1 Archival Tumor Tissue 
All subjects’ archived primary tumor in paraffin-embedded blocks/slides will be 
requested for correlative studies.  
  
mRNA sequencing will be performed for definition of tumor molecular subtypes, 
quantification of PD-1 ligand mRNA expression, and evaluation of gene 
expression signatures associated with immune activation and suppression. Whole 
exome sequencing will be done on tumors and matched blood samples for 
identification of somatic mutations and predicted MHC class I and class II 
neoantigens. T cell receptor (TCR) and B cell receptor (BCR) repertoires will be 
amplified, sequenced, and analyzed to discover receptor profiles that correlate 
with response to therapy.  Tissue blocks/slides may be stained for coexpression 
using the following panel of fluorescent antibodies (can include but not limited 
to): CD4/FoxP3, CD8/PD1, CD19/CD27, CD11b/CD33, CD47/CD68, along with 
immunohistochemistry staining using the following antibodies: PD-L1, IFN-γ, 
TNF-α, CTLA4, KIR3DL1, LAG3, CD200, Tim3 [HAVCR2], BTLA, CD137 
[TNFRSF9], CD40, OX40, CD27, ICOS, and GITR [TNFRSF18], which 
combined will enable quantification and localization of effector T cells, 
regulatory T cells, myeloid derived suppressor cells, antigen-experienced vs. non-
experienced B cells, and suppressive macrophages, and enable definition of 
specific mechanisms of intratumoral cellular immune suppression.   
 
Some of the specific correlative details regarding specific antibodies, repertoires 
etc. may vary from this protocol, but will be maintained and updated in the 
corresponding laboratory manual. 
 
Slides of the pre-treatment TURBT will also be shipped to an external lab of the 
sponsor for assessment of PD-L1 expression. 
6.7.2 Blood samples 
Patients will have a seven ACD tubes (whole blood, 7 x 8.5 mL) collected at pre-
study, on cycle 2 day 1, and at the time of cystectomy. Sample collection, storage, 

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and shipment instructions for serum samples will be provided in the Laboratory 
Manual. 
6.7.3 Tumor and Lymph Node Tissue from Cystectomy  
Tissue from primary tumor samples and lymph nodes removed at cystectomy will 
be collected as standard of care. Tissue reserved for correlative studies will 
undergo the same studies as outlined in section 6.7.1. 
 
Tissue remaining after protocol-directed studies are complete will be destroyed, 
or, if requested, any unused slides will be returned to the site of origin. Additional 
details of correlative studies are provided in the accompanying Laboratory 
Manual. 
6.7.4 Handling of Biospecimens Collected for Correlative Research 
Biospecimens collected for this study will be stored in the Lineberger 
Comprehensive Cancer Center (LCCC) Tissue Procurement Facility (TPF), or if 
needed, in a secure off-site storage facility. All biospecimen samples will be 
obtained in accordance with procedures outlined in the LCCC1520 Study 
Laboratory Manual and stored in containers with controlled access. Each sample 
will be assigned a unique code number and no identifiable personal health 
information (PHI) will be on the specimen label. Information about the patient’s 
disease will be linked to the specimens stored in the repository database. TPF-
associated research staff, LCCC Bioinformatics staff who support the TPF 
database and the LCCC Data Warehouse, and researchers with IRB-approval for 
access to PHI for each subject in this study will be able to link specimens to 
relevant medical information. Some results from laboratory analyses that occurred 
during the patient’s participation in the clinical study may also be included. This 
information may be important for understanding how the patient’s cancer 
developed and responded to treatment. 
Storage Time: 
• 
The biospecimen will be used first and foremost for research purposes 
outlined within the confines of this protocol. Samples will be 
discarded/destroyed after relevant data are collected for this study; unless 
consent was obtained from the patient to use tissue for other research 
purposes (Specimen Consent checkbox was checked, and consent was 
signed).  
• 
Leftover biospecimen material collected during this study may be stored and 
used for other research purposes including genetic research only if patient 
assent was obtained. In this circumstance, there is no time limit on how long 
biospecimens may be stored. 
 
 
Compliance Statement 

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Biospecimen collection for this study will be conducted in full accordance to all 
applicable University of North Carolina (UNC) Research Policies and Procedures 
and all applicable Federal and state laws and regulations including 45 CFR 46, 
and the Health Insurance Portability and Accountability Act (HIPAA) Privacy 
Rule. Any episode of noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will 
obtain consent and assent (unless a waiver is granted), and will report unexpected 
problems in accordance with The UNC IRB Policies and Procedures and all 
federal requirements. Collection, recording, and reporting of data will be accurate 
and will ensure the privacy, health, and welfare of research subjects during and 
after the study.  
6.8 
Assessment of Safety  
All patients who enroll and receive at least 1 dose of pembrolizumab will be 
evaluable for toxicity. Each patient will be assessed for the development of any 
toxicity according to the Time and Events table (section 6.0). Toxicity will be 
assessed according to the NCI CTCAE v. 4.03. 
6.9 
Assessment of Efficacy 
All patients who enroll and receive at least 1 dose of pembrolizumab will be 
evaluable for the primary endpoint of pathologic downstaging. Those who 
undergo surgery will be evaluated for pathological downstaging at the time of 
surgery, and those who do not undergo surgery (due to progression of disease) 
will be considered to not have achieved pathologic downstaging. 
6.9.1 Pathological Downstaging and Complete Response 
The primary endpoint of this study is pathological downstaging. The rate of 
downstaging is defined as the proportion of patients who achieve absence of 
muscle-invasive disease at the time of cystectomy (<pT2). The proportion of 
patients with a pathologic complete response (no evidence of primary tumor 
(pT0)) is a secondary endpoint. 
 
Pathologic staging is based on the operative and pathology report from 
cystectomy at the local site. Patients not undergoing surgery due to disease 
progression will be considered a nonresponder. 
 
 
TX 
Primary tumor cannot be assessed 
T0  
No evidence of primary tumor 
Ta 
Noninvasive papillary carcinoma 
Tis  
Carcinoma in situ: “flat tumor” 
T1 
Tumor invades subepithelial connective tissue 
T2 
Tumor invades muscularis propia 
pT2a Tumor invades superficial muscularis propia (inner half) 
pT2b Tumor invades deep muscularis propia (outer half) 
T3 
Tumor invades perivesical tissue 

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pT3a Microscopically 
pT3b Macroscopically (extravesical mass) 
T4 
Tumor invades any of the following: prostatic stroma, seminal vesicles, 
uterus, vagina, pelvic wall, abdominal wall 
T4a 
Tumor invades prostatic stroma, uterus, vagina 
T4b 
Tumor invades pelvic wall, abdominal wall 
 
NX 
Lymph nodes cannot be assessed 
N0 
No lymph node metastasis 
N1 
Single regional lymph node metastasis in the true pelvis (hypogastric, 
obturator, external iliac, or presacral lymph node) 
N2 
Multiple regional lymph metastases in the true pelvis (hypogastric, 
obturator, external iliac, or presacral lymph nodes) 
N3 
Lymph node metastases to the common iliac lymph nodes 
 
M0 
No distant metastasis 
M1  
Distant metastasis 
6.9.2 Recurrence Criteria 
Criteria for recurrence will include new measurable disease on cross-sectional 
imaging or plain radiography targeting lung, liver, and bone as most common 
sites for recurrence as per RECIST v1.1. 
6.9.3 Event-Free Survival 
The event-free time interval is from D1 of neoadjuvant treatment to date of first 
documentation of disease progression (in those who progress prior to surgery) or 
until recurrence (post-surgery) or death due to any cause. Recurrence includes the 
development of second primary urothelial malignancies. Patients last known to be 
alive without report of relapse/recurrence are censored at date of last contact. 
Criteria for recurrence will include measurable disease on cross-sectional imaging 
or plain radiography targeting lung, liver, and bone as most common sites for 
recurrence.  
6.9.4 Overall Survival 
Overall survival is measured from day 1 of treatment to date of death from any 
cause. Patients known to be alive are censored at date of last contact. 
6.9.5 Overall Survival at 3 years 
Overall survival at 3 years is defined as the proportion of patients alive at 3 years, 
measured from day 1 of treatment. 
 

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7.0 
ADVERSE EVENTS 
7.1 
Definitions  
7.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a 
drug) in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not related to the 
medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) need not be considered 
AEs and should not be recorded as an AE.  Disease progression should not be 
recorded as an AE, unless it is attributable by the investigator to the study therapy. 
7.1.2 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug is the cause. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the drug and the AE.  A 
suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.   
 
Causality assessment to a study drug is a medical judgment made in consideration 
of the following factors: temporal relationship of the AE to study drug exposure, 
known mechanism of action or side effect profile of study treatment, other recent 
or concomitant drug exposures, normal clinical course of the disease under 
investigation, and any other underlying or concurrent medical conditions.  Other 
factors to consider in considering drug as the cause of the AE: 
• Single occurrence of an uncommon event known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
• One or more occurrences of an event not commonly associated with drug 
exposure, but otherwise uncommon in the population (e.g., tendon 
rupture); often more than once occurrence from one or multiple studies 
would be needed before the sponsor could determine that there is 
reasonable possibility that the drug caused the event   
• An aggregate analysis of specific events observed in a clinical trial that 
indicates the events occur more frequently in the drug treatment group 
than in a concurrent or historical control group 
 
 

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7.1.3 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., Investigator’s Brochure 
(IB) for an unapproved investigational product or package insert/summary of 
product characteristics for an approved product).  Unexpected also refers to AEs 
or SARs that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug but are not 
specifically mentioned as occurring with the particular drug under investigation.   
7.1.4 Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• Death; 
• Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 
• Requires inpatient hospitalization (>24 hours) or prolongation of 
existing hospitalization;* 
• Results in congenital anomaly/birth defect; 
• Results in a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions; 
• Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in the definition. For reporting purposes, also consider the occurrences 
of pregnancy as an event which must be reported as an important 
medical event. 
 
*Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered 
serious adverse events. 
• Note: In addition to the above criteria, adverse events meeting either of the 
below criteria, although not serious per ICH definition, are reportable to the 
Merck in the same timeframe as SAEs to meet certain local requirements. 
Therefore, these events are considered serious by Merck for collection 
purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
 
Pregnancy that occurs during the study must be reported as an SAE within 120 
days of completing the trial or within 30 days following cessation of treatment if 
the subject initiates new anticancer therapy. See section 7.3.3 for details on 
reporting requirements for pregnancy. 

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7.2 
Documentation of non-serious AEs or SARs 
For non-serious AEs or SARs, documentation must begin from day 1 of study 
treatment and continue through the 30-day follow-up period after treatment is 
discontinued.   
 
Collected information should be recorded in the Case Report Forms (CRF) for 
that patient.  Please include a description of the event, its severity or toxicity 
grade, onset and resolved dates (if applicable), and the relationship to the study 
drug. Documentation should occur at least monthly.  
 
NOTE: As a part of continuous monitoring for toxicity, any treatment related 
grade 4 or 5 adverse events occurring during the first cycle of concomitant 
therapy must be reported to the UNC Multicenter Project Manager at 
CPOMulticenter@med.unc.edu immediately when they occur.  
 
7.3 
SAEs or Serious SARs and Events of Clinical Interest 
7.3.1 Timing 
After informed consent but prior to initiation of study medications, only SAEs 
caused by a protocol-mandated intervention will be collected (e.g. SAEs related to 
invasive procedures such as biopsies, medication washout).  
 
For any other experience or condition that meets the definition of an SAE or a 
serious SAR, recording of the event must begin from day 1 of study treatment and 
continue through the 90-day follow-up period after treatment is discontinued (or 
to the initiation of new anti-cancer treatment, whichever is earliest).  
7.3.2 Documentation and Notification 
These events (SAEs or Serious SARs) must be recorded in the SAE console 
within OnCore® for that patient within 24 hours of learning of its occurrence.  For 
Affiliate sites, an email must also be sent to the University of North Carolina 
Cancer Network UNC Multicenter Project Manager indicating that an SAE or 
Serious SAR has been entered into Oncore (email contact will be provided at 
study start-up).  
 
In addition, SAE and SARS reports and any other relevant safety information are to 
be forwarded to the Merck Global Safety facsimile number:  +1-215-993-1220 
within 2 working days. This includes death due to any cause other than 
progression of the cancer under study that occurs to any subject from the time the 
consent is signed through 90 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related 
to Merck product.  All subjects with serious adverse events must be followed up 
for outcome. 
 

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Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Merck product that is brought to the attention 
of the investigator at any time following consent through the end of the specified 
safety follow-up period specified in the paragraph above, or at any time outside of 
the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck Global Safety. 
7.3.3 Reporting  
IRB Reporting Requirements: 
UNC: 
• The UNC-IRB will be notified of all SAEs that qualify as an 
Unanticipated Problem as per the UNC IRB Policies using the IRB’s web-
based reporting system (see section 9.5.3) within 7 days of the Investigator 
becoming aware of the problem.   
 
Affiliate sites:   
• For affiliate sites using a local IRB of record, please submit adverse events 
per local IRB policy. 
In addition, any SAEs that qualify as an Unanticipated Problem will be 
entered into Oncore and reported to the UNC IRB by the UNC Multicenter  
Project Manager using the IRB’s web-based reporting system (see section 
9.5.3) within 7 days of the Investigator becoming aware of the problem.   
 
Pregnancy 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or 
lactation in a subject (spontaneously reported to them) that occurs during the 
trial. 
 
Pregnancies and lactations that occur after the consent form is signed but before 
treatment must be reported by the investigator if they cause the subject to be 
excluded from the trial or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure.   
 
It is the responsibility of investigators or their designees to report any pregnancy 
or lactation in a subject (spontaneously reported to them), including the 
pregnancy of a male subject's female partner that occurs during the trial or 
within 120 days of completing the trial completing the trial, or 30 days 
following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, as a serious adverse event.  The patient is to be 
discontinued immediately from any protocol directed therapy. All subjects and 
female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous 

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abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious 
adverse events.  If the pregnancy continues to term, the outcome (health of 
infant) must also be reported. Such events must be reported within 24 hours to 
the Sponsor and within 2 days to Merck Global Safety. (Attn: Worldwide 
Product Safety; Fax: 215 993-1220).    
 
For Affiliate sites, the pregnancy, suspected pregnancy, or positive pregnancy 
test must be reported to the UNC Multicenter Project Manager within 24 hours 
via facsimile to 919-966-4300.  The female subject should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity 
for further evaluation and counseling. 
7.3.4 FDA Expedited Reporting requirements for studies conducted 
under an IND:  
A sponsor must report any suspected adverse reaction that is both serious and 
unexpected to the FDA. The sponsor must report an adverse event as a 
suspected adverse reaction only if there is evidence to suggest a causal 
relationship between the drug and the adverse event, such as: 
• A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure (e.g., angioedema, hepatic injury, 
Stevens-Johnson Syndrome); 
• One or more occurrences of an event that is not commonly associated 
with drug exposure, but is otherwise uncommon in the population 
exposed to the drug (e.g. tendon rupture); 
• An aggregate analysis of specific events observed in a clinical trial (such 
as known consequences of underlying disease or condition under 
investigation or other events that commonly occur in the study population 
independent of drug therapy) that indicates those events occur more 
frequently in the drug treatment group than in a concurrent or historical 
control group. 
The sponsor must submit each IND safety report on FDA Form 3500A. Each 
notification to FDA must bear prominent identification of its contents, i.e., “IND 
Safety Report,” and must be transmitted to the review division that has the 
responsibility for review of the IND. For this study, the review division is the 
Center for Drug Evaluation and Research. In each IND safety report, the sponsor 
must identify all IND safety reports previously submitted to FDA concerning a 
similar suspected adverse reaction and must analyze the significance of the 
suspected adverse reaction in light of previous, similar reports or any other 
relevant information.  
 
Timing 
FDA must be notified of potential serious risks within 15 calendar days after the 
sponsor determines the event requires reporting. FDA must be notified of 
unexpected fatal or life-threatening suspected adverse reactions as soon as 

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possible but in no case later than 7 calendar days after the sponsor’s initial receipt 
of the information. The sponsor must be notified of the SAE by the investigator 
within 24 hours of the event. If the results of a sponsor’s investigation show that 
an adverse event not initially determined to be reportable is reportable, the 
sponsor must report such suspected adverse reaction in an IND safety report as 
soon as possible, but in no case later than 15 calendar days after the determination 
is made. 
 
Follow-up 
The sponsor must promptly investigate all safety information it receives. Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such, i.e., “Follow-up IND 
Safety Report.” Additionally, upon request from FDA, the sponsor must submit to 
FDA any additional data or information that the agency deems necessary, as soon 
as possible, but in no case later than 15 calendar days after receiving the request.  
 
Notification of Investigators 
The sponsor must notify all participating investigators (i.e., all investigators to 
whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks, from clinical trials or any 
other source, as soon as possible, but in no case later than 15 calendar days after 
the sponsor determines that the information qualifies for reporting.  
 
Process 
If the sponsor deems that an event is both a serious adverse reaction (SAR) AND 
unexpected, it must also (in addition to OnCore®) be recorded on the MedWatch 
Form 3500A as per 21 CFR 312.32. Unexpected adverse events or adverse reaction 
refers to an event or reaction that is not listed in the investigator’s brochure or is not 
listed at the specificity or severity that has been observed; or if an investigator’s 
brochure is not required or available, is not consistent with the risk information 
described in the general investigation plan or elsewhere in the current IND 
application.   
 
The MedWatch form should be faxed to the UNC Multicenter Project Manager at 
919-966-4300 (or emailed, with address provided at the Start up Meeting (SIM)) 
along with supporting documentation defining the event and causality.  The UNC 
Multicenter Project Manager will then send the report to the Funding Source. The 
MedWatch 3500A form can be accessed at: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm.  
 
(Please be sure and access form 3500A, and not form 3500).  
 
Once the UNC Principal Investigator works with the sponsor to determine an event 
is a serious SAR AND unexpected, the MedWatch 3500A form will be submitted to 
the FDA.  If the event is serious, unexpected and considered to be possibly-, 
probably- or definitely-related to the study treatment, the UCCN Project Manager 

LCCC 1520 
 
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September 25, 2018 
 
 
 
Amendment 11 
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will inform the Regulatory Associate at UNC, who with the aid of the IND 
Specialist, will submit the IND Safety Report via IND serial submission to the FDA 
review division.  
 
All IND safety reports must be submitted on Form 3500A and be accompanied by 
Form 1571. The FDA must be notified or any unexpected or life-threatening 
suspected adverse reactions as soon as possible, but no later than 7 calendar days of 
learning of the event. 
 
The UNC Multicenter Project Manager will also be responsible for informing each 
Affiliate site of all serious and unexpected SARs reported to the FDA via fax as 
soon as possible.   
 
Additional Reporting Requirements 
The following additional items must be reported via IND safety report: 
• Findings from other studies. The sponsor must report any findings from 
epidemiological studies, pooled analysis of multiple studies, or clinical 
studies, whether or not conducted under an IND, and whether or not 
conducted by the sponsor, that suggest a significant risk to humans 
exposed to the drug.  
• Findings from animal or in vitro testing. The sponsor must report any 
findings from animal or in vitro testing, whether or not conducted by the 
sponsor, that suggest a significant risk in humans exposed to the drug, 
such as reports of mutagenicity, teratogenicity, or carcinogenicity, or 
reports of significant organ toxicity t or near the expected human 
exposure. 
• Increased rate of occurrence of serious suspected adverse reactions. 
 
Additional Guidance 
Please refer to 21CFR312.32 and “Guidance for Industry and Investigators: Safety 
Reporting Requirements for INDs and BA/BE Studies” for additional information 
and reporting requirements. All IND Safety Reports will be submitted in 
accordance with these regulations/guidances.  
 
Merck Reporting Requirements: 
 
As noted SAE/SAR reports and any other relevant safety information are to be 
forwarded to the Merck Global Safety facsimile number:  +1-215-993-1220 
 
All 15-Day Reports and Annual Progress Reports must be submitted as required 
to FDA. Investigators will cross-reference these reports to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally, investigators will submit a copy of these reports to Merck & Co., 
Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of 
submission to FDA. 
 

LCCC 1520 
 
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PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
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In addition to SAE and SARS reports, Non-serious Events of Clinical Interest will 
also be forwarded to Merck Global Safety and will be handled in the same manner 
as SAEs.  
 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of 
Clinical Interest (ECI). ECI must be recorded as such on the Adverse Event case 
report forms/worksheets and reported within 24 hours to the Sponsor and within 2 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 
215 993-1220) 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any 
subject must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
 
For the time period beginning at treatment through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether 
or not related to Merck product, must be reported within 24 hours to the Sponsor 
and within 24 hours to Merck Global Safety. 
 
Events of clinical interest for this trial include: 
1.  An overdose of Merck product, as defined 5.1.14  
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the 
upper limit of normal and an elevated total bilirubin lab value that is greater than 
or equal to 2X the upper limit of normal (or greater than or equal to 3X the upper 
limit of normal in patients with Gilbert’s syndrome) and, at the same time, an 
alkaline phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.* *Note: These criteria are based upon available regulatory 
guidance documents. The purpose of the criteria is to specify a threshold of 
abnormal hepatic tests that may require an additional evaluation for an underlying 
etiology.   
 
Overdose 
If a dose of Merck’s product meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the 
overdose is reported as a non-serious Event of Clinical Interest (ECI), using the 
terminology “accidental or intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 
24 hours to the Sponsor and within 2 working days hours to Merck Global Safety. 
(Attn: Worldwide Product Safety; Fax: 215 993-1220). 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
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7.4 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in 
this trial with periodic reporting to the Data and Safety Monitoring Committee 
(DSMC).  
 
Meetings/teleconferences will be held at a frequency dependent on study accrual, 
and in consultation with the study Biostatistician.  These meetings will include the 
investigators as well as protocol nurses, clinical research associates, regulatory 
associates, data managers, biostatisticians, and any other relevant personnel the 
principal investigators may deem appropriate.  At these meetings, the research 
team will discuss all issues relevant to study progress, including enrollment, 
safety, regulatory, data collection, etc. 
 
The team will produce summaries or minutes of these meetings. These summaries 
will be available for inspection when requested by any of the regulatory bodies 
charged with the safety of human subjects and the integrity of data including, but 
not limited to, the oversight (Office of Human Research Ethics (OHRE) 
Biomedical IRB, the Oncology Protocol Review Committee (PRC) or the North 
Carolina TraCS Institute Data and Safety Monitoring Board (DSMB).   
 
The UNC LCCC Data and Safety Monitoring Committee (DSMC) will review the 
study on a regular (quarterly to annually) basis, with the frequency of review 
based on risk and complexity as determined by the UNC Protocol Review 
Committee.  The UNC PI will be responsible for submitting the following 
information for review: 1) safety and accrual data including the number of 
patients treated; 2) significant developments reported in the literature that may 
affect the safety of participants or the ethics of the study; 3) preliminary response 
data; and 4) summaries of team meetings that have occurred since the last report.  
Findings of the DSMC review will be disseminated by memo to the UNC PI, 
PRC, and the UNC IRB and DSMB.   
 
 

LCCC 1520 
 
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PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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8.0 
STATISTICAL CONSIDERATIONS 
8.1 
Study Design/Study Endpoints 
This multicenter phase II trial seeks to evaluate pembrolizumab in combination 
with gemcitabine and cisplatin as neoadjuvant therapy prior to radical cystectomy 
using a Simon’s two-stage design. This is an open-label trial; therefore, the 
Sponsor, investigator, and subject will know the treatment administered. 
The study will enroll 39 evaluable patients, using a Simon’s two-stage design, 
with a primary objective of estimating the rate of pathological downstaging to 
<pT2. Secondary objectives include toxicity assessment, complete pathologic 
response rate (pT0), event-free survival (EFS), overall survival (OS), and OS at 3 
years. Exploratory objectives include an evaluation of the predictive capacity of 
PD-L1 expression, immune gene signatures, and RNA subtypes of bladder cancer, 
and a characterization of the change in phenotype in tumor-infiltrating 
lymphocytes before and after neoadjuvant therapy. 
8.2 
Sample Size and Accrual 
The primary endpoint of this study is rate of pathological downstaging, defined as 
the proportion of patients who achieve absence of muscle-invasive disease at the 
time of cystectomy (<pT2).  Based on a prior retrospective study [14] and two 
prospective randomized clinical trials (MRC/EORTC trial and Intergroup 0080 
trial) utilizing a conventional schedule of cisplatin-based neoadjuvant 
chemotherapy, the null pathological downstaging rate is 35%.[5, 16] 
 
A Simon’s two-stage minimax design will be used for this study.[66] The null 
hypothesis that the true pathological downstaging rate is 35% will be tested 
against a one-sided alternative that it is higher.  In the first stage, 21 patients will 
be accrued. If there are 8 or fewer patients with pathologic downstaging (<pT2) in 
these 21 patients, then the study will be stopped for futility, and the treatment 
regimen would be considered as uninteresting.  Otherwise, 18 additional patients 
will be accrued for a total of 39. The null hypothesis will be rejected if 19 or more 
of the 39 patients have been downstaged to <pT2, and the treatment regimen will 
be considered worthy of future investigation.  This design yields a type I error rate 
of 0.05 and power of 80% when the true response rate is 55%, representing a 20% 
improvement on the pathological downstaging rate previously reported. 
(http://cancer.unc.edu/biostatistics/program/ivanova/SimonsTwoStageDesign.asp
x)  
Accrual of 39 patients is estimated to take 3 years. 
8.3 
Continuous Monitoring for Toxicity 
Sequential boundaries will be used to suspend the trial if unacceptable toxicity is 
seen in subjects enrolled after the approval of Amendment 9 of this protocol. If 
the study reaches a stopping boundary, it may be terminated by the PI, or 
submitted to the Data and Safety Monitoring Committee with a description of the 

LCCC 1520 
 
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PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
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failures to date and a rationale for why the study should be continued. An 
unacceptable toxicity is defined as any treatment-related grade 4-5 toxicity 
through the first cycle of concomitant therapy. The accrual will be halted if the 
number of patients with unacceptable toxicities is equal to or exceeds bn out of n 
patients (see table below). This is a Pocock-type stopping boundary that yields the 
probability of crossing the boundary at most 0.10 when the rate of unacceptable 
toxicity is equal to the acceptable rate, 0.2. 
[http://cancer.unc.edu/biostatistics/program/ivanova/ContinuosMonitoringForTox
icity.aspx] 
 
Number of 
Patients, n 
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary, bn 
- 
- 
3 3 4 4 5 5 5 6 6 6 6 7 7 7 8 8 8 8 
Number of 
Patients, n 
21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39  
Boundary, bn 
9 9 9 10 10 10 10 11 11 11 11 12 12 12 13 13 13 13 14  
 
8.4 
Data Analysis Plans 
The proportion of patients who have pathological downstaging to <pT2 will be 
reported along with a 95% confidence interval. Patients who progress prior to 
surgery (expected to be a small number), and do not have surgery, will still be 
included in this estimate and will be considered to have not been downstaged.  
Similarly, the proportion of patients who have a complete response (pT0) will be 
estimated.   
 
The Kaplan-Meier method will be used to estimate median times, along with 95% 
confidence intervals, for the secondary objectives of EFS and OS, as defined in 
6.9.3 and 6.9.4. Toxicity data will be summarized and reported, and continuously 
monitored, as described in 8.3. Quality of life data from PRO will also be 
summarized and reported. To further summarize safety, we will report on 
treatment delays and the percentage of patients who are unable to proceed to 
cystectomy due to treatment-related toxicities. 
For exploratory objectives, the association of biological markers with EFS and OS 
will be analyzed using Log Rank tests and Cox regression models. Fisher’s Exact 
tests will be used to compare the response rates between subtypes of MIBC 
(basals versus luminals). For each T cell phenotype, the change in percentage of T 
cells will be calculated at the patient level, and descriptive statistics will be 
provided.  TCR and BCR repertoire profiles will be characterized as having high 
or low sequence diversity, and the association of these categorical variables with 
response rate and EFS/OS will be made using Fisher’s Exact tests and Log Rank 
tests. 
 
 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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9.0 
STUDY MANAGEMENT 
9.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s) and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
9.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Protocol Office (CPO) at the University of North 
Carolina. 
 
• A copy of the official IRB approval letter for the protocol and 
informed consent 
• IRB membership list 
• Financial Disclosures 
• CVs and medical licensure for the principal investigator and any sub-
investigators who will be involved in the study. 
• Form FDA 1572 appropriately filled out and signed with appropriate 
documentation  
• CAP and CLIA Laboratory certification numbers and institution lab 
normal values 
• Executed clinical research contract 
9.3 
Registration Procedures 
All patients must be registered with the CPO at the University of North Carolina 
before enrollment to study.  For UNC patients, prior to registration, eligibility 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
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criteria must be confirmed with the UNC Project Manager. To register a patient, 
call the Oncology Protocol Office at 919-966-7359 Monday through Friday, 
9:00AM-5:00PM.  
 
Affiliate sites: All subjects must be registered with the LCCC CPO Multicenter 
Office at the University of North Carolina before enrollment to study.  To register 
a subject call the Multicenter office at 919-966-7359 Monday-Friday 8:30 am – 
5:00 
pm 
EST. 
 
Scan 
and 
email 
the 
UNC 
Project 
Manager 
(CPOMultiCenter@med.unc.edu; preferred) or fax (919-966-4300) the registration 
form, signed informed consents, signed eligibility form and all source documents 
to confirm eligibility. Eligibility may be confirmed by the UNC Study Coordinator 
for subjects treated at UNC. When sending registration request with eligibility 
documentation, please allow 24 hours for source to be reviewed. 
 
9.4 
Data Management and Monitoring/Auditing 
The CPO of the UNC LCCC will serve as the coordinating center for this trial. 
Data will be collected through a web based clinical research platform, OnCore®.  
Other study institutions will be given a password to directly enter their own data 
onto the web site via electronic case report forms (eCRFs). UNC Multicenter 
personnel will coordinate and manage data for quality control assurance and 
integrity. 
 
All data will be collected and entered into OnCore® by Clinical Research 
Associates (CRAs) from UNC LCCC and participating institutions. The 
investigators at each site will allow monitors to review all source documents 
supporting data entered into OnCore®. The UNC Multicenter Data Coordinator 
can be reached at 919-843-2742 or 1-877-668-0683. 
 
All data will be monitored, and source data will be verified on selected subjects. 
Participating sites must send source documents to LCCC upon request, for remote 
monitoring review.  Queries will be issued on an ongoing basis on all subjects. 
Participating sites should respond to data queries within 14 days of receipt. 
 
As an investigator initiated study, this trial will also be audited by the Lineberger 
Cancer Center compliance committee every six or twelve months, depending on 
the participation of affiliate sites. 
9.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.   
9.5.1 Emergency Modifications 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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UNC and Affiliate investigators may implement a deviation from, or a change of, 
the protocol to eliminate an immediate hazard(s) to trial subjects without prior 
UNC or their respective institution’s IRB/IEC approval/favorable opinion.  
 
For Institutions Relying on UNC’s IRB: 
For any such emergency modification implemented, a UNC IRB modification 
form must be completed by UNC Research Personnel within five (5) business 
days of making the change.   
 
For Institutions Relying on Their Own IRB: 
For Affiliate investigators relying on their own institution’s IRB, as soon as 
possible after the modification has been made, the implemented deviation or 
change and the reasons for it should be submitted to: 
 
• To UNC Principal Investigator for agreement  
• The Affiliate institution’s IRB for review and approval.  (Once 
IRB’s response is received, this should be forwarded to the UNC 
Multicenter Regulatory Associate). 
9.5.2 Single Patient/Subject Exceptions 
Eligibility single subject exceptions are not permitted for Lineberger 
Comprehensive Cancer Center Investigator Initiated Trials under any 
circumstances. Other types of single subject exceptions may be allowed if 
proper regulatory review has been completed in accordance with Lineberger 
Comprehensive Cancer Center’s Single Subject Exceptions Policy.   
9.5.3 Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria:  
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 

LCCC 1520 
 
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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
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regulations, State laws, or University policies. 
 
If a deviation or violation occurs, please follow the guidelines below: 
 
For Institutions Relying on UNC’s IRB: 
Protocol Deviations: UNC or Affiliate personnel will record the deviation in 
OnCore®, and report to any sponsor or data and safety monitoring committee in 
accordance with their policies.  Deviations should be summarized and reported to 
the IRB at the time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems.   
 
For Institutions Relying on Their Own IRB: 
In addition to adhering to the policies regarding protocol compliance set forth by 
your institution’s IRB, the following is also required: 
 
Protocol Deviations: In the event a deviation from protocol procedures is 
identified, record the deviation in OnCore®. 
 
Protocol Violations: Any protocol violation that occurs must be reported to your 
IRB per institutional policies and reported to the UNC Multicenter Project 
Manager within 5 days. UNC-CH will determine if the violation affects the safety 
of the patient and integrity of the data.  Once your institution’s IRB response is 
received, please forward to the UNC Multicenter Regulatory Associate. 
 
Unanticipated Problems: 
Affiliate Sites: 
Any events that meet the criteria for “Unanticipated Problems (UPs)” as defined 
by UNC’s IRB must also be reported to the UNC Multicenter Project Manager.   
The UNC Multicenter Project Manager will report the event to the UNC IRB 
using the IRB’s web-based reporting system.  Examples of such UPs include a 
lost or stolen laptop computer that contains sensitive study information. 
 
UNC 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB must be reported by the study team using the IRB’s web-based 
reporting system.   
9.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator at UNC.  It should also 
be noted that when an amendment to the protocol substantially alters the study 
design or the potential risk to the patient, a revised consent form might be 
required.   

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
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For Institutions Relying on UNC’s IRB: 
The written amendment, and if required the amended consent form, must be sent 
to UNC’s IRB for approval prior to implementation.   
 
For Institutions Relying on Their Own IRB: 
Investigators must submit the UNC IRB approved amendment to their 
institution’s IRB for approval.  For multi-center studies, any affiliate site must 
submit their informed consent revisions to the UNC Multicenter Regulatory 
Associate prior to submission to their IRB.   
9.7 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
9.8 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act 
(FDAMA) and the Food and Drug Administration Amendments Act (FDAAA), 
the Sponsor of the trial is solely responsible for determining whether the trial and 
its results are subject to the requirements for submission to the Clinical Trials 
Data Bank, http://www.clinicaltrials.gov. Information posted will allow subjects 
to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information.     
9.9 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018 
 
 
 
Amendment 11 
80 
 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered into the eCRFs. 
Periodically, monitoring visits will be conducted and the Principal Investigator 
will provide access to his/her original records to permit verification of proper 
entry of data. At the completion of the study, all eCRFs will be reviewed by the 
Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018  
 
 
Amendment 11 
81 
 
10.0 REFERENCES 
 
1. 
Siegel, R., et al., Cancer statistics, 2014. CA Cancer J Clin, 2014. 64(1): p. 9-29. 
2. 
Nowak, A.K., B.W. Robinson, and R.A. Lake, Gemcitabine exerts a selective effect on 
the humoral immune response: implications for combination chemo-immunotherapy. 
Cancer Res, 2002. 62(8): p. 2353-8. 
3. 
Grossman, H.B., et al., Neoadjuvant chemotherapy plus cystectomy compared with 
cystectomy alone for locally advanced bladder cancer. N Engl J Med, 2003. 349(9): p. 
859-66. 
4. 
Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive 
bladder cancer: a randomised controlled trial. International collaboration of trialists. 
Lancet, 1999. 354(9178): p. 533-40. 
5. 
Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review 
and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-
analysis collaboration. Eur Urol, 2005. 48(2): p. 202-5; discussion 205-6. 
6. 
Stein, J.P., et al., Radical cystectomy in the treatment of invasive bladder cancer: long-
term results in 1,054 patients. J Clin Oncol, 2001. 19(3): p. 666-75. 
7. 
Sternberg, C.N., et al., Preliminary results of M-VAC (methotrexate, vinblastine, 
doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol, 
1985. 133(3): p. 403-7. 
8. 
Loehrer, P.J., Sr., et al., A randomized comparison of cisplatin alone or in combination 
with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial 
carcinoma: a cooperative group study. J Clin Oncol, 1992. 10(7): p. 1066-73. 
9. 
von der Maase, H., et al., Long-term survival results of a randomized trial comparing 
gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in 
patients with bladder cancer. J Clin Oncol, 2005. 23(21): p. 4602-8. 
10. 
Adamo, V., et al., Phase II study of gemcitabine and cisplatin in patients with advanced 
or metastatic bladder cancer: long-term follow-up of a 3-week regimen. Oncology, 2005. 
69(5): p. 391-8. 
11. 
Soto Parra, H., et al., Three-week versus four-week schedule of cisplatin and 
gemcitabine: results of a randomized phase II study. Ann Oncol, 2002. 13(7): p. 1080-6. 
12. 
Maughan, B.L., et al., Pooled analysis of phase II trials evaluating weekly or 
conventional cisplatin as first-line therapy for advanced urothelial carcinoma. Clin 
Genitourin Cancer, 2013. 11(3): p. 316-20. 
13. 
Hussain, S.A., et al., A study of split-dose cisplatin-based neo-adjuvant chemotherapy in 
muscle-invasive bladder cancer. Oncol Lett, 2012. 3(4): p. 855-859. 
14. 
Dash, A., et al., A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive 
urothelial carcinoma of the bladder: a retrospective experience. Cancer, 2008. 113(9): p. 
2471-7. 
15. 
Chism, D.D., M.E. Woods, and M.I. Milowsky, Neoadjuvant paradigm for accelerated 
drug development: an ideal model in bladder cancer. Oncologist, 2013. 18(8): p. 933-40. 
16. 
Griffiths, G., et al., International phase III trial assessing neoadjuvant cisplatin, 
methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-
term results of the BA06 30894 trial. J Clin Oncol, 2011. 29(16): p. 2171-7. 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018  
 
 
Amendment 11 
82 
 
17. 
Sonpavde, G., et al., Single agent taxane versus taxane-containing combination 
chemotherapy as salvage therapy for advanced urothelial carcinoma. European Urology 
(in press), 2015. 
18. 
Ko, H.J., et al., A combination of chemoimmunotherapies can efficiently break self-
tolerance and induce antitumor immunity in a tolerogenic murine tumor model. Cancer 
Res, 2007. 67(15): p. 7477-86. 
19. 
Suzuki, E., et al., Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid 
suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin 
Cancer Res, 2005. 11(18): p. 6713-21. 
20. 
Tongu, M., et al., Metronomic chemotherapy with low-dose cyclophosphamide plus 
gemcitabine can induce anti-tumor T cell immunity in vivo. Cancer Immunol 
Immunother, 2013. 62(2): p. 383-91. 
21. 
Shevchenko, I., et al., Low-dose gemcitabine depletes regulatory T cells and improves 
survival in the orthotopic Panc02 model of pancreatic cancer. Int J Cancer, 2013. 133(1): 
p. 98-107. 
22. 
de Biasi, A.R., J. Villena-Vargas, and P.S. Adusumilli, Cisplatin-induced antitumor 
immunomodulation: a review of preclinical and clinical evidence. Clin Cancer Res, 2014. 
20(21): p. 5384-91. 
23. 
Disis, M.L., Immune regulation of cancer. J Clin Oncol, 2010. 28(29): p. 4531-8. 
24. 
Dong, H.D., et al., Tumor-associated B7-H1 promotes T-cell apoptosis: A potential 
mechanism of immune evasion (vol 8, pg 793, 2002). Nature Medicine, 2002. 8(9). 
25. 
Sharpe, A.H. and G.J. Freeman, The B7-CD28 superfamily. Nat Rev Immunol, 2002. 
2(2): p. 116-26. 
26. 
Brown, J.A., et al., Blockade of programmed death-1 ligands on dendritic cells enhances 
T cell activation and cytokine production. J Immunol, 2003. 170(3): p. 1257-66. 
27. 
Francisco, L.M., P.T. Sage, and A.H. Sharpe, The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev, 2010. 236: p. 219-42. 
28. 
Thompson, R.H., et al., PD-1 is expressed by tumor-infiltrating immune cells and is 
associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res, 
2007. 13(6): p. 1757-61. 
29. 
Talmadge, J.E., M. Donkor, and E. Scholar, Inflammatory cell infiltration of tumors: 
Jekyll or Hyde. Cancer Metastasis Rev, 2007. 26(3-4): p. 373-400. 
30. 
Usubutun, A., et al., Prognostic factors in renal cell carcinoma. J Exp Clin Cancer Res, 
1998. 17(1): p. 77-81. 
31. 
Al-Shibli, K.I., et al., Prognostic effect of epithelial and stromal lymphocyte infiltration 
in non-small cell lung cancer. Clin Cancer Res, 2008. 14(16): p. 5220-7. 
32. 
Deschoolmeester, V., et al., Tumor infiltrating lymphocytes: an intriguing player in the 
survival of colorectal cancer patients. BMC Immunol, 2010. 11: p. 19. 
33. 
Diez, M., et al., Histopathologic prognostic score in colorectal adenocarcinomas. 
Anticancer Res, 1998. 18(1B): p. 689-94. 
34. 
Galon, J., et al., Type, density, and location of immune cells within human colorectal 
tumors predict clinical outcome. Science, 2006. 313(5795): p. 1960-4. 
35. 
Hiraoka, N., Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol, 2010. 15(6): p. 544-51. 

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36. 
Nobili, C., et al., Prolonged survival of a patient affected by pancreatic adenocarcinoma 
with massive lymphocyte and dendritic cell infiltration after interleukin-2 
immunotherapy. Report of a case. Tumori, 2008. 94(3): p. 426-30. 
37. 
Hodi, F.S. and G. Dranoff, The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol, 2010. 37 Suppl 1: p. 48-53. 
38. 
Kloor, M., Lymphocyte infiltration and prognosis in colorectal cancer. Lancet Oncol, 
2009. 10(9): p. 840-1. 
39. 
Hillen, F., et al., Leukocyte infiltration and tumor cell plasticity are parameters of 
aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother, 2008. 
57(1): p. 97-106. 
40. 
Lee, H.E., et al., Prognostic implications of type and density of tumour-infiltrating 
lymphocytes in gastric cancer. Br J Cancer, 2008. 99(10): p. 1704-11. 
41. 
Leffers, N., et al., Prognostic significance of tumor-infiltrating T-lymphocytes in primary 
and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother, 
2009. 58(3): p. 449-59. 
42. 
Nishimura, H., T. Honjo, and N. Minato, Facilitation of beta selection and modification 
of positive selection in the thymus of PD-1-deficient mice. J Exp Med, 2000. 191(5): p. 
891-8. 
43. 
Liotta, F., et al., Frequency of regulatory T cells in peripheral blood and in tumour-
infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma. BJU Int, 
2011. 107(9): p. 1500-6. 
44. 
Maude, S.L., et al., Chimeric antigen receptor T cells for sustained remissions in 
leukemia. N Engl J Med, 2014. 371(16): p. 1507-17. 
45. 
Kandoth, C., et al., Mutational landscape and significance across 12 major cancer types. 
Nature, 2013. 502(7471): p. 333-9. 
46. 
Herbst, R.S., et al., A study of MPDL3280A, an engineered PD-L1 antibody in patients 
with locally advanced or metastatic tumors. ASCO Meeting Abstracts, 2013. 
31(15_suppl): p. 3000. 
47. 
Soria, J., et al., Clinical activity, safety and biomarkers of PD-L1 blockade in non-small 
cell lung cancer (NSCLC): Additional analyses from a clinical study of the engineered 
antibody MPDL3280A (anti-PDL1). European Journal of Cancer, 2013. 49(Supplement 
2). 
48. 
Powles, T., et al., MPDL3280A (anti-PD-L1) treatment leads to clinical activity in 
metastatic bladder cancer. Nature, 2014. 515(7528): p. 558-62. 
49. 
Plimack, E.R., et al., LBA23 - A phase 1b study of pembrolizumab (Pembro; MK-3475) in 
patients (Pts) with advanced urothelial tract cancer. 2014. 
50. 
Rosenberg, J.E., et al., Atezolizumab in patients with locally advanced and metastatic 
urothelial carcinoma who have progressed following treatment with platinum-based 
chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet, 2016. 
51. 
Balar, A.V., et al., Atezolizumab as first-line treatment in cisplatin-ineligible patients 
with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, 
phase 2 trial. Lancet, 2017. 389(10064): p. 67-76. 
52. 
Sharma, P., et al., Nivolumab in metastatic urothelial carcinoma after platinum therapy 
(CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol, 2017. 

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53. 
Massard, C., et al., Safety and Efficacy of Durvalumab (MEDI4736), an Anti-
Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With 
Advanced Urothelial Bladder Cancer. J Clin Oncol, 2016. 34(26): p. 3119-25. 
54. 
Bellmunt, J., et al., Pembrolizumab as Second-Line Therapy for Advanced Urothelial 
Carcinoma. N Engl J Med, 2017. 
55. 
Merck, Investigator's Brochure Pembrolizumab (MK-3475). 2014. 
56. 
Zaid, H.B., et al., Trends in the utilization of neoadjuvant chemotherapy in muscle-
invasive bladder cancer: results from the National Cancer Database. Urology, 2014. 
83(1): p. 75-80. 
57. 
Splinter, T.A., et al., The prognostic value of the pathological response to combination 
chemotherapy before cystectomy in patients with invasive bladder cancer. European 
Organization for Research on Treatment of Cancer--Genitourinary Group. J Urol, 1992. 
147(3): p. 606-8. 
58. 
Schultz, P.K., et al., Neoadjuvant chemotherapy for invasive bladder cancer: prognostic 
factors for survival of patients treated with M-VAC with 5-year follow-up. J Clin Oncol, 
1994. 12(7): p. 1394-401. 
59. 
Epstein, J.I., et al., The World Health Organization/International Society of Urological 
Pathology consensus classification of urothelial (transitional cell) neoplasms of the 
urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol, 1998. 
22(12): p. 1435-48. 
60. 
Damrauer, J.S., et al., Intrinsic subtypes of high-grade bladder cancer reflect the 
hallmarks of breast cancer biology. Proc Natl Acad Sci U S A, 2014. 111(8): p. 3110-5. 
61. 
Siefker-Radtke, A., et al., The basal subtype to predict clinical benefit from neoadjuvant 
chemotherapy: Final results from a phase II clinical trial of DDMVAC plus 
bevacizumab. ASCO Meeting Abstracts, 2015. 33(Suppl 6): p. Abstr 291. 
62. 
Choi, W., et al., Identification of distinct basal and luminal subtypes of muscle-invasive 
bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell, 2014. 
25(2): p. 152-65. 
63. 
Kardos, J., et al., Claudin-low bladder tumors are immune infiltrated and actively 
immune suppressed. JCI Insight, 2016. 1(3): p. e85902. 
64. 
Levey, A.S., et al., A new equation to estimate glomerular filtration rate. Ann Intern 
Med, 2009. 150(9): p. 604-12. 
65. 
Johnson, D.B., et al., Fulminant Myocarditis with Combination Immune Checkpoint 
Blockade. N Engl J Med, 2016. 375(18): p. 1749-1755. 
66. 
Simon, R., Optimal two-stage designs for phase II clinical trials. Control Clin Trials, 
1989. 10(1): p. 1-10. 
 
 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018  
 
 
Amendment 11 
85 
 
 
11.0 APPENDICES 
 
11.1 
Appendix A:  ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Capable of only limited self-care, 
confined to bed or chair 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. 
 
 
 
 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018  
 
 
Amendment 11 
86 
 
 
11.2 
Appendix B: Patient-Reported Symptom Assessment 
 
Subject ID:___________ 
 
 
 
 
Date:_______________ 
 
Please respond to each item by marking one box per row 
 
General Health 
Excellent 
Very Good 
Good 
Fair 
Poor 
1. In general, would you say 
your health is... 
☐ 
☐ 
 
☐ 
 
☐ 
 
☐ 
 
 
 
 
 
 
 
Physical Function 
Completely 
Mostly 
Moderately 
A little 
Not at all 
2. To what extent are you able 
to carry out your everyday 
physical activities such as 
walking, climbing stairs, 
carrying groceries, or 
moving a chair? 
☐ 
 
☐ 
 
☐ 
 
☐ 
 
☐ 
 
 
 
 
 
 
 
 
 
 
 
 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018  
 
 
Amendment 11 
87 
 
 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018  
 
 
Amendment 11 
88 
 
 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018  
 
 
Amendment 11 
89 
 
 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018  
 
 
Amendment 11 
90 
 
 

LCCC 1520 
 
CONFIDENTIAL 
PI: Matthew Milowsky 
 
UNIVERSITY OF NORTH CAROLINA 
September 25, 2018  
 
 
Amendment 11 
91 
 
 
 
11.3 
Appendix C: The CKD-EPI Creatinine Equation 
The CKD-EPI creatinine equation is based on the same four variables as the MDRD Study 
equation, but uses a 2-slope spline to model the relationship between estimated GFR and serum 
creatinine, and a different relationship for age, sex and race. The equation was reported to 
perform better and with less bias than the MDRD Study equation, especially in patients with 
higher GFR. This results in reduced misclassification of CKD. As of November 2009, very few 
clinical laboratories report the estimated GFR using the CKD-EPI creatinine equation. In the 
future, other GFR estimating equations may outperform CKD-EPI.  
The CKD-EPI creatinine equation is:  
GFR = 141 x min(Scr/κ, 1)α x max(Scr/κ, 1)-1.209 0.993Age x 1.018 [if female] x 1.159 [if black] 
κ = 0.7 if female 
κ = 0.9 if male 
α = -0.329 if female 
α = -0.411 if male 
min = the minimum of Scr/κ or 1 
min = the maximum of Scr/κ or 1 
Scr = serum creatinine (mg/dL) 
 
 
 
 
 
 
 
 

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UNIVERSITY OF NORTH CAROLINA 
September 25, 2018  
 
 
Amendment 11 
92 
 
Ref: Levey AS, Stevens LA, et al. A New Equation to Estimate Glomerular Filtration Rate. Ann Intern Med. 
2009; 150:604-612.