Clinical trial NCT02768792
Conditions: Acute Myeloid Leukemia, in Relapse
Sponsor: UNC Lineberger Comprehensive Cancer Center
Start date: 2016-08-22; Completion date: 2024-06-20
Enrollment: 38 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Rationale:The purpose of this research study is to test the effectiveness of the standard high dose cytarabine (HiDAC) on days 1 through 5 followed by a single dose of pembrolizumab on day 14 as induction therapy in patients with relapsed and refractory acute myeloid leukemia (AML). Patients who achieve a response to treatment will continue on the study drug (pembrolizumab) every 3 weeks for up to 2 years maintenance therapy.

Purpose:This is a study about a new investigative drug, pembrolizumab (MK-3475) that is being studied in a clinical research trial together with standard chemotherapy (HiDAC) in relapsed and refractory AML. The study will also explore the association between potential immune biomarkers and clinical outcomes with pembrolizumab; therefore all patients will have blood and bone marrow samples collected before and after treatment to determine the dynamic nature of immune signatures pre and post-treatment.

Detailed description:
Primary Objective

1\. Estimate the objective overall rate of CR (CR+CRi) for age-adjusted HiDAC (age \<60 years: 2 gm/m2 IV Q12hours days 1-5; age \>60 years: 1.5 gm/m2 IV Q12hours days 1-5) followed by pembrolizumab 200 mg IV on day 14 in relapsed and refractory AML patients

Secondary Objectives

1. Estimate the rate of unacceptable toxicity associated with HiDAC followed by pembrolizumab as induction therapy
2. Estimate the objective overall response rates (PR+CR+CRi) for HiDAC followed by pembrolizumab.
3. Characterize the toxicity associated with HiDAC followed by pembrolizumab as induction therapy
4. Characterize the toxicity associated with pembrolizumab 200 mg IV Q3weeks when used as monotherapy maintenance after an initial response to induction phase HiDAC followed by pembrolizumab
5. Estimate the relapse-free survival (RFS) and progression-free survival (PFS) of patients receiving maintenance pembrolizumab
6. Estimate the overall survival (OS) of patients who received induction phase treatment.

Arms: arm 1: Pembrolizumab 200 mg is administered IV once as monotherapy, 14 days after the initiation of HiDAC salvage induction chemotherapy. Patients who have a response (i.e., PR/CR/CRi) to induction phase will receive maintenance pembrolizumab at 200 mg IV every 3 weeks for up to 2-years of maintenance therapy (i.e., beginning on day 1 of maintenance). Patients who are ineligible for pembrolizumab administration by day 21 will be removed from the study.
Interventions: intervention 1: pembrolizumab,
Intervention descriptions: intervention 1: Pembrolizumab 200 mg is administered IV once as monotherapy, 14 days after the initiation of HiDAC salvage induction chemotherapy. Patients who have a response (i.e., PR/CR/CRi) to induction phase will receive maintenance pembrolizumab at 200 mg IV every 3 weeks for up to 2 years of maintenance therapy (i.e., beginning on day 1 of maintenance).

Protocol documents:
Prot_SAP_000.pdf: 
LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT # 7 
 
 
LCCC 1522: : Phase 2 Study of High Dose Cytarabine Followed by Pembrolizumab in 
Relapsed and Refractory Acute Myeloid Leukemia  
 
AMENDMENT #7  INCOPORATES (CHECK ALL THAT APPLY) 
 
X Editorial, Administrative Changes  
X Scientific Changes 
X Therapy Changes 
X Eligibility Changes 
 
The purpose of this amendment is to update the eligibility criteria to reflect that liposomal 
cytarabine combined with daunorubicin (CPX-351) may be considered one of the 
allowed types of induction therapy for front-line AML that subjects must undergo prior to 
enrollment on this study. This change is the result of changes in standard of care AML 
therapy.  Also, an echocardiogram is now required as a pre-study assessment.  
 
Additional major changes to the protocol include: subjects will be allowed to receive 2 
years of pembrolizumab therapy on this clinical trial as opposed of the before allowed 1 
year of therapy, subjects will be allowed to undergo allogeneic stem cell infusion after 
greater than 21 days have elapsed as opposed to the previously mandated 30 days, an 
additional correlative objective will be assessed to determine the presence of minimal 
residual disease after pembrolizumab therapy and dose modification and supportive care 
guidelines for pembrolizumab will be based on the updated package insert 
recommendations. 
 
 
Editorial, Administrative Changes 
• Removal of UNCCN  to change to  LCCC CPO Multicenter/LCCC Multicenter 
• Added in LCCC CPO Multicenter e-mail address throughout 
“(CPOMulticenter@med.unc.edu” as a source of contact 
• Table 3- change formatting and changed title to “Dose Modifications” 
• Section 6.8 assessment of safety was clarified to indicated that only subjects who 
receive pembrolizumab will be evaluable for safety assessments. Additional 
clarification was made to sections 2.4.2 and 4.6 to clarify removing subjects from 
study due to unacceptable AEs refers to the section of the study when subjects are 
receiving pembrolizumab therapy and not the induction therapy phase. 
 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
Scientific and Therapy Change 
• Section 1.4.3- updated language to reflect updated  IB dated 29June2018 
• 
Section 1.7 – added correlative study goal #4 -“to assess for minimal residual 
disease after pembrolizumab. 
• Section  3.1.5- added “liposomal cytarabine and daunorubicin (CPX-351)”, 
• Section 4.3 - Maintenance Phase- Updated –To reflect that the allogeneic stem 
cell infusion day 0 should occur  now > 21 days after the last infusion of 
pembrolizumab 
• Section 4.10- updated to provide clarity by bulleted points  
• Section 6.1- addition of screening echocardiogram as baseline prior to treatment. 
As a pre-study assessment for a baseline for standard of care monitoring given 
risk of fluid overload in patients with AML as well as risk of myocarditis with 
pembrolizumab.  
Section 6.2- add Transthoracic Echocardiogram as a part of the assessment 
• Section  6.5- End of Treatment- Subjects are now to reach a 2 years of treatment 
• Section 6.7.4 - added “Minimal Residual Disease Analysis” for  clarity for 
Cryopreserved mononuclear cells from bone marrow aspirate and/or peripheral 
blood will be analyzed for minimal residual disease assays via flow cytometry, 
DNA or RNA PCR.  
• Section 7.3.3- updated FDA Expedited Reporting requirements – to provide 
details on FDA safety reporting  
• Section 9.2- add “Financial Disclosures” to required documents and removed 
(NOTE: this is required if UNC holds the IND.  Otherwise, the Investigator’s 
signature documenting understanding of the protocol and providing commitment 
that this trial will be conducted according to all stipulations of the protocol is 
sufficient to ensure compliance) as it is no longer needed. 
• Section 9.5- added paragraph to add more detail on monitoring and source date 
queries  
Section 9.6.2 – Updated to language to refer Lineberger Comprehensive Cancer 
Center’s Single Subject Exceptions Policy. 
• Section 9.6.3- added information on how deviation should be reported. 
• Section 11.1 –  Appendix A updated to reflect the updated IB for supportive care 
• Section 11.2 –Appendix B updated to reflect updated IB AE 
 
Eligibility Changes 
• Section  3.1.5- Inclusion Criteria updated to include “liposomal cytarabine and 
daunorubicin (CPX-351)” as part of the induction therapy for front-line AML 
 
 
 
The attached version dated June 2, 2018 incorporates the above revisions 
 
 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
 
PROTOCOL AMENDMENT # 6 
 
 
 
LCCC 1522: : Phase 2 Study of High Dose Cytarabine Followed by Pembrolizumab in 
Relapsed and Refractory Acute Myeloid Leukemia  
 
AMENDMENT #6 INCOPORATES (CHECK ALL THAT APPLY) 
 
X Editorial 
Scientific Changes 
X Therapy Changes 
 Eligibility Changes 
 
 
1) Section 4.2 Changed to clarify the inpatient duration to reflect institutional 
standards to discharge patients so that there is not a specific requirement to stay in 
the hospital until early recovery.  
2) Section 4.2.1- changed the cytarabine administration to “approximately” 2 hours, 
per institutional guidelines 
3) Section 6.1. Added footnote 13 to T&E calendar about three times weekly labs if 
patients discharged before early recovery 
4) Section 6.1 Time and events table. Added buccal swab to be collected at 
screening. Those patients who did not have buccal swab collected at screening 
should have this sample collected at any time during follow up (clarified in 
footnote 12) 
5) Sections: 6.2., 6.3.3, 6.4.1.1, 6.4.2.1: The following Section were updated to 
reflect the Thyroid function tests to be done: TSH, T3, and free T4. 
 
 
 
 
 
The attached version dated November 1, 2017 incorporates the above revisions 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT # 5 
 
LCCC 1522: Phase 2 Study of High Dose Cytarabine Followed by Pembrolizumab in 
Relapsed and Refractory Acute Myeloid Leukemia  
 
AMENDMENT #5 INCORPORATES ( Check all that apply): 
 X  Editorial 
X Scientific Changes 
   Therapy Changes 
   Eligibility Changes 
 
This protocol is amended to update definition of disease progression for PFS secondary 
endpoint based on revisions to AML Leukemia Net criteria in 2017. The protocol is 
revised to include adverse event management language provided in a Dear Investigator 
Letter issued on 10 February 2017 by Merck and Co., Inc. regarding cases of Stevens-
Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Immune-mediated 
myocarditis with pembrolizumab. 
 
Editorial 
1. Section 10 Reference #2 revised to include online reference to revised AML 
criteria in 2017.  
 
Scientific  
2. Updated sections 4.4.6 include supportive care guidelines for SJS, TEN and 
immune-mediated myocarditis. 
3. Added SJS, TEN and myocarditis to adverse events associated with 
pembrolizumab in section 5.1.6 
4. Updated section 6.9.1 to include revised definition of disease progression for PFS 
based on revisions to Leukemia Net criteria for AML in 2017 
5. Thyroid Function tests are now required and no longer optional. Thyroid function 
will be monitored periodically during pembrolizumab maintenance therapy. The 
following sections were updated to reflect this change, Time and Events table in 
section 6.1 and footnote #10 to this table, and Sections 6.2, 6.3.3, 6.4.1 and 6.4.2 
 
 
 
 
The attached version dated June 7, 2017 incorporates the above revisions 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT # 4 
 
LCCC 1522: Phase 2 Study of High Dose Cytarabine Followed by Pembrolizumab in 
Relapsed and Refractory Acute Myeloid Leukemia  
 
AMENDMENT #4 INCORPORATES ( Check all that apply): 
X   Editorial, Administrative Changes 
X   Scientific Changes 
X   Therapy Changes 
X   Eligibility Changes 
 
Editorial, Administrative 
1. Eligibility criterion 3.1.5 was subdivided for clarity 
2. Study schema in section 4.1 revised to reflect up to 2 years of maintenance 
pembrolizumab (instead of 1 year)  
3. Minor editorial changes made to Section 4.2 
4. Edit to section 4.6 duration of therapy changed from 1 year to 2 years of maintenance 
therapy with pembrolizumab 
5. Eliminated the need to obtain ECOG PS on Day 14 in the Time and Events table 
(section 6.1) and assessment section 6.3.3 
6. Editorial revision required to have section heading 6.4.1 for Year 1 of maintenance 
and the corresponding assessments as 6.4.1.1 (Day1 of each cycle) and 6.4.1.2 (After 
every 6th cycle) during year 1 of maintenance  
 
Eligibility changes 
1. Inclusion criterion 3.1.3 changed to ECOG PS = 0-1 (previously 0-2) 
 
Therapy Changes 
1. Increased duration of pembrolizumab maintenance therapy to 2 years (instead of 1 
year) as noted in Time and Event table (section 6.1) 
2. Added text to section 4.5.2 to allow for intrathecal chemotherapy on maintenance 
phase of the protocol as long as the subject is continuing to have a clinical response to 
treatment  
 
Scientific Changes 
1. Subjects receiving pembrolizumab maintenance therapy will be given the option to 
complete a quality of life (QOL) questionnaire. Assessment of QOL was added as an 
exploratory objective to section 2.3 and a corresponding endpoint was added to the 
section 2.4.3 Exploratory endpoints.  The Promis Global Health QOL assessment has 
been added as Appendix 11.1 to the protocol. This assessment was also added to the 
Time and Events table in section 6.1, footnote  #13 added to Tand E table related to 
this assessment. Mention of this optional assessment added to sections 6.4.1 and 6.4.2 
which address maintenance therapy with pembrolizumab. 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
2. Exploratory Objective (2.3.3) and exploratory endpoint (2.4.3.2) were added to assess 
for MRD after Pembrolizumab therapy 
3. Footnotes #11 and #12 to Time and Events table changed to collect additional 
biopsies and blood samples due to extension of maintenance therapy with 
pembrolizumab out to 2 years 
4. Because duration of maintenance pembrolizumab extended to year 2, new treatment 
assessment visits added i.e., 6.4.2 Year 2 of Maintenance, section 6.4.2.1 (Day 1 of 
each cycle) and section 6.4.2.2 (After every 6th cycle) during year 2.   
5. Sections 4.2.1 and 4.2.2 modified regarding dose reductions of cytarabine due to 
organ dysfunction and allowance for administration of pembrolizumab in patients 
who have had dose reductions of cytarabine 
6. Section 4.3 Maintenance section of protocol revised to allow for 2 years of 
maintenance pembrolizumab, thus bone marrow biopsies after every 4 (not 3) cycles 
of treatment (i.e., every 12 (not 9) weeks) for the first year, and then after every 6 
cycles of treatment (i.e. every 18 weeks) during years 1-2. Plus up to 34 doses (not 
17) of pembrolizumab may be administered. 
 
The attached version dated March 17, 2017 incorporates the above revisions  
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT # 3 
 
LCCC 1522: Phase 2 Study of High Dose Cytarabine Followed by Pembrolizumab in 
Relapsed and Refractory Acute Myeloid Leukemia  
 
AMENDMENT #3 INCORPORATES ( Check all that apply): 
X Editorial, Administrative Changes 
    Scientific Changes 
    Therapy Changes 
    Eligibility Changes 
 
1. A clarification was made to inclusion criterion 3.1.4 that recurrent AML will be 
defined by ≥5% myeloblasts in bone marrow aspirate and/or biopsy 
2. Added Callie Coombs to list of Co-investigators 
3. Modified section 9.4 registration procedures to allow for the UNC Site study 
coordinator to review/confirm eligibility and register patients without using the 
network (LCCC CPO Multicenter). This process only applies to the UNC Site. 
Affiliate sites must register patients through the LCCC CPO Multicenter) 
4. Minor editorial clarifications were added to Section 4.2, Section 6.1 (Time and 
Events Table Headings) and to table footnotes 2, 5, 11 and 12. Sections 6.3.4 and 
6.3.5 headings were aligned with headings revised in the Table of Assessments, and 
finally, a cross reference was corrected in Section 7.3.4.1. 
5. Corrected the heading and a footnote in the Dose Modification Table for 
Pembrolizumab in Section 4.3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The attached version dated November 9, 2016 incorporates the above revisions 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT # 2 
 
LCCC 1522: Phase 2 Study of High Dose Cytarabine Followed by Pembrolizumab in 
Relapsed and Refractory Acute Myeloid Leukemia  
 
AMENDMENT #2 INCORPORATES ( Check all that apply): 
X Editorial, Administrative Changes 
X  Scientific Changes 
     Therapy Changes 
X  Eligibility Changes 
 
A summary of revisions is provided as follows: 
1. Updated language on required contraception for male and female participants 
(inclusion criteria 3.1.19 and 3.1.2) + added Section 4.2.2.1 outlining definitions of 
adequate contraception. 
2. Revised exclusion criterion 3.2.10. 
3. Revised wording in Section 4.3.2 and Table 3 in this section. 
4. Revised and simplified instructions in section 4.4.6 to align with MERCK provided 
protocol template language. 
5. Updated overdose definition in Section 5.1.10. 
6. Removed LDH from Serum Chemistries in sections 6.2-6.3. LDH only included in 
tumor lysis labs  
7. Footnote 3 of T&E calendar, specified that pembrolizumab maintenance should be 
given every 21 days (instead of 3 weeks) +/- 3 days to accommodate clinic schedules 
and holidays. This change was noted in 6.4.1 as well.  
8. Revised wording in 6.4.2 to make bone marrow biopsies LESS frequent ie, Bone 
marrow biopsy should be performed after treatment of every 4th cycle at least 1 day 
prior to the next treatment cycle.  
9. Footnote 11of T&E calendar revised to indicate repeat biopsy after every 4 cycles of 
maintenance.  
10. Updated language in 7.1.4 to include additional Merck definitions of reportable AEs 
11. Revised Merck Reporting requirements in section (7.3.4) to align with MERCK 
provided protocol template language.  
12. Section 7.3.4.1 Events of clinical interest (ECI) provides updated definitions/MERCK 
reporting requirements for ECI  
13. Section 7.3.4.2 defines reportable pregnancy events and requirement for reporting 
these events to MERCK 
14. Section 7.3.4.3 defines protocol-specific exceptions to SAE reporting 
15. Typos corrected in Table in Section 8.2 outlining Pocock-stopping boundaries  
16. Updated list of co-investigators on the title page of the protocol 
17. Revised language around treatment for hyperphosphatemia in section 4.4.5 
 
The attached version dated August 24, 2016 incorporates the above revisions 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
PROTOCOL AMENDMENT # 1 
 
LCCC 1522: Phase 2 Study of High Dose Cytarabine Followed by Pembrolizumab in 
Relapsed and Refractory Acute Myeloid Leukemia  
 
AMENDMENT #1 INCORPORATES ( Check all that apply): 
X Editorial, Administrative Changes 
    Scientific Changes 
X Therapy Changes 
X  Eligibility Changes 
 
AMENDMENT RATIONALE AND SUMMARY 
Editorial Administrative changes 
Minor editorial changes made throughout:  
• Removed Dr. Voorhees as Co-Investigator  
• Requirement of collection of some tissue samples has been removed  ( section 
6.7.4) 
Eligibility 
• On page 14 under Inclusion Criteria- 3.1.5- it should state the following: ‘Must 
have received at least 1 cycle of induction therapy for front-line AML including 
cytarabine continuous infusion + anthracycline +/- cladribine or etoposide for 1 or 
2 cycles.’’ 
• cladribine in the above sentence which is a standard therapy that patients receive 
for front-line AML. 
• On page 15 Eligibility 3.1.12 deleted   
Samples 
• Section 6.7.4 Minimal Residue disease assessment removed as these samples will 
not be shipped to MMS-NHLBI at NIH in Bethesda. 
• Section 1.7 Correlative Studies 
Objective # 6 removed since the minimal residue assessment will not be done at this 
point 
 
 
The attached version dated August 24, 2016 incorporates the above revisions 
 
 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC 1522: Phase 2 Study of High Dose Cytarabine Followed by Pembrolizumab in 
Relapsed and Refractory Acute Myeloid Leukemia  
 
 
Principal Investigator 
Joshua F. Zeidner, MD 
Department of Medicine 
Division of Hematology/Oncology 
170 Manning Drive, 3rd floor 
Physicians Office Building, CB# 7305 
Chapel Hill, NC 27599-7305 
919-962-5164 (PHONE) 919-966-7748 (FAX) 
Email: Joshua_Zeidner@med.unc.edu 
 
Non-UNC Co-Investigators:  
Ivana Gojo, MD, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center 
 
Biostatistician  
Anastasia Ivanova, PhD 
aivanova@bios.unc.edu 
919-843-8086 (PHONE) 
 
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 
 
University of North Carolina LCCC Multicenter Project Manager: 
Phone: 919-966-7359 
Fax: 919-966-4300 
Email: CPOMulticenter@med.unc.edu 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
Funding Source: Merck, Inc.  
Version: Amendment #7 
Version Date: June 02, 2018 
 
IND#129615


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC 1522: Phase 2 Study of High Dose Cytarabine Followed by Pembrolizumab in 
Relapsed and Refractory Acute Myeloid Leukemia  
 
Principal Investigator 
Joshua F. Zeidner, MD. 
Department of Medicine 
Division of Hematology/Oncology 
170 Manning Drive, 3rd floor 
Physicians Office Building, CB# 7305 
Chapel Hill, NC 27599-7305 
919-962-5164 (PHONE) 919-966-7748 (FAX) 
Email: Joshua_Zeidner@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:  
 
PI Signature: ___________________ 
 
Date: ____________________ 
 
Version Date: June 02, 2018 
 
 


LCCC 1522 
 
CONFIDENTIAL 
PI: Zeidner 
 
UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
Amendment 07 
 
 
i 
TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE ..................................................................4 
1.1 
Study Synopsis ......................................................................................................4 
1.2 
Relapsed and Refractory AML .............................................................................4 
1.3 
Cytarabine .............................................................................................................5 
1.4 
Pembrolizumab......................................................................................................6 
1.5 
Rationale for Pembrolizumab in AML................................................................10 
1.6 
Rationale for HiDAC Salvage Chemotherapy Followed by Pembrolizumab .....11 
1.7 
Correlative Studies ..............................................................................................12 
2.0 
STUDY OBJECTIVES .........................................................................................12 
2.1 
Primary Objective ...............................................................................................12 
2.2 
Secondary Objectives ..........................................................................................13 
2.3 
Exploratory Objectives ........................................................................................13 
2.4 
Endpoints .............................................................................................................13 
3.0 
PATIENT ELIGIBILITY ....................................................................................14 
3.1 
Inclusion Criteria .................................................................................................14 
3.2 
Exclusion Criteria ................................................................................................16 
4.0 
TREATMENT PLAN ...........................................................................................19 
4.1 
Schema ................................................................................................................19 
4.2 
Induction Phase ...................................................................................................19 
4.3 
Maintenance Phase ..............................................................................................24 
4.4 
Rescue Medications & Supportive Care .............................................................28 
4.5 
Concomitant Medications/Vaccinations (allowed & prohibited)........................33 


LCCC 1522 
 
CONFIDENTIAL 
PI: Zeidner 
 
UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
Amendment 07 
 
 
ii 
4.6 
Duration of Therapy ............................................................................................34 
4.7 
Duration of Follow-Up ........................................................................................34 
4.8 
Removal of Patients from Protocol Therapy .......................................................35 
4.9 
Patient Replacement ............................................................................................35 
4.10 
Study Withdrawal ................................................................................................35 
5.0 
DRUG INFORMATION ......................................................................................36 
5.1 
Pembrolizumab....................................................................................................36 
5.2 
Cytarabine ...........................................................................................................40 
5.3 
Adverse Events Associated with Cytarabine ......................................................41 
6.0 
EVALUATIONS AND ASSESSMENTS ............................................................42 
6.1 
Time and Events Table ........................................................................................42 
6.2 
Pre-Study Assessments .......................................................................................46 
6.3 
Treatment Assessments-INDUCTION CYCLE (CYCLE 1)..............................46 
6.4 
Treatment Assessments-Maintenance .................................................................48 
6.5 
End of Treatment .................................................................................................49 
6.6 
Follow-up ............................................................................................................50 
6.7 
Correlative Studies Procedures ...........................................................................50 
6.8 
Assessment of Safety ..........................................................................................51 
6.9 
Assessment of Efficacy .......................................................................................51 
7.0 
ADVERSE EVENTS ............................................................................................52 
7.1 
Definitions ...........................................................................................................52 
7.2 
Documentation of non-serious AEs or SARs ......................................................54 
7.3 
SAEs or Serious SARs and Events of Clinical Interest ......................................55 
7.4 
Data and Safety Monitoring Plan ........................................................................61 


LCCC 1522 
 
CONFIDENTIAL 
PI: Zeidner 
 
UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
Amendment 07 
 
 
iii 
8.0 
STATISTICAL CONSIDERATIONS ................................................................62 
8.1 
Study Design and Sample Size ...........................................................................62 
8.2 
Continuous Monitoring for Toxicity ...................................................................62 
8.3 
Data Analysis Plans .............................................................................................63 
9.0 
STUDY MANAGEMENT ....................................................................................64 
9.1 
Institutional Review Board (IRB) Approval and Consent ..................................64 
9.2 
Required Documentation.....................................................................................64 
9.3 
Compliance with Trial Registration and Results Posting Requirements ............65 
9.4 
Registration Procedures.......................................................................................65 
9.5 
Data Management and Monitoring/Auditing ......................................................65 
9.6 
Adherence to the Protocol ...................................................................................66 
9.7 
Amendments to the Protocol ...............................................................................68 
9.8 
Record Retention .................................................................................................68 
9.9 
Obligations of Investigators ................................................................................69 
10.0 REFERENCES ......................................................................................................70 
11.0 Appendices .............................................................................................................74 
11.1 
Quality of Life Assessment ................................. Error! Bookmark not defined. 


LCCC 1522 
 
CONFIDENTIAL 
PI: Zeidner 
 
UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
Amendment 07 
 
 
4 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
This is an open-label, single arm, multicenter phase 2 study of standard salvage 
high dose cytarabine (HiDAC) on days 1 through 5 followed by a single dose of 
the humanized monoclonal antibody targeted against cell surface receptor 
programmed cell death-1 (PD-1), pembrolizumab, on day 14 as induction therapy 
in patients with relapsed and refractory acute myeloid leukemia (AML). Patients 
who achieve at least a partial response (PR) post-induction will continue on 
pembrolizumab every 3 weeks for up to 1 year of maintenance therapy. We plan 
to enroll 37 patients in a Simon’s two-stage design.  
 
The hypothesis of this study is that HiDAC followed by pembrolizumab will be 
effective in relapsed and refractory AML with a combined complete remission 
(CR)/CR with incomplete recovery (CRi)) rate of >40%, superior to a historical 
control of 20%. We also hypothesize that the rate of unacceptable toxicity 
associated with HiDAC followed by pembrolizumab will not significantly exceed 
20% (see section 2.4.2). Secondary endpoints include toxicity of this combination 
when used as induction, overall objective response rate (CR+CRi +PR) post-
induction, toxicity of pembrolizumab maintenance in those patients with a 
response after induction, and progression-free survival (PFS), relapse-free 
survival (RFS) and overall survival (OS) in patients who receive maintenance 
pembrolizumab. We will also explore for an association between potential 
immune biomarkers and clinical outcomes with pembrolizumab. The overarching 
goals of these correlative studies are: 1) to identify and characterize mechanisms 
involved in T cell dysfunction in AML, 2) to identify potential predictive 
biomarker candidates to allow better selection of AML patients who may benefit 
from pembrolizumab, and 3) to identify new pathways that could be targeted to 
enhance the efficacy of pembrolizumab in AML. 
1.2 
Relapsed and Refractory AML 
AML has an extremely poor prognosis with conventional chemotherapy agents. 
While approximately 70% of patients are expected to achieve a CR following 
intensive induction chemotherapy, the majority of these patients ultimately 
relapse and die of AML.1 The European LeukemiaNet analyzed the 3-year 
relapse-free survival (RFS) rates of 1,550 patients treated on front-line Cancer and 
Leukemia Group B (CALGB) studies in AML between 1985 and 2006. Patients 
were stratified on this study based on cytogenetic and molecular risk factors into 4 
risk groups: favorable, intermediate-1, intermediate-2 and adverse. The 3-year 
RFS rates were 55%, 23%, 34%, and 10% among younger (<60 years) patients in 
the favorable, intermediate-1, intermediate-2, and adverse risk groups, 
respectively. In comparison, older patients (>60 years) had distinctively worse 
outcomes across each subset with 3-year RFS rates of 24%, 10%, 11%, and 6% 
among favorable, intermediate-1, intermediate-2, and adverse risk, respectively.2  


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Patients who do not respond to intensive induction chemotherapy (i.e., primary 
refractory disease) have an even worse outcome with an overall response rate of 
<20% with salvage chemotherapy agents.3 Long-term survival in primary 
refractory AML patients is <5-10%.4   In contrast, the overall outcome of patients 
with relapsed AML is dependent on multiple factors such as total duration of CR, 
age, performance status, cytogenetics/molecular markers, and previous allogeneic 
stem cell transplantation.5 Based on these factors, Breems et al. stratified first 
relapse patients into 3 prognostic groups: favorable, intermediate and poor-risk. 
One-year overall survival (OS) was 70%, 49% and 16%, for favorable, 
intermediate, and poor-risk relapsed AML patients, respectively. 5  
 
Advanced age appears to be the most negative predictor of overall outcome in 
patients with relapsed AML. Rowe et al. reported in abstract form results from 
various Eastern Cooperative Oncology Group (ECOG) studies of 362 patients 
>55 years who initially achieved a CR with induction therapy. Sixty-five percent 
of these patients subsequently relapsed with a median overall survival (OS) <5 
months and 5-year OS of 6% after disease relapse.6,7  
 
The management of relapsed and refractory AML continues to be a major 
challenge. There is no accepted standard chemotherapeutic regimen for relapsed 
and refractory AML. A multitude of chemotherapeutic regimens exist but none of 
these regimens have consistently proven to be superior. High dose cytarabine 
(HiDAC) 3 gm/m2 administered intravenously (IV) Q12hours for 12 doses is one 
commonly used treatment in this setting, and has been evaluated with and without 
the addition of anthracyclines in patients with relapsed and refractory AML. Data 
on this regimen are summarized in the next section. 
1.3 
Cytarabine 
Cytarabine (cytosine arabinoside) is a nucleoside analog that incorporates into 
human DNA in the S phase of the cell cycle. Cytarabine is widely considered the 
most effective anti-leukemic chemotherapeutic agent in AML. HiDAC, with and 
without anthracyclines, has been evaluated in 78 relapsed and refractory AML 
patients (age range: 12-72 years). Thirty-four of these patients received HiDAC 
alone (3 gm/m2 IV Q12hours days 1-6) and 44 patients received HiDAC (same 
dose and schedule) + daunorubicin 30 mg/m2 IV days 7-9. The overall CR rates 
were similar between HiDAC and HiDAC + daunorubicin (44% vs. 59%, 
respectively; p=0.09). Median duration of response was only 5 months in both 
arms. In the HiDAC alone arm, there was a clear difference in CR rates between 
relapsed disease (CR rates = 63%) and primary refractory AML (CR rates = 
20%).  
 
In the HiDAC alone arm, all patients achieved bone marrow aplasia, and 91% of 
patients in both arms developed fevers. The percentage of patients with non-
hematologic toxicities by organ system in the HiDAC alone arm were as follows: 


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eye (23% when eye drops were used; 76% when they were not); skin (32%), 
nausea and vomiting (88%), diarrhea (39%), and abnormal liver chemistries 
(79%). Moreover, 12% of patients had CNS toxicity with HiDAC alone, typically 
manifested as mild-moderate neurologic impairment, with 6% (n=2) experiencing 
Grade 3 CNS toxicity that resolved after treatment discontinuation.8 For 
additional information regarding adverse events and possible risks of cytarabine, 
please see section 5.0.  
 
Recent studies have suggested that cytarabine alone has response rates 15-20% in 
relapsed and refractory AML patients. A randomized phase III study compared 
vosaroxin + cytarabine versus cytarabine alone (1 gm/m2 IV daily for 5 days) in 
relapsed and refractory AML patients. The CR rate for patients on the vosaroxin + 
cytarabine arm was 30% versus 16% in patients on the cytarabine only arm.9 An 
international randomized phase III study of elacytarabine compared with 
physicians choice, which included high dose cytarabine, also showed CR rates of 
approximately 20% in the physician’s choice arm. 10Additionally, a randomized 
phase II study by ECOG recently compared three different promising regimens 
for relapsed and refractory AML: Arm A: carboplatin + topotecan, Arm B: 
flavopiridol + cytarabine + mitoxantrone (FLAM), Arm C: Sirolimus + 
Mitoxantrone + Etoposide + Cytarabine. FLAM was shown to be the most 
effective regimen in this trial, with a CR rate of 28%, while Arm A and Arm C 
produced CR rates of 14% and 15%, respectively.11  
 
It is unclear whether 3 gm/m2 of cytarabine is necessary and whether this dose is 
superior to 2 gm/m2. Moreover, high doses of cytarabine (>2 gm/m2) appear to 
increase the risk for cerebellar toxicity, especially in older patients and those with 
renal disease.12 HiDAC at doses of 1-2 gm/m2 has also been evaluated in 
combination with other chemotherapy agents in relapsed and refractory AML 
patients, such as topoisomerase inhibitors (mitoxantrone and etoposide),3,13-15 
fludarabine16, cladribine17,18, and clofarabine.19,20 Response rates seen with these 
combinations range from 20-50% (median duration of response <9 months), with 
significant toxicities; 30-day mortality rates of these regimens range from 10-
30%.  
 
Given these data, there is a high unmet need to develop safe and effective novel 
therapeutic regimens for patients with refractory and relapsed AML. 
Investigational therapies are warranted in relapsed and refractory AML and are 
highly recommended over other conventional chemotherapy regimens.21,22 
1.4 
Pembrolizumab 
Pembrolizumab (MK-3475) is a potent and highly selective IV humanized 
monoclonal antibody (mAb) of the immunoglobulin (Ig) G4/kappa isotype that 
directly blocks the interaction between Programmed Death-1 (PD-1) and its 
ligands, PD-L1 and PDL-2. This immune checkpoint blockade enhances 
functional activity of the target lymphocytes to facilitate an antitumor immune 


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response, leading to tumor regression and immune rejection of the tumor. 
Indications currently under investigation by the manufacturer of pembrolizumab 
include non-small cell lung cancer (NSCLC) and glioblastoma. KeytrudaTM 
(Pembrolizumab) has recently been approved (at a dose of 2 mg/kg IV every 3 
weeks) in the United Stated for the treatment of patients with unresectable or 
metastatic melanoma and disease progression following ipilumumab and, if 
BRAF V600 mutation positive, a BRAF inhibitor. Further development of 
pembrolizumab in non-metastatic melanoma is ongoing. See section 5.1 and the 
latest pembrolizumab prescribing information and Investigator’s Brochure for 
detailed information. 
1.4.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of 
neoplastic transformation has been known for decades.23 Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes (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. 
 
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 that has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2). 29,30 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, all of 
which are involved in the CD3 T-cell signaling cascade.29,31-33 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.34  
PD-1 is expressed on activated lymphocytes including peripheral CD4+ and CD8+ 
T-cells, B-cells, T regs and Natural Killer cells.35,36  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well 
as subsets of macrophages and dendritic cells.37   
 


L C C C 1 5 2 2  
 
C O N FI D E N TI A L  
PI:  Zei d ner  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
J u ne 0 2, 2 0 1 8   
 
A me n d me nt 0 7  
 
 
8 
T he li ga n ds f or P D- 1 ( P D - L 1 a n d P D-L 2) are c o nstit uti vel y e x presse d or ca n be 
i n d uce d i n a vari et y of cell t y p es, i ncl u di n g n o n-he mat o p oietic tiss ues as well as 
i n vari o us t u m ors.3 7 -4 0  B ot h li ga n ds are t y pe I tra ns me m bra ne rece pt ors 
c o ntai ni n g b ot h I g V- a n d I g C -li ke d o mai ns i n t he e xtracell ular re gi o n a n d s h ort 
c yt o plas mic re gi o ns wit h n o k n o w n si g nali n g m otifs.  Bi n di n g of eit her P D- 1 
li ga n d t o P D- 1 i n hi bits T-cell acti vati o n tri g gere d t hr o u g h t he T-cell rece pt or.  
P D - L 1 is e x presse d at l o w le vels o n vari o us n o n-he mat o p oietic tiss ues, m ost 
n ota bl y o n vas c ular e n d ot heli u m, w hereas P D- L 2 pr otei n is o nl y detecta bl y 
e x presse d o n a nti ge n- pr ese nti n g cells f o u n d i n l y m p h oi d tiss ue or c hr o nic 
i nfla m mat or y e n vir o n me nts.  P D- L 2 is t h o u g ht t o c o ntr ol i m m u ne T-cell 
acti vati o n i n l y m p h oi d or ga ns, w hereas P D- L 1 ser ves t o da m pe n u n warra nt e d T-
cell f u ncti o n i n peri p heral tiss ues. 3 4  Alt h o u g h healt h y or ga ns e x press little (if 
a n y)  P D - L 1, a v ariet y of ca ncers are k n o w n t o e x press a b u n da nt le v els of t his T-
cell i n hi bit or.  P D- 1 has bee n s u g geste d t o re g ulat e t u m or-s pecifi c T-cell 
e x pa nsi o n i n s u bjects wit h mela n o ma ( M E L). 4 1  T his s u g gests t hat t he P D- 1/ P D-
L 1 pat h w a y pla ys a critical r ole i n t u m or i m m u ne e vasi o n a n d s h o ul d be 
c o nsi dere d as a n attr acti v e tar get f or t hera pe utic i nter ve nti o n.  
1. 4. 2  Precli nic al Fi n di n gs  
I n precli nical st u dies, T-l y m p h oc yte res p o nses i n cells fr o m healt h y h u ma n 
s u bjects, patie nts wit h ca ncer, as well as i n pri mat es were str o n gl y e n ha n ce d b y 
pe m br oliz u ma b. T he E C 5 0 (i.e., c o nce ntrati o n i n w hic h 5 0 % of t he ma xi m u m 
effect is see n) i n h u ma n d o n or bl o o d cells e x p ose d t o pe m br oliz u ma b has bee n 
re p orte d t o be b et wee n ~ 0. 1 a n d 0. 3 n M base d o n T-cell acti vati o n assa ys, a n d 
le vels of c yt o ki nes, i ncl u di n g b ut n ot li mite d t o i nterle u ki n-2 (I L - 2), t u m or 
necr osis fact or al p ha ( T N F α) a n d i nterfer o n ga m m a (I F N ) w ere c ha n ge d b y t his 
a nti b o d y. Of n ote, pe m br oliz u ma b d oes n ot i m pact i m m u ne res p o nses u nless 
a nti ge n is pr ese nt.   I n s y n ge n eic m uri ne t u m or m o dels, a n a nti- m uri ne P D- 1 
a nal o g si g nifi ca ntl y i n hi bite d t u m or gr o wt h, a n d w as s y n er gistic wit h 
c he m ot hera p y a ge nts r es ulti n g i n i ncreas e d c o m pl ete t u m or re gressi o n rates.  
 
Safet y p h ar mac ol o g y/t o xic ol o g y st u dies of pe m br oliz u ma b were c o n d ucte d i n 
c y n o m ol g us m o n ke ys a n d i ncl u de d b ot h a 1- m o nt h a n d 6- m o nt h re peat d osi n g 
peri o d st u d y. T h e ma xi m u m d ose a d mi nistere d i n eac h  w as 2 0 0 m g/ k g, 
a d mi nistere d wee kl y i n t he 1- m o nt h st u d y a n d e v er y ot her w ee k i n t he 6- m o nt h 
st u d y.  T he a nti b o d y w as well t olerate d i n b ot h st u dies, wit h a n i ncrease d 
i nci de nce of i n g ui nal s w elli n g a n d i ncreas e d s ple nic wei g hts at t he 2 0 0 m g/ k g 
d ose t he o nl y n ota bl e fi n di n gs i n t he 1- m o nt h st u d y, neit her of w hic h was 
c o nsi dere d a d vers e. A nti- pe m br oli uz ma b a nti b o dies were detecte d i n b ot h st u dies, 
b ut n ot at t he 2 0 0 m g/ k g d ose. F urt her, base d o n t he le vel of tar get e n ga ge me nt, 
t he a nti b o dies d o n ot see m t o i m pact pe m br oliz u ma b p har mac o d y n a mics. T he n o 
o bser va ble a d v ers e effect le vel ( N O A E L) bas e d o n b ot h st u dies is 
≥2 0 0 m g/ k g/ d os e. See t he m ost rece nt pe m br oliz u ma b I n v esti gat or’s Br oc h ure f or 
a d diti o nal details.  


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1.4.3 Clinical Findings 
Pharmacokinetics and Dosing 
Pharmacokinetic (PK) parameters were assessed during an open-label phase I trial 
of pembrolizumab  (NCT01295827) that evaluated three dose levels of 
monotherapy in patients with advanced solid tumors (1mg/kg, 3mg/kg, and 
10mg/kg every 2 weeks). No dose-limiting toxicities (DLTs) were observed and 
all three dose levels were well-tolerated. This first in human study of 
pembrolizumab showed evidence of target engagement and objective evidence of 
tumor size reduction at all dose levels evaluated.  No maximally tolerated dose 
(MTD) has been identified to date. 
 
Two dose levels are being evaluated in several phase II or III trials in metastatic 
melanoma and NSCLC (2mg/kg and 10mg/kg every 3 weeks) (NCT01704287, 
NCT01905657) after initial data showed that every 2 week and 3 week dosing 
appeared equivalent. Based on these studies, it was determined that 2mg/kg and 
10mg/kg dosing in melanoma had similar efficacy and safety with flat exposure-
response relationships of pembrolizumab for efficacy and safety in the dose range 
of 2-10mg/kg q3weeks. In addition, there was no effect of tumor burden or 
disease indication on the distribution behavior of pembrolizumab as assessed by a 
population pharmacokinetic model. The half-life of pembrolizumab is estimated 
at 14-21 days. 
 
A population pharmacokinetic (PK) analysis of pembrolizumab has been 
performed using serum concentration time data from 476 patients. Within the 
resulting population PK model, clearance and volume parameters of 
pembrolizumab 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 supports both body weight 
normalized dosing or a fixed dose across all body weights (Merck, written 
communication).   
 
The choice of the 200 mg every 3 weeks as an appropriate dose for the switch to 
fixed dosing of pembrolizumab (which is pending FDA approval, and which is 
incorporated into this study) 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 (the current FDA approved dose), 
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 (Merck, written communication).  The fixed dosing 
regimen will also reduce potential for dosing errors and reduce the complexity 
associated with weight-based dosing.  
 
Clinical Safety 


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As of June 2017 pembrolizumab monotherapy and combination therapy have 
been administered to, 14,0444 subjects, with hematologic malignancies and solid 
tumors, in a total of 19 Phase I, II, and III clinical trials sponsored by Merck. 
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 AE, 
and 2062 (73.7%) experienced 1 or more AE reported as drug-related by the 
investigator.  Various dose-schedules, including 10mg/kg administered IV over 
30 minutes every 2 weeks, have been studied. The most commonly reported 
treatment emergent adverse events (TEAEs) experienced in monotherapy trials 
are fatigue (37.3%), nausea (24.5%), decreased appetite (22.5%), cough (22.0%), 
pruritus (20.1%), dyspnea (19.1%), arthralgia (18.0%), diarrhea (22.3%) and rash 
(17.8%).  
 
1.5 
Rationale for Pembrolizumab in AML 
Models of AML suggest that the PD-1 pathway is exploited by leukemic cells to 
evade immune surveillance.42-48 Tumor progression in a murine AML model was 
associated with up-regulation of PD-1 on CD8+ T cells and an increase in 
regulatory T cells (Tregs).42 These experiments further demonstrated that PD-1 
knockout mice had less leukemia burden and increased OS upon AML challenge 
compared to wild-type mice, despite the presence of a similar percentage of 
Tregs. Blockade of PD-L1, furthermore, led to an increase in proliferation of 
CD8+ T cells specific for leukemic blasts and reduced leukemic burden.42 Thus, 
the interaction between PD-1 and PD-L1 can facilitate Treg-induced suppression 
of CD8+ effector T cells (Teff) and dampen the anti-tumor immune response. In 
primary leukemia samples, PD-L1 was shown to be up-regulated on AML blasts 
(including de novo expression), more so at relapse than at diagnosis, and was 
induced by inflammatory molecules, such as IFN- γ and TNF-α.43,44 These data 
suggest that leukemia cells up-regulate expression of PD-L1 in the setting of 
inflammation, such as after receiving chemotherapy.  
 
Up-regulation of PD-L1 and PD-L2 was also seen on leukemic cells after initial 
T-cell activation, which led to suppression of T helper response and cytokine 
production, with a resultant increase in Tregs. Blocking the PD-1 pathway on 
these leukemic cells with a PD-1-Ig fusion protein largely abolished this 
suppression. An intriguing phenomenon of “adaptive resistance” was seen in 
these experiments, whereby initial expression of co-stimulatory molecules on 
AML blasts, such as CD86 and ICOS ligand, led to specific T-cell expansion and 
activation. Leukemic cells in turn up-regulate PD-L1 and other co-inhibitory 
molecules and down-regulate co-stimulatory molecules in order to suppress 
subsequent T-cell activation.46,47 This concept of adaptive resistance is also 
supported by data suggesting that the presence of co-stimulatory molecules such 
as CD-86 and ICOS ligand were associated with worse outcomes in AML, as T-
cell activation eventually contributes to induction of immune escape mechanisms 
(i.e., PD-1/PD-L1 and CTLA-4).48 Recently, Kronig et al.45 demonstrated that 


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IFN- γ induced PD-L1 expression in AML patients in CR and relapse more so 
than at initial diagnosis. The increased PD-L1 expression observed in these 
patients was due to both up-regulation as well as de novo expression on 
previously PD-L1 negative precursor cells. These data further support the concept 
of adaptive resistance in AML, whereby tumor cells utilize the PD-1/PD-L1 
pathway for tissue protection in light of an ongoing anti-tumor immune 
response.45-48   
1.6 
Rationale for HiDAC Salvage Chemotherapy Followed by Pembrolizumab  
There is no accepted standard chemotherapeutic regimen for patients with 
relapsed or refractory AML. High doses of cytarabine (1-3 gm/m2) have been 
shown to be effective in induction, consolidation, and the treatment of relapsed 
and refractory disease.8,12,49 The MTD of cytarabine is 3 gm/m2 administered 
every 12 hours for up to 12 doses.8 However, 3 gm/m2 increases the risk for 
cerebellar toxicities (as outlined earlier), conjunctival toxicities, and prolonged 
myelosuppression. Further, patients >60 years appear to have heightened toxicity 
with HiDAC with increased rates of cerebellar toxicity.12 It is also unclear 
whether 3 gm/m2 is superior to moderate doses (i.e., 1-2 gm/m2) of cytarabine, the 
latter doses which have been investigated in combination with other 
chemotherapy agents. Based on these considerations, we plan to administer age-
adjusted HiDAC (age <60 years: 2 gm/m2 IV Q12hours days 1-5 for a total of 10 
doses; age >60 years: 1.5 gm/m2 IV Q12hours days 1-5 for a total of 10 doses) to 
minimize toxicities at the time of pembrolizumab administration on day 14.  
Investigational agents and regimens remain the priority in relapsed and refractory 
AML.21,22 Chemotherapy is hypothesized to exacerbate immune exhaustion in 
tumor cells.50 HiDAC provides an effective anti-leukemic cytotoxic effect, but 
response rates are low and not durable (see section 1.3). Pembrolizumab will be 
administered on day 14, 9 days after the completion of HiDAC chemotherapy, 
while patients are still aplastic.  
 
The common toxicities of pembrolizumab outlined in section 1.4.3 do not overlap 
with the major toxicities of cytarabine, and the mechanism of action of each is 
unique. Therefore, we expect no more than additive toxicity.  Further, 
pembrolizumab administration will not be given concomitantly with cytarabine, 
but on day 14, 9 days after cytarabine therapy is completed.  Additionally, 
delaying pembrolizumab until day 14 should theoretically create a maximally 
exhausted immune state in leukemia cells due to “adaptive resistance” after 
chemotherapy (see section 1.5). Patients who achieve a response (i.e., 
PR/CR/CRi) to the induction phase will receive pembrolizumab 200 mg IV 
Q3weeks maintenance treatment to prevent or delay relapse from occurring by 
potentially creating a long-lasting anti-leukemic immune effect. 
 
In this trial, toxicity will be monitored continuously, with sequential boundaries 
employed to suspend the trial if excessive toxicity is seen. If the study reaches a 
stopping boundary, it may be terminated by the PI, or submitted to the Data and 


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Safety Monitoring Committee (DSMC) with a description of the toxicities and a 
rationale for why the study should be discontinued.   
1.7 
Correlative Studies 
We will be conducting a comprehensive, multifaceted correlative approach to 
evaluate leukemic cells and host immune responses before and after 
pembrolizumab treatment. The overarching goals of these correlative studies are: 
1) to identify and characterize mechanisms involved in T cell dysfunction in 
AML, 2) to identify potential predictive biomarker candidates to allow better 
selection of AML patients who may benefit from pembrolizumab, 3) to identify 
new pathways that could be targeted to enhance the efficacy of pembrolizumab in 
AML, and 4) to assess for minimal residual disease after pembrolizumab. To 
accomplish these goals, we will perform Multiplex next generation sequencing of 
DNA and RNA from tumor cells, comprehensive kinome analyses to seek 
predictors of pembrolizumab activity, epigenetic studies of T cells via ChIP 
sequencing, multi-color flow cytometric analyses of immune markers pre and 
post-pembrolizumab to determine markers of activity, and high-throughput DNA 
sequencing of T cell receptors IGH loci to determine T cell receptor repertoire 
and diversity in AML before and after pembrolizumab treatment.  
 
We hypothesize that response to pembrolizumab will be associated with: 1) 
increased mRNA expression of PD-L1, 2) increased expression of general 
immune gene signatures associated with immune regulation, 3) clonal restriction 
in T-cell receptor (TCR) and B-cell receptor (BCR) repertoires, 4) increased 
tumor infiltration with effector cells of multiple lineages, 5) decreased tumor 
infiltration by regulatory cells of multiple lineages. 
 
Some or all of these correlative studies may be conducted under the auspices of 
the UNC Master Biomarker Protocol for Pembrolizumab Studies (PI: Jonathan 
Serody, MD UNC), currently under final review for funding. 
 
All patients will have pre- and post-treatment tumor tissue (i.e., bone marrow 
biopsies) as well as serial blood samples submitted for correlative studies to 
determine the dynamic nature of immune signatures pre and post-pembrolizumab.  
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
Estimate the objective overall rate of CR (CR+CRi) for age-adjusted HiDAC (age 
<60 years: 2 gm/m2 IV Q12hours days 1-5; age >60 years: 1.5 gm/m2 IV 
Q12hours days 1-5) followed by pembrolizumab 200 mg IV on day 14 in relapsed 
and refractory AML patients 
  
 
 


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2.2 
Secondary Objectives  
2.2.1 Estimate the rate of unacceptable toxicity associated with HiDAC followed by 
pembrolizumab as induction therapy  
2.2.2 Estimate the objective overall response rates (PR+CR+CRi) for HiDAC followed 
by pembrolizumab. 
2.2.3 Characterize the toxicity associated with HiDAC followed by pembrolizumab as 
induction therapy  
2.2.4 Characterize the toxicity associated with pembrolizumab 200 mg IV Q3weeks 
when used as monotherapy maintenance after an initial response to induction 
phase HiDAC followed by pembrolizumab 
2.2.5 Estimate the relapse-free survival (RFS) and progression-free survival (PFS) of 
patients receiving maintenance pembrolizumab 
2.2.6 Estimate the overall survival (OS) of patients who received induction phase 
treatment.  
 
 
 
   
 
 
2.4 
Endpoints 
2.4.1 Primary Endpoint 
The rate of CR+CRi as defined by the International European LeukemiaNet 
Guidelines in AML21  
 
2.4.2 Secondary Endpoints 
• The rate of unacceptable toxicity is defined as drug-related grade 3 non-
hematologic toxicity (with exception of infusion reactions, rash, fever, 
infection, nausea, fatigue, and anorexia) persisting for >7 days with 
supportive care, or any drug-related non-hematologic grade >4 toxicity 
(excluding infection). Toxicity will be classified and graded according to 
National Cancer Institute’s (NCI) Common Terminology Criteria for 


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Adverse Events (CTCAE, version 4.0). Any patient who receives 
pembrolizumab treatment on this protocol will be evaluable for toxicity. 
• Clinician assessed toxicity of HiDAC followed by pembrolizumab, and 
toxicity of pembrolizumab maintenance monotherapy classified and 
graded according to NCI CTCAEv4 
• PR+CR+CRi as determined by International European LeukemiaNet 
Guidelines in AML21  
• RFS will be defined as time from day 1 of CR/CRi to relapse or death 
from any cause.  
• PFS will be defined as time from day 1 of response (i.e., PR/CR/CRi) to 
progression or death from any cause.  
• OS will be defined as time from day 1 of treatment until date of last 
known follow up or death of any cause.  
 
 
 
 
 
 
 
 
 
 
 
 
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to participate in this 
study: 


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3.1.1 Willing and able to provide written informed consent for the trial 
3.1.2 >18 years and <70 years of age on day of signing informed consent 
3.1.3 ECOG Performance Status 0-1 
3.1.4 Have histologically or cytologically confirmed recurrent AML as defined by >5% 
myeloblasts in the bone marrow aspirate and/or biopsy  
3.1.5 Must have received at least 1 cycle of induction therapy for front-line AML 
including:  
• cytarabine continuous infusion + anthracycline +/- cladribine or etoposide 
for 1 or 2 cycles OR 
• liposomal cytarabine and daunorubicin (CPX-351) OR 
•  high dose cytarabine with or without fludarabine OR 
• cladribine or clofarabine OR 
•  >4 cycles of azacitidine/decitabine OR 
•  the equivalent experimental therapy (the latter as confirmed by the PI)  
3.1.6 Cytoreduction allowed with hydroxyurea and/or leukapheresis for up to 14 days 
prior to D1 of treatment under LCCC1522. Patients must be off hydroxyurea for 
>12 hours prior to D1 of treatment under LCCC1522  
3.1.7 Demonstrate adequate organ function as defined in the table below. All screening 
labs should performed within 14 days of D1 of treatment under LCCC1522.  
 
System 
Laboratory Value 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤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 unless due to Gilbert’s Disease, hemolysis or leukemic 
infiltration OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
 
≤ 5 X ULN  
 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
≤1.5 X ULN unless subject is receiving anticoagulant therapy as long 
as PT or PTT is within therapeutic range of intended use of 
anticoagulants or patient has disseminated intravascular coagulation 


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UNIVERSITY OF NORTH CAROLINA 
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Activated Partial Thromboplastin Time 
(aPTT) 
deemed by investigator to be due to leukemia 
 
≤1.5 X ULN unless subject is receiving anticoagulant therapy as long 
as PT or PTT is within therapeutic range of intended use of 
anticoagulants or patient has disseminated intravascular coagulation 
deemed by investigator to be due to leukemia 
aCreatinine clearance should be calculated per institutional standard.  
3.1.8 Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of HiDAC treatment 
and again prior to D1 of pembrolizumab treatment.  If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.   
3.1.9 Female subjects of childbearing potential should be willing to use   adequate 
method of contraception as outlined in Section 4.2.2.1 - Contraception for the 
course of the study through 120 days after the last dose of study medication. 
Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year. The two birth control 
methods can be two barrier methods or a barrier method plus a hormonal method 
to prevent pregnancy. Subjects should start using birth control from the screening 
visit throughout the study period up to 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. 
3.1.10 Male subjects must agree to use an adequate method of contraception as outlined 
in section 4.2.2.1 – Contraception, starting with D1 of HiDAC 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. 
3.1.11 As determined by the enrolling physician or protocol designee, ability of the 
patient to understand and comply with study procedures  
 
3.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria will not be able to 
participate in this study: 
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 
treatment. 
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 


LCCC 1522 
 
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UNIVERSITY OF NORTH CAROLINA 
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of HiDAC treatment. NOTE: use of steroid eye drops starting at the time of 
HiDAC administration is 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:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
- 
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 that has undergone potentially curative therapy, or in situ 
cervical cancer that has undergone potentially curative therapy.   
3.2.8 Has known active central nervous system (CNS) leukemia; subjects with 
previously treated CNS disease may participate provided they are stable (without 
evidence of active disease by imaging for at least 4 weeks prior to the first dose of 
treatment, and any neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases, and are not using steroids for at 
least 7 days prior to D1 of treatment.  
3.2.9 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.  
3.2.10 Has evidence of interstitial lung disease or a history of (non-infectious) 
pneumonitis that required steroids or current pneumonitis. 
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 


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UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
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18 
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 a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
3.2.16 Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA qualitative is detected). 
3.2.17 Has received a live vaccine within 30 days prior to the first dose of trial treatment 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) 
are live attenuated vaccines, and are not allowed. 
3.2.18 Has uncontrolled intercurrent illness including, but not limited to, active and 
uncontrolled infection, symptomatic congestive heart failure, unstable angina 
pectoris, and uncontrolled symptomatic cardiac arrhythmia. Patients with 
infection under active treatment and controlled with antibiotics are eligible.  
3.2.19 Diagnosed with acute promyelocytic leukemia (APL, M3) 
3.2.20 Receipt of previous allogeneic stem cell transplant; receipt of previous autologous 
transplant for AML or non-AML condition is allowed  
 
 
 
 


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UNIVERSITY OF NORTH CAROLINA 
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19 
4.0 
TREATMENT PLAN 
4.1 
Schema 
This is a phase 2, open-label, multicenter, single-arm study evaluating HiDAC 
salvage induction chemotherapy followed by pembrolizumab in the 
relapsed/refractory AML setting. Toxicity will be assessed during treatment via 
NCI CTCAE v4.0. Tumor specimens from a pre-study bone marrow biopsy and 
post-treatment bone marrow biopsies as well as serial blood samples will be 
collected for correlative studies.  
 
Pembrolizumab 200 mg is administered IV once as monotherapy, 14 days after 
the initiation of HiDAC salvage induction chemotherapy. Patients who have a 
response (i.e., PR/CR/CRi) to induction phase will receive maintenance 
pembrolizumab at 200 mg IV every 3 weeks for up to 2-years of maintenance 
therapy (i.e., beginning on day 1 of maintenance).   
4.2 
Induction Phase 
Treatment will be administered as an inpatient. Patients will be discharged from 
the inpatient unit after receiving pembrolizumab per institutional standards. All 
patients will receive standard high dose cytarabine (HiDAC) for salvage induction 
therapy dose-adjusted for age. Patients <60 years will receive HiDAC 2 gm/m2 IV 
Q12hours days 1-5 while patients >60 years will receive HiDAC 1.5 gm/m2 IV 
Q12hours days 1-5. Pembrolizumab will be administered as a fixed dose of 200 
mg IV on day 14. Prior to pembrolizumab administration, patients must continue 
to meet eligibility for laboratory parameters as outlined in section 3.1. If 


LCCC 1522 
 
CONFIDENTIAL 
PI: Zeidner 
 
UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
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20 
laboratory abnormalities exist on day 14, (or any patient with uncontrolled 
intercurrent illness or other abnormalities deemed by the PI to be unsafe to 
administer pembrolizumab), pembrolizumab administration can be delayed for 1 
week, up to day 21, provided laboratory abnormalities correct themselves to 
levels defined in section 3.1 with supportive care. Patients who are ineligible for 
pembrolizumab administration by day 21 will be removed from the study and 
replaced by another subject. A disease assessment with a bone marrow biopsy 
will occur after patients have achieved full hematologic recovery as per standard 
of care, defined as absolute neutrophil count >1,000/mcL and platelet count 
>100,000/mcL. If full hematologic recovery does not occur by day 45 +/- 2 days, 
a bone marrow biopsy will take place regardless. Patients without evidence of 
active leukemia on disease assessment but without full hematologic recovery by 
day 45 +/-2 days will require a repeat bone marrow biopsy upon full hematologic 
recovery. Patients who achieve a CRi, will be followed with serial blood counts 
(weekly) for up to 30 days after bone marrow biopsy post-induction is performed. 
Those who achieve subsequent full hematologic recovery (within 30 days of CRi) 
will require an additional bone marrow biopsy to document full CR status. If they 
do not achieve full hematologic recovery within 30 days, they will remain 
designated as a CRi. Patients who have achieved a PR, CR or CRi will receive 
maintenance pembrolizumab (see section 4.3). Please see section 6.9 for response 
definitions.  
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cytarabine 
Dexamethasone 
0.1% ophthalmic 
eye drops 1 hour 
before cytarabine 
and Q6 hours both 
eyes days 1-12. 
 
See section 4.4.5 
for prevention of 
tumor lysis 
syndrome 
 
2 gm/m2 
Q12hours (1.5 
gm/m2 in >60 
years) 
IV over 
approximately 
2 hours, per 
institutional 
guidelines  
Days 1-5 
Pembrolizumab 
None 
200 mg  
IV 
over 
30 
minutes  
Day 14 
 
4.2.1 Cytarabine 
Cytarabine will be administered on day 1, dose-adjusted for age (<60 years: 2 
gm/m2 IV Q12hours days 1-5; >60 years: 1.5 gm/m2 IV Q12hours days 1-5). If 
organ dysfunction (i.e. renal dysfunction) arises during cytarabine administration, 
cytarabine can be dose-reduced after discussion with study team and PI. 
Cytarabine will be administered as an IV infusion over approximately 2 hours, per 
institutional guidelines. To prevent kerato-conjunctivitis, dexamethasone 0.1% 


LCCC 1522 
 
CONFIDENTIAL 
PI: Zeidner 
 
UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
Amendment 07 
 
 
21 
ophthalmic eye drops will be administered to both eyes Q6 hours at least 1 hour 
prior to cytarabine initiation and continued through day 12 of therapy (see 
Supportive Care).  
 
Cerebellar exams should be performed prior to each dose of cytarabine. Any new 
symptoms suggestive of cerebellar toxicity should result in temporary 
discontinuation of cytarabine until symptoms resolve, as per institutional policy.  
4.2.2 Pembrolizumab 
All patients will receive pembrolizumab 200 mg IV for 1 dose on day 14 of 
therapy, as long as they have received >50% of planned doses of cytarabine (see 
4.2.1). Pembrolizumab 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). The Pharmacy Manual contains specific instructions 
for the preparation of the pembrolizumab infusion fluid and administration of 
infusion solution. This manual is provided as a document separate from the 
protocol. 
 
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 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor 
symptoms. 
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 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 
mg po (or equivalent dose of 
antipyretic). 


LCCC 1522 
 
CONFIDENTIAL 
PI: Zeidner 
 
UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
Amendment 07 
 
 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
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. 
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. 
 
4.2.2.1 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).   
 
Female subjects will be considered of non-reproductive potential if they are 
either:  


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UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
Amendment 07 
 
 
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(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) have 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)   
• 
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, 


LCCC 1522 
 
CONFIDENTIAL 
PI: Zeidner 
 
UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
Amendment 07 
 
 
24 
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. 
4.3 
Maintenance Phase 
Patients who achieve a PR, CR, or CRi (see section 6.9) will receive 
pembrolizumab 200 mg IV Q3weeks on an outpatient basis. In order to qualify for 
pembrolizumab maintenance, all patients will be required to meet laboratory 
eligibility criteria as outlined in Section 3.1.7 and prior drug-related toxicities 
must have resolved to <grade 1 or baseline. Any patient experiencing 
unacceptable toxicity during induction, as defined in section 2.4.2, will not be 
eligible for maintenance, but will be discontinued from protocol-directed therapy 
and followed-up per protocol. In those who have achieved a CR or PR, 
pembrolizumab maintenance will begin 10-60 days following full hematologic 
recovery (absolute neutrophil count >1,000/mcL and platelet count 
>100,000/mcL). Patients who achieve CRi will begin maintenance 
pembrolizumab 10-60 days following a bone marrow biopsy disease assessment 
after induction phase (a repeat bone marrow biopsy should be performed if CRi 
patients subsequently achieve full hematologic recovery prior to pembrolizumab 
maintenance, as detailed in Section 4.2: Induction Phase). Patients eligible to 
receive maintenance therapy should begin maintenance as early as possible (>10 
days after hematologic recovery occurs, and once recovery from drug-related 
toxicities <grade 1 or baseline). Those who do not receive maintenance therapy 
by day 60 of hematologic recovery or by day 60 of post-induction bone marrow 
biopsy in CRi patients will be taken off study protocol.  
 
All patients who continue pembrolizumab maintenance therapy will have disease 
assessments with bone marrow biopsies after every 4 cycles of treatment (i.e., 
every 12 weeks) for the first year, and then after every 6 cycles of treatment (i.e. 
every 18 weeks) during years 1-2. If there is suspicion for disease progression, a 
disease assessment via bone marrow biopsy will occur at any time during the 
maintenance phase. Patients will continue pembrolizumab 200 mg IV Q3weeks 


LCCC 1522 
 
CONFIDENTIAL 
PI: Zeidner 
 
UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
Amendment 07 
 
 
25 
for up to 2 years (i.e., 34 cycles of treatment) until disease progression, 
unacceptable toxicity, receipt of allogeneic stem cell transplantation or 
investigator and/or patient chooses to discontinue treatment.  
 
Patients will be eligible to undergo an allogeneic stem cell transplantation after 
induction phase. Pembrolizumab maintenance can be continued prior to an 
allogeneic stem cell transplant. The allogeneic stem cell infusion day 0 should 
occur >21 days after the last infusion of pembrolizumab.  
4.3.1 Toxicities and Dose Modifications for Pembrolizumab Maintenance 
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 3 below. See section 4.4 for supportive care 
guidelines, including use of corticosteroids. 
 
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 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in 
the patient's study record. 
 
If a dose of pembrolizumab is delayed, then the subsequent dose should be 
administered 3 weeks later.  Patients may receive up to 1 year of treatment with 
pembrolizumab beginning on day 1 of maintenance therapy. In the event of dose 
delays/interruptions, subjects may not receive more than 1 total year of treatment 
beginning with day 1 of maintenance therapy.  
 
 
Table 3. Dose Modifications 
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 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or 
other therapies  
Monitor and 
follow-up  


LCCC 1522 
 
CONFIDENTIAL 
PI: Zeidner 
 
UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
Amendment 07 
 
 
26 
(CTCAEv4.
0) 
Pneumonitis  
Grade 2 
Withhold  
• Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper 
 
• 
Monitor 
participants for 
signs and 
symptoms of 
pneumonitis 
• 
Evaluate 
participants 
with suspected 
pneumonitis 
with 
radiographic 
imaging and 
initiate 
corticosteroid 
treatment 
• 
Add 
prophylactic 
antibiotics for 
opportunistic 
infections 
Grade 3 or 
4, or 
recurrent 
Grade 2 
Permanently 
discontinue 
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 
Grade 4 
Permanently 
discontinue 


LCCC 1522 
 
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PI: Zeidner 
 
UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
Amendment 07 
 
 
27 
drink liberal 
quantities of 
clear fluids.  If 
sufficient oral 
fluid intake is 
not feasible, 
fluid and 
electrolytes 
should be 
substituted via 
IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer 
corticosteroids (initial 
dose of 0.5- 1 mg/kg 
prednisone or 
equivalent) followed by 
taper 
• 
Monitor with 
liver function 
tests (consider 
weekly or 
more 
frequently until 
liver enzyme 
value returned 
to baseline or 
is stable 
Grade 3 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 
hyperglyce
mia 
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 
hypopituitaris
m 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.  
 


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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 administer 
corticosteroids 
• 
Ensure 
adequate 
evaluation to 
confirm 
etiology and/or 
exclude other 
causes 
 
Grade 3 or 4 
Permanently 
discontinue 
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).   
 
 
4.4 
Rescue Medications & Supportive Care 
4.4.1 Cytarabine-related Kerato-conjunctivitis 
To prevent cytarabine-related kerato-conjunctivitis, dexamethasone 0.1% 
ophthalmic eye drops (or per institutional formulary) must begin at least 1 hour 
prior to cytarabine initiation. Eye drops should be performed every 6 hours to 
both eyes until day 12 of induction phase treatment.  
4.4.2 Antiemetics 
Antiemetics will be used according to standard practices with the exception of 
systemic steroids (i.e., dexamethasone). Use of systemic steroids during this trial 
is not allowed. Any 5-hydroxytryptamine (5-HT3) receptor inhibitor (e.g., 


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ondansetron) combined with haloperidol or prochlorperazine as needed, will be 
used during chemotherapy infusions and during pembrolizumab administration, as 
needed.  
4.4.3 Antimicrobial prophylaxis 
Patients will receive prophylaxis against gram-negative gastrointestinal infections 
(GI), candidiasis, and herpes simplex virus (HSV), while patients are aplastic, 
during induction phase, and as per standard of care. Antimicrobial prophylaxis 
will only occur in the maintenance phase if patients develop neutropenia (absolute 
neutrophil count <500/mcL).  
4.4.4 Colony Stimulating Factors 
The routine use of colony stimulating factors is not allowed. The use of colony 
stimulating factors in the presence of severe or life-threatening infection should 
be discussed with the principal investigator before implementation. 
4.4.5 Prevention and Management of Tumor Lysis Syndrome (TLS) 
Tumor lysis occurs as part of initial cytoreductive therapy. In its most extreme 
form, TLS, is characterized by hyperuricemia, hyperphosphatemia, increased 
lactate dehydrogenase (LDH), coagulopathy, and a potential cytokine release 
syndrome.  
 
Tumor lysis labs consisting of basic metabolic panel, uric acid, calcium, and 
phosphate must be drawn a minimum of twice daily at least through day 5 of 
chemotherapy and once daily through day 10, until maximum tumor lysis has 
abated. The following precautionary and prophylaxis regimens are suggested prior 
to and during initial chemotherapy administration: 
• To prevent hyperuricemia, all patients without known allergy will receive 
allopurinol 300-600 mg PO qday 24 hours prior to beginning chemotherapy 
and the allopurinol 300-600 mg PO qday continuing through the period of 
maximal tumor lysis (at least through day 8) or other antiuricemia regimen per 
institutional practice. Rasburicase may be used per institutional policy for 
hyperuricemia. Screening for G6PD deficiency should be obtained in 
susceptible populations before beginning rasburicase. 
• To decrease the risk of hyperphosphatemia, an oral phosphate binder per 
institutional practice (e.g. sevelamer 400-800 mg) will be administered orally 
every  8 hours beginning on day 1 of induction phase and continued as 
tolerated until maximum tumor lysis has occurred (at least day 8). 
• Cytokine release syndrome can occur shortly after completion of drug 
infusion, accompany severe TLS, and present with fever, bronchospasm with 
dyspnea and/or respiratory distress, altered blood pressure, myalgias, 
arthralgias, tumor pain and/or urticarial rash. Any patient with cytokine 
release syndrome should receive 20 mg dexamethasone (or equivalent steroid) 
IV immediately. Pembrolizumab must begin at least 7 days after the last dose 


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of steroids for cytokine release syndrome.  
4.4.6 Rescue Medications & Supportive Care for Pembrolizumab Cycles 
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.  
 
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 in 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. 
 
 
 
 


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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 (TIDM) (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: 
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 


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treatment, and as indicated based on clinical evaluation) and for clinical signs and 
symptoms of thyroid disorders. 
 
Grade 2 hyperthyroidism events (and Grade 2-4 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. 
 
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. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.  
• 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.  
Section 4.2.2 shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
Steven’s Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) 
o For signs and symptoms of SJS or TEN, withhold pembrolizumab and refer 
the patient for specialized care for assessment and treatment 
o If SJS or TEN is confirmed, permanently discontinue pembrolizumab 


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Immune-mediated myocarditis management 
o For suspected immune-mediated myocarditis, ensure adequate evaluation 
to exclude other etiologies and administer corticosteroids as appropriate 
 
Infusion Reaction 
See section 4.2.2. 
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 
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 
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 7.2.  
4.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the 
Screening and Treatment Phase  
 
• Anti-cancer systemic chemotherapy or biological therapy with the exception 
of hydroxyurea and intrathecal chemotherapy (cytarabine and/or 
methotrexate) for CNS disease. Intrathecal chemotherapy will be permissible 
on maintenance phase of the protocol as long as the subject is continuing to 
have a clinical response to treatment. This should be discussed with the PI 
prior to administering intrathecal chemotherapy. Intrathecal chemotherapy 
should be administered at least 72 hours before/after pembrolizumab infusion. 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab  


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• 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, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however intranasal influenza 
vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed. 
• Systemic Corticosteroids for any purpose other than to modulate symptoms 
from an event of clinical interest of suspected immunologic etiology.  The use 
of physiologic doses of corticosteroids may be approved after consultation with 
the Sponsor.  
• Radiation therapy 
• Growth factor support (G-CSF or GM-CSF) 
 
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.  Subjects may receive other medications that the investigator deems to be 
medically necessary 
4.6 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies: 
• Failure to achieve a PR, CR, or CRi after induction phase 
• Disease progression/relapse at any time during induction or maintenance 
phase 
• Receipt of allogeneic stem cell transplantation  
• Completion of 2 years of pembrolizumab maintenance therapy 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) while on pembrolizumab therapy as 
defined in section 2.4.2 
• Patient decides to withdraw from study  
• Patient unable to comply with protocol requirements 
• General or specific changes in the patient’s condition that render the 
patient unacceptable for further treatment in the judgment of the 
investigator. 
4.7 
Duration of Follow-Up 
Patients will be followed for up to 5 years after removal from study treatment or 
until death, whichever occurs first. Patients removed from study for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse 
event.  After 2 years of follow-up as described in the time and events table, 
subsequent follow-up will be per standard of care and the study will follow only 
for progression and for survival for up to 3 additional years, for a total of 5 years 
of follow-up after study completion. 


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4.8 
Removal of Patients from Protocol Therapy 
Patients will be removed from protocol therapy and the PI notified when any of 
the criteria listed in section 4.6 apply.  Patients will also be removed from 
protocol therapy if they fail to meet eligibility criteria for the first dose of 
pembrolizumab following HiDAC induction (see section 4.2). 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. 
4.9 
Patient Replacement 
If laboratory abnormalities exist on day 14 during induction, pembrolizumab 
administration can be delayed for 1 week, up to day 21, provided laboratory 
abnormalities correct themselves to levels defined in section 3.1 with supportive 
care. Patients who are ineligible for pembrolizumab administration by day 21 will 
be removed from the study and replaced by another subject. 
4.10 
Study Withdrawal 
If a subject 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 subject 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 subject’s study withdrawal 
should be obtained with an explanation of why the subject is withdrawing 
from the study.   
• 
If the subject 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 subject from the study is an adverse event, 
the principal specific event will be recorded on the eCRF.  
 
Excessive subject withdrawals from protocol therapy or from the study can render 
the study un-interpretable; therefore, unnecessary withdrawal of subjects should 
be avoided. 
 
 
 
 
 


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5.0 
DRUG INFORMATION 
5.1 
Pembrolizumab 
5.1.1 Description 
 
Clinical Supplies will be provided by Merck as summarized in the table below. 
 
Product Name & Potency 
Dosage Form 
pembrolizumab 50 mg 
Lyophilized Powder for Injection 
pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
5.1.2 Supplier/How Supplied 
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 Handling and Dispensing 
Clinical supplies must be stored in a secure, limited-access location under the 
storage conditions specified on the label.   
 
Receipt and dispensing of trial medication must be recorded by an authorized 
person at the trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the 
protocol. 
5.1.4 Storage and Stability 
See the Pharmacy Manual provided as a document separate from this protocol. 
5.1.5 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.  
 
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 
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according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
5.1.6 Adverse Events Associated with Pembrolizumab 
The most common adverse reactions (reported in ≥20% of patients 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 
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  


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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 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 was1.5 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 thyroidhormone 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. 
 
Across clinical studies with pembrolizumab in approximately 2000 patients, the 
following additional clinically significant, immune-mediated adverse reactions 
were reported in less than 1% of patients: myasthenic syndrome, optic neuritis, 
and rhabdomyolysis. 
 
 


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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/PDL-1 
signaling pathway with maintenance of pregnancy through induction of maternal 
immune tolerance to fetal tissue.  
 
Steven’s 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. 
 
5.1.7 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.   
5.1.8 Use in Pregnancy 
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 LCCC Multicenter Project Manager who will 
report the event 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 LCCC 
Multicenter Project Manager. If a male subject impregnates his female partner the 
study personnel at the site must be informed immediately and the pregnancy 


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reported to the LCCC Multicenter Project Manager who will report the event to 
Merck, and followed as described above and in Section 7.3.3. 
5.1.9 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many 
drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, subjects who are breast-feeding are not eligible for 
enrollment. 
5.1.10 Overdose 
For purposes of this trial, an overdose 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. In the event of overdose, 
pembrolizumab should be discontinued and 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 LCCC Multicenter Project Manager who will report the event 
within 2 working days hours to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) (see section 7.3.3). 
5.2 
Cytarabine 
Mechanism of action: Cytarabine works by inhibition of DNA synthesis. Cytosine 
gains entry into cells by a carrier process, and then must be converted to its active 
compound, aracytidine triphosphate. Cytosine is a pyrimidine analog, which is 
incorporated into DNA; however, its primary action is inhibition of DNA 
polymerase resulting in decreased DNA synthesis and repair. 
 
Product description: Cytarabine (conventional) is commercially available in vials 
containing 20 mg/ml (25 ml) and 100 mg/ml (20 ml) solution for injection and are 
stable at room temperature.  
 
Solution preparation: Cytarabine can be compounded in 100-1000 ml of NS or 
D5W and is stable at room temperature for 48 hours once compounded. Cytarabine 
solutions reconstituted with diluents containing benzyl alcohol should not be used 
for intrathecal injections or for IV administration of high dose cytarabine (> 1 


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gm/m2). Solutions for parenteral administration are generally reconstituted to 
concentrations ranging from 20-100 mg/ml, depending on the dose and the route of 
administration.  
 
Solutions are stable at room temperature for 7 days, but use within 48 hours of 
preparation, or refrigerated for 24 hours beyond use date, is recommended by the 
manufacturer.  Furthermore, solutions prepared with diluents which do not contain 
preservative or bacteriostat, should be used within 8 hrs of vial entry to minimize 
the risk of bacterial contamination. 
 
Premedication: Dexamethasone 0.1% ophthalmic eye drops should be administered 
>1 hour prior to cytarabine infusion to both eyes and continued Q6hours through 
day 12 of treatment.  
 
Route of administration: Cytarabine will be administered intravenously in a dose 
that adjusted due to age: <60 years: 2 gm/m2 IV Q12hours days 1-5; >60 years: 1.5 
gm/m2 IV Q12hours days 1-5 over 2 hours. The infusion should not be interrupted 
for the delivery of blood products, antibiotics, etc.  
 
Handling and Disposal: Please see policy on hazardous drugs: 
http://intranet.unchealthcare.org/intranet/hospitaldepartments/safetynet/policies/ha
zardousdrugs.pdf/view 
 
5.3 
Adverse Events Associated with Cytarabine 
Serious and Common Adverse Effects:  
The most common toxicities associated with cytarabine, even when used at doses 
≤200mg/m2 include hematologic (neutropenia, thrombocytopenia, anemia), 
gastrointestinal (nausea & vomiting (this agent is highly emetogenic), diarrhea 
and mucositis), dermatologic (rash), hepatic (hepatic dysfunction, mild jaundice, 
transaminase elevations), non-infectious fever, and alopecia. Additional toxicities 
associated with high dose cytarabine (≥ 1gm/m2) include neurologic (primarily 
cerebellar such as nystagmus, ataxia, abnormal gait), but also cerebral such as 
somnolence, psychosis, confusion seizures), ocular toxicity, and rarely pulmonary 
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6.0 
EVALUATIONS AND ASSESSMENTS 
6.1 
Time and Events Table 
 
Assessment 
Treatment Schedule for Cycle 1 (INDUCTION) 
RECOVERY PERIOD (30-45 DAYS)2 
Full 
Heme 
Recovery 
or on 
D45 +/- 2 
days2 
For patients in 
≥PR post 
recovery3 
EOT4 
Follow-
up5 
Pre-
study1 
D1 
Cycle 1 
D2 
Cycle 1 
D3 
Cycle 1 
D4 
Cycle 1 
D5 
Cycle 1 
D 
6-13 
Cycle 1 
D14 
Cycle 1 
Daily from D15 
until early 
heme 
recovery or 
discharge 
from 
hospital13 
D1 each cycle; 
continue cycles 
for 2 years of 
MAINTENANCE 
Informed Consent 
X 
 
 
 
 
 
History6 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X6 
X6 
X 
Physical exam6 
X 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
Performance Status 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Pregnancy Test7 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistries8 
X 
 BID 
 BID 
BID 
  BID 
 BID 
X 
X 
X 
X 
X 
X 
 
LDH, Uric acid, phosphate8 
X 
BID 
BID 
BID 
BID 
 BID 
X8 
X 
 
 
 
 
 
Liver function tests9 
X 
X 
X 
X 
X 
X 
X9 
X 
X9 
X 
X 
X 
 
Coagulation labs9 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
Thyroid function tests10 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
Concomitant meds 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
Toxicity Assessment  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X4 
X3 
Bone marrow 
X11 
 
 
 
 
 
 
 
 
X11 
X11 
 
 
Blood sample for biomarkers 
and buccal cell collection 
X12 
 
 
 
 
 
 
X12 
Weekly12 
X12 
X12 
 
 
Cytarabine IV every 12 
hours 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 


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Pembrolizumab  200mg IV  
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Survival analysis 
 
 
 
 
 
 
 
 
 
 
 
 
X 
QOL Questionnaire14 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


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Key to Time and Events Table Footnotes 
 
1 Unless otherwise noted, evaluations may be performed up to 2 weeks prior to Cycle 1 Day 1 of treatment. 
Cycle 1 Day 1 laboratory assessments do not need to be repeated if they have been performed up to 72 
hours prior to the scheduled visit.  NOTE: A window of 2 days will be applied to all study visits. 
 
2Full hematologic recovery is defined as absolute neutrophil count >1,000/mcL and platelet count 
>100,000/mcL. All assessments listed including a disease assessment via bone marrow biopsy will occur at 
hematologic recovery, or by day 45 +/- 2 days, whichever comes first. See section 4.2 for additional details 
regarding D14 pembrolizumab delay.  
 
3Patients in ≥PR based on BM biopsy may continue to receive pembrolizumab every 21 days +/-3 days (1 
cycle) until maintenance treatment duration totals 1 year (see section 4.3 for additional details), disease 
progression, or intolerable toxicity, whichever occurs first. Pembrolizumab will start 10-60 days post full 
hematologic recovery in those who achieve PR or CR, and 10-60 days post the post induction bone marrow 
biopsy in those who achieve CRi. Patients who do not achieve at least a PR, or receive pembrolizumab 
maintenance by day 60 of hematologic recovery (or day 60 post-induction bone marrow biopsy in CRi 
patients) will be taken off of protocol-mandated therapy and followed up per protocol.  
  
4This end of treatment (EOT) visit should occur in patients when they stop treatment whether due to disease 
progression, unmanageable toxicity, or they have reached 2years of treatment, and will take place ~30 days 
post last dose of pembrolizumab. Patients who experience ≥Grade 2 treatment-related adverse event will be 
contacted very 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. 
 
5The first long-term follow-up visits will take place ~ 60 days after the EOT visit (+/- 15 days) and will 
focus on any serious adverse events (SAEs) or any grade of Events of Clinical Interest (see section7.3.4.1) 
that occur within 90 days of the end of pembrolizumab (or prior to start of new anti-cancer therapy).  Any 
such events must be recorded.   Subsequent long-term follow up visits will take place at a schedule as per 
institutional standard of care (i.e., usually every ~3-6 months) and will be limited to history of any 
subsequent cancer treatments, an assessment of any SAE’s considered to be possibly or probably related to 
study treatment until resolution, and survival status.   
 
6Complete history at baseline only, thereafter focused history on symptoms/toxicity.  Physical exam to 
include height (baseline only), weight (D1 and D14 of cycle 1, D1 of all cycles of maintenance 
pembrolizumab and all follow-up visits) and vital signs 
 
7Serum or urine B-HCG within 72 hours prior to D1 of HiDAC and prior to D14 pembrolizumab, and only 
if clinically appropriate; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required. 
 
8Serum chemistries include Na, K, Cl, creatinine, BUN, calcium, magnesium, bicarbonate,, and glucose; 
serum chemistries along with LDH, uric acid, and phosphate comprise tumor lysis labs. During induction, 
tumor lysis labs should be assessed BID (twice daily) D1-5, and once daily from D6 until tumor lysis 
syndrome is resolved, which usually occurs by D10. Repeat LDH, uric acid and phosphate on D14.     
 
9Liver function tests (LFTs) include total protein, albumin, total bilirubin, alkaline phosphatase, ALT, and 
AST (NOTE: on D6-13, and on D15 through recovery, LFTs only required every other day); coagulation 
labs include PT/INR, aPTT, D-Dimer and fibrinogen 


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10Thyroid tests include T3, free T4, TSH as denoted during induction therapy. These tests should be 
performed on D1/C1 prior to starting maintenance therapy with pembrolizumab and repeated every 3 
cycles thereafter (i.e., cycles 3, 6, 9, 12, etc.) until treatment discontinuation. 
 
11Initial (pre-treatment) bone marrow biopsy should be obtained within 14 days prior to D1 of HiDAC as 
per standard of care. Patients will undergo repeat bone marrow at time of full hematologic recovery or on 
D45 +/- 2 days whichever comes first as per standard of care. Repeat biopsy after every 4 cycles of 
maintenance during year 1 and every 6 cycles of maintenance during year 1-2. Each time a bone marrow 
biopsy is done as per standard of care, additional 4x8mL will be collected in green top ACD tubes (~32 
mL) for correlative studies. See section 6.7 and the laboratory manual for additional details.  Repeat biopsy 
at any time if there is a suspicion of leukemia recurrence either during maintenance phase or in follow-up.  
 
12 Buccal cell collection should be collected from all patients during screening. If not done during 
screening, this can be performed at any point during follow-up. Please see laboratory manual for details. 
For peripheral blood samples for research, collect 5 x8mL ACD green top tubes of blood (~40mLs) pre-
treatment within 14 days prior to D1 of HiDAC, D14 (1-12 hours prior to pembrolizumab administration), 
weekly between D14 and hematologic recovery (i.e. D21, D28, D35, and D42 (the latter if no full 
hematologic recovery by this time) and at full hematologic recovery or on D45+/- 2 days whichever occurs 
first. Repeat blood sample on D1 of each maintenance cycle of pembrolizumab during year 1 and every 
even cycle of maintenance during year 1-2. Repeat blood sample at any time if there is a suspicion of 
leukemia recurrence either during maintenance phase or in follow-up. See section 6.7 and the laboratory 
manual for additional details.   
 
13Patients discharged from the hospital prior to early recovery should receive CBC, serum chemistries, and 
liver function tests at minimum three times weekly until early recovery 
 
14Should be completed during each cycle of maintenance therapy (ie, day 1 of each cycle). Completion of 
the questionnaire will be optional. 
 
 


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6.2 
Pre-Study Assessments 
Clinical evaluation:  complete history, physical examination to include height 
(baseline only) and weight, ECOG performance status. 
Transthoracic Echocardiogram 
Laboratory studies:   
 Pregnancy Test: A serum or urine pregnancy test (β-HCG) is 
required for all women of childbearing potential at screening within 
72 hours prior to the first dose of HiDAC. If urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be 
required. 
 CBC with differential and platelets 
 Serum Chemistries: These include the following parameters: 
sodium, potassium, chloride, bicarbonate, BUN, serum creatinine, 
glucose, calcium, and magnesium. 
 LFTs: These include total protein, albumin, total bilirubin (direct and 
indirect), alkaline phosphatase, AST (SGOT), ALT (SGPT) 
 Thyroid Function Tests: TSH, T3, free T4 
 Coagulation Tests: These include PT/INR, aPTT, D-Dimer and 
fibrinogen 
 LDH, Uric acid & phosphorus: These along with serum chemistries 
and coagulation labs comprise tumor lysis labs 
Concomitant Medications: Review (see section 4.4.6) 
Tissue Acquisition/Disease Assessment: Primary tumor will be collected by 
peripheral blood and bone marrow biopsy. Buccal cell collection will be 
collected. Bone marrow biopsy and blood sample should be obtained within 14 
days prior to day 1 of HiDAC. See section 6.7 and the laboratory manual for 
additional details.  
6.3 
Treatment Assessments-INDUCTION CYCLE (CYCLE 1) 
6.3.1 Daily (or twice daily* as noted), D1-5 (High Dose Cytarabine administration) 
Clinical evaluation: physical examination and ECOG performance status day 1 
only, focused history on symptoms/toxicity days 1-5.  
Laboratory studies:  
• CBC with differential and platelets 
• Serum Chemistries*: twice daily: sodium, potassium, chloride, 
bicarbonate, BUN, serum creatinine, glucose, calcium, magnesium. 
• LFTs: total protein, albumin, bilirubin (direct and indirect), alkaline 
phosphatase, AST, ALT 
• LDH, Uric acid, phosphate*: twice daily 
• Coagulation Tests: PT/INR/aPTT, D-Dimer, fibrinogen 
Concomitant Medications: Review 
Toxicity Assessment: via NCI CTCAEv4 


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6.3.2 Daily (unless otherwise noted) D6-13 
Laboratory Studies: 
• CBC with differential and platelets 
• Serum Chemistries: sodium, potassium, chloride, bicarbonate, BUN, 
serum creatinine, glucose, calcium, magnesium. 
• LDH, Uric acid, phosphate: NOTE, once tumor lysis syndrome has 
resolved, these labs do not need to be repeated until D14 
• LFT’s: total protein, albumin, bilirubin (direct and indirect), alkaline 
phosphatase, AST, ALT: NOTE: to be drawn every other day 
Concomitant Medications: Review 
Toxicity Assessment: via NCI CTCAE V4 
6.3.3 Day 14 (Day of Pembrolizumab infusion) 
Clinical evaluation:  focused history on symptoms/toxicity, physical examination 
to include weight. 
Laboratory studies:   
• Pregnancy Test: A serum or urine pregnancy test (β-HCG) is required for all 
women of childbearing potential prior to dose of pembrolizumab. If urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be 
required. 
• CBC with differential and platelets 
• Serum Chemistries: sodium, potassium, chloride, bicarbonate, BUN, serum 
creatinine, glucose, calcium, magnesium. 
• LFTs: total protein, albumin, total bilirubin (direct and indirect), alkaline 
phosphatase, AST (SGOT), ALT (SGPT) 
• Thyroid Function Tests: TSH, T3, free T4 
• Coagulation Tests: PT/INR, aPTT, D-Dimer, fibrinogen 
• LDH, Uric acid & phosphate:  
Concomitant Medications: Review (see section 4.4.6) 
Toxicity Assessment: via NCI CTCAE v4 
Blood sample for Biomarkers: Collect blood sample: see section 6.7 and the 
laboratory manual for additional details.  
6.3.4 Daily (unless otherwise noted) Day 15 until Early Hematologic Recovery or 
Discharge from Hospital (see footnote #2 for definition) 
Laboratory Studies: 
• CBC with differential and platelets 
• Serum Chemistries: sodium, potassium, chloride, bicarbonate, BUN, serum 
creatinine, glucose, calcium, magnesium. 
• LFTs: total protein, albumin, total bilirubin (direct and indirect), alkaline 
phosphatase, AST, ALT: Note: To be drawn every other day 
Blood sample for biomarkers: Collect blood sample weekly between day 14 and 
hematologic recovery (i.e., day 21, day 28, day 35, day 42 (the latter 2 dates if no 
hematologic recovery by this time).  


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• Toxicity Assessment: via NCI CTCAEv4 
 
6.3.5 At Full Hematologic Recovery or on Day 45 +/- 2 days (whichever comes 
first) 
Clinical Evaluation: Physical exam including weight 
Laboratory Studies: 
• CBC with differential and platelets 
• Serum Chemistries: sodium, potassium, chloride, bicarbonate, BUN, serum 
creatinine, glucose, calcium, magnesium 
• LFTs: Total protein, albumin, bilirubin (direct and indirect), alkaline 
phosphatase, AST, ALT 
Toxicity Assessment: via NCI CTCAE v4 
Disease Assessment and Biomarkers: Repeat bone marrow biopsy; collect blood 
sample for biomarkers; see section TBD and laboratory manual for additional details. 
6.4 
Treatment Assessments-Maintenance  
6.4.1 Year 1 of Maintenance 
6.4.1.1 Day 1 each Cycle 
Clinical evaluation:  focused history on symptoms/toxicity, physical examination 
to include weight, ECOG performance status. 
Laboratory studies:   
• CBC with differential and platelets 
• Serum Chemistries: sodium, potassium, chloride, bicarbonate, BUN, serum 
creatinine, glucose, calcium, magnesium 
• LFTs: total protein, albumin, total bilirubin (direct and indirect), alkaline 
phosphatase, AST (SGOT), ALT (SGPT) 
• Thyroid Function Tests: These include TSH, T3, free T4 (D1/C1 and 
then repeat every 3rd cycle (ie, cycles 3, 6, 9, etc) 
Concomitant Medications: Review (see section 4.4.6) 
Toxicity Assessment: via NCI CTCAE v4 
Blood sample for Biomarkers: Collect blood sample, see section 6.7 and laboratory 
manual for details 
Pembrolizumab administration: 200 mg IV, every 21 days +/- 3 days  
Administer QOL Promis SF v1.1 –Global Health questionnaire (optional) 
6.4.1.2 After every 4th cycle 
Collect bone marrow biopsy for disease assessment and biomarkers: Bone 
marrow biopsy should be performed after treatment of every 4th cycle at least one 
day prior to the next treatment cycle; see section 6.7 and laboratory manual for 
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6.4.2 Year 2 of Maintenance 
6.4.2.1 Day 1 of each cycle 
Clinical evaluation:  focused history on symptoms/toxicity, physical examination 
to include weight, ECOG performance status. 
Laboratory studies:   
• CBC with differential and platelets 
• Serum Chemistries: sodium, potassium, chloride, bicarbonate, BUN, serum 
creatinine, glucose, calcium, magnesium 
• LFTs: total protein, albumin, total bilirubin (direct and indirect), alkaline 
phosphatase, AST (SGOT), ALT (SGPT) 
• Thyroid Function Tests: These include TSH, T3, free T4 (D1/C1 and then 
repeat every 3rd cycle (ie, cycles 3, 6, 9, etc) 
Concomitant Medications: Review (see section 4.4.6) 
Toxicity Assessment: via NCI CTCAE v4 
Blood sample for Biomarkers: Collect blood samples every even cycle of treatment (i.e. 
every other cycle), see section 6.7 and laboratory manual for details 
Pembrolizumab administration: 200 mg IV, every 21 days +/- 3 days  
Administer QOL Promis SF v1.1 –Global Health questionnaire (optional) 
 
6.4.2.2 After every 6th cycle 
Collect bone marrow biopsy for disease assessment and biomarkers: Bone 
marrow biopsy should be performed after treatment of every 6th cycle (during 
years 1-2) at least one day prior to the next treatment cycle; see section 6.7 and 
laboratory manual for details. 
 
6.5 
End of Treatment 
This visit should occur in patients when they stop treatment whether due to 
disease progression, unmanageable toxicity, or they have reached 2 years of 
treatment. In subjects who reach 2 full years of treatment, this visit will take place 
~30 days post last dose of pembrolizumab. 
Clinical evaluation:  Focused history on symptoms/toxicity, physical examination 
to include weight, ECOG performance status. 
Laboratory studies:   
• CBC with differential and platelets 
• Serum Chemistries: sodium, potassium, chloride, bicarbonate, BUN, serum 
creatinine, glucose, calcium, magnesium 
• LFTs: total protein, albumin, total bilirubin (direct and indirect), alkaline 
phosphatase, AST (SGOT), ALT (SGPT) 
Concomitant Medications: Review (see section 4.4.6) 
Toxicity Assessment: via NCI CTCAE v4; patients who experience ≥Grade 2 
treatment-related adverse event will be contacted very 2 weeks until the event is 


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resolved to Grade 0 or 1, determined to be irreversible by the investigator, or until the 
patient begins an alternate form of drug treatment. 
6.6 
Follow-up 
The first long-term follow-up visit will take place ~ 60 days after the EOT visit 
(+/- 15 days) and will focus on any serious adverse events (SAEs) or any grade of 
Events of Clinical Interest that occur within 90 days of the end of pembrolizumab 
(or prior to start of new anti-cancer therapy).  Any such events must be recorded.   
Subsequent long-term follow up visits will take place as per institutional standard 
of care (i.e., typically every 3-6 months) and will be limited to history of any 
subsequent cancer treatments, 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 
These are described in more detail in the laboratory manual. NOTE: A tumor 
sample will be sent to Merck or their designated laboratory for evaluation of PD-
L1 expression at baseline. See laboratory manual for additional details. 
 
Samples will be processed within 24 hours of collection as outlined in the 
Standard Operating Procedure Guidelines in the Laboratory Manual.  
 
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. 
6.7.1 mRNA Sequencing (mRNA-seq) and Proteonomics 
mRNA-seq of bulk bone marrow leukocyte samples from diagnostic specimens 
will be performed for definition of tumor genetic subtypes, quantification of PD-
L1 mRNA expression, and evaluation of gene expression signatures associated 
with immune activation and suppression.  Bulk bone marrow leukocyte samples 
will also be sorted into CD34+ and CD34- subpopulations, and the CD34+ 
populations will undergo 1) mRNA-seq for neoantigen prediction and analysis of 
differential splicing, and 2) mass spectrometry for neoantigen confirmation. The 
CD34- fraction will be stored for the generation of cytotoxic T lymphocyte 
cultures for confirmation of biologically valid neoantigens.   
 
The mRNA-seq studies will involve genetic research where tumor gene 
expression profiling and analysis of somatic mutations will be included.  
Appropriate informed consent for genetic research will be obtained prior to 
patient samples being processed. 
6.7.2 High-Throughput DNA sequencing  
Whole exome sequencing of CD34+ AML blasts from bone marrow samples will 
be performed for somatic mutation detection and neoantigen prediction. From 


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bone marrow and peripheral blood leukocyte samples, T cell functional studies 
will be performed, and 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.  
6.7.3 Flow Cytometry/Immunohistochemistry of Immune Markers  
Bone marrow core biopsy 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. 
6.7.4 Minimal Residual Disease Analysis 
Cryopreserved mononuclear cells from bone marrow aspirate and/or peripheral 
blood will be analyzed for minimal residual disease assays via flow cytometry, 
DNA or RNA PCR.  
6.8 
Assessment of Safety  
Any patient who receives pembrolizumab 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 (6.0). 
Toxicity will be assessed according to NCI CTCAE v4. Toxicities will be 
characterized in terms of seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
 
For subjects receiving treatment with pembrolizumab, all AEs of unknown 
etiology associated with pembrolizumab exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially 
immunologic etiology (termed immune-related adverse events, or irAEs); see the 
separate ECI guidance document (provided as a document separate from this 
protocol) regarding the identification, evaluation and management of potential 
irAEs.   
 
Please refer to section 7.0 for detailed information regarding the assessment and 
recording of AEs.   
6.9 
Assessment of Efficacy 
Patients who have received pembrolizumab within the induction phase (cycle) 
will be evaluable for assessment of response and progression. Efficacy of 
treatment will be assessed by a bone marrow biopsy at the time of hematologic 
recovery (i.e., absolute neutrophil count >1,000/mcL and platelet count 


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>100,000/mcL), or by day 45 +/- 2 days of induction treatment, whichever occurs 
first. Response will be assessed by standard international criteria proposed by the 
European LeukemiaNet Guidelines in AML.21  
 
Complete remission (CR): Bone marrow blasts <5%; absence of Auer rods; 
absence of extramedullary disease; absolute neutrophil count >1,000/mcL; 
platelet count >100,000/mcL; independence of red cell transfusions 
 
Complete remission with incomplete recovery (CRi): All CR criteria except for 
residual neutropenia (<1,000/mcL) or thrombocytopenia (<100,000/mcL) plus 
independent of platelet transfusions.  
 
Partial response (PR): bone marrow blasts 5-25% and decrease of pretreatment 
bone marrow blast % by >50%; all hematologic criteria of CR. 
 
Patients who achieve a PR to induction phase and then achieve CR after 
maintenance pembrolizumab will be assessed as an overall CR to study treatment.  
6.9.1 Progression-Free Survival and Relapse 
Progression-free survival (PFS) will be defined as time from response (i.e., 
PR/CR/CRi) until disease progression or death. In patients who achieve a PR after 
Induction Phase, progression will be defined as  >50% increase in bone marrow 
blast % over baseline from beginning Maintenance Phase with a minimum 15% 
point increase in blasts, loss of PR (i.e., >25% bone marrow blasts), leukemia-
related complications such as transfusion dependence, presence of extramedullary 
disease (including symptomatic CNS disease), or circulating blasts. This is 
consistent with European LeukemiaNet Guidelines 2017.2 Progression will be 
defined as relapse (i.e., >5% bone marrow blasts) in patients who initially 
achieved a CR or CRi with induction phase. Patients who undergo an allogeneic 
stem cell transplant will be censored for PFS.  
6.9.2 Relapse-Free Survival 
Relapse-free survival (RFS) will be defined as time from CR or CRi until relapse 
or death. Relapse will be defined as bone marrow blasts >5% in a patient who 
initially achieved a CR or CRi after induction phase. Patients who undergo an 
allogeneic stem cell transplant will be censored for RFS.  
 
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 


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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 
 
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 


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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. 
 
Pregnancy that occurs during the study must also be reported as an SAE. 
• 
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. 
 
 
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.   
 


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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.  
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 
SAEs or Serious SARs must be recorded in the SAE console within Oncore™ for 
that patient within 24 hours of learning of its occurrence.  Additionally, the LCCC 
Multicenter Project Manager must also be notified via email of all SAEs within 
24 hours of learning of its occurrence.  
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. 
• For affiliate sites relying on the UNC-IRB any SAEs that qualify as an 
Unanticipated Problem will be entered into Oncore and reported to the 
UNC IRB by the LCCC Multicenter 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 or lactation 
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 


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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 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 LCCC Multicenter Project Manager who will 
report the event within 2 days to the manufacturer (Merck; see below 7.3.4.2). 
 
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported 
to the LCCC Multicenter Project Manager within 24 hours via email 
(CPOMulticenter@med.unc.edu) or 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. 
 
 
FDA Expedited Reporting requirements: 
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 


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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 
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 emailed or faxed to the Multicenter Project 
Manager at CPOMulticenter@med.unc.edu or 919-966-4300  along with supporting 
documentation defining the event and causality.  The Multicenter Project Manager 
will then send the report to the Funding Source. The MedWatch 3500A form can be 


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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 Multicenter Project 
Manager 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 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.  
 


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7.3.4 Merck Reporting Requirements: 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the 
cancer under study 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 allocation/randomization 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 serious 
adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study whether or not related to 
the Merck product, must be reported within 24 hours to the Sponsor and within 2 
working days to Merck Global Safety. 
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. 
All subjects with serious adverse events must be followed up for outcome. 
 
SAE reports and any other relevant safety information are to be forwarded to 
the Merck Global Safety facsimile number:  +1-215-993-1220 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as 
required by FDA, European Union (EU), Pharmaceutical and Medical Devices 
agency (PMDA) or other local regulators. Investigators will cross reference this 
submission according to local regulations 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. 
7.3.4.1 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of 
Clinical Interest (ECI) and must be reported within 24 hours to the LCCC 
Multicenter Project Manager who will report the event 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 


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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 allocation/randomization 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  in Section 5.1.10 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is 
not associated with clinical symptoms or abnormal laboratory results. 
  
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 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.  
7.3.4.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered AEs, 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. Pregnancies and lactations 
that occur after the consent form is signed but before treatment allocation/ 
randomization 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.   
 
Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days of completing the trial completing the 
trial following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.  All subjects and female partners of male subjects 
who become pregnant reported pregnancies must be followed to the completion/ 


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termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, 
intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical 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 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 
215 993-1220) 
7.3.4.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported as AEs to Merck 
or FDA, unless there is evidence suggesting a causal relationship between the 
drug and the event. Any such event will be submitted to Merck Global Safety 
within 2 working days either by electronic or paper media. 
 
Specifically, the suspected/actual events covered in this exception include any 
event that is disease progression of the cancer under study. 
 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be 
considered a SAE. 
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 


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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.   
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
Study Design and Sample Size 
This is a multi-center prospective open-label single arm phase 2 study assessing 
the activity of age-adjusted HiDAC (<60 years: 2 gm/m2 IV Q12hours days 1-5; 
>60 years: 1.5 gm/m2 IV Q12hours days 1-5) salvage induction treatment 
followed by pembrolizumab 200 mg IV on day 14 for relapsed or refractory AML 
patients.  
 
The subjects who achieve a response (CR, CRi, or PR) to induction phase HiDAC 
followed by pembrolizumab 200 mg IV on day 14, as assessed by standard 
international European LeukemiaNet Guidelines in AML,21 will receive 
pembrolizumab 200 mg IV Q3weeks of maintenance therapy beginning 10-30 
days following full hematologic recovery from induction phase. Maintenance 
treatment will continue until disease progression, toxicity, physician and/or 
patient discretion, or up to 1 year of treatment.  
 
Simon’s like two-stage design with relaxed stopping for futility will be used.53 
The null hypothesis that the true CR rate (CR/CRi) for HiDAC followed by 
pembrolizumab is 20% will be tested against a one-sided alternative hypothesis. 
In this study, “relaxed stopping” refers to inclusion of PR in the first stage as 
some of these PRs may convert to a CR during maintenance. In the first stage, 19 
patients will be enrolled. If the number of patients who achieve a CR/CRi plus the 
number of patients with PR is equal to 4 or fewer in these 19 patients, the study 
will be stopped. Otherwise, 18 additional patients will be enrolled for a total of 37 
patients. The null hypothesis will be rejected if 12 or more CR/CRi’s are observed 
in 37 patients.. Assuming that the PR rate has a uniform distribution, Uniform (0, 
0.05), under H0, this design yields a type 1 error rate of at most 5% and power of 
at least 84% when the true CR rate for HiDAC followed by pembrolizumab is 0.4.  
8.2 
Continuous Monitoring for Toxicity 
Sequential boundaries will be used to monitor unacceptable toxicity rate in the 
trial. An unacceptable toxicity is defined as any drug-related grade 3 non-
hematologic toxicity (exceptions include infusion reactions, rash, fever, infection, 
nausea, fatigue and anorexia) persisting for >7 days despite supportive care), or 
any drug-related grade 4-5 non-hematologic toxicity (excluding infection). The 
accrual will be halted if excessive numbers of unacceptable toxicities is equal to 


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or exceeds bn out of n patients with full follow-up (see Table below). This is a 
Pocock-type stopping boundary that yields the probability of crossing the 
boundary at most 0.05 when the rate of unacceptable toxicity is equal to the 
acceptable rate of 0.2.  
 
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 4 4 5 5 5 6 6 6 7 7 7 8 8 8 8 9 9 
Number of Patients, n 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37  
 
 
Boundary, bn 
9 10 10 10 11 11 11 11 12 12 12 13 13 13 13 14 14  
 
 
 
The stopping boundary above will guide enrollment as well as suspension of 
accrual (i.e., when to stop the trial if necessary). Initially 3 patients will be 
enrolled. Since the study is stopped when 3 unacceptable toxicities are observed 
in the first 3 patients, we will not enroll a new patient until at least one of the first 
3 patients completes follow-up (i.e., reaches full hematologic recovery, deemed as 
refractory or CRi) and is confirmed not to have unacceptable toxicity. The 
enrollment will be continued in the same manner so that at any point in the trial 
the number of patients with unacceptable toxicities and the number of patients in 
the follow-up does not exceed bn where n is the total number of patients accrued 
so far.   
8.3 
Data Analysis Plans 
The primary endpoint of this study is the overall CR rate (CR+CRi) after HiDAC 
salvage followed by pembrolizumab on day 14. Responses will be assessed by 
standard international European LeukemiaNet Guidelines.21 
 
Secondary endpoints include the following: 
• Rates of unacceptable toxicity defined as any drug-related grade 3 non-
hematologic toxicity (exceptions: fever, rash, infection, infusion reactions, 
nausea, fatigue and anorexia) lasting for >7days despite supportive care, or 
any drug-related grade >4 non-hematologic toxicity (excluding infection) 
• Clinician assessed toxicity of HiDAC followed by pembrolizumab will be 
classified and graded according to NCI CTCAE, version 4.0. 
• Objective overall response rates will be defined as PR+CR+CRi as 
determined by international European LeukemiaNet Guidelines in AML.21  
• Clinician assessed toxicity of pembrolizumab maintenance will be 
classified and graded according to NCI CTCAE, version 4.0 
• RFS will be defined as time from day 1 of CR/CRi to relapse or death 
from any cause.  
• PFS will be defined as time from day 1 of response (i.e., PR/CR/CRi) to 
progression or death from any cause.  
• OS will be defined as time from day 1 of treatment until date of last 
known follow up or death of any cause.  


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Survival distributions will be summarized using the method of Kaplan and 
Meier. We will report median time where possible. All demographic and analytic 
data will be summarized by descriptive statistics.  Categorical data will be 
summarized using frequency tables while summary statistics such as means, 
medians, standard deviation, range, etc., will be provided for continuous data.  
95% confidence intervals will be reported as well.  
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 
• CVs and medical licensure for the principal investigator and any sub-
investigators who will be involved in the study. 


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• Form FDA 1572 appropriately filled out and signed with appropriate 
documentation  
• Financial Disclosures 
•  CAP and CLIA Laboratory certification numbers and institution lab 
normal values 
• Executed clinical research contract 
9.3 
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.     
9.4 
Registration Procedures 
All patients at affiliate sites must be registered with the LCCC CPO Multicenter  
at the University of North Carolina before enrollment to study.  To register a 
patient call the LCCC Multicenter at 919-966-7359 M-F 8:30am- 5pm EST. 
Securely scan and email the Multicenter Project Manager (preferred) or fax (919-
966-4300) the registration form, signed informed consents, signed eligibility form 
and all source documents to confirm eligibility.  
 
All UNC LCCC patients eligible for enrollment in this trial may be registered by 
the UNC site coordinator without using the network. The UNC site coordinator 
may review eligibility and register patients in the trial.  This process only applies 
to the UNC site and not to external sites. 
9.5 
Data Management and Monitoring/Auditing 
The CPO Multicenter 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).  LCCC 
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 LCCC Multicenter Data Coordinator 
can be reached at 919-843-2742 or 1-877-668-0683. 
 


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All data will be monitored and source data will be verified on selected 
subjects.  Queries will be issued on an ongoing basis on all subjects. Participating 
sites should respond to data queries within 14 days of receipt. The LCCC 
compliance committee or their designee will audit trial sites every twelve months 
while still enrolling or subjects are still on treatment. Participating sites must send 
source and regulatory documents to LCCC upon request, for remote monitoring 
and/or audit review. 
 
9.6 
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.   
9.6.1 Emergency Modifications 
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 LCCC 
Multicenter Regulatory Associate). 
9.6.2 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. 
 


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9.6.3 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 
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 reported per the UNC IRB 
policies. 
 
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 LCCC 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 LCCC Multicenter Regulatory Associate. 


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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 LCCC Multicenter Project Manager.   
The LCCC 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 Coordinator using the IRB’s web-
based reporting system.   
 
9.7 
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.   
 
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 LCCC Multicenter Regulatory 
Associate prior to submission to their IRB.   
9.8 
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 


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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. 
9.9 
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 
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. 
 
 


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10.0 REFERENCES 
 
1. 
Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. 
Blood 2006;107:3481-5. 
2. 
Mrozek K, Marcucci G, Nicolet D, et al. Prognostic significance of the European 
LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in 
adults with acute myeloid leukemia. J Clin Oncol 2012;30:4515-23. (Updated guidelines 
for 2017 availalble at http://www.bloodjournal.org/content/early/2016/11/28/blood-2016-
08-733196).   
3. 
Greenberg PL, Lee SJ, Advani R, et al. Mitoxantrone, etoposide, and cytarabine 
with or without valspodar in patients with relapsed or refractory acute myeloid leukemia 
and high-risk myelodysplastic syndrome: a phase III trial (E2995). Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2004;22:1078-
86. 
4. 
Forman SJ, Rowe JM. The myth of the second remission of acute leukemia in the 
adult. Blood 2013;121:1077-82. 
5. 
Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for adult 
patients with acute myeloid leukemia in first relapse. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 2005;23:1969-78. 
6. 
Ravandi F. Relapsed acute myeloid leukemia: why is there no standard of care? 
Best practice & research Clinical haematology 2013;26:253-9. 
7. 
Rowe JM LX, Cassileth PA, et al. . Very poor survival of patients with AML who 
relapse after achieving a first complete remission: the Eastern Cooperative Oncology 
Group Experience. Blood 2005:162a (abst 546). 
8. 
Herzig RH, Lazarus HM, Wolff SN, Phillips GL, Herzig GP. High-dose cytosine 
arabinoside therapy with and without anthracycline antibiotics for remission reinduction 
of acute nonlymphoblastic leukemia. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 1985;3:992-7. 
9. 
Ravandi F, Ritchie EK, Sayar H, et al. Vosaroxin plus cytarabine versus placebo 
plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia 
(VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. The 
lancet oncology 2015;16:1025-36. 
10. 
Roboz GJ, Rosenblat T, Arellano M, et al. International randomized phase III 
study of elacytarabine versus investigator choice in patients with relapsed/refractory 
acute myeloid leukemia. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 2014;32:1919-26. 
11. 
Litzow MR, Wang XV, Carroll MP, et al. A Randomized Phase II Trial of Three 
Novel Regimens for Relapsed/Refractory Acute Myeloid Leukemia (AML) Demonstrates 
Encouraging Results with a Flavopiridol-Based Regimen: Results of Eastern Cooperative 
Oncology Group (ECOG) Trial E1906. Blood 2014;124:3742. 
12. 
Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in 
adults with acute myeloid leukemia. Cancer and Leukemia Group B. The New England 
journal of medicine 1994;331:896-903. 


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June 02, 2018 
 
Amendment 07 
 
 
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13. 
Ho AD, Lipp T, Ehninger G, et al. Combination of mitoxantrone and etoposide in 
refractory acute myelogenous leukemia--an active and well-tolerated regimen. J Clin 
Oncol 1988;6:213-7. 
14. 
Amadori S, Arcese W, Isacchi G, et al. Mitoxantrone, etoposide, and 
intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of 
refractory acute myeloid leukemia. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 1991;9:1210-4. 
15. 
Trifilio SM, Rademaker AW, Newman D, et al. Mitoxantrone and etoposide with 
or without intermediate dose cytarabine for the treatment of primary induction failure or 
relapsed acute myeloid leukemia. Leukemia research 2012;36:394-6. 
16. 
Montillo M, Mirto S, Petti MC, et al. Fludarabine, cytarabine, and G-CSF 
(FLAG) for the treatment of poor risk acute myeloid leukemia. American journal of 
hematology 1998;58:105-9. 
17. 
Wrzesien-Kus A, Robak T, Lech-Maranda E, et al. A multicenter, open, non-
comparative, phase II study of the combination of cladribine (2-chlorodeoxyadenosine), 
cytarabine, and G-CSF as induction therapy in refractory acute myeloid leukemia - a 
report of the Polish Adult Leukemia Group (PALG). European journal of haematology 
2003;71:155-62. 
18. 
Wierzbowska A, Robak T, Pluta A, et al. Cladribine combined with high doses of 
arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage 
regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: 
a final report of the Polish Adult Leukemia Group. European journal of haematology 
2008;80:115-26. 
19. 
Becker PS, Kantarjian HM, Appelbaum FR, et al. Clofarabine with high dose 
cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and 
refractory acute myeloid leukaemia. British journal of haematology 2011;155:182-9. 
20. 
Faderl S, Wetzler M, Rizzieri D, et al. Clofarabine plus cytarabine compared with 
cytarabine alone in older patients with relapsed or refractory acute myelogenous 
leukemia: results from the CLASSIC I Trial. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2012;30:2492-9. 
21. 
Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute 
myeloid leukemia in adults: recommendations from an international expert panel, on 
behalf of the European LeukemiaNet. Blood 2010;115:453-74. 
22. 
O'Donnell MR, Abboud CN, Altman J, et al. Acute myeloid leukemia. Journal of 
the National Comprehensive Cancer Network : JNCCN 2012;10:984-1021. 
23. 
Disis ML. Immune regulation of cancer. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2010;28:4531-8. 
24. 
Brown JA, Dorfman DM, Ma FR, et al. Blockade of programmed death-1 ligands 
on dendritic cells enhances T cell activation and cytokine production. Journal of 
immunology (Baltimore, Md : 1950) 2003;170:1257-66. 
25. 
Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-
cell apoptosis: a potential mechanism of immune evasion. Nature medicine 2002;8:793-
800. 
26. 
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunological reviews 2010;236:219-42. 


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27. 
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature reviews 
Immunology 2002;2:116-26. 
28. 
Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-infiltrating 
immune cells and is associated with poor outcome for patients with renal cell carcinoma. 
Clinical cancer research : an official journal of the American Association for Cancer 
Research 2007;13:1757-61. 
29. 
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: 
Jekyll or Hyde. Cancer metastasis reviews 2007;26:373-400. 
30. 
Usubutun A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic 
factors in renal cell carcinoma. Journal of experimental & clinical cancer research : CR 
1998;17:77-81. 
31. 
Deschoolmeester V, Baay M, Van Marck E, et al. Tumor infiltrating 
lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC 
immunology 2010;11:19. 
32. 
Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune 
cells within human colorectal tumors predict clinical outcome. Science (New York, NY) 
2006;313:1960-4. 
33. 
Diez M, Pollan M, Enriquez JM, et al. Histopathologic prognostic score in 
colorectal adenocarcinomas. Anticancer research 1998;18:689-94. 
34. 
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: 
molecular biology. International journal of clinical oncology 2010;15:544-51. 
35. 
Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. 
Journal of cutaneous pathology 2010;37 Suppl 1:48-53. 
36. 
Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. The lancet 
oncology 2009;10:840-1. 
37. 
Hillen F, Baeten CI, van de Winkel A, et al. Leukocyte infiltration and tumor cell 
plasticity are parameters of aggressiveness in primary cutaneous melanoma. Cancer 
immunology, immunotherapy : CII 2008;57:97-106. 
38. 
Lee HE, Chae SW, Lee YJ, et al. Prognostic implications of type and density of 
tumour-infiltrating lymphocytes in gastric cancer. British journal of cancer 
2008;99:1704-11. 
39. 
Leffers N, Gooden MJ, de Jong RA, et al. Prognostic significance of tumor-
infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian 
cancer. Cancer immunology, immunotherapy : CII 2009;58:449-59. 
40. 
Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification 
of positive selection in the thymus of PD-1-deficient mice. The Journal of experimental 
medicine 2000;191:891-8. 
41. 
Liotta F, Gacci M, Frosali 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 international 2011;107:1500-6. 
42. 
Zhou Q, Munger ME, Highfill SL, et al. Program death-1 signaling and regulatory 
T cells collaborate to resist the function of adoptively transferred cytotoxic T 
lymphocytes in advanced acute myeloid leukemia. Blood 2010;116:2484-93. 
43. 
Berthon C, Driss V, Liu J, et al. In acute myeloid leukemia, B7-H1 (PD-L1) 
protection of blasts from cytotoxic T cells is induced by TLR ligands and interferon-


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gamma and can be reversed using MEK inhibitors. Cancer immunology, immunotherapy 
: CII 2010;59:1839-49. 
44. 
Kondo A, Yamashita T, Tamura H, et al. Interferon-gamma and tumor necrosis 
factor-alpha induce an immunoinhibitory molecule, B7-H1, via nuclear factor-kappaB 
activation in blasts in myelodysplastic syndromes. Blood 2010;116:1124-31. 
45. 
Kronig H, Kremmler L, Haller B, et al. Interferon-induced programmed death-
ligand 1 (PD-L1/B7-H1) expression increases on human acute myeloid leukemia blast 
cells during treatment. European journal of haematology 2014;92:195-203. 
46. 
Dolen Y, Esendagli G. Myeloid leukemia cells with a B7-2(+) subpopulation 
provoke Th-cell responses and become immuno-suppressive through the modulation of 
B7 ligands. European journal of immunology 2013;43:747-57. 
47. 
Yao S, Chen L. Adaptive resistance: a tumor strategy to evade immune attack. 
European journal of immunology 2013;43:576-9. 
48. 
Graf M, Reif S, Hecht K, et al. High expression of costimulatory molecules 
correlates with low relapse-free survival probability in acute myeloid leukemia (AML). 
Annals of hematology 2005;84:287-97. 
49. 
Bishop JF, Matthews JP, Young GA, et al. A randomized study of high-dose 
cytarabine in induction in acute myeloid leukemia. Blood 1996;87:1710-7. 
50. 
Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--
preclinical background: CTLA-4 and PD-1 blockade. Seminars in oncology 2010;37:430-
9. 
51. 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates 
of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-54. doi: 
10.1056/NEJMoa1200690. Epub 2012 Jun 2. 
52. 
Goswami M, McGowan KS, Lu K, et al. A multigene array for measurable 
residual disease detection in AML patients undergoing SCT. Bone Marrow Transplant 
2015. 
53. 
Ivanova A, Deal A. Two-stage design for phase II oncology trials with relaxed 
futility stopping. Statistics and Its Interface 2015;5. 
 
 
 


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11.0 Appendices 
11.1 
Appendix A. PROMIS SF v1.1 Global Health Questionnaire 
 
 


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Please respond to each item by 
marking one box per row 
Excellent 
Very good 
 
Good 
Fair 
Poor 
Global 01 
In general, would you say your health 
is: 
5 □ 
4 □ 
3 □ 
2 □ 
1 □ 
Global 02 
In general, would you say your quality 
of life is: 
5 □ 
4 □ 
3 □ 
2 □ 
1 □ 
Global 03 
In general, how would you rate your 
physical health? 
5 □ 
4 □ 
3 □ 
2 □ 
1 □ 
Global 04 
In general, how would you rate your 
mental health, including your mood 
and your ability to think? 
5 □ 
4 □ 
3 □ 
2 □ 
1 □ 
Global 05 
In general, how would you rate your 
satisfaction with your social activities 
and relationships? 
5 □ 
4 □ 
3 □ 
2 □ 
1 □ 
Global 09 
In general, please rate how well you 
carry out your usual social activities 
and roles. (This includes activities at 
home, at work and in your community, 
and responsibilities as a parent, child, 
spouse, employee, friend, etc.) 
5 □ 
4 □ 
3 □ 
2 □ 
1 □ 
 
 
 
Complete
ly  
Mostly  
Moderately  
A Little  
Not At 
All  
Global 06 
To what extent are you able to carry 
out your everyday physical activities 
such as walking, climbing stairs, 
carrying groceries, or moving a chair?  
5 □ 
4 □ 
3 □ 
2 □ 
1 □ 
 
 
In the past 7 days  
Never  
Rarely  
Sometimes  
Often  
Always  
Global 10 
How often have you been bothered by 
emotional problems such as feeling 
anxious, depressed or irritable?  
5 □ 
4 □ 
3 □ 
2 □ 
1 □ 
 
 
None  
Mild  
Moderate  
Severe  
Very 
Severe  
Global 08 
How would you rate your fatigue on 
average?  
5 □ 
4 □ 
3 □ 
2 □ 
1 □ 
Global 07  
How would you rate your pain on 
average?  
□      □      □     □       □      □     □      □       □      □     □ 
0       1      2      3       4      5      6      7        8      9     10 
No pain                                                                Worst  pain 


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11.2 
Appendix B. Dose modification and toxicity management guidelines for immune-related AEs associated with 
pembrolizumab 
General instructions: 
4. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
5. 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.  
6. 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) 
followed by taper 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
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 
Grade 4 
Permanently 
discontinue 


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feasible, fluid and electrolytes should be 
substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 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 
• 
Monitor for signs and symptoms of thyroid 
disorders.  


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or liothyroinine) per standard 
of care 
 
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 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
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 
2. 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).   
 
Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs 
and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of 


LCCC 1522 
 
CONFIDENTIAL 
PI: Zeidner 
 
UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
Amendment 07 
 
 
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completion of infusion. Dose modification and toxicity management guidelines on pembrolizumab associated infusion reaction 
are provided in Table 4.  
 
Table 4   Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 


LCCC 1522 
 
CONFIDENTIAL 
PI: Zeidner 
 
UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
Amendment 07 
 
 
80 
 
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 
participant is deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption 
but responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, 
IV fluids); 
prophylactic 
medications indicated 
for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the 
infusion may be restarted at 50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug treatment 
Participant may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
_____ with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 


LCCC 1522 
 
CONFIDENTIAL 
PI: Zeidner 
 
UNIVERSITY OF NORTH CAROLINA 
June 02, 2018 
 
Amendment 07 
 
 
81 
 
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: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used 
immediately. 
Participant is permanently discontinued from further study 
drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov