A Phase II Randomized, Placebo-Controlled, Multicenter Trial to Evaluate Protective Function of an Optimized Dose of CMVPepVax in Recipients of an Allogeneic Hematopoietic Stem Cell Transplant
Phase: PHASE2
Conditions: Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Myeloid Leukemia in Remission, Adult Hodgkin Lymphoma, Adult Non-Hodgkin Lymphoma, Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Cytomegaloviral Infection, Hematopoietic and Lymphoid Cell Neoplasm, HLA-A*0201 Positive Cells Present, Myelodysplastic Syndrome, Adult Lymphoblastic Lymphoma, Chronic Lymphocytic Leukemia, Myelofibrosis, Myeloproliferative Neoplasm
Sponsor: City of Hope Medical Center

 
IRB # 13494 
 
02/19/2020      
Version: 28 
CITY OF HOPE MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
Department of Hematology and Hematopoietic Cell Transplantation       
                                             
TITLE:          A PHASE II RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER TRIAL TO EVALUATE PROTECTIVE FUNCTION 
OF AN OPTIMIZED DOSE OF CMVPepVax IN RECIPIENTS OF AN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT 
 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 
13494  
VERSION: 28 
 
 
                   
DATE(S) OF AMENDMENTS/REVISIONS: 
 
 
COH Initial Approval               Protocol Dated 03/30/15                                                              Version 00 
COH Amendment 01              Title Page Dated 04/22/15                                                            Version 01 
 
COH Amendment 02              Protocol Dated 04/28/15                                                               Version 02 
 
COH Amendment 03              Protocol Dated 05/05/15                                                               Version 03 
COH Amendment 04              Title Page Dated 05/26/15                                                            Version 04        
COH Amendment 05              Title Page Dated 06/09/15                                                            Version 05 
COH Amendment 06              Protocol/TP Dated 08/10/15                                                        Version 06 
COH Amendment 07              Protocol/TP Dated 09/01/15                                                        Version 07 
COH Amendment 08              Protocol/TP Dated 11/09/15                                                        Version 08 
COH Amendment 09              Protocol/TP Dated 12/08/15                                                        Version 09 
COH Amendment 10              Protocol/TP Dated 1/19/16                                                          Version 10 
COH Amendment 11              TP only Dated 02/02/16                                                                Version 11 
COH Amendment 12              TP/Protocol Dated 03/08/16                                                        Version 12 
COH Amendment 13              TP/Protocol Dated 04/12/16                                                        Version 13 
COH Amendment 14              TP/Protocol Dated 05/12/16                                                        Version 14 
COH Amendment 15              TP/Protocol Dated 06/09/16                                                        Version 15 
COH Amendment 16              TP/Protocol Dated 07/12/16                                                        Version 16 
COH Amendment 17              TP/Protocol Dated 10/24/16                                                        Version 17 
COH Amendment 18              TP/Protocol Dated 11/01/16                                                        Version 18 
COH Amendment 19              TP/Protocol Dated 12/21/16                                                        Version 19 
COH Amendment 20              Title Page Dated 04/25/17                                              
Version 20 
COH Amendment 21              TP/Protocol Dated 04/03/17                                             
Version 21 
COH Amendment 22              TP/Protocol Dated 07/14/17                                             
Version 22 
COH Amendment 23              TP/Protocol Dated 10/03/17                                             
Version 23 
COH Amendment 24              TP/Protocol Dated 11/01/17                                             
Version 24 
COH Amendment 25  
TP/Protocol Dated 04/08/2019 
 
 
 
Version 25 
COH Amendment 26  
TP only Dated 05/15/2019 
 
 
 
 
Version 26 
COH Amendment 27  
TP only Dated 07/02/2019 
 
 
 
 
Version 27 
COH Amendment 28  
TP/Protocol Dated 02/19/2020 
 
 
 
Version 28 
 

 
IRB # 13494 
 
02/19/2020      
Version: 28 
 
 
 
 
 
 
 
DISEASE SITE:                                               Hematopoietic System 
 
 
 
 
   SPONSOR/IND NUMBER: 
City of Hope / IND#  BB-13124 
 
 
TYPE (e.g., Pilot, Phase I, etc.):               Phase II, Therapeutic 
  
 
 
 
 
PRINCIPAL INVESTIGATOR: 
              Ryotaro Nakamura, M.D. (Study PI), Armin Rashidi, M.D. (UMN Site PI) 
COLLABORATING INVESTIGATORS:         Don J. Diamond Ph.D., Corinna La Rosa Ph.D., Joycelynne Palmer, Ph.D. 
 
 
 
PARTICIPATING CLINICIANS: 
Haris Ali M.D., Ibrahim Aldoss, M.D., Shukaib Arslan, M.D.,  Andrew Artz, M.D., Elizabeth 
Budde, M.D., Ji-Lian Cai, M.D., Thai Cao    M.D., Len Farol M.D., Stephen Forman, M.D., 
Alex Herrera M.D., Myo Htut M.D., Chatchada Karanes M.D., Samer Khaled M.D., Paul 
Koller, M.D., Amrita Krishnan M.D., Guido Marcucci, M.D., Matthew Mei, M.D., Al Malki 
M.D., Joshua Mansour, M.D., Auayporn Nademanee M.D., Liana Nikolaenko, M.D., Leslie 
Popplewell M.D., Vinod Pullarkat M.d., Firoozeh Sahebi M.D., Amandeep Salhotra M.D., 
Karamjeet Sandhu, M.D., Tanya Siddiqi, M.D., Eileen Smith M.D., David Snyder M.D., 
Ricardo Spielberger M.D., Anthony Stein M.D., Michael Rosenzweig M.D, Ahmed Aribi 
M.D, Nitya Nathwani M.D., John Zaia, M.D. Jasmine Zain, M.D. 
 
 
STUDY STATISTICIAN:   Dongyun Yang, Ph.D. 
 
 
PARTICIPATING SITES:  City of Hope, Duarte, CA (Lead Institution), University of Minnesota Masonic Cancer Center,  
MN, Fred Hutchinson Cancer Research Center, WA, Ohio State University, OH, Emory University, GA.  

Page 1 of 91 
 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
DEPARTMENT OF HEMATOLOGIC ONCOLOGY AND HEMATOPOIETIC CELL TRANSPLANTATION 
TITLE:  A PHASE II RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER TRIAL TO EVALUATE 
PROTECTIVE FUNCTION OF AN OPTIMIZED DOSE OF CMVPepVax IN RECIPIENTS OF AN ALLOGENEIC 
HEMATOPOIETIC STEM CELL TRANSPLANT 
CITY OF HOPE PROTOCOL NUMBER: 
13494 
VERSION: 28   
 
 
 
SPONSOR/IND NUMBER: 
City of Hope / IND#  BB-13124 
PRINCIPAL INVESTIGATORS  
Ryotaro Nakamura M.D. (Study PI; Lead Institution PI) 
Department of Hematology and HCT 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 
Phone: 626-256-4673 
Fax: 626-301-8116 
e-mail: RNakamura@coh.org 
 
Armin Rashidi, M.D (Site PI) 
Division of Hematology, Oncology, and Transplantation 
University of Minnesota, Department of Medicine 
14-152 Phillips Wangensteen Building 
516 Delaware Street SE 
Minneapolis, MN 55455    
Phone: 612-624-0123 
Fax: 612-625-6919 
Email: arashidi@umn.edu 
 
Joshua Hill, M.D. (Site PI) 
Vaccine and Infectious Disease Division 
Fred Hutchinson Cancer Research Center 
1100 Fairview Ave. N, Seattle, WA  
Phone: 206-667-6504 
Fax: 206-667-4411 
Email: jahill@fredhutch.org 
 
Hannah Choe, M.D. (Site PI) 
Ohio State University, 
B316 Starling Loving Hall 
320 W 10th Avenue, Columbus, Ohio 43210 
Phone: 614-293-5655 
Email: Hannah.Choe@osumc.edu 
 
Ned Waller, M.D., PhD (Site PI) 
Department of Hematology and Medical Oncology, 

Page 2 of 91 
 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Winship Cancer Institute, Emory University, 
Bldg C, 1365 Clifton Road NE, Atlanta, GA 30322 
Phone: (404) 778-1900 
Fax: (404) 778-3110 
Email: ewaller@emory.edu 
 
COLLABORATING INVESTIGATORS 
 
Don J. Diamond, Ph.D. 
Department of Hematology and HCT 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 
Phone: 626-256-4673 
Fax: 626-301-8981 
e-mail: DDiamond@coh.org 
 
Corinna La Rosa, Ph.D. 
Department of Hematology and HCT 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 
Phone: 626-256-4673 
Fax: 626-301-8981 
e-mail: Clarosa@coh.org 
 
Jeffrey S. Miller, M.D. 
University of Minnesota Medical Center 
Medicine/Blood and Marrow Transplantation 
425 E. River Rd, CCRB 654 
Minneapolis, MN 55455 
Phone: 612-626-4024 
Fax: 612-626-3941 
e-mail: mille011@umn.edu 
 
STUDY STATISTICIAN: 
 
 
Jeff Longmate, Ph.D. 
Department of Information Sciences 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 
Phone: 626-256-4673 
Fax: 626-471-7106 
e-mail: JLongmate@coh.org 
 
PARTICIPATING SITES: 
City of Hope, Duarte, CA (Lead Institution) 
Participating sites:                  
University of Minnesota Masonic Cancer Center, MN  
Fred Hutchinson Cancer Research Center, WA,  
Ohio State University, OH. 
Emory University, Atlanta, GA. 
 
 
 
 
 

Page 3 of 91 
 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
AGENT NSC#  
NSC#  721434   
 
COORDINATING CENTER 
 
Data Coordinating Center 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 
Phone: 626-256-4673 x 63968 
e-mail: DCC@coh.org 
 
 
 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 4 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
First 100 Days Post HCT 
 
Allocation to study arm based on CMV donor status 
CMVPepVax N=30 (1)* 
Placebo N=30(1)*  
CMV
+ adults undergoing  8/8 high resolution HLA donor allele matched 
hematopoeitic stem cell transplant (HCT) for treatment of a hematologic 
malignancy 
Projected enrollment of ~106-115 participants to meet 
-60 to
 
0 days 
Pre-
HCT 
HCT (Day 0) 
Informed Consent, Screening Procedures, Eligibility Review 
                       Up to 365 Days Post HCT  
p
(1-2x/week) 
- 
 Engraftment 
- 
 Physical Exam 
- 
 Clinical labs 
- 
 CMV-PCR 
- 
 CMV disease 
- 
Disease relapse 
Monitoring and assessments 
per SOC 
 -Physical Exam 
 -Clinical labs 
 -CMV-PCR 
 -CMV disease 
 -Engraftment 
- Disease relapse 
- Acute/chronic GVHD 
Randomization 
- 
Allocation communicated to 
pharmacy ~Day 21.  
- 
Pharmacists, biostatistician, staff 
and monitors will know the 
randomization status.  Remaining 
study team members and 
participants will be blinded. 
Day 28 Evaluation for Vaccination  
- 
Participants who do not meet the 
Day 28 vaccine criteria are 
removed from the study and 
replaced: 
- 
Primary engraftment without 
secondary graft failure 
- 
Absence of CMV disease and CMV 
viremia (qPCR ≤ 500 gc/ml) 
- 
Disease has not relapsed 
- 
No ongoing ≥ Grade 3 AEs 
- 
Prednisone or equivalent must be 
<1 mg/kg/day for 7 days 
- 
Only participants who receive a 
Day 28 vaccine are considered 
“randomized”. 
Vaccine Administration 
- 
Vaccine must be administered 
within 90 minutes of preparation 
start time. 
- 
 1 ml subcutaneous injection to 
upper arm. 
Disease Relapse 
- 
Participants who experience 
disease relapse are followed for 
survival only through Day 365. 
Clinical Care During Trial  
- 
Clinical care will be per SOC except: 
- 
Vaccines are prohibited to Day 70 
Post-HCT 
- 
Prophylactic use of anti-viral 
therapy is prohibited 
- 
Prophylactic use of CMV IgG 
prohibited 
- 
In vivo T-cell depleting agents are 
prohibited 
- 
Prednisone or equivalent must be 
<1 or 1.5 mg/kg/day for 7 days 
prior to Day 28 and Day 56 vaccine 
to meet vaccine administration 
criteria 
Day 28 
Research blood sample + SOC assessments 
Review of vaccine administration criteria 
Vaccine administration 
Day 42 
Research blood sample + SOC assessments 
Day 56 
Research blood sample + SOC assessments 
Review of vaccine administration criteria 
Vaccine administration 
Day 70 
Research blood sample + SOC assessments 
Day 100 
Research blood sample + SOC assessments 
Day 84 
Research blood sample + SOC assessments 
Day 140 
Research blood sample + SOC assessments 
Day 180 
Research blood sample + SOC assessments 
Day 270 
Research blood sample + SOC assessments. 
Day 365 
Research blood sample + SOC assessments 
Experimental Design Schema 
CMVPepVax + Prevymis   
Prevymis   N=18 
* The first cohort consisting of 61 patients is still blinded, so it is not known which arm has 30, and which 31 patients 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 5 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Summary of the amendment 
The protocol is being revised with inclusion of an additional cohort that would allow testing a 
combination of the CMVPepVax vaccine and a newly approved anti-viral agent Prevymis (letermovir) in 
order to address possible synergy between CMV suppression by Prevymis and boosting anti-CMV 
immunity by CMVPepVax vaccine. For this purpose the accrual of the cohort including 61 patients not 
administered Prevymis is closed, and accrual of a new cohort of 36 patients is proposed where all 
patients would be administered Prevymis and co-administered CMVPepVax or placebo (blinded and 
randomized 1:1).  
This new design will allow addressing the unmet need of stimulating CMV-specific immunity and 
lowering reactivation risk for patients after cessation of Prevymis dosing. 
Protocol Synopsis 
Protocol Title: 
A Phase II randomized, placebo-controlled, multicenter trial to evaluate protective function of an 
optimized dose of CMVPepVax in recipients of an allogeneic HSCT. 
Brief Protocol Title for the Lay Public (if applicable): 
CMVPepVax, a new vaccine to prevent cytomegalovirus infection after allogeneic stem cell 
transplantation 
Sponsor, IND 
COH under IND# BB-13124 
Study Phase: 
Phase II, Randomized, Blinded, Interventional 
Participating Sites: 
City of Hope National Medical Center, University of Minnesota, Fred Hutchinson Cancer Research 
Center, Ohio State University, Emory University 
Rationale for this Study: 
Cytomegalovirus (CMV) reactivation with ensuing viremia is one of the main infectious complications 
in the first 100 days following allogeneic hematopoietic cell transplant (HCT) [1-6].   While anti-viral 
agents that limit viral replication may keep CMV viremia initially in check, they may also result in 
significant toxicity and fail to protect against late-onset CMV disease, including reactivation and failure 
to reconstitute CMV-specific immunity.  
CMVPepVax (IND BB-13124) is a peptide vaccine composed of an antigenic HLA A*0201 restricted 
pp65495-503 CMV CD8 cytotoxic T cell (CTL) epitope, covalently linked to a universal tetanus T helper 
(TH) epitope [7] and co-administered with Pfizer PF-03512676 adjuvant [8].  HLA-restricted peptide 
epitopes are a promising option to develop a safe, non-infectious subunit CMV vaccine, avoiding CMV 
immune-evasion mechanisms [9]. Moreover, it has been reported that T cells specific for CMV-pp65, a 
principal target for CTLs can protect HCT recipients from CMV complications [9, 10]. The PF-03512676 
adjuvant is a single strand DNA-based sequence containing bacterial CpG DNA motifs, which activates 
Toll-like Receptor 9 (TLR9) leading to potent immunostimulatory effects, such as B cell and NK cell 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 6 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
activation and proinflammatory cytokine production. 
A Phase Ib trial conducted in HLA A*0201 healthy adults (COH IRB 03121) indicates that CMVPepVax is 
safe and induces robust expansion of CMV-pp65 CD8 T cells in the healthy adult population [8]. A 
second Phase 1b pilot trial (COH IRB 12022) was conducted in CMV seropositive HLA A*0201 adult 
recipients of matched related donor (MRD) or unrelated donor (MUD) HCT. A total of 36 patients were 
randomized to Vaccine Arm (VA) or Observation Arm (OA); those who were assigned to VA received 
CMVPepVax on days 28 and 56 post-HCT and those in OA were followed for clinical and immunologic 
data monitoring (open label).  
Preliminary results from this target population indicate excellent tolerability, safety and 
immunogenicity of CMVPepVax compared to the observation arm. CMV viremia (DNAemia) was 
observed in 6 of 18 patients in OA compared with 1 of 18 patients in VA. Furthermore preliminary data 
from this study suggest that CMVPepVax may improve transplant related outcomes such as chronic 
GVHD (cGVHD) and disease relapse. Now that safety and preliminary immunogenicity have been 
established in the target population with the day 28 and 56 post-HCT vaccination schedule, a Phase II 
study is necessary to assess the efficacy of CMVPepVax administered with this schedule and in the 
target population to assess efficacy in protecting against CMV reactivation and disease.   
 
Rationale for the revised aims and design based on the interim analysis: 
The interim analysis (after 48 patients reached day 100 follow up) for the primary endpoint (Section 
12.4 Data Analysis Plan) unexpectedly showed that more CMV events observed on the vaccine arm (5 
events) than on the placebo arm (3 events), thus meeting the futility stopping rule. Additional data on 
these 48 patients (24 in CMVPepVax arm, 24 in placebo arm) are detailed in Table 2.5.  While the 
clinical efficacy was not seen for the primary endpoint, the immunologic recovery was favorable for 
the CMVPepVax arm, and no safety issues have been found. Taking the abovementioned finding into 
account the cohort of patients that were enrolled initially (61 patient) is now closed for accrual. Anti-
viral agent Prevymis was approved for CMV prophylaxis after the study was initiated, and while 
CMVPepVax is not currently thought to be a suitable alternative for Prevymis administration, it can 
possibly address the significant risk of CMV reactivation that occurs after the completion of Prevymis 
administration [11]. This unmet need motivated the amendment of the protocol for the study to 
include an additional cohort, which could verify a possible synergy in treatment of the patients with a 
combination of Prevymis and CMVPepVax. Complementing antivirals with a vaccine that harnesses the 
abundant native immune response to CMV may improve outcomes for HCT recipients [12]. In addition, 
this approach may allow achieving protective immunity ahead of the early reactivation that may occur 
during the prophylaxis period and was observed in the absence of Prevymis prophylaxis. Because 7 of 
the 8 primary outcomes occurred prior to the second planned injection, the rationale for using 
CMVPepVax in the context of Prevymis prophylaxis is thought to be directly relevant to the nature of 
the events that led to early stopping. 
 
Objectives: 
Primary Objective:  
For the entire cohort (n=97): 
1) To determine if CMVPepVax increases levels, function and kinetics of CMV-specific T cell immunity 
in vaccinated compared to placebo treated HLA A*0201, CMV seropositive HCT-recipients,  

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 7 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
For the Prevymis combination cohort (n=36) 
1) To provide a preliminary evaluation of the incidence of CMV reactivation between day 28 and 
day 180 in patients who receive standard Prevymis prophylaxis (from day 14 through day 
100), comparable to the evaluation of an expansion cohort in a pilot study, or the futility 
stage of a phase II trial. 
2)   To determine if CMVPepVax increases levels, function and kinetics of CMV-specific T cell 
immunity in vaccinated HCT patients who receive standard Prevymis prophylaxis. 
 
Secondary Objectives:  
1. To determine, within the constraints of a pilot cohort, if CMVPepVax reduces the 
frequency of CMV events alone or in combination with Prevymis defined as reactivation or 
CMV disease in HLA A*0201 allogeneic HCT-R+.  A CMV event encompasses any detection 
of CMV by either qPCR (termed “reactivation”: DNAemia ≥500 gc/ml or by tissue histology 
(end-organ disease).  
2. To evaluate the safety and tolerability of CMVPepVax by assessing the following:  non-
relapse mortality (NRM) at 100 days post HCT, severe (grade 3-4) acute GVHD (aGVHD), 
and grade 3-4 AEs (CTCAE 4.0) probably or definitely related to the vaccination within 2 
weeks from each vaccination. 
3. To characterize CMV reactivation and CMV disease in recipients of CMVPepVax compared 
to placebo by assessing time to viremia (defined as number of days from transplantation 
to the date of ≥500 CMV gc/mL), duration of viremia, recurrence of viremia, incidence of 
late CMV viremia/disease (>100 and ≤ 360 days post HCT), use of antiviral drugs (triggered 
by clinically significant viremia, cumulative number of CMV specific antiviral treatment 
days. To evaluate the impact of CMVPepVax on transplant related outcomes by assessing 
the incidence of acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, non-relapse 
mortality, all-cause mortality, non-CMV infections.  
4. To determine whether vaccination induces adaptive NK cell population changes, and 
increase in the highly cytotoxic memory NKG2C+ NK cells,  
5. To determine the impact of CMVPepvax on CMV immune reconstitution in patients who 
undergo treatment with antiviral agent Prevymis 
6. To explore GVHD biomarkers and compare between the vaccine and placebo groups, 
7. To characterize CMV reactivation after day 180 
 
 
Study Design: 
Overall design: 
 This is a multi-center, randomized, blinded, placebo-controlled, parallel-group Phase II trial to 
evaluate: a) increase in CMV cellular immunity, in HLA A*0201 allogeneic HCT-R+ vaccinated with 
CMVPepVax relative to those injected with placebo, b) reduction in the frequency of CMV reactivation 
and disease (CMV events). This trial is designed to 1:1 randomly allocate 97 HLA A*0201 allogeneic 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 8 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
HCT-R+ at risk for CMV complications to CMVPepVax arm or placebo arm [13].  
The revised protocol after the interim analysis will enroll 36 patients (18 in the CMVPepVax arm, 18 in 
the placebo arm) to provide an initial evaluation of vaccination in combination with Prevymis to help 
plan future studies if the futility endpoint is not met and T-cell results are favorable. Final immunologic 
analysis will include both the new (n=36) cohort as a subgroup and combined cohorts (n=97). 
Treatment categories for the 18 vs 18 cohort include either Prevymis + CMVPepVax, or Prevymis + 
Placebo. No treatment category in this cohort includes CMVPepVax only, placebo only, or CMVPepVax 
+ placebo. 
 
Enrollment and randomization:  
The enrolment and randomization of the Prevymis cohort will continue as originally planned. Eligible 
HCT-R+ will be consented and enrolled pre-HCT, and registered through the COH data coordinating 
center (COH-DCC). A computer-generated randomization program, stratified by donor CMV serostatus 
will assign registered participants to the CMVPepVax or placebo arm; the treatment assignment will be 
generated and provided to site pharmacists, who are unmasked to treatment-group allocation, in 
advance of planned vaccination. Registered participants will be followed for the course of transplant 
and be assessed for vaccine administration criteria for ‘Day-28 post-HCT’ vaccination. Participants who 
meet vaccine administration criteria will receive the vaccine; participants who do not meet criteria will 
discontinue study participation and be replaced.  Only participants who receive a vaccine (CMVPepVax 
or placebo) will be considered “randomized”. Information regarding registered participants who do 
not receive vaccine will be entered into the computer-generated randomization program to inform the 
randomization algorithm for subsequent treatment assignments.  
After the interim analysis of 61 enrolled patients resulted in reaching futility in regard to the primary 
endpoint, the study has been amended to provide a preliminary evaluation of clinical benefit, and 
immunological outcomes, comparing two study arms that were added to evaluate CMVPepVax 
efficacy in combination with Prevymis compared to Prevymis alone. For this reason, we have closed 
accrual of the initial cohort (61 patients) who did not receive Prevymis and propose to enroll a new 
cohort of 36 patients to be assigned to either CMVPepVax, or placebo groups, and all of whom will 
concurrently receive Prevymis. Every patient in the new cohort of 36 patients (18 vs 18) will receive 
Prevymis as standard of care. The combined enrollment will be conducted up to a total of 97 patients. 
Administration of CMVPepVax/Placebo: A 1 ml volume of vaccine (CMVPepVax or placebo) is 
administered subcutaneously (SC) on days 28 and 56 post-HCT.  
Administration of Prevymis: Patients in both Prevymis arms will receive Prevymis at a dose of 480 mg 
per day through week 14, up to 100 days post-HCT. 
Duration of participation: Study participation will be completed on Day 365 Post-HCT for all 
participants who receive vaccine or placebo administration. Participants who do not receive a vaccine 
or placebo administration will discontinue further follow-up once the determination is made that the 
injection will not be administered.  
Stopping rules and planned interim analysis:  Rigorous stopping rules will be implemented, and will 
include three major safety endpoints; non-relapse mortality (NRM) at 100 days post HCT, severe 
(grade 3-4) acute GVHD (aGVHD), and serious AEs (SAE, grade 3-4) related to the vaccination within 2 
weeks from each vaccination. There will be an interim futility analysis when the first 48 patients are 
evaluable for the primary endpoint (frequency of CMV reactivation before day 100). If the observed 
CMV event-rate in the  CMVPepVax arm is higher than on the placebo arm, the study will be 
suspended for NCI and DSMC review [14].   The loss of power of invoking a stopping rule at 50% of 
accrual is less than 0.02 [14], under the event rates assumed for planning.  In light of the lower 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 9 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
observed rates, the false alarm rate should be revised upward. 
Monitoring of the Prevymis cohort will be done by applying the original monitoring rules for NRM, 
severe aGVHD, and SAE in two ways, firstly treating subjects on Prevymis and CMVPepVax as a 
continuation of the CMVPepVax arm, and secondly, treating subjects on Prevymis and CMVPepVax as 
a novel therapy and applying the monitoring rules for the first 12 subjects.  There will be no further 
interim analysis for futility, as the entire Prevymis cohort is motivated, in part, as an opportunity to 
subject the combination of CMVPepVax with Prevymis to a futility evaluation. 
Endpoints: 
Primary endpoints:     
For the entire cohort (n=97): Immunological endpoints - levels of CD8+ T cells binding to A2-CMV-
dextramers®, combined with T and NK cell phenotype and function. 
For the combination cohort (n=36): CMV reactivation [≥1,250 IU/mL] or CMV disease between day 56 
and day 180 post-HCT in patients who receive standard Prevymis prophylaxis (from day 14 through 
day 100). 
Secondary endpoints:  
Key safety endpoints: Non-relapse mortality (NRM) at 100 days post HCT, severe (grade 3-4) aGVHD, 
and grade 3-4 AEs (CTCAE 4.0) probably or definitely related to the vaccination within 2 weeks from 
each vaccination. 
CMV reactivation [≥1,250 IU/mL] or CMV disease prior to day 100 post-HCT. Timing and recurrence of 
events are included in the primary analysis. 
CMV-related endpoints:  Duration of viremia, incidence of late CMV viremia (>100 and ≤ 360 days post 
HCT), use of antiviral drugs (triggered by clinically significant viremia), cumulative number of CMV 
specific antiviral treatment days. 
Clinical endpoints: Time to engraftment, incidence of aGVHD, chronic GVHD (cGVHD), relapse, non-
relapse mortality, all-cause mortality, non-CMV infections.   
Immunologic endpoints for the combination cohort (n=36): Immune reconstitution measured as levels, 
function and kinetics of CMV-specific T cells through day 180 post-HCT in patients who receive 
standard Prevymis prophylaxis (day 14 through day 100). 
Sample Size: 
The target of this Phase II multicenter study was originally to randomize 97 HLA A*0201 allogeneic 
HCT-R+ to either the CMVPepVax vaccine arm (N=48), or to the placebo arm (N=48). With the expected 
dropout rate of 10-15% prior to randomization, the total accrual is expected to be 106-115.   
Following the results of the interim analysis the original cohort (n=61) that included patients without 
Prevymis administration is closed for accrual. 
New cohort (Prevymis cohort) is opening for accrual in which 36 patients will be randomized 1:1 
(18/18) for CMVPepVax or Placebo. The number of patients for this cohort (36 patients) is based on 
budgetary constraints, the futility rules for the new cohort are independent and are based on the 
original futility rules.  Based on a Phase III trial of Prevymis, we expect 17 percent of placebo subjects 
to reactivate after second vaccination on week 8. This is based on the expectation that 33 percent will 
be high-risk subjects. Assuming that CMVPepVax vaccination during prophylaxis can reduce the week 8 
through week 26 reactivation rate to 5 percent, the probability that there are more reactivations on 
the placebo arm than on the CMVPepVax arm is approximately 88 percent, which can be regarded as 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 10 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
the power for a non-futile finding.  
If CMVPepVax offers no protection, there would be a 50 percent chance of a futility finding, and T-cell 
data would likely indicate many subjects with poor CMVPepVax antigen recognition. If CMVPepVax has 
strong protection (5% reactivation), a finding of futility is unlikely (12 percent) and an evident 
biological effect would be expected in most patients. 
 
Estimated Duration of the Study 
Over the past five years, COH and UMN combined have performed on-average ~ 300 adult allogeneic 
HCT procedures annually. We anticipate about 70 to be eligible annually being HLA A*0201 and CMV 
seropositive. It is estimated that accrual will be completed in <5 years from the start date of the trial, 
and that trial we anticipate 1 year of follow up and data analysis.  
Summary of Subject Eligibility Criteria: 
Pre-HCT Inclusion Criteria 
 
Age 18 to 75 years.  
 
Planned HCT for the treatment of hematologic malignancy (some exceptions including 
multiple myeloma) 
 
Planned related or unrelated HCT, with 8/8 (A,B,C,DRB1)  HLA donor allele matching and with 
minimal to no T-cell depletion of graft 
 
HLA A*0201, CMV seropositive (recipient)  
 
Seronegative for HIV, HCV and active HBV 
Pre-HCT Exclusion Criteria 
 
Patients undergoing a second allo-HCT are not eligible (patients who have undergone a 
previous  autologous HCT are eligible) 
 
Prior investigational CMV vaccine, Experimental anti-CMV chemotherapy in the last 6 months 
 
No planned use of the following after HCT: Live attenuated vaccines, medically indicated 
subunit or killed vaccines, alemtuzumab or any equivalent in vivo T-cell depleting agent 
 
Aplastic anemia 
 
Patients with active autoimmune conditions requiring systemic immunosuppressive therapy 
within the previous 5 years are not eligible  
 
Pregnant women and women who are lactating.  
Post-HCT Day 28 Vaccine Administration Criteria* 
 
No patients with CMV reactivation between days 0-28 post HCT, defined as having a 
detectable CMV level according to City of Hope institutional standard 
 
No ≥ Grade 3 GVHD between days 0-28 post HCT 
 
Disease has not relapsed since HCT 
 
Successful primary engraftment without secondary graft failure 
 
No ongoing post-HCT ≥ Grade 3 non-hem AE’s, with the exception of grade 3 glucose 
intolerance, cholesterol, triglyceride, and hyperglycemia 
 
No for CMV viremia: CMV qPCR < 500 gc/ml from samples collected and resulted within the 
past 7 days 
 
Negative for CMV end organ disease (biopsy proven CMV disease) post-HCT 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 11 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
 
All prednisone doses within the past 7 days have been ≤ 1 mg/kg/day (or prednisone 
equivalent)  
 
Not received any medications that might interfere with CMVPepVax 
 
For Prevymis cohort patients: patients who received Prevymis for at least 7 days before day 
+28 post HCT 
*Participants who do not meet vaccine administration criteria will be removed from the trial and 
replaced. This is not an eligibility criteria for the trial. 
Investigational Product Dosage and Administration: 
Participants will be randomized to receive either CMVPepVax vaccine or the placebo vaccine.  The 
pharmacy will know the randomization status of participants, while the clinical study team and 
participants will remain blinded. Vaccine (1 ml of placebo or CMVPepVax) will be administered 
subcutaneously in the upper arm on Days 28 and 56 post-HCT. Time window for the administration is 
+/- 7 days. There are no dose modifications, although participants must meet vaccine administration 
criteria in order to receive the vaccine. 
CMVPepVax vaccine is constituted of approx. 2.5 mg Tet-CMV + 1.08 mg PF-03512676[8] adjuvant 
diluted in normal saline and sodium acetate.   
Placebo vaccine comprises an isotonic solution of cGMP-grade solution of sodium acetate and NeutTM 
(0.4% Sodium Bicarbonate Additive Solution).   
 
Clinical Observations and Tests to be Performed: 
Clinical observations/clinical tests: Medical history, physical exams, performance status, routine 
laboratory tests (CBC, chemistry panel), CMV qPCR, GVHD assessment, AE assessment, diagnostics for 
disease relapse assessment (bone marrow and imaging studies), diagnostics for CMV disease 
assessment,  according to institutional standard of care. All of the study endpoints listed above will be 
monitored and recorded. Clinical CMV disease and use of anti-viral drugs will be prospectively 
monitored and recorded. 
Immunologic studies:  Immunologic studies will include monitoring levels of CD8+ T cells binding to 
pp65 A2-CMV-dextramers®, combined with immunophenotyping studies [15, 16].  The phenotypic 
ratios of CMV-specific T cells will be related to improvement in control of CMV viremia. Highly 
cytotoxic memory NKG2C+ NK cells [17], linked to CMV reactivation and critical for CMV adaptive 
immune response will be characterized at UMN [18-20].   
Statistical Considerations: 
Planning for measures of immune function is based on results of COH protocol 12022, the open-label 
analog of this placebo-controlled protocol.  In that trial, 10 of 18 vaccinated subjects developed CMV 
pp65-specific CD8+ T-cells that were strongly concentrated (> 80%) in effector memory phenotypes, 
and did so without CMV reactivation.  This can be compared to 1 of 14 non-vaccinated subjects who 
did not reactivate.  In the current study, the planned sample size of 48 subjects per arm would provide 
approximately 80% power for a one-sided 0.05-level test assuming a 50% rate of this event from a 25% 
rate on the placebo arm.  Beyond this measure of vaccine-induced immune function, the data will be 
used to describe the longitudinal changes in immune function with and without vaccine, in subjects to 
do and do not reactivate CMV. With this amendment, we will similarly describe the longitudinal 
changes in patients receiving Prevymis as prophylaxis. The combined analysis T-cell data using all 
subjects will be stratified by Prevymis, and the original power calculation remains relevant to this 
comparison. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 12 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
 
With regard to the incidence of CMV events, the sample  size  of  48  individuals per arm was originally 
designed to detect a reduction in CMV reactivation from 40% to 15% at 100 days post-HCT, providing 
90% power at one-sided 10% significance level (these are the typical operational characteristics in  
randomized Phase II trials [21]).  The aim of detecting an overall benefit in all vaccinate patients has 
been abandoned after the interim analysis for futility, and continued enrollment is based on the new 
primary aims. 
 
The comparison of CMV event rates across CMVPepVax arms for the new Prevymis cohort is motivated 
as a futility analysis, for informing a subsequent decision about further development of CMVPepVax.  
The Operating characteristics of that evaluation, analogous to the power of a hypothesis test, are 
described above, under Sample size.  
Formal stopping rules for safety are embedded in the design of this study. Clinical data will be 
monitored as they accumulate, and investigation of CMVPepVax will be suspended for safety review if 
there is evidence of serious treatment-related AEs. 
Monitoring of the Prevymis cohort will, as described above, be done conservatively as both a 
continued monitoring of a series of patients receiving CMVPepVax, and as monitoring of a new series 
of patients receiving CMVPepVax in combination with Prevymis. 
 
Specifically: 
(1) 100 days NRM will be monitored as the 12th, 24th and 36th subject on the vaccine arm reaches the 
100 day evaluation point. Operationally, the CRA will notify the monitoring statistician as cohorts of 24 
patients (12 vaccinated) near the 100 day mark. If NRM frequencies exceed 4, 6, or 8, at the 
designated 100 day evaluation point, then the trial will be suspended for safety review by the COH and 
external site DSMCs. These numbers were selected to limit the overall false-alarm probability for this 
endpoint to less than 0.02 when there is no additional risk due to immunization. 
 (2) Severe acute GVHD (aGVHD, grade 3-4) will be monitored as every 12th subject on the vaccine arm 
reaches the 100 day evaluation point. aGVHD will be scored using Keystone consensus criteria[22]. The 
trial will be interrupted at each respective center for safety review by the COH and external site 
DSMCs if 6 or more of the first 12 recipients, or 9 of 24, or 11 of 36, experience Grade 3-4 aGVHD. This 
would be a significant elevation from the COH/UMN historical benchmark of 15% of allogeneic HCT 
recipients with matched sibling donors [23].  These rules are determined to limit the overall aGVHD 
false alarm probability to 0.02 if vaccination does not increase risk [23].  
(3) Any serious AEs (SAE, grade 3-4) related to the vaccination within 2 weeks from each vaccination 
will be reviewed by the PMT when each 12th patient on the CMVPepVax arm passes the 2 week post-
injection time for their second injection. 
 
 
 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 13 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Table of Contents 
SECTION 
 
 
 
 
 
 
 
 
 
 
PAGE 
Experimental Design Schema ......................................................................................................................... 4 
Protocol Synopsis............................................................................................................................................ 5 
Table of Contents ......................................................................................................................................... 13 
List of Tables and Figures .............................................................................................................................. 15 
1.0 
Goals and Objectives (Scientific Aims) ........................................................................................... 18 
2.0 
Background..................................................................................................................................... 19 
2.1 
Introduction/Rationale for Development ........................................................................ 19 
2.2 
Overview and Rationale of Study Design ......................................................................... 21 
2.3 
Preclinical Studies ............................................................................................................ 23 
2.4 
Human Studies ................................................................................................................. 24 
2.5 
Interim analysis and rationale for continuation of the trial ............................................. 35 
3.0 
Participant Eligibility Criteria .......................................................................................................... 39 
3.1 
Pre-HCT Inclusion Criteria ................................................................................................ 39 
3.2 
Pre-HCT Exclusion Criteria ................................................................................................ 40 
3.3 
Participation of Special Populations ................................................................................ 41 
4.0 
Participant Enrollment and Randomization ................................................................................... 41 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures ........................................ 41 
4.2 
Participant registration .................................................................................................... 41 
4.3 
Randomization ................................................................................................................. 42 
4.4 
Emergency De-Blinding Procedures ................................................................................. 43 
5.0 
Treatment Program ........................................................................................................................ 43 
5.1 
Treatment Overview ........................................................................................................ 43 
5.2 
Maintaining a blinded randomization .............................................................................. 43 
5.3 
Vaccine Administration and Pre-Vaccination Prophylaxis ............................................... 44 
5.4 
Assessments ..................................................................................................................... 44 
5.5 
Criteria for Completing/Discontinuing Study Participation ............................................. 46 
5.6 
Follow-Up and Duration of Participation ......................................................................... 46 
5.7 
Supportive Care, Other Concomitant Therapy, Prohibited Medications ......................... 47 
6.0 
Vaccine Administration Criteria ..................................................................................................... 48 
6.1 
Day 28-Post-HCT Vaccine Administration Criteria ........................................................... 48 
6.2 
Day 56-Post-HCT Vaccine Administration Criteria ........................................................... 48 
7.0 
Adverse Events List and Reporting of Unanticipated Problems and Adverse EventS .................... 49 
7.1 
Toxicities to CMVPepVax ................................................................................................. 49 
7.2 
Toxicities to the Placebo Vaccine ..................................................................................... 49 
7.3 
Definitions ........................................................................................................................ 49 
7.4 
Routine Reporting of Adverse Events by Site Investigators ............................................. 51 
7.5 
Expedited Reporting of Unanticipated Problems and SAEs by Site Investigators ............ 51 
7.6 
Reporting of Adverse events by the Study PI ................................................................... 52 
8.0 
Agent Information .......................................................................................................................... 54 
8.1 
CMVPepVax and Placebo Vaccine –information applicable to vaccine components ...... 54 
8.2 
Tet-CMV, the synthetic peptide contained in CMVPepVax ............................................. 55 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 14 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
8.3 
PF-03512676, the adjuvant of CMVPepVax ..................................................................... 56 
8.4 
Sodium acetate, the synthetic peptide diluent contained in CMVPepVax ...................... 56 
8.5 
Neut™ Sodium Bicarbonate Additive Solution for the Placebo Vaccine .......................... 57 
8.6 
Preparation of CMVPepVax ............................................................................................. 58 
8.7 
Preparation of Placebo Vaccine ....................................................................................... 59 
9.0 
Correlative/Special Studies ............................................................................................................ 60 
9.1 
Immunogenicity testing ................................................................................................... 60 
10.0 
Study Calendar ............................................................................................................................... 62 
11.0 
Endpoint Evaluation Criteria/Measurement of Effect .................................................................... 64 
12.0 
Statistical Considerations ............................................................................................................... 65 
12.1 
Study Design..................................................................................................................... 65 
12.2 
Randomization ................................................................................................................. 66 
12.3 
Sample Size Accrual Rate ................................................................................................. 66 
12.4 
Data Analysis Plan ............................................................................................................ 67 
12.5 
Safety Monitoring ............................................................................................................ 68 
13.0 
Data Handling, Data Management, Record Keeping ...................................................................... 68 
13.1 
Source Documents ........................................................................................................... 68 
13.2 
Data Capture Methods and Management ....................................................................... 69 
13.3 
Case Report Forms/Data Submission Schedule ............................................................... 69 
13.4 
Regulatory Records .......................................................................................................... 70 
14.0 
Adherence to the Protocol ............................................................................................................. 70 
15.0 
Study Oversight, Quality Assurance, and Data & Safety Monitoring ............................................. 71 
15.1 
Site Principal Investigator ................................................................................................ 71 
15.2 
Study Principal Investigator ............................................................................................. 71 
15.3 
Protocol Management Team (PMT) ................................................................................. 72 
15.4 
Monitoring ....................................................................................................................... 72 
15.5 
Quality Assurance ............................................................................................................ 72 
15.6 
City of Hope Data and Safety Monitoring Committee ..................................................... 72 
16.0 
Ethical and Regulatory Considerations ........................................................................................... 73 
16.1 
Ethical Standard ............................................................................................................... 73 
16.2 
Regulatory Compliance .................................................................................................... 73 
16.3 
Institutional Review Board ............................................................................................... 74 
16.4 
Informed Consent ............................................................................................................ 74 
16.5 
Women, Minorities, Children, HIV-Positive Individuals (Special Populations) ................ 74 
16.6 
Participant Confidentiality ............................................................................................... 75 
16.7 
Conflict of Interest ........................................................................................................... 76 
16.8 
Financial Obligations, Compensation, and Reimbursement of Participants .................... 76 
16.9 
Publication/Data Sharing ................................................................................................. 76 
17.0 
References ...................................................................................................................................... 78 
Appendix A: List of Supplemental Materials................................................................................................. 83 
Appendix B: Acute GVHD Staging ................................................................................................................. 84 
Appendix C: Chronic GVHD Grading ............................................................................................................. 85 
Appendix D: Karnofsky Performance Scale................................................................................................... 86 
 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 15 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Appendix E: Reagents, Equipment and Supplies Necessary for Vaccine Preparation .................................. 87 
Appendix F: PREPARATION OF CMVPEPVAX USING INITIAL LOT (#L0402009) OF TET-CMV ....................... 88 
Appendix G: SAE/UP Reporting Coversheet ................................................................................................. 90 
Appendix H: Registration Coversheet ........................................................................................................... 91 
 
 
List of Tables and Figures 
Figure 2.3.1 
Potency of GMP-grade Tet-CMV with and without PF03152676 adjuvant in HLA A*0201 
HHDII transgenic mice ................................................................................................................. 24 
Table 2.4.1a 
Adverse events at least possibly related to CMV peptide (Tet-CMV and PADRE-CMV) with or 
without adjuvant in healthy volunteers ...................................................................................... 25 
Table 2.4.1b 
Adverse events at least possibly related to CMVPepVax in CMV positive healthy volunteers 
vaccinated with 2.5 mg Tet-CMV peptide with adjuvant (CMVPepVax) ..................................... 26 
Figure 2.4.1a Longitudinal profiles of dsDNA autoantibody levels in sera of healthy volunteers vaccinated 
with CMVPepVax or CMV peptide without adjuvant. ................................................................. 27 
Figure 2.4.1b Longitudinal profiles of ex vivo pp65495-503 tetramer+ CD8+ T cell levels in response to CMV 
peptide with and without adjuvant, grouped by strength of pre-vaccination ex vivo pp65495-
503 tetramer+ CD8+ T cell level ...................................................................................................... 28 
Figure 2.4.1c 
IVS pp65495-503 or the HIVgag77-85 CD8+ T-cells as a percentage of all IVS CD8+ T-cells in 
healthy volunteers vaccinated with CMV peptide + PF-03512676 .............................................. 29 
Table 2.4.2 
List of SAEs in CMVPepVax vaccinated HCT recipients (N=17) .................................................... 30 
Figure 2.4.2a Longitudinal profiles of dsDNA IgG autoantibody levels (AAU/ml) in sera of HCT recipients 
vaccinated with CMVPepVax ....................................................................................................... 31 
Figure 2.4.2b aGVHD and cGVHD in HCT recipients vaccinated with CMVPepVax and control HCT patients .. 32 
Figure 2.4.2c 
CMV-pp65 495-503 pentamer CD8+ T cell amplification in HCT recipients vaccinated with 
CMVPepVax ................................................................................................................................. 33 
Figure 2.4.2d  CD8 T cells binding to CMV pp65 and HIV gag (control) MHC class I pentamers in a 
representative HCT recipient vaccinated with CMVPepVax (UPN8) ........................................... 33 
Figure 2.4.2d Kinetics of CD8+ T cells/ul binding to CMV- pp65 and HIV gag (control) MHC class I 
pentamers in a representative HCT recipient vaccinated with CMVPepVax (UPN 14) ............... 34 
Table 2.5           Interim Analysis ............................................................................................................................29 
Table 10.0  
Study Activity Calendar ................................................................................................................ 62 
Table 13.3  
Data Submission Schedule ........................................................................................................... 69 
 
 
ABBREVIATIONS 
Abbreviation 
Meaning 
AE 
Adverse Event 
aGVHD 
BDP 
CBC 
cGVHD 
Acute Graft Versus Host Disease 
Biopharmaceutical Development Program NCI-Frederick, MD 
Complete Blood Count 
Chronic Graft Versus Host Disease 
cGMP 
Current Good Manufacturing Practice  
CLIA 
Clinical Laboratory Improvement Amendments 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 16 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
CMV  
CMVPepVax 
Cytomegalovirus 
Tet-CMV co-injected with PF-03512676  
COH 
City of Hope 
CRA/CRC 
Clinical Research Associate/Coordinator 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTL 
Cytotoxic T lymphocytes  
DET 
DSMC 
Department of Experimental Therapeutics 
Data Safety Monitoring Committee 
FDA 
Food and Drug Administration 
FOS 
Foscarnet 
GCP 
Good Clinical Practice 
GCV 
Ganciclovir 
GVHD  
Graft versus host disease  
HBV 
Hepatitis B virus 
HCT 
Hematopoietic Stem Cell Transplant 
HCT-R+ 
CMV positive HCT recipients 
HCV 
Hepatitis C virus 
HHV6 
Human herpes virus 6 
HIV 
Human immunodeficiency virus 
HPV 
Human papilloma virus 
HSV 
Herpes simplex virus 
HVTN/DAIDS 
HIV Vaccine Trials Network/Division of AIDS 
IB 
Investigator Brochure 
IDS 
ICF 
Investigational Drug Service 
Informed Consent Form 
IM  
Intramuscular  
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IV  
Intravenous  
IVS 
In vitro stimulation 
MRD  
MUD 
NCI 
Matched  Related Donor  
Matched  Unrelated Donor  
National Cancer Institute 
NRM 
Non-relapse mortality 
OIDRA 
PBMC 
Office of IND Development and Regulatory Affairs 
Peripheral Blood Mononuclear Cells  
PD-1 
Program death receptor-1 
PF-03512676 
PI 
R+ 
Pfizer synthetic single stranded CpG DNA adjuvant  
Principal Investigator 
CMV positive HCT recipients 
PMT 
Protocol Monitoring Team 
SAE 
Serious Adverse Event 
SAIC 
Science Applications International Corporation  
SC 
Subcutaneous  
SOC 
Standard Of Care 
Tet-CMV 
Tetanus-CMV 
Tg 
Transgenic 
TH 
T helper 
TLR9() 
 
Toll-like receptor 9 
TTL  
UMN 
Translational Therapy Laboratory 
University of Minnesota Medical Center  
VAL 
Valganciclovir 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 17 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
 
 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 18 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
Primary Objectives:  
For the entire cohort (n=97): 
1) To determine if CMVPepVax increases levels, function and kinetics of CMV-specific T cell immunity in 
vaccinated compared to placebo treated HLA A*0201, CMV seropositive HCT-recipients,  
For the Prevymis combination cohort (n=36) 
1) To provide a preliminary evaluation of the incidence of CMV reactivation between day 56 and 
day 180 in patients who receive standard Prevymis prophylaxis (from day 14 through day 100), 
comparable to the evaluation of an expansion cohort in a pilot study, or the futility stage of a 
phase II trial 
2)  To determine if CMVPepVax increases levels, function and kinetics of CMV-specific T cell 
immunity in vaccinated HCT patients who receive standard Prevymis prophylaxis. 
 
Secondary Objectives:  
1. To determine, within the constraints of a pilot cohort, if CMVPepVax reduces the frequency of 
CMV events alone or in combination with Prevymis defined as reactivation or CMV disease in 
HLA A*0201 allogeneic HCT-R+.  A CMV event encompasses any detection of CMV by either 
qPCR (termed “reactivation”: DNAemia ≥500 gc/ml or by tissue histology (end-organ disease).  
2. To evaluate the safety and tolerability of CMVPepVax by assessing the following:  non-relapse 
mortality (NRM) at 100 days post HCT, severe (grade 3-4) acute GVHD (aGVHD), and grade 3-4 
AEs (CTCAE 4.0) probably or definitely related to the vaccination within 2 weeks from each 
vaccination. 
3. To characterize CMV reactivation and CMV disease in recipients of CMVPepVax compared to 
placebo by assessing time to viremia (defined as number of days from transplantation to the 
date of ≥500 CMV gc/mL), duration of viremia, recurrence of viremia, incidence of late CMV 
viremia/disease (>100 and ≤ 360 days post HCT), use of antiviral drugs (triggered by clinically 
significant viremia, cumulative number of CMV specific antiviral treatment days. To evaluate the 
impact of CMVPepVax on transplant related outcomes by assessing the incidence of acute GVHD 
(aGVHD), chronic GVHD (cGVHD), relapse, non-relapse mortality, all-cause mortality, non-CMV 
infections.  
4. To determine whether vaccination induces adaptive NK cell population changes, and increase in 
the highly cytotoxic memory NKG2C+ NK cells,  
5. To determine the impact of CMVPepVax on CMV immune reconstitution in patients who 
undergo treatment with antiviral agent Prevymis 
6. To explore GVHD biomarkers and compare between the vaccine and placebo groups, 
7. To characterize CMV reactivation after day 180 
 
 
 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 19 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
2.0 
BACKGROUND 
2.1 Introduction/Rationale for Development 
Human CMV is a highly prevalent, globally-occurring infection that rarely elicits disease in healthy 
immunocompetent hosts. The human immune system is unable to clear CMV infection and latency, but 
mounts a spirited immune-defense targeting multiple immune-evasion genes encoded by this double-
stranded DNA β-herpes virus. Encoding around 165 genes, CMV is among the largest and most complex 
of known viruses [9]. The size of the CMV-specific cellular immune response is the most striking aspect 
of the dynamic, life-long interaction between the host and CMV. CMV-specific T cells are essential to 
restrain CMV viral replication and prevent disease, though do not eliminate the virus or preclude 
transmission. 
Significant suppression of host antiviral immunity can alter the life-or-death immune surveillance 
homeostasis, allowing either CMV reactivation to become detectable or primary infection to cause 
clinical symptoms. Uncontrolled viral replication and dissemination results in the development of life-
threatening end-organ damage (CMV disease) [24-26]. CMV infection is the cause of major 
complications and significant morbidity in the recovery of immune-compromised recipients both at early 
and late times post- HCT [3, 5, 6]. HCT patients are vulnerable to herpes virus infections, including CMV, 
as a result of immunosuppression associated with treatment strategies aimed at preventing rejection or 
GVHD [27-29]. Pharmacologic agents used to limit virus replication, such as, GCV or its oral form VAL, 
and FOS have become the methods of choice for prophylaxis of CMV infection [3, 30]. Despite this, CMV 
remains an important cause of mortality after HCT diminishing the full curative potential of this 
successful cancer therapy [10, 31]. Furthermore, anti-viral chemotherapy has major side effects, 
including nephrotoxicity, neutropenia, and delayed immune reconstitution which exposes HCT 
recipients to other opportunistic viral, bacterial and fungal infections [6, 32]. For example, the use of 
GCV/VAL is associated with a higher proportion of recipients becoming neutropenic and increased 
numbers of concomitant fatal infections [6, 32]. As GCV/VAL therapy has become ubiquitous in practice, 
delayed onset of CMV-pneumonia (interstitial pneumonitis, IP) is more frequent which suggests that 
GCV/VAL impairs immunologic reconstitution [33, 34]. When antivirals are stopped or when virus 
resistance occurs, the same disease symptoms appear; only frame shifted to ~180 days post-HCT [5, 35-
37]. Thus, different strategies to control CMV are eagerly sought, since  antivirals are at best a stop-gap 
measure, and their use does not address the major risks of late-onset CMV-IP including early CMV 
reactivation and failure to reconstitute CMV-specific immunity [31]. Additionally costs associated with 
the usage of antivirals are significant, with one single course of GCV/VAL reaching $25,000. 
Prevymis has been approved by the FDA for all CMV seropositive HCT recipients to minimize the chance 
of CMV disease development and the use of Prevymis for this purpose is now adopted into the HCT SOP. 
In a separate cohort we are intending to study the highly novel combination of Prevymis and 
CMVPepVax vaccine developed by COH. This combination has no overlapping toxicities, and is 
potentially synergistic, or at least should possess additive protective effect for CMV infection. This is 
particularly promising since CMV-specific T cell immune reconstitution has not been described in 
patients receiving Prevymis, and late CMV reactivation after stopping Prevymis on day 100 remains a 
major clinical problem. This problem can be potentially overcome by the combination of Prevymis and 
CMVPepVax.  
Substituting or combining antivirals with a vaccine that harnesses the abundant native immune 
response to CMV may improve outcomes for HCT recipients. In particular, a CMV vaccine that confers 
protective immunity early post-transplant, until normal immunocompetence is re-established in the HCT 
recipient (6 months or earlier post-HCT) may reduce CMV morbidity and the use of antivirals [12]. It has 
been shown that control of CMV infection is primarily associated with cellular immune responses [38].  
The abundant tegument pp65 protein is a major contributor to shaping the T cell repertoire in CMV-

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 20 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
exposed individuals [39-41], and is a principal target for HLA Class I-restricted CD8+ CTL [9]. CMV-
infected cells express pp65 both early and late after infection, making it an appropriate vaccine target 
[42-45]. Early clinical studies showed that pp65 CTL development is necessary to overcome CMV disease 
in HCT recipients [2, 46, 47]. Adoptive transfer of pp65-specific CTL reduced CMV viremia after HCT in 
Phase I trials [48-52].  In patients who have measurable CMV viremia, expansion of pp65 specific CD8+ T 
cells occurs, especially after viral reactivation [53, 54].  In agreement with those observations, studies 
showed that CMV reactivation and disease were detectable only in patients with low level of CMV-
tetramer+ CD8+ T cells [10, 55]. Importantly, several reports have associated protection from CMV 
complications in HCT recipients with CMV-specific CD8+ T cell levels (including pp65-specific T cells) 
between 7-10/µL [10, 13]. A vaccine that induces protective levels of pp65 CTL has the potential to be of 
therapeutic benefit to an HCT recipient by limiting CMV viremia or disease [9, 10, 43-45, 48, 52, 56].  
Our group has identified a repertoire of CTL epitopes within the pp65 protein that can expand human 
pp65-specific memory CTLs in vitro [39, 40, 57]. The pp65495-503 epitope restricted to the high frequency 
HLA A*0201 allele has been extensively characterized [39-41]. Usage of the pp65495-503 CTL epitope is 
conserved with limited sequence variation among viral isolates [40, 57, 58]. Additionally, using HLA-
restricted CTL epitopes to develop a non-infectious subunit CMV vaccine can eliminate the safety 
concerns for HCT recipients of live-attenuated CMV or recombinant live viral vaccines, while avoiding 
the many CMV-encoded products involved in immune-evasion [43, 59, 60].  
We discovered that covalently linking the pp65 CTL epitope to native tetanus epitopes by solid phase 
synthesis, dramatically enhanced the immunogenicity of epitope vaccines [7, 8]. In HLA A*0201 Tg mice, 
two candidate vaccine peptides containing the HLA A*0201  pp65495-503 CD8+ T cell epitope fused to 
universal TH epitopes (either the synthetic PADRE or a natural Tetanus sequence) showed favorable 
immunogenicity profiles [7, 8, 61, 62].  The vaccine peptides were named PADRE-CMV and Tet-CMV, 
respectively [8]. Co-injection with PF-03512676 adjuvant (a synthetic single stranded CpG DNA with 
immunostimulatory activity [63]) further augmented their activity, providing a means to lower vaccine 
dosage [7, 64].  
cGMP-grade PADRE-CMV and Tet-CMV, with or without PF-03512676 adjuvant were clinically evaluated 
for safety and immunogenicity. The Phase Ib dose-escalation clinical trial (COH IRB 03121, 
NCT00722839@www.clinicaltrials.gov.) was conducted in HLA A*0201 healthy adults and indicated that 
the CMV peptides co-injected with PF-03512676 were safe and immunogenic. In particular, 2.5 mg Tet-
CMV +  PF-03512676 adjuvant in a final 1.0 ml volume, administered in the upper arm by SC route had a 
favorable safety profile and led to substantial expansion of pp65495-503 T cells after 2 vaccine injections. 
These data supported further evaluation in the HCT setting [8] of this formulation of Tet-CMV combined 
with PF-03512676, which was renamed CMVPepVax.   
In HCT recipients with nascent hematopoietic reconstitution and prolonged CD4+ T cell deficit, 
stimulation of TLR9 by PF-03512676 may substitute for the requirement of CD4-TH to sustain immune 
responses [65]. TLR9 is implicated as an endosomal receptor for bacterial CpG DNA motifs exemplified 
by PF-03512676 [63, 66]. While immune-reconstitution can be limited in allo-HCT population, 
CMVPepVax has the potential for greater potency when injected into CMV+ HCT recipients, since 
massive expansion of pp65-specific T cells have been shown in HCT patients under the conditions of 
CMV infection [10, 52]. Based on these findings, we performed an evaluation of safety and 
immunogenicity of two injections of CMVPepVax, in HLA A*0201 CMV-positive adult recipients of an 
HLA-matched 
allogeneic 
HCT 
for 
hematologic 
malignancies 
(COH 
IRB 
12022 
NCT01588015@www.clinicaltrials.gov.) which as of January 15th, 2015 has completed enrollment. 
In this open label Phase Ib trial, 36 allogenic HCT CMV positive recipients (R+) are randomized either to 
the CMVPepVax vaccine arm or the observational arm. HCT recipients in the vaccine arm are injected 
twice on days 28 and 56 post-HCT with CMVPepVax, during the critical period in which primary CMV 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 21 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
reactivation most predictably occurs (~day 40-100) [35, 67].  CMVPepVax has been safely administered 
to 18 HLA A*0201 R+ patients. Preliminary results indicate excellent tolerability, safety and substantial 
increases of CMV pp65495-503 CD8 T cells, without increased incidence of GVHD, in patients immunized 
with CMVPepVax. In particular, we observe a reduction in CMV reactivation and a significantly lower 
incidence of cGVHD in the CMVPepVax arm compared to the observational arm. Interestingly, all 
CMVPepVax vaccinated recipients continue to remain cancer free, while 3 observational patients 
experienced relapse of their hematological malignancy. Thus, we have safely treated HCT-R+ with 
CMVPepVax, but a crucial unattained objective is to assess vaccine protection against CMV reactivation 
and disease by the vaccine itself or in combination with Prevymis administration. Consequently, there is 
a strong rationale to test CMVPepVax using a randomized, blinded and placebo controlled Phase II 
efficacy trial. This proposed clinical study is designed to be a multicenter trial. Moreover, NCI NExT is 
providing a new lot of vaccine to support this multi-center Phase II study.  
2.2 Overview and Rationale of Study Design 
This is a randomized, blinded and placebo controlled Phase II efficacy trial which will be conducted as a 
multicenter clinical trial at COH and collaborating, external sites. This study has been designed to have 
sufficient statistical power for testing clinically significant endpoints. In particular, the goal of this Phase 
II clinical trial is to assess efficacy of CMVPepVax by itself and in combination with Prevymis 
administration, in protecting against CMV reactivation and disease in HLA A*0201 HLA-matched 
allogeneic (related or unrelated donor) HCT R+ (CMV positive HCT recipients) who are at significant risk 
for CMV complications [13]. The primary hypothesis to be tested is that immunizing HLA A*0201 
allogeneic HCT-R+ with CMVPepVax will provide superior protective benefit compared to a placebo.  The 
secondary hypothesis is that CMVPepVax immunizations will induce protective levels of CMV cellular 
immunity in HCT-R+ [63, 68, 69]. It is anticipated that the trial will provide definitive data on vaccine-
induced protective immunity against CMV reactivation and disease, in allogeneic HCT recipients [10].  
Participants must be planned recipients of a first 8/8 HLA-matched [70-73] allogeneic HCT for 
hematological malignancies, be HLA A*0201, CMV-positive, age 18-75 (chronologic age is no longer 
considered a contraindication for HCT [74, 75]), and willing to be monitored for 12 months following 
HCT. Exclusion criteria include receiving T cell depleted HCT, autoimmune disease, HIV, HCV and HBV 
positivity. Excluded diagnosis are aplastic anemia and multiple myeloma. Screening, enrollment and 
informed consent procedures will occur prior to the HCT procedure, as the prospective participant is 
likely better able to fully consider the study and provide an informed decision as the prospective 
participant’s status is more stable during this period. Vaccine administration criteria will be assessed on 
the day of planned vaccine administration (Day 28 post-HCT). The Day-28-Post-HCT criteria exclude 
participants who, post HCT, have experienced relapse of disease, have experienced CMV viremia or end 
organ disease, have received anti-viral treatment, have received high doses of steroids within 7 days of 
planned vaccine administration, or are experiencing ongoing grade 3 toxicities.   
This phase II efficacy trial will enroll and vaccinate 97 HLA A*0201 allogeneic HCT-R+, randomized 1:1 to 
either the CMVPepVax arm (N=48), or to the placebo arm (N=48). The first 61 subjects did not receive 
Prevymis, and were closed to accrual after the interim analysis, while the next cohort consisting of 36 of 
these randomized subjects will receive Prevymis treatment in addition to CMVPepVax or placebo. The 
resulting data will be stratified by agent administration (vaccine or placebo) and Prevymis 
administration (Prevymis or no Prevymis). Thus, the study will be blinded for CMVPepVax and open label 
for Prevymis. Because approximately 10-15% of enrolled participants may fail to meet post-HCT vaccine 
administration criteria, the total study accrual is expected to reach 106-115 participants. All patients in 
the new cohort (36 patients, 18 vs 18) will receive Prevymis as a standard of care. The size of the new 
cohort is based on the budgetary constraints of the original study plan. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 22 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
A computer-generated 1:1 randomization stratified by donor CMV serostatus will assign participants to 
the CMVPepVax or placebo arms. The registrar located at the COH Data Coordinating Center will contact 
either COH or the external sites to provide treatment assignment to the site pharmacists, who are 
unmasked to treatment-group allocation. Because visual inspection of the vaccine at the time of 
administration may reveal the arm to which a participant has been assigned, persons administering the 
vaccine will receive training about how not to reveal the treatment arm to the  participant and 
colleagues.  All study team members will receive orientation about the importance of maintaining a 
blinded randomization status.  
Participants meeting vaccine administration criteria will receive injections of either CMVPepVax or 
placebo on days 28 and 56 post-HCT, during the critical period in which primary CMV reactivation most 
predictably occurs (~day 40-100)[35, 67]. Both the CMVPepVax and placebo agents are administered at 
a final 1.0 ml volume, in the upper arm by subcutaneous route. 
CMVPepVax vaccine formulation and dosage (approx. 2.5 mg Tet-CMV + 1.08 mg PF-03512676 adjuvant 
diluted in sodium acetate) were chosen based on the data from the Phase Ib trial in healthy adults (COH 
IRB 03121), indicating mild reactogenicity and a favorable safety profile for this specific formulation when 
up to 4 SC injections were administered to healthy volunteers [8].  Preliminary results from the 
completed Phase Ib trial (COH IRB 12022) in  HLA A*0201 MRD and MUD  HCT R+ indicate excellent 
tolerability, safety and substantial increases of CMV pp65495-503 CD8 T cells in patients immunized with 
CMVPepVax using this formulation and dosage on Day 28 and Day 56 post-HCT, the same schedule to be 
used in this study.  
CMVPepVax administration provides a dose of 2.48mg Tet-CMV Peptide + 1.06mg PF-03512676 when 
the vaccine is prepared using the currently available Tet-CMV (LOT# L0402009, 11mg/1.1mL vial). 
CMVPepVax administration provides a dose of 2.64mg Tet-CMV Peptide + 1.08mg PF-03512676 when 
the vaccine is prepared using the new lot of Tet-CMV (LOT#L1501005, 3.3 mg/ml, fill volume 1.2mL ). 
 
Participants in the placebo arm will be vaccinated with an isotonic solution of cGMP-grade solution of 
sodium acetate/ NeutTM (4% Sodium Bicarbonate Additive Solution), the diluent used in the Phase Ib 
dose-escalation clinical trial (COH IRB 03121, NCT00722839@www.clinicaltrials.gov.) for Tet-CMV 
without PF-03512676 adjuvant. Participants who do not receive the first (Day 28) vaccine will be replaced 
and removed from the study. All participants who receive the first vaccine will be followed and assessed 
through Day 365 post-HCT, except for participants who demonstrated disease relapse.  Participants with 
relapsed disease will be in need of starting other therapies to control their disease, and therefore will be 
followed for survival only through Day 365.  
HCT recipients are heavily monitored for safety according to institutional standard of care practices, 
which recommend intense monitoring through the first 100 days following the HCT procedure. This 
study will depend on the standard of care (SOC) practices through Day 100 post-HCT of weekly or 
biweekly SOC assessments of CMV qPCR, clinical laboratory tests, engraftment assessment, GVHD 
assessment and physical exam, and, when clinically indicated, CMV disease assessment and disease 
relapse assessment; disease relapse is also routinely assessed at pre-determined time points per SOC. 
The procedures and clinical care provided to participants should not differ from that provided routinely 
to all post-HCT patients with the exception of restrictions on concomitant medications that might 
impact study endpoints such as prophylactic antiviral treatment, and T-cell depleting agents, and the 
administration of other vaccines whose prohibition is lifted after the second vaccination.   
From Day 28 through Day 100, study visits will occur bi-weekly, to coincide with vaccine administration 
and research blood sample collection, however information relevant to study endpoints will be obtained 
from any clinic visit, not just the at the corresponding study clinic visit. After Day 100, an additional four 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 23 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
study visits will occur up to and including Day 365 to ensure periodic documentation and/or evaluation 
of clinical endpoints and for the collection of research blood samples.  
Because data from the phase 1b study in HCT CMV-positive recipients demonstrated decreased disease 
relapse and chronic GVHD in CMVPepVax recipients, the study will investigate the impact of CMVPepVax 
on transplant related outcomes such as GVHD, disease relapse, mortality, and infection rate.  
Rigorous stopping rules will be implemented, and will include three major safety endpoints; non-relapse 
mortality (NRM) at 100 days post HCT, severe (grade 3-4) acute GVHD (aGVHD), and grade 3-4 AEs 
(CTCAEv4) related to the vaccination within 2 weeks from each vaccination. There will be an interim 
futility analysis once the first 48 patients are evaluable for the frequency of CMV reactivation before day 
100 (included in the primary endpoint). If the observed CMV viremia-rate in the CMVPepVax arm is 
higher than on the placebo arm, the study will be suspended for NCI and DSMC review [14].   The loss of 
power of invoking a stopping rule at 50% of accrual is less than 0.02[14].  
CMV-specific immunogenicity (included in the secondary endpoints) will be evaluated in all vaccinated 
participants from all arms (N=97) every 2 weeks from day 28 until day 100 post-HCT, and afterward on 
days 140, 180, 270, 365. Immunologic studies will include monitoring levels of CD8+ T cells binding to 
pp65 A2-CMV-dextramers®, combined with immunophenotyping studies [15, 16].  The phenotypic ratios 
of CMV-specific T cells will be related to improvement in control of CMV viremia. Based on the 
encouraging results of the pilot Phase Ib (COH IRB 12022), levels of pp65-specific T cells associated with 
protection from CMV viremia and disease are anticipated to be detected in a significantly higher 
proportion of vaccine recipients compared to those enrolled in the placebo arm [10]. Additional 
correlative immunogenicity studies (included in the secondary endpoints) will include measuring levels 
of highly cytotoxic memory NKG2C+ NK cells, linked to CMV reactivation, critical for CMV adaptive 
immune response and potentially linked to relapse reduction [17]. In the phase Ib trial of CMVPepVax in 
HCT recipients (COH IRB 12022) CMVPepVax administration was associated with reduced risk of chronic 
GVHD while there was no increase in acute GVHD. To further investigate potential immunologic impacts 
of CMVPepVax on GVHD, various GVHD biomarkers will be evaluated including various cytokines and 
hepatocyte growth factor  for systemic GVHD [76, 77],  elafin for skin GVHD [78], regenerating islet-
derived 3α (REG3α) for gastrointestinal GVHD [79], suppression of tumorigenicity 2 (ST2) for steroid-
refractoriness 5 [80], and CXCL9 [81, 82]and B cell–activating factor (BAFF) for chronic GVHD [81, 82]. 
The levels of these GVHD biomarkers will be compared between the vaccine group and placebo group, 
as well as between GVHD+ and – groups.   
 
2.3 Preclinical Studies 
2.3.1 
cGMP-grade Tet-CMV ± PF-03512676 adjuvant 
Tet-CMV ± PF-03512676 adjuvant (CMVPepVax = 2.5 mg Tet-CMV + 1 mg PF-03512676) has been 
extensively tested in Tg mouse models adults [7]. The cGMP-grade CMV vaccine products were evaluated 
in HLA A*0201 HHDII Tg mice, and potency results were confirmed, as illustrated in Figure 2.3.1 [8]. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 24 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Figure 2.3.1 
Potency of GMP-grade Tet-CMV with and without PF03152676 adjuvant in HLA 
A*0201 HHDII transgenic mice 
 
HLA A*0201 HHDII transgenic mice  were immunized with 100 nmoles of Tet-CMV (left) and Tet-CMV + 
PF03512676 (right). The plots show percentages of cytotoxicity at different effector to target rations 
(E:T) detected in a 4-h chromium release assay against either relevant (pp65495-503, black circles) or 
control (p53149-157, white circles) target cells. Data in each plot are representative of at least 6 
immunized mice. 
2.3.2 
Animal Toxicology 
Pre-clinical toxicology studies in rats revealed little to no toxicity of the cGMP-grade CMV peptides at all 
investigated dosages (from Southern Research Institute, Protocol 11200.11.01). 
2.4 Human Studies 
The proposed Phase II clinical trial in the HCT setting is supported by the promising safety data and 
immunogenicity profiles obtained using this vaccine formulation first in a clinical study performed in a 
cohort of healthy volunteers (IRB 03121), and subsequently in a single center pilot Phase Ib in HCT 
patients, that was completed at COH (IRB 12022).  
In particular, based on IRB (03121) and FDA (IND, BB-13124) approval, cGMP-grade PADRE-CMV and Tet-
CMV, with or without PF-03512676 adjuvant were clinically evaluated for safety and immunogenicity 
(Phase Ib trial) in healthy adults, expressing the HLA A*0201 MHC Class I allele sequence. The healthy 
adult study indicated that CMVPepVax was safe and induced robust expansion of CMV-pp65 CD8 T cells. 
These data supported further evaluation of  CMVPepVax in HLA A*0201 HCT recipients[8]. The 
completed Phase Ib pilot trial (IRB 12022) is designed to evaluate safety of administering CMVPepVax to 
HLA A*0201 MRD or MUD R+ at risk for CMV complications [13]. The published results have shown 
reliable safety, reduced CMV reactivation and cGVHD in HCT recipients injected with CMVPepVax 
compared to HCT recipients in the observation arm . 
2.4.1 
Phase Ib clinical trial in healthy adults (COH IRB 03121) 
The Phase Ib safety and immunogenicity clinical trial, performed at COH in healthy individuals was a 
non-randomized, open label, dose escalating study (NCT00722839@www.clinicaltrials.gov)[8]. Healthy 
male and female volunteers, 18 and 55 years old, CMV-seropositive or seronegative, and molecularly 
subtyped as HLA A*0201-positive were enrolled after signing informed consent. Participants were 
eligible unless they had ≥1 of the following exclusion criteria: abnormal serum chemistry and blood 
count; hepatitis B or C positive; immunodeficiency, including HIV; taking daily medications for chronic 
illness, surgery within 6 months of vaccination requiring general anesthesia; known cardiac disease 
including patients being treated for hypertension and high cholesterol; positive urine pregnancy 
test/planning to become pregnant within 6 months from vaccination; immunization with other vaccines 
within 1 month of the study period; participation in a CMV immunotherapy trial in the previous 6 months; 
history of cancer, depression, allergic diatheses, frequent migraines.  

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 25 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
The safety (primary endpoint) and immunogenicity (secondary endpoint) evaluation of CMV peptides (Tet-
CMV, and PADRE-CMV) was performed separately in two concomitant stages:  Tet-CMV or PADRE-CMV 
peptide alone and Tet-CMV or PADRE-CMV peptide co-injected with 1 mg PF-03512676 adjuvant [83].  The 
vaccine dose escalation (0.5, 2.5, 10 mg vaccine) was based on previous peptide vaccine studies[84]. A 
cGMP-grade sodium acetate solution was used as peptide diluent. Tet-CMV peptide formulation was 
comprised of 1 ml of peptide solution and 0.1 ml sodium bicarbonate USP to adjust pH; Tet-CMV peptide 
with adjuvant was comprised of 1.0 ml of peptide solution and 0.1 ml PF-03512676 (1 mg). The final 1.0 
ml injection volume was administered SC in the upper arm. To assess safety of multiple injections, 
booster doses of vaccine ± PF-03512676 (1 mg) were given at day 21, 42, 63. Six volunteers were allotted 
to each dose level and the vaccine was administered by SC injection in the upper arm.  
Safety in Healthy Adults: Adverse Events 
The peptide vaccines were safe and tolerated in most subjects, though addition of the PF-03512676 (1 
mg) adjuvant increased reactogenicity (Table 2.4.1a). Most common AEs included mild to moderate 
cutaneous reactions at the injection site and systemic flu-like symptoms. The duration of related Grade 
1 and 2 AEs ranged from 1-2 days. Grade 3 AEs included marked malaise, 39.4–40.5C fever, urticaria 
and were resolved with non-prescription analgesics (acetaminophen and antihistamine respectively), 
within 8 days. Of participants receiving Tet-CMV + PF-03512676 2 (15.3%) subjects experienced Grade 2 
and 1 (7.7%) Grade 3 AEs.  No association was found between severity or grade of AEs and pp65-specific 
immunity. 
Table 2.4.1a 
Adverse events at least possibly related to CMV peptide (Tet-CMV and PADRE-
CMV) with or without adjuvant in healthy volunteers  
 
Reactogenicity to the synthetic immunogens in all vaccinees regardless of dosage of Tet-CMV. AEs  are 
graded (top grey row) according to the HVTN/DAIDS intensityscale: Grade 1: Mild, Grade 2: Moderate, 
Grade 3: Severe, Grade 4: Life-threatening. The table shows the number of volunteers who experienced 
Grade 1, 2, or 3 AEs. No toxicity Grade 4 AEs were reported. N=number of vaccinated subjects. Last 
column shows the percentages of the post-vaccination related AEs in the total vaccinated population. 
AEs that were considered unrelated or unlikely to be related to the investigational agent are not 
provided.  
In particular, in the cohort immunized with 2.5 mg Tet-CMV +  1 mg PF-03512676 adjuvant (the vaccine 
formulation used in HCT recipients and re-named CMVPepVax ) a single Grade 2 AE (38.7–39.3C fever) 
resolved in 1 day was reported for one vaccinated volunteer (Table 2.4.1b). 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 26 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Table 2.4.1b 
Adverse events at least possibly related to CMVPepVax in CMV positive healthy 
volunteers vaccinated with 2.5 mg Tet-CMV peptide with adjuvant (CMVPepVax) 
 
AE grades for the cohort of CMV positive (+ve) volunteers vaccinated SC four times with 2.5 mg Tet-CMV 
peptide vaccine + 1 mg PF03512676 (with the exception of UPN 228 who received 3 injections).  For AE 
Grade definition see Table 2.4.1a. Only AEs that were considered possibly, probably or definitely related 
to the investigational agent are provided (as reported on the top of the right column).  
Safety in Healthy Adults: Analysis of Double Stranded DNA Autoantibodies 
Sera from immunized volunteers were longitudinally evaluated during the whole study observation 
period (from day -120 to ~1 year after the 1st immunization), for levels of double stranded (ds) DNA 
autoantibodies. These analyses were performed since mouse models of systemic autoimmune diseases 
have indicated  involvement of TLRs in the generation of autoreactive immune responses[85]. The semi-
quantitative detection of human dsDNA IgG autoantibodies in serum was performed using the dsDNA 
ELISA kit system, by Wampole Laboratories (Princeton, NJ) at COH General Clinic Research Centre. As 
shown in Figure 2.4.1a (lowest plot), no individuals (N=21) vaccinated with the CMV peptides only 
showed levels of dsDNA autoantibodies above the positivity threshold (>180 AAU/ml). In contrast, 
66.7% (total N=18, not shown) and 36.4% (total N=11, Figure 2.4.1a top plots) of the healthy volunteers 
vaccinated respectively with Tet-CMV + PF-03512676 adjuvant demonstrated levels of dsDNA 
autoantibodies transiently raised above the positivity threshold following vaccination; by day 360 these 
levels returned within the normal range. Importantly, none of the immunized volunteers co-injected 
with PF-03512676 CpGDNA had any evidence of developing autoimmune disease or ever reported 
autoimmunity-related pathologies, including UPN 228 (2.5 mg Tet-CMV + PF-03512676) who maintained 
the same levels of dsDNA autoantibodies slightly above positivity threshold, before and after 
vaccination.  

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 27 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Figure 2.4.1a Longitudinal profiles of dsDNA autoantibody levels in sera of healthy volunteers 
vaccinated with CMVPepVax or CMV peptide without adjuvant. 
 
The addition of PF-03512676 adjuvant to CMV-Tet transiently raises the levels of dsDNA above the 
positivity threshold. The lower plot summarizes all results from vaccinees who received CMV-peptide 
(PADRE or CMV-Tet) without adjuvant. Numbers on the threshold red line indicate the fraction of 
immunized subjects with AAU/mL levels above positivity threshold. 
Immunogenicity of CMVPepVax in Healthy Adults 
The induction of post-vaccination ex vivo immune responses was monitored by flow cytometry analyses, 
using FACSCantoTM with FACSDiva software (BD Biosciences)[7]. Positive post-vaccination responses, 
defined as a >3 fold increase in either MHC class I pp65495-503 tetramer binding or IFN-γ expression by 
CD8+ T cells compared to baseline were exclusively detected in volunteers who received the vaccine co-
administered with PF-03512676 (Figure 2.4.1b)[44]. 
Comparing the longitudinal profiles of ex vivo pp65495-503 tetramer+ CD8+ T cell levels, a striking difference 
(Figure 2.4.1b; p=0.004, Wilcoxon rank-sum test comparing post-vaccination averages between d14-77) 
was noted in immunized volunteers whose pre-vaccination pp65495-503 tetramer CD8+ T cell levels were 
minimal-low (<0.2%, referred as CMV+ <0.2%). For these CMV pp65495-503 -immune-negative volunteers, 
recipients of the CMV peptide without adjuvant did not elicit a tetramer level increase during the whole 
observation period which included repeated vaccinations (Figure 2.4.1b, left bottom plot), whereas 
recipients of the CMV peptide vaccine with adjuvant frequently demonstrated increases in pp65495-503 
CD8+ T cells after each vaccination (Figure 2.4.1b, right bottom plot).  

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 28 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Figure 2.4.1b Longitudinal profiles of ex vivo pp65495-503 tetramer+ CD8+ T cell levels in response to 
CMV peptide with and without adjuvant, grouped by strength of pre-vaccination ex 
vivo pp65495-503 tetramer+ CD8+ T cell level 
 
Longitudinal profiles of ex-vivo pp65495-503 specific tetramer binding (expressed in percentages) for 
recipients of CMV peptide alone and CMV peptide with PF-03512676. Upper plots: CMV-seropositives 
who had at baseline ≥ 0.2% pp65495-503 tetramer binding. Lowev plots: baseline CMV+<0.2% pp65495-503 
tetramer binding. The p value indicates the difference between CMV peptide vaccinees with and without 
adjuvant in CMV+<0.2% subjects calculated by Wilcoxon rank-sum test. comparing post-vaccination 
averages between day 14-77. 
In all responders, ex vivo CMV responses were still detectable at day 77 (Figure 2.4.1b, right bottom 
plot). These results suggest that PF-03512676 adjuvant contributed to stimulating CMV vaccine responses, 
though its effect varied in the vaccinated CMV+<0.2% population.  Limited variation in pp65495-503 tetramer 
levels were observed post-vaccination in the CMV-seropositive population (baseline ≥0.2% pp65495-503 
tetramer binding) when vaccinated with or without adjuvant (Figure 2.4.1b, top plots).  
Though volunteers vaccinated with CMV peptide alone(without adjuvant) did not show ex vivo post-
vaccination increases in pp65495-503 CD8+ T cells, by using IVS we were able to detect priming of memory 
T cell responses (>10 fold expansions)  in ~30% (4 of 14)  of CMV+<0.2% and ~40% (3 of 7) of CMV-
seronegatives. In addition, pp65495-503 CD8+ T cells could be consistently expanded in all 4 CMV-
seronegatives and in 4 CMV-seropositive volunteers vaccinated with CMV peptide + PF-03512676 who 
failed to demonstrate ex vivo responses. Confirming the ex vivo data, the correlative IVS studies showed 
that usage of PF-03512676 adjuvant induced significantly higher (p=0.002, two-sided Fisher’s exact test) 
post-vaccination responses when comparing responses of recipients CMV peptide + PF-03512676 to 
those of CMV peptide without adjuvant. 
Stimulation strategies to evaluate vaccine immunogenicity in clinical trials can have limitations, due to 
length and conditions of the in vitro culture [44, 45]. However, breadth and consistency of post-IVS 
responses detected in recipients of the CMV peptide + PF-03512676 (Figure 2.4.1c) after brief exposure 
of PBMC to the pp65495-503 peptide are promising. In fact, the vaccine elicited pp65495-503 T cells could be 
significantly expanded upon exposure to CMV antigens in a viremic individual. In particular, the CMV 
peptide vaccines may have the potential for greater potency when injected into CMV positive HCT 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 29 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
recipients, as further massive expansion has been reported to occur under the natural stimulation of 
CMV infection[52]. The resulting pp65495-503 T cell increase in HCT recipients can be critical to control CMV 
viremia [43-45]. In summary, the correlative IVS studies indicate that the CMV peptide vaccines + PF-
03512676 are effective in consistently priming pp65-specific T cells. 
 Figure 2.4.1c IVS pp65495-503 or the HIVgag77-85 CD8+ T-cells as a percentage of all IVS CD8+ T-cells in 
healthy volunteers vaccinated with CMV peptide + PF-03512676  
 
Median levels of CD8+ T-cells specific for either the pp65495-503 (filled symbols) or the HIVgag77-85 
(control, open symbols) tetramers are shown as a function of CMV peptide+ PF-03512676 vaccinations 
in healthy volunteers. p value was calculated by Wilcoxon rank-sum test to assess the significance of 
post-vaccination binding difference between pp65495-503 and control (HIVgag77-85) tetramer in the IVS 
expanded CD8+ T cells. 
In healthy volunteers, a dose response to the vaccine CMV peptide component was not apparent. 
However data collected from healthy volunteers immunized with Tet-CMV + PF-03512676 strongly 
support further evaluation of this vaccine in the HCT setting, due to its satisfactory safety profiles (Table 
2.4.1a) and favorable immunogenicity (Figure 2.4.1b, right plot)[8].    
 
2.4.2 
Phase Ib pilot trial (COH IRB 12022) of CMVPepVax in HCT recipients  
The completed Phase Ib trial in HCT recipients (COH IRB 12022; NCT01588015@www.clinicaltrials.gov) 
was performed to evaluate safety and immunogenicity of two injections of CMVPepVax (2.5 mg Tet-
CMV + 1.08 mg PF-03512676), in HLA A*0201 CMV-positive adult recipients of an HLA-matched 
allogeneic HCT for hematologic malignancies. The primary study objective is safety, with secondary 
objectives including immunologic responses of HCT recipients to CMVPepVax.  
Participants in this open label trial are randomized to two arms, the CMVPepVax vaccine arm and the 
observational arm. HCT recipients in the vaccine arm are injected twice on days 28 and 56 post-HCT with 
CMVPepVax, during the critical period in which primary CMV reactivation most predictably occurs (~day 
40-100)[35, 67].  As of January 15th, 2015, CMVPepVax has been safely administered to 18 HLA A*0201 
R+ participants (total 32 vaccine injections). In order to meet the goal of randomizing 36 participants on 
Day 28 post-HCT, 46 participants were enrolled pre-HCT, ten of whom did not meet the Day 28 post-HCT 
vaccine administration criteria. 
Eligible CMV positive HCT recipients (R+) were HLA-A*0201, between 18-75 years (y) receiving allogeneic 
T-replete HCT for hematologic malignancy from matched-related (MRD) or 8/8 and 7/8 matched 
unrelated donors (MUD), excluding those with acute leukemia not in remission. The median age was 50 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 30 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
years (range: 19-75), with 24 (52%) donor CMV positive, 22 (48%) donor CMV negative, and 22 (48%) 
MRD to 24 (52%) MUD. 
Safety of CMVPepVax in HCT recipients: Adverse events  
Interim results from 17 (out of 18 planned) vaccinated R+ indicate excellent tolerability and safety of 
CMVPepVax in all vaccinated HCT patients, and no patient met the safety stopping rule per-protocol. As 
shown in Table 2.4.2,  there were  no serious SAE or any AE exceeding Grade 2 that are definitely, 
probably, or possibly related to the vaccine formulation in the CMVPepVax treatment arm.  
Table 2.4.2 
List of SAEs in CMVPepVax vaccinated HCT recipients (N=18-) 
Patient 
Identifier 
Date of Event 
Outcome 
Resolved 
Adverse Event 
Term 
Attribution 
UPN 08 
05/21/2013 
(day of vaccination) 
Hospitalization – 
Initial 
05/22/2013 
Grade 1 Fever 
Probably related 
UPN 07 
05/31/2013 
(30 days post vacc.) 
Hospitalization – 
Initial 
06/06/2013 
Grade 3 Device 
Related Infection 
Unlikely related 
UPN 26 
04/28/2014 
(7 days post vacc.) 
Hospitalization – 
Initial 
05/01/2014 
Grade 3 Diarrhea 
Unlikely related 
UPN 29 
05/29/2014 
( 30 days post vacc.) 
Hospitalization –
Initial 
06/06/2014 
Grade 3 Nausea 
Unlikely related 
UPN 34 
08/07/2014 
(7 days post vacc.) 
Hospitalization 
-Initial 
08/20/2014 
Grade 2 Nausea 
Unrelated 
 
Safety of CMVPepVax in HCT recipients: double stranded DNA autoantibodies  
Sera from vaccinated HCT recipients were longitudinally evaluated during the 6 month observation 
period for levels of double stranded (ds) DNA autoantibodies. These analyses were performed since 
mouse models of systemic autoimmune diseases have indicated  involvement of TLRs in the generation 
of autoreactive immune responses[85]. The semi-quantitative detection of human dsDNA IgG 
autoantibodies in serum was performed using the dsDNA ELISA kit system, by Wampole Laboratories 
(Princeton, NJ) at COH. Interestingly, none of the 14 R+ patients vaccinated with CMVPepVax showed 
levels of dsDNA autoantibodies above the positivity threshold (>180 AAU/ml). Furthermore, none of 
them reached the so called equivocal threshold (>150 AAU/ml, Figure 2.4.2a) being all levels <150 
AAU/ml.  
These results in HCT recipients are distinct from the results from healthy volunteers in which transient 
increases in levels of dsDNA autoantibodies were detected in CMVPepVax vaccinated healthy adults, 
This difference is likely due to defects in cellular and humoral immunity which persist for over one year 
after HCT, with delayed immune reconstitution especially marked for B cells[86, 87]. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 31 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Figure 2.4.2a Longitudinal profiles of dsDNA IgG autoantibody levels (AAU/ml) in sera of HCT 
recipients vaccinated with CMVPepVax 
 
 
Longitudinal profiles of sDNA autoantibody levels (AAU/ml) in sera of HCT patients (UPN) vaccinated 
with CMVPepVax. Segmented lines indicate the ELISA thresholds. ELISA kit system, Wampole 
Laboratories. 
 
 
Safety of CMVPepVax in HCT recipients: Impact on GVHD 
Importantly, there was no increased incidence of aGVHD, in patients immunized with CMVPepVax. An 
unexpected and striking finding was the difference in rates of cGVHD in patients who reached day 180 in 
the vaccine arm (3/11) vs. the observational arm (8/13, p=0.0347), as shown in Figure 2.4.2b. 
Noteworthy is that the vaccine formulation is more likely to stimulate TH1 responses, yet TH2 immunity 
is mechanistically associated with cGVHD. Additionally, CpG DNA PF03512676 the adjuvant in 
CMVPepVax is known to leading to potent immunostimulatory effects, such NK cell activation [63] which 
have been described to be inversely correlated to cGVHD onset [88]. Thus CMVPepVax vaccinated HCT 
recipients could have higher levels of NK cells limiting cGVHD. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 32 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Figure 2.4.2b aGVHD and cGVHD in HCT recipients vaccinated with CMVPepVax and control HCT 
patients 
 
aGVHD and cVHD in vaccine (upper plot) and observational (lower plot) HCT patients (UPN). t test was 
used to assess the difference (p value in red box) between groups. 
Safety of CMVPepVax in HCT recipients: Impact on Disease Relapse 
Interestingly, all CMVPepVax vaccinated recipients continue to remain cancer free, while 3 observational 
patients experienced relapse of their hematological malignancy. Recent observations relating CMV 
reactivation and reduced relapse have driven strong interest in a mechanistic understanding of the 
phenomena observed in this trial related to CMV vaccine or the adjuvant, PF03512676 [18-20, 89].   
CMVPepVax in HCT recipients: Immunogenicity studies 
Vaccine specific immune responses have been evaluated by monitoring CMV-specific CD8+ T cells, using 
multi-color flow cytometric analysis. Levels of CD8+ T cells (cells/µL) binding to CMV-pp65495-503 HLA 
*0201 pentamers (Proimmune, Oxford. UK) have been measured for thirty-one participants; fourteen of 
them were from the CMVPepVax vaccine intervention and seventeen from the observational arm. All 
HCT recipient participants vaccinated with CMVPepVax showed a measurable and consistent increase in 
pp65 levels post-vaccination, as plotted in Figure 2.4.2c (upper plot).  
This pattern is consistent with a vaccine effect, and a formal statistical analysis has been performed. In 
nine vaccine arm patients and in ten observational patients who reached day 180 without CMV 
reactivation, increases in CMV pp65 levels after first and second injections were compared using 
generalized estimating equations. The model indicates an average 6.5 fold positive vaccine effect 
(p=0.02). Thus CMVPepVax significantly expanded CMV-pp65 CD8 T cells which have been described to 
protect HCT recipients from CMV complications [9, 10]. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 33 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Figure 2.4.2c CMV-pp65 495-503 pentamer CD8+ T cell amplification in HCT recipients vaccinated 
with CMVPepVax 
 
Increase in specific CMV-pp65 495-503 T cells, during the first 6 months post-HCT. Vaccine arm UPN 07, 
and observational arm UPN 06, 12, 15, 19, 27 and 28 who CMV reactivated are not included in this 
figure. 
Moreover, CMV-pp65495-503 T cells levels remain sustained through day 180 as shown in the 
representative FACS plots of HLA A*0201 CMV pp65 and HIV gag (control) pentamer binding assay, in 
CMVPepVax vaccinated UPN 8 (Figure 2.4.2d).  
Figure 2.4.2d  CD8 T cells binding to CMV pp65 and HIV gag (control) MHC class I pentamers in a 
representative HCT recipient vaccinated with CMVPepVax (UPN8) 
 
FACS plots of CD8 T cells specific for CMV pp65 and HIV gag (control) MHC class I pentamers 
(Proimmune®, Oxford, UK) in CMVPepVax vaccinee UPN8. CMV pp65 CD8 T cells are detected up to 180 
days after HCT. 
 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 34 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
 
The steady increase in levels of CMV-pp65 495-503 T cells consistently follows vaccine injection time 
points, and appears to diminish at later time points post-vaccination, as seen in representative HCT 
recipient vaccinated with CMVPepVax UPN 14 (Figure 2.4.2d). 
 
Figure 2.4.2d Kinetics of CD8+ T cells/ul binding to CMV- pp65 and HIV gag (control) MHC class I 
pentamers in a representative HCT recipient vaccinated with CMVPepVax (UPN 14) 
 
CD8 T cells/ul specific for CMV pp65 and HIV gag (control) MHC class I pentamers (Proimmune®, 
Oxford, UK) in CMVPepVax vaccinee UPN8. CMV pp65 CD8 T cells are detected up to 180 days after HCT. 
UPN 14 is D+MRD, A 0201/0202, B 5204/5301. 
CMVPepVax in HCT recipients: CMV reactivation 
Though the current safety and immunogenicity trial was not powered to assess differences in CMV 
reactivation rates, we did observe a 5.5 fold CMV reactivation decrease in CMVPepVax vaccinated HCT 
recipients (1/16=6%) compared to the observational arm patients, in whom expected CMV reactivation 
rates of 33% (6/18) were reached[67, 90].   
In conclusion, trial IRB 12022 results indicate safety of injecting CMVPepVax in HCT recipients on day 28 
and day 56, with no increase in aGVHD, and reduced CMV reactivation associated with vaccine-
stimulated immunity. Compelling observations of reduced cGVHD and relapse requires further testing in 
the proposed Phase II efficacy trial, which has been NIH-funded as a multi-institution clinical trial.  
 
Immune reconstitution in HCT recipients vaccinated with CMVPepVax 
We assessed the phenotypes and time-course of the pp65-specific CD8 T cell subsets that expanded in 
response to CMVPepVax vaccination. The functionality and antiviral role of CMV-specific T cells have 
been linked to immune reconstitution profiles characterized predominantly by differentiated effector 
memory T (TEM) subsets that have lost membrane expression of the costimulatory molecule CD28, and 
often re-express the RA isoform of CD45 (TEMRA). Major histocompatibility complex class I pp65495–503 
multimers, as well as CD28 and CD45 memory markers, were used to detect immune reconstitution in 
blood specimens from HCT recipients enrolled in the Phase 1b clinical trial. Specimens from the 10 (out 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 35 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
of N=18) vaccine patients who had adequate (≥0.2%) multimer binding to allow for memory analysis 
showed highly differentiated TEM and TEMRA phenotypes for  pp65495-503-specific CD8 T cells during the 
first 100 days post-transplant. In particular, by day 70, during the period of highest risk for CMV 
reactivation, combined TEM and TEMRA phenotypes constituted a median of 90% of pp65495-503-specific 
CD8 T cells in these vaccinated patients. CMV viremia was not detectable in the CMVPepVax patients, 
although their pp65495-503-specific CD8 T cell profiles were strikingly similar to those observed in viremic 
patients, who did not receive the vaccine. Collectively, our analysis indicates that, in the absence of 
clinically relevant viremia, CMVPepVax reconstituted significant levels of differentiated effector memory 
pp65495-503-specific CD8 T cells early post-HCT. The body of data from this current study indicates that the 
rapid reconstitution of CMV-specific T cells, with marked levels of effector phenotypes may have been 
key to the favorable outcomes of the CMVPepVax clinical trial. ([91], [92]) 
 
 
2.5 Interim analysis and rationale for continuation of the trial 
The interim analysis for the primary endpoint (Section 12.4 Data Analysis Plan) unexpectedly showed 
that more CMV events observed on the vaccine arm (5 events) than on the placebo arm (3 events), thus 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 36 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
meeting the futility stopping rule. Accordingly, the study held further accrual and continued to 
treat/monitor patients (total N= 60) who have been consented and enrolled prior to the interim analysis 
data became available.  The study statistic team derived the following data on the interim analysis based 
on 48 patients. 
 
Table 2.5 Interim analysis of IRB#13494 
N=48 pts with immunologic data 
CMVPepVax 
(n=24) 
Placebo 
(n=24) 
CMV PCR >500 or Disease through d100 (Primary) 
5* 
3 
Median days of CMV reactivation (in patients who had 
reactivation)  
17 
42.5 
Median days of anti-viral therapy through d100 (in patients 
who had reactivation) 
37.5 
36 
Median days of anti-viral therapy through d365 (in patients 
who had reactivation) 
46 
38 
Relapse through D365 (or last f/u) 
4 
5 
Death through D365 (or last f/u) 
4 
3 
Acute GVHD grade 2-4 
10 
10 
Acute GVHD grade 3-4 
0 
5 
# of patients who achieved 4-fold increase in pp65-dex from 
d28 to d56 
5 
1 
# of patients who achieved 2-fold increase in pp65-dex from 
d28 to d56 
8 
4 
# of patients who achieved 4-fold increase in pp65-dex from 
d28 to d84 
9 
5 
Mean relative change from d28 to d56 
mean=.70; 
sd=1.6 
mean=.10; 
sd=.93 
Mean relative change from d28 to d84 
mean=.75; 
sd=1.5 
n=23 
mean=.56; 
sd=1.2 
n=22 
 
(*)  Includes a patient who met reactivation criterion but resolved w/o antivirals. 
(**) Events through d365 include events before d100.                           
 (***)  last day – first day 
 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 37 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Unanticipated features of the interim analysis: 
- 
The overall CMV reactivation rate was lower than past clinical experience at COH, yielding only 8 
events at the interim analysis. If the vaccine was effective, 13 events would be expected. If it 
were ineffective, 19 events would be expected.  The lower overall event rate increases the 
chance of inappropriately stopping at the interim analysis from about 2% as originally planned, 
to about 27%, assuming the vaccine still prevents half of all CMV reactivations.   
 
- 
A second unanticipated feature was the early timing of most reactivations: 7 of the 8 events 
occurred before day 100 which is prior to the second vaccination (scheduled for day 56).   
 
Safety and immunologic data at the interim analysis: 
- 
There have been no safety concerns to date. The immunologic recovery based on the number of 
patients achieving 2-fold or 4-fold increase in CMV-specific T cells was favorable in the vaccine 
arm (Table 2.5).  
 
Rationale/justification for continued accrual: 
1) 
 For the entire cohort of 97 patients 
After the interim analysis the trial was redirected toward the combination approach with the currently 
approved Prevymis prophylaxis regimen as a result of still unmet need to address the rise in CMV 
reactivation past week 18 despite the use of the antiviral. 
The combined reactivation rate at this point was 8/48, or 17%, very close to the 15% rate that was 
hoped for on the vaccine arm, but much lower than expected for the placebo arm.  At such low 
reactivation rates, the futility rule has a much higher false alarm rate than planned.  If the vaccine offers 
the same degree of protection originally planned, (i.e. preventing 25 of 40 reactivations) then the futility 
rule would have a false alarm rate of approximately 27%.  The interim result is thus not inconsistent with 
the original targeted effect size, and does not provide a satisfactory contradictory signal to the success 
seen in protocol IRB#12022.  
There will be a useful gain in clinical and scientific knowledge by continuing the trial through the 
planned 97 patients even when the primary hypothesis test was futile at the low reactivation rates for 
the initial cohort.  
In addition, there are further factors that likely contributed to the current results such as more liberal 
eligibility criteria in 13494 compared with the previous successful pilot trial (IRB#12022, detailed in 
section 2.4.2 above), and heterogeneity in CMV detection methods and preemptive therapy across 
participating sites, with some events occurring early.  Therefore, to be more consistent with the original 
pilot trial IRB#12022, we will exclude any grade 3-4 aGVHD before randomization (day 28) and any level 
of detectable viremia prior to day 28. In addition, we will remove from efficacy analysis if a patient was 
found to be viremic on the day of vaccination (retroactive since the result will be available only after 1-2 
days from the vaccination). 
2) 
 For the new cohort of 36 patients with the combination of CMVPepvax and Prevymis 
The new cohort size is based on the original study plan budgetary constraints. The amended study 
design will allow for establishing a possible positive effect of CMVPepVax in patients who experience 
CMV reactivation during or after the administration of Prevymis – an antiviral agent used for CMV 
disease prophylaxis. Prevymis has been approved by the FDA for all CMV seropositive HCT recipients, 
and accordingly, the City of Hope HCT SOP has adopted the use of Prevymis.   

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 38 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
While the interim results indicate that CMVPepVax is likely not a suitable alternative to Prevymis 
prophylaxis, there remains a need to prevent the significant risk of reactivation after anti-viral therapy 
ends on day 100. In addition, the period of prophylaxis represents an opportunity to achieve protective 
immunity ahead of the early reactivations that were observed in the absence of Prevymis prophylaxis.  
This need and opportunity motivate the amendment of the trial to address the effect of CMVPepVax 
administered during Prevymis prophylaxis. 
There is no known or theoretical overlapping toxicity between CMVPepVax and Prevymis.   
Clinical and scientific significance 
- Late CMV reactivation after stopping Prevymis on day 100 remains a major clinical problem, which can 
potentially be overcome by the combination approach of CMVPepVax plus Prevymis. 
Novelty 
- The combination of CMVPepVax (developed at COH, IND held by COH) and Prevymis is a highly novel 
combination. 
- CMV-specific T cell immune reconstitution has not been described in patients receiving Prevymis. Thus 
the immunologic data of patients receiving Prevymis, even in a small cohort of 18, are highly informative 
and novel. 
- The clinical and immunological impact of CMVPepVax when combined with Prevymis has not been 
studied. The proposed amendment allows better understanding the vaccine-induced immunologic 
protection for CMV reactivation occurring after day 100. 
 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 39 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
3.0 
PARTICIPANT ELIGIBILITY CRITERIA 
3.1 Pre-HCT Inclusion Criteria 
Participants must meet all of the following criteria on screening examination to be eligible to participate 
in the study:  
Informed Consent and Willingness to Participate 
___ 1. 
All subjects must have the ability to understand and the willingness to sign a 
written informed consent. 
___ 2. 
Participant must be willing to comply with study and/or follow-up procedures, 
including willingness to be followed for one year post-HCT. 
Age Criteria 
___ 3. 
Age 18 to 75 years.  
Nature of Illness and Transplant Related Criteria 
___ 4. 
Planned HCT for the treatment of the following hematologic malignancies: 
o Lymphoma (Hodgkin and Non-Hodgkin) 
o Myelodysplastic syndrome 
o Acute lymphoblastic leukemia in first or second remission (For Acute 
Lymphoblastic Leukemia/Lymphoblastic Lymphoma, the disease status 
needs to be in hematologic remission by bone marrow and peripheral 
blood. Persistent lymphadenopathy on CT or CT/PET scan without 
progression is allowed.) 
o Acute myeloid leukemia in first or second remission 
o Chronic myelogenous leukemia in first chronic or accelerated phase, or 
in second chronic phase 
o Other hematologic malignancies including chronic lyphocytic leukemia, 
myeloproliferative disorders and myelofibrosis.  Patients with multiple 
myeloma and those with non-malignant disease such as aplastic anemia 
are excluded. 
___ 5. 
HLA A*0201 High resolution, 4-digit typing is required at HLA-A2 to ensure 
A*0201 status. 
___ 6. 
CMV seropositive (recipient) 
___ 7. 
Planned related or unrelated HCT, with  HLA donor allele matching. Related 
donor must be an 8/8 match for HLA-A, -B, and –C at intermediate (or higher) 
resolution, and -DRB1 at high resolution using DNA-based typing. Unrelated donor 
must be an 8/8 match at HLA-A, -B, -C and –DRB1 at high resolution using DNA-based 
typing. Patients undergoing a second allo HCT are not eligible (patients who have 
undergone a previous autologous HCT are eligible). 
___ 8. 
Planned HCT with no ex-vivo T cell depletion of graft. Conditioning and 
immunosuppressive regimens according to institutional guidelines are permitted. 
Clinical laboratory parameters  
___ 9. 
Negative serum or urine β-HCG test (female patient of childbearing potential 
only) within two weeks of registration. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 40 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
___ 10. Seronegative for HIV, HCV and active HBV (Surface Antigen Negative) within 2 
months of registration. 
Child Bearing Potential 
___ 11. Agreement by females of childbearing potential and sexually active males to use 
an effective method of contraception (hormonal or barrier method of birth control or 
abstinence) prior to study entry and for up to 90 days post-HCT. PF-03512676, the 
adjuvant co-injected with the CMV peptide, has been determined to be embryolethal 
and teratogenic in animal testing. Should a woman become pregnant or suspect that 
she is pregnant while participating on the trial, she should inform her treating 
physician immediately.  
 
3.2 Pre-HCT Exclusion Criteria 
Prospective participants who meet any of the following criteria will not be eligible for admission into the 
study: 
Previous therapies 
___ 1. 
Any prior investigational CMV vaccine 
___ 2. 
Experimental anti-CMV chemotherapy in the last 6 months 
Planned medications from the time of HCT to day 70 post-HCT 
___ 3. 
Live attenuated vaccines  
___ 4. 
Medically indicated subunit (Engerix-B for HBV; Gardasil for HPV) or killed 
vaccines (e.g. influenza, pneumococcal, or allergy treatment with antigen injections) 
___ 5. 
Allergy treatment with antigens injections  
___ 6. 
Alemtuzumab or any equivalent in vivo T-cell depleting agent. This includes ATG 
and post-transplant cyclophosphamide. 
___ 7. 
Antiviral medications with known therapeutic effects against CMV such as   
GCV/VAL, FOS, Cidofovir, CMX-001 and maribavir. Accylovir has no therapeutic 
efficacy against CMV and is allowable as standard of care to prevent HSV. 
___ 8. 
Other investigational product – concurrent enrollment in other clinical trials 
using an investigational product is prohibited 
___ 9. 
Other medications that might interfere with the evaluation of the 
investigational product  
Other illnesses or conditions 
___ 10. Patients 
with 
active 
 
autoimmune 
conditions 
requiring 
systemic 
immunosuppressive therapy within the previous 5 years are not eligible   
___ 11. Pregnant women and women who are lactating. CMVPepVax has the potential 
for teratogenic or abortifacient effects.  Because there is an unknown but potential 
risk for adverse events in nursing infants secondary to treatment of the mother with 
the administered vaccine, breastfeeding should be discontinued if the mother is 
enrolled on this study.   

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 41 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
___ 12. Any other condition that would, in the Investigator’s judgment, contraindicate 
the patient’s participation in the clinical study due to safety concerns or compliance 
with clinical study procedures, e.g., social/ psychological issues, etc. 
Noncompliance 
___ 13. Prospective participants who, in the opinion of the investigator, may not be able 
to comply with all study procedures (including compliance issues related to 
feasibility/logistics). 
3.3 Participation of Special Populations 
A discussion of the inclusion, exclusion, and representation participation of women, minorities, children 
and HIV positive individuals is provided in Section 16.5.  
 
4.0 
PARTICIPANT ENROLLMENT AND RANDOMIZATION 
4.1 Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility will be done only after 
obtaining written informed consent.  Studies or procedures that are performed for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values and/or to determine pre-
eligibility, even if the studies were done before informed consent was obtained. The informed consent 
process is to be fully documented, and the prospective participant must receive a copy of the signed 
informed consent document.  See Table 10 footnote f and Section 16.4 for more information regarding 
informed consent. Screening procedures are listed in Section 10, Table 10 Study Activity Calendar.  
4.2 Participant registration 
4.2.1 
COH DCC Availability and Contact Information 
Eligible subjects will be registered on the study centrally by the Data Coordinating Center (DCC) at City of 
Hope.  DCC staff are available between the hours of 8:00 a.m. and 5:00p.m. PST, Monday through 
Friday (except holidays).   DCC contact information is as follows: 
 
phone: (626) 256-4673 ext. 63968 
 
e-mail: DCC@coh.org 
4.2.2 
Slot verification and reservation 
As the study nears completion of accrual, study team personnel (including physicians, protocol nurses 
and/or CRCs) may wish to contact the DCC to verify slot availability and to reserve an open slot or be 
placed in queue for slot opening.  Slots may only be held for a limited time which will be determined by 
the PMT. The Data Coordinating Center should be notified of cancellations of prospective participants 
holding slots as soon as possible. 
4.2.3 
Registration procedure 
To register a participant, the subsequent procedure is to be followed. 
1. The participating site’s data manager/coordinator/research nurse should contact the DCC 
via telephone or email to provide notification regarding the pending registration and 
communicate desired timeline of the registration, especially if it must be completed 
promptly to meet the registration window (60 days to 0 days before planned HCT). 
2. The data manager/coordinator/research nurse should then e-mail copies to 
DCC@coh.org  of the following documents to the DCC:  

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 42 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
o Registration Cover Sheet (Appendix H ) 
o Completed Eligibility Criteria List (printed from Section 3.1-2 of the 
protocol) 
o Source documentation to support eligibility criteria**  
o Signed informed consent document 
o Signed HIPAA authorization form (if separate from the informed consent 
document) 
o Signed subject’s Bill of Rights (COH only)  
**For COH participants, provide copies of source documentation only if not readily 
available as a finalized record in the COH EMR  
3. After having received all transferred documentation, the DCC will review the documents 
to verify eligibility, working with the participating site as needed to resolve any missing 
required source elements. A subject failing to meet all protocol eligibility requirements 
will not be registered.  
4. Once eligibility has been confirmed, DCC staff will register the participant by: assigning a 
subject accession number, register the subject on study centrally into MIDAS for 
external site participants (the COH CRC will directly accession into MIDAS), and enter the 
subject into the eCRF system, Medidata RAVE. 
5. Once registration has been completed, DCC staff will send a Confirmation of Registration 
Form, including the participant study number and planned date of HCT procedure to:  
o the site study team: site PI, treating physician, protocol nurse, CRC and 
pharmacy 
o the sponsor team: (Drs. Nakamura, La Rosa, and the COH CRC) 
 
4.3 Randomization 
The vaccine treatment assignment will be masked from patients and health care providers, but known 
to the DCC coordinators, study monitors, auditors, pharmacy personnel, and the statistician.   See 
Section 5.2 for additional information about maintaining a blinded randomization. 
The DCC staff will use a computer-generated randomization program, stratified by donor CMV 
serostatus to assign registered participants to the CMVPepVax or placebo arm. The treatment 
assignment will be generated and provided to pharmacists in advance (usually ~day 21 post-HCT) of 
planned vaccination. The DCC staff will confirm that the treatment assignment was received by the 
pharmacy.  
The DCC specialist will request a copy of source documents regarding donor CMV serostatus, if not 
already provided/available. The DCC staff may contact the study team coordinator to confirm the HCT 
procedure did occur prior to generating the treatment assignment. 
As soon as the study team is aware that a registered participant will not meet the criteria to receive the 
initial vaccine, this should be promptly communicated to the DCC.  This information will be entered into 
the computer-generated randomization program to inform subsequent treatment assignments. 
Only participants who receive a vaccination (CMVPepVax or Placebo) will be considered “randomized”.   
 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 43 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
4.4 Emergency De-Blinding Procedures 
Participant’s randomization status will be un-blinded in the event a patient on this study develops a life-
threatening toxicity or serious adverse event for which the participant’s physician or other health care 
professional feels that it is in the patient’s best interest to know the randomization status of the 
participant. 
The following procedure should be followed:  
Information regarding the rationale for de-blinding will be provided to the Site PI, the COH DCC, 
and the Study PI.  
The Site PI will communicate with the site pharmacy and will provide authorization to un-
blind patient’s treatment.  
In this very unlikely event, the PMT will determine if and how the de-blinding should impact the 
participant’s continued participation in the study or analysis of collection points post de-blinding. This 
plan will be provided to the IRB of record and the COH IRB and DSMC as per COH institutional 
requirements. The date and reason for de-blinding must be noted in the medical record and captured in 
the eCRF. 
 
5.0 
TREATMENT PROGRAM 
5.1 Treatment Overview 
The study intervention will consist of a vaccine administration of either CMVPepVax (N=48) or placebo 
(N=48), depending on participant randomization. All patients in the new cohort (36 patients, 18 vs 18) 
will receive Prevymis as a standard of care. 
Participants will receive vaccine administration on days 28 and 56 post-HCT if vaccine administration 
criteria are met (Sections 6.1 and 6.2) and confirmed by the DCC (who will notify the study team 
pharmacy of the confirmation). 
Participants who do not receive the Day 28 Post HCT vaccine administration will be replaced. 
Participants who receive at least one vaccine administration will complete all procedures detailed in 
Section 10, except for participants who experience relapsed disease for whom all post-relapse 
assessments will cease and will be followed only for survival through day 365-Post-HCT.  
Windows for vaccine administration are detailed in Section 10, Study Activity Calendar. 
All participants in the new cohort (36 patients, 18 vs 18) will be assigned to Prevymis standard of care 
group and will receive Prevymis at the dose of 240 or 480 mg per day for approximately 14 weeks, up to 
day 100 post-HCT. 
5.2 Maintaining blinded randomization 
The vaccine treatment assignment will be masked from patients and health care providers, but known 
to the DCC coordinators, study monitors, auditors, pharmacy personnel, and the statistician. Due to 
differences in appearance of the active agent and the placebo, the person administering the vaccine 
(placebo or active agent) should limit discussions regarding the characteristics regarding the agent’s 
appearance or administration (i.e. ease or difficulty of administration) to the study pharmacist. Since the 
person administering the vaccine may detect a difference in appearance between placebo or active 
agent, he/she will be furthermore excluded from performing any protocol-required procedures or 
providing day-to-day medical care of the participant for the duration of the trial. The pharmacist will 
keep the treatment assignments and accountability documentation such that the documents cannot be 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 44 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
accessed by the individuals who conduct protocol-required assessments, follow-up assessments, or 
those involved in the day-to-day medical care of the subjects during the trial. Jennifer Drake will be the 
designated un-blinded PMT contact for Pharmacy. Disclosure of any knowledge of the randomization 
status to persons other than those permitted to know the randomization status would result in a 
protocol violation. 
5.3 Vaccine Administration and Pre-Vaccination Prophylaxis 
Note: the vaccine must be administered within 90 minutes of start of vaccine preparation. As such, 
coordination between the pharmacy and the staff administering the vaccine is essential.   
5.3.1 
Pre-vaccination preemptive therapy 
At the discretion of the treating investigator and/or participant, within 15 minutes prior to vaccine 
administration a single dose of oral acetaminophen (Tylenol) at a recommended dose of 500 mg may be 
administered to the participant. 
While allergic reactions were seen in healthy volunteers receiving CMVPepVax, no allergic reactions 
were seen in HCT recipients receiving CMVPepVax even in the absence of diphenhydramine.  
Diphenhydramine (Benadryl) 25 mg oral, or IV if unable to give orally, may be administered within 15 
minutes prior to vaccine administration at the discretion of the treating investigator.  
5.3.2 
Vaccine administration and post-administration monitoring 
The time limit that may not be exceeded when the agent should be administered will be noted on the 
vial label, or accompanying pharmacy documents. 
During the agent administration process, the syringe should remain unseen by the participant to help 
maintain the study blind status.  The syringe containing a 1 ml final volume will be administered 
subcutaneously in the upper arm, per standard clinical practice. Following administration, the 
participant will be monitored for 30 minutes for apparent vital sign changes, and local and systemic 
reactogenicity.  
The time when the agent was administered (as noted on the vaccine label or accompanying pharmacy 
documents) and the time of vaccination will be noted in the medical record. 
5.4 Assessments 
Patients undergoing HCT are extensively monitored for safety according to institutional SOC practices. 
The following assessments will occur for safety and/or endpoint analysis with the schedule indicated in 
Study Activity Calendar (Section 10), per institutional SOC, and as clinically indicated.  
5.4.1 
GVHD assessment and performance status 
Acute GVHD will be assessed and graded according to the Keystone Consensus grading system 
(Appendix B). Chronic GVHD will be classified per Appendix C by type of onset (progressive, interrupted, 
de novo, or chronic); basis of diagnosis (histologic/biopsy proven, clinical evidence, both, or unknown); 
Limited or Extensive chronic GVHD; and overall severity of GVHD (mild, moderate, or severe). 
Performance status will be evaluated utilizing the Karnofsky Performance Scale (Appendix D).  
5.4.2 
CMV monitoring 
For CMV monitoring, standard qPCR clinical laboratory methods will be required to evaluate CMV viral 
load and possible agent failure at least once per calendar week  (usually twice weekly) or as required by 
SOC from  day 21 to 100. From day 100 to day 180, CMV viral load will be monitored at least once every 
2 weeks.  

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 45 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
COH:  Focus 3M Integrated Cycler and Simplexa CMV Kit for in vitro diagnostic use, detection limit 250 
gc/ml, reported in WHO IU/ml (conversion factor 2.5; 250gc/ml=625IU/ml, note all PCR values in this 
protocol are expressed by gc/ml based on the COH assay). 
Clinical CMV disease status will be documented at each study visit, which may include the absence or 
presence of suspected CMV disease.  When clinically indicated and per SOC, CMV disease will be 
assessed and, when present, the site (upper GI, lower GI, other, specify) and method of detection in the 
tissue (tissue culture, pathology etc.) will be documented. Presentations or suspected presentations of 
CMV disease in the absence of qPCR ≥500 gc/ml will be evaluated by the treating investigator in 
conjunction with the blinded PMT before a determination is made.  
5.4.3 
Engraftment assessment 
Engraftment will be assessed by monitoring the recipient’s absolute neutrophil count. The date of 
engraftment is defined as the first of 3 consecutive days when the peripheral blood absolute neutrophil 
count is ≥ 500/mm3; for the purposes of recording into the case report form, the date of engraftment 
can be derived from the ANC values in the clinical laboratory results so long as there is accompanying 
documentation in the medical record that engraftment did occur.  
Graft failure following engraftment (secondary graft failure) is defined as a fall in the absolute neutrophil 
count below 500/mm3 for greater than 3 consecutive days following initial engraftment that is not due 
to disease relapse/progression, infection or secondary medication effect; the date of graft failure will be 
defined as the date when the criteria for graft failure are confirmed by the clinician-investigator. 
5.4.4 
Disease relapse 
Disease relapse will be assessed (including timing of assessment) according to institutional SOC practice 
for the participant’s specific hematologic malignancy. At defined clinic visits, the disease relapse status 
should be documented, which may include the presence or absence of clinical signs of disease relapse. 
Relapse is defined as “morphologic relapse” for acute/chronic leukemia including AML, ALL, MDS, CML. 
Patients who are found to be in relapse only by molecular methods or cytogenetics will continue with 
the protocol therapy, except for cases which received conventional cytotoxic chemotherapy. The 
following FDA-approved tyrosine kinase inhibitors/hypomethylating agents are allowed in case of 
molecular/cytogenetic relapse: imatinib, nilotinib, dasatinib, ponatinib, sorafenib, azacitidine and 
decitabine. 
 
5.4.5 
Clinical laboratory chemistry, hematology, and pregnancy test 
A complete metabolic panel will include the following 18 blood chemistry parameters (CMP): glucose, 
BUN (blood urea nitrogen), creatinine, uric acid, total proteins, albumin, calcium, phosphorous, sodium, 
potassium, chlorine, total CO2, total bilirubin, alkaline phosphatase, ALT (alanine transaminase), AST 
(aspartate aminotransferase), LDH (lactate dehydrogenase), total cholesterol. 
For women of child bearing potential, a serum or urine pregnancy test is acceptable.   
The hematology testing will include a complete blood count (CBC) with differential. 
5.4.6 
Adverse event assessment (CTCAE) 
All adverse events will be assessed using NCI CTCAE v. 4.0, which can be found at the following link: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf8.1. 
Adverse 
events recorded in the case report forms include: 
o All events considered possibly, probably or definitely related to study agent 
o All grade 3/4/5 events 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 46 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
o All serious adverse events 
5.4.7 
Physical exam, vital signs, medical history and demographics 
Physical exam including a review of skin will be performed. Vital signs will include review of weight, 
heart rate, blood pressure, respiration rate, and temperature.  Height will only be required at baseline. 
5.4.8 
Concomitant medications 
All medications, supportive care, blood products or radiation therapy taken or administered during the 
trial will be documented in the subject’s clinical/hospital record, using COH and participating sites 
documentation guidelines. Additional documentation will be made, where necessary, to support the 
concomitant medication data collected in the study case report forms:  
o Anti-viral medications, including indication, start and stop date 
o Immunosuppressive agents 
o Prednisone dosage for the 7 days prior to vaccine administration 
o Prohibited medications 
5.4.9 
Immunogenicity testing 
All participants will undergo serial blood sampling for future immunogenicity testing. Section 9.0 details 
regarding sample collection, storage, and processing procedures for immunogenicity studies.  
5.5 Criteria for Completing/Discontinuing Study Participation 
Participation may continue until one of the following criteria applies: 
o Participant does not meet criteria for Day 28 vaccine  (such participant are not 
randomized and will be replaced) 
o Completion of study procedures 
o Participant withdraws from the study 
o General or specific changes in the participant's condition that render the participant 
unacceptable for participation in the opinion of the treating investigator. 
Documentation of the reason for completing study participation and the date effective should be made 
in the medical record and appropriate eCRF.  The COH DCC should be promptly notified of the change in 
participant status. 
5.6 Follow-Up and Duration of Participation 
The length and involvement of study participation will vary based on vaccine administration, disease 
relapse, or decision to withdraw from the study, as detailed in the subsections that follow:  
5.6.1 
Participants who do not receive Day 28 vaccine administration 
Participants who do not meet criteria for Day 28 vaccine will discontinue any further follow-up. 
5.6.2 
Participants who reactivate CMV on Day 28 
Participants who receive Day 28 vaccination, but have detectable levels of CMV in Day 28 test sample 
will not be included in the analysis. 
5.6.3 
Participants who relapse after receiving vaccine administration 
Participants who relapse after receiving vaccine administration will have procedures performed and 
documented up to that time of determination of relapse, and then will be followed for survival only 
(including reason for mortality) until Day 365 post-HCT.   

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 47 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
5.6.4 
Participants who withdraw from the study after receiving a vaccine administration 
Participants who withdraw from the study after receiving a vaccine administration may continue with 
follow-up per the participant’s agreement: 
– 
may elect to continue study monitoring procedures without Day 56 vaccine (if not already 
administered). 
 
– 
may elect to continue to be monitored for survival (including reason for mortality) until Day 365 only, 
or  
– 
may elect to withdraw completely; further follow-up or assessments will not occur. 
 
5.6.5 
All other participants (vaccine administered, have not relapsed or withdrawn)  
All participants who received at least one vaccine, have yet to have disease relapse, and have not 
withdrawn from the study, will continue follow up assessments and research blood draws as indicated in 
the Study Activity Calendar (Section 10) through day 365 post HCT. Study participation will be completed 
on Day 365 Post-HCT.   
 
5.7 Supportive Care, Other Concomitant Therapy, Prohibited Medications 
Optional preemptive treatment prior to vaccine administration is detailed in Section 5.3. 
In general, the use of any concomitant medication/therapies and supportive care deemed 
necessary/appropriate for the care of the participant are allowed, with the following exceptions: 
o No other investigational agents may be given to patients 
o Alemtuzumab or any equivalent in vivo T-cell depleting agent is not permitted in this study 
following HCT, because its administration results in in vivo depletion of B, T and dendritic 
cells, potentially negating any positive effect of vaccinating the recipient with CMVPepVax. 
o Prophylactic therapy with CMV immunoglobulin or prophylactic antiviral CMV treatment 
(GCV/VAL, FOS, Cidofovir, CMX-001) is not allowed following HCT with the exception of 
Prevymis administration in Prevymis cohort. GCV/VAL, FOS, Cidofovir, CMX-001 may be used 
according to institutional  SOC for preemptive management of CMV viraemia. In general, 
preemptive therapy should not commence until after CMV qPCR ≥500 gc/ml; for preemptive 
therapy for qPCR<500, the study PIs are to be consulted. 
o Prophylatic antiviral treatment for HSV, HHV6, EBV and adenovirus including the use of 
GCV/VAL, FOS, Cidofovir, CMX-001 may also suppress reactivation of CMV, thus it will not be 
allowed in this study following HCT. Therapeutic use of these agents is permitted per 
institutional standard practice. Acyclovir has no therapeutic efficacy against CMV and is 
allowed as standard of care to prevent HSV. 
o Medications that might interfere with the evaluation of the investigational product are 
prohibited up to 14 days after the second vaccination (day 70 post-HCT). Medications in this 
category include, but are not limited to:  
 
Live attenuated vaccines  
 
Medically indicated subunit (Engerix-B for HBV; Gardasil for HPV) or killed vaccines 
(e.g. influenza, pneumococcal, or allergy treatment with antigen injections) 
o Steroid therapy with prednisone, or equivalent, is permitted (see section 6.0 for specific 
steroid dose criteria for vaccinations). 
 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 48 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
 
 
6.0 
VACCINE ADMINISTRATION CRITERIA 
6.1 Day 28-Post-HCT Vaccine Administration Criteria 
In instances where the criteria are not clear cut, the treating clinician and both Site PIs will collaborate 
to make a determination. This consultation should be documented.  
Following randomization, a first injection (Day 28 vaccine) shall be administered if the following criteria 
are met on the day of vaccination: 
___ 1. NOT experienced ≥ Grade 3 GVHD between days 0-28 post HCT 
___ 2. NO detectable viremia between days 0-28 post HCT 
___ 3. Disease has NOT relapsed since HCT 
___ 4. Successful primary engraftment WITHOUT secondary graft failure 
___ 5. NO ongoing post-HCT ≥ Grade 3 non-hem AE’s, with the exception of grade 3 glucose 
intolerance, cholesterol, triglyceride, and hyperglycemia 
___ 6. Negative for CMV viraemia within the past 7 days 
___ 7. Negative for CMV end organ disease (biopsy proven) post-HCT 
___ 8. All prednisone doses within the past 7 days have been ≤ 1 mg/kg/day (or prednisone equivalent)  
___ 9. NOT received any prohibited medications (Section 5.7) 
___ 10. Negative pregnancy test result for females of child bearing potential 
___ 11. For Prevymis cohort patients: patients who received Prevymis  for at least 7 days before day +28 
post HCT 
The DCC should be promptly notified by the study team of registered participants who fail to meet Day-
28 Post-HCT vaccine administration criteria. 
 
6.2 Day 56-Post-HCT Vaccine Administration Criteria 
In instances where the criteria are not clear cut, the treating clinician and both Site PIs will collaborate 
to make a determination. This consultation should be documented.  
Day 56 vaccine shall be administered if the following criteria are met: 
___ 1. 
NOT experienced  Grade 4 GVHD since Day-28 vaccination 
___ 2. 
NO Grade 3 GVHD within the past 7 days 
___ 3. 
Disease has NOT relapsed since HCT 
___ 4. 
NO secondary graft failure 
___ 5. 
NO ongoing post-HCT ≥ Grade 3 non-hem AE’s, with the exception of grade 3 
glucose intolerance, cholesterol, triglyceride, and hyperglycemia 
___ 6. 
All prednisone doses within the past 7 days have been ≤ 1.5 mg/kg/day (or 
prednisone equivalent)  
___ 7. 
NOT received any prohibited medications (Section 5.7) 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 49 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
___ 8. 
Negative pregnancy test result for females of child bearing potential 
7.0 
ADVERSE EVENTS LIST AND REPORTING OF UNANTICIPATED PROBLEMS AND ADVERSE EVENTS 
7.1 Toxicities to CMVPepVax 
7.1.1 
Expected (known) toxicities to CMVPepVax 
Expected (known) to be associated with CMVPepVax (in agreement with IB) in healthy volunteers and 
HCT recipients, with the highest grade indicated: 
Arthralgia (grade 3), Chills (grade 1), Fever (grade 2), Malaise (grade 3), Allergic reaction (grade 
3), Myalgia (grade 1), Nausea (grade 2), Vomiting (grade 2), Headache (grade 2), Cutaneous 
reaction (pruritus, erythema) (grade 1) 
7.1.2 
Anticipated toxicities to CMVPepVax 
Anticipated toxicities that have not yet been seen from the agent but are foreseeable based on other 
similar agents include: 
Bruise at the site of injection, hypotension. 
7.2 Toxicities to the Placebo  
7.2.1 
Expected (known) toxicities to placebo 
There were no (known) toxicities associated with administering neither vaccine norplacebo.  
7.2.2 
Anticipated toxicities to placebo 
Anticipated toxicities that have not yet been seen from the placebo but are foreseeable based on other 
similar agents include: 
Bruise at the site of injection, hypotension. 
7.3 Definitions 
7.3.1 
Adverse event (AE) 
An adverse event is any untoward medical experience or change of an existing condition that occurs 
during or after treatment, whether or not it is considered to be related to the protocol intervention.  
7.3.2 
Unexpected Adverse Event [21 CFR 312.32 (a)] 
An adverse event is unexpected if it is not listed in the investigator’s brochure and/or package insert; is 
not listed at the specificity or severity that has been observed; is not consistent with the risk information 
described in the protocol and/or consent; is not an expected natural progression of any underlying 
disease, disorder, condition, or predisposed risk factor of the research participant experiencing the 
adverse event. 
7.3.3 
Expected Adverse Event  
Any event that does not meet the criteria for an unexpected event OR is an expected natural 
progression of any underlying disease, disorder, condition, or predisposed risk factor of the research 
participant experiencing the adverse event 
7.3.4 
Serious Adverse Event (SAE) [Modified from 21 CFR 312.32]  
A serious adverse event is defined as any expected or unexpected adverse event that results in any of 
the following outcomes: 
 
Death 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 50 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
 
Life-threatening (places the subject at immediate risk of death from the event as it 
occurred)  
 
Unplanned hospitalization (equal or greater than 24 hours) or prolongation of 
existing hospitalization 
 
A persistent or significant disability/incapacity  
 
A congenital anomaly/birth defect 
 
Secondary Malignancy 
 
Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention to 
prevent one of the outcomes listed above (examples of such events include allergic 
bronchospasm requiring intensive treatment in the emergency room or at home, 
blood dyscrasisas or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse). 
7.3.5 
Unanticipated problems Involving Risk to Subjects or Others  
An unanticipated problem is any incident, experience or outcome that meets all three of the following 
criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given the following: a) the research 
procedures described in the protocol-related documents such as the IRB approved research 
protocol, informed consent document or Investigator Brochure (IB); and b) the characteristics of 
the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcomes may have been caused by the 
drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm) than previously known or recognized. 
7.3.6 
AE Description and Grade 
The descriptions and grading scales found in the most recent version of Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized to characterize AEs, a copy of which can be found 
at http://evs.nci.nih.gov/ftp1/CTCAE/About.html. AEs not covered by specific terminology listed should be 
reported with common medical terminology, and documented according to the grading scales provided 
in the CTCAE Version 4. 
7.3.7 
AE Attribution 
The relationship of event to study drug will be documented by the Investigator as follows: 
 
Unrelated: The event is clearly related to other factors such as the participant’s clinical state, other 
therapeutic interventions or concomitant drugs administered to the participant. 
 
Unlikely: The event is doubtfully related to investigational agent(s). The event was most likely 
related to other factors such as the participant’s clinical state, other therapeutic interventions, or 
concomitant drugs. 
 
Possible: The event follows a reasonable temporal sequence from the time of drug administration, 
but could have been produced by other factors such as the participant’s clinical state, other 
therapeutic interventions or concomitant drugs. 
 
Probable: The event follows a reasonable temporal sequence from the time of drug administration, 
and follows a known response pattern to the study drug. The event cannot be reasonably explained 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 51 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
by other factors such as the participant’s clinical state, therapeutic interventions or concomitant 
drugs. 
 
Definite: The event follows a reasonable temporal sequence from the time of drug administration, 
follows a known response pattern to the study drug, cannot be reasonably explained by other 
factors such as the participant’s condition, therapeutic interventions or concomitant drugs; AND 
occurs immediately following study drug administration, improves upon stopping the drug, or 
reappears on re-exposure.  
7.4 Routine Reporting of Adverse Events by Site Investigators 
Routine AE reporting will occur via data entry into the study eCRF.  Adverse events experienced from the 
time of initial study treatment (Day 28 Post-HCT vaccine administration) to Day 100 post-HCT or until 
disease relapse (whichever occurs sooner) will be reported into the eCRF. AEs reported through 
expedited processes (e.g., reported to the IRB, FDA, etc.) must also be reported in routine study data 
submissions.  
Adverse events recorded in the case report forms include: 
o All events considered possibly, probably or definitely related to study agent 
o All grade 3/4/5 events 
o All serious adverse events 
7.5 Expedited Reporting of Unanticipated Problems and SAEs by Site Investigators 
Each adverse event will be assessed to determine if it meets the criteria for reporting Adverse event 
reporting is to occur according to the site’s specific IRB guidelines, and as outlined in this Section.  
7.5.1 
Adverse Event Reporting to Local IRB 
Sites are to report to their local IRB per their site’s specific institutional and IRB guidelines.  As soon as 
possible, non-COH sites will provide to the Data Coordinating Center copies of the IRB submission and 
corresponding IRB response.   
7.5.2 
Adverse Event Reporting to Coordinating Center/ Study PI 
Adverse events that meet the specified below are to be reported to the Data Coordinating Center and 
Study PI within the timelines and per the procedures in the sections that follow.  
Rationale for reportable events is derived from FDA expedited reporting criteria, COH reporting criteria, 
and Pfizer reporting criteria.  
Report the following to the Coordinating Center/Study PI within 24 hours of being aware that the event 
met reporting criteria: 
Report the following from the signing of consent to study completion 
 All unanticipated problems 
Report the following from first vaccine administration up to 30 days after the last dose of 
vaccine 
All serious adverse events regardless of relationship to study agent, study procedure, 
underlying disease or concomitant treatment 
 AEs that meet the definition of an unanticipated problem 
Report after 30 days after the last dose of vaccine 
All serious adverse events that are considered possibly, probably, or definitely related to 
the study agent. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 52 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Note: follow-up reports must be submitted for all events that require expedited reporting when the 
status of the event changes and until the resolution or stabilization of the event. 
Reportable adverse events must be followed until the event is resolved, stabilized, or determined to be 
irreversible by the participating investigator; for ongoing reportable adverse events that are unrelated 
to study agent, the follow-up period may end at the 30-days post study-drug assessment. The 
Coordinating Center should be consulted prior to ending the follow-up of events that have stabilized. 
How to report an SAE/UP to the Coordinating Center/Overall PI – Non COH Sites: 
1. Document/describe AE/UP f the UP/SAE Coversheet. The SAE Coversheet is found in 
Appendix G.  A modifiable Microsoft Word document is also available from the Data 
Coordinating Center.  An electronic signature on the document will be accepted. 
 
2. Scan and email above documents to DCC@coh.org with the subject title as “CMV SAE”.   
All SAE reports received at this account are forwarded immediately to study Principal Investigator, and 
to Coordinating Center personnel.  While not required, if available and applicable, please also include 
the local IRB submission for this event in the submission.  
3. 
If an email receipt from Coordinating Center personnel is not received within one 
working day, please call 626-256-4673 x 63968 and/or email DCC@COH.org. 
 
How to report AEs to the Coordinating Center/Overall PI –COH Investigative Sites 
1. Email the following information to DCC@coh.org and rnakamura@coh.org.   
a. Participant ID, date the event met criteria for reporting, whether the event meets 
the definition of serious, whether the event is an unanticipated problem, grade of 
event, attribution of event, whether the event is a known expected toxicity to study 
agent. 
2. Complete the iRIS AE/UP reporting form per COH reporting timeline 
 
7.6 Reporting of Adverse events by the Study PI  
 The Study PI (or designee) will: 
 
Report to COH IRB and DSMC all reportable adverse events that meet COH IRB and DSMC 
reporting criteria and occur at non-COH sites according to City of Hope’s Institutional policy 
on reporting adverse events  and indicate whether or not a protocol and/or consent form 
change is required. 
 
Report all expedited reportable adverse events to participating investigators as an IND Safety 
Report occurring within 30 calendar days of receipt of sponsor (lead site) notification, and 
indicate whether or not a protocol and/or consent form change is required.  A cover letter will 
indicate the protocol title, the IND#, whether the FDA was informed, and, for non-COH sites, a 
statement that the report should be submitted to their local IRB for review as an IND safety 
report if applicable per local IRB policy. 
 
Report to the FDA, (via COH Office of IND Development and Regulatory Affairs (OIDRA)) 
regardless of the site of occurrence, any serious adverse event that meets the FDA’s criteria 
for expedited reporting following the reporting requirements and timelines set by the FDA. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 53 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
 
Report to Pfizer, (via COH OIDRA) regardless of the site of occurrence, any serious adverse 
event that meets the FDA’s criteria for expedited reporting following the reporting 
requirements and timelines set by the FDA. 
 
Submit annually within 60 days (via COH OIDRA) of the anniversary date of when the IND 
went into effect, an annual report to the FDA which is to include a narrative summary and 
analysis of the information of all FDA reports within the reporting interval, a summary report 
adverse drug experiences, history of actions taken since the last report because of adverse 
drug experiences. 
 
Report every three months to the COH DSMC a Protocol Management Team report, to include 
aggregate analysis of safety information and accrual and participant status. 
 
Circulate to all participating sites for submission to their IRBs the above Protocol 
Management Team (DSMC) report and DSMC recommendation, in accordance with NIH 
guidance. 
 
Report to Pfizer summary safety information every three months. 
 
Forward to participating sites all reportable adverse events to participating investigators as an 
IND Safety Report occurring within 30 calendar days of receipt of lead site notification, and 
indicate whether or not a protocol and/or consent form change is required.  A cover letter will 
indicate the protocol title, the IND#, whether the FDA was informed, and, for non-COH sites, a 
statement that the report should be submitted to their local IRB for review as an IND safety 
report if applicable per local IRB policy. 
 
Forward to participating sites all IND safety reports received from Pfizer for the CMVPepVax 
adjuvant, PF-03512676, that have not occurred directly on this protocol, indicating whether a 
consent form or protocol change is required within 30 days of notification to Study PI. 
 
Submit to participating sites all IND safety reports for CMVPepVax, that have not occurred 
directly on this protocol, indicating whether a consent form or protocol change is required 
within 30 days of notification to Study PI. 
 
 
 
 
 
 
 
 
 
 
 
 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 54 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
8.0 
AGENT INFORMATION 
8.1 CMVPepVax and Placebo Vaccine –information applicable to vaccine components 
CMVPepVax will be prepared by the investigational pharmacy from the following components provided 
by the Sponsor and detailed further in the sections that follow:  
 
Tet-CMV peptide 
 
PF-03512676 adjuvant  
 
Normal saline 
 
Sodium acetate (10mM) 
 
The Placebo Vaccine will be prepared by the investigational pharmacy from the following components 
provided by the Sponsor and detailed further in the sections that follow: 
 
Neut™ (0.4%) Sodium Bicarbonate Additive 
 
Sodium acetate (10mM).  
For all of the above listed components, the following elements apply: 
8.1.1 
Accountability,  
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of each of the agents using the NCI Drug Accountability Record or another 
comparable drug accountability form.  
In addition, documentation of the preparation of the vaccine (placebo or CMVPepVax) is required. See 
Sections 8.6 and 8.7 for details.  
The sponsor should be promptly notified of any deviations to the procedures related to the study agent. 
8.1.2 
Handling 
Qualified personnel, familiar with aseptic technique and procedures that ensure the quality of the agent 
and minimize undue exposure to themselves and the environment, should undertake the preparation, 
handling, and, when applicable, safe disposal of the agent.  
8.1.3 
Ordering 
The COH IDS pharmacy will order all agents from the respective supplier (COH Center for Biomedicine 
and Genetics; Biopharmaceutical Development Program at the Frederick National Laboratory for Cancer 
Research, Pfizer) in coordination with and as approved by Dr. Diamond (ddiamond@coh.org) and Dr. 
Nakamura (rnakamura@coh.org). 
 External site Pharmacies will order all agents from the COH IDS pharmacy.  
8.1.4 
Destruction and Return 
Vials used in the preparation of vaccine for administration and any residual agents there in may be 
disposed of by the research pharmacy standard practice. Unused agent will either be returned to the 
sponsor or disposed of via pharmacy standard practice. No unused agent will be disposed of without 
prior written approval by Dr. Don Diamond (ddiamond@coh.org).   
 
 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 55 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
8.2 Tet-CMV, the synthetic peptide contained in CMVPepVax 
Additional information about Tet-CMV can be found in the City of Hope CMVPepVax IB.   
8.2.1 
Description 
Tet-CMV peptide (=Tetanus-CMV; CODE NAME: NSC-721434; IND, BB-13124) which consists of the HLA 
A*0201-restricted CMV pp65495-503 epitope covalently attached to the tetanus toxin tt830-843 epitope (P2). 
Tet-CMV peptide is a 29 amino acid and 3052.6 dalton peptide. Its Molecular Formula is: Tet-CMV = 
C137H227N35O41S1.Its Amino Acid Sequence is: Tet-CMV: H-Lys-Ser-Ser-Gln-Tyr-Ile-Lys-Ala-Asn-Ser-Lys-Phe-
Ile-Gly-Ile-Thr-Glu-Ala-Ala-Asn-Leu-Val-Pro-Met-Val-Ala-Thr-Val-OH.  The Pharmacologic Class is: Peptide 
Vaccine. 
8.2.2 
Toxicology 
Most common AEs included mild to moderate cutaneous reactions at the injection site. The duration of 
related Grade 1 and 2 AEs ranged from 1-2 days. No grade 3 AEs were reported with CMVPepVax, the 
same formulation selected to be used in HCT recipients (approx 2.5 mg Tet-CMV peptide co-injected 
with 1.08 mg of PF-03512676).  
8.2.3 
Supplier  
Tet-CMV study drug is being provided to COH by the National Cancer Institute sponsored NExT (NCI- 
NExT) program, which contracted with Bachem Incorporated (Torrance, CA) for cGMP-grade production 
of Tet-CMV. COH Center for Biomedicine and Genetics (CBG) stores  and supplies Tet-CMV to COH IDS 
pharmacy for this study. The CBG or COH IDS pharmacy will supply Tet-CMV to all external trial sites. 
8.2.4 
Form 
The trial will initiate using the initial lot of Tet-CMV (Lot#L0402009), which was used in IRB#12022. This 
was provided to COH by the National Cancer Institute sponsored NEXT (NCI-NEXT) program, which 
contracted with Bachem Incorporated (Torrance, CA) for cGMP-grade production of Tet-CMV. Tet-CMV 
is supplied frozen in 10 mM sodium acetate (pH 4.2), as a sterile, preservative-free, solution for SC 
injection at  11 mg/1.1 ml vial , and packaged in 2-ml USP Type I clear glass vials with gray butyl, 
FluroTec®-coated stoppers and aluminum flip-off seals. The new Lot of Tet-CMV will be  supplied frozen 
at  3.3 mg/ml in 10 mM sodium acetate (pH 4.2), as a sterile, preservative-free, solution (fill volume 1.2 
mL ) packaged in 2-ml USP Type I clear glass vials with gray butyl, FluroTec®-coated stoppers and 
aluminum flip-off seals.  
CMVPepVax administration provides a dose of 2.48mg Tet-CMV Peptide when the vaccine is prepared 
using the currently available Tet-CMV (LOT# L0402009, 11mg/1.1mL vial). 
CMVPepVax administration provides a dose of  2.64 mg Tet-CMV Peptide when the vaccine is prepared 
using the new lot of Tet-CMV  (LOT#L1501005, 3.3 mg/mL, fill volume 1.2 mL) 
 
8.2.5 
Storage and stability 
Tet-CMV peptide is to be stored in a monitored freezer at -60oC to -90oC.  Stability analyses of Tet-CMV 
are performed every 6 months.  
 
8.2.6 
Handling, Ordering, Accountability, Destruction and Return 
See Sections 8.1 
 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 56 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
8.3 PF-03512676, the adjuvant of CMVPepVax  
Additional information about PF-03512676 can be found in the Pfizer PF0351276 IB.   
8.3.1 
Description 
Pfizer PF-03512676 (previously referred as CPG 7909 and CPG ODN 2006[66]) adjuvant is a pure 
substance named Agatolimod Sodium, and is classified as an investigational agent.  PF-03512676 is an 
immunostimulatory 
single-stranded, 
phosphorothioate 
oligodeoxynucleotide 
containing 
four 
unmethylated deoxycytosine-deoxyguanine dinucleotide (CpG) motifs and synthesized with a nuclease-
resistant phosphorothioate backbone. PF-03512676 is 24 nucleotides in length. Its structural formula is: 
(3'-5')d(P-thio)(T-C-G-T-C-G-T-T-T-T-G-T-C-G-T-T-T-T-G-T-C-G-T-T) tricosasodium salt. Its molecular 
formula is: C236/H303/N70/O133/P23/S23/Na23.  
8.3.2 
Toxicology 
Use of PF-03512676 as a vaccine adjuvant at doses of 1.08 mg SC/injection results in an AE profile 
consisting of frequently reported mild to moderate injection site reactions and flu-like symptoms.  
At dosing significantly higher than the dose/injection proposed in this trial, e.g., in monkeys the no-
effect dose level for complement activation is 2-5 mg/kg. The toxicity of PF-03512676 includes effects of 
immune stimulation (liver and spleen enlargement and inflammatory infiltrates in rodents), activation of 
the alternative complement pathway and inhibition of the intrinsic coagulation pathway (shock-like 
syndrome in monkeys following rapid infusion), and dose-related histopathologic changes in liver and 
kidney during subacute and chronic administration.  PF-03512676 had been determined to be 
embryolethal in rabbits and teratogenic in developing rats and rabbits.   
8.3.3 
Form 
PF-03512676 is supplied as a sterile, preservative-free, isotonic, phosphate buffered saline solution at a 
concentration of 15 mg/ml, pH 7.4 and packaged in 2-ml USP Type I clear glass vials with gray butyl, 
FluroTec®-coated stoppers and aluminum flip-off seals.  Each vial contains a total of 23.25 mg in 1.55ml, 
with 1.2 ml of extractable volume (18 mg/1.2 ml of PF-03512676).  
CMVPepVax administration provides a dose of 1.06mg PF-03512676 when the vaccine is prepared using 
the currently available lot of Tet-CMV (LOT# L0402009, 11mg/1.1mL vial) 
CMVPepVax administration provides a dose of 1.08mg PF-03512676 when the vaccine is prepared using 
the new lot of Tet-CMV  (LOT#L1501005, 3.3 mg/ml, 1.2 mL fill volume) 
8.3.1 
Supplier 
PF-03512676 is supplied as an investigational agent by Pfizer.  
8.3.2 
Storage and Stability 
PF-03512676 will be stored under refrigeration (2 to 8°C) in a secure temperature controlled 
refrigerator. Stability tests on PF-03512676 are routinely performed by Pfizer. 
8.3.3 
Handling, Availability, Ordering, Accountability, Destruction and Return 
See section 8.1. 
8.4 Sodium acetate, the synthetic peptide diluent contained in CMVPepVax 
Additional information about 10mM Sodium Acetate can be found in the City of Hope CMVPepVax IB.   
8.4.1 
Description 
10 mM sodium acetate (CH3COONa), pH 4.2 (Lot#L0910005) will be used as a diluent for CMVPepVax.  

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 57 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
8.4.2 
Toxicology 
There are no data available on the toxicology of 10 mM sodium acetate, pH 4.2, administered by SC 
route. Sterile, nonpyrogenic, 40 mEq (2 mEq/ml) USP solution of sodium acetate are typically 
administered, after dilution, by the IV route as an electrolyte replenisher. The solution is intended as an 
alternative to sodium chloride to provide sodium ion (Na+) for addition to large volume infusion fluids 
for IV use. 
8.4.3 
Formulation 
Sodium acetate will be supplied as a sterile, preservative-free, solution at 10mM, 1.1 ml volume, pH 4.2, 
and packaged in 2-ml USP Type I clear glass vials with gray butyl, FluroTec®-coated stoppers and 
aluminum flip-off seals. 
8.4.1 
Supplier 
cGMP-grade sodium acetate solution (SAIC (NSC 733084)) will be supplied by Biopharmaceutical 
Development Program, NCI-Frederick in the formulation described above. 
8.4.2 
Storage and Stability 
The sodium acetate 10mM vials will be stored under refrigeration (2 to 8°C) in a secure temperature 
controlled refrigerator. The sodium acetate 10mM solution has passed a safety test, sterility and 
stability tests, which are performed every 6 months.  
8.4.1 
Handling, Availability, Ordering, Accountability, Destruction and Return 
See section 8.1. 
 
8.5 Neut™ Sodium Bicarbonate Additive Solution for the Placebo Vaccine 
Additional information about Neut™ Sodium Bicarbonate Additive Solution can be found in the City of 
Hope CMVPepVax IB and at 
http://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ca2906bc-7d85-449b-bc86-
ed627bf69a9f  
8.5.1 
Description 
Neut™ (0.4% sodium bicarbonate additive solution) is a sterile, nonpyrogenic solution of sodium 
bicarbonate in water which will be used to bring the pH of the placebo injection to a pH similar to 
CMVPepVax. Since the sodium acetate solution is at pH 4.2, addition of Neut™ will raise the pH of the 
placebo injection closer to a physiological pH.  
Neut (0.4% sodium bicarbonate additive solution) is indicated for use as an additive to raise the pH of 
acid solutions administered intravenously to reduce the incidence of chemical phlebitis and patient 
discomfort due to vein irritation at or near the site of infusion.  
8.5.2 
Toxicology 
There are no known warnings. It is administered by the intravenous route only after addition as a 
neutralizing agent to an acidic large volume parenteral solution. It is not for use as a systemic alkalizer. 
8.5.3 
Formulation 
Neut™ will be supplied as Neut™ 0.4%, 1 ml volume packaged in a 2 ml flip-top vial. Neut™ 0.4% is 
formulated from Neut™ 4% diluted 1:10 in sterile water.  
Each 5 mL of  Neut™ 4% contains sodium bicarbonate 0.2 g (2.4 mEq each of Na+ and HCO3‾ ); edetate 
disodium, anhydrous 10 mg added as a stabilizer. Total sodium (Na+) content of each 5 mL is 56.1 mg 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 58 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
(11.2 mg/mL). The solutions contain no bacteriostat, antimicrobial agent or added buffer; pH 8.0 (7.0 to 
9.5). Sodium Bicarbonate, USP is chemically designated as NaHCO3, a white crystalline powder soluble in 
water.  
8.5.4 
Supplier 
Neut™ 4% sodium bicarbonate additive solution is produced by Hospira, Lake Forest, IL.  Neut™4% 
sodium is supplied in 5 ml fliptop vials. The COH Center for Biomedicine and Genetics (CBG) formulates 
and supplies a 1:10  dilution of Neut™ in sterile water, which is vialed as Neut™ 0.4% (2mL fliptop vials). 
The COH CBG is a California Food and Drug Brand (CFDB) licensed manufacturing facility which operates 
under the principles of Current Good Manufacturing Practice regulations for the manufacture of phase 
I/II biologics. The COH IDS pharmacy will supply Tet-CMV to all external trial sites. 
8.5.5 
Storage and Stability 
Neut™ Sodium Bicarbonate Additive Solution should be maintained at room temperature. 
The release testing for Neut™ 0.4% fill includes sterility, bacteriostasis and fungistasis, endotoxin, pH 
and particulate testing. The testing will be performed until the end of the study. 
8.5.1 
Handling, Availability, Ordering, Accountability, Destruction and Return 
See section 8.1. 
 
8.6 Preparation of CMVPepVax 
A list of reagents, equipment and supplies needed to prepare the vaccine is located in Appendix E.  
Preparation of CMVPepVax using the initial lot of Tet-CMV (Lot # L0402009) are detailed in Appendix 
F. 
Note: the CMVPepVax vaccine must be administered within 90 minutes after the Tet-CMV has thawed. 
Thawing and preparing CMVPepVax components (using Lot#L1501005 of Tet-CMV) 
 
Put cooling block in hood and set to 4°C. Once the LCD on the cooling 
block reads 4°C, measure the temperature of the cooling block using the 
NIST thermometer and  "Enviro-Safe liquid', or digital thermometer. 
Adjust LCD until NIST or digital thermometer reads 4°C.  Only the  
thermometer should be relied upon for accuracy. Record the LCD and 
NIST/digital temperature readings on the Vaccine Compounding Record.   
 
Obtain frozen Tet-CMV vial (LOT#L1501005, 3.3 mg/mL, 1.2 mL) from 
the -70C freezer; record the time at which the Tet-CMV vial is removed 
from the freezer.  Allow vaccine vial to thaw at room temperature 
(approximately 15-30 minutes).  Record the time at which the vial is 
completely thawed.  This is the start time of the CMVPepVax vaccine 
dose preparation. Administration of the vaccine must occur within 90 
minutes after start time of preparation. 
 
Once thawed, place vial on the cooling block cooled to 4°C (based only 
on NIST or digital thermometer reading, not the LCD) to keep cold.   
 
Obtain 10mM sodium acetate, pH 4.2 vial (1.1 mL), PF-03512676 and 
Normal Saline from Pharmacy refrigerator.  Keep sodium acetate and 
PF-03512676 cold by placing them on the cooling block. Preparation of 
vaccine must be done at approximately 4°C to minimize “clouding” of 
solution. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 59 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
 
For the PF-03512676 only, using sterile procedures, inject 0.6 ml Normal 
Saline solution into the PF-03512676 vial (containing a total of 23.25 mg 
in 1.55ml, with an extractable volume of 18 mg/1.2 ml of PF-03512676), 
mix thoroughly and keep on ice. The final concentration of PF-03512676 
will be 10.81 mg/ml in 2.15 ml total volume. 
CMVPepVax injection preparation 
 
 Add 0.15mL of 10mM sodium acetate, PH 4.2 to the thawed vial of Tet-
CMV .   
 
Add 0.15 ml of diluted PF-03512676 (10.81mg/ml) to the thawed  vial of 
Tet-CMV + sodium acetate. 
 
Vortex the vial (containing 1.5 ml of Tet-CMV + sodium acetate + PF-
03512676 ) for 30 seconds at highest setting.  
 
Withdraw 1 ml for the subject’s dose and cap syringe. This will provide a 
final dosage of 2.64  mg Tet-CMV and 1.08 mg of PF-03512676. After 
labeling appropriately, place syringe in sealable plastic amber bag and 
place in an insulated cooler .   
 
Record the time that the CMVPepVax vaccine is placed in an insulated 
cooler  and is ready for transport.  
Labeling of the vaccine to communicate necessary information and maintain the blind 
 
The prepared syringe or accompanying documents should be labeled in 
a manner to maintain a blind randomization status with the clinical 
study team and participant. 
 
The time by which the vaccine needs to be administered – start time + 
90 minutes – must be clearly noted in order to inform the person 
administering the vaccine (e.g. “Administer before xx:xx am/pm”). 
 
8.7 Preparation of Placebo 
Note: the placebo vaccine must be administered within 90 minutes after the Neut™ vial is uncapped. 
Preparation 
 
Obtain 10mM sodium acetate, pH 4.2 vial from Pharmacy refrigerator.  
Obtain NeutTM 0.4% flip top vial from RT shelf. 
 
Record the time at which the Neut™ vial is opened; this is the start time 
of the placebo dose preparation.  Place vials on the cooling block.  
 
Add 0.4 ml of Neut™ 0.4% into the 1.1 ml sodium acetate, pH 4.2 vial. 
 
Vortex the vial (containing 1.5 ml of volume) for 30 seconds at highest 
setting.  
 
Withdraw 1 ml for the subject’s dose and cap syringe.  
 
 After labeling appropriately, place syringe in sealable plastic amber bag 
and place in an insulated cooler.  Record the time that the placebo is 
placed in insulated cooler and is ready for transport. 
Labeling of the placebo to communicate necessary information and maintain the blind 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 60 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
 
The prepared syringe or accompanying documents should be labeled in 
a manner to maintain a blind randomization status with the clinical 
study team and participant. 
 
The time by which the placebo needs to be administered – start time + 
90 minutes – must be clearly noted in order to inform the person 
administering the vaccine (e.g. “Administer before xx:xx am/pm”). 
 
9.0 
CORRELATIVE/SPECIAL STUDIES 
9.1 Immunogenicity testing 
The correlative immunogenicity studies will include monitoring levels and quality of CMV-specific CD8+ T 
cells and highly cytotoxic memory NKG2C+ NK cells, by multi-color flow cytometric analyses. 
9.1.1 
Specimen Collection and Transport to Processing Laboratory 
All participants will undergo serial blood sampling for immunogenicity testing at the schedule indicated 
in the Study Activity Calendar (Section 10), which, in general, includes days 28, 42, 56, 70, 84, 100, 140, 
180, 270 and 365 post-HCT.  
 Approximately 30 ml of blood in heparin (green-top) tubes, gently inverted several times to mix anti-
coagulant,  will be kept at room temperature and  transported to authorized personnel of the 
Department of Experimental Therapeutics (DET) at COH or an assigned Laboratory at external trial sites.  
Where sample processing at an external site is not possible, whole blood will be shipped at room 
temperature to COH for processing. Patient name, MRN and date of birth should be defaced on the 
blood tube label. UPN and visit date only for the sample should be recorded on a sheet of paper sent 
with the blood draw. 
9.1.2 
Initial specimen processing, storage, and shipping 
Sample processing and storage will occur in Fox South, 1002 or the external trial sites. PBMC will be 
separated from heparinized blood by standard density gradient centrifugation methods*, washed, re-
suspended in fetal calf serum (FCS) with 10% DMSO, aliquoted, and cryopreserved in a centrally 
monitored liquid nitrogen tanks at the COH DET and or external trial sites . Samples will be processed 
and stored according to institutional SOP; it is recommended to freeze 5 million cells per aliquot.  
Samples will be labeled with the study timepoint (e.g. Day 42), date of collection, and study protocol 
number (COH 13494) and participant study number (e.g. UMN-006). 
*During the processing of the PBMCs, 3 mls of plasma will be set aside, aliquoted and stored at -70C.  
When requested by the laboratory performing the analysis, samples will be batch shipped to COH 
overnight on dry ice.  
9.1.3 
Analytical Method 
CMV-specific CD8+ T cells  
Immunogenicity studies of CMV-specific CD8+ T cells will be performed at the COH DET and will include 
immune-monitoring of levels of CD8+ T cells binding to A2-CMV-dextramers® (Immudex, Copenhagen, 
Denmark) and PD-1 expression on pp65-specific T cells, poly functionality and phenotype assessment of 
CMV-specific T cells[8, 10, 67]. Additionally, CMV-specific T cell growth kinetics and early cell death we 
be monitored. The proposed Phase II blinded placebo controlled study will definitively assess the level of 
association between reduced CMV reactivation and CMV pp65 specific T cells. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 61 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Multicolor FACS analyses will be used to assess poly functionality and phenotype of CMV-specific T 
cells[8, 10, 67]. All immune-monitoring studies will be performed by flow cytometry techniques using 
the Gallios TM with Kaluza software (Beckman Coulter Inc, Brea CA). 
All immunophenotyping will be conducted on freshly thawed PBMC without cultivation or stimulation in 
vitro.  PBMC will be stained with each fluorochrome-conjugated antibody combination using standard 
methods with commercially fluoresceinated antibodies (BD Biosciences, San Jose, CA), as described in 
our published studies [93, 94].  Briefly, PBMC will be stained with either CMV pp65495-503 or HIVgag77-85 
(as control) APC-conjugated dextramers® and antibodies against CD3, CD8 and PD-1 labeled with APC-
Cy7, FITC and PE, respectively (BD Biosciences, San Jose, CA). PBMC will be analyzed for levels of CD8+ T 
cells binding to the dextramers and PD-1 expression by FACS. In combination with CBC, we will be able 
to calculate the absolute number of pp65495-503–specific CD8+ T cells/L.   
Assessment of CMV-specific T cell growth kinetics will be performed using the carboxyfluorescein 
diacetate succinimidyl ester (CFSE) dilution method for cell division tracking as previously detailed [95]. 
Briefly, proliferation will be analyzed using the CFSE dilution method, according to the manufacturer’s 
procedure (Molecular Probes, Carlsbad, CA). To assess CD8 T cell proliferation, PBMC will CFSE labeled 
and incubated for 6 days with 1 µg/ml pp65495-503 peptide or DMSO  diluent as control, in the presence of 
anti-CD49b and CD28 (1 µg/ml). Cells will be then washed and co-stained with anti-CD8 (all antibodies 
from BD Biosciences) and FACS analyzed for CFSE fluorescence levels. Early cell death will be determined 
using the BD ApoAlert annexin V-FITC Apoptosis Kit (BD Biosciences) according to the manufacturer’s 
instructions, and cells will be analyzed by  FACS [89]. 
Natural Killer cell phenotype and function 
Assessment of NK phenotype and function (cytotoxicity and cytokine production) will be performed at 
UMN TLL. These studies will determine whether vaccination of HLA A*0201 allogeneic HCT-R+ induces 
adaptive NK cell population changes, and increase in the highly cytotoxic memory NKG2C+ NK cells, 
linked to CMV reactivation, critical for CMV adaptive immune response and potentially linked to relapse 
reduction[17-20]. Since in the pilot Phase Ib, CMVPepVax appeared to reduce reactivation, cGVHD and 
relapse we will assess whether vaccinated patients have increased levels of this potent subset of NK 
cells[18-20]. The NK analyses will be performed at a single cell level by using a 9-color flow 
approach[18]. COH will provide aliquots of patient PBMC for this analysis. 
 GVHD Biomarkers 
In the phase Ib trial of CMVPepVax in HCT recipients (COH IRB 12022) CMVPepVax administration was 
associated with reduced risk of chronic GVHD while there was no increase in acute GVHD. To further 
investigate potential immunologic impacts of CMVPepVax on GVHD, the following GVHD biomarkers will 
be evaluated in Fox South, 1002. 
o interleukin-2 receptor α (IL2Ra), tumor necrosis factor receptor 1 (TNFR1), hepatocyte 
growth factor (HGF), interleukin 6 (IL6) and interleukin-8 (IL8) for systemic GVHD[76, 77] 
o elafin for skin GVHD[78] 
o regenerating islet-derived 3α (REG3α) for gastrointestinal GVHD[79] 
o suppression of tumorigenicity 2 (ST2) for steroid-refractoriness [80] 
o CXCL9 and B cell–activating factor (BAFF) for chronic GVHD[81, 82] 
The levels of these GVHD biomarkers will be compared between the vaccine group and placebo group, 
as well as between GVHD+ and – groups.   

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 62 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
10.0 STUDY CALENDAR 
Table 10.0 Study Activity Calendar  
 
Pre-HCT 
HCT Day 0 
Vaccination and Bi-Weekly 
Visits b 
Post-100 Day 
Follow-Up c 
Study day a 
*(-60-0) 
28d 42 56d 70e 84 100 140 180 270 365 
Informed Consent f 
X 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics g 
X 
 
 
 
 
 
 
 
 
 
 
Concurrent medications h 
X i 
X j 
X j X j X j X j X j 
X k 
X k 
X k X k 
Physical exam and vital signs l 
X 
X 
 
X 
 
 
 
 
 
 
 
KPS performance status m 
X 
X 
 
X 
 
 
 
 
 
 
 
Adverse event (CTCAE) assessment n 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Engraftment status o 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease relapse p 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GVHD assessment and grading q 
 
X r 
X 
X s 
X 
X 
X 
X 
X 
X 
X 
CMV disease t 
 
X u 
 
X u 
 
 
 
 
 
 
X v 
CMV qPCR w 
 
X 
X 
X 
X 
X 
X 
      X----X 
HIV, HCV, CMV, active HBV x 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test y 
X 
X 
 
X 
 
 
 
 
 
 
 
Chemistry/metabolic panel z 
X 
X 
 
X 
 
 
 
 
 
 
 
CBC with differential aa 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research blood sample bb 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Criteria review 
X cc 
X dd 
 X ee 
 
 
 
 
 
 
 
Registration/verify with DCC 
X ff 
 
 
 
 
 
 
 
 
 
 
Vaccine administration  
 
X gg 
 
X gg 
 
 
 
 
 
 
 
* Criteria review, screening, consent and Registration with DCC permitted Day -60 to Day 0 
a. Study day is defined relative to the day of HCT which is defined as Day 0. 
b. Window for post-HCT Day 28 and 56 vaccinations and Bi-Weekly Assessment procedures is the 
assigned day +/- 7 days.  
c. Windows for the ‘Post-100 Day Follow-Up’ visits is the assigned day +/- 15 days. 
d. All assessments to be performed and reviewed on the day of and prior to vaccine administration, 
except for CMV qPCR for which the result may remain pending.  
e. On Day 70 post-HCT, 14 days after the second vaccination, administration of other vaccines is no 
longer prohibited (Section 5.7). 
f. Informed consent process to be fully documented: e.g. prospective participant had sufficient time 
for deliberation, all questions were answered, treatment options provided by MD, full study 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 63 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
reviewed including risks, and a copy of signed consent given to participant. Informed consent must 
occur prior to any research only (non-SOC) screening procedures. 
g. Medical history and demographics – to include any ongoing medical conditions and medical history 
pertaining to eligibility on study and involvement during study.  
h. Concurrent medications, supportive care, blood products, or radiation therapy taken or 
administered during the trial will be documented in the subject’s medical record using institutional 
documentation guidelines. 
i. 
Concurrent medications pertaining to eligibility criteria will be reviewed. 
j. 
Concurrent medication data collected in CRFs pertains to anti-viral medications (including start and 
stop date), immunosuppressive agents, daily prednisone dose for the 7 days prior to vaccine 
administration, and prohibited medications (Section 5.7).   
k. Concurrent medication data collected after 100 days is limited to anti-viral medications (including 
start and stop date). 
l. 
Physical exam to include skin assessment. Vital signs:  Weight, heart rate, blood pressure, 
respiration rate, temp.  Height required only at baseline. 
m. KPS scale is found in Appendix D.  
n. Adverse events (AEs) will be assessed and documented from Day 28 to Day 100 at the defined 
study visits and at standard of care visits. Documentation should support adverse events recorded 
in the CRFs: all AEs considered possibly, probably or definitely related to study agent, all grade 
3/4/5 events, and all serious adverse events. See Section 7.0 for adverse event reporting. 
o. Engraftment status should be documented at each study visit, and if engraftment failure occurs the 
date of engraftment failure should be noted (see Section 5.4 for definitions).  
p. See Section 5.4.4. for definition of relapse. Disease relapse will be  assessed according to and per 
the timing of institutional SOC practice for the participant’s specific hematologic malignancy. Note: 
participants who undergo disease relapse will cease all future study visits/procedures and will be 
followed only for survival through Day 365. 
q. Acute and chronic GVHD grading scales are found in Appendix B and C, respectively. The final 
grading may occur after a clinic visit has ended, using all diagnostic information available to 
determine the GVHD grade at the time of the visit. In the study CRF, the grade at the time of the 
study visit will be recorded, and the highest grade and date of onset during the interim period 
between visits (assessed at SOC visits), if higher than the grade at the visit. 
r. For the Day 28 visit, assessment and grading of GVHD for the 7 days prior to the visit must be 
determined and documented on the day of the visit to assess/support vaccine administration 
criteria. The determination may be revised as more information is available, but will be 
documented in the medical record and in the CRF as a revised GVHD assessment and grading 
following new information obtained after vaccine administration. 
s. For the Day 56 visit, assessment and grading of GVHD between the initial vaccination and Day 56 
must be determined and documented on the day of the visit to assess/support vaccine 
administration criteria. The determination may be revised as more information is available, but will 
be documented in the medical record and in the CRF as a revised GVHD assessment and grading 
following new information obtained after vaccine administration. 
t. Clinically confirmed CMV disease will be captured in the case report forms. Presentations or 
suspected presentations of CMV disease in the absence of qPCR ≥500 gc/ml will be evaluated by 
the treating investigator in conjunction with the blinded PMT before a determination is made.  

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 64 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
u. Participants with suspected CMV disease on the day of planned vaccination must have testing to 
confirm the presence or absence of CMV disease prior to determining for the CMV disease 
vaccination administration criterion.  
v. For the Day-365 visit, the treating investigator will investigate and document whether CMV disease 
occurred Day 100 onward, and so note the findings accordingly.  The case report forms will be 
updated to record any positive results not yet documented. 
w. CMV qPCR will be performed per institutional SOC (usually twice-weekly, and at minimum once per 
calendar week) between days 21 and day 100 post-HCT. All CMV qPCR results will be collected in 
the case report forms. Post Day 100 until day 180, CMV qPCR to be performed at least every 2 
weeks. All CMV qPCR results will be collected in the case file.  
x. CMV serostatus, HIV antibody, Hepatitis C antibody, Hepatitis B surface antigen test must be 
performed if results are not available within 2 months of registration. If CMV seropositive status 
not already documented, CMV serotesting may be performed for eligible review. 
y. Serum or urine pregnancy test to be performed for women of child bearing potential. 
z. Chemistry/metabolic panel to include: glucose, BUN, creatinine, uric acid, total proteins, albumin, 
calcium, phosphorous, sodium, potassium, chlorine, total CO2, total bilirubin, alkaline phosphatase, 
ALT, AST, LDH, total cholesterol. 
aa. CBC with differential is to be taken at the same time as the research blood sample.  
bb. Research blood samples are to be collected at the same time as the CBC with differential. A volume 
of approximately 30 ml of blood in heparin (green-top) tubes, gently inverted several times to mix 
anti-coagulant, and then kept at room temperature until transport to authorized personnel at Fox 
South, 1002 or external site Research Laboratory. 27 ml and 3 ml are allocated for PBMC and 
plasma isolation respectively.  
cc. Eligibility criteria for enrollment in the clinical trial are found in Section 3.0. 
dd.  Day-28 Vaccine Administration Criteria are found in Section 6.1. Participants failing to meet Day-28 
vaccine criteria will complete the study at this time and be replaced and the study team should 
promptly inform the DCC.  
ee. Day-56 Vaccine Administration Criteria are found in Section 6.2. Participants failing to meet Day-56  
vaccine criteria will continue with remaining study procedures; participants with disease relapse 
will continue for survival follow-up only.  
ff. The study team will submit copies of source documentation, the eligibility criteria list, signed 
consent, and registration cover sheet to the DCC who will proceed to confirm study eligibility and 
register the participant.  See Section 4.2 for details.  
gg. Vaccine administration is detailed in Section 5.3. 
 
 
 
 
 
11.0 ENDPOINT EVALUATION CRITERIA/MEASUREMENT OF EFFECT 
The primary endpoint of this trial will be CMV-related. Secondary endpoints will include safety, 
immunological and clinical parameters. In detail: 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 65 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Primary endpoints:     
1. For the entire cohort (n=97): Immunological endpoints: levels of CD8+ T cells binding to A2-CMV-
dextramers®, combined with T and NK cell phenotype and function. 
2. For the combination cohort (n=36): CMV reactivation [≥1,250 IU/mL] or CMV disease between 
day 56 and day 180 post-HCT in patients who receive standard Prevymis prophylaxis (from day 
14 through day 100). 
 
Secondary endpoints:  
1. Key safety endpoints: non-relapse mortality (NRM) at 100 days post HCT, severe (grade 3-4) 
aGVHD, and grade 3-4 AEs (CTCAE 4.0) probably or definitely related to the vaccination within 2 
weeks from each vaccination. 
2. CMV reactivation [≥1,250 IU/mL] or CMV disease prior to day 100 post-HCT. Timing and 
recurrence of events are included in the primary analysis. 
3. CMV-related endpoints:  Duration of viremia, incidence of late CMV viremia (>100 and ≤ 360 
days post HCT), use of antiviral drugs (triggered by clinically significant viremia), cumulative 
number of CMV specific antiviral treatment days. 
4. Clinical endpoints: time to engraftment, incidence of aGVHD, chronic GVHD (cGVHD), relapse,  
non-relapse mortality, all-cause mortality, non-CMV infections.   
5. Immunologic endpoints for the combination cohort (n=36): Immune reconstitution measured as 
levels, function and kinetics of CMV-specific T cells through day 180 post-HCT in patients who 
receive standard Prevymis prophylaxis (day 14 through day 100). 
 
12.0 STATISTICAL CONSIDERATIONS 
12.1 Study Design 
This is a randomized, blinded and placebo controlled Phase II trial conducted at multiple centers, with 
data coordination at COH.  After the trial met its futility stopping criterion, the trial has been amended 
to include a cohort of patients on Prevymis prophylaxis.  This constitutes a major change of the clinical 
setting, with Prevymis prophylaxis required for eligibility.  Because 7 of the 8 primary outcome events in 
the initial trial occurred prior to the second CMVPepVax injection, the change in eligibility is thought to 
be directly relevant to the reason for the futility outcome.    The primary aims are given in the previous 
section 1, and include evaluation of cellular immunity both in general, via stratified analysis, and in the 
Prevymis cohort as a subgroup.  Evaluation of CMV events will expose the therapeutic concept to a 
futility assessment, a strategy that often motivates expansion cohorts in early-phase trials.  The study 
includes rules for periodic safety monitoring, but futility assessment now applies to the full CMVPepVax 
arm of the Prevymis cohort. and an interim analysis for futility. 
Update at the time of amendment 
Enrollment was stopped when 48 subjects had been followed for 100 days, because 8 of the subjects 
with reactivation events by d100, more than half (5 of the 8) were on the vaccine arm, these events 
triggered the futility stopping rule.  The combined reactivation rate at this point was 8/48, or 17%, very 
close to the 15% rate that was expected for the vaccine arm, but much lower than expected for the 
placebo arm.  At such low reactivation rates, the futility rule has a much higher false alarm rate that 
planned.  If the vaccine offers the same degree of protection originally planned for (i.e. preventing 25 of 
40 reactivations) the futility rule would have a false alarm rate of approximately 27%.  The interim result 
is thus not inconsistent with the original targeted effect size, and does not provide a satisfactory 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 66 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
contradictory signal to the success seen in protocol 12022.  The interim result do, however, indicate the 
likely futility of the original primary analysis, and the problem of reactivations occurring too early to 
complete CMVPepVax administration may be avoided in the context of Prevymis prophylaxis.   The 
amended protocol abandons the hypothesis test on the original primary endpoint in favor of estimating 
and characterizing the incidence and timing of CMV reactivation when CMVPepVax is used in 
combination with Prevymis prophylaxis.  This will inform further development both by subjecting 
CMVPepVax to a futility evaluation with regard to the relative incidence of CMV events, and by 
providing novel longitudinal measurements of immune function in response to the vaccine while CMV 
load is suppressed by Prevymis. 
 
12.2 Randomization 
The trial has a target of 97 randomized HCT recipients.  Eligible HCT-R+ will be consented and enrolled 
pre-HCT, and registered through COH DCC.  A computer-generated randomization program, stratified by 
donor CMV serostatus will assign registered participants to the CMVPepVax or placebo arm; the 
treatment assignment will be generated and provided to site pharmacists, who are unmasked to 
treatment-group allocation, in advance of planned vaccination. Registered participants will be followed 
for the course of transplant and be assessed for the eligibility for ‘Day 28 post-HCT’ vaccination.  
Participants who meet the initial vaccine administration criteria will receive an injection; participants 
failing to meet the criteria will discontinue study participation and be replaced.  Only participants who 
receive an injection will be considered “randomized”. Information regarding registered participants who 
do not receive vaccine will be entered into the computer-generated randomization program to inform 
subsequent treatment assignments. Participants who do not meet the criteria to receive the first 
vaccine (CMVPepVax or placebo) will leave the study, without further treatment or follow-up, but their 
data collected up to study departure will be included in the trial dataset as non-randomized subjects, 
and these data will be incorporated into estimates of event rates post-HCT based on the intention to 
treat.   
12.3 Sample Size Accrual Rate 
This trial was originally planned to randomize 97 HCT-R+, in a 1:1 ratio, to either the CMVPepVax vaccine 
arm (N=48 or 49), or to the placebo arm (N=49 or 48).  The amended trial will use the same 
randomization procedures to assign the final 36 subjects, 18 to each arm.  Each patient in the new 
cohort (36 patients, 18 vs 18) will receive Prevymis as standard of care. The uncertainty in the per-arm 
totals is due to continued masking at the time of amendment.  With the expected dropout rate of 10-
15% prior to randomization, the total accrual is expected to be 106-115. Over the past five years, COH, 
UMN, FHCRC, OSUMC, and Emory University combined have performed on-average ~500 adult 
allogeneic HCT procedures annually. We anticipate about 70 to be eligible annually being HLA A*0201 
and CMV seropositive. Accrual should be completed in <4 years from the start date of the trial, and we 
anticipate 1 year of follow up and data analysis.  
Planning for measures of immune function is based on results of COH protocol 12022, the open-label 
analog of this placebo-controlled protocol.  In that trial, 10 of 18 vaccinated subjects developed CMV 
pp65-specific CD8+ T-cells that were strongly concentrated (> 80%) in effector memory phenotypes, and 
did so without CMV reactivation.  This can be compared to 1 of 14 non-vaccinated subjects who did not 
reactivate.  In the current study, the planned sample size of 48 subjects per arm would provide 
approximately 80% power for a one-sided 0.05-level test assuming a 50% rate of this event from a 25% 
rate on the placebo arm.  Beyond this measure of vaccine-induced immune function, the data will be 
used to describe the longitudinal changes in immune function with and without vaccine, in subjects who  

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 67 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
do and do not reactivate CMV, to serve as a reference for comparison of future immune function data 
which will include patients receiving Prevymis as prophylaxis. 
 
With regard to the incidence of CMV events, the  sample  size  of  48  individuals per arm was originally 
designed to detect a reduction in CMV reactivation from 40% to 15% at 100 days post-HCT, providing 
90% power at one-sided 10% significance level (these are the typical operational characteristics in  
randomized Phase II trials [21]).  The aim of this hypothesis test has been abandoned after the interim 
analysis and substituted with a preliminary analysis of patients receiving Prevymis prophylaxis.  For the 
Prevymis cohort the 36 patients will be randomized 1:1 (18/18) to receive CMVPepVax or Placebo. 
Based on a Phase III trial of Prevymis, we expect 17 percent of placebo subjects to reactivate after 
second vaccination on week 8. This is based on the expectation that 33 percent will be high-risk 
subjects. Assuming that CMVPepVax vaccination during prophylaxis can reduce the week 8 through 
week 26 reactivation rate to 5 percent, the probability that there are more reactivations on the placebo 
arm than on the CMVPepVax arm is approximately 88 percent, which can be regarded as the power for a 
non-futile finding.   If CMVPepVax offers no protection, there would be a 50 percent chance of a futility 
finding, and T-cell data would likely indicate many subjects with poor CMVPepVax antigen recognition. If 
CMVPepvax has strong protection (5% reactivation), a finding of futility is unlikely (12 percent) and an 
evident biological effect would be expected in most patients. 
 
12.4 Data Analysis Plan 
Cellular immunity 
The data analysis for the first primary objective is the secondary analysis of aim of estimating the effect 
of vaccination on cellular immunity in the full set of approximately 97 subjects.  This will necessarily be 
exploratory in nature, because of the multivariate and longitudinal nature of cellular immunity.  The 
information gained may enable the construction of a more detailed analysis, capable of a priori 
registration in a subsequent trial.  A comparison across arms of the number of subjects who achieve an 
elevated concentration of antigen-specific T-cells in the TEM and TEMRA category, stratified by Prevymis 
usage, will serve as the pre-specified primary analysis for this objective.  The estimated power for this 
analysis is given in section 12.3.  The same analysis will also be applied to the Prevymis cohort as a 
subgroup.  The longitudinal CMV-specific cellular assay data will be modeled on a logarithmic scale, 
using a generalized estimating equation approach to accommodate the stochastic dependence through 
time.  This produces an estimated multiplicative effect of vaccination, qualified by a valid estimate of 
variability. 
Clinical Efficacy  
 The primary analysis of efficacy in the amended trial is restricted to the Prevymis cohort.  Each 
randomized study subject will be followed according to the study calendar (section 11) for the 
occurrence of CMV reactivation events, which are defined in section 11 in terms of either viremia, low-
level viremia treated with antivirals, or CMV disease.  Both initial and recurrent events will be recorded, 
with patients considered at risk for recurrent events after completion of a full planned course of anti-
viral therapy.  If PCR results from blood drawn on the day of first injection should indicate reactivation, 
the subject will be replaced and excluded from the primary comparison, but the subject will, in all other 
respects, continue on the study with all planned treatments and data collections. The primary analysis 
will focus on arm-specific counts of subjects with events in the defined period, with binomial confidence 
intervals, and comparison by Fisher’s exact test.  In addition, vaccine and placebo groups will be 
compared with regard to (a) the hazard of CMV events, using time to event models; and (b) the total 
days of CMV-directed antiviral therapy per individual, using the Mann-Whitney statistic.   

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 68 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Futility 
An interim analysis for futility was conducted when the first 48 randomized subjects were evaluable for 
the primary endpoint (i.e. had a CMV event or reached 100 days without a CMV event).  Among the 36 
subjects planned for the Prevymis cohort, the incidence of more CMV events on the CMVPepVax arm 
than the placebo arm would constitute a futility signal, so there will be no separate interim analysis for 
futility. 
12.5 Safety Monitoring 
Clinical data will be monitored as they accumulate, and investigation of CMVPepVax will be suspended 
for safety review if there is evidence of serious treatment-related AEs.  
Monitoring of the Prevymis cohort will be done conservatively as both a continuation of the original 
monitoring plan, and as a restart of that same monitoring plan applied to the new patients receiving 
CMVPepVax in combination with Prevymis. 
 
Specifically: 
(1) 100 days non-relapse mortality (NRM) will be monitored as the 12th, 24th and 36th subject on the 
vaccine arm reaches the 100 day evaluation point. Operationally, the CRA will notify the 
monitoring statistician as cohorts of 24 patients (12 vaccinated) near the 100 day mark. If NRM 
frequencies exceed 4, 6, or 8, at the designated 100 day evaluation point, then the trial will be 
suspended for safety review by the COH and external site  DSMCs. These numbers were selected 
to limit the overall false-alarm probability for this endpoint to less than 0.02 when there is no 
additional risk due to immunization and were based on a benchmark risk of 10%. 
(2) Severe acute GVHD (aGVHD, grade 3-4) will be monitored as every 12th subject on the vaccine 
arm reaches the 100 day evaluation point. The trial will be interrupted if 6 or more of the first 12 
recipients, or 9 of 24, or 11 of 36, experience Grade 3-4 aGVHD. This would be a significant 
elevation from the COH/UMN historical benchmark of 15% of allogeneic HCT recipients with 
matched sibling donors[23].  These rules are determined to limit the overall aGVHD false alarm 
probability to 0.02 if vaccination does not increase risk[23].  
(3) Any serious AEs (SAE, grade 3-4) related to the vaccination within 2 weeks from each vaccination 
will be reviewed by the PMT when each 12th patient on the CMVPepVax arm passes the 2 week 
post-injection time for their second injection. 
 
 
13.0 DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING 
13.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, pharmacy 
dispensing records, recorded data from automated instruments, laboratory data) that are relevant to 
the clinical trial.  The Site Investigator or their designee will prepare and maintain adequate and 
accurate source documents.  These documents are designed to record all observations and other 
pertinent data for each patient enrolled in this clinical trial.  Source documents must be adequate to 
reconstruct all data transcribed onto the case report forms. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 69 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
13.2 Data Capture Methods and Management 
Data for this trial will be collected using Medidata RAVE, City of Hope’s electronic capture system. 
Medidata RAVE is a web based, password protected system that is fully compliant with global regulatory 
requirements, including 21CRF Part 11 compliant.  
Study personnel at each site will enter data from source documents corresponding to a subject’s visit 
into the protocol-specific electronic Case Report Form (eCRF).  A system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. Queries are entered, 
tracked, and resolved through the EDC system directly. The study database will be updated in 
accordance with the resolved queries.  All changes to the study database will be documented. 
The Data Coordinating Center will run monthly data expectation reports that will list any outstanding 
and overdue data. The Data Coordinating Center will send via email to the participating site a report 
monthly on any missing and/or overdue data forms.  The participating site will be required to complete 
the missing and/or overdue data forms within 1 week of receipt of the report. 
Query reports will be generated on a monthly basis by the Data Coordinating Center. The Data 
Coordinating Center will send via email to the participating site a report monthly on any outstanding 
queries.   
The participating site staff (whether Principal Investigator or the staff collecting data at site) are 
required to take an eLearning Module within Medidata RAVE in order to obtain full access. The 
participating site staff will receive training via teleconference by COH DCC staff to review eCRFs that are 
specific to this protocol.  Continuous training will be offered to participating sites if any amendments 
affect changes to the eCRFs during the course of the trial. The eCRFs within Medidata RAVE for this trial 
will have detailed instructions in the form of Help Text that provide instructions for completing each 
required field on each form. 
13.3 Case Report Forms/Data Submission Schedule 
Study personnel at each site will enter data from source documents corresponding to a subject’s visit 
into the protocol-specific electronic Case Report Form (eCRF) when the information corresponding to 
that visit is available.  
The Investigator is responsible for all information collected on subjects enrolled in this study.  All data 
collected during the course of this study must be reviewed and verified for completeness and accuracy 
by the Investigator.  All case report forms must be completed by designated study personnel.  The 
completed case report forms must be reviewed, signed and dated by the Site Investigator or designee in 
a timely fashion. 
All data will be collected using electronic data collection system described in Section 13.2, and will be 
submitted according to the timelines indicated in Table 13.1.3. 
Table 13.3 Data Submission Schedule 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration  
On Study Forms 
Within 14 calendar days of registration 
Baseline Assessment Forms 
Within 14 calendar days of registration 
Treatment Forms 
Within 14 calendar days of treatment administration 
Adverse Event Report Forms 
Within 14 calendar days of the study visit 
Response Assessment Forms 
Within 10 calendar days of the response assessment 
Other Assessment Forms 
Within 10 calendar days of the assessment 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 70 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
(concomitant medications, chemistry, 
hematology etc.) 
Off Treatment/Off Study Forms 
Within 10 calendar days of completing treatment or being 
taken off study for any reason 
13.4 Regulatory Records 
The Investigator will maintain records, including updating records in accordance with Good Clinical 
Practice guidelines and FDA regulations. Additional information regarding required documents is 
provided in the DCC Operations Manual, a supplement to this protocol. 
14.0 ADHERENCE TO THE PROTOCOL 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. Protocol deviations may be on the part of the 
subject, the investigator, or study staff.  As a result of deviations, corrective actions are to be developed 
by the study staff and implemented promptly. 
All deviations from the protocol must be documented in study subject source documents and promptly 
reported to the Study PI and to the local IRB according to its policies requirements.  The Study PI will 
report the deviation according to City of Hope’s deviation policy for reporting deviations.  
14.1.1 Emergency Modifications 
Investigators may implement a deviation from the protocol to eliminate an immediate hazard(s) for the 
protection, safety, and well-being of the study patient to trial subjects without prior IRB or Sponsor 
approval.  
For any such emergency modification implemented,  
o the local IRB and/or DSMC must be notified according to local institutional policies.  
o The Study Principal Investigator must be notified as soon as practicable (within 24 
hours) via email to rnakamura@coh.org and dcc@coh.org.  This email should provide 
input on the following: 
– Description of the event 
– Impact on participant safety or the safety to others 
– Impact on the study design 
14.1.2 Planned Non-Emergency Deviations 
All non-emergency planned deviations from the protocol must have prior approval by the Study 
Principal Investigator, the Site Principal Investigator and the local IRB, and if applicable the COH IRB 
Unplanned Deviations – Deviations Discovered After They Have Occurred 
For deviations to the protocol discovered after they have occurred,  
o the local IRB and/or DSMC must be notified according to local institutional policies.  
o The Study Principal Investigator must be notified as soon as practicable (within 24 hours 
of awareness of event) via email to rnakamura@coh.org and dcc@coh.org.  This email 
should provide input on the following: 
– Description of the event 
– Impact on participant safety or the safety to others 
– Impact on the study design 
– A corrective and preventative action plan 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 71 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
A list of deviations from all participating sites will be submitted along with the Protocol Management 
Team (PMT) progress report to the COH DSMC. 
15.0 STUDY OVERSIGHT, QUALITY ASSURANCE, AND DATA & SAFETY MONITORING 
15.1 Site Principal Investigator  
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. 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. 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events, 
deviations, and unanticipated problems.  
The Principal Investigator at each institution or site will be responsible for assuring that all the required 
data will be collected and entered onto the Case Report Forms. 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 case report forms will be 
reviewed by the Principal Investigator and will require his/her final signature to verify the accuracy of 
the data. 
An investigator is responsible for ensuring that an investigation is conducted according to the signed 
investigator statement, the investigational plan, and applicable regulations; for protecting the rights, 
safety, and welfare of subjects under the investigator's care; and for the control of drugs under 
investigation.  
The Investigator agrees to: Conduct the study in accordance with the protocol and only make changes 
after notifying the Sponsor (or designee), except when necessary to protect the safety, rights or welfare 
of subjects. Personally conduct or supervise the study (or investigation). Ensure that the requirements 
relating to obtaining informed consent and IRB review and approval meet federal guidelines, as stated in 
§ 21 CFR, parts 50 and 56. Report to the Sponsor or designee any AEs that occur in the course of the 
study, in accordance with §21 CFR 312.64. Ensure that all associates, colleagues and employees assisting 
in the conduct of the study are informed about their obligations in meeting the above commitments. 
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make those records 
available for inspection with the Sponsor (or designee). Ensure that an IRB that complies with the 
requirements of §21 CFR part 56 will be responsible for initial and continuing review and approval of the 
clinical study. Promptly report to the IRB and the Sponsor (see Section 14) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to include amendments and 
IND safety reports). Seek IRB and Sponsor (see Section 14) approval before any changes are made in the 
research study, except when necessary to eliminate hazards to the patients/subjects. Comply with all 
other requirements regarding the obligations of clinical investigators and all other pertinent 
requirements listed in § 21 CFR part 312. 
15.2 Study Principal Investigator 
The Study Principal Investigator is responsible for the conduct of the clinical trial, including overseeing 
that sponsor responsibilities as defined in § 21 CFR 312. Subpart D are executed in accordance with 
federal regulations.  

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 72 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
15.3 Protocol Management Team (PMT) 
The Protocol Management Team (PMT) minimally consisting of the study principal investigator, site 
principal investigators, collaborating investigators, the research nurse, the clinical research 
associate/coordinator, and the study biostatistician is responsible for ongoing monitoring of the data 
and safety of this study, including implementation of the stopping rules for safety and efficacy. 
The PMT will meet (in person or via teleconference) at least monthly, and will meet at least quarterly 
with the study biostatistician, to review study status. This review will include, but not be limited to, 
reportable AEs and UPs, and an update of the ongoing study summary that describes study progress in 
terms of the study schema. The meeting will be a forum to discuss study related issues including accrual, 
SAE/AEs experienced, study response, deviations/violations and study management issues. The 
appropriateness of further subject enrollment and the specific intervention for subsequent subject 
enrollment are addressed.  
 
15.4 Monitoring  
The Investigator/Institution will permit direct access of the study monitors and appropriate regulatory 
authorities to the study data and to the corresponding source data and documents to verify the 
accuracy of this data. 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given access to all the 
above noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 
Clinical site monitoring is conducted to ensure that the rights of human subjects are protected, that the 
study is implemented in accordance with the protocol and regulatory requirements, and that the quality 
and integrity of study data and data collection methods are maintained.  Monitoring for this study will 
be performed by the City of Hope Office of Clinical Trials Auditing and Monitoring (OCTAM), whose SOP 
is provided as a supplement to this document. 
Staff from OCTAM will conduct monitoring activities and provide reports of the findings and associated 
action items in accordance with the City of Hope OCTAM SOP document.  Documentation of monitoring 
activities and findings will be provided to the site study team, the site PI, study PI, and the COH DSMC. 
 
15.5 Quality Assurance  
The City of Hope Clinical Research Information Support will provide quality assurance as detailed in the 
COH DCC Operations Plan provided as a supplement to this document.  
 
15.6 City of Hope Data and Safety Monitoring Committee 
This is a Risk Level 4 study, as defined in the City of Hope Data and Safety Monitoring Plan because the 
trial involves COH as IND holder. 
The DSMC is a multidisciplinary committee charged with overseeing the monitoring of safety of 
participants in clinical trials, and the conduct, progress, validity, and integrity of the data for all clinical 
trials that are sponsored by City of Hope. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. The committee reviews the 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 73 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
progress and safety of all active research protocols that are not monitored by another safety and data 
monitoring committee or board. 
The COH Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual 
data from this trial. Information that raises any questions about participant safety will be addressed with 
the Principal Investigator, statistician and study team. The COH DSMC Charter is a supplement to this 
protocol. 
The DSMC will review the study’s status quarterly and/or more often if necessary. The DSMC will review 
up-to-date participant accrual; summary of all adverse events captured via routine and expedited 
reporting; a summary of deviations; any response information; monitoring reports, and summary 
comments provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. A review of outcome results (response, toxicity and adverse events) and factors 
external to the study (such as scientific or therapeutic developments) is discussed, and the Committee 
votes on the status of each study.  
Data and safety will be reported to the COH DSMC using the PMT report and submitted quarterly from 
the date of activation.   
 
16.0 ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission for 
the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the 
Declaration of Helsinki. 
 
16.2 Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to the 
following considerations: 
 
US Code of Federal Regulations (CFR) governing clinical study conduct 
o Title 21 Part 11 – Electronic Records; Electronic Signatures  
o Title 21 Part 50 – Protection of Human Subjects  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
o Title 21 Part 56 – Institutional Review Boards  
o Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory 
Studies  
o Title 21 Part 312 – Investigational New Drug Application  
o Title 45 Part 46 – Protection of Human Subjects  
 
US Federal legislation, including but not limited to 
o Health Insurance Portability and Accountability Act of 1996  
o Section 801 of the Food and Drug Administration Amendments Act   
 
Applicable state and local laws. For research occurring in California, this includes 
but is not limited to State of California Health and Safety Code, Title 17 
 
Applicable institutional research policies and procedures  

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 74 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
 
16.3 Institutional Review Board 
Each participating institution must provide for the review and approval of this protocol and the 
associated informed consent documents by an appropriate IRB holding a current US Federalwide 
Assurance issued by and registered with the Office for Human Research Protections (OHRP). Any 
documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol amendments, 
Investigator’s Brochure, consent forms, information concerning patient recruitment, payment or 
compensation procedures, or other pertinent information) will be submitted to the IRB.  The IRB’s 
written unconditional approval of the study protocol and the informed consent document will be in the 
possession of the Investigator, and, for sites external to COH, the possession of the coordinating center, 
before the study is initiated. The Investigator will obtain assurance of IRB/IEC compliance with 
regulations. 
The IRB will be informed of revisions to other documents originally submitted for review; serious 
unexpected or unanticipated adverse experiences occurring during the study, and any additional 
adverse experiences in accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; an annual 
update and/or request for re-approval; and when the study has been completed. 
Any amendment to the protocol document and accompanying informed consent document/template, 
as developed and provided by the Study PI, will require review and approval by the IRB before the 
changes are implemented in the study.  The protocol and consent will reviewed and approved by the 
COH IRB before submission to a participating site IRB. 
16.4 Informed Consent 
For a multi-site study, each participating institution will be provided with a model informed consent 
form. Each institution may revise or add information to comply with local and/or institutional 
requirements, but may not remove procedural or risk content from the model consent form. 
Furthermore, prior to submission to the IRB (initial submission and amendments), the consent and 
accompanying HIPAA form, if separate to the consent, must be reviewed and approved by the Data 
Coordinating Center. 
After the study has been fully explained, written informed consent will be obtained from either the 
patient or his/her guardian or legal representative before study participation.  The method of obtaining 
and documenting the informed consent and the contents of the consent must comply with the ICH-GCP 
and all applicable regulatory requirements. 
Before implementing any study procedure, informed consent shall be documented by the use of a 
written consent form approved by the IRB/IEC and signed and dated by the patient or the patient’s 
legally authorized representative at the time of consent.  A copy of the signed informed consent will be 
given to the patient or patient’s legally authorized representative.  The original signed consent must be 
maintained by the Site Investigator and available for inspection sponsor designated representatives, or 
regulatory authority at any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation.  
 
16.5 
Women, Minorities, Children, HIV-Positive Individuals (Special Populations) 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 75 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
16.5.1 Inclusion of Women and Minorities 
The study is open anyone regardless of gender or ethnicity.  Efforts will be made to extend the accrual to 
a representative population, but in a trial which will accrue and randomize approximately 97 subjects, a 
balance must be struck between subject safety considerations and limitations on the number of 
individuals exposed to potentially toxic or ineffective treatments on the one hand and the need to 
explore gender, racial, and ethnic aspects of clinical research on the other.  If differences in outcome 
that correlate to gender, racial, or ethnic identity are noted, accrual may be expanded or additional 
studies may be performed to investigate those differences more fully. 
Women who are pregnant or plan to become pregnant are excluded from participation because PF-
03512676, the adjuvant used in CMVPepVax, has been determined to be embryolethal and teratogenic 
in animal testing, and as such, CMVPepVax has the potential for teratogenic or abortifacient effects.  
Because there is an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with the administered vaccine, breastfeeding should be discontinued if the 
mother is enrolled on this study.   
16.5.2 Exclusion of Pediatric Patients 
Pediatric recipients (children <18 years old of age) are excluded from this study because insufficient data 
are available in adults to judge potential risks in children.  Additionally, vaccine dosage and the blood 
volume established for immune-monitoring in adults cannot be applicable for both adults and children. 
Finally, the risk of CMV complications is inversely related to age, and the inclusion of younger children 
could bias the endpoint observations.  
16.5.3 Exclusion of HIV Positive Individuals 
Individuals who are positive for HIV are expected to have very different underlying immune functions 
and therefore may respond to the CMVPepVax vaccine differently from individuals negative for HIV.  
 
16.6 
Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and 
their agents.  This confidentiality is extended to cover testing of biological samples in addition to any 
study information relating to participants. 
This research will be conducted in compliance with federal and state requirements relating to protected 
health information (PHI), including the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  HIPAA regulations require a signed subject authorization informing 
the subject of the nature of the PHI to be collected, who will have access to that information and why, 
who will use or disclose that information, ant the rights of a research participant to revoke their 
authorization for use of their PHI. In the event that a subject revokes authorization to collect or use PHI, 
the investigator, by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the 
end of their scheduled study period. 
Release of research results should preserve the privacy of medical information and must be carried out 
in accordance with Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed and no identifiers will be 
used. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 76 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
Medical records of subjects will be securely maintained in the strictest confidence, according to current 
legal requirements.  Data will be entered, analyzed and stored in encrypted, password protected, secure 
computers that meet all HIPAA requirements.   All data capture records, drug accountability records, 
study reports and communications will identify the patient by initials and the assigned patient number. 
Source documents provided to coordinating center for the purpose of auditing or monitoring will be de-
identified and labeled with the study number, subject ID, and patient initials. 
The investigator/institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities.  The access may consist of trial-
related monitoring, including remote monitoring, audits, IRB/IEC reviews, and FDA/regulatory authority 
inspections. .  The patient’s confidentiality will be maintained and will not be made publicly available to 
the extent permitted by the applicable laws and regulations. 
16.7 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study Sponsor prior to participation in this study.  All 
City of Hope investigators will follow the City of Hope conflict of interest policy. 
16.8 
Financial Obligations, Compensation, and Reimbursement of Participants 
The investigational drug including Tet-CMV diluted in Na acetate and co-injected with PF-03512676 
adjuvant, will be provided free of charge by NCI and Pfizer, respectively.   
Neither the research participant nor the insurance carrier will be responsible for the research 
procedures related to this study. 
The standard of care drugs or procedures provided during the course of study participation will be the 
responsibility of the research participant and/or the insurance carrier. The research participant will be 
responsible for all copayments, deductibles, and other costs of treatment and diagnostic procedures as 
set forth by the insurance carrier.  The research participant and/or the insurance carrier will be billed for 
the costs of treatment and diagnostic procedures in the same way as if the research participant were 
not in a research study.   
In the event of physical injury to a research participant resulting from research procedures, appropriate 
medical treatment will be available at City of Hope to the injured research participant. There are no 
plans for City of Hope to provide financial compensation in the event of physical injury to a research 
participant.  
The research participant will not receive reimbursement or payment for taking part in this study. 
16.9 Publication/Data Sharing  
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by City of Hope for the purposes of performing the study, will be published or 
passed on to any third party without the written approval of Dr. Don Diamond.  Any investigator 
involved with this study is obligated to provide City of Hope with complete test results and all data 
derived from the study. 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement among the City of Hope and 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 77 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
participating institutions.  The publication or presentation of any study results shall comply with all 
applicable privacy laws, including, but not limited to, the Health Insurance Portability and Accountability 
Act of 1996.  
This study will comply with the NIH Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
In accordance with the U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 
or FDAAA), Title VIII, Section 801, this trial will be registered onto ClinicalTrials.gov and results will be 
reported on ClinicalTrials.gov within 12 months of the estimated or actual completion date of the trial, 
whichever date is earlier.  
The results should be made public within 24 months of reaching the end of the study. The end of the 
study is the time point at which the last data items are to be reported, or after the outcome data are 
sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and Study 
Duration. If a report is planned to be published in a peer-reviewed journal, then that initial release may 
be an abstract that meets the requirements of the International Committee of Medical Journal Editors. A 
full report of the outcomes should be made public no later than three (3) years after the end of the 
study.  
 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 78 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
17.0 REFERENCES 
1. 
Applebaum, F.R., et al., Nonbacterial nonfungal pneumonia following marrow transplantation in 100 
identical twins. Transplantation, 1982. 33(3): p. 265-8. 
2. 
Quinnan, G.V., Jr., et al., Cytotoxic T cells in cytomegalovirus infection: HLA-restricted T- lymphocyte and 
non-T-lymphocyte cytotoxic responses correlate with recovery from cytomegalovirus infection in bone-
marrow- transplant recipients. N.Engl.J.Med., 1982. 307: p. 7-13. 
3. 
Reusser, P., et al., Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of 
cytomegalovirus infection after allogeneic stem cell transplantation. Blood, 2002. 99(4): p. 1159-1164. 
4. 
Winston, D.J., et al., Infectious complications of human bone marrow transplantation. Medicine 
(Baltimore), 1979. 58(1): p. 1-31. 
5. 
Boeckh, M. and W.G. Nichols, The impact of cytomegalovirus serostatus of donor and recipient before 
hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood, 
2004. 103(6): p. 2003-2008. 
6. 
Nichols, W.G., et al., High Risk of Death Due to Bacterial and Fungal Infection among Cytomegalovirus 
(CMV)-Seronegative Recipients of Stem Cell Transplants from Seropositive Donors: Evidence for Indirect 
Effects of Primary CMV Infection. J.Infect.Dis., 2002. 185(3): p. 273-282. 
7. 
La Rosa, C., et al., Preclinical development of an adjuvant-free peptide vaccine with activity against CMV 
pp65 in HLA transgenic mice. Blood, 2002. 100(10): p. 3681-3689. 
8. 
La Rosa, C., et al., Clinical evaluation of safety and immunogenicity of PADRE-cytomegalovirus (CMV) and 
Tetanus-CMV fusion peptide vaccines with or without PF03512676 adjuvant. J.Infect.Dis., 2012. 205(8): p. 
1294-1304. 
9. 
Sylwester, A.W., et al., Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate 
the memory compartments of exposed subjects. J.Exp.Med., 2005. 202(5): p. 673-685. 
10. 
Gratama, J.W., et al., Immune monitoring with iTAg MHC Tetramers for prediction of recurrent or 
persistent cytomegalovirus infection or disease in allogeneic hematopoietic stem cell transplant recipients: 
a prospective multicenter study. Blood, 2010. 116(10): p. 1655-1662. 
11. 
Marty, F.M., et al., Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N 
Engl J Med, 2017. 377(25): p. 2433-2444. 
12. 
Khanna, R. and D.J. Diamond, Human cytomegalovirus vaccine: time to look for alternative options. Trends 
Mol.Med., 2006. 12(1): p. 26-33. 
13. 
Aubert, G., et al., Cytomegalovirus-specific cellular immune responses and viremia in recipients of 
allogeneic stem cell transplants. J.Infect.Dis., 2001. 184(8): p. 955-963. 
14. 
Wieand, S., G. Schroeder, and J.R. O'Fallon, Stopping when the experimental regimen does not appear to 
help. Stat.Med., 1994. 13(13-14): p. 1453-1458. 
15. 
Lacey, S.F., et al., Characterization of cytotoxic function of CMV-pp65-specific CD8+ T- lymphocytes 
identified by HLA tetramers in recipients and donors of stem-cell transplants. Transplantation, 2002. 74(5): 
p. 722-732. 
16. 
Villacres, M.C., et al., Human immunodeficiency virus-infected patients receiving highly active 
antiretroviral therapy maintain activated cd8+ t cell subsets as a strong adaptive immune response to 
cytomegalovirus. J.Infect.Dis., 2001. 184(3): p. 256-267. 
17. 
Foley, B., et al., Human cytomegalovirus (CMV)-induced memory-like NKG2C(+) NK cells are transplantable 
and expand in vivo in response to recipient CMV antigen. J.Immunol., 2012. 189(10): p. 5082-5088. 
18. 
Foley, B., et al., Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase 
in educated NKG2C+ natural killer cells with potent function. Blood, 2012. 119(11): p. 2665-2674. 
19. 
Lopez-Verges, S., et al., Expansion of a unique CD57(+)NKG2Chi natural killer cell subset during acute 
human cytomegalovirus infection. Proc.Natl.Acad.Sci.U.S.A, 2011. 108(36): p. 14725-14732. 
20. 
Kuijpers, T.W., et al., Human NK cells can control CMV infection in the absence of T cells. Blood, 2008. 
112(3): p. 914-915. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 79 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
21. 
Rubinstein, L.V., et al., Design issues of randomized phase II trials and a proposal for phase II screening 
trials. J.Clin.Oncol., 2005. 23(28): p. 7199-7206. 
22. 
Przepiorka, D., et al., 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant, 
1995. 15(6): p. 825-8. 
23. 
Bensinger, W.I., et al., Transplantation of bone marrow as compared with peripheral-blood cells from HLA-
identical relatives in patients with hematologic cancers. N.Engl.J.Med., 2001. 344(3): p. 175-181. 
24. 
Steininger, C., Clinical relevance of cytomegalovirus infection in patients with disorders of the immune 
system. Clin.Microbiol.Infect., 2007. 13(10): p. 953-963. 
25. 
Limaye, A.P., et al., Impact of cytomegalovirus in organ transplant recipients in the era of antiviral 
prophylaxis. Transplantation, 2006. 81(12): p. 1645-1652. 
26. 
Griffiths, P., et al., Contemporary management of cytomegalovirus infection in transplant recipients: 
guidelines from an IHMF workshop, 2007. Herpes., 2008. 15(1): p. 4-12. 
27. 
Boeckh, M., et al., Cytomegalovirus in hematopoietic stem cell transplant recipients: Current status, known 
challenges, and future strategies. Biol.Blood Marrow Transplant., 2003. 9(9): p. 543-558. 
28. 
Tomblyn, M., et al., Guidelines for preventing infectious complications among hematopoietic cell 
transplantation recipients: a global perspective. Biol.Blood Marrow Transplant, 2009. 15(10): p. 1143-
1238. 
29. 
Zerr, D.M., et al., HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic 
cell transplantation recipients. Blood, 2011. 117(19): p. 5243-5249. 
30. 
Reusser, P., Oral valganciclovir: a new option for treatment of cytomegalovirus infection and disease in 
immunocompromised hosts. Expert.Opin.Investig.Drugs, 2001. 10(9): p. 1745-1753. 
31. 
Ljungman, P., M. Hakki, and M. Boeckh, Cytomegalovirus in hematopoietic stem cell transplant recipients. 
Infect.Dis.Clin.North Am., 2010. 24(2): p. 319-337. 
32. 
Hakki, M., et al., Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell 
transplantation: impact of host factors, drug therapy, and subclinical reactivation. Blood, 2003. 102(8): p. 
3060-3067. 
33. 
Nguyen, Q., et al., Late cytomegalovirus pneumonia in adult allogeneic blood and marrow transplant 
recipients. Clin.Infect.Dis., 1999. 28(3): p. 618-623. 
34. 
Razonable, R.R., et al., Allograft rejection predicts the occurrence of late-onset cytomegalovirus (CMV) 
disease among CMV-mismatched solid organ transplant patients receiving prophylaxis with oral 
ganciclovir. J.Infect.Dis., 2001. 184(11): p. 1461-1464. 
35. 
Boeckh, M., et al., Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic 
stem cell transplants: importance of viral load and T-cell immunity. Blood, 2003. 101(2): p. 407-414. 
36. 
Peggs, K.S. and S. Mackinnon, Immune reconstitution following haematopoietic stem cell transplantation. 
Br.J.Haematol., 2004. 124(4): p. 407-420. 
37. 
Singh, N., Delayed occurrence of cytomegalovirus disease in organ transplant recipients receiving antiviral 
prophylaxis: are we winning the battle only to lose the war? Eur.J.Clin.Microbiol.Infect.Dis., 2002. 21(12): 
p. 902. 
38. 
Gamadia, L.E., et al., Primary immune responses to human CMV: a critical role for IFN-gamma -producing 
CD4+ T cells in protection against CMV disease. Blood, 2003. 101(7): p. 2686-2692. 
39. 
Diamond, D.J., et al., Development of a candidate HLA A*0201 restricted peptide-based vaccine against 
human cytomegalovirus infection. Blood, 1997. 90(5): p. 1751-1767. 
40. 
La Rosa, C., et al., Enhanced immune activity of cytotoxic T-lymphocyte epitope analogs derived from 
positional scanning synthetic combinatorial libraries. Blood, 2001. 97(6): p. 1776-1786. 
41. 
Wills, M.R., et al., The human CTL response to cytomegalovirus is dominanted by structural protein pp65: 
Frequency, specificity, and T Cell Receptor usage of pp65-Specific CTL. J.Virol., 1996. 70(11): p. 7569-7579. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 80 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
42. 
Riddell, S.R., et al., Class I MHC-restricted cytotoxic T lymphocyte recognition of cells infected with human 
cytomegalovirus does not require endogenous viral gene expression. J.Immunol., 1991. 146(8): p. 2795-
2804. 
43. 
Bernstein, D.I., et al., Randomized, double-blind, Phase 1 trial of an alphavirus replicon vaccine for 
cytomegalovirus in CMV seronegative adult volunteers. Vaccine, 2009. 28(2): p. 484-493. 
44. 
Wloch, M.K., et al., Safety and immunogenicity of a bivalent cytomegalovirus DNA vaccine in healthy adult 
subjects. J.Infect.Dis., 2008. 197(12): p. 1634-1642. 
45. 
Berencsi, K., et al., A canarypox vector-expressing cytomegalovirus (cmv) phosphoprotein 65 induces long-
lasting cytotoxic t cell responses in human cmv- seronegative subjects. J.Infect.Dis., 2001. 183(8): p. 1171-
1179. 
46. 
Reusser, P., et al., Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone 
marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. 
Blood, 1991. 78(5): p. 1373-1380. 
47. 
Rook, A.H., et al., Importance of cytotoxic lymphocytes during cytomegalovirus infection in renal 
transplant recipients. Am.J.Med., 1984. 76: p. 385-392. 
48. 
Cobbold, M., et al., Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after 
selection by HLA-peptide tetramers. J.Exp.Med., 2005. 202(3): p. 379-386. 
49. 
Walter, E.A., et al., Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic 
bone marrow by transfer of T-cell clones from the donor. N.Engl.J.Med., 1995. 333: p. 1038-1044. 
50. 
Feuchtinger, T., et al., Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory 
cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell 
transplantation. Blood, 2010. 116(20): p. 4360-4367. 
51. 
Einsele, H., et al., Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not 
responding to antiviral chemotherapy. Blood, 2002. 99(11): p. 3916-3922. 
52. 
Peggs, K.S., et al., Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell 
transplantation with virus-specific T-cell lines. Lancet, 2003. 362(9393): p. 1375-1377. 
53. 
Cwynarski, K., et al., Direct visualization of cytomegalovirus-specific T-cell reconstitution after allogeneic 
stem cell transplantation. Blood, 2001. 97(5): p. 1232-1240. 
54. 
Gallez-Hawkins, G., et al., Cytomegalovirus immune reconstitution occurs in recipients of allogeneic 
hematopoietic cell transplants irrespective of detectable cytomegalovirus infection. Biol.Blood Marrow 
Transplant., 2005. 11(11): p. 890-902. 
55. 
Gratama, J.W., et al., Tetramer-based quantification of cytomegalovirus (CMV)-specific CD8+ T 
lymphocytes in T-cell-depleted stem cell grafts and after transplantation may identify patients at risk for 
progressive CMV infection. Blood, 2001. 98(5): p. 1358-1364. 
56. 
Einsele, H. and H. Hebart, Cellular immunity to viral and fungal antigens after stem cell transplantation. 
Curr.Opin.Hematol., 2002. 9(6): p. 485-489. 
57. 
Longmate, J., et al., Population coverage by HLA class-I restricted cytotoxic T-lymphocyte epitopes. 
Immunogenetics, 2001. 52(3-4): p. 165-173. 
58. 
Zaia, J.A., et al., Infrequent Occurrence of Natural Mutations in the pp65(495-503) Epitope Sequence 
Presented by the HLA A*0201 Allele among Human Cytomegalovirus Isolates. J.Virol., 2001. 75(5): p. 2472-
2474. 
59. 
Mocarski, E.S., Jr., Immunomodulation by cytomegaloviruses: manipulative strategies beyond evasion. 
Trends Microbiol., 2002. 10(7): p. 332-339. 
60. 
Adler, S.P., et al., Safety and immunogenicity of the Towne strain cytomegalovirus vaccine. 
Pediatr.Infect.Dis.J., 1998. 17(3): p. 200-206. 
61. 
Alexander, J., et al., Development of high potency universal DR-restricted helper epitopes by modification 
of high affinity DR-blocking peptides. Immunity., 1994. 1: p. 751-761. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 81 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
62. 
Panina-Bordignon, P., et al., Universally immunogenic T cell epitopes: promiscuous binding to human MHC 
class II and promiscuous recognition by T cells. Eur.J.Immunol., 1989. 19(12): p. 2237-2242. 
63. 
Krieg, A.M., CpG motifs in bacterial DNA and their immune effects. Annu.Rev.Immunol., 2002. 20: p. 709-
760. 
64. 
Rothenfusser, S., et al., CpG-A and CpG-B oligonucleotides differentially enhance human peptide-specific 
primary and memory CD8+ T-cell responses in vitro. Blood, 2004. 103(6): p. 2162-2169. 
65. 
Cooper, C.L., et al., CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-
treated HIV-infected adults. AIDS, 2005. 19(14): p. 1473-1479. 
66. 
Hartmann, G. and A.M. Krieg, Mechanism and function of a newly identified CpG DNA motif in human 
primary B cells. J.Immunol., 2000. 164(2): p. 944-953. 
67. 
Zhou, W., et al., Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-
specific T cells in CMV-positive transplant recipients. Blood, 2009. 113(25): p. 6465-6476. 
68. 
Davila, E., et al., Creating space: an antigen-independent, CpG-induced peripheral expansion of naive and 
memory T lymphocytes in a full T-cell compartment. Blood, 2002. 100(7): p. 2537-2545. 
69. 
Kuo, C.C., S.M. Liang, and C.M. Liang, CpG-B oligodeoxynucleotide promotes cell survival via up-regulation 
of Hsp70 to increase Bcl-xL and to decrease apoptosis-inducing factor translocation. J.Biol.Chem., 2006. 
281(50): p. 38200-38207. 
70. 
Woolfrey, A., et al., HLA-C antigen mismatch is associated with worse outcome in unrelated donor 
peripheral blood stem cell transplantation. Biol Blood Marrow Transplant, 2011. 17(6): p. 885-92. 
71. 
Saber, W., et al., Outcomes after matched unrelated donor versus identical sibling hematopoietic cell 
transplantation in adults with acute myelogenous leukemia. Blood, 2012. 119(17): p. 3908-16. 
72. 
Bacigalupo, A., Matched and mismatched unrelated donor transplantation: is the outcome the same as for 
matched sibling donor transplantation? Hematology Am Soc Hematol Educ Program, 2012. 2012: p. 223-9. 
73. 
Anasetti, C., What are the most important donor and recipient factors affecting the outcome of related 
and unrelated allogeneic transplantation? Best Pract Res Clin Haematol, 2008. 21(4): p. 691-7. 
74. 
Sorror, M.L., et al., Long-term outcomes among older patients following nonmyeloablative conditioning 
and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. JAMA, 2011. 
306(17): p. 1874-1883. 
75. 
Warlick, E., et al., Reduced intensity conditioning is superior to nonmyeloablative conditioning for older 
chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine 
kinase inhibitor era. Blood, 2012. 119(17): p. 4083-4090. 
76. 
Paczesny, S., et al., A biomarker panel for acute graft-versus-host disease. Blood, 2009. 113(2): p. 273-8. 
77. 
Levine, J.E., et al., Acute graft-versus-host disease biomarkers measured during therapy can predict 
treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood, 2012. 119(16): 
p. 3854-60. 
78. 
Paczesny, S., et al., Elafin is a biomarker of graft-versus-host disease of the skin. Sci Transl Med, 2010. 
2(13): p. 13ra2. 
79. 
Ferrara, J.L., et al., Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host 
disease. Blood, 2011. 118(25): p. 6702-8. 
80. 
Vander Lugt, M.T., et al., ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. 
N Engl J Med, 2013. 369(6): p. 529-39. 
81. 
Kennedy, G.A., et al., Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host 
disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol, 2014. 
15(13): p. 1451-9. 
82. 
Sarantopoulos, S., et al., Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host 
disease. Blood, 2009. 113(16): p. 3865-74. 

CMVPepVax vs. Placebo for the control of CMV in HCT recipients 
Page 82 of 91 
IRB Protocol No. 13494     Version:  28      Dated: 02/19/2020            
83. 
Cooper, C.L., et al., CPG 7909, an immunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to 
Engerix-B HBV vaccine in healthy adults: a double-blind phase I/II study. J.Clin.Immunol., 2004. 24(6): p. 
693-701. 
84. 
Vitiello, A., et al., Development of a lipopeptide-based therapeutic vaccine to treat chronic HBV infection. I. 
Induction of a primary cytotoxic T lymphocyte response in humans. J.Clin.Invest., 1995. 95: p. 341-349. 
85. 
Waldner, H., The role of innate immune responses in autoimmune disease development. Autoimmun.Rev., 
2009. 8(5): p. 400-404. 
86. 
Maury, S., et al., Prolonged immune deficiency following allogeneic stem cell transplantation: risk factors 
and complications in adult patients. Br.J.Haematol., 2001. 115(3): p. 630-641. 
87. 
Storek, J., et al., Immune reconstitution after allogeneic marrow transplantation compared with blood 
stem cell transplantation. Blood, 2001. 97(11): p. 3380-3389. 
88. 
Skert, C., et al., Kinetics of Th1/Th2 cytokines and lymphocyte subsets to predict chronic GVHD after allo-
SCT: results of a prospective study. Bone Marrow Transplant., 2009. 44(11): p. 729-737. 
89. 
Elmaagacli, A.H., et al., Early human cytomegalovirus replication after transplantation is associated with a 
decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia 
patients. Blood, 2011. 118(5): p. 1402-1412. 
90. 
Green, M.L., et al., CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in 
acute myeloid leukemia. Blood, 2013. 122(7): p. 1316-1324. 
91. 
La Rosa, C., et al., Rapid Acquisition of Cytomegalovirus-Specific T Cells with a Differentiated Phenotype, in 
Nonviremic Hematopoietic Stem Transplant Recipients Vaccinated with CMVPepVax. Biol Blood Marrow 
Transplant, 2018. 
92. 
Nakamura, R., et al., Viraemia, immunogenicity, and survival outcomes of cytomegalovirus chimeric 
epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haemopoietic stem-cell 
transplantation: randomised phase 1b trial. Lancet Haematol, 2016. 3(2): p. e87-98. 
93. 
La Rosa, C., et al., Longitudinal assessment of cytomegalovirus (CMV)-specific immune responses in liver 
transplant recipients at high risk for late CMV disease. J.Infect.Dis., 2007. 195(5): p. 633-644. 
94. 
La Rosa, C., et al., Programmed death-1 expression in liver transplant recipients as a prognostic indicator 
of cytomegalovirus disease. J.Infect.Dis., 2008. 197(1): p. 25-33. 
95. 
Krishnan, A., et al., Programmed death-1 receptor and interleukin-10 in liver transplant recipients at high 
risk for late cytomegalovirus disease. Transpl.Infect.Dis., 2010. 12(4): p. 363-370.