Phase 2 Study of an Immune Therapy, DPX-Survivac With Low Dose Cyclophosphamide Administered With Pembrolizumab in Patients With Persistent or Recurrent/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Phase: PHASE2
Conditions: Adult Diffuse Large Cell Lymphoma, Recurrent, Adult Refractory Diffuse Large B-Cell Lymphoma
Sponsor: Sunnybrook Health Sciences Centre

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DPX-Survivac and checkpoint inhibitor in DLBCL 
 
 
Phase 2 Study of an Immune Therapy, DPX-Survivac 
with Low Dose Cyclophosphamide administered with 
Pembrolizumab in Patients with persistent or 
Recurrent/refractory Diffuse Large B-Cell Lymphoma 
(DLBCL)  
(SPiReL) 
 
Protocol Number: 0891 
 
   
Principal Investigator: Dr. Neil Berinstein 
Regulatory Sponsor: Sunnybrook Research Institute 
Funder: IMV Inc. 
Investigational Product: Pembrolizumab/ DPX Survivac 
Coordinating Centre: 
 
 
 
 
 
 
 
Centre for Clinical Trial Support 
Sunnybrook Research Institute 
C8-2075 Bayview Avenue 
Toronto, ON M4N 3M5 
Canada 
Email:SPiReL@sunnybrook.ca    
Fax:  (416) 480-5633 
 

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SPONSOR STATEMENT OF COMPLIANCE 
This study will comply with the International Conference on Harmonization Good Clinical 
Practice E6 (ICH-GCP), World Medical Association Declaration of Helsinki: Ethical Principles for 
Medical Research Involving Human Participants, as well as applicable regulatory and 
institutional requirements.  
 
Personnel listed below are authorized to sign the protocol and any subsequent protocol 
amendments on behalf of the Sponsor:  
Name: 
(Print) 
Dr. Neil Berinstein 
Title:  
(Print) 
 
Professor of Medicine 
University of Toronto 
Sunnybrook Research Institute 
Sunnybrook Health Sciences Centre 
Odette Cancer Centre 
2075 Bayview Avenue 
Toronto, Ontario, M4N3M5 
 
Signature: 
 
Date of Approval: 
(yyyy-mmm-dd) 
 
 

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PROTOCOL SIGNATURE PAGE 
 
I have read this protocol in its entirety and its appendices.  I agree to comply with the 
requirements of the study protocol and procedures for data recording/reporting and 
acknowledge my responsibility for the well-being of each research participant, and to ensure 
that all persons involved in study activities are adequately informed about the protocol, the 
investigational product, and their trial-related duties.  The signature below constitutes the 
agreement to conduct this study in accordance with the REB approved protocol, GCP and  
applicable regulatory requirements, including confidentiality, ethical guidelines and regulations 
regarding the conduct of research in humans. 
 
Qualified Investigator: 
Name: 
(Print) 
 
Title & Institution:  
(Print) 
 
Signature: 
 
Date of signature: 
(yyyy-mmm-dd) 
 
 
 
 
 

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TABLE OF CONTENTS 
PAGE 
SPONSOR STATEMENT OF COMPLIANCE .............................................................................................. II 
PROTOCOL SIGNATURE PAGE ............................................................................................................... III 
TABLE OF CONTENTS .............................................................................................................................. IV 
LIST OF ABBREVIATIONS ........................................................................................................................ VII 
1 
KEY ROLES AND CONTACT INFORMATION .................................................................................. 1 
2 
INTRODUCTION ................................................................................................................................. 2 
2.1 
Background .............................................................................................................. 2 
2.2 
Pharmaceutical and Therapeutic Background ......................................................... 3 
2.3 
Preclinical Data ........................................................................................................ 5 
2.4 
Clinical Data to Date ................................................................................................. 5 
2.5 
Potential Risks/Benefits and Rationale .................................................................... 5 
2.5.1 
Rationale for the Trial and Selected Subject Population .............................. 5 
2.5.2 
Rationale for Dose Selection/Regimen/Modification..................................... 6 
3 
STUDY OBJECTIVES ...................................................................................................................... 11 
3.1 
Primary Objective ................................................................................................... 11 
3.2 
Secondary Objective(s) .......................................................................................... 11 
3.3 
Exploratory Objective(s) ......................................................................................... 11 
4 
STUDY DESIGN ............................................................................................................................... 12 
4.1 
General Design ...................................................................................................... 12 
4.2 
Trial Diagram .......................................................................................................... 12 
4.3 
Primary Outcomes/Endpoint(s) .............................................................................. 12 
4.4 
Secondary Outcome(s)/Endpoint(s) ....................................................................... 12 
4.5 
Exploratory Outcomes/Endpoint(s) ........................................................................ 13 
4.5.1 
Biomarker Research ................................................................................... 13 
4.6 
Primary Safety Outcomes/Endpoints ..................................................................... 13 
5 
PARTICIPANT SELECTION AND WITHDRAWAL ......................................................................... 14 
5.1 
Inclusion Criteria ..................................................................................................... 14 
5.2 
Exclusion Criteria ................................................................................................... 16 
5.3 
Participant Recruitment .......................................................................................... 18 
5.3.1 
Randomization Procedures (if applicable) .................................................. 18 
5.3.2 
Blinding and Unblinding Procedures (if applicable) .................................... 18 
5.4 
Participant Withdrawal and Discontinuation of IP ................................................... 18 
5.4.1 
Reasons for Withdrawal from study or Discontinuation of IP...................... 18 
5.4.2 
Subject Replacement Strategy ................................................................... 19 
5.4.3 
Clinical Criteria for Early Trial Termination ................................................. 19 
5.4.4 
Data Collection & Follow-up for Withdrawn/Discontinued Subjects ............ 20 
6 
INTERVENTIONS ............................................................................................................................. 21 
6.1 
Investigational Product ........................................................................................... 21 
6.1.1 
Acquisition Formulation and Packaging ..................................................... 21 
6.1.2 
Treatment Assignment Procedures ............................................................ 23 
6.1.3 
Dosage, Preparation and Administration .................................................... 23 
6.1.4 
Dose Selection/Modification ....................................................................... 24 
6.1.5 
Receiving, Storage, Dispensing and Return ............................................... 30 
6.2 
Concomitant Medications (Acceptable & Prohibited) ............................................. 31 
6.3 
Rescue Medications & Supportive Care ................................................................. 33 
6.4 
Diet/Activity/Other Considerations .......................................................................... 39 
6.5 
Administration of Intervention ................................................................................. 40 

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6.5.1 
Procedures for Intervention Training and Monitoring.................................. 40 
6.6 
Assessment of Subject Compliance ....................................................................... 40 
7 
STUDY SCHEDULE AND PROCEDURES ...................................................................................... 41 
7.1 
Administrative Procedures ..................................................................................... 41 
7.1.1 
Informed Consent ....................................................................................... 41 
7.1.2 
Inclusion/Exclusion Criteria ........................................................................ 41 
7.1.3 
Medical History ........................................................................................... 41 
7.1.4 
Prior and Concomitant Medications Review ............................................... 41 
7.1.5 
Disease Details and Treatments ................................................................ 42 
7.1.6 
Assignment of Screening Number .............................................................. 42 
7.1.7 
Clinical Procedures/Assessments .............................................................. 42 
7.1.8 
Immune Evaluations ................................................................................... 46 
7.1.9 
Other Procedures ....................................................................................... 46 
7.1.10 
Visit Requirements ..................................................................................... 46 
7.2 
Screening ............................................................................................................... 47 
7.3 
Enrollment .............................................................................................................. 47 
7.3.1 
Adverse Events/Concomitant Medications ................................................. 47 
7.3.2 
Disease Staging ......................................................................................... 48 
7.3.3 
Confirmation of Eligibility ............................................................................ 48 
7.4 
Study Visits ............................................................................................................. 48 
7.4.1 
Visit 1 (SD0) ............................................................................................... 48 
7.4.2 
Visit 2 (SD7) ............................................................................................... 49 
7.4.3 
Visit 3 (SD28) ............................................................................................. 49 
7.4.4 
Visit 4 (SD49) ............................................................................................. 49 
7.4.5 
Visit 5 (SD70) ............................................................................................. 50 
7.4.6 
Visit 6 (SD84) ............................................................................................. 50 
7.4.7 
Visit 7 (SD91) ............................................................................................. 51 
7.4.8 
Visit 8 (SD 112) .......................................................................................... 51 
7.4.9 
Visit 9 (SD133) ........................................................................................... 51 
7.4.10 
Visit 10 (SD140) ......................................................................................... 52 
7.4.11 
Visit 11 (SD 154) ........................................................................................ 52 
7.4.12 
Visit 12 (SD 175) ........................................................................................ 52 
7.4.13 
Visit 13 (SD 196) ........................................................................................ 52 
7.4.14 
Visit 14 (SD217) ......................................................................................... 53 
7.4.15 
Visit 15 (SD238) ......................................................................................... 53 
7.4.16 
Visit 16 (SD252) ......................................................................................... 53 
7.4.17 
Visit 17 (SD259) ......................................................................................... 54 
7.4.18 
Visit 18 (SD280) ......................................................................................... 54 
7.4.19 
Visit 19 (SD301) ......................................................................................... 54 
7.4.20 
Visit 20 (SD308) ......................................................................................... 54 
7.4.21 
Visit 21 (SD322) ......................................................................................... 55 
7.4.22 
Visit 22 (SD343) ......................................................................................... 55 
7.4.23 
Visit 23 (SD364) ......................................................................................... 55 
7.4.24 
End of Study (EOS) Visit ............................................................................ 55 
7.4.25 
Follow-up Visits .......................................................................................... 56 
7.5 
Unscheduled Study Visits ....................................................................................... 58 
7.6 
Pregnancy Visit(s) .................................................................................................. 58 
7.7 
Protocol Deviations ................................................................................................ 58 
8 
ASSESSMENT OF SAFETY ............................................................................................................ 60 
8.1 
Adverse Events ...................................................................................................... 60 

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8.1.1 
Assessment of an Adverse Event ............................................................... 60 
8.1.2 
Evaluating Adverse Events ......................................................................... 62 
8.2 
Serious Adverse Events ......................................................................................... 62 
8.2.1 
Unexpected Adverse Event ..................................................................... 63 
8.2.2 
Unexpected Adverse Drug Reaction (ADR) ........................................... 63 
8.2.3 
Follow-up of SAEs ...................................................................................... 63 
8.3 
Investigational Product Overdose: pembrolizumab ................................................ 64 
8.4 
Adverse Event Recording/Reporting ...................................................................... 69 
8.4.1 
Reporting of Pregnancy and Lactation to the Sponsor ............................... 69 
8.4.2 
Investigator Reporting ................................................................................ 69 
8.4.3 
Sponsor Reporting of SUADRs and ECIs .................................................. 70 
8.4.4 
Reporting and Entry Timelines of Site to Sponsor ...................................... 70 
8.5 
Events of Clinical Interest ....................................................................................... 70 
8.6 
Data and Safety Monitoring Board (DSMB) ........................................................... 71 
8.7 
Steering Committee ................................................................................................ 71 
9 
SITE MONITORING, AUDITING AND INSPECTING....................................................................... 72 
9.1 
Site Monitoring Plan ............................................................................................... 72 
9.2 
Auditing and Inspecting .......................................................................................... 72 
10 
STATISTICAL CONSIDERATIONS ................................................................................................. 73 
10.1 Study Hypotheses .................................................................................................. 73 
10.2 Populations of Interest ............................................................................................ 73 
10.3 Planned Interim Analyses ....................................................................................... 73 
10.3.1 
Safety Review ............................................................................................. 74 
10.3.2 
Efficacy Review .......................................................................................... 74 
10.4 Stopping Rules ....................................................................................................... 74 
10.5 Final Analysis Plan ................................................................................................. 74 
11 
DATA HANDLING AND RECORD KEEPING .................................................................................. 76 
11.1 Confidentiality ......................................................................................................... 76 
11.2 Source Documents ................................................................................................. 76 
11.3 Data Management Responsibilities ........................................................................ 77 
11.4 Data Capture .......................................................................................................... 77 
11.4.1 
Case Report Forms .................................................................................... 77 
11.5 Records Retention .................................................................................................. 78 
11.6 Clinical Trial Registration ........................................................................................ 78 
12 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 79 
13 
ETHICS CONSIDERATIONS ............................................................................................................ 80 
13.1 Ethical Standard ..................................................................................................... 80 
13.2 Research Ethics Board (REB) ................................................................................ 80 
13.3 Consent .................................................................................................................. 80 
14 
PUBLICATION/DATA SHARING POLICY ....................................................................................... 81 
15 
LITERATURE REFERENCES .......................................................................................................... 82 
16 
APPENDICES ................................................................................................................................... 85 
APPENDIX A: Schedule of Events for Screening Period ................................................ 85 
APPENDIX B: Schedule of Events for Treatment Visits.................................................. 87 
APPENDIX C: Modified Cheson Criteria (2007) ............................................................. 91 
APPENDIX D: Immune Related Response Criteria (IrRC)46 ........................................... 92 
APPENDIX E: Common Termiology Criteria for Adverse Events V4.03 (CTCAE) ......... 93 
APPENDIX F: ECOG Performance Status48 ................................................................... 96 
APPENDIX G: Dose Modification Guidelines for Drug-Related Adverse Events for  
Pembrolizumab (July 2019) ............................................................................................ 97 

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LIST OF ABBREVIATIONS 
The following abbreviations describe terms, documents and study personnel used in the 
conduct of this study protocol. 
AE 
 
 
Adverse Events/Adverse Experience 
ASCT 
 
 
Autologous Stem Cell Transplant 
CC 
 
 
Coordinating Centre 
CIOMS  
 
Council for international Organizations of Medical Sciences 
CRF 
 
 
Case Report Form 
CTCAE  
 
Common Terminology Criteria for Adverse Events 
CCTS 
 
 
Centre for Clinical Trial Support 
DLBCL  
 
Diffuse Large B Cell Lymphoma 
EC 
 
 
Ethics Committee 
EOS 
 
 
End Of Study 
ECOG  
 
Eastern Cooperative Oncology Group 
HLA 
 
 
Human Leucocyte Antigen 
IB 
 
 
Investigator’s Brochure 
ICH 
 
 
International Conference on Harmonisation 
IP 
 
 
Investigational Product 
DSMB 
 
 
Data and Safety Monitoring Board 
eCRF 
 
 
Electronic Case Report Form 
pCRF 
 
 
Paper Case Report Form 
EDC 
 
 
Electronic Data Capture 
GCP 
 
 
Good Clinical Practice 
ICF 
 
 
Informed Consent Form 
ISR 
 
 
Injection Site Reaction 
MedDRA 
 
Medical Dictionary for Regulatory Authorities 
MTD 
 
 
Maximum Tolerated Dose 
NSCLC  
 
Non-Small Cell Lung Cancer 
PBMC 
 
 
Peripheral Blood Mononuclear Cells 
PHI 
 
 
Personal Health Information 
PI 
 
 
Principal Investigator 
PM 
 
 
Product Monograph 
QI 
 
 
Qualified Investigator 
REB 
 
 
Research Ethics Board 
SAE 
 
 
Serious Adverse Event/Serious Adverse Experience 
SOP 
 
 
Standard Operating Procedure 
SPC 
 
 
Summary of Product Characteristics 
SRI 
 
 
Sunnybrook Research Institute 
SUADR  
 
Serious and Unexpected Adverse Drug Reaction 
TMF 
 
 
Trial Master File 

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PROTOCOL SUMMARY 
Protocol Title (Short 
Title) 
Phase 2 Study of an Immune Therapy, DPX-Survivac with Low Dose 
Cyclophosphamide administered with Pembrolizumab in Patients with 
persistent or recurrent/refractory Diffuse Large B-Cell Lymphoma 
(DLBCL) 
Protocol Number 
0891 
Phase 
II 
Study Design 
This is a Phase 2 non-randomized, open label, uncontrolled, efficacy 
and safety study.  Study participants will receive two priming doses of 
0.5 mL of DPX-Survivac 21 days apart and up to six 0.1 mL 
maintenance injections every two months with low dose metronomic 
oral cyclophosphamide (50 mg BID) for one year or until disease 
progression, whichever occurs first.   
Pembrolizumab 200 mg will be administered every 3 weeks for up to 
one year or until disease progression, whichever occurs first. 
Study Duration 
42 months 
Setting 
National multi-centre  
Sample Size 
25 patients  
Main Inclusion 
Criteria 
Measurable persistent or recurrent/refractory Diffuse Large B-cell 
Lymphoma (DLBCL) 
Primary Outcome(s): 
To document a minimal objective response rate of 24% to treatment 
with DPX-Survivac and low dose cyclophosphamide administered 
together with anti-PD-1 (Pembrolizumab) in patients with recurrent, 
survivin-expressing B cell lymphomas using modified Cheson criteria. 
Secondary 
Outcome(s): 
1) To document evidence of  regression using waterfall analyses 
2) To document the toxicity profile 
3) To document duration of response using modified Cheson criteria 
and immune-related response criteria (irRc) 
4) To document time to next treatment and survival 
Exploratory 
Outcomes(s): 
1) To document the changes in circulating T cell immune responses 
to survivin and relationship to peripheral B cell numbers 
2) To document changes in T cell and T cell subset infiltration and 
gene expression pathways in treatment compared to pre-treatment 
tumour biopsies 
3) To assess potential biomarkers of immune and clinical 
response from subject clinical, biological and immunologic 
data, and pre-treatment and on-treatment tumor biopsies. 

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4) To evaluate other relevant biologic assays that may be 
identified during the conduct of the trial that may have immune 
or clinical relevance on samples already collected. 
 
Investigational 
Product and Planned 
Use 
Study participants will receive two priming doses of 0.5 mL of DPX-
Survivac 21 days apart and up to six maintenance injections every two 
months in alternating upper thigh regions for one year or until disease 
progression, whichever occurs first.   
Pembrolizumab 200 mg will be administered as a 30-minute IV 
infusion every 3 weeks for up to one year or until disease progression, 
whichever occurs first. 
Statistical Analysis: 
The safety population is defined as all subjects who receive at least 
one immunization.  The efficacy population is defined as all subjects 
who received at least three injections, four infusions of pembrolizumab 
and one on-treatment CT-scan between study days 70 and 104. The 
design has more than 90% power to conclude that the treatment is 
effective if its true response rate were equal to 35% or more.  The 
design also has less than 5% probability to conclude that the treatment 
is effective if its true response rate were equal to 10% or less.  
Standard descriptive statistical methods will be used to summarize the 
data. The response rate will be estimated along with its exact 95% 
confidence interval. 
 

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1 KEY ROLES AND CONTACT INFORMATION  
 
Regulatory Sponsor: 
 
Sunnybrook Research Institute (SRI) 
2075 Bayview Avenue 
Toronto, ON Canada M4N 3M5 
Principal Investigator:   
Dr. Neil Berinstein 
Academic Research 
Organization: 
Centre for Clinical Trial Support, SRI 
2075 Bayview Avenue 
Toronto, ON Canada M4N 3M5 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
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2 INTRODUCTION  
 
This study document is the protocol for research involving human participants.  This study is to 
be conducted according to Canadian and international standards, and in compliance with the 
protocol, International Conference on Harmonisation Good Clinical Practice E6 (ICH-GCP), 
World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research 
Involving Human Participants, as well as applicable regulatory and institutional requirements 
and research policies.  
 
2.1 
Background  
 
Although many diffuse large cell B cell lymphomas (DLBCL) may be cured or have prolonged 
remissions with initial therapy using R-CHOP (rituximab, cyclophosphamide, doxorubicin 
hydrochloride, vincristine sulfate, and prednisone), patients with recurrent DLBCL (other than 
those who are eligible for high dose therapy and autologous stem cell transplantation (ASCT) 
will eventually die of their disease.  Effective salvage therapies for non-transplant-eligible or 
post-transplant patients with DLBCL is an unmet medical need.  There is an opportunity to 
develop a successful immune therapy combination treatment against B cell lymphomas, 
particularly one that could work in concert with other treatments and further extend remissions.  
 
Many different therapeutic vaccines have been evaluated in phase 1, 2, and even phase 3 trials. 
With the exception of the sipuluecel T dendritic cell based vaccine1 , these trials have not shown 
significant clinical activity. Much has been learned, however, about the principles of applying 
immune-based therapies to cancer patients and about developing vaccines that are sufficiently 
immunogenic to break tolerance to self tumour antigens2 . Cancer vaccines appear to have their 
greatest impact earlier in the disease course or in situations with minimal residual disease. In 
addition, cancer vaccines alone are not likely to be clinically effective in patients with 
measurable disease and combinations with immune modulators are essential to overcome 
some of the immunosuppressive pathways that cancers utilize to avoid immune rejection. The 
principle behind this trial is to combine a T-cell activating therapy (formerly identified as a highly 
immunogenic vaccine formulation) to the tumour antigen survivin with an active 
immunomodulator aimed at reversing T cell anergy. A component of this combination therapy 
with this immune modulator -metronomic cyclophosphamide- has already been shown to 
mediate anti-tumour activity in the patient population to be studied3 . 
 
The programmed cell death 1 (PD-1) pathway represents a major immune control switch, which 
may be engaged by tumour cells to overcome active T-cell immune surveillance. MK-
3475/prembrolizumab (anti-PD-1/checkpoint inhibitor) is a potent and highly selective 
humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L24. This blockade enhances 
functional activity of the target lymphocytes to facilitate tumour regression and ultimately 
immune rejection. Merck is studying MK-3475 for various oncology indications.  For additional 
information on Merck clinical studies please refer to the Investigator’s Brochure (IB)/approved 
labeling for detailed background information on MK-3475. MK-3475 has already been approved 
by regulatory agencies for treatment of metastatic melanoma that is recurrent after dacarbazine 
and Ipilimumab and is being studied in many other indications either as monotherapy or as a 
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The principle behind this trial is to combine a highly immunogenic drug formulation (DepoVax) to 
the tumour antigen survivin (DPX-Survivac) with an active T cell activator aimed at reversing T 
cell anergy.  The tumour-associated antigen survivin is expressed in approximately 60% of 
DLBCL.  DPX-Survivac has already been shown to be highly immunogenic in patients with 
ovarian cancer particularly when combined with metronomic cyclophosphamide to suppress 
regulatory T cells.  In fact a clinical objective response of patients with recurrent ovarian and 
gynaecological cancers has been documented5. For additional information on IMV clinical 
studies and DPX-Survivac please refer to the IB.     
2.2 
Pharmaceutical and Therapeutic Background  
A. Investigation Product Background of MK-3475  (Pembrolizumab) 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades6.  Accumulating evidence shows a correlation 
between tumour-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumours. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumours to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-cells 
under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2)7,8.  The structure of 
murine PD-1 has been resolved9. PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and 
a cytoplasmic tail which is responsible for the binding of signaling molecules.  The cytoplasmic 
tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-
cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif 
within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ and ZAP70, which are involved in the CD3 T-cell signaling cascade10-12.  The mechanism 
by which PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 
as both molecules regulate an overlapping set of signaling proteins13,14.  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells15,16.  Expression has also been shown during thymic development 
on CD4-CD8- (double negative) T-cells17 as well as subsets of macrophages and dendritic cells.  
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumours6,14,18,19.  
Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in 
the extracellular region and contain short cytoplasmic regions with no known signaling motifs.  
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably 
on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is 
thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to 

 
 
 
 
 
 
 
 
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dampen unwarranted T-cell function in peripheral tissues14.  Although healthy organs express 
little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this 
T-cell inhibitor20-22.  PD-1 has been suggested to regulate tumour-specific T-cell expansion in 
subjects with melanoma23.  This suggests that the PD-1/PD-L1 pathway plays a critical role in 
tumour immune evasion and should be considered as an attractive target for therapeutic 
intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated 
for the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor.  In Canada, 
pembrolizumab is approved for renal call carcinoma, baldder cancer, non-small cell lung 
carcinoma, melanoma, classical Hodgkins lymphoma and urothelia carcinoma.   
 
B. Investigational Product Background:  DPX-Survivac 
 
IMV, formerly ImmunoVaccine Technologies Inc. has developed a patented prophylactic/ 
immune therapy platform demonstrated to enhance peptide immunogenicity in animal models 
with its ability to maintain an immune response to the peptides delivered after repeated 
immunizations24.  The DepoVax (DPX) platform is a lipid-based depot formulation able to 
enhance cellular immune responses.  It is oil based; making it particularly well suited for 
therapeutic cancer treatment applications since it allows for practical delivery of peptide 
antigens without having to resort to cumbersome emulsification.  DepoVax also includes a T-
helper peptide, a polynucleotide immunostimulant, synthetic lipid and cholesterol inactive 
ingredients to enhance and sustain the immune response.  
 
The safety concerns with therapeutic cancer treatments emanate from the risk of antigen-
specific autoimmune disease as well as non-specific side effects (local and systemic) from the 
adjuvant system itself.  The proposed DPX-Survivac immune therapy is designed to target 
survivin, a member of the inhibitor of apoptosis protein family.  Survivin over-expression has 
been detected in many cancer types, yet expression in normal adult tissues is limited.  It was 
identified as the fourth most highly abundant transcript in several common cancers such as 
melanoma, colon, brain, breast, and ovarian cancers25,26. In blood cancers, survivin over-
expression has been consistently demonstrated, particularly in lymphomas and multiple 
myeloma27.  Animal studies performed by others using mouse tumour cell lines expressing 
survivin have demonstrated that targeting survivin inhibits tumour growth28,29, without affecting 
any normal tissue with survivin expression.  Survivin-specific T cells have been detected in 
cancer patients, but not in healthy individuals suggesting a differential presentation of survivin 
epitopes by cancer cells30.  The presence of persistent survivin-specific T cells in cancer 
patients also suggests that the presence of anti-survivin immunity may not induce autoimmunity.   
 
DLBCL is the lymphoma subtype consistently expressing “high and strong” expression of 
survivin compared to other types of lymphoma31.  Independent studies have shown survivin 
expression in 60% (134/222) of DLBCL patients by IHC with survivin expression negatively 
correlated with survival32 and survivin expression (>45% positive tumour cells) in 39% of DLBCL 
patients (22/56) with the survivin expression correlated with shorter survival33. Survivin is utilized 
by tumours to evade apoptosis and promote malignancy.  Survivin is involved in multiple 

 
 
 
 
 
 
 
 
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signaling pathways that are critical for cancer cell survival and has been described as a “cross-
road signaling molecule” in cancer cells34.  It is extensively studied as an inhibitor of apoptosis, 
yet is also directly involved in cell cycle progression and mitosis, response to cellular stress, 
including responses to cancer therapeutics, and through interactions with NF-κB, involved in the 
promotion of tumour cell invasion and metastasis.  It is a molecule within cancer cells, that when 
targeted, is very difficult for cancer cells to down-regulate without extensively sacrificing its 
unlimited growth and resistance to standard therapies.  This makes survivin a particularly 
interesting antigen to target with immune therapy.  
 
DPX-Survivac is a T cell activating  immune therapy containing one decapeptide and four 
nonapeptides derived from the protein sequence of survivin.  The five peptides have different 
HLA restrictions (HLA-A1, A2, A3, A24, B7), and this combination covers approximately 85% of 
the North American population (Table 1).  The presumed primary mechanism of action of DPX-
Survivac is to elicit a cytotoxic T lymphocyte response against tumour cells presenting the 
survivin peptides on HLA class I molecules.  These peptides were initially developed by Merck 
KGaA as Survivac (EMD640744, which used a Montanide ISA 51 VG emulsion).  This product 
was tested in a phase 1 clinical trial (EMR-200032-001) that enrolled 53 patients with advanced 
solid tumours to evaluate the immunogenicity (primary endpoint) and safety of multiple weekly 
injections of increasing doses of Survivac in Montanide ISA 51 VG35.  There was evidence of 
vaccine induced T cell responses.  Adverse events possibly or likely related to EMD640744 
were mild to moderate (grade 2-3) and mostly represented injection site reactions and there 
were no reports of autoimmunity.  
Table 1: Five survivin peptides in DPX-Survivac 
Name 
Sequence 
Restriction 
% of 
Population 
SurA1.T 
FTELTLGEF 
HLA-A1 
11-27% 
SurA2.M 
LMLGEFLKL 
HLA-A2 
22-46% 
SurA3.K 
RISTFKNWPK 
HLA-A3 
14-24% 
SurA24 
STFKNWPFL 
HLA-A24 
12-24% 
SurB7 
LPPAWQPFL 
HLA-B7 
13-18% 
2.3 
Preclinical Data  
 
Refer to the Merck and IMV Investigator’s Brochures for Preclinical data. 
 
2.4 
Clinical Data to Date 
Refer to the Merck and IMV Investigator’s Brochures for Clinical data. 
 
2.5 
Potential Risks/Benefits and Rationale 
2.5.1 Rationale for the Trial and Selected Subject Population 
 
Study subjects will have recurrent diffuse large cell B cell lymphomas (DLBCL) and are not 
eligible for high dose therapy and autologous stem cell transplantation (ASCT).  This defined 
population will eventually die of their disease because effective salvage therapies are not 
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2.5.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumours.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of MK-3475 showed evidence of target engagement 
and objective evidence of tumour size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 
mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose tested in 
PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to test 
for initial tumour activity.  Recent data from other clinical studies within the MK-3475 program 
has shown that a lower dose of MK-3475 and a less frequent schedule may be sufficient for 
target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days).  This early 
PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing 
schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship between 
clearance and body weight, with an allometric exponent of 0.59, is within the range observed for 
other antibodies and would support both body weight normalized dosing or a fixed dose across 
all body weights.  MK-3475 has been found to have a wide therapeutic range based on the 
melanoma indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 
2 mg/kg Q3W body weight based regimen are anticipated to remain well within the established 
exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins 
are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the 
proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population 
PK evaluation revealed that there was no significant impact of tumour burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there 
are no anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of Pembrolizumab in 
solid tumours is based on: 1) similar efficacy and safety of Pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
Pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumour burden or indication on distribution behavior of 
Pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of Pembrolizumab target engagement will not vary meaningfully with tumour type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of Pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with 
those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established in 

 
 
 
 
 
 
 
 
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melanoma that are well tolerated and safe.  
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
 
IMV completed a phase 1 ovarian cancer vaccine clinical trial with DPX-Survivac (ONC-DPX-
Survivac-01)36.  The study  involved a lead-in cohort evaluating the safety of the Survivac 
peptides formulated in DepoVax, followed by a dose finding safety and immunologic evaluation 
of two dose levels of DPX-Survivac with low dose cyclophosphamide.  In this study nineteen 
subjects were successfully treated with at least one dose of DPX-Survivac.  Six subjects in each 
of cohort A (0.5 mL of DPX-Survivac), cohort B (0.1 mL of DPX-Survivac plus 
cyclophosphamide), and cohort C (0.5 mL DPX-Survivac plus cyclophosphamide) received all 
three scheduled doses, three weeks apart.  One subject in cohort A withdrew consent after first 
dose.  The majority of  treatment related adverse events were grade 1-2 injection site reactions 
such as induration, erythema, pain, edema, pruritus, and/or warmth.  There were three grade 3 
ulcerations reported for DPX-Survivac.  One of the grade 3 ulcerations in cohort C was reported 
as a related SAE but as indicated in the IB and protocol, this is an expected AE.  Grade 3 site of 
injection reactions occurred after the third dose and at the third injection site.  These reactions 
are likely immune mediated, based on the evaluation of a biopsy from one subject with a grade 
3 reaction.  Three weeks after the second dose there is a strong circulating T cell response, we 
speculate therefore that placing a large antigen load with the third dose initiates a persistent 
immune attack at the site of injection increasing the likelihood of severe reactions.  Reducing 
the dose volume and/or delaying subsequent dosing was therefore tested in a Phase 1b study 
(ONC-DPX-Survivac-03)..  Immune monitoring of phase 1 study subjects has established a 
clear dose response and an enhancement of the immune response when the vaccine is 
combined with cyclophosphamide.  Thus the best antigen-specific immune responses occurred 
in Cohort C.  Robust immune responses were generated after 1-2 vaccinations, and these 
immune responses were maintained by subsequent vaccinations.   
 
IMV completed ONC-DPX-Survivac-03, the Phase 1b clinical trial with DPX-Survivac in ovarian 
cancer patients in centers in both Canada  in 2018.  Subjects in all 5 study cohorts received 
subcutaneous DPX-Survivac with intermittent low dose cyclophosphamide, similar to 
ONC0DPX-Survivac-01, but the dose was reduced to 0.25mL from 0.5mL the safety and 
efficacy of up to six subcutaneous doses of DPX-Survivac.  In cohorts 1 and 2 two priming 
doses of 0.25 mL were delivered 3 weeks apart followed by four 0.1 mL maintenance doses 
administered 8 weeks apart. Cohort 1 received both 0.25mL doses in the same upper thigh 
region, while in Cohort 2, the 0.25mL doses were administered in opposite limbs. Cohort 3 
received three 0.25 mL doses of DPX-Survivac spread 8 weeks apart, while Cohort 4 received 
five doses of 0.25mL 6 weeks apart. Cohort 5 received two doses of 0.25mL 4 weeks apart plus 
three doses of 0.5mL 4 weeks apart.  A total of 38 subjects were enrolled into the study; six in 
Cohort 1, 9 in Cohort 2, 7 in Cohorts 3 and 4, and 9 in Cohort 5. 37 subjects were included in 
the analysis, as one subject withdrew consent. Of the 38 enrolled, 23 completed the study, 
which was defined as subjects having completed all their cohort-specific visits. Subjects were 
treated for up to 38 weeks. The study protocol was designed to incorporate dose omission in the 
presence of significant injection site reactions, making it an integral part of the study design.  All 
37 subjects receiving at least one dose of study treatment experienced at least 1 injection site 
reaction, ranging from Grade 1 – 3. No subject experienced a Grade 4 injection site reaction. 

 
 
 
 
 
 
 
 
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Most injection site reactions were low-Grade; induration Grade 1 was 54% and Grade 2 was 
35%, Grade 1 erythema was 43% and Grade 2 was 23%, Grade 1 discoloration was 40%. 
Reports of Grade 3 erythema and induration were highest overall prior to use of CTCAE version 
4.03, occurring in Cohort 1 and Cohort 2, and therefore, may have been overestimated in these 
cohorts. There were 7 subjects with reported injection site ulcerations in this study: one Grade 
1, two Grade 2, and four Grade 3. The highest frequency of ulcerations occurred in Cohort 1, 
which has led to the recommendation that all doses of DPX-Survivac be administered to 
alternating limbs. The most commonly observed systemic adverse event was fatigue, and no 
trends in clinically significant findings in hematology or chemistry parameters were observed.  
No SAEs were determined to be related to the study drug. Immune responses were assessed 
by 2 methods of analysis performed on PBMC samples collected from the subjects throughout 
the study; ELISpot and MHC-tetrameter staining for antigen specific CD8+ T cells. DPX-Survivac 
induced detectable immune responses in 31 out of 37 subjects evaluated. A secondary 
objective of the study was to determine if there was any clinical and biochemical evidence of 
disease regression using standard-of-care radiologic investigations and from cancer antigen 
125 test (CA-125). Two subjects demonstrated a CA-125 response and four showed CA-125 
progression. One subject from Cohort 1, and one subject from Cohort 5 demonstrated a CA-125 
response during the course of the study and completed the study. Two of these subjects 
completed the study with no radiologic evidence of disease progression, one completed the 
study but with radiologic evidence of disease progression at study end and one discontinued 
early due to disease progression. One subject enrolled in Cohort 1 demonstrated a partial 
response to the treatment, with a measurable reduction in tumour size and positive response to 
CA-125. This subject also showed remarkably high antigen-specific immune responses as 
measured by ELISpot and tetrameter analysis. Although the subject did experience a 
progression of disease approximately 2 months after completing the study, it is interesting to 
note that the subject’s progression-free interval between second chemotherapy and recurrence, 
which included the DPX-Survivac study, exceeded the progression-free interval between first 
chemotherapy and first recurrence 
 
IMV conducted a Phase 2 study, which enrolled 4 subjects, but was terminated early to support 
this trial. Up to 24 subjects were expected to receive two doses of 0.25mL DPX-Survivac 3 
weeks apart and four 0.1mL doses 8 weeks apart with intermittent low-dose cyclophosphamide. 
No new safety or immunogenicity findings were gained from those 4 enrolled subjects. 
 
IMV is conducting a Phase1b/2 study (ONC-DPX-Survivac-06) in subjects with recurrent, 
fallopian and peritoneal cancers. Two doses of 0.25mL DPX-Survivac 3 weeks apart, and up to 
six 0.1mL doses every 8 weeks, with intermittent cyclophosphamide and with or without an oral 
idoleamine 2.3-dioxygenase 1 (epacadostat IDO-1) inhibitor. The Phase 1b study, now 
complete, was a single-arm non-randomized dose escalation study using the IDO-1 inhibitor as 
a means to reverse tumour associated immune suppression. A total of 53 subjects were 
enrolled, all of whom are evaluable for safety The ongoing Phase 2 portion of the study began 
as a double-arm, randomized, open-label, non-controlled study. Subjects were initially 
randomized 1:1 to treatment with DPX-Survivac and cyclophosphamide with or without IDO-1 
inhibitor. Following a review of the emerging data, the arm receiving the IDO-1 inhibitor was 
dropped and enrollment continued as a single arm study. 12 subjects were enrolled into the 
"with" and "without" IDO-1 inhibitor, and 22 were enrolled into the single arm Phase 2. 
Enrollment is complete, however, treatment is ongoing. The relatedness of adverse events was 
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events are attributable to the IDO-1 inhibitor and not DPX-Survivac. Injection site reactions: 
induration Grade 1 was 49% and Grade 2 was 9.4%, erythema Grade 1 was 50.9% and Grade 
2 was 7.5% and Grade 3 was 2%, and ulceration Grade 2 was 5.7% and Grade 3 was 3.8%. 
There were no Grade 4 injection site reactions. Of systemic adverse events, nausea (15%), 
fatigue (7.5%), diarrhea (7.5%) and blood alkaline phosphatase increased (7.5%) were the most 
common Grade 2 events, and the most common Grade 1 events were fatigue (28.3%) and 
nausea (43.4%). The most common Grade 3 events reported were fatigue (11.3%), rash (9.4%), 
anemia (4%), lipase increased (3.8%), followed by hyponatremia, alanine aminotransferase 
increased, asparate aminotransferase increased, gama glutaminotransferase increased and 
abdominal pain (1.9%). There was one Grade 4 event reported, a lipase increased. 5 subjects 
had a best response of PR, 20 subjects had stable disease, and 19 subjects had disease 
progression. 10 of 44 subjects showed a decrease in target lesion measurements. In the Phase 
2 portion of the trial, 1 suspected unexpected serious adverse reaction (SUSAR) was reported 
in one study subject; grade 3 myositis at the site of DPX-Survivac administration. 
 
IMV is currently conducting a Phase 2 study (P1719-SUR-Z11) in selected advanced and 
recurrent solid tumours, as an open-label, multi-indications, safety lead-in study to assess the 
safety 
and 
efficacy 
of 
the 
combination 
of 
DPX-Survivac, 
intermittent 
low-dose 
cyclophosphamide and pembrolizumab. Two ovarian cancer arms are being recruited for, one 
with and one without cyclophosphamide. The DPX-Survivac is administered as two 0.25mL 
doses 3 weeks apart, followed by up to 11 0.1mL doses every 9 weeks. The cyclophosphamide 
is 50 mg BID for 7 days on and 7 days off, and 200mg of pembrolizumab is administered by IV 
every 3 weeks for up to 35 cycles. The safety lead-in data for the first 14 subjects were 
reviewed and accepted for continued enrollment. Subjects with ovarian cancer, hepatocellular 
carcinoma, non-small cell lung cancer, bladder cancer and microsatellite instability high solid 
tumours are being recruited.   
 
Since the immune therapy is a Montanide ISA 51 VG-based depot treatment, it will be delivered 
subcutaneously to the front, upper half of the thigh region, close to the inguinal lymph nodes to 
promote uptake and processing by the immune system.   All injections will alternate between 
limbs, and not be administered any closer than 10cm to prior injection sites.  Previous studies 
with Montanide-based treatments have shown that multiple, repeated immunizations over 
extended periods were critical to maintain the desired T cell responses37.  The goal of the 
maintenance cycles is to maintain the immune response when it is starting to decline.  
 
A major barrier to the efficacy of cancer immune therapies has been the immunosuppressive 
environment in cancer patients, including the induction of regulatory T (T reg) cells that inhibit 
the anti-tumour T cells induced by immune therapies.  Recent studies have indicated that the 
use of low dose administration of chemotherapeutic agents such as cyclophosphamide can 
have positive effects on immune therapies.  At low doses, cyclophosphamide has been 
demonstrated to act, not as a strict cytotoxic agent, but as a “biological response modifier”, in 
that it has been shown to have selective effects on the immune system, such as altering the 
number and efficacy of the T reg population.  Prior treatment with low dose cyclophosphamide 
administered intravenously prior to injections has been shown to reduce Treg cells in cancer 
patients in a transient fashion, and it may augment the efficacy of immunotherapies38-40.  
However, a key paper published in 2007, describes a clinical trial in stage IV cancer patients 
where the oral metronomic delivery of cyclophosphamide (50 mg twice a day, one week on, one 
week off) resulted in a significant and selective depletion of T regs38.  The side effect profile was 

 
 
 
 
 
 
 
 
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not clearly defined in this key publication.  Although this regimen of treatment is widely accepted 
as having low toxicity, it is difficult to report the grades and frequencies of toxicities since it 
varies between studies.  The variability amongst the studies is due to the different dosing 
regimens and the multiple tumour types41-44.  Some subjects may experience one or more of 
leukopenia, lymphopenia, thrombocytopenia, anemia, fatigue, nausea, and/or vomiting.  In the 
phase 1 clinical trial with DPX-Survivac in ovarian cancer patients(ONC-DPX-Survivac-01), the 
immune responses seen in Cohort C, where subjects received DPX-Survivac at 0.5 mL with 
cyclophosphamide, were clearly better than Cohort A, where subjects received 0.5mL DPX-
Survivac without the cyclophosphamide.  We do not expect low doses of cyclophosphamide to 
have significant anti-tumour activity on its own and to date there are no publications 
demonstrating clinical benefits of low dose cyclophosphamide alone in lymphoma. One 
publication combined low doses of metronomic cyclophosphamide with high doses of celecoxib 
and this combination resulted in a 37% objective response rate with a PFS of 4.67 months in a 
similar patient population3.  
 
In the phase 1b ovarian cancer trial (ONC-DPX-Survivac-03), the administration of 
cyclophosphamide during the maintenance cycle was modified to reduce the overall exposure to 
cyclophosphamide and to avoid toxicities that may possibly occur due to chronic dosing.  
Cyclophosphamide was administered seven days prior to the first injection and then continuing 
for seven days off and seven days on for 9 weeks during the priming phase.  During the 
maintenance cycles, cyclophosphamide was administered 7 days before the maintenance 
injection, then continuing for 7 days off and 7 days on with a five week break between injections. 
This allowed the immune therapy to be processed by the immune system in the continued 
absence of cancer induced immune suppression.  However, given that continuous low dose 
cyclophosphamide is well tolerated in DLBCL and is associated with clinical objective response 
we will increase the exposure to cyclophosphamide by alternating one week on with one off 
throughout the dosing of DPX-survivac. If platelet levels decrease below 75,000/mm3 or if 
absolute neutrophil counts decrease below 1000/mm2 in any cycle then the dose of 
cyclophosphamide can be reduced to 50 mg once daily in that subject for the duration of their 
treatment.  
 
 
 

 
 
 
 
 
 
 
 
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3 STUDY OBJECTIVES 
 
3.1 
Primary Objective 
 
To document a minimal objective response rate of 24% to treatment with DPX-Survivac and low 
dose cyclophosphamide administered together with anti-PD-1 (pembrolizumab) in patients with 
recurrent, survivin-expressing B cell lymphomas using modified Cheson criteria45. 
3.2 
Secondary Objective(s) 
 
1. To document changes in tumour volume using waterfall analyses. 
 
2. To document the toxicity profile. 
 
3. To document duration of response using modified Cheson criteria and immune-related 
response criteria46 (irRc). 
 
 
4. To document time to next treatment and survival 
 
3.3 
Exploratory Objective(s) 
 
1. To document the changes in circulating T cell immune responses to survivin and 
relationship to peripheral B cell numbers. 
 
2. To document changes in T cell and T cell subset infiltration and gene expression 
pathways in treatment compared to pre-treatment tumour biopsies. 
 
3. To assess potential biomarkers of immune and clinical response from subject clinical, 
biological and immunologic data from pre-treatment and on-treatment tumour biopsies.  
 
4. To evaluate other relevant biologic assays that may be identified during the conduct of 
the trial that may have immune or clinical relevance on samples already collected. 
 

 
 
 
 
 
 
 
 
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4 STUDY DESIGN 
 
4.1 
 General Design 
 
Treatment, non-randomized, open label, uncontrolled, efficacy and safety study.  Study 
participants will receive two priming doses of 0.5 mL of DPX-Survivac 21 days apart and up to 
six 0.1 mL maintenance injections every two months with low dose metronomic oral 
cyclophosphamide (50 mg BID; 7 days on, 7 days off) for one year or until disease progression, 
whichever occurs first.  Pembrolizumab 200 mg will be administered every 3 weeks for up to 
one year or until disease progression, whichever occurs first. 
 
4.2 
Trial Diagram 
 
An overview of the clinical design and the time points for DPX Survivac injections, 
cyclophosphamide and pembrolizumab administration, blood collection for immune monitoring, 
radiology and biopsy is depicted below. This is only a schematic diagram and the screening 
period is not included (See Appendix B for details).  
 
 
 
4.3 
Primary Outcomes/Endpoint(s) 
 
Objective clinical and radiologic response rate will be determined using Modified Cheson 
Criteria (Appendix C)  
4.4 
Secondary Outcome(s)/Endpoint(s) 
Tumour volume recorded at screening will be compared to treatment and end of study (EOS) 
imaging. Data such as the degree of change or total tumour volume,  from baseline through 
end-of-study, will be plotted on a waterfall plot to demonstrate individual responses using 
modified Cheson Criteria and irRC. The irRC criteria will also be utilized to evaluate the duration 
of response. Evidence of toxicity will be assessed at each visit and graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 (Appendix E).  When 
subjects have completed their participation in the study, by either remaining on trial to SD364, or 
discontinuing study participation early, they will be followed up to document time to next 
treatment and obtain survival times. 
 

 
 
 
 
 
 
 
 
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4.5 
Exploratory Outcomes/Endpoint(s) 
 
T Cell activation therapy induced generation or enhancement of pre-existing immunity to 
survivin is considered a prerequisite for the anti-tumour effect of DPX-Survivac.  Therapy with 
DPX-Survivac is expected to increase the frequency and activity of survivin-specific anti-tumour 
T cells.  Survivin-peptide specific T cell immune response will be measured by methods such as 
ELISpot assay to enumerate T cells that produce molecules associated with anti-tumour 
immune responses such as IFN-γ and/or Granzyme-B.   Other exploratory immunologic 
assessments may be performed on frozen PBMC samples and subject plasma if a novel 
method becomes available during the course of the study.  Tumour-specific T cells must migrate 
to the tumour site to mediate anti-tumour activity. Both DPX-Survivac and pembrolizumab 
should facilitate the migration of antigen-specific T cells into tumour sites.  We will quantitate 
changes in T cell infiltration and the expression profile of this T cells in tumour sites using pre- 
and on-treatment biopsies. If the subject ends trial participation due to progression and soon 
after undergoes a post-study tumour biopsy just prior to starting another therapy, we will aim to 
obtain a sample for comparison of immune and pathologic data to the pre- and on- treatment 
samples. Analysis will be performed  on the collected clinical, biologic and immunologic data 
obtained from subjects to look for features that distinguish subjects that progress early while on 
treatment and those that have longer durations of response or are able to remain on treatment 
for the entire length of the trial without progression.  
Other novel exploratory assays such as quantitation of periperhal blood survivin levels may also 
be explored as new scientific literature arises.  
4.5.1 Biomarker Research 
 
Peripheral blood will be obtained pre-treatment, before each injection, 2 months after the 
second injection, and at the end of study visit for immune analyses. Plasma Survivin levels will 
be obtained as per schedule of events.  
 
Tumour biopsies will be obtained pre-treatment and on-treatment, and where possible when the 
subject is just off-treatment (usually as standard of care before starting another course of 
therapy), to assess for changes in lymphocyte infiltrates, lymphocyte subsets, and gene 
expression profiles with treatment.  Novel biomarkers predictive of immune or clinical response 
will be assessed in pre-treatment tumour biopsies and will include the immune and gene 
expression profiles. If an injection site biopsy is required for clinical management during the 
course of this trial, portions of this biopsy may be studied for evidence of antigen specific T cell 
infiltrates, other biomarkers, or immune activity. The extent and type of analysis on these types 
of samples will depend on several factors such as, but not limited to; amount and quality of 
tissue, format (slides vs. block), etc. 
 
4.6 
Primary Safety Outcomes/Endpoints 
 
Safety will be assessed through patient reported and investigator observed AE’s. This will also 
include physical examination and clinical laboratory tests. Specific attention will be placed upon 
injection site reactions and potential immune mediated AE’s.  
 
Injection Site Reactions will be graded using the NCI CTCAE v 4.03 (see Appendix E). 
 

 
 
 
 
 
 
 
 
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5 PARTICIPANT SELECTION AND WITHDRAWAL   
 
 
5.1 
Inclusion Criteria 
 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial.  
2. Male or female  ≥ 18 years of age on day of signing informed consent and of any 
racial or ethnic group  
3. Has:  
a. histologically proven DLBCL with recurrence after first, second or tertiary 
treatment regimens for DLBCL or,  
b. evidence of transformed lymphoma with past history of indolent lymphoma 
with current biopsy showing DLBCL) or,  
c. double hit or high grade lymphomas, including Burkitts lymphoma and High 
Grade B-Cell lymphoma unclassifiable (with features intermediate between 
Burkitts and diffuse large B cell lymphoma) 
4. Has had: 
a. recurrence requiring therapy at least 90 days post aggressive first line 
combination chemotherapy (e.g. RCHOP, Hyper-CVAD or other aggressive 
”curative” combination), autologous stem cell transplantation (ASCT), CART 
therapy, or aggressive second line combination therapy or,  
b. partial response or measureable disease after first line therapy (who are not 
candidates for ASCT) or after second or third line therapy without disease 
progression or, 
c. recurrence any time after non-aggressive combination or single agent therapy 
with or without Rituximab  (i.e. CVP, CHL or, VP16) for first, second or third 
line disease or, 
d. for subjects with transformed lymphoma, a treatment for indolent lymphoma 
within the last 2 years 
5. Have at least one measurable site of disease based on Cheson Criteria using 
standard CT imaging.  
6. Be willing to provide tissue from a newly obtained (up to 3 months + 7 days prior to 
Study Day 0) biopsy of a tumour lesion. If this is not available, the patient must be 

 
 
 
 
 
 
 
 
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willing to undergo a core biopsy prior to starting treatment.  They must also be willing 
to provide an on-treatment biopsy.  
7. Have a performance status of 0-1 on the ECOG Performance Scale. 
8. Demonstrate adequate organ function as defined in Table 2, within 48 hours prior to 
receiving the first dose of study medication (SD0).   Patients with abnormal liver 
enzymes of up to 5 times the upper limit of normal and/or reduced GFR of 50-100% 
normal range can be considered for enrolment if the alteration is due to lymphoma.  
9. Previous localized surgery, radiotherapy, chemotherapy, and immunotherapy more 
than 21 days prior to SD0. Cyclophosphamide, up to 100 mg/day, may be 
administered until SD-1 for subjects already receiving as a single agent therapy. 
10. A life expectancy > 6 months. 
11. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 48 hours prior to receiving the first dose of study medication (SD0).  
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.   
12. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication. Subjects of 
childbearing potential are those who have not been surgically sterilized or have not 
been free from menses for > 1 year.  
13. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through to 120 days from the last dose of study 
medication. 
14. Ability to comply with protocol requirements. 
 
Table 2: Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count 
(ANC) 
≥1,000/mcL 
Platelets 
≥50,000/mcL 
Hemoglobin 
≥8 g/dL or ≥5.6 mmol/L without EPO dependency  
Renal 
 
Serum creatinine OR 
Measured or calculateda 
creatinine clearance 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 

 
 
 
 
 
 
 
 
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(GFR can also be used in place 
of creatinine or CrCl) 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN Unless history of Gilbert’s disease OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
Activated Partial 
Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
 
5.2 
Exclusion Criteria 
 
The subject must be excluded from participating in the trial if the subject:  
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 21 days of the first dose of treatment (SD0).  
2. Patients eligible for possible curative therapies such as ASCT. 
3. LDH greater than 5 times the upper limit of normal47. 
4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 35 days prior to the first dose of trial 
treatment (SD0), except that used as pre-medication for chemotherapy or contrast-
enhanced studies are eligible. Subjects may be on physiologic doses of replacement 
prednisone or equivalent doses of corticosteroid (<10 mg daily). 
5. Has had previous allogeneic stem cell transplant 
6. Has known active TB (Bacillus Tuberculosis) 
7. Hypersensitivity to pembrolizumab or any of its excipients. 
8. Has had a prior anti-cancer monoclonal antibody (mAb) within 21 days prior to SD0 
or who has not recovered (i.e., ≤ Grade 1) from adverse events due to agents 
administered more than 21 days earlier. 

 
 
 
 
 
 
 
 
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9. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 21 days prior to SD0. Subjects must have recovered from all acute toxicities 
from prior treatments; peripheral neuropathy must be ≤ grade 2. 
10. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include in situ cervical cancer, basal cell carcinoma of the skin or 
squamous cell carcinoma of the skin that has undergone potentially curative therapy. 
11. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided; they are stable (without evidence of progression by imaging) for at least 
four weeks prior to the first dose of trial treatment; and any neurologic symptoms 
have returned to baseline; have no evidence of new or enlarging brain metastases; 
and are not using steroids for at least 35 days prior to trial treatment.  
12. Progressive CNS lymphoma requiring treatment within 35 days prior to SD0. 
13. Has history of active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment. 
14. Has known history of, or any evidence of active, non-infectious pneumonitis. 
15. Thyroiditis within the past 5 years. 
16. Has an active infection requiring systemic therapy.  Subjects completing a course of 
antibiotic for acute infection 7 days prior to SD0 and who do not experience a 
recurrence of symptoms or fever are eligible. 
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
18. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
19. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with screening visit to 120 days after last dose 
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20. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
21. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
22. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).  Evidence of Hepatitis B surface antigen without 
transaminitis is allowed provided patient is treated with anti-viral therapy (Heptavir or 
Tenofovir). 
23. Patients who have received prior survivin based vaccines.  
24. Acute or chronic skin disorders that will interfere with subcutaneous injection of the 
DPX-Survivac or subsequent assessment of potential skin reactions. 
25. Serious intercurrent chronic or acute illness, such as cardiac disease (New York 
Heart Association class III or IV), hepatic disease, or other illness considered by the 
investigator as an unwarranted high risk for an investigational product. 
26. Allergies to any vaccine, that after discussion with the medical monitor are serious 
enough to warrant exclusion from this study.  
27. Received a live vaccine within 30 days of planned start of study therapy. Seasonal 
influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed 
5.3 
Participant Recruitment  
Patients considered suitable for study selection will be identified by the site investigators at each 
participating site. Patients may be identified from the local population of patients or from 
referrals from other physicians aware of the trial. 
5.3.1 Randomization Procedures (if applicable) 
 
All  enrolled subjects will be receiving the same treatment and will be accrued without pause. 
5.3.2 Blinding and Unblinding Procedures (if applicable) 
 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.4 
Participant Withdrawal and Discontinuation of IP 
5.4.1 Reasons for Withdrawal from study or Discontinuation of IP 
 
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discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative reasons.  Participants whose cancer progresses or who 
experience other adverse effects that negatively impact patient safety, will be discontinued from 
IP and study participation.  These subjects will be considered to be withdrawn from the study, 
and to have completed their study participation, excluding follow-up contact or health review 
(survival) as permitted by consent.  
 
A subject may be withdrawn from the trial for any of the following reasons: 
• 
The subject or legal representative (such as a parent or legal guardian) 
withdraws consent. 
• 
Investigator’s decision to withdraw the subject. 
• 
The subject has a confirmed positive serum pregnancy test. 
• 
Noncompliance with trial treatment or procedure requirements. 
• 
The subject is lost to follow-up. 
• 
Administrative reasons. 
 
A subject must be discontinued from IP and the trial for any of the following reasons: 
• 
Disease progression at any time after study entry if the treating physician 
feels that some other treatment is indicated based upon standard clinical 
practice parameters. 
• 
Serious adverse experiences as described in Sections 8.2. or 8.3 or life 
threatening reactions secondary to active immunotherapy. 
• 
Intercurrent illness that prevents further administration of treatment. 
• 
Other reasons not listed. 
 
5.4.2 Subject Replacement Strategy 
 
If a subject is removed from the trial prior to the completion of 4 doses of pembrolizumab,  3 
injections of DPX-Survivac and an on-treatment CT scan between study days 70-104, that 
subject may be replaced to determine the efficacy of treatment in a minimum of 16 subjects. 
 
5.4.3 Clinical Criteria for Early Trial Termination 
 
Early trial termination will be the result of the criteria specified below: 
 
1. Quality or quantity of data recording is inaccurate or incomplete. 
2. Poor adherence to protocol and regulatory requirements. 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects, such as: 
 
• 
Two or more grade 4 SAEs possibly, probably or definitely related to 
pembrolizumab or DPX-Survivac.  
 

 
 
 
 
 
 
 
 
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• 
Any single death, possibly, probably or definitely related to pembrolizumab or 
DPX-Survivac. 
 
4.   Plans to modify or discontinue the development of the study drugs. In the event that 
Merck or IMV decide to no longer supply study drugs, ample notification will be provided 
so that appropriate adjustments to subject treatment can be made. 
 
5.4.4 Data Collection & Follow-up for Withdrawn/Discontinued Subjects 
 
A subject will be permitted to delay a visit up to two weeks or omit a visit before being taken off 
study.   
 
If the subject is discontinued from IP and study participation, the reason(s) for discontinuation 
should be clearly documented. When a subject is discontinued from the study after the first dose 
of pembrolizumab or DPX-Survivac, an end of study (EOS) visit should be completed prior to 
initiating another treatment. This visit will allow collection of data necessary to define events 
leading up to discontinuation.  A full follow up visit (as outlined in Section 7.4.25) should be 
scheduled and completed 30 days after the last DPX-Survivac and pembrolizumab 
administration, and again at 90 days after the last pembrolizumab infusion, whenever possible.   
 
When a subject withdraws, or is withdrawn from the study, whenever possible and irrespective 
of the reason for withdrawal, the subject should be examined as soon as possible with an end-
of-study (EOS) visit (as outlined in Section 7.4.24).  In the event that a subject withdraws from 
the study, prior to initiating another treatment, the subject will be requested to have 
approximately 90 mL of blood drawn for immunologic testing.  If the subject agrees, they should 
also complete a follow up visit (as outlined in Section 7.4.24) at 30 days after the last DPX-
Survivac and pembrolizumab administration, and again at 90 days after the last pembrolizumab 
infusion to ensure patient safety. There will be no further study visits scheduled.  If a subject 
does not return for a scheduled visit, every effort should be made to contact the subject.  For 
each subject, every effort should be made to document subject outcome. In addition, a chart 
review will be performed at 6 months and 12 months after the end of their trial participation to 
obtain survival data. If a biopsy is performed just after trial discontinuation as part of standard of 
care and before the commencement of another therapy, efforts will be made to obtain samples 
of this biopsy, with the consent of the patient, for the purpose of additional 
immunohistochemistry testing and analysis. 
 
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6 INTERVENTIONS  
6.1 
Investigational Product  
6.1.1 Acquisition Formulation and Packaging  
 
The site investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
The DPX-Survivac and pembrolizumab and  18F-fluorodeoxyglucose will comply with Health 
Canada requirements for investigational products.  The cyclophosphamide will be received with 
commercial labels.  
 
The DPX-Survivac labels will comply with FDA and Health Canada requirements for IP’s, will be 
in local languages, and will state that use is limited by federal law to investigational use only. 
 
A. 
Pembrolizumab 
 
Clinical Supplies will be provided by Merck as summarized in Table 3. 
 
Table 3 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
B. 
DPX-Survivac composition 
 
The clinical formulation will consist of two vials provided by IMV.  Vial 1 contains the 
lyophilized formulated drug substance, and vial two contains Montanide ISA 51 VG 
(Seppic) which is used as a diluent and comprised of mannide monooleate and 
mineral oil.  Vials 1 and 2 will be mixed prior to injection (Table 4).   
 
Table 4 DepoVax Formulation 
Vials 
Component 
Vial 1 (lyophilized) 
Liposome  
Phosphotidyl choline: DOPC synthetic lipid (GMP 
grade) 
Cholesterol: Sheep’s wool, high purity, non-BSE 
countrites (GMP grade) 
Polynucleotide immunostimulant (didC) 
Short synthetic polynucleotide (GMP grade) 
Antigen (MHC Class II, T-helper) 
Tetanus toxoid peptide A16L: AQYIKANSKFIGITEL 
(GMP grade) 
Antigens (MHC Class I, Tumour specific) 
Five synthetic peptides targeting survivin, see Table 1 
(GMP grade)  

 
 
 
 
 
 
 
 
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Vial 2 (oil diluent) 
Hydrophobic carrier (oil diluent) 
Montanide ISA51 VG (GMP grade) 
 
Lipids 
The lipids are composed of a mixture of the synthetic phosphatidylcholine molecule DOPC 
in a 10:1 (w:w) ratio with cholesterol.  This mixture is supplied as a blend from the supplier, 
Lipoid GmbH (Ludwigshafen, Germany) and is used without further processing.   
 
Polynucleotide immunostimulant 
IMV has demonstrated the enhanced efficacy of DepoVax formulations containing a 
synthetic polynucleotide-based immunostimulant in nonclinical cancer models.  The 
synthetic short polynucleotide (less than 30 bases) contained in DPX-Survivac is the same 
as that used in DPX-0907.  This adjuvant is favored over others for several reasons: 1) it is 
effective in tumour challenge models, 2) it can be produced by chemical synthesis and is 
characterizable by several analytical techniques, and 3) it has been used in clinical trials. 
 
T-helper Peptide 
A peptide from the tetanus toxoid, A16L (TT829-843), is included in all formulations of 
DepoVax-based products.  The T-helper epitope A16L has been used extensively in the 
clinic.  
 
Survivin Antigens for DPX-Survivac  
The five survivin peptides within DPX-Survivac were licensed from Merck KGaA and 
originally developed as Survivac.  The Survivac product was formulated by emulsifying an 
aqueous mixture of the peptides with Montanide ISA 51 VG.  The peptides range between 9 
and 10 amino acid residues.   
 
Oil Diluent  
The oil component, sterile Montanide ISA51 VG, will be provided for the treatment pre-
packaged in 3 mL vials by the supplier, Seppic (Paris, France).  It is composed of mannide 
monoleate in a mineral solution and is a clear viscous, slightly yellow liquid that is stable at both 
room temperature and 4oC.  The oil is non-animal based and has been used for both DPX-
Survivac and DPX-0907 formulations (phase 1 trials).  The oil has also been extensively used in 
other cancer vaccine clinical trials (phase I and II).  
 
C. 
18F-fluorodeoxyglucose (FDG) 
 
Commercially available (i.e. Health Canada approved) FDG will be sourced from Canadian 
market by the clinical sites and used and handled according to the manufacturer’s instructions.   
 
 
D. 
Cyclophosphamide (Non-Investigational) 
 
Commercially available (i.e. Health Canada approved) cyclophosphamide 50 mg will be 
provided by the clinical sites and used and stored according to the manufacturer’s instructions.   
 
 

 
 
 
 
 
 
 
 
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6.1.2 Treatment Assignment Procedures 
 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
 
6.1.3 Dosage, Preparation and Administration  
 
The treatment to be used in this trial is outlined below in Table 5. 
 
Table 5: Trial Treatment 
Drug 
Dose 
Frequency 
Route 
of 
Administration 
Regimen 
Pembrolizumab 
200 mg 
18 doses 3 weeks 
apart  
IV infusion 
Study Days  7, 28, 
49, 70, 91, 112,133, 
154, 175, 196, 217, 
238, 259, 280, 301, 
322, 343, 364 
DPX-Survivac 
0.5 mL 
2 doses 21 days apart 
Subcutaneous* 
 
Study Days 7 and 28 
0.1 mL  
6 doses 8 weeks apart  
Study Days 84, 140, 
196, 252, 308, 364 
Cyclophosphamide 
50 mg 
BIDt 
orally 
Study Days 0-6 then 
7 days off and 7 days 
on. This sequence 
will be repeated for 
the duration of the 
study. 
 
*alternating legs in the upper thigh region. Details provided in the Manual of Operations 
t if starting platelet value is between 50 and 75 k then starting dose will be 50 mg daily 
6.1.3.1 Timing of Dose Administration 
 
Trial treatment should be administered according to schedule of events (Appendix B).   
 
Visits can occur +/- 3 days of the protocol-specified day and over the course of 2 days, except 
for visit 1 (SD0) and visit 2 (SD7) which must be 7 days apart.   
 
Pembrolizumab 200 mg will be administered as a 30 minute  (-5 min/+10 min) IV infusion every 
3 weeks.   
 
On injection days, subjects will be monitored with blood pressure, pulse, and temperature 
assessments at pre-injection, and at approximately 15 +/- 5 minutes after injection.  

 
 
 
 
 
 
 
 
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Low dose cyclophosphamide (50 mg twice a day) will be taken orally.  Cyclophosphamide will 
be dispensed according to institutional guidelines. Cyclophosphamide will be taken, starting on 
SD0, for 7 days prior to the first injection and then continuing for 7 days off. This schedule will 
be continued throughout the length of the study. Cyclophosphamide compliance should be 
completed by site staff, and is calculated when the drug is returned after each cycle, or as per 
institutional guidelines. Subjects may be withdrawn from the trial if they miss more than 50% of 
the tablets during either the priming or maintenance cycles of treatment. The dose of 
cyclophosphamide may be reduced as described for hematologic toxicity.   
6.1.4 Dose Selection/Modification 
 
The rationale for selection of doses to be used in this trial is provided in Section 2.5.2.   
 
Details on preparation and administration of pembrolizumab (MK-3475) and DPX-Survivac are 
provided in the Pharmacy Manual.   
6.1.4.1 DPX-Survivac 
 
If a subject experiences any grade 2 or greater injection site reaction(s) or any grade injection 
site ulceration within 4 weeks prior to an injection time point, that has not resolved to a grade 1 
or better, the injection will be omitted.  The omitted injection can be given up to one week after 
the initial omission, provided the injection site reaction has resolved to a grade 1 or better. If an 
injection was missed/ omitted, continue on the injection schedule, as per the Schedule of Events 
(Appendix B). This same evaluation will be repeated at each injection time point. All other study 
procedures scheduled for that clinic visit will still be conducted including the ongoing 
administration of the oral cyclophosphamide and the pembrolizumab infusion. Investigators are 
strongly encouraged to contact the study Sponsor on the day of injection to discuss cases of 
concern.  
 
If two consecutive grade 3 injection site reactions occur in the same subject, it is up to the 
investigator’s discretion whether to continue with DPX-Survivac (after the reaction has resolved 
to a grade 1 or better) or to stop all further injections for that subject due to safety concerns.  
The investigator should contact the study Sponsor if a grade3 injection site reaction or any 
grade injection site ulceration occurs. 
 
In the event that an individual’s immune response has dropped or is not being maintained at the 
level of their initial response (as measured by the severity of their injection site reaction(s), or 
observation of an injection site induration – a hallmark of DPX-Survivac immune therapy) they 
should be given a “re-priming” dose of 0.5 mL DPX-Survivac instead of the planned 0.1 mL 
maintenance injection. If the immune response has not returned to the expected level, and/or 
injection site induration is not observed within 4 weeks of the re-priming dose, subjects will 
receive another re-priming dose in place of their next scheduled maintenance injection.  All 
other study related procedures at this visit will remain as per protocol. Re-priming doses should 
only be substituted for 2 consecutive maintenance injections. If the subject is not showing signs 
of immune response, the site should contact the Sponsor for guidance and approval of 
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Table 6: Dose Modification Guidelines for Drug-Related Adverse Events for DPX-
Survivac 
 
 
Severity (Grade) 
Treatment Modification 
Injection Site Reaction 
Grade 2 or greater 
Hold DPX-Survivac until 
resolved to Grade 1 or 
better.  
Reassess at each visit. 
Administer DPX-Survivac if 
within 1 week of omitted 
injection. 
Injection Site Ulceration 
Any grade within 4 
weeks of next 
injection 
 
 
 
 
6.1.4.2 Pembrolizumab and Combination Therapy    
 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure, 
including coadministration with additional compounds, may represent an immunologic etiology.  
These adverse events may occur shortly after the first dose or several months after the last 
dose of treatment/combination therapy, and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical study data, most AEs were reversible and could be 
managed with interruptions of pembrolizumab/combination treatment, administration of 
corticosteroids and/or other supportive care. For suspected AEs, ensure adequate evaluation to 
confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. 
 
See Table 7 for the dose modification guidelines for pembrolizumab/combination therapy related 
adverse events. Events not listed below are to be discussed with the Sponsor, and may require 
additional medical guidance from Merck. Infusions should follow that outlined in the  Schedule of 
Events (Appendix B). A missed or omitted dose of pembrolizumab may be given a maximum of 
+3 days after originally scheduled, and if the omission was due to an Adverse Event, the AE 
should be resolved to Grade 1 or better before administration.  
 
Tapering up or down of pembrolizumab is prohibited. Pembrolizumab should always be given at 
the full and intended dose (200 mg). 
 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events and/or unforeseen circumstances not related to study intervention. 
However, intervention is to be restarted within 3 weeks of the originally scheduled dose and 
within 42 days of the previously administered dose, unless otherwise discussed with the 
Sponsor. The reason for study intervention interruption is to be documented in the participant 
study record. 
 
Attribution of Toxicity: 

 
 
 
 
 
 
 
 
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When study interventions are administered in combination, attribution of an adverse event to a 
single component is likely to be difficult.  Therefore, while the investigator may attribute a toxicity 
event to the combination, to DPX-Survivac or Cyclophosphamide alone, or to pembrolizumab 
alone, for adverse events listed in Table 7, both interventions must be held according to the 
criteria in Table 7 Dose Modification and Toxicity Management Guidelines for Immune-Related 
Adverse Events Associated with Pembrolizumab Monotherapy and IO Combination. 
Holding Study Interventions: 
When study interventions are administered in combination, if the AE is considered immune-
related, both interventions should be held according to recommended dose modifications. 
Restarting Study Interventions: 
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 7. 
• 
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study interventions. 
 
If the toxicities do resolve and conditions are aligned with what is defined in Table 7, the 
combination of DPX-Survivac, cyclophosphamide and pembrolizumab may be restarted at the 
discretion of the investigator. In these cases where the toxicity is attributed to the combination or 
to DPX-Survivac or cyclophosphamide alone, re-initiation of pembrolizumab as a monotherapy 
may be considered at the principal investigator’s discretion .] 
 
Table 7: Dose Modification Guidelines for Immune-Related Adverse Events for  
Pembrolizumab Monotherapy and IO combination (March 2021) 
 
*note that this guidance uses CTCAE V5.0 as per the manufacturer guidance, however, for consistency in the 
trial, we will continue to use CTCAE v4.03 (see Appendix C). 
 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. 
Other immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to 
≤ Grade 1 after corticosteroid taper. 
 
irAEs 
Toxicity Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
•  Administer corticosteroids 
(initial dose of 1 to 
•  Monitor participants for signs 
and symptoms of 

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

 
 
 
 
 
 
 
 
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equivalent) followed by 
taper 
enzyme value returned to 
baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
•  Administer corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone or 
equivalent) followed by 
taper 
T1DM or 
Hyperglycemia 
New onset T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold d 
•  Initiate insulin replacement 
therapy for participants 
with T1DM 
•  Administer 
antihyperglycemic in 
participants with 
hyperglycemia 
 
•  Monitor participants for 
hyperglycemia or other signs 
and symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 
•  Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated 
•  Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism 
and adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Continue 
•  Treat with nonselective 
beta-blockers (eg, 
propranolol) or 
thionamides as 
appropriate 
•  Monitor for signs and 
symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
•  Initiate thyroid replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per standard 
of care 
•  Monitor for signs and 
symptoms of thyroid 
disorders 
Nephritis: 
grading 
Grade 2 
Withhold 
•  Administer corticosteroids 
•  Monitor changes of renal 

 
 
 
 
 
 
 
 
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according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 3 or 4 
Permanently 
discontinue 
(prednisone 1 to 2 mg/kg 
or equivalent) followed by 
taper 
function 
Neurological 
Toxicities 
Grade 2 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, TEN, 
or DRESS 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation 
to confirm etiology or 
exclude other causes 
Confirmed SJS, TEN, 
or DRESS 
Permanently 
discontinue 
All Other irAEs 
Persistent Grade 2 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation 
to confirm etiology or 
exclude other causes 
Grade 3 
Withhold or 
discontinue 
based on the 
event e  
Recurrent Grade 3 or 
Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology 
Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; 
IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes 
mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x 
ULN if baseline normal; >3.0 to 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to:encephalitisand other clinically important irAEs. 
 
 
† ULN = Upper Limit of Normal 
*If corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks or a 
treatment-related toxicity does not resolve to Grade 0-1 within 12 weeks after last dose of Pembrolizumab, then 
Pembrolizumab should be permanently discontinued 
 

 
 
 
 
 
 
 
 
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6.1.4.3 Cyclophosphamide 
 
Possible side effects from low dose cyclophosphamide are: grade 1 nausea and/or vomiting, 
grade 1 and 2 anemia, neutropenia, leukopenia, and lymphopenia as well as low-grade fatigue. 
 
If platelet levels decrease below 75,000/mm3 or if absolute neutrophil count decreases below 
1000/mm2 in any cycle, then the dose of cyclophosphamide can be reduced to 50 mg once daily 
in that subject once neutrophils increase and severity is reduced to grade 2 or better.  Growth 
factors  may be used if grade 3 or 4 neutropenia occurs even after dose reduction of 
cyclophosphamide.  For ongoing grade 3 or 4 neutropenia not responsive to dose reduction and 
growth factor support, cyclophosphamide may be discontinued after discussion with the 
Sponsor.  The role of pembrolizumab and holding pembrolizumab needs to be considered 
for refractory neutropenia not responsive to the above measures.   
 
Grade 3 or 4 thrombocytopenia and or anemia may be managed with transfusions as required 
and dose reduction of cyclophosphamide (50 mg daily) after anemia or thrombocytopenia has 
recovered to grade 2 or better. 
 
If Cyclophosphamide was reduced to 50 mg for an adverse event which has since resolved to 
grade 1 or better, it can be increased to the expected dose (100 mg daily) if, in the opinion of 
the investigator, it would benefit the subject to do so. 
 
6.1.4.4 Dosing Interruption 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 2 weeks of the 
scheduled interruption, or up to 4 weeks at the discretion of the study Sponsor. The reason for 
interruption should be documented in the patient's study record. 
6.1.5 Receiving, Storage, Dispensing and Return 
6.1.5.1 Receipt of Investigational Product 
 
Upon receipt of the investigational product and/or study supplies, an inventory must be 
performed and a receipt log filled out and signed by the research team member accepting the 
shipment.  It is important that the designated study staff counts and verifies that the shipment 
contains all the items noted in the shipment inventory.  Any damaged or unusable product in a 
given shipment will be documented in the study files.  The site must notify the study Sponsor of 
any damaged or unusable product that was supplied to the site. Additional instructions are 
supplied by the manufacturer with each shipment and can also be found in the Manual of 
Operations. 
 
 

 
 
 
 
 
 
 
 
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6.1.5.2 Storage and Stability 
 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  This includes 24 hour temperature monitoring, and logs 
maintained by pharmacy staff. 
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
• 
Pembrolizumab will be stored under refrigerated conditions (2° to 8°C). Protect 
from light. Do not freeze. Do not shake. 
 
• 
A bulk supply of DPX-Survivac Vial 1 will be provided in a box to be stored at 2 to 
8 °C in the pharmacy.   Vial 2 (oil diluent) and the ancillary components will be 
stored at ambient temperature.  
 
• 
Cyclophosphamide will be stored according to the storage conditions in the 
package insert.   
6.1.5.3 Dispensing of Investigational Product 
 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck and IMV or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial.  
6.1.5.4 Return and/or Destruction of Investigational Product 
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product provided by Merck or designee will be destroyed at the site per institutional policy. It is 
the Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept.  
 
IMV must be contacted prior to destruction of any unused and/or partially used clinical trial 
material provided by them. 
6.2 
Concomitant Medications (Acceptable & Prohibited) 
 
Medications specifically prohibited in the exclusion criteria are not allowed during the subject’s 
participation in the trial.  If there is a clinical indication for one of these or other medications, 
therapies or vaccinations specifically prohibited during the trial, discontinuation from trial therapy 
may be required.  The investigator should discuss any questions regarding this with the study 
Sponsor. The final decision on any supportive therapy rests with the investigator and/or the 

 
 
 
 
 
 
 
 
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subject's primary physician.  
6.2.1.1 Acceptable Concomitant Medications 
 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medications and/or therapies will be recorded on the case report 
form (CRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date should also be included on the CRF. 
 
Erythropoietins or granulocyte stimulating factors are acceptable if felt necessary by the treating 
physician. 
 
All concomitant medications received from the date of consent to the last dose of trial treatment 
should be recorded.  Specifically these include systemic steroid therapy or any other form of 
immunosuppressive therapy within 35 days prior to the first dose of trial treatment (SD0), except 
those used as pre-medication for contrast-enhanced studies are eligible. Subjects may be on 
physiologic doses of replacement prednisone or equivalent doses of corticosteroid (<10 mg 
daily). Concomitant medications administered after 30 days after the last dose of trial treatment 
should be recorded as per the guidance of follow-up visits for SAEs and Events of Clinical 
Importance (ECIs).   
 
6.2.1.2 Prohibited Concomitant Medications 
 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
 
• 
Antineoplastic systemic chemotherapy or biological therapy  
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than pembrolizumab, DPX-Survivac, low dose 
metronomic cyclophosphamide 
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited 
to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, 
rabies, BCG, and typhoid vaccine.  
• 
No adjuvant vaccine or live attenuated vaccine (such as Flumist) should be 
given while on this study.  Non-adjuvant vaccines (such as most influenza 
vaccines) can be given.  For subjects receiving the flu vaccine, study Sponsor 
strongly recommends the shot be given at least one week before 
immunological assessments (such as investigational blood draw) and DPX-
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• 
Systemic glucocorticoids for any purpose other than to modulate symptoms 
from an event of clinical interest of suspected immunologic etiology.  The use 
of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial, with the 
exception of systemic corticosteroids as described in section 6.1.6.1, or as part of rescue 
medication.  Subjects may receive other medications that the investigator deems to be 
medically necessary.  
 
The Exclusion Criteria describes other medications which are prohibited in this trial. These 
include systemic steroid therapy or any other form of immunosuppressive therapy within 35 
days prior to the first dose of trial treatment (SD0), except that used as pre-medication for 
contrast-enhanced studies are eligible. Subjects may be on physiologic doses of replacement 
prednisone or equivalent doses of corticosteroid (<10 mg daily). 
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
6.3 
Rescue Medications & Supportive Care 
6.3.1.1 Supportive Care Guidelines 
 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to pembrolizumab. 
 
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance as outlined below. Refer to Section 6.1.4 for dose 
modification.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. These, and the respective results, should 
be recorded in the Source and Case Report Forms. 
 
Pneumonitis:  
 

 
 
 
 
 
 
 
 
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• 
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
• 
For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
• 
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
Diarrhea/Colitis:  
 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
 
• 
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis. 
• 
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer 
oral corticosteroids.  
• 
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with 
intravenous steroids followed by high dose oral steroids.   
• 
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) 
or ≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA): 
 
• 
For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 
Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
Hypophysitis: 
 
• 
For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks. Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
• 
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 

 
 
 
 
 
 
 
 
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Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
 
 
 
Hyperthyroidism or Hypothyroidism:  
 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
 
• 
Grade 2 hyperthyroidism events (and Grade 3-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
• 
Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
Hepatic: 
• 
For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 
Treat with IV or oral corticosteroids 
• 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.  
• 
When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks. 
 
Renal Failure or Nephritis: 
• 
For Grade 2 events, treat with corticosteroids. 
• 
For Grade 3-4 events, treat with systemic corticosteroids. 
• 
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.  
 
Management of Infusion Reactions: Signs and symptoms usually develop during 
or shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
 
 
 
 

 
 
 
 
 
 
 
 
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Table 8, below, shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
 
 
Table 8: Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically 
stable in the opinion of the 
investigator. 
None 

 
 
 
 
 
 
 
 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent 
dosing 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically 
stable in the opinion of the 
investigator. 
If symptoms resolve within one 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be 
held until symptoms resolve and 
the subject should be 
premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued 
from further trial treatment 
administration. 
Subject may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of study 
intervention with: 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 

 
 
 
 
 
 
 
 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent 
dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically 
stable in the opinion of the 
investigator. 
Hospitalization may be 
indicated. 
Subject is permanently 
discontinued from further trial 
treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
 
 
At the discretion of the study team, the subjects may remain for an additional 30 minutes to 1 
hour for observation.  Diphendydramine 50 mg, solumedrol 100 mg, and epinephrine 1:1000 (1 
mL) and a code cart must be readily available for emergency use.  If hypotension (systolic blood 
pressure (SBP) <90 mmHg for subjects with a baseline SBP >110 mmHg or >20 mmHg 
decrease for those with a baseline SBP <110 mmHg), urticaria, orofacial or laryngeal edema, or 
bronchospasm occur, an intravenous catheter will be placed and the diphendydramine 50 mg 
and solumedrol 100 mg will be administered.  The physician in charge will be notified and the 
epinephrine will be administered for reactions that do not begin to resolve within 10 minutes or 
continue to become more severe.  In this event, subject will be transported immediately to the 
emergency room if stabilized, or the code team will be contacted if subject continues to have 
progression of symptoms or worsening hypotension.    
 
Possible immediate side effects from injections, including DPX-Survivac, may include allergic 
reactions such as fever, hives, or rash.  For fever >101.5 oF (>39 oC), acetaminophen (650 mg) 
may be given orally.  The induction of autoimmunity (manifests as arthritis, serositis, nephritis, 

 
 
 
 
 
 
 
 
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thyroiditis, colitis, neutropenia, etc.) is theoretically possible.    Delayed events such as rash or 
hives maybe treated with diphenhydramine (25-50 mg); topical steroids should not be given 
without consultation with the study’s principle investigator. 
 
For possible infected injection site reactions, proper wound care is appropriate.  It is 
recommended that infected areas should be kept clean and exposed.  Topical antibiotics such 
as fucidin or polysporin may be applied.  Cultures should be sent for infections and treated 
promptly with oral antibiotics. Topical corticosteroid (hydrocortisone ointment) may be used to 
help reduce inflammation. 
 
Possible side effects from Montanide ISA 51 VG are granuloma, abscess, and fever.  
Acetaminophen 650 mg every 4 hours may be given for fever after appropriate blood cultures 
are taken.  Referral to a surgeon is encouraged for abscess. 
 
6.4 
Diet/Activity/Other Considerations 
6.4.1.1 Diet 
 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea, dehydration or vomiting. 
6.4.1.2 Contraception 
 
Pembrolizumab or DPX-Survivac may have adverse effects on a fetus in utero.  Furthermore, it 
is not known if pembrolizumab or DPX-Survivac has transient adverse effects on the 
composition of sperm.  Non-pregnant, non-breast-feeding women may be enrolled if they are 
willing to use 2 methods of birth control or are considered highly unlikely to conceive.  Highly 
unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is 
≥45 years of age and has not had menses for greater than 1 year will be considered 
postmenopausal), or 3) not heterosexually active for the duration of the study.  The two birth 
control methods can be; two barrier methods; or a barrier method plus a hormonal method to 
prevent pregnancy. Subjects should start using birth control from study Visit 1 throughout the 
study period until 120 days after the last dose of study medication. 
 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study, subjects must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in Section 8.4.1:Reporting of Pregnancy 
and Lactation to the Sponsor. If there is any question that a subject will not reliably comply with 
the requirements for contraception, that subject should not be entered into the study. 

 
 
 
 
 
 
 
 
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6.4.1.3 Use in Nursing Women 
 
It is unknown whether pembrolizumab or DPX-Survivac is excreted in human milk.  Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions in 
the nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
6.5 
Administration of Intervention 
Subjects will attend on their assigned day. They will have blood samples and physical 
examinations, including injection site assessment, as outlined in Schedule of Events (Appendix 
B).  Compliance with Cyclophosphamide will be reviewed routinely.  A record of concomitant 
medications/therapies and AE’s will be sought at each review.  Radiological imaging and repeat 
biopsies will be performed as detailed in the Schedule of Events (Appendix B).   Participants will 
receive DPX-Survivac and pembrolizumab in accordance with the product SPC.  There are no 
dietary restrictions or fasting requirements prior to treatment initiation or routine laboratory 
sample collection.  
6.5.1 Procedures for Intervention Training and Monitoring  
All QI’s at each study site will attend a study initiation meeting to ensure protocol, study 
requirements and data capturing processes are clearly understood. This will be completed prior 
to any study activity.  Study sites are responsible to ensure that existing and new staff are 
adequately trained, that training is documented and that they are delegated to the tasks for 
which they have been trained. 
6.6 
Assessment of Subject Compliance  
 
Subject compliance with study protocol will be assessed on a regular basis. This will be 
confirmed by study staff.  Subjects with less than 50% compliance with cyclophosphamide will 
be considered for withdrawal.  Compliance to DPX-Survivac and pembrolizumab will be 
determined by attendance for treatment.  

 
 
 
 
 
 
 
 
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7 STUDY SCHEDULE AND PROCEDURES 
 
The Schedule of Events (Appendix B) summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
See Section 7.5 for additional information on types of visits that may be considered an 
“Unscheduled Study Visit”. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor for 
reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1 
Administrative Procedures 
7.1.1 Informed Consent 
 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
 
7.1.2 Inclusion/Exclusion Criteria 
 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial.  
7.1.3 Medical History 
 
A medical history will be obtained by the investigator or qualified designee.  Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.1.4 Prior and Concomitant Medications Review 
7.1.4.1 Prior Medications 
 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 21 days 
before starting the trial.  Treatment for the disease for which the subject has enrolled in this 
study will be recorded separately and not listed as a prior medication.  
 
 

 
 
 
 
 
 
 
 
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7.1.4.2 Concomitant Medications 
 
The investigator or qualified designee will record medication, if any, taken by the subject during 
the trial.  All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 8. 
 
7.1.5 Disease Details and Treatments 
 
7.1.5.1 Disease Details 
 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.5.2 Prior Treatment Details 
 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments (maximum 3), radiation and surgeries.  
7.1.6 Assignment of Screening Number 
 
Subjects will be assigned a screening identification number after consenting to participate, as it 
will be used while documenting eligibility for the study.  This identification will consist of the site 
number followed by a hyphen and then chronologically defined digits.  Additional details can be 
found in the study Manual of Operations. 
 
7.1.7 Clinical Procedures/Assessments 
 
7.1.7.1 Adverse Event (AE) Monitoring 
 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs at each study visit and more frequently if clinically indicated.  Adverse 
experiences will be graded and recorded throughout the study according to NCI CTCAE v4.03 
(see Appendix E). Injection site reactions are considered adverse events and should be 
documented and evaluated using NCI CTCAE v 4.03 (see Appendix E). Injection Site Reactions 
are also to be graded by their individual events such as; pain, induration, erythema, edema and 
ulceration.   Toxicities will be characterized in terms regarding seriousness, causality, toxicity 
grading, and action taken with regard to trial treatment.  
 
Please refer to Section 8 for detailed information regarding the assessment and recording of 
AEs.   
7.1.7.2 Full Physical Exam 
 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant or abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening, and as per the Schedule of 
Events (Appendix B), prior to trial treatment administration at those visits. Investigators should 

 
 
 
 
 
 
 
 
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pay special attention to clinical signs related to previous serious illnesses. 
7.1.7.3 Directed Physical Exam 
 
For all other treatment days that do not require a full physical exam per the Schedule of Events 
(Appendix B), the investigator or qualified designee will perform a directed physical exam as 
clinically indicated, prior to trial treatment administration.  Investigators should pay special 
attention to clinical signs related to previous serious illnesses. 
 
7.1.7.4 Vital Signs 
 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each IP dose of trial treatment and at treatment discontinuation as specified in 
the Schedule of Events (Appendix B).  Vital signs should include temperature, pulse, respiratory 
rate, pulse oximetry, weight and blood pressure.  Height will be measured at screening only. 
7.1.7.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
 
The investigator or qualified designee will assess ECOG status (Appendix F) at Screening, 
disease staging (SD112 and SD196) and again at EOS (see Schedule of Events Appendix B).  
7.1.7.6 Tumour Imaging and Assessment of Disease 
 
Tumour imaging will be done during the screening period, at SD70 or SD91 (based on evidence 
of injection site reaction of grade 2 or higher or any grade ulceration at SD49), at SD175 and 
EOS or SD364, whichever comes first, to document progression using Modified Cheson Criteria 
(Appendix C). Tumour Imaging will be done prior to EOS visit or 30 days after any other 
suspected disease progression to rule out pseudo-progression and evaluate using IrRC 
(Appendix D) whenever possible. Tumour imaging will be performed based on the Modified 
Cheson Criteria (Appendix C). A maximum of six (6) target lesions, selected at Screening, will 
be followed through the course of the study. While only one tumour is required to meet the 
Modified Cheson Criteria for the purpose of eligibility, all tumours selected at screening for 
study follow through, should meet the Modified Cheson Criteria (Appendix C). Sites are 
encouraged to specify these instructions to radiologists. Additional guidance can be found in the 
Manual of Operations. 
 
7.1.7.7 Tumour Tissue Collection and Correlative Studies Blood Sampling 
 
Tumour biopsy samples will be collected for evidence of survivin expression and for other 
biomarker analyses. Samples will be collected during the screening period, and again while on-
treatment at approximately 3 months. If possible, samples will be collected from the participant 
soon after trial completion, as part of standard of care, and prior to the start of a new course of 
therapy. Samples, ideally 5 cores, will be processed and handled by the site pathology lab for 
study related procedures. The Lab Manual contains the specific instructions for sample 
collection and processing. The screening biopsy may be eliminated if a biopsy has been 
obtained within three months (+ 7 days) of SD0 and  FFPE slides and /or a tissue block are 

 
 
 
 
 
 
 
 
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available. Patients with less than 5 cores can still be included. 
 
Investigational Blood Draw (PBMC), for both routine monitoring and investigational assessment 
(HLA, Survivin levels, and PBMC T cell responses to survivin) will be obtained as per Schedule 
of Events (Appendix B). 
 
The samples may be stored for up to 5 years after the study is completed for future analysis as 
new immune monitoring assays are being developed.  Any sample not completely used in 
analysis will be destroyed after the 5 years has elapsed 
7.1.7.8 Laboratory Procedures/Assessments 
 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below, and further specified in Table 9. 
 
Laboratory tests for screening should be performed within 35 days prior to SD0. Laboratory 
samples will be taken again prior to enrollment (<48 hours of SD0) to confirm eligibility criteria 
for adequate organ function. After first infusion of pembrolizumab, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee for clinical significance prior to each dose of trial treatment.  
Blood draw for research tests (PBMCs and plasma isolation) may also be drawn at the same 
time as the pre-dose laboratory procedures, up to 72 hours prior to dosing as long as staff are 
available to process the PBMCs and plasma within 4 hours of collection. 
7.1.7.9 18F-Fluorodeoxyglucose (18F-FDG) Injection and PET Imaging  
 
PET imaging will be performed following the institutional standard protocol and guidelines. 5 
MBq/kg of 18FDG with a maximum dose of 12 mCi will be administered. Imaging will begin 60 
minutes post injection. The participant will be observed carefully throughout the scanning 
session. AE’s attributable to 18F-fluorodeoxyglucose have not been reported in previous studies 
that have used 18F-fluorodeoxyglucose (FDG) for PET imaging49. The risks associated with 18F-
fluorodeoxyglucose include discomfort, bruising, bleeding or clotting at the site of insertion of the 
intravenous catheter. These side effects occur occasionally.  All AEs experienced by the 
participants will be recorded and reported.  
 

 
 
 
 
 
 
 
 
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Table 9 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit  
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase 
(ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate 
aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase 
(LDH) 
Microscopic exam (If 
abnormal)  
Total triiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
  (CO2 or bicarbonate) 
results are noted 
Free thyroxine (T4) 
Absolute Lymphocyte Count 
Urine pregnancy test † 
Thyroid stimulating hormone 
(TSH) 
Red cell distribution width 
Uric Acid 
 
 HIV Ab* 
Mean corpuscular hemoglobin 
Calcium 
 
 Hepatitis BsAg* 
Mean corpuscular volume 
Chloride 
 
 Hepatitis C Ab* 
%Reticulocytes 
Glucose 
 
 Blood for correlative studies 
• 
Whole blood for HLA 
typing 
• 
Whole blood for 
PBMC isolation  
• 
Plasma for Survivin 
levels 
 
Phosphorus 
 
 
Potassium   
 
 
Sodium 
 
 
Magnesium 
 
 
Total Bilirubin 
 
 
Direct Bilirubin (If total 
bilirubin is elevated above 
the upper limit of normal) 
 
 
Total protein 
 
 
Blood Urea Nitrogen 
 
 
Creatinine 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
*  Not required but recommended if status unknown or unclear

 
 
 
 
 
 
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7.1.8 Immune Evaluations 
7.1.8.1 Blood Collection for Plasma Survivin levels 
 
Sample collection, storage and shipment instructions for plasma samples will be provided in the 
Laboratory Manual. 
 
The time points for  blood sampling are described in Schedule of Events (Appendix A & B).  
 
7.1.8.2 Blood Collection for PBMCs 
 
Sample collection, storage and shipment instructions for blood samples will be provided in the 
Laboratory Manual.  Peripheral Blood Mononuclear Cells (PBMC) will be collected for immune 
monitoring at the time points specified in the Schedule of Events (Appendix B). Blood samples 
will be processed by the local laboratory and frozen PBMC vials stored according to the 
Laboratory Manual. These will be used to assess antigen specific T cell responses. 
 
7.1.8.3 Blood Collection for HLA typing 
 
HLA typing will be performed at SD0 via blood test  by either a central or a local lab.  When 
sending a request for HLA-typing, the study staff will ask for two a low-resolution (2 digit) HLA 
typing or high resolution (4 digit) HLA-sub-typing. Note that subjects can be positive for one or 
more HLA super type.  If a patient has previously undergone HLA typing and subtyping at a 
certified laboratory and the documented results are available, then HLA typing and subtyping 
will not have to be repeated for study purposes. 
7.1.9 Other Procedures 
7.1.9.1 Injection Site Reaction Biopsy 
 
If the investigator feels a biopsy of an injection site reaction is warranted, the Sponsor should be 
contacted in advance to discuss the case. This biopsy would be used for additional immune 
profiling, which would be useful in addition to any clinical indications.  .  If a tissue biopsy is 
collected, it is recommended to include the following tests:  
 
• 
Sections of formalin fixed paraffin embedded (FFPE) tissue for standard H&E stain 
• 
Any other standard immunohistochemistry (IHC) method 
 
Samples may be sent for additional analysis if the participant consents. Before the collection of 
tissue sample, the subject has to explicitly agree to the donation of the tissue sample on the 
informed consent.  The samples may be stored for up to 5 years after the study is completed for 
future analysis as new immune monitoring assays are being developed.  Any sample not 
completely used in analysis will be destroyed after the 5 years has elapsed. 
7.1.10 Visit Requirements 
 
Visit requirements are outlined in Appendix B: Schedule of Events and detailed in Section 7.4.   
Specific procedure-related details are provided above in Section 7 – Study Schedule and 
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7.2 
Screening 
 
Subjects will be screened for eligibility between 35 and 1 day prior to the first day of treatment 
(SD0). Subjects must be off previous treatment for 21 days prior to SD0.  Fresh biopsy samples 
will be sent to a central lab for evaluation of survivin expression. This biopsy may be performed 
with an image-guided core biopsy.  Archived tumour samples may also be assessed for 
evidence of survivin expression but will not replace the pre-treatment biopsy unless obtained 
less than 3 months (+7 days) prior to SD0 and unless at least 10 FFPE slides or a tumour block 
are available.  
 
The CT scan results will need to show at least one site of measurable disease as per Cheson 
Criteria (2007). The site will be responsible for the initial selection of “target” nodes to be 
followed during the study.  
 
Survivin expression will be sent on tumour biopsy from the  screening tumour sample.  
Results of this will be collected but do not need to be obtained prior to enrollment into study. 
Lymphoma survivin expression is not an inclusion/exclusion critera.   Patients with survivin 
expression less than 10% will be analyzed for safety but will be analyzed separately for 
efficacy and will not be included in the efficacy evaluation for evaluable paitents. 
 
Assessments in Appendix A will be performed to assess the subject’s eligibility for the study.  
Assessments may occur over the course of multiple days within the screening period. Adverse 
Event recording begins at the time of consent. Any medical events occurring prior to screening 
will be captured as medical history. 
 
7.3 
Enrollment 
Potential candidates for the trial will be identified at local sites.  Subjects meeting the eligibility 
criteria can be enrolled into the study.  Study enrollment can only commence once the local site 
training has been completed.  The study will close to recruitment once 25 subjects have met the 
definition of “evaluable”, as defined by having received 4 doses of pembrolizumab and 3 
injections of DPX-Survivac and one on-treatment CT scan between SD70 and SD104.  
Lab results obtained during screening and used to determine adequate organ function as 
required to meet eligibility criteria # 6 (Table 2), can be used for subject enrollment, provided 
they are completed no more than 48 hours prior to SD0. If enrollment is the same day as SD0, 
laboratory results and SD0 physical exam, vitals and results from other procedures can be used 
for both purposes and do not need to be duplicated. However, if the date of enrollment will be 
different than SD0, physical exam, vitals, and all screening bloodwork will need to be repeated.  
It is highly reccommended that Enrollment and SD0 be the same day. 
 
At the time of Enrollment/Baseline, the following additional details will be obtained: 
7.3.1 Adverse Events/Concomitant Medications 
 
Any adverse events and concomitant medications since the commencement of screening will be 
collected at enrollment regardless of timeframe. 
 

 
 
 
 
 
 
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7.3.2 Disease Staging 
 
Disease staging: ECOG, LDH, physical exam, disease stage and modifiers, or other procedures 
as needed. These same assessments are to be used for disease re-staging throughout the 
study (SD112 and SD196) and EOS.  
7.3.3 Confirmation of Eligibility 
Investigator’s confirmation of eligibility should be documented as the date of enrollment, 
where the subject met all eligibility criteria. This does not need to be the same day as SD0, 
but is recommended. 
7.4 
Study Visits 
 
Once the subject’s eligibility has been confirmed, the subject will begin the study treatment at 
Visit 1/SD0 and continue in the treatment period for 1 year, up to Visit 23/SD364, followed by an 
End of Study Visit, 30 days after trial completion. Visit 1 (SD0) and Visit 2 (SD7) must occur 7 
days apart. All other study visits can occur +/- 3 days of the scheduled time. Blood tests can be 
performed 72 hours prior to visits if necessary (excluding SD0 and SD7).  
 
At the start of every visit during the treatment period, the following assessments will be 
conducted: 
 
• 
Blood for hematology and clinical chemistry (see Table 9) 
• 
Adverse events (AE)  
• 
Concomitant medications  
• 
Vital signs: temperature, pulse, pulse oximetry, respiratory rate, weight and 
blood pressure 
• 
Pregnancy verification (if subject is of childbearing potential as per eligibility 
criteria)  
• 
Cyclophosphamide Accountability (including compliance and dispensing as per 
institutional policy) 
 
7.4.1 
Visit 1 (SD0) 
 
The following assessments will be conducted at the start of the visit prior to cyclophosphamide 
dispensing:   
 
• 
Procedures listed in Section 7.4 
• 
PBMC blood draw (~ 90 mL)  
• 
Human leukocyte antigen (HLA) haplotype testing blood sample and 
subtyping (Not an eligibility requirement) 
• 
Aerial photograph of thighs* 
 
At the end of the visit, after all blood draws are completed and blood counts are confirmed as 
normal, the subject will be provided with cyclophosphamide and instructed to take it SD0 to SD6 
and to repeat taking the cyclophosphamide every second week. If the first dose is taken before 
2 pm, the subject should be instructed to take the evening dose of cyclophosphamide as 
instructed on the label.  However, if the first dose of cyclophosphamide is taken after 2 pm on 
SD0, then the subject should not take the second dose that day.  This will result in one extra 
tablet being returned at the next visit. 

 
 
 
 
 
 
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*The aerial photograph of the Left and Right thigh will be used as baseline to identify any marks 
on the skin that might confound the results of a suspected Injection Site Reaction.  
 
7.4.2 Visit 2 (SD7) 
 
The following assessments will be conducted at the start of the visit prior to injection: 
 
• 
Procedures listed in Section 7.4 
• 
PBMC blood draw (~ 90 mL)  
• 
Directed physical examination 
 
After these assessments, the subject will be administered a 0.5 mL priming dose of DPX-
Survivac as detailed in Section 6.1.3.  Vital signs will be collected approximately 15 +/- 5 
minutes after injection.   
 
At least 30 minutes following the injection of DPX-Survivac, the infusion of 200 mg 
pembrolizumab will begin.  The infusion will take place over a 30 minute (-5/+10) time period. 
 
7.4.3 Visit 3 (SD28) 
 
The following assessments will be conducted at the start of the visit prior to injection: 
 
• 
Procedures listed in Section 7.4 
• 
PBMC blood draw (~ 90 mL)  
• 
Directed physical examination 
• 
Injection site evaluation* (for injection #1 SD7)  
 
 
After these assessments, the subject will be administered a 0.5 mL injection as detailed in 
section 6.1.3.  Vital signs will be collected approximately 15 +/- 5 minutes after injection.   
 
At least thirty minutes following the injection, the infusion of 200 mg pembrolizumab will begin.  
The infusion will take place over a 30 minute (-5, +10 mins) time period. 
 
* Injection site evaluations for injection site reactions (ISRs) will be performed and graded using 
the NCI CTCAE version 4.03 criteria (see Appendix E).  ISRs must also be broken down and 
evaluated according to the individual “events”: pain, induration, erythema, edema and 
ulceration. Injection site number, location, grade and description must be recorded in the 
Source and Electronic Case Report Form (eCRF).  When applicable, measure and record the 
size of each ISR and each individual event as necessary. Close-up photographs of the ISR 
should be taken at each subsequent visit. Additional instruction on the expectations of ISR 
photographs can be found in the study Manual of Operations.   
 
7.4.4 Visit 4 (SD49) 
 
The following assessments will be conducted at the start of the visit prior to infusion: 
 
• 
Procedures listed in Section 7.4 
• 
PBMC blood draw (~ 90 mL)  

 
 
 
 
 
 
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• 
Directed physical examination  
• 
Injection site evaluation* (for injection #1 SD7 and injection #2 SD28) 
 
After these assessments, the infusion of 200 mg pembrolizumab will begin.  The infusion will 
take place over 30 minutes (-5, +10mins). 
 
*For those subjects who present at this visit with any grade 2 or greater ISR or any grade 
injection site ulceration, a routine CT scan will be scheduled for SD70 and a tumour 
biopsy will be scheduled between SD77 - SD83 (see Section 7.4.5).  A grade 2 ISR, or any 
grade ulceration that was observed before this visit, but has resolved to grade 1 or 
better, does not qualify for an early CT or biopsy. 
 
7.4.5 Visit 5 (SD70) 
  
The following assessments will be conducted at the start of the visit prior to infusion: 
 
• 
Procedures listed in Section 7.4 
• 
PBMC blood draw (~ 90 mL)  
• 
Complete or Directed Physical examination* 
• 
Injection site evaluation (for injection #1 SD7 and injection #2 SD28) 
• 
CT Scan** 
• 
Bone Marrow Aspirate & Trephine** (only if results were positive at 
Screening) 
 
After these assessments, the infusion of 200 mg pembrolizumab will begin.  The infusion will 
take place over 30 minutes (-5, +10mins). 
 
*If a subject has a tumour biopsy scheduled for SD77 - SD83, Visit 5 should include a Complete 
physical examination.   
 
** Required only for subjects that presented at the visit with a grade 2 or greater ISR, or any 
grade injection site ulceration. Reminder to book tumour biopsy between SD77 - SD83. 
 
7.4.6 Visit 6 (SD84) 
 
The following assessments will be conducted at the start of the visit prior to injection: 
 
• 
Procedures listed in Section 7.4 
• 
PBMC blood draw (~ 90 mL)  
• 
Cyclophosphamide accountability 
• 
Directed Physical examination 
• 
Injection site evaluation (for injection #1 SD7 and injection #2 SD28) 
 
After these assessments, the subject will be administered a 0.1 mL maintenance injection as 
detailed in Section 6.1.3.  Vital signs will be collected approximately 15 +/- 5 minutes after 
injection.     
 
For subjects whose CT scan and biopsy were not scheduled early at SD70 & SD77-SD83, 
a CT scan will be scheduled for SD91 and a tumour biopsy will be scheduled between 
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7.4.7 Visit 7 (SD91) 
 
The following assessments will be conducted at this study visit prior to infusion: 
 
• 
Procedures listed in Section 7.4 
• 
Complete or Directed Physical examination*  
• 
Injection site evaluation (for injection #1 SD7, injection #2 SD28 and injection 
#3 SD84) 
• 
CT Scan** 
• 
Bone Marrow Aspirate & Trephine** (only if results were positive at 
Screening) 
 
After these assessments, the infusion of 200 mg pembrolizumab will begin.  The infusion will 
take place over 30 minutes (-5, +10 mins). 
 
* For subjects who had an early CT and Tumour biopsy, complete only a directed physical exam 
at this visit 
 
**Required for subjects that did not have an early CT at SD70. Reminder to book tumour biopsy 
between SD98– SD104. 
 
7.4.8 Visit 8 (SD 112) 
 
At this visit, subjects will be re-staged using the same procedures outlined in Section 7.3.2. The 
following assessments will be conducted at this study visit prior to infusion: 
 
• 
Procedures listed in Section 6.4 
• 
Directed physical examination 
• 
Re-staging of disease. See Section 7.3.2 
• 
Injection site evaluation (for injection #1 SD7, injection #2 SD28 and injection 
#3 SD84) 
 
After these assessments, the infusion of 200 mg pembrolizumab will begin.  The infusion will 
take place over 30 minutes. 
 
7.4.9 Visit 9 (SD133) 
 
The following assessments will be conducted at the start of the visit prior to infusion: 
 
• 
Procedures listed in Section 7.4 
• 
Directed physical examination 
• 
Injection site evaluation (for injection #1 SD7, injection #2 SD28 and injection 
#3 SD84) 
 
After these assessments, the infusion of 200 mg pembrolizumab will begin.  The infusion will 
take place over 30 minutes. 
 
 

 
 
 
 
 
 
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7.4.10 Visit 10 (SD140) 
 
The following assessments will be conducted at the start of the visit prior to injection: 
 
• 
Procedures listed in Section 7.4 
• 
PBMC blood draw (~ 90 mL)  
• 
Directed physical examination 
• 
Injection site evaluation (for injection #1 SD7, injection #2 SD28 and injection 
#3 SD84) 
 
After these assessments, the subject will be administered a 0.1 mL maintenance injection.  Vital 
signs will be collected approximately 15 +/- 5 minutes after injection.   
 
7.4.11 Visit 11 (SD 154) 
 
The following assessments will be conducted at this study visit prior to infusion: 
 
• 
Procedures listed in Section 7.4 
• 
Directed physical examination 
• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84 and #4 
SD140) 
 
After these assessments, the infusion of 200 mg pembrolizumab will begin.  The infusion will 
take place over 30 minutes (-5, +10 mins). 
 
Reminder to book a routine CT scan for SD175. 
 
7.4.12 Visit 12 (SD 175) 
 
The following assessments will be conducted at the start of the visit prior to infusion:  
 
• 
Procedures listed in Section 7.4 
• 
Directed physical examination 
• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84 and #4 
SD140) 
• 
CT Scan 
• 
Bone Marrow Aspirate & Trephine (only if results were positive at Screening) 
 
After these assessments, the infusion of 200 mg pembrolizumab will begin.  The infusion will 
take place over 30 minutes (-5, +10mins). 
 
7.4.13 Visit 13 (SD 196) 
 
At this visit, subjects will be re-staged using the same procedures outlined in Section 7.3.2. The 
following assessments will be conducted at this study visit prior to infusion: 
 
• 
Procedures listed in Section Section 7.4 
• 
PBMC blood draw (~ 90 mL)  
• 
Complete physical examination 
• 
Re-staging of disease. See Section 7.3.2 

 
 
 
 
 
 
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• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84 and #4 
SD140) 
 
After these assessments, the subject will be administered a 0.1 mL maintenance injection.  Vital 
signs will be collected approximately 15 +/- 5 minutes after injection.   
 
At least thirty minutes after the injection, the infusion of 200 mg pembrolizumab will begin.  The 
infusion will take place over 30 minutes (-5, +10mins). 
 
7.4.14 Visit 14 (SD217) 
 
The following assessments will be conducted at the start of the visit prior to infusion: 
 
• 
Procedures listed in Section 7.4 
• 
Directed physical examination 
• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84, #4 SD140 
and #5 SD196) 
 
After these assessments, the infusion of 200 mg pembrolizumab will begin.  The infusion will 
take place over 30 minutes (-5, +10mins). 
 
7.4.15 Visit 15 (SD238) 
 
The following assessments will be conducted at the start of the visit prior to infusion:  
 
• 
Procedures listed in Section 7.4 
• 
Directed physical examination 
• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84, #4 SD140 
and #5 SD196) 
 
After these assessments, the infusion of 200 mg pembrolizumab will begin.  The infusion will 
take place over 30 minutes (-5, +10mins). 
 
7.4.16 Visit 16 (SD252) 
 
The following assessments will be conducted at the start of the visit prior to injection: 
 
• 
Procedures listed in Section 7.4 
• 
PBMC blood draw (~ 90 mL)  
• 
Complete Physical exam 
• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84, #4 SD140 
and #5 SD196) 
 
 
After these assessments, the subject will be administered a 0.1 mL maintenance injection.  Vital 
signs will be collected approximately 15 +/- 5 minutes after injection.   
 
 
 

 
 
 
 
 
 
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7.4.17 Visit 17 (SD259) 
 
The following assessments will be conducted at the start of the visit prior to infusion:  
 
• 
Procedures listed in Section 7.4 
• 
Directed physical examination 
• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84, #4 SD140, 
#5 SD196 and SD#6 SD252) 
 
 
After these assessments, the infusion of 200 mg pembrolizumab will begin.  The infusion will 
take place over 30 minutes (-5, +10mins). 
 
7.4.18 Visit 18 (SD280) 
 
The following assessments will be conducted at the start of the visit prior to infusion: 
 
• 
Procedures listed in Section 7.4 
• 
Directed physical examination 
• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84, #4 SD140, 
#5 SD196 and SD#6 SD252) 
 
After these assessments, the infusion of 200 mg pembrolizumab will begin.  The infusion will 
take place over 30 minutes (-5, +10mins). 
 
7.4.19 Visit 19 (SD301) 
 
The following assessments will be conducted at the start of the visit prior to infusion: 
 
• 
Procedures listed in Section 7.4 
• 
Directed physical examination 
• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84, #4 SD140, 
#5 SD196 and SD#6 SD252) 
 
After these assessments, the infusion of 200 mg pembrolizumab will begin.  The infusion will 
take place over 30 minutes (-5, +10mins). 
 
7.4.20 Visit 20 (SD308) 
 
The following assessments will be conducted at the start of the visit prior to injection: 
 
• 
Procedures listed in Section 7.4 
• 
PBMC blood draw (~ 90 mL) 
• 
Directed physical examination 
• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84, #4 SD140, 
#5 SD196 and SD#6 SD252) 
 
After these assessments, the subject will be administered a 0.1 mL maintenance injection.  Vital 
signs will be collected approximately 15 +/- 5 minutes after injection.   
 

 
 
 
 
 
 
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7.4.21 Visit 21 (SD322) 
 
The following assessments will be conducted at the start of the visit prior to infusion: 
 
• 
Procedures listed in Section 7.4 
• 
Directed physical examination 
• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84, #4 SD140, 
#5 SD196 and SD#6 SD252 and #7 SD308) 
 
After these assessments, the infusion of 200 mg pembrolizumab will begin.  The infusion will 
take place over 30 minutes (-5, +10mins). 
 
7.4.22 Visit 22 (SD343) 
 
The following assessments will be conducted at the start of the visit prior to infusion: 
 
• 
Procedures listed in Section 7.4 
• 
Directed physical examination 
• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84, #4 SD140, 
#5 SD196 and SD#6 SD252 and #7 SD308) 
 
After these assessments, the infusion of 200 mg pembrolizumab will begin.  The infusion will 
take place over 30 minutes (-5, +10mins). 
 
7.4.23 Visit 23 (SD364) 
 
The following assessments will be conducted at the start of the visit prior to injection: 
 
• 
Procedures listed in Section 7.4 
• 
PBMC blood draw (~ 90 mL)  
• 
Physical exam 
• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84, #4 SD140, 
#5 SD196 and SD#6 SD252 and #7 SD308) 
• 
CT Scan 
 
After these assessments, the subject will be administered a 0.1 mL maintenance injection. Vital 
signs will be collected approximately 15 +/- 5 minutes after injection.   
 
At least thirty minutes after the injection, the infusion of 200 mg pembrolizumab will begin.  The 
infusion will take place over 30 minutes (-5, +10mins). 
 
7.4.24 End of Study (EOS) Visit 
 
This visit can occur under two different circumstances: (1) after subjects have completed one 
year of treatment (SD364/V23), or (2) sooner for any subject who progresses during the study 
or withdraws early for any reason. In both instances, an EOS visit should be scheduled 30 days 
after a DPX-Survivac injection unless the subject progresses and needs immediate and urgent 
treatment.  
 

 
 
 
 
 
 
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7.4.24.1 Suspected Disease Progression/pseudo-progression 
When disease progression is suspected, but the subject is not in urgent need of immediate 
treatment, they should remain on study protocol and have a CT scan performed at the time of 
suspected progression and again approximately 4 weeks after the first documented 
progression to rule out pseudo-progression.   
 
7.4.24.2 Confirmed Disease Progression 
For subjects who have confirmed progression, either by CT scan or other assessment, and 
need immediate and urgent treatment, every attempt should be made to conduct the EOS visit 
in conjunction with a CT scan before new treatment begins. The EOS visit may occur less than 
30 days beyond the last injection, so that new treatment can begin quickly. 
7.4.24.3 immune-related Response Criteria 
To document irRC, a CT scan should be performed approximately 4 weeks after disease 
progression, if the subject consents, and has not started another form of cancer therapy. 
 
At an EOS visit, all subjects will be re-staged using the same procedures outlined in Section 
7.3.2. The following assessments will be conducted for the EOS visit: 
 
• 
Procedures listed in Section 7.4 
• 
PBMC blood draw (~ 90 mL)   
• 
Complete Physical exam 
• 
Re-staging of disease. See Section 7.3.2 
• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84, #4 SD140, 
#5 SD196 and SD#6 SD252, #7 SD308 and #8 SD364) 
• 
CT scan*  
• 
Bone Marrow Aspirate & Trephine (only if results were positive at Screening) 
• 
18F-FDG PET scan** 
• 
Tumour Biopsy*** 
 
* When possible. Not required for subjects who have completed trial and received a CT scan 
at SD364 
** This should be performed if there is equivocal evidence of disease at EOS, and is 
considered necessary in the opinion of the investigator. 
*** Not required. Samples are to be obtained if: (1) the participant consents to sharing and 
(2) in the judgment of the investigator, a tumour biopsy is needed to better determine next 
course of therapy for that participant. The biopsy should be done before the start of a new 
treatment. 
 
7.4.25 Follow-up Visits  
 
Information on disease progression, general health and survival will be collected at each follow-
up visit. These visits are recommended to be completed in person, but may also be completed 
by phone call or chart review, as per the consent requests of the subject.  
 
 
 

 
 
 
 
 
 
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7.4.25.1 For Subjects that Completed Treatment/ Did Not Progress on Study 
 
After the EOS visit, subjects who did not progress will be followed every 2 months for 1 year, or 
until progression and the start of a new therapy, whichever occurs first. Whenever possible, the 
following should be collected: 
 
• 
Procedures listed in Section 7.4* 
• 
Physical exam 
• 
Injection site evaluation (for injection #1 SD7, #2 SD28, #3 SD84, #4 SD140, 
#5 SD196 and SD#6 SD252, #7 SD308 and #8 SD364)  
• 
Disease Status  
• 
Tumour therapy 
• 
Subject Status (survival) 
 
*Procedures in Section 7.4 are only to be followed as appropriate. For example: pregnancy 
questions asked for 120 days after last pembrolizumab infusion, AEs and Concomitant 
Medications to be collected until the start of a new therapy, etc. 
7.4.25.2 Follow-up Visits for Discontinued/Withdrawn Subjects  
 
It is recommended that for subjects who; progress while on treatment, are discontinued from the 
study due to an adverse event or condition (defined in Section 5.5.1), or who withdraw from the 
study for any reason, be followed-up every 2 months if possible. At month 6 and month 12, after 
EOS/study discontinuation, the following should be collected:   
 
• 
Procedures listed in Section 7.4 
• 
Physical exam 
• 
Injection site evaluation (for any and all injections received)  
• 
Disease Status*  
• 
Tumour therapy* 
• 
Subject Status (survival)* 
 
* May be collected from a chart review depending on subject consent and ability to 
successfully contact.  
7.4.25.3 Follow-Up for Subjects of Childbearing Potential 
 
As part of the expected follow-up, questions regarding pregnancy for both female participants of 
childbearing potential, and male participants with partners of childbearing potential, should only 
continue for 120 days (4 months) after last pembrolizumab infusion.  
7.4.25.4 Follow-Up Visits for Subject Safety 
 
All subjects, regardless of trial status (completion or withdrawal), will require a follow up 
visit at 30 days after receiving their last injection and last infusion, which may be the same 
as their EOS visit or different. An additional follow-up will be conducted at 90 days after 
receiving their last infusion of pembrolizumab, to assess the occurrence of any Serious 
Adverse Events. This is only to be completed as per subject consent requests and if the 
subject is not on another form of treatment. 

 
 
 
 
 
 
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It is also recommended that if an 18F-FDG PET was performed, that the subject be 
contacted, as per institutional guidelines, to determine if there are any adverse events to 
report from the procedure. 
 
7.5 
Unscheduled Study Visits 
It is possible that a subject requires a visit in addition to those outlined in Section 7.4. These 
visits include, but are not limited to; adverse events (including injection site reactions); serious 
adverse events (or other reasons for hospitalization); medical imaging performed for reasons 
not related to study procedures, such as MRI, DVT, CT Scan, Ultrasound, etc.; reasons related 
to study procedures, such as a previously omitted injection or infusion; imaging, specialist 
appointments, etc. not previously identified as being necessitated in the subject’s medical 
history at Screening; additional laboratory test(s) or imaging directly related to study procedures. 
Unscheduled study visits do not need to be attended, or requested, by study staff to be 
considered significant or relevant to the study.  
Imaging, laboratory results, appointments or conditions being followed by a specialist, and not 
previously identified in a subject’s medical history, whereby results can be obtained by study 
staff, should be reviewed by the investigator for clinical significance. If the visit or the results are 
deemed clinically significant by the site investigator, all attempts should be made to document 
the details in the Source and eCRF as appropriate. If the unscheduled visit, and or results, are 
deemed not clinically significant by the investigator, it should be noted as such in Source only. 
7.6 
Pregnancy Visit(s)  
 
The Sponsor should be notified within 24 hours of site awareness in the case of a pregnancy in 
either a female subject, or the partner of a male subject. 
 
If a female subject inadvertently becomes pregnant while on study, the subject will immediately 
be withdrawn from the study. 
 
The site will contact the subject, or the subject’s partner (when possible) on a monthly basis to 
document the pregnancy and outcome.  The outcome of the pregnancy will be reported to the 
Sponsor within 24 hours of site awareness. The study investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the subject 
and newborn/fetus to the Sponsor.  
 
The Sponsor will notify the Data Safety Monitoring Board (DSMB) within 24 hours awareness of 
a pregnancy and if at which time, the outcome is a serious adverse experience for the mother or 
newborn/fetus (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication).  Additional reporting requirements can be found in Section 8.4.1. 
7.7 
Protocol Deviations 
It is the responsibility of the investigator to ensure that only investigative procedures, as outlined 
in this protocol are performed on study participants; the occurrence of deviations from the 
protocol are limited; and compliance with the regulations is maintained.  Planned deviations 
from the protocol must not be implemented without prior agreement from the Sponsor and 
approval from the local REB/ethics committee (EC), as required, unless to eliminate an 
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Planned or unplanned deviations may occur on the part of the subject, the investigator, or study 
research team. In resolution to a deviation, corrective/preventative actions are to be developed 
and implemented in a timely manner. Protocol deviations will be documented and reported as 
required and assessed where necessary during analysis. 

 
 
 
 
 
 
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8 ASSESSMENT OF SAFETY 
The safety of research participants is foremost and should always be considered throughout the 
conduct of research.  
8.1 
Adverse Events 
An adverse event (AE) means any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment, and includes an adverse drug reaction 
(ADR). 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product or protocol-specified procedure, 
whether or not considered related to the medicinal product or protocol-specified procedure.  Any 
worsening (i.e. any clinically significant adverse change in frequency and/or intensity) of a 
preexisting condition that is temporally associated with the use of either DPX-Survivac or 
pembrolizumab, is also an adverse event. 
 
• 
Adverse events may occur during the course of the use of DPX-Survivac, 
pembrolizumab, or cyclophosphamide in clinical trials or within the follow-up period 
specified by the protocol, or prescribed in clinical practice, from overdose (whether 
accidental or intentional), from abuse and from withdrawal. 
• 
Adverse events may also occur in screened subjects during any pre-allocation 
baseline period as a result of a protocol-specified intervention, including washout 
or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
• 
Progression of the cancer under study is not considered an adverse event 
unless it is considered to be drug related by the investigator. 
• 
Changes resulting from normal growth and development that do not vary 
significantly in frequency or severity from expected levels are not to be considered 
adverse events.  Examples of this may include, but are not limited to, teething, 
typical crying in infants and children and onset of menses or menopause occurring 
at a physiologically appropriate time. 
8.1.1 Assessment of an Adverse Event 
 
To assess the severity of an adverse event the investigators will use the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) v 4.03 (Appendix E).  The Investigator’s 
opinion of the following should be documented on an Adverse Event Log: 
8.1.1.1 Relationship (Causality/Relatedness) 
The causality assessment is the determination, according to the investigator’s clinical judgment, 
of the existence of a reasonable possibility that the study drug caused or contributed to an 
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If the site investigator is unsure about whether or not the study drug caused or is related to the 
event, then the event will be handled as “related” to the study drug for reporting purposes of the 
trial.  If the causality assessment is "unrelated” to the study drug, this should be clearly 
documented in the source documents.  
 
The site investigator is obligated to estimate the relationship between the study drugs listed in 
Section 6.1  and the occurrence of each AE or SAE using their best clinical judgment. Other 
causes, such as the history of the underlying disease, concomitant therapy, other risk factors, 
and the temporal relationship of the event to the study drug will be considered and investigated.  
The site investigator will also consult the Investigator Brochure (IB) or Product Monograph (PM) 
in the determination of the assessment. If more information is needed to determine 
“relatedness”, the site should contact the Sponsor for guidance.  
 
When reporting an SAE, the causality assessment is one of the criteria used to determine 
regulatory reporting requirements and should not be left blank. The site investigator may change 
his or her opinion of the causality in light of follow-up information, amending the SAE report.   
8.1.1.2 Expectedness  
Events are classified as unforeseen or unexpected if the nature, severity or frequency is not 
consistent with the risk information set out in IB or PM. 
An expected AE is one that is consistent with the known risk information described in current IB 
or PM, therefore and unexpected AE is defined as any AE where the specificity or severity of 
which is not consistent with the known risk information described in current IB or PM.   
Expectedness will be determined by the site investigator with discussion with the global principal 
investigator as required.  
8.1.1.3 Seriousness 
Events are classified as serious if associated with effects threatening the life or physiological 
functions of a participant.  Refer to the definition for “Serious Adverse Events” in Section 8.2. All 
adverse events, regardless of grade, must also be evaluated for seriousness. 
8.1.1.4 Severity  
The term "severe" is often used to describe the intensity (severity) of a specific event (e.g. mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as "serious," which is 
based on participant/event outcome or action criteria usually associated with events that pose a 
threat to a participant's life or functioning. The terms “serious” and “severe” are not 
synonymous.  Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
To assess the severity of an adverse event the investigators will use the NCI CTCAE v 4.03 
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8.1.2 Evaluating Adverse Events 
 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
CTCAE v 4.03 (Appendix E). Any adverse event which changes grade over the course of a 
given episode will have each change of grade recorded on the adverse event case report 
forms/worksheets. See Table 10 for additional guidance. 
 
All adverse events regardless of grade must also be evaluated for seriousness. 
 
The investigator will also attempt to establish a diagnosis of the event based on the signs, 
symptoms, or other clinical information.  In such cases, the diagnosis, not the individual signs 
and symptoms, should be documented on the appropriate eCRF as the AE or SAE Report Form 
– CIOMS I. 
8.2 
Serious Adverse Events 
 
A serious adverse event is any adverse event occurring from the time consent is signed through 
90 days following cessation of treatment, or the initiation of new anti-cancer therapy, whichever 
is earlier, whether or not related to pembrolizumab or DPX-Survivac or at any dose during the 
any use of pembrolizumab or DPX-Survivac, that: 
 
• 
Results in death; 
• 
Is life threatening*; 
• 
Results in persistent or significant disability/incapacity; 
• 
Results in or prolongs an existing inpatient hospitalization; 
• 
Is a congenital anomaly/birth defect; 
• 
Is a new cancer (that is not a condition of the study); 
• 
Is associated with an overdose; 
• 
Is another important medical event  
• 
Progression of cancer under study only if it results in hospitalization or death 
 
*The term "life-threatening" in the definition of "serious" refers to an event in which the 
participant was at risk of death at the time of the event; it does not refer to an event, which 
hypothetically might have caused death if it were more severe.  
 
Hematological adverse events (such as low absolute neutrophil count or low white blood cell 
count) identified as a serious adverse event based grading of lab values obtained for study 
purposes, are in fact common, known and expected in this disease population, and should not 
be considered a serious adverse event. See Section 8.5: Events of Clinical Interest for further 
instruction. 
 
Any serious adverse event must be reported within 24 hours to the Sponsor using the SAE 
Report Form – CIOMS I, and within 1 working day to the Manufacturer. Additionally, any serious 
adverse event, considered by an investigator, who is a qualified physician, to be related to 
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even if outside of the time period specified in the trial design, must also be reported immediately 
to the Sponsor. 
8.2.1 Unexpected Adverse Event 
 
An unexpected adverse event is any AE that is not identified in nature, severity or frequency in 
the current Investigator’s Brochure or Product Monograph 
8.2.2 Unexpected Adverse Drug Reaction (ADR) 
An ADR is an adverse reaction, the severity of which is not consistent with the applicable 
Investigator’s Brochure or Product Monograph.   All noxious and unintended responses to a 
medicinal product related to any dose should be considered an ADR.  
The phrase "responses to a medicinal product" means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out.  
 
The expression “causal relationship” is meant to convey that in general there are facts, evidence 
or arguments to suggest a reasonable causal relationship, a Serious Unexpected Adverse Drug 
Reaction (SUADR).  All SUADRs will have expedited reporting to regulatory agencies following 
ICH-GCP and local regulatory requirements. 
8.2.3 Follow-up of SAEs 
 
After the initial SAE report, the site investigator is required to follow the subject and provide 
further information with regards to the subject’s condition.  All SAE(s) will be followed until: 
 
• 
Resolution; 
• 
The condition stabilizes; 
• 
The event is otherwise explained; 
• 
Death; 
• 
The subject is lost to follow-up; 
 
Or to a maximum of 90 days after onset, whichever occurs first 
 
Once the event is resolved, the SAE Report Form – CIOMS I and the eCRF will be updated.  
The site investigator will also ensure that the follow-up includes any supplemental information, 
excluding source documents that may explain the causality of the event(s). 
New or updated information will be recorded on the originally completed SAE Report Form – 
CIOMS I, with all changes signed and dated by the site investigator or designee.  The updated 
SAE Report Form  - CIOMS I will then be signed by the investigator and resubmitted to the 
Sponsor. 
 
 

 
 
 
 
 
 
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8.3 
Investigational Product Overdose: pembrolizumab 
 
For purposes of this trial, an overdose will be defined as any dose of 1,000 mg or greater (≥5 
times the indicated dose) of pembrolizumab.  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided 
if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. If an 
adverse event(s) is associated with (“results from”) the overdose of Pembrolizumab, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met. 
 
If a dose of pembrolizumab meeting the protocol definition of “overdose” is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as an 
Event of Clinical Interest (Section 8.5), using the terminology “accidental or intentional 
overdose without adverse effect.” 
 
All reports of overdose with or without an associated adverse event must be reported within 24 
hours to the Sponsor. 
 
    
 
 

 
 
 
 
 
 
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Table 10 Evaluating Adverse Events  
V4.03 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation or hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any IP use that: 
 
Results in death; or 
 
Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the 
event as it occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, 
might have caused death.); or 
 
Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct 
normal life functions); or 
 
Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient 
admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued 
observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to 
diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is 
considered a serious adverse event. An overdose that is not associated with an adverse event is considered a 
non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require 
hospitalization may be considered a serious adverse event when, based upon appropriate medical judgment, 

 
 
 
 
 
 
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the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed previously (designated above by a ). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time 
and units 
Action taken  
Did the adverse event cause IP to be discontinued? 
Relationship to 
test drug  
Did IP cause the adverse event? The determination of the likelihood that IP caused the adverse event will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source 
document or worksheet that supports the causality noted on the AE form, ensures that a medically qualified 
assessment of causality was done. This initialed document must be retained for the required regulatory time 
frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the 
likelihood of a relationship between the test drug and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between IP and the AE; the greater 
the correlation with the components and their respective elements (in number and/or intensity), the more likely 
IP  caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to IP such as: reliable history, 
acceptable compliance assessment (pill count, etc.), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of IP?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)), or other host or environmental factors 
 
  
Dechallenge 
Was IP discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) 
the AE resolved/improved despite continuation of IP; or (3) the trial is a single-dose drug trial); 
or (4) IP only used one time.) 

 
 
 
 
 
 
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Relationship 
to IP 
(continued) 
The following components are to be used to assess the relationship between IP and the AE: 
(continued) 
Rechallenge 
Was the subject re-exposed to IP in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the trial is a single-dose drug trial); or (3) IP is/ used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS 
SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY PEMBROLIZUMAB, OR IF 
REEXPOSURE TO PEMBROLIZUMAB POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE 
BY THE PRINCIPAL INVESTIGATOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge 
regarding IP or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified 
physician according to his/her best clinical judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of IP relationship). 
Yes, there is a reasonable 
possibility of IP relationship. 
There is evidence of exposure to IP.  The temporal sequence of the AE onset relative to the 
administration of  IP is reasonable.  The AE is more likely explained by IP than by another 
cause. 
No, there is not a reasonable 
possibility IP relationship 
Subject did not receive IP OR temporal sequence of the AE onset relative to administration of 
IP t is not reasonable OR there is another obvious cause of the AE.  (Also entered for a 
subject with overdose without an associated AE.) 

 
 
 
 
 
 
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8.4 
Adverse Event Recording/Reporting 
 
Adverse events will be recorded from the time the consent form is signed through the end of 
study participation (completion or withdrawal) and includes follow-up visits outlined in the trial 
design, or through 90 days following cessation of pembrolizumab. Information on all adverse 
events should be recorded promptly in the source document, and assessed by an investigator in 
a timely manner allowing sufficient time to meet required reporting timelines for SAEs and 
SUADRs as described. Adverse event logs should be completed using source documents by a 
delegated research team member in a timely manner. Additional instructions on reporting 
timelines can be found in the study Manual of Operations. 
8.4.1 Reporting of Pregnancy and Lactation to the Sponsor 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject, including 
that of a male subject's female partner. The Sponsor should be notified within 24 hours of 
site awareness of such instances which occur during the trial or within 120 days of 
completing the trial, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier. 
 
The outcome of the pregnancy will be reported to the Sponsor within 24 hours of site 
awareness. The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the subject and newborn/fetus to the 
Sponsor.  
 
All subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If the 
pregnancy continues to term, the outcome (health of infant) must also be reported. Such events 
must be reported within 24 hours to the Sponsor. 
8.4.2 Investigator Reporting 
 
In all instances of SUADRs, the investigator should record and report to the REB in accordance 
with local reporting requirements and timelines and to the Sponsor in 24 hours. 
 
Reporting for SUADRs should include a description of the event in sufficient detail to allow for a 
complete medical assessment of the case and independent determination of possible causality.  
The minimum information required includes at least one identifiable subject, one identifiable 
reporter, one serious reaction, and one suspect product.  
 
Additionally, a Suspect Adverse Reaction Report – CIOMS I Form must be completed by the 
investigator and forwarded to the Sponsor within 24 hours of site awareness.  Information on 
other possible causes of the event, such as concomitant medications and illnesses should also 
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8.4.3 Sponsor Reporting of SUADRs and ECIs 
 
The regulatory Sponsor is responsible for reporting all relevant SAEs, overdoses, pregnancies 
and Events of Clinical Interest to Merck and IMV Inc. in 2 working days of learning of the event;   
 
• 
Report by Fax to Merck Canada Inc. : Attn: Worldwide Product Safety; FAX 1-800-369-
3090 
• 
Report to IMV Inc.: Attn: Safety Reporting; FAX 902-492-0888. 
 
The regulatory Sponsor is also responsible for reporting SUADRs to regulatory authorities in 
accordance with local expedited reporting requirements and timelines.  In addition, the Sponsor 
will complete the ADR Expedited Reporting Summary Form and submit this form in conjunction 
with the completed CIOMS Form to the appropriate Health Canada directorate.    
The regulatory Sponsor is responsible for distributing blinded expedited reports of SUADRs to 
each investigator for submission to local Ethics Committees within 15 days of Sponsor 
awareness. 
8.4.4 Reporting and Entry Timelines of Site to Sponsor 
8.4.4.1 SAE’s 
All deaths and immediately life-threatening events, whether related or unrelated, will be 
recorded and reported to the Sponsor within 24 hours of site awareness.  
Serious adverse events other than death and immediately life-threatening events, 
regardless of relationship, will be reported to the Sponsor within 24 hours of site awareness.  
Serious adverse event information will be entered into the eCRF in a timely manner (within 72 
hours) from the time the investigator becomes aware of the event. 
8.4.4.2 AE’s 
 
Adverse event information will be entered into the eCRF in a timely manner and no later than 
15 days from the time the investigator becomes aware of the event. 
8.5 
Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event Log and reported within 24 hours to 
the Sponsor. Events of clinical interest for this trial include: 
 
• 
An overdose of pembrolizumab, as defined in Section 8.3 with or without symptoms. 
• 
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal with an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory 
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*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Manual of Operations. 
8.6 
Data and Safety Monitoring Board (DSMB) 
 
Data and Safety Monitoring Board (DSMB) will comprise of clinician scientists with pertinent 
expertise, and who are considered independent of the study Sponsor. DSMB members will 
meet to assess at regular intervals the progress of a trial, the safety data and the critical efficacy 
endpoints and will recommend to the Principal Investigator whether to continue, modify or stop 
the trial. The roles and the responsibilities of the DSMB will be defined in the form of a charter. 
This Charter will serve as the Standard Operating Procedure (SOP) for the DSMB. 
8.7 
Steering Committee 
A steering committee will be established. This will consist of investigators, other experts not 
otherwise involved in the trial and representatives of the Sponsors. The steering committee will 
oversee the maintenance of the quality of study conduct, monitoring of toxicities and AEs, 
determining the need and generation of trial amendments and coordinating writing of 
publications. They will also generate idea’s around extension or additional related studies that 
may be conducted. All publications and presentations pertaining to this trial and any 
future/extension trials must first be approved by the Steering Committee. 
 
 

 
 
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9 SITE MONITORING, AUDITING AND INSPECTING 
9.1 
Site Monitoring Plan 
 
Site monitoring is conducted to ensure the safety of human study subjects and the protection of 
their rights and well-being.  Monitoring also verifies that collected study data is accurate, 
complete and verifiable by source documentation and that the study is conducted in accordance 
with the protocol and operating procedures. 
 
Monitoring for this study is the responsibility of the Sponsor.  The delegated monitor will 
evaluate study processes and documentation based on the approved protocol/amendment(s), 
Part C, Division 5 of the Food and Drug Regulations, the International Council for Harmonisation 
(ICH), E6: Good Clinical Practice guidelines (GCP) and institutional policies. 
 
The extent and nature of monitoring will be outlined in the Monitoring Plan. The monitoring plan 
specifies the frequency of monitoring, monitoring procedures, the level of site monitoring 
activities (e.g., the percentage of subject data to be reviewed), and the distribution of monitoring 
reports.  Monitoring activities will be performed both in person and remotely.  Reports of findings 
identified during monitoring activities will be provided to sites detailing any required actions.  
Documentation of monitoring activities and findings will be provided to the site study team and 
the study QI. The institution and/or local REB reserves the right to conduct independent audits 
as necessary. 
 
The Investigator is responsible for ensuring monitors and/or quality assurance reviewers are 
given access to all study-related documents noted above and study related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.), and have adequate space to conduct the monitoring visit 
or audit. 
9.2 
 Auditing and Inspecting 
 
The investigator will provide direct access to source data/documents for the purposes of study-
related monitoring, audits, and inspections by the REB, the Sponsor, and applicable regulatory 
bodies.  The investigator will permit the review of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.) and will ensure 
access to applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 

 
 
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10 STATISTICAL CONSIDERATIONS 
10.1 
Study Hypotheses 
 
We hypothesize that combining DPX-Survivac and metronomic cyclophosphamide with 
pembrolizumab in patients with measurable or recurrent DLBCL will result in a clinically 
significant objective response level that will be at least 24%. 
 
We also hypothesize that combining DPX-Survivac and metronomic cyclophosphamide with 
pembrolizumab in patients with measurable or recurrent DLBCL will enhance the activation of 
the polyfunctional T cells in the peripheral blood activated by DPX-Survivac and increase the 
infiltration of tumour sites with lymphocytes compared to pre-treatment biopsies.  This will be 
evidence that both mechanisms of anti-tumour activity are elicited by this combination 
immunotherapy. 
10.2 
Populations of Interest 
 
Patients with recurrent or refractory DLBCL, both de novo and transformed disease, post 
primary, secondary or subsequent regimens will be enrolled. Patients must not be eligible for 
alternative curative strategies and must meet the inclusion and exclusion criteria.  Subjects will 
be continuously monitored.  Data from all subjects entered will be presented and summarized.  
The safety population is defined as all subjects who receive at least one immunization.  The 
efficacy population is defined as all subjects who received at least three injections and four 
infusions of pembrolizumab. 
 
10.3 
Planned Interim Analyses  
 
An initial interim report based upon immunologic and/or safety results may be performed after 
the first four subjects have received at least three injections.  The primary function of this 
analysis is to document safety profile and immunologic responses. 
 
An additional interim analysis will be performed once 12 subjects are enrolled, to further assess 
safety and immunological responses and also review efficacy of the approach. 
 
The DSMB and Steering Committee will review the interim reports.  There is no plan to interrupt 
recruitment during the planned interim analysis. Based on study progression, safety or 
immunologic results analysis may occur at different time points. 
 
If, after the first few subjects are evaluated, the immune responses are not at the level expected 
then, after consultation with the steering committee, 0.5 mL maintenance doses of DPX-
Survivac may be considered for subsequent subjects.  
 
There will be a lead-in cohort of 6 patients.  If 2 or more grade 3 injection site ulcerations occur 
then the priming two doses of DPX-Survivac will be decreased to 0.25 mL each.  Patient accrual 
will not be held after the 6th patient is treated in the lead-in cohort but the dose will be reduced 
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10.3.1 
Safety Review 
 
Safety will be assessed by using NCI CTCAE v 4.03 (Appendix E).  The safety assessments up 
to the final study visit (EOS) will be based on reported adverse events and the results of vital 
sign measurements, physical examinations, and clinical laboratory tests.  The incidence of 
adverse events will be tabulated and reviewed for potential significance and clinical importance.  
A subject will be considered evaluable for safety if treated with at least one dose of DPX-
Survivac.  
10.3.2 
Efficacy Review 
 
The primary objective is to determine the objective response rate to treatment with DPX-
Survivac and low dose cyclophosphamide and pembrolizumab, in patients with recurrent 
survivin-expressing B cell lymphomas, using Modified Cheson criteria (Appendix C).  The 
response rate will also be calculated for all subjects for descriptive purposes. 
 
Secondary objectives are to document evidence of tumour regression using clinical and 
radiologic criteria for waterfall analysis.  The duration of response will be determined using 
routine clinical and radiologic criteria (Modified Cheson criteria – Appendix C) as well as using 
irRC (Appendix D).   
 
Exploratory analyses will be included in interim analyses when available. Exploratory  efficacy 
analysis will  look at the percentage of subjects with a positive immune response to one or more 
antigens in the drug.  Survivin-peptide specific T cell immune response will be measured in the 
peripheral blood primarily by ELISpot assay, by stimulating subject PBMC with pooled as well 
as HLA-matched survivin peptides.  Other exploratory immunologic assessments may be 
performed on remaining blood samples.  The rate of immune response is defined as the 
percentage of subjects with a positive immune response to one or more epitopes in the drug.  
For ELISpot analysis, antigen-specific response rate greater than Mean±2SD value obtained 
from pre-treatment and/or unstimulated/background cells will be considered a positive response.    
 
Tumour biopsy samples will be obtained pre-treatment and on-treatment to assess for changes 
in lymphocyte infiltrates, lymphocyte subsets, and gene expression profiles with treatment.  
Other novel biomarkers may be evaluated as they become available.  If an injection site biopsy 
is required for clinical management during the course of this trial, portions of this biopsy may be 
studied for evidence of antigen specific T cell infiltrates, other biomarkers or immune activity.  
10.4 
Stopping Rules 
 
This study will be stopped prior to its completion if: (1) the intervention is associated with 
adverse events that call into question the safety of the intervention; (2) difficulty in study 
recruitment or retention will significantly impact the ability to evaluate the study endpoints; or (3) 
any new information becomes available during the trial that necessitates stopping the trial. 
10.5 
Final Analysis Plan 
 
A one-stage design requires treating and evaluating 25 subjects for response. The intended 
sample size is 25 evaluable subjects. Subjects who are survivin positive (>10% survivin 

 
 
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expression) and who that have received at least 4 doses of pembrolizumab, 3 injections of DPX-
Survivac and have an on-treatment CT scan (between SD70 and SD104) will be considered 
evaluable. Other analyses addressing total patients enrolled (evaluable  and non-evaluable) will 
also be explored particularly to indentify factors that may predict the likelihood of identifying 
evaluable versus non evaluable enrolled patients. 
 
If objective responses are observed in at least 6 of 25 subjects, the treatment will be considered 
worthy of further testing.  The design has more than 90% power to conclude that the treatment 
is effective if its true response rate were equal to 35% or more.  The design also has less than 
5% probability to conclude that the treatment is effective if its true response rate were equal to 
10% or less.  (If the power is 0.5 then the trial has a less than 5% chance to conclude that the 
trial is ineffective if its true response rate is greater than 10%).  
 
Standard descriptive statistical methods will be used to summarize the data. The response rate 
will be estimated along with its exact 95% confidence interval.  
 
Secondary objectives are to document evidence of tumour regression using clinical and 
radiologic criteria for waterfall analysis. Tumour volume recorded at baseline imaging will be 
compared to interim and end of study imaging. The degree of change/volume of response will 
be plotted on a waterfall plot to demonstrate the degree of individual responses. The duration of 
response will be determined using routine clinical and radiologic criteria (modified Cheson 
criteria) as well as using irRC.  Evidence of toxicity will be assessed at each visit and graded 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE v 4.03).   
 
Exploratory endpoints will be evaluated as per Section 3.3 and will be important in determining 
whether the treatment is promising and worthy of further clinical evaluation assuming activity 
(i.e. minimal response rate of 24%, or 6 responses among 25 patients).  We expect that both 
previously documented mechanisms of immune activity should be elicited by this 
immunotherapy combination.  That is we would expect to see evidence of increases in 
circulating survivin specific T cells in the majority of patients.  We would also expect to see 
increases in lymphocyte infiltration and gene expression in at least 24% of patients (i.e. 6 of 25 
patients).  Quantitative assessments of both of these parameters will be obtained and standard 
paired t-tests will be used to compare pre- and post-treatment assessments. Descriptive 
analyses will be used to describe the levels of Survivin in the plasma pre and during treatment. 
 
Analyses will be performed to identify baseline and/or on-treatment clinical, immune and 
biologic parameters that predict for patients likely to have long clinical responses to the 
treatment versus those with no or shorter clinical responses. Similary these parameters will also 
be used to identify patients more likely to have peripheral and intra-tumour immune responses 
to survivin or to the tumour.  
 
The final report will be conducted once 25 patients have reached evaluable or if the trial has 
been terminated early. 
 
 
 

 
 
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11 DATA HANDLING AND RECORD KEEPING 
11.1 Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the extent 
permitted by all applicable provincial, local, and federal data protection/privacy laws and/or 
regulations, and will not be made publicly available.  Where consent is required, each subject 
must be informed of the following:  
 
• What PHI will be collected during this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• 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 may use 
all information collected prior to the revocation of subject authorization.  For subject 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. 
11.2 Source Documents 
 
Source data/documents are original documents, data and records in a clinical study that are 
necessary for the reconstruction and evaluation of the study.  Examples of these original 
documents and data records include, but are not limited to: 
• 
Worksheets 
• 
hospital records  
• 
medical records 
• 
memorandum  
• 
subjects’ diaries or evaluation checklists  
• 
pharmacy dispensing records  
• 
recorded data from automated instruments (i.e. ECGs) 
• 
copies or transcriptions certified after verification as being accurate and complete  
• 
subject files and records kept at the pharmacy  
• 
entries entered directly into the printed CRF 
 
Each participating site will maintain appropriate medical and research records for this study, in 
addition to regulatory and institutional requirements for the protection of confidentiality of 
subjects.  If electronic source data documents are printed, it should be signed and dated by the 
investigator to confirm content and filed with other source documents.  
The investigator(s) and research team members listed on the Task Delegation Log (TDL) will 
have access to subject medical records and will collect only the information needed for the 
study.  Sponsor delegated monitors, representatives of institutional committees and regulatory 
authority representatives of the country in which the study is being conducted will also have 

 
 
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access to examine records for the purposes of quality assurance reviews, audits and evaluation 
of study safety and progress. 
11.3 Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study personnel under 
the supervision of the investigator.  All source documents and applicable laboratory reports 
should be reviewed as needed and used to ensure that data collected for the purposes of the 
study are accurate and complete.  Contemporaneous review of laboratory results and the 
assessment of clinical significance for those results considered out of range should be 
documented by means of dated signature by the reviewing investigator. Study personnel, 
including data entry team members, should use source documents to complete case report 
forms (eCRFs).  
As part of the safety plan for this study, the investigator will review individual study subject 
records to ensure that appropriate mechanisms to protect the safety of study subjects are being 
followed, that protocol requirements are being adhered to, and that data is accurate, complete, 
and secure. Subject records include, but are not limited to: consent forms, case report forms, 
data forms, laboratory specimen records, inclusion/exclusion forms, and medical charts. All 
study data will be collected by a member of the study research team and recorded in 
accordance with applicable procedures. 
11.4 Data Capture 
11.4.1 
Case Report Forms 
 
Data collection for this protocol is done using an electronic data capture (EDC) system and  the 
clinical study sites will be provided with instructions for accessing the EDC system using a 
controlled unique username and password. eCRFs will be completed by the study site in a 
timely fashion following the subject visits according to the instructions in the eCRF Completion 
Guidelines. All data corrections will be made by the investigational site within the EDC system.  
It is the responsibility of the investigator to make sure each page of the eCRF accurately reflects 
the subject’s medical record.   
 
CRFs or eCRFs will be reviewed and source verified by the study monitor during periodic site 
visits.  Prior to or between visits, the study monitor and/or data management group may request 
copies of the CRFs or study monitor may review the eCRFs for preliminary medical review.  
Once the CRFs or eCRFs are complete and source-verified, the investigator must sign and date 
all required pages, verifying the accuracy of all data contained within the CRF or eCRF.  
 
Only the subject number and subject initials will be recorded on the CRF or eCRF, and if the 
subject name appears on any other document, it must be hidden or masked and replaced by 
subject number and initials before a copy is supplied to a data management group.  Any 
discrepancies found will be sent to the sites for clarification. 
 

 
 
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11.5 Records Retention 
Study essential documents must be maintained in a secure and confidential manner for 
participating Canadian sites for a period of 25 years.  For the purposes of this study, the start 
date of the retention period is the date of the final report of the trial.  Exceptions may be made 
for sites that close prematurely, wherein the start date for the retention period will be the date of 
notification to Health Canada of the sites closure. Sites conducting this study outside of Canada 
must maintain study records for the required retention period as stipulated by local regulatory 
authorities. All study records are then to be destroyed according to local and national policy and 
requirements. It is the investigator’s responsibility to request authorization for destruction at the 
completion of the retention period and/or for the Sponsor to inform the investigator/institution 
when these documents may be destroyed.  
11.6 Clinical Trial Registration 
In accordance with Health Canada’s Notice “Registration and Disclosure of Clinical Trial 
Information, November 30, 2007”, the Sponsor will be responsible for registering the study on 
Clinicaltrials.gov (www.clinicaltrials.gov), a publically available registry that conforms to 
international standards for registries. 

 
 
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12 QUALITY CONTROL AND QUALITY ASSURANCE 
As per ICH-GCP and local regulations, the Sponsor is responsible for ensuring the 
implementation and maintenance of systems that support quality assurance and quality control.  
The study must be conducted in compliance with the study protocol and all data collected must 
be accurate and verifiable by source document(s). For the purpose of monitoring and auditing 
by the Sponsor, and inspection by regulatory authorities, the site will provide direct access to all 
study related source data/documents. The Sponsor will verify that the study is conducted and 
data has been collected, documented (recorded), and reported in compliance with the protocol, 
GCP, and applicable regulatory requirements.  
Data for the study will be centrally stored and managed by the Centre for Clinical Trial Support 
(CCTS). To ensure the quality of study data, quality assurance and control systems will be 
implemented using validated electronic quality control checks within the electronic data capture 
system.  These verification measures will identify missing data, inconsistencies and/or data 
anomalies.  Both electronic and manual queries will be generated for resolution and review by 
sites.   
Access to secure and validated electronic systems used for the purposes of this study will be 
controlled by the Sponsor.  Access will only be granted to individual research team members 
upon review of training and qualification and authorization by delegation of the investigator.   
Quality assurance and control measures will be implemented to ensure training for specific trial–
related tasks beyond the usual scope of practice.   
For the purposes of this study, “research equipment” is defined as equipment used solely for the 
purposes of this study and that are unrelated to the delivery of standard-of-care treatment or 
procedures.  In accordance with this definition, performance verification and /or calibration 
documentation will only be maintained for the following pieces of research equipment:  
• 
Fridges, Freezers and Liquid Nitrogen tanks where biological specimens are stored 
• 
Fridges where investigational products are stored 
• 
Centrifuges used in biological sample processing 
 

 
 
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13 ETHICS CONSIDERATIONS 
13.1 
Ethical Standard 
The investigator will ensure that this study is conducted in accordance with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Participants of Research, and codified in the Tri-Council Policy Statement and/or the ICH E6.  
13.2 
Research Ethics Board (REB)  
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the REB for review and approval.  Approval of both the protocol and the consent 
form must be obtained before any participant is screened.  Any amendment to the protocol will 
require review and approval by the REB before the changes are implemented in the study, 
unless to eliminate an immediate hazard.   
13.3 
Consent  
Informed consent is a process that is initiated prior to the individual agreeing to participate in the 
study and continues throughout study participation.    A consent form describing in detail the 
study procedures and risks will be reviewed with and given to each participant.  Consent forms 
will be REB-approved, and the participant is required to read and review the document or have 
the document read to him or her.  The investigator or designee will explain the research study to 
the participant and answer any questions that may arise.  The participant will sign the informed 
consent document prior to any study-related assessments or procedures.  Participants will be 
given the opportunity to discuss the study with their surrogates or think about it prior to agreeing 
to participate.  They may withdraw consent at any time throughout the course of the study.  A 
copy of the signed informed consent document will be given to participants for their records.   
Prior to involvement in any study-related activities, consent must be obtained in writing for each 
participant using the current REB approved informed consent from.  It is the responsibility of the 
investigator to ensure that all advertisements and written information, including the informed 
consent form, disseminated to participants has been approved by the local REB prior to use. 
The ethics approved Informed Consent Form (ICF) and any other written information, must be 
provided to each participant, allowing ample time to ask and have answered any questions prior 
to making a decision regarding participation.  Neither the investigator nor study staff should 
unduly influence or coerce a participant to participate in the study.   
 
The ICF will be signed and dated by the participant and individual obtaining consent.  The 
consent process will be documented in the clinical or research record.   
The original ICF, in its entirety, will be maintained by the site, and a complete copy of the signed 
ICF provided to the participant.  The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their clinical care will not be adversely affected if they 
decline to participate in this study. The provision of consent is an ongoing process and should 
be maintained throughout the duration of the study.   Participants may withdraw consent at any 
time throughout the course of the study. 
 

 
 
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14 PUBLICATION/DATA SHARING POLICY 
The Steering Committee will lead and/or approve the generation of any publications obtained 
from this study. Authorship on study publications will adhere to the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals of the International Committee of Medical 
Journal Editors. These requirements state “Authorship credit should be based on: 
 1) Substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data;  
2) Drafting the article or revising it critically for important intellectual content; and  
3) Final approval of the version to be published.  
Authors should meet conditions 1, 2, and 3.” Where journal policies permit, all study site 
investigators who played a contributing role in the trial, including to its accrual, will be included 
in an Acknowledgement section. 
 

 
 
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Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in Patients With Relapsed or 
Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol. 
2016;34(23):2698-2704. 
48. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 
49. 
https://www.fda.gov:80/FDAgov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm182668.htm  

 
 
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16 APPENDICES  
APPENDIX A: Schedule of Events for Screening Period 
Table A1: Screening Procedures for SD-21 to SD-1 
Type of Visit 
Screening 
Procedure/Test 
SD-35  to SD-1 
Informed Consent 
X 
Inclusion/Exclusion Criteria 
X 
Demographics 
X 
Complete Medical History 
X 
β-HCG 
X 
Urinalysis 
X 
T3, T4, TSH 
X 
Organ function lab tests  see Table 2 
X 
ECOG Performance Scale 
X 
Hematology and Clinical Chemistry see Table 9 
X 
Concomitant Medications 
X 
Physical Examination 
X 
Vital Signs and Weight 
X 
Routine CT Scan 
X 
Tumour Biopsy* 
X 
Disease Staging 
X 
Bone Marrow Aspirate & Trephine** 
X 
Lumbar Puncture with CSF analyses† 
X 
Adverse Events 
X 
 
 
* Archived tumour samples may also be assessed for evidence of survivin expression but will not 
replace the pre-treatment biopsy unless obtained less than 3 months prior to SD0 and unless at least 10 
FFPE slides or a tumour block are available. 
Note: The timeline for pre-treatment biopsies is 3 months + 7 days for subject eligibility and enrollment. 
**See Lab manual for sample requirements. See study Manual of Operations for guidance regarding 
results 
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APPENDIX B: Schedule of Events for Treatment Visits 
 
    Type of Visit 
Treatment a 
Procedure/Test 
SD0 
V1 
SD7 
V2 
SD28 
V3 
SD49 
V4 
SD70 
V5 
SD84 
V6 
SD91 
V7 
SD112 
V8 
SD133 
V9 
SD140 
V10 
SD154 
V11 
SD175 
V12 
ECOG Performance Scale 
 
 
 
 
 
 
 
X 
 
 
 
 
HLA Testing/Subtyping 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology and Clinical Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy verificationb  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Examination  
 
 
 
 
Xc 
 
Xc 
 
 
 
 
 
Directed Physical Examination 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Vital Signs and Weight 
X 
Xd 
Xd 
X 
X 
Xd 
X 
X 
X 
Xd 
X 
X 
Routine CT Scan 
 
 
 
 
Xe 
 
Xe 
 
 
 
 
X 
Bone Marrow Aspirate & Trephinef 
 
 
 
 
Xf 
 
Xf 
 
 
 
 
Xf 
Tumour Biopsy 
 
 
 
 
Xg 
 
Xg 
 
 
 
 
 
Disease Staging h 
 
 
 
 
 
 
 
X 
 
 
 
 
Investigational Blood Draw 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
0.5 mL Priming Injections 
 
X 
X 
 
 
 
 
 
 
 
 
 
0.1 mL Maintenance Injections 
 
 
 
 
 
X 
 
 
 
X 
 
 
200 mg Pembrolizumab 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
ISR Evaluation and Photographs  
 
 
X 
X 
X 
 
X 
X 
 
 
X 
X 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
18FDG PETi 
 
 
 
 
 
 
 
 
 
 
 
 
CT = computed tomography, ECOG = Eastern Cooperative Oncology Group performance status, EOS=End of Study, β-HCG = human chorionic gonadotrophin, HepBsAg 
= hepatitis B surface antigen, HIV = human immunodeficiency virus, HLA = human leukocyte antigen, ISR = Injection Site Reaction, PBMC = peripheral blood 
mononuclear cells, SD = Study Day  

 
 
 
 
 
 
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APPENDIX B: (continued) 
                       Type of Visit 
Treatment a 
EOS 
F-UL 
Procedure/ Test 
SD196 
V13 
SD217 
V14 
SD238 
V15 
SD252 
V16 
SD259 
V17 
SD280 
V18 
SD301 
V19 
SD308 
V20 
SD322 
V21 
SD343 
V22 
SD364 
V23 
ECOG Performance Scale 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
HLA Testing/Subtyping 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and Clinical Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy screening/verificationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complete Physical Examination  
X 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Directed Physical Examination 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Vital Signs and Weight 
Xd 
X 
X 
Xd 
X 
X 
X 
Xd 
X 
X 
Xd 
X 
X 
Routine CT Scan 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Bone Marrow Aspirate & Trephinef 
 
 
 
 
 
 
 
 
 
 
 
Xf 
 
Tumour Biopsy 
 
 
 
 
 
 
 
 
 
 
 
XK 
 
Disease Staging h 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Investigational  Blood Draw 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
0.5 mL Priming Injections 
 
 
 
 
 
 
 
 
 
 
 
 
 
0.1 mL Maintenance Injections 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
200 mg Pembrolizumab 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
ISR Evaluation  
 
X 
X 
 
X 
X 
 
 
X 
X 
 
X 
X 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FDG PETJ 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
a visits can occur +/-3 days of the protocol specified day, except for SD0 and SD7; b pregnancy verification at SD0 only for subjects of childbearing potential; c for subjects receiving an early 
biopsy (i.e. SD77-83) a physical exam will be completed at SD70 instead of SD91; d vital signs at these visits will be collected pre-injection and at 15 + 5 minutes after injection; e most 
subjects are to complete a routine CT scan at SD91, for subjects with any grade 2 or greater ISR or any injection site ulceration on SD49, the CT scan will be completed early at SD70. 
Subjects who complete the trial will have a CT scan on SD364, all other subjects will have a CT as part of EOS visit, whichever occurs firs f Bone Marrow Aspirate & Trephine to be done as 
SOC at same visit as CT Scan, only if results from Screening were positive g most subjects are to complete a post-treatment biopsy between SD98 and SD104, for subjects with any grade 2 or 
greater ISR or any injection site ulceration on SD49 the biopsy will be completed early, between SD77 and SD83-note CT will be done at visit 5 or 7 but not both depending on whether the 
patient is experiencing grade 2 ISR or ulceration; h disease staging by physical exam and routine radiologic and laboratory assessments; J PET scans are optional and should be performed at 
EOS if there is equivocal evidence of disease; K Tumour Biopsy at EOS is not required. Samples can be collected if the subject undergoes the procedure as part of standard of care to determine 
next best therapy; L Follow-up visits for all subjects include safety/adverse event review at 30 & 90 days post pembrolizumab infusion, non-progressors every 2 months up to 1 year or until 

 
 
 
 
 
 
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progress, 
for 
progressors 
at 
6 
and 
12 
months 
post 
EOS 
for 
survival.

 
 
 
 
 
 
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APPENDIX C: Modified Cheson Criteria (2007) 
 
Modified Cheson Criteria45 will be used in this study for assessment of tumour response, using standard CT imaging.   
  

 
 
 
 
 
 
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APPENDIX D: Immune Related Response Criteria (IrRC)46 
 

 
 
 
 
 
 
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APPENDIX E: Common Termiology Criteria for Adverse Events V4.03 (CTCAE)  
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03 will be utilized for adverse event reporting. (http://ctep.cancer.gov/reporting/ctc.html) 
 
MedDRA 
v12.0 Code 
CTCAE v4.0 SOC 
CTCAE v4.0 
Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 
5 
CTCAE v4.0 
AE Term 
Definition 
10022095 
General disorders 
and administration 
site conditions 
Injection site 
reaction 
Tenderness with 
or without 
associated 
symptoms (e.g., 
warmth, 
erythema, 
itching) 
Pain; 
lipodystrophy; 
edema; 
phlebitis 
Ulceration or 
necrosis; 
severe tissue 
damage; 
operative 
intervention 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
A disorder 
characterized 
by an intense 
adverse 
reaction 
(usually 
immunologic) 
developing at 
the site of an 
injection. 

 
 
 
 
 
 
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10033371 
General disorders 
and administration 
site conditions 
Pain 
Mild pain 
Moderate pain; 
limiting 
instrumental 
ADL 
 
Severe pain; 
limiting self-
care ADL 
 
- 
- 
A disorder 
characterized 
by the 
sensation of 
marked 
discomfort, 
distress or 
agony 
10062466 
General disorders 
and administration 
site conditions 
Edema 
Localized to 
dependent 
areas, no 
disability or 
functional 
impairment 
Moderate 
localized 
edema and 
intervention 
indicated; 
limiting 
instrumental 
ADL 
Severe 
localized 
edema and 
intervention 
indicated; 
limiting self-
care ADL 
- 
- 
A disorder 
characterized 
by swelling due 
to excessive 
fluid 
accumulation at 
a specific 
anatomic site 
10015277 
Skin & 
subcutaneous 
tissue disorders 
Erythema 
(erythroderma 
- 
Erythema 
covering >90% 
BSA without 
associated 
symptoms; 
limiting 
instrumental 
ADL 
Erythema 
covering >90% 
BSA with 
associated 
symptoms (e.g. 
Pruritus or 
tenderness); 
limiting self-
care ADL 
Erythema 
covering >90% 
BSA with 
associated 
fluid or 
electrolyte 
abnormalities; 
ICU care or 
burn unit 
indicated 
Death 
A disorder 
characterized 
by generalized 
inflammatory 
erythema and 
exfoliation. The 
inflammatory 
process 
involves >90 of 
the Body 
Surface Area 
10051837 
Skin & 
subcutaneous 
tissue disorders 
Skin Induration 
Mild induration, 
able to move 
skin parallel to 
plane (sliding) 
and 
perpendicular to 
skin (pinching 
up) 
Moderate 
induration, able 
to slide skin, 
unable to pinch 
skin; limiting 
instrumental 
ADL 
Severe 
induration, 
unable to slide 
or pinch skin; 
limiting joint 
movement; 
limiting self-
care ADL 
Generalized; 
associated with 
signs and 
symptoms of 
impaired 
breathing or 
feeding 
Death 
A disorder 
characterized 
by an area of 
hardness in the 
skin 
10040947 
Skin & 
subcutaneous 
tissue disorders 
Skin Ulceration 
Combined area 
of ulcers <1cm; 
non-blanchable  
erythema of 
intact skin with 
associated 
warmth or 
edema 
Combined area 
of ulcers 1 - 
2cm; partial 
thickness skin 
loss involving 
skin or 
subcutaneous 
fat 
Combined area 
of ulcers >2cm; 
full-thickness 
skin loss 
involving 
damage to or 
necrosis of 
subcutaneous 
Any size ulcer 
with extensive 
destruction, 
tissue 
necrosis, or 
damage to 
muscle, bone, 
or supporting 
Death 
A disorder 
characterized 
by 
circumscribed, 
inflammatory 
and necrotic 
erosive lesion 
on the skin 

 
 
 
 
 
 
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tissue that may 
extend down to 
fascia 
structures with 
or without full 
thickness skin 
loss 
 

 
 
 
 
 
 
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APPENDIX F: ECOG Performance Status48 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-
disease performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically 
strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all 
self-care, but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-
care, confined to bed or chair more than 50% of waking 
hours. 
4 
100% bedridden. Completely disabled. Cannot carry on 
any self-care. Totally confined to bed or chair. 
5 
Dead. 
 
 

 
 
 
 
 
 
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APPENDIX G: Dose Modification Guidelines for Drug-Related Adverse Events for  Pembrolizumab (July 
2019)  
 
Immune Related Adverse 
Reactions 
Severity (Grade) 
Treatment Modification 
Pneumonitis 
Moderate (Grade 2) 
Withhold pembrolizumab until adverse 
reaction recovers to Grade 0-1* 
 
Severe or life threatening (Grade 3 or 4) 
or recurrent moderate Grade 2 
 
Permanently discontinue pembrolizumab 
Colitis 
Moderate or Severe (Grade 2 or 3) 
Withhold pembrolizumab until adverse 
reaction recovers to Grade 0-1* 
 
Life threatening (Grade 4) or recurrent 
severe (Grade 3) 
 
Permanently discontinue pembrolizumab 
Nephritis 
Moderate (Grade 2) with creatinine >1.5 
to ≤ 3 times ULN†  
 
Withhold pembrolizumab until adverse 
reaction recovers to Grade 0-1* 
Severe or life-threatening (Grade 3 or 4) 
(Grade ≥ 3 with creatinine > 3 times ULN) 
 
Permanently discontinue pembrolizumab 
Endocrinopathies 
-Severe or life-threatening (Grade 3 or 4) 
symptomatic hypophystitis  
-Type I diabetes associated with Grade 
>3 hyperglycaemia (glucose >250mg/dL 
or > 13.9 mmol/L) or associated with 
ketoacidosis 
-Hyperthyroidism Grade ≥ 3 
Withhold pembrolizumab until adverse 
reaction recovers to Grade 0-1* 
 
For patients with severe (Grade 3) or life 
threatening (Grade 4) endocrinopathy that 
improved to Grade 2 or lower and is 
controlled with hormone replacement, if 
indicated, continuation of pembrolizumab 
may be considered after corticosteroid 
taper, if needed. Otherwise treatment 

 
 
 
 
 
 
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should be discontinued 
 
Hypothyroidism may be managed with 
replacement therapy without treatment 
interruption 
 
Hepatitis 
Moderate (Grade 2) with asparate 
aminotransferase (AST) or alanine 
aminotransferase (ALT) > 3 to 5 times 
ULN or bilirubin > 1.5 to 3 times ULN 
 
Withhold pembrolizumab until adverse 
reaction recovers to Grade 0-1* 
-Grade ≥ 3 with AST or ALT >5 ULN or 
total bilirubin > 3 times ULN 
-for patients with liver metastasis who 
begin treatment with moderate (Grade 2) 
elevation of AST or ALT, if AST or ALT 
increases ≥ 50% relative to baseline and 
lasts ≥ 1 week 
 
Permanently discontinue pembrolizumab 
Skin Reactions or Stevens-
Johnson Syndrome (SJS) or toxic 
epidermal necrolysis (TEN) 
Severe skin reactions (Grade 3) or 
suspected SJS or TEN 
 
Withhold pembrolizumab until adverse 
reaction recovers to Grade 0-1* 
Severe skin reactions (Grade 4) or 
confirmed SJS or TEN 
 
Permanently discontinue pembrolizumab 
Other Immune-related adverse 
reactions 
Based on severity and type of reaction 
(Grade 2 or 3) 
 
Withhold pembrolizumab until adverse 
reaction recovers to Grade 0-1* 
Severe of life-threatening (Grade 3 or 4) 
myocarditis, encephalitis, or Guillain-
Barre Syndrome 
 
Permanently discontinue pembrolizumab 
Life threatening (Grade 4) or recurrent 
sever (Grade 3) 
 
Permanently discontinue pembrolizumab 

 
 
 
 
 
 
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Infusion related reactions 
Severe or life-threatening (Grade 3 or 4) 
 
Permanently discontinue pembrolizumab