The Seena Magowitz Phase IB/II Trial of CMP-001 (a TLR9 Agonist) in Combination With INCAGN01949 (an Activating Anti-OX40 Antibody) for In Situ Intratumoral Injection for Patients With Stage IV Pancreatic and Other Cancers Except Melanoma
Phase: PHASE1
Conditions: Locally Advanced Malignant Solid Neoplasm, Metastatic Pancreatic Adenocarcinoma, Stage IV Pancreatic Cancer AJCC v8, Unresectable Malignant Solid Neoplasm
Sponsor: University of Southern California

 
 
Local Protocol #: 0C-19-19 
Protocol Title: The Seena Magowitz Phase IB/II Trial of CMP-001 (a 
TLR9 agonist) in Combination with INCAGN01949 (an activating 
anti-OX40 antibody) for In Situ Intratumoral Injection for Patients 
with Stage IV Pancreatic and other Cancers except Melanoma 
Protocol version date: 03/12/2021 
 
ClinicalTrialsgov #: NCT04387071 
 
 

 
Protocol # 0C-19-19/TGen 19-001 
 
 
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The Seena Magowitz Phase IB/II Trial of CMP-001 (a TLR9 agonist) in 
Combination with INCAGN01949 (an activating anti-OX40 antibody) for In 
Situ Intratumoral Injection for Patients with Stage IV Pancreatic and other 
Cancers except Melanoma 
IND 19516 
SPONSOR: 
UNIVERSITY OF SOUTHERN CALIFORNIA (USC) 
 
STUDY SITES: 
HONORHEALTH, SCOTTSDALE, AZ 
USC Norris Comprehensive Cancer Center, Los Angeles, CA 
Hoag Memorial Hospital Presbyterian, Newport Beach, CA 
Stanford University, Stanford, CA 
Protocol No. 0C-19-19/TGen 19-001 
March 12, 2021 
 
 
Lead Principal Investigators: 
 
Diana L. Hanna, MD 
USC Norris Comprehensive Cancer Center 
Hoag Memorial Hospital 
One Hoag Drive, Building 41  
Newport Beach, CA 92663 
Phone: (949) 764-6147 
Fax: (949) 764-4267 
Diana.Hanna@med.usc.edu 
 
 
 
This study is funded and administered by the research teams at: 

 
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CONFIDENTIAL 
 
 
 
 
 
 
 
     
  
Funding Provided By: Seena Magowitz Foundation  
 

 
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Senior Scientific Investigator: 
Ron Levy, MD 
Stanford University  
Professor and Chief 
Division of Oncology 
269 Campus Drive,  
CCSR 1105,  
Stanford, CA 94305 
Ph: (650) 725-6452 
Fax: (650) 725-1420 
 
Consulting Investigator: 
Daniel D. Von Hoff, MD, FACP 
Translational Genomics Research Institute (TGen) an 
affiliate of City of Hope 
HonorHealth Research Institute 
10510 N. 92nd St 
Scottsdale, AZ 85258 
Tel: 480-323-1263 
dvh@tgen.org 
Scientific Investigator: 
Derek Cridebring, PhD 
Translational Genomics Research Institute (TGen) an 
affiliate of City of Hope 
445 N. 5th St 
Tel: 602-323-8629 
dcridebring@tgen.org 
 
Scientific Investigator: 
John Altin, PhD 
Translational Genomics Research Institute (TGen) an affiliate of City of Hope 
445 N. 5th St 
Tel: 928-226-6373 
jaltin@tgen.org  
Site Principal Investigators (PIs at their institution) 
Erkut Borazanci, MD,  
HonorHealth Research Institute 
10510 N. 92nd St 
Scottsdale, AZ 85258 
Tel: 480-323-1350 
erkut.borazanci@honorhealth.com  
 
 
Ron Levy, MD 
Stanford University 
Professor and Chief 
Division of Oncology 
269 Campus Drive,  
CCSR 1105,  
Stanford, CA 94305 
Ph: (650) 725-6452 
Fax: (650) 725-1420 
levy@stanford.edu 
 
Diana L. Hanna, MD 
USC Norris Comprehensive 
Cancer Center 
Hoag Memorial Hospital 
One Hoag Drive, Building 41  
Newport Beach, CA 92663 
Phone: (949) 764-6147 
Fax: (949) 764-4267 
Diana.Hanna@med.usc.edu 
Sub-Investigators: 
Gavin Slethaug, MD 
Interventional Radiologist 
Adjunct Professor, TGEN 
Scottsdale Medical Imaging, Ltd 
9700 N 91st St 
Suite C200 
Scottsdale, AZ 85258 
480-425-5000 
gslethaug@esmil.com 
Rolf Hultsch, MD 
Interventional Radiologist 
Scottsdale Medical Imaging, Ltd 
9700 N 91st St 
Suite C200 
Scottsdale, AZ 85258 
480-425-5000 
RHultsch@esmil.com 
 
 
Gayle S. Jameson, MSN, ACNP-BC, AOCN           
HonorHealth Research Institute                     
10510 N. 92nd Street                             
Scottsdale, AZ 85258                             
Jacob Thomas, MD 
Assistant Clinical Professor of Medicine 
USC Norris Comprehensive Cancer Center 
Hoag Memorial Hospital Presbyterian 
Phone: 949-764-6130 

 
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Tel: 480-323-1350                               
Fax: 480-323-1359   
Email: gayle.jameson@honorhealth.com     
                                              
Fax: 949-764-4267 
Jacob.Thomas@med.usc.edu 
 
Anthony El-Khoueiry, MD 
Associate Professor of Clinical Medicine 
Medical Director of Clinical Investigations Support 
Office 
Phase I program director 
USC Norris Comprehensive Cancer Center 
1441 Eastlake Ave, Suite 3440 
Los Angeles, CA 90033 
Phone: (323) 865 3967  
 
Biostatistician: 
Denise J. Roe, DrPH 
The University of Arizona Cancer Center 
1515 N. Campbell Ave 
Campus PO Box: 245024 
Levy Building 1933 
Tucson, AZ 85724 
Tel. 520-626-2281 
droe@email.arizona.edu 
 
 
 
Study Drug: 
 
 
CMP001, INCAGN01949 
 
IND Number: 
 
 
19516 
 
IND Holder Name: 
 
University of Southern California 
 
Funding Source:  
Seena Magowitz Foundation 
 
Research Office:                       CLINICAL INVESTIGATIONS SUPPORT OFFICE (CISO) 
                                                    1441 Eastlake Avenue, Room 7310E 
                                                    Los Angeles, California 90089-9177 
                                                    Telephone (323) 865-0451 
Email: ciso.clinical@med.usc.edu 
 
 

 
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INVESTIGATOR PROTOCOL AGREEMENT 
 
Protocol#: 
 
 
0C-19-19/TGen 19-001 
Protocol Title:  
The Seena Magowitz Phase IB/II Trial of CMP-001 (a TLR9 agonist) in 
Combination with INCAGN01949 (an activating anti-OX40 antibody) for In 
Situ Intratumoral Injection for Patients with Stage IV Pancreatic and other 
Cancers except Melanoma 
Protocol Version/Date:  
March 12, 2021 
 
I confirm that my staff and I have carefully read and understand this protocol. I/we agree to comply 
with the procedures and terms of the clinical trial specified herein. In particular, I/we have agreed 
to: 
• 
Abide by all obligations as required by local and federal regulatory authorities. 
• 
Comply with Good Clinical Practice (GCP) and all applicable regulatory requirements. 
• 
Maintain confidentiality and assure security of Sponsor and confidential documents 
• 
Obtain Institutional Review Board (IRB) approval of the protocol, any amendment to the protocol, 
and periodic re-approval as required, and to keep the IRB informed of any adverse events and 
periodically report the status of the trial to them. 
• 
Not implement any deviations from or changes to the protocol without agreement from the 
sponsor and prior review and written approval from the IRB, except where necessary to eliminate 
an immediate hazard to the patients or for administrative aspects of the trial (where permitted by 
all applicable regulatory requirements). 
• 
Assure that each patient enrolled into the trial has read, understands, and has signed the informed 
consent. 
• 
Ensure that I and all persons assisting me with the trial are adequately informed and trained about 
the investigational drug and of their trial-related duties and functions as described in the protocol. 
• 
Make prompt reports of serious adverse events (SAEs) and deaths (within 1 business day of 
learning of the death and/or of learning of the SAE) to Sponsor. 
• 
Assure access by Sponsor including assigned CRO and/or FDA to original source documents. 
• 
Prepare and maintain adequate and accurate case histories designed to record all observations 
and other data pertinent to the investigation on each individual treated in the investigation. 
• 
Arrange for the transfer of appropriate data from case histories to case report forms for the 
collection and transmission of data to the Sponsor. 
• 
Retain records and documents related to this trial for at least 3 years after the completion of the 
trial as confirmed by the sponsor. 
• 
Cooperate fully with any trial-related GCP audit as performed by the assurance group specified 
by the Sponsor. 
• 
Abide by the stipulations in the Disclosure of Data section and the manuscript 
preparation/authorship guidelines established at the outset of the trial. 
The signature below constitutes the approval of this protocol and the attachments, and provides the necessary 
assurances that this trial will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
Investigator’s Printed Name: ________________________ 
 
Institutional Name:  _______________________________ 
 
Investigator’ Signature: ____________________________  
Date: ___________ 

 
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Glossary of Abbreviations 
Term 
Definition 
ADA 
Antidrug antibody 
ADL 
Activity of Daily Living 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANA 
Anti-nuclear antibody  
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
BPI 
Brief Pain Index 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CA-125 
Cancer Antigen 125 
CA 19-9 
Carbohydrate Antigen 19-9  
CBC 
Complete Blood Count 
CEA 
Carcinoembryonic Antigen 
CFR 
Code of Federal Regulations  
CIC 
Clinical investigations committee 
CISO 
Clinical investigations support office 
CNS 
Central Nervous System 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRS 
Cytokine release syndrome 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHHS 
Department of Health and Human Services 
DLT 
Dose Limiting Toxicity 
DSMC 
Data Safety and Monitoring Committee  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
ERC 
Ethics Review Committee 
FDA 
Food and Drug Administration 
 
 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonisation 

 
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Glossary of Abbreviations 
Term 
Definition 
IDO 
Indoleamine 2,3- dioxygenase 
IFNα 
Interferon alpha  
INR 
International Normalized Ratio 
IO 
Immuno-oncology  
irAE 
Immune-related Adverse Event 
IRB 
Institutional Review Board 
iRECIST 
Immunotherapy Response Evaluation Criteria in Solid Tumours 
IT 
Intra-tumor 
IUD 
Intrauterine Device 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
mAb 
Monoclonal Antibody  
MTD 
Maximum Tolerated Dose 
MRD 
Minimal Residual Disease 
MRI 
Magnetic Resonance Imaging 
NCCC 
Noriss comprehensive cancer center 
NCI 
National Cancer Institute 
NIH 
National Institutes for Health 
NS 
Normal saline 
ODN 
Oligodeoxynucleotide  
OS 
Overall Survival 
OTC 
Over-the-counter 
PD 
Progressive Disease 
PDAC 
Pancreatic Ductal Adenocarcinoma 
pDC 
Plasmacytoid dendritic cell  
PFS 
Progression Free Survival  
PR 
Partial Response 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
QbG10 
Qb packaged with the oligonucleotide G10 (referred to as the active drug 
substance)  
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROA 
Route of administration  
SAE 
Serious Adverse Event 
SC  
Subcutaneous  
SD 
Stable Disease  
SOP 
Standard Operating Procedure  
SubQ 
Subcutaneous 
TGen 
Translation Genomic Research Institute 
TLR9 
Toll-like receptor 9  
ULN 
Upper Limit of Normal 

 
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Glossary of Abbreviations 
Term 
Definition 
VLP 
Virus-like particle 
WOCBP 
Woman Of Childbearing Potential  

UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR. 
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
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TRIAL SCHEMATIC 
The study is divided into two phases: 
 
 
 
MTD Phase II Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase IB  
N = 3-21 patients 
 
Patients with previously treated (for 
their metastatic disease) pancreatic 
ductal adenocarcinoma and other 
types of cancer, except melanoma, 
will be enrolled (1-3 pts each dose 
level) in up to 6 dose cohorts of a 
fixed dose of CMP-001 (TLR9 
agonist) + INCAGN01949 (OX40 
agonist).      
 
Note: Dosing schedule is done on a 
weekly basis. Week 1 day 1 is the 
first dose of CMP-001 given SC. The 
first two weeks of treatment (dose 1 
and 2) are only with CMP-001 
administered subcutaneously (SC) at 
a dose of 5mg. After this priming 
period 
with 
CMP-001 
both 
investigational agents (CMP-001 and 
INCAGN01949) will be given via 
intratumor (IT) administration. The 
remaining 4 weeks (doses 3-6) of the 
study both agents will be given IT 
(CMP-001 will be given at 10mg 
during IT administration).  Biopsies 
will be done before the first SC 
treatment, 
before 
the 
2nd 
IT 
treatment and before the 4th IT 
treatment (e.g. before week 1, before 
week 4 and week 6).                            
 
Endpoint for this phase IB portion 
of the study is determining the 
doses and tolerance, effect on 
biomarkers and recommended 
Phase II  
N = 10-21 patients 
 
Determine 
the 
efficacy 
(Disease 
Control Rate defined as CR+ PR+ SD 
X 16 weeks) of Phase I (MTD) 
selected dose of CMP-001 (TLR9 
agonist) 
in 
combination 
with 
INCAGN01949 (anti-OX40 antibody) 
for patients with previously treated (for 
their metastatic disease) pancreatic 
ductal adenocarcinoma 
 
CMP-001 
INCAGN01949 
Wk1 
5mg SC 
No dose, CMP-001 SC only 
Wk2 
5mg SC 
No dose, CMP-001 SC only 
Wk3 
10mg IT 
Dose level 1, 2, 3, 4, 5, 6 
Wk4 
10mg IT 
Dose level 1, 2, 3, 4, 5, 6 
Wk5 
10mg IT 
Dose level 1, 2, 3, 4, 5, 6 
Wk6 
10mg IT 
Dose level 1, 2, 3, 4, 5, 6 
 

 
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TRIAL SYNOPSIS 
 
Protocol#: 
0C-19-19/TGen 19-001 
Protocol Title: 
The Seena Magowitz Phase IB/II Trial of CMP-001 (a TLR9 agonist) 
in Combination with INCAGN01949 (an activating anti-OX40 
antibody) for In Situ Intratumoral Injection for Patients with Stage IV 
Pancreatic and other Cancers except Melanoma  
Short Title: 
Intratumoral TLR9 agonist plus OX40 Agonist in PDAC and other 
Cancers (except melanoma) 
Protocol Version/Date: 
March 12, 2021      
Sponsor: 
University of Southern California (USC) 
Trial Sites:  
HonorHealth, Scottsdale, AZ 
USC Norris Comprehensive Cancer Center, Los Angeles, CA 
Hoag Memorial Hospital, Newport Beach, CA 
Stanford University, Stanford, CA 
Lead Principal 
Investigators:  
Diana Hanna, MD 
 
Clinical Phase: 
Phase IB/II 
 
Trial Design: 
Phase IB/II Pilot Trial 
 
Objectives: 
Primary:   
• 
Phase IB: To determine the maximum tolerated dose and 
tolerance of CMP-001 (TLR9 agonist) in combination with 
INCAGN01949 (an activating antibody against OX40) both 
given intratumorally for patients with previously treated (for 
their metastatic disease) pancreatic ductal adenocarcinoma 
and other types of cancer except melanoma. 
 
• 
Phase II:  To determine the efficacy (Disease control rate - 
CR + PR + SD X 16 weeks) of CMP-001 (TLR9 agonist) in 
combination with INCAGN01949 (OX40 agonist antibody) for 
patients with previously treated (for their metastatic disease) 
pancreatic ductal adenocarcinoma.   
 
• 
To determine effects on tumor markers. 
 
Secondary: 
• 
Define the toxicity of the combination of CMP-001 (TLR9 
agonist) + INCAGN01949 (OX40 agonist antibody) 
 
• 
Determine progression free survival and overall survival 
 
Exploratory: 
• 
Using flow cytometry on peripheral blood, OX40 expression 
will be analyzed within the lymphocyte subsets (Teffs and 
Tregs).   
 
• 
On tissue samples collected prior to, and during treatment, 
we will: 

 
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– Use flow cytometry to enumerate CD4+ and CD8+ T cell 
subsets, and the expression of activation/differentiation 
markers (including CD127, HLA-DR, CD45RO, CCR7, 
CXCR3) on each 
 
– Use RT-PCR and sequencing to amplify and characterize 
the TCRa and b sequences of tumor-infiltrating T cells, 
looking for evidence of oligo-clonal T cell expansion, OX40 
expression 
 
- 
If there is adequate tumor tissue, perform RNAseq to 
determine different immune cell populations, including T 
cells and macrophages  
 
 
Endpoints: 
Primary:  
• 
Phase IB: Doses and tolerance and recommended Phase II 
dose   
 
• 
Phase II: Disease control rate (CR+PR+SD x 16 weeks via 
RECIST and iRECIST) and effects on tumor markers 
 
Secondary:  
• 
Incidence of toxicities 
 
• 
Progression free survival and overall survival 
 
Exploratory: 
• 
To determine OX40 expression within the lymphocyte 
subsets (Teff and Treg) 
 
• 
On tissue samples collected prior to, and during, treatment, 
we will: 
 
– Use flow cytometry to enumerate CD4+ and CD8+ T cell 
subsets, 
tumor 
cells, 
and 
the 
expression 
of 
activation/differentiation markers (including CD127, HLA-DR, 
CD45RO, CCR7, CXCR3) on each 
 
– Use RT-PCR and sequencing to amplify and characterize 
the TCRa and b sequences of tumor-infiltrating T cells, 
looking for evidence of oligo-clonal T cell expansion, OX40 
expression 
 
- 
If there is adequate tumor tissue, perform RNAseq to 
determine different immune cell populations, including T 
cells and macrophages  
 
 
 
Statistical Methods: 
The sample size of this pilot study will be up to 21 patients in Phase 
IB. In phase II, we will treat an initial cohort of 10 patients, and if there 

 
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are no patients with disease control defined as (CR+PR+stable 
disease x 16 weeks) the trial will be closed. If there are 1 or more 
patients with disease control, the trial will be expanded to 21 patients 
with pancreatic cancer. Four or more patients with disease control 
out of 21 patients will be sufficient evidence for rejection of the null 
hypothesis of insufficient activity of the regimen. This design has a 
power of 90% at a one-sided Type I error rate of 2.5%. 
 
Statistical Methods for 
Efficacy: 
The efficacy analysis will include summaries for the following 
parameters: complete response rate (CR), objective response rate 
(CR + PR), disease control rate (CR + PR + SD at 16 weeks), percent 
of patients who have decrease in tumor marker, progression-free 
survival (PFS), and overall survival (OS). The efficacy analysis will 
only be conducted on patients who have received at least one dose 
of CMP-001 and of INCAGN01949 and have at least one post 
baseline tumor assessment. 
 
Objective responses will be evaluated using the Response 
Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1) and iRECIST. 
Changes (i.e. improvements) in tumor measurements from baseline 
values will be assigned a status of CR or PR or SD. Objective 
response measurements will comprise the sum of CR plus PR. The 
overall response rate, as well as the rates for the individual 
categories of response (i.e. CR, PR, SD, and PD) will be estimated 
by the percentage of patients who have received at least one dose 
of CMP-001 and of INCAGN01949 achieving these criteria. The 
disease control rate will consist of the sum of CR + PR + SD for 16 
weeks. All proportions will be estimated using an exact 95% binomial 
confidence interval.  For the estimation of progression-free and 
overall survival, a Kaplan-Meier analysis will be performed.  
 
Tumor assessments for evaluation of response will be conducted 
using CT or MRI, approximately every 8 weeks until study 
discontinuation or disease progression, whichever is later. All sites of 
disease must be followed using the same baseline assessment 
method. Confirmatory assessment of complete response (CR) or 
partial response (PR) must be performed no less than 4 weeks after 
the initial documentation of response. All target lesions will be 
measured by consistent imaging techniques for each patient 
throughout the study. Suitable imaging techniques include CT-scan, 
or MRI. The same technique should be used for each evaluation in 
an individual patient. Copies of the scans must be available for 
review.  
 
Progression-free survival is defined as the interval from the date of 
registration (i.e. assignment of patient number) to the earliest date of 
documented evidence of recurrent or progressive disease, or the 
date of death due to any cause, whichever occurs first. Patients who 
do not progress and remain alive will be censored at their last 
radiographic assessment date. Overall survival will be measured 
from the date of registration (i.e. assignment of patient number) to 

 
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the date of death due to any cause, or the date of last contact 
(censored observations). 
 
Statistics for Safety: All patients who receive any dose of CMP-001 or INCAGN01949 will 
be included in the following safety analyses: 
 
• 
The incidence, severity, duration, causality, seriousness, and 
type of AEs 
 
• 
Changes in the patient’s physical examination, vital signs, 
and clinical laboratory results 
 
• 
Grading of clinical laboratory results per CTCAE version 5.0 
criteria for selected laboratory parameters 
 
• 
Deaths 
 
• 
Concomitant medications 
 
Name, dose of 
investigational agents:  
The first two doses of CMP-001 are given subQ at a dose of 5mg 
while the remaining doses are given intratumorally (IT) at 10mg. All 
doses of INCAGN01949 are given 
IT 
 
 
 
 
 
Dose 
Level 
CMP-001  
 (mg) 
INCAGN01949  
(mcg/m2) 
-1 
5 (IT) 
250 (IT) 
1 
10 (IT) 
500** (IT) 
2 
10 (IT) 
1000  (IT) 
3 
10 (IT) 
1670  (IT) 
4 
10 (IT) 
2505  (IT) 
5 
10 (IT) 
3507  (IT) 
6 
10 (IT) 
4559* (IT)  
* If higher dose levels are needed, escalation will be in 50% increments  
** The 500mcg/m2 dose of INCAGN01949 will be reconstituted to a 
volume of 1ml  INCAGN01949 will be supplied as 5 mL of aqueous 
solution in 10 mL glass vials with 10 mg/mL.   
 
• 
Note: One patient per dose level until grade greater than or 
equal to grade 2 toxicity. Then 3 patients per level. Our 
recommended dose will be determined by induction of 
expression of OX40 on the CD4+ T cells.   
 
• 
The dose escalation scheme used is a conservative modified 
Fibonacci method 
 
• 
As currently designed, the first two CMP-001 doses will be 
given subcutaneously, and the following doses 3-6 will be 
CAUTION: 
INCAGN01949 is in 
micrograms per 
meter squared  

 
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given intratumorally (IT). All 4 doses of INCAGN01949 will be 
given IT. If the patient is judged to be having clinical benefit 
the possibility of being treated with additional doses will have 
to be dealt with via an amendment to this protocol.   
 
• 
The starting dose for intratumoral injection of INCAGN01949 
is based on the known safety profile of intravenous 
INCAGN01949 at doses ranging from 7-1400 mg.  The 
proposed starting dose is less than 10% of the intravenous 
route of administration and provides an additional margin for 
safety in the trial.  There is the potential for OX40 upregulation 
following TLR9 agonist administration and its binding could 
produce cytokine release. 
 
Total # of Patients: 
Total of up to 21 in the Phase IB portion and up to 21 in the Phase II 
portion 
 
Treatment Arms: 
Arm 1: CMP-001 (TLR9 agonist) + INCAGN01949 (OX40 agonist 
antibody) 
 
Patient Population: 
Patients previously treated with stage IV pancreatic cancer and other 
appropriate types of metastatic cancers except melanoma.  
 
Inclusion criteria:  
1. Be willing and able to provide written informed consent for the 
trial. 
 
2. Be ≥ 18 years of age. 
 
3. Histologically 
or 
cytologically 
confirmed 
pancreatic 
adenocarcinoma with metastasis or other locally advanced un-
resectable solid tumor malignancies (during the phase Ib and 
pancreatic cancer during phase II) deemed appropriate by the 
Investigator except melanoma. 
 
4. Have a performance status of 0 or 1 on the ECOG performance 
scale. 
 
5. Subjects must have at least one extra-central nervous system 
(CNS), non-bone tumor lesion amenable for IT injection ≥ 1.5 cm 
and that is not in close proximity or encasing crucial structures 
such as major blood vessels, trachea, nerve bundles etc. 
Measurable disease is required in a minimum of two lesions (one 
injected and one other) and there must be at least one 
measurable lesion in addition to the one being injected. 
 
6. Be willing to undergo a needle biopsy of a tumor lesion at 
baseline, after 2 weeks of IT injection and 4 weeks of IT injection 
(Week 4 and 6), unless tumor is considered inaccessible or 
biopsy is otherwise considered not in the patients best interest. 
 
7. Demonstrate adequate organ function as defined in Table 2.  

 
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8. Female participants of childbearing potential should have a 
negative serum pregnancy test within 24 hours prior to receiving 
first dose of trial medication.  
 
9. A female participant is eligible to participate if she is not pregnant, 
not breastfeeding, and at least one of the following conditions 
applies:  
 
a.) Not a woman of childbearing potential (WOCBP) 
 
OR 
 
b.) A WOCBP who agrees to follow the contraceptive guidance 
during the treatment period and for at least 180 days after 
the last dose of trial treatment.  
 
10. Male participants must agree to use contraception as detailed in 
the full protocol during the treatment period and for at least 120 
days after the last dose of trial treatment and refrain from donating 
sperm during this period. 
 
11. Patients will have had at least 2 prior therapies for locally 
advanced, un-resectable and/or metastatic disease. Adjuvant 
therapy will count as one line of therapy if disease progression 
occurred during treatment or within 6 months of completion.  
 
      Patients with metastatic pancreatic cancer must have 
received either FOLFIRINOX or a gemcitabine-based 
regimen as one of their prior lines of therapy. Patients with 
germline BRCA mutations must have received olaparib as 
maintenance therapy. 
 
Exclusion criteria: 
1. Is currently participating and receiving trial therapy or has 
participated in a trial of an investigational agent and received trial 
therapy or used an investigational device within 3 weeks (or 5 
half-lives, whichever is shorter) of the first dose of trial treatment. 
 
2. Has a diagnosis of immunodeficiency or is receiving systemic 
steroid therapy or any other form of immunosuppressive therapy 
within 7 days prior to the first dose of trial treatment.  The use of 
physiologic doses of corticosteroids (not to exceed a daily 
equivalent of Prednisone 10mg daily) may be approved after 
consultation with the Sponsor. 
If 
patients 
received 
prior 
ipilimumab 
or 
anti-CTLA4 
compound 
and 
had 
adrenal 
insufficiency, treat these subjects with stress dose steroids prior 
to intratumoral injections. If patients are receiving stress steroids 
orally but if not able to have orally then they would be given IV 
before the procedure.    
 

 
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3. Hypersensitivity to CMP-001 (TLR9 agonist) or INCAGN01949 
(OX40 agonist antibody) or any of its excipients. 
4. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 
weeks prior to Week 1/Day 1 or who has not recovered (i.e., ≤ 
Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier. 
 
5. Has had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 3 weeks prior to Week1/ Day 1 or who 
has not recovered (i.e., ≤ Grade 1 or to baseline) from adverse 
events due to a previously administered agent(s). 
 
Note:  Patients with ≤ Grade 2 neuropathy are an exception to 
this criterion and may qualify for the trial. 
 
Note: If patient received major surgery, they must have 
recovered adequately from the toxicity and/or complications 
from the intervention prior to starting therapy.   
6. Has a known additional malignancy that is progressing or 
requires active treatment.  Exceptions include basal cell 
carcinoma of the skin or squamous cell carcinoma of the skin that 
has undergone potentially curative therapy or in situ cervical 
cancer. Other malignancies which have been treated with 
curative intent, or for which patients are not receiving active 
therapy, may be considered upon discussion with the 
Investigator. 
7. Has known active central nervous system (CNS) metastases 
and/or carcinomatous meningitis. Patients 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 7 days prior to trial treatment. Use of prophylactic anti-
epileptic drugs is permitted. This exception does not include 
carcinomatous meningitis, which is excluded regardless of clinical 
stability.   
8. Has active autoimmune disease that has required systemic 
treatment in the past 2 years (i.e. with use of disease modifying 
agents, 
corticosteroids 
or 
immunosuppressive 
drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment.  
9. Has history of (non-infectious) pneumonitis that required steroids 
or currently has pneumonitis. 

 
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10. Has an active infection requiring systemic therapy. 
11. Has a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, 
interfere with the patient’s participation for the full duration of the 
trial, or is not in the best interest of the patient to participate, in 
the opinion of the treating investigator.   
12. Has known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
 
13. Has a known history of Human Immunodeficiency Virus (HIV) 
(HIV 1/2 antibodies). 
 
14. Has a known history of or is positive for Hepatitis B (e.g., HBsAg 
reactive) or untreated Hepatitis C. Treated Hepatitis C with 
sustained virologic response and patients who are negative for 
Hepatitis BsAg are not excluded. 
 
Note: Without known history, testing needs to be performed to 
determine eligibility.  
15. Current, serious, clinically significant cardiac arrhythmias as 
determined by the treating investigator. 
16. Has received a live vaccine within 30 days of planned start of trial 
therapy. 
 
Note:  Seasonal influenza vaccines for injection are generally 
inactivated flu vaccines and are allowed; however intranasal 
influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
 
17. Patients must not be receiving any anticoagulation. Low 
molecular weight heparin at full dose or prophylactic dose is 
allowed as long as the treating physician deems it safe to hold 
the LMWH on the day before and the day of the intra-tumoral 
injection.  
 
 
 
 

 
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TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE ............................................................ 23 
Overview ............................................................................................................... 23 
Rationale for the use of TLR9 + OX40 .................................................................. 23 
CMP-001 (TLR9 agonist) Background................................................................... 25 
1.1.1 Study CMP-001-001 Treatment-Emergent Adverse Events ....................... 26 
1.1.2 CMP-001 Potential Autoimmunity ............................................................... 31 
1.1.3 CMP-001 Potential Effects Related to IFNα Induction ................................ 32 
1.1.4 CMP-001 Potential Drug Interactions ......................................................... 33 
INCAGN01949 (OX40 agonist) Background ......................................................... 33 
1.1.5 Potential Risks of INCAGN01949 (OX40 agonist) ...................................... 34 
2.0 
HYPOTHESIS ............................................................................................. 35 
3.0 
OBJECTIVES ............................................................................................. 35 
Primary Objective .................................................................................................. 35 
Secondary Objective ............................................................................................. 35 
Exploratory Objectives ........................................................................................... 35 
Primary Endpoints ................................................................................................. 36 
Secondary Endpoints ............................................................................................ 36 
Exploratory Endpoints ........................................................................................... 36 
4.0 
PATIENT ELIGIBILITY ............................................................................... 37 
4.1 
Eligibility ...................................................................................................... 37 
4.1.1 Inclusion Criteria ......................................................................................... 37 
4.1.2 Exclusion Criteria ........................................................................................ 39 
5.0 
TRIAL TREATMENTS ................................................................................ 41 
5.1.1 Body Surface Area Calculation ................................................................... 42 
5.1.2 Dose Escalation in Phase IB....................................................................... 42 
5.1.3 Dose Modification for Toxicity ..................................................................... 43 
5.1.4 Injection Site Reactions .............................................................................. 44 
5.1.5 CMP-001 Symptoms Associated with Cytokine ReleaseError! Bookmark not 
defined. 
5.1.6 Dose Limiting Toxicity ................................................................................. 47 
5.1.7 Rules for discontinuation of CMP-001 (TLR9) + INCAGN01949 (OX40) .... 48 
5.1.8 Intended Dose Delays ................................................................................ 49 

 
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Concomitant Medications/Vaccinations (allowed & prohibited) ............................. 49 
5.1.9 Acceptable Concomitant Medications ......................................................... 49 
5.1.10 Prohibited Concomitant Medications .......................................................... 49 
Diet/Activity/Other Considerations ......................................................................... 50 
5.1.11 Diet ............................................................................................................. 50 
5.1.12 Contraception ............................................................................................. 50 
5.1.13 Use in Pregnancy ....................................................................................... 52 
5.1.14 Use in Nursing Women ............................................................................... 52 
Patient Withdrawal/Discontinuation Criteria ........................................................... 52 
Patient Replacement Strategy ............................................................................... 53 
Clinical Criteria for Early Trial Termination ............................................................ 53 
6.0 
TRIAL SCHEDULE ..................................................................................... 55 
7.0 
TRIAL PROCEDURES ............................................................................... 58 
7.1 
Trial Procedures ......................................................................................... 58 
7.1.1 Administrative Procedures .......................................................................... 58 
7.1.2 Clinical Procedures/Assessments ............................................................... 60 
7.1.3 Blood and Tumor Tissue Collection ............................................................ 62 
7.1.4 Laboratory Procedures/Assessments ......................................................... 63 
7.1.5 Visit Requirements ...................................................................................... 65 
7.1.6 Use of Prophylaxis Prior to and After CMP-001 Dosing .............................. 71 
7.1.7 Subcutaneous Injections with CMP-001 ..................................................... 72 
7.1.8 Intratumoral Injections with CMP-001 and INCAGN01949 ......................... 73 
7.1.9 Observation Period Following CMP-001 and INCAGN01949 Dosing ......... 74 
8.0 
MEASUREMENT OF EFFECT ................................................................... 74 
8.1 
Definitions ................................................................................................... 74 
8.1.1 Evaluable for response ............................................................................... 74 
RECIST 1.1 Response and Evaluation Endpoints ................................................. 75 
8.1.2 Measurable Disease. .................................................................................. 75 
8.1.3 Non-measurable Disease. .......................................................................... 75 
8.1.4 Target Lesions. ........................................................................................... 75 
8.1.5 Non-target Lesions. .................................................................................... 76 
8.1.6 Response.................................................................................................... 76 
8.1.7 iRECIST Response Assessment ................................................................ 77 

 
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8.1.8 Confirming Progression .............................................................................. 78 
8.1.9 New Lesions ............................................................................................... 78 
8.1.10 Response and Stable Disease Duration (RECIST 1.1 and iRECIST) ......... 81 
8.1.11 Methods of Measurement ........................................................................... 81 
8.1.12 Clinical Lesions. .......................................................................................... 82 
8.1.13 Chest X-ray. ................................................................................................ 82 
8.1.14 CT, MRI. ..................................................................................................... 82 
8.1.15 Ultrasound. ................................................................................................. 82 
8.1.16 Endoscopy, Laparoscopy............................................................................ 82 
8.1.17 Tumor Markers. .......................................................................................... 83 
8.1.18 Cytology, Histology. .................................................................................... 83 
9.0 
ASSESSING AND REPORTING ADVERSE EVENTS ............................... 83 
9.1 
Definition of Adverse Event......................................................................... 83 
9.1.1 Reporting of Pregnancy and Lactation ........................................................ 84 
9.1.2 Immediate Reporting of Adverse Events to the Sponsor  ........................... 84 
9.1.3 Serious Adverse Events ............................................................................. 85 
9.1.4 Evaluating Adverse Events ......................................................................... 86 
9.1.5 Sponsor Responsibility for Reporting Adverse Events ................................ 89 
10.0 
STATISTICAL CONSIDERATIONS ............................................................ 89 
10.1 
Study Design .............................................................................................. 89 
10.2 
Sample Size Considerations ....................................................................... 89 
Statistical Analysis Plan ......................................................................................... 90 
10.3 
Analysis of the Conduct of the Study .......................................................... 90 
10.4 
Analysis of Patient Characteristics .............................................................. 90 
10.5 
Analysis of Trial Treatment Administration ................................................. 90 
10.6 
Analysis of Toxicities .................................................................................. 90 
10.7 
Analysis of Primary Endpoint ...................................................................... 90 
11.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................. 91 
11.1 
Investigational Product ............................................................................... 91 
11.2 
Packaging and Labeling Information ........................................................... 91 
11.2.1 CMP-001..................................................................................................... 91 
11.3 
Storage and Handling Requirements .......................................................... 92 

 
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11.3.1 CMP-001..................................................................................................... 92 
11.3.2 INCAGN01949 ............................................................................................ 93 
12.0 
ADMINISTRATIVE AND REGULATORY DETAILS .................................... 94 
12.1 
Institutional Review Board/Ethics Committee Approval and Consent Process
 
94 
12.2 
Investigators Protocol Agreement and Required Documentation ............... 95 
12.3 
Investigator Obligations .............................................................................. 95 
12.4 
Registration Procedures ............................................................................. 95 
12.5 
Slot Assignment .......................................................................................... 96 
12.6 
Confidentiality ............................................................................................. 96 
12.7 
Compliance with Financial Disclosure Requirements ................................. 96 
12.7.1 Compliance with Trial Registration and Results Posting Requirements ..... 97 
12.8 
Quality Management System ...................................................................... 97 
12.9 
Data Monitoring Plan .................................................................................. 97 
12.10 Data Management ...................................................................................... 97 
12.10.1 Case Report Forms ……………………………………………………………97 
12.10.2 Patient Consent Form………………………………………………………….98 
12.10.3 Registration Eligibility Worksheet.…………………………………………….98 
12.10.4 Data Collection Forms and Submission Schedule………………………….98 
12.10.5 Source Documents……………………………………………………………..98 
12.11 Record Retention ........................................................................................ 98 
12.12 Data Management and Monitoring/Auditing ................................................ 99 
12.13 Quality Assurance Monitoring Committee (QAMC) Oversight .................. 100 
12.14 Phase I Committee Oversight ................................................................... 101 
12.15 Adherence to the Protocol ........................................................................ 101 
12.15.1 Emergency Modifications……………………………………………………...101 
12.15.2 Non-Emergency Departures from Protocol………………………………….102 
12.15.3 Amendments to the Protocol………………………………………………….102 
12.16 Data Safety and Monitoring Committee .................................................... 102 
REFERENCES .................................................................................................... 104 
APPENDICES ..................................................................................................... 106 
Appendix 1 - NCI CTCAE version 5.0 .................................................................. 107 
Appendix 2 – ECOG Performance Status ........................................................... 108 

 
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TABLES 
Table 1: CMP-001-001 Treatment-Emergent Adverse Events Related to 
Combination Study Treatment .................................... Error! Bookmark not defined. 
Table 2: CMP-001-002 Treatment-Emergent Adverse Events Related to 
Combination Study Treatment .................................... Error! Bookmark not defined. 
Table 3. CMP-001-001 Treatment-emergent Adverse Events Reported in 5% or 
More of Subjects for All Grades, Grade 3 or Higher, and Treatment-related Grade 3 
or Higher, Part 1 Dose Escalation and Part 1 Dose Expansion Phases ............ Error! 
Bookmark not defined. 
Table 4.  Adequate Organ Function Laboratory Values........................................... 39 
Table 5.  Trial Treatments ....................................................................................... 41 
Table 6.  Screening – Treatment Period .................................................................. 55 
Table 7.  End of Treatment –Follow-Up ................................................................... 57 
Table 8.  Laboratory Tests – performed locally ....................................................... 63 
 
 

 
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1.0 BACKGROUND AND RATIONALE 
Overview 
Pancreatic cancer continues to be a very lethal disease.  It is estimated that in 2019,  
56,770 Americans will be diagnosed with pancreatic ductal adenocarcinoma (PDAC), 
and 45,750 will die from the disease.  This makes pancreatic cancer the third leading 
cause of death from cancer in the US (Siegel et al 2019). Furthermore, it is projected 
that by 2030, PDAC will be the second leading cause of death from cancer in the US. 
Worldwide, PDAC is the twelfth most common cancer, accounting for an estimate of 
> 300,000 deaths a year (Rahib et al 2014).  
 
Detection of pancreatic cancer has been notoriously very late in the disease and 
therefore the 5-year survival rate is only 8%. Right now, the only potential cure for 
pancreatic cancer is surgical resection (if the disease is caught early).  However, only 
about 20% of PDAC patients are eligible for potentially curable resection and 
unfortunately most (> 80%) have reoccurrence of their cancer within 2 years of 
resection, and those reoccurrences are almost universally fatal (Oettle et al 2013 and 
Neoptolemos et al 2010). Improved strategies for early detection and for treatment of 
PDAC are desperately needed. 
 
Immunotherapy has become an effective treatment for many cancer types with cures 
in previously untreatable cancers (Ascierto et al 2017). However, these 
immunotherapies have largely proven unsuccessful in pancreatic cancer. One of the 
reasons for this may be due to an unfavorable microenvironment that makes pancreas 
tumors immunologically "cold" (non-responsive) (Skelton et al 2017).  
 
Rationale for the use of TLR9 + OX40 
A promising new area of immunotherapy involves activating both the innate and the 
adaptive immune systems. This approach is called in-situ vaccination where 
immunoenhancing agents are injected into the tumor, which triggers a T cell response 
throughout the body (attacking local and metastatic tumors). The combination 
proposed here uses a TLR9 agonist (CMP-001) and an OX40 agonist 
(INCAGN01949). This technique is particularly interesting because it doesn't require 
prior knowledge of the unique tumor antigens in the patient (Sagiv-Barfi et al 2018).   
 
The paper by Sagiv-Barfi et. al. showed how in situ vaccination could cure several 
different mouse models of cancer via a single course (intratumor injection on days 1, 
3, and 5) of two immune-enhancing agents (Fig 1). The first agent is CpG, a Toll-like 
receptor 9 (TLR9) agonist known as CMP-001 followed by an anti-OX40 antibody 
(INCAGN01949) that acts as an agonist triggering a T cell immune response. This 
approach not only cured tumors that were injected with both agents but also distant 
tumors that were not injected. This combination also led to cures in a spontaneous 
mouse tumor model. We believe the intratumor injection and immunoenhancing 
properties of the approach will result in responses not previously seen using IO agents 

 
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in pancreatic and other cancers. In addition, local injections can likely avoid systemic 
side effects experienced by intravenously administered IO agents.  
 
 
 
 
 
Fig. 1. Tumor growth curves. Left 
column: Treated tumors (Tr). Right 
column: Nontreated tumors (NT). 
Top to bottom: Vehicle, CpG, aOX40, 
and CpG and aOX40 and survival 
plots of the treated mice (n = 10 
mice per group). ****P <0.0001, 
unpaired t test. Shown is one 
representative experiment out of 
nine. (C) Effect of CD4/CD8 
depletion. Mice were implanted with 
bilateral tumors, and one tumor was 
injected with CpG and aOX40 
antibody according to the schema in 
(A). CD4 (0.5 mg)–and CD8 (0.1 mg)–
depleting antibodies were injected 
intraperitoneally on days 6, 8, 12, 
and 15 (n = 10 mice per group). (D) 
CD8 T cell immune response. 
Splenocytes from the indicated 
groups obtained on day 7 after 
treatment were cocultured with 
media, 1 × 106 irradiated 4T1 cells 
(unrelated control tumor), or A20 
cells (homologous tumor) for 24 
hours. Intracellular IFN-g was 
measured in CD8+ T cells by flow 
cytometry as a percentage of CD44hi 
(memory CD8) T cells shown in dot 
plots and bar graph, summarizing 
data from three experiments (n = 9 
mice per group). ****P < 0.0001, 
unpaired t test 
 
Sagiv-Barfi et al Sci. Transl. Med. 
2018 

 
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CMP-001 Background 
CMP-001 is an immunostimulatory therapeutic agent that may have anti-tumor activity 
for a variety of different types of cancer. The initial Phase 1b study CMP-001-001, A 
Multicenter, Open-Label, Phase 1b Clinical Study of CMP-001 in Combination with 
Pembrolizumab in Subjects with Advanced Melanoma (NCT02680184) has 
completed enrollment (Milhelm et al., SITC, 2020). 
 
CMP-001 is composed of (i) a virus-like particle (VLP) comprised of capsid proteins 
derived 
from 
bacteriophage 
Qbeta, 
which 
encapsulate 
(ii) 
a 
CpG-A 
oligodeoxynucleotide (ODN) known as G10, which is a Toll-like receptor 9 (TLR9) 
agonist designed to induce high levels of type I interferon production and an anti-
tumor CD8+ T cell response through activation of TLR9 in plasmacytoid dendritic cells 
(pDCs). The therapeutic agent is a VLP referred to as QbG10. 
 
QbG10 has been previously studied in clinical trials under the name CYT003. In the 
Investigator’s Brochure, the name CYT003 referred to historical data using the 
investigational drug product in non-oncology settings. In this present study the name 
CMP-001 will refer to the Checkmate Pharmaceuticals’ (Checkmate) investigational 
drug product. CYT003 was renamed CMP-001 when Checkmate took over 
development in oncology settings, but the two are the same drug.  
 
Administration of CMP-001 is intended to activate TLR9 in pDC within the tumor or 
the tumor-draining lymph nodes (tumor-associated pDC). In order for this response to 
be specific for the tumor, the pDC should have taken up the tumor antigens already, 
which requires them to be activated either within the tumor via IT administration, or in 
the draining lymph nodes via SC administration. CMP-001 has been tested at doses 
of 1mg, 3mg, 5mg, 7.5mg, 10 mg, 12.5 mg, 15 mg and 17.5 mg  in clinical trials either 
as monotherapy or in combination with Pembrolizumab (Milhelm et al., SITC, 2020), 
Atezolizumab (Negrao et al., WCLC, 2021) or Nivolumab (Davar et al., SITC, 2020).    
 
CMP-001 is currently being evaluated in 3 ongoing Checkmate-sponsored Phase 1b 
dose escalation and expansion studies:  
 
1. CMP-001-001:  A Multicenter, Open-Label, Phase 1b Clinical Study of CMP-
001 Administered Either in Combination With Pembrolizumab or as 
Monotherapy in Subjects With Advanced Melanoma (IT route of administration 
[ROA])  
 
2. CMP-001-002:  A Multicenter, Two Part, Phase 1b Study Evaluating Alternative 
Routes of Administration of CMP-001 in Combination With Pembrolizumab in 
Subjects With Advanced Melanoma (SC and SC/IT ROA)  
 

 
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3. CMP-001-003:  A Multicenter, Two-Part, Phase 1b Clinical Study of CMP-001 
in Combination With Atezolizumab With and Without Radiation Therapy in 
Subjects With Advanced Non-Small Cell Lung Cancer (NSCLC) (SC/IT ROA) 
 
A total of 255 subjects have received at least 1 dose of CMP-001 in 3 Checkmate-
sponsored studies as of 01 June 2020, including 226 subjects with advanced 
melanoma who received CMP 001 as monotherapy or in combination with 
pembrolizumab, and 29 subjects with NSCLC who received CMP 001 in combination 
with atezolizumab with or without radiation therapy. CMP-001 has also been 
combined with other PD-1 blocking antibodies (nivolumab, atezolizumab, avelumab).  
 
In the 3 Checkmate-sponsored studies (with the exception of the CMP-001 
monotherapy arm in Study CMP-001-001 Part 2), treatment-emergent adverse events 
([TEAEs], defined as an adverse event [AE] that started or worsened in severity on or 
after the date that study treatment was first administered), are assessed in relation to 
study treatment and are not attributed individually to CMP-001, pembrolizumab, 
atezolizumab, or radiation therapy. In all future Checkmate-sponsored studies, 
relationship of an AE will be assessed to each of the individual components of the 
study treatment. 
 
 
1.1.1 Clinical Safety & Clinical Efficacy  
Study CMP-001-001 
 
As of 01 June 2020, 199 subjects have received CMP-001 IT at doses ranging from 
1 mg to 10 mg in combination with pembrolizumab or as monotherapy in Study CMP-
001-001. Some subjects received CMP-001 SC per protocol. 
 
Part 1: CMP-001 in Combination with Pembrolizumab 
 
In the Part 1 Dose Escalation and Dose Expansion portion of the study, 159 subjects 
received at least 1 dose of CMP-001 IT at starting doses ranging from 1 mg to 10 mg 
in combination with pembrolizumab IV on 2 different dosing schedules. The median 
duration of treatment with CMP 001 (includes subjects currently on and off treatment) 
for the 159 subjects in the Part 1 is 2.4 months (range: 0 to 47 months).  
 
For the combined Part 1 Dose Escalation and Part 1 Dose Expansion Phases of Study 
CMP 001 001 (N=159), the most commonly occurring TEAEs (all causality TEAEs 
occurring in at least 20% of subjects) for CMP 001 in combination with pembrolizumab 
by highest incidence were chills, pyrexia, fatigue, nausea, vomiting, headache, 
injection site pain, diarrhoea, decreased appetite, back pain, hypotension, and 
constipation. Twenty-seven (17.0%) subjects experienced a serious adverse event 
(SAE) assessed as related to study treatment. Treatment-related SAEs reported in 
more than 1 subject include hypotension (7 subjects; 4.4%) and pyrexia, muscular 
weakness and cytokine release syndrome (2 subjects, each event; 1.3 %).  

 
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A total of 16 (10.1%) subjects discontinued study treatment due to a TEAE. 
Treatment-related TEAEs that led to discontinuation included pneumonitis (2 
subjects) and dyspnoea, pancreatitis, chills, disseminated intravascular coagulation, 
diarrhoea, generalised oedema, atrial fibrillation, and muscular weakness (1 subject, 
each event).  
 
There have been 4 fatal SAEs in Part 1 of Study CMP-001-001: 2 events of respiratory 
failure, 1 event of sepsis, and 1 event of death, not otherwise specified. None of the 
deaths are considered related to study treatment. 
 
Part 2: CMP-001 Monotherapy 
 
In Part 2 Monotherapy, 40 subjects received at least 1 dose of CMP-001 IT at starting 
doses of 5 mg or 10 mg on 1 dosing schedule. The median duration of treatment with 
CMP 001 (includes subjects currently on and off treatment) for the 40 subjects in the 
Part 2 is 1.7 months (range: 1 to 21 months).  
 
The most commonly occurring TEAEs (all causality TEAEs occurring in at least 20% 
of subjects) in Part 2 Monotherapy by highest incidence were nausea, chills, pyrexia, 
headache, fatigue, hypotension, oedema peripheral, back pain, constipation, 
decreased appetite, diarrhoea, vomiting, hypertension, and pruritus. Serious AEs 
assessed as related to CMP-001 were reported in 6 (15%) subjects. Treatment-
related SAEs that occurred in more than 1 subject included hypotension (3 subjects; 
7.5%). Treatment-related SAEs that led to discontinuation of study drug included 
bradycardia, hypotension, and presyncope (in 1 subject); headache, nausea, and 
chills (in 1 subject); and injection site reaction (1 subject). 
 
No TEAEs with an outcome of death have been reported in Part 2 monotherapy. 
 
Part 2 Crossover 
 
In Part 2 Monotherapy Crossover (CMP-001 in combination with pembrolizumab), 15 
of the 40 subjects from Part 2 Monotherapy crossed over to receive at least 1 dose of 
CMP-001 in combination with pembrolizumab after PD was observed and 
documented. 
 
In Part 2 Monotherapy Crossover (CMP-001 in combination with pembrolizumab), the 
most commonly reported (all causality TEAEs occurring in a least 20% of subjects) by 
highest incidence were chills, pyrexia, injection site pain, hypertension, constipation, 
and cough. One subject had an SAE reported as death (not otherwise specified) that 
was assessed by the Investigator as not related to study treatment. 
 
 
 
 
 
 

 
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Study CMP-001-002 
 
As of 01 June 2020, in the Part 1 Dose Escalation Phase of Study CMP-001-002, 27 
subjects have received at least 1 dose of CMP-001 by SC injection at doses ranging 
from 5 mg to 17.5 mg in combination with pembrolizumab. 
 
The most commonly occurring TEAEs (all causality TEAEs occurring in at least 20% 
of subjects) for CMP-001 in combination with pembrolizumab by highest incidence 
were fatigue, nausea, diarrhoea, hypertension, arthralgia, chills, and rash. Serious 
AEs assessed as related to study treatment were tumor pain and erythema multiform 
(1 subject, each event). No subjects discontinued study treatment because of a 
treatment-related TEAE. No TEAEs with an outcome of death have been reported. 
 
 
Study CMP-001-003 
 
Part A Stage 1 
 
In Part A Stage 1 of Study CMP-001-003, 13 subjects with advanced NSCLC received 
at least 1 dose of CMP 001 SC or IT in combination with atezolizumab IV.  
 
The most commonly occurring TEAEs (all causality TEAEs occurring in at least 20% 
of subjects) for CMP-001 in combination with atezolizumab in Part 1 by highest 
incidence were pyrexia, hypotension, chills, fatigue, decreased appetite, nausea, back 
pain, headache, dyspnea, platelet count decreased, anaemia, hyponatraemia, 
hypophosphataemia, pneumonia, and rash. A total of 9 (69.2%) subjects have 
experienced at least 1 SAE. SAEs assessed as treatment-related occurred in 4 
subjects and included pyrexia, flushing, and hypotension (in 1 subject); chills, pyrexia, 
and tachycardia (in 1 subject); brain oedema, mental status changes, and fatigue (in 
1 subject); and pneumonitis and diabetes mellitus (in 1 subject).  
 
One subject discontinued study treatment in Part A due to a non-fatal SAE of Grade 
3 pneumonitis that was assessed by the Investigator as related to study treatment. 
There were no deaths reported in Part A of the study. 
 
Part B Stage 1 
 
In Part B Stage 1 of the study, 16 subjects received radiation and at least 1 dose of 
CMP-001 in combination with atezolizumab. 
 
The most commonly occurring TEAEs (all causality TEAEs occurring in at least 20% 
of subjects) for subjects receiving radiation and at least 1 dose of CMP-001 in 
combination with atezolizumab includes anaemia, pyrexia, hypotension, chills, 
decreased appetite, hypokalaemia, hypophosphataemia, nausea, fatigue, and platelet 
count decreased. A total of 9 (56.3%) subjects experienced at least 1 SAE including 
7 subjects who experienced an SAE that was assessed as related to study treatment. 
Treatment-related SAEs included hypotension, blood bilirubin increased, and 

 
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anaemia (in 1 subject); hypotension and flushing (in 1 subject); vomiting, pyrexia, 
nausea, hypotension, chills, and tachycardia (in 1 subject); and hypotension, atrial 
flutter, sepsis, asthenia (each occurring in 1 subject). There was 1 fatal SAE of cardio-
respiratory arrest, which was considered unrelated to treatment by the Investigator. 
No subjects discontinued study treatment because of a treatment-related TEAE. 
 
The most frequently reported TEAEs with CMP-001 + other agents can be found in  
the CMP-001 Investigator Brochure.  
 
Analysis of Safety Data to Date 
 
In the 3 Checkmate-sponsored studies (with the exception of the CMP-001 
monotherapy arm in Study CMP-001-001 Part 2), TEAEs are assessed in relation to 
study treatment and are not attributed to the individual components, CMP-001, 
pembrolizumab, atezolizumab, or radiation therapy. There is no evidence to suggest 
that CMP-001 monotherapy or CMP-001 in combination with pembrolizumab, 
atezolizumab, or atezolizumab with radiation therapy, increases the frequency or 
severity of immune related AEs. 
 
Analysis of safety data demonstrates a similar safety profile for all 3 Checkmate-
sponsored studies in patients with cancer that predominately consists of Grade 1 and 
Grade 2 AEs. Commonly reported TEAEs (occurring in 20% or more subjects) that 
have been observed across these clinical studies with CMP-001 were chills, pyrexia, 
fatigue, hypotension, nausea, and vomiting. The frequency of AEs that are Grade 3 
or higher peaks with the third to sixth injections of CMP-001. 
 
Based on the SAEs reported in 255 subjects treated with CMP-001 to date, expected 
events are hypotension (17 subjects; 6.7%), pyrexia (7 subjects; 2.8%), and cytokine 
release syndrome (3 subjects, 1.2%). All other SAEs were seen in 2 or fewer (1% or 
less) subjects. 
 
Clinical Efficacy 
 
All statements related to data and all data summaries are based on data entered into 
the study-specific EDC systems as of 01 June 2020 for the 3 Checkmate-sponsored 
studies. 
 
Data for the intent-to-treat analysis set for each study, defined as all subjects receiving 
at least 1 dose of CMP-001, are based on Response Evaluation Criteria for Solid 
Tumors version 1.1 (RECIST v1.1) by Investigator assessment. 
 
Study CMP-001-001 
 
Preliminary efficacy data for the combined Part 1 Dose Escalation and Part 1 Dose 
Expansion Phases of the ongoing Study CMP-001-001 included responses in subjects 
who received CMP 001 at doses ranging from 3 mg to 10 mg in combination with 
pembrolizumab. The protocol-specified efficacy endpoint of best objective response 

 
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rate (ORR) was 18.9% (30 of 159 subjects; 95% CI = 13.1%, 25.9%) and included 8 
CRs and 22 PRs. The best ORR including post-progression responders (n=7) was 
23.3% (37 of 159 subjects; 95% CI = 17.0%, 30.7%). There were 35 (22.0%) subjects 
with a RECIST best response of stable disease (SD), 74 (46.5%) subjects with a 
RECIST best response of PD, and 13 (8.2%) subjects who discontinued prior to 
having a post-baseline scan. The median duration of response (DOR) for the 30 
RECIST responders was 13.9 months.  
 
Subjects treated at the CMP-001 10 mg dose administered QW for 7 weeks and Q3W 
thereafter (ie, the recommended Phase 2 dose [RP2D]) had a best ORR of 23.0% (14 
of 61 subjects; 95% CI = 13.2%, 35.6%) and included 3 CRs and 11 PRs. The best 
ORR including post-progression responders (n = 3) was 27.9% (17 of 61) subjects; 
95% CI = 17.2%, 40.9%).  
 
Preliminary efficacy data for the Part 2 CMP-001Monotherapy Arm of Study CMP-
001-001 included a best ORR of 17.5% (7 of 40 subjects; 95% CI = 7.3%, 32.8%). All 
responders had a PR. Best response for the remaining subjects included 13 (32.5%) 
subjects with SD and 20 (50.0%) subjects with progressive disease (PD).  
 
Based upon these data, 10 mg CMP-001 IT administered QW for 7 weeks and Q3W 
thereafter in combination with a PD-1 blocking antibody was chosen as the RP2D. 
 
Study CMP-001-002 
 
Preliminary efficacy data for the 25 evaluable subjects in the ongoing Part 1 Dose 
Escalation Phase of Study CMP-001-002 included a best ORR of 8.0% (2 of 25 
subjects; 95% CI = 1.0% to 26.0%) and included best responses of 1 CR and 1 PR, 
both in the 10 mg SC dose group. Eight (32.0%) subjects had a RECIST best 
response of SD, 11 (44.0%) subjects had a RECIST best response of PD, and 4 
(16.0%) subjects discontinued prior to having a post baseline tumor assessment. Two 
of the 27 subjects dosed were pending their first post baseline scan at the time of data 
cutoff and are not evaluable for response. 
 
Study CMP-001-003 
 
In the completed Study CMP-001-003 in subjects with NSCLC who had progressed 
on prior PD 1/PD-L1 therapy, no RECIST responses were observed in 13 subjects in 
Part A Stage 1 and 16 subjects in Part B. This study was stopped after interim analysis 
at the conclusion of Stage 1 and all data are final. In Part A of the study, 3 (23.1%) 
subjects had a RECIST best response of SD, 8 (61.5%) subjects had a RECIST best 
response of PD, and 2 (15.4%) subjects discontinued from the study before having a 
post-baseline tumor assessment. In Part B of the study, 8 (50.0%) subjects had a 
RECIST best response of SD, 5 (31.3%) subjects had a RECIST best response of 
PD, 3 (18.8%) subjects discontinued prior to post-baseline follow-up scans; 1 of these 
3 subjects had an incomplete follow-up scan and was not evaluable per RECIST. 

 
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CMP-001 Clinical Safety and Efficacy Summary 
CMP-001 is an immune activator that consists of a CpG-A ODN (G10) contained 
within a recombinantly-expressed protein capsid as carrier (Qb). The postulated 
mechanism of action after IT or SC injection includes local uptake by pDCs in the 
tumor and tumor-draining lymph nodes. Upon uptake, the Qb capsid enters an 
endosome where the G10 CpG-A ODN is released from the CMP-001 VLP and 
stimulates TLR9 in pDC, inducing the production of large amounts of type I IFN, and 
promoting a Th1 type immune response with the generation of large numbers of anti-
tumor CD8+ T cells able to traffic systemically to distant metastatic sites.  
In the ongoing Checkmate-sponsored Studies CMP-001-001 and CMP-001-002, and 
the completed Checkmate-sponsored Study CMP-001-003, preliminary analysis of 
CMP-001 safety data in 255 subjects who have received at least 1 dose of CMP-001 
in combination with a PD 1/PD-L1 blocking antibody or as monotherapy demonstrates 
a safety profile that predominantly consists of Grade 1 to Grade 2 AEs, including fever 
(pyrexia), chills, nausea, vomiting, diarrhoea, headache, rash, and hypotension.  
Preliminary efficacy data for the Part 1 Dose Escalation and Part 1 Dose Expansion 
Phases of Study CMP-001-001 in subjects with advanced melanoma included a best 
ORR of 18.9% per RECIST and 23.3% for RECIST and post-progression responders. 
Subjects treated at the RP2D (CMP-001 10 mg dose administered QW for 7 weeks 
and Q3W thereafter) had a best ORR of 23.0%. Responses included CRs and PRs. 
The median DOR for the RECIST responders was 13.9 months and 19.9 months 
when including post-progression responders. Preliminary efficacy data for the Part 2 
CMP-001 Monotherapy Arm included a best ORR of 17.5% with all responders having 
a PR.  
Preliminary efficacy data for the Part 1 Dose Escalation Phase of Study CMP-001 002 
in subjects with advanced melanoma included a best ORR of 8.0%, with 1 CR and 1 
PR.  
Final efficacy data from Study CMP-001-003 in subjects with advanced NSCLC who 
had progressed on prior PD-1/PD-L1 therapy included no RECIST responders in the 
13 subjects in Part A Stage 1 and 16 subjects in Part B Stage 1 of the study. 
1.1.2 CMP-001 Potential Autoimmunity  
The potential of CMP-001 to induce anti-dsDNA antibodies is considered very low. 
The ODN G10 is not readily visible to the B cell receptor as it is encapsulated by a 
spherical particle. Accordingly, a clinically relevant increase in anti-dsDNA antibodies 
or antinuclear antibodies, or clinical evidence of autoimmunity, was not detected in 
any of the patients treated with CMP-001 after follow-up times of 1 to 2 years. 
Induction or exacerbation of autoimmune diseases is not expected for CMP-001 

 
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because this has not been observed previously with other TLR9 agonists administered 
for longer periods of time at higher dosages. Patients with a diagnosis of systemic 
autoimmune diseases were excluded from prior clinical studies of CMP-001. All 
enrolled patients were monitored for induction of antinuclear (ANA) and anti-dsDNA 
antibodies. No clinical signs indicative for autoimmune disease have been reported to 
date.  
 
Early hypotheses that exposure to DNA containing CpG motifs generally induce 
autoimmunity have proven unfounded (Krieg and Vollmer 2007, Krieg, 2012). 
Nevertheless, in some mouse models of autoimmunity, CpG oligonucleotide 
treatment exacerbated disease, while in others it prevented autoimmune or 
inflammatory disease (Krieg and Vollmer 2007). In addition, as TLR9 signaling is 
involved in the immune defense mechanisms against bacteria, several feedback 
suppression mechanisms have evolved to regulate TLR9 activity such as expression 
of indoleamine 2,3- dioxygenase (IDO), cyclooxygenase-2, suppression of cytokine 
signaling, etc. In accordance, the clinical experience to date indicates that CpG ODN 
treatment of healthy humans, cancer patients, or individuals infected with HIV or HCV 
does not readily induce early markers of autoimmune disease (Krieg, 2012).  
 
1.1.3 CMP-001 Potential Effects Related to IFNα Induction  
In consideration of the postulated mode of action through stimulation of Th1 cytokines, 
the occurrence of symptoms as described for therapeutic use of IFNα should be 
considered. Elevated body temperature and fever, shivering, feeling cold, headache, 
and myalgia are potential adverse events, which might be attributed to stimulation of 
cytokines by QbG10. The incidence of such symptoms was generally low. With B cell 
vaccines which use the native Qb capsid (containing bacterial RNA instead of a CpG) 
to induce specific antibodies against various targets, such reactions had a higher 
incidence showing that the CpG component in QbG10 and associated induction of 
IFNα hardly contribute to these symptoms (Ambuhl et al., 2007; Cornuz et al., 2008; 
Kundig et al., 2006; Maurer et al., 2005; Tissot et al., 2010). Symptoms of systemic 
reactogenicity would usually appear within 6-8 hours after the second and subsequent 
injections (once the anti-Qb antibody response had been induced), and usually 
disappear within 24 hours and respond well to usual doses of acetaminophen, if 
required.  
 
Other symptoms frequently observed after therapeutic doses of IFNα such as 
gastrointestinal symptoms, depression, dermatological symptoms and cardiovascular 
disorders were rarely reported after QbG10 as well as after placebo and considered 
not of suspected relationship.  
 
No IFNα could be detected 12 h and 24 h after injection in sera of subjects treated 
with 0.3 mg QbG10 (detection limit 39 pg/mL). In contrast, IFNα serum levels after 
therapeutic doses of recombinant IFNα are in the ng/mL range (e.g., Pegasys®, 
Roche; Intron A®, Schering).  
 

 
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1.1.4 CMP-001 Potential Drug Interactions  
Pharmacokinetic interactions between the CMP-001 and anti-OX40 antibodies are not 
expected.   
 
INCAGN01949 (OX40 Agonist) Background  
INCAGN01949 is a fully human monoclonal antibody with an IgG1 heavy chain and κ 
light chain, expressed by recombinant DNA technology in a CHO cell line.  
INCAGN0149 has two potential mechanisms of actions. It can stimulate T cell 
proliferation by engagement of the OX40 receptor on T effector populations or 
eliminate T regulatory cells through an ADCC mechanism as an IgG1 antibody.  
 
INCAGN01949 binds selectively to the extracellular domain of human OX40 with a 
KD of 0.12 nM. INCAGN01949 functions as an OX40 agonist antibody in human cells, 
activating NFκB signaling and providing T cell costimulation in the context of 
suboptimal TCR activation. INCAGN01949 has the ability to increase T cell function.  
 
Two clinical studies are ongoing, and 136 participants have been exposed to at least 
1 dose of INCAGN01949 by intravenous drug administration.  Study INCAGN 1949-
101 is a Phase 1/2, open-label, dose-escalation, safety and tolerability study in 
participants with advanced or metastatic solid tumors.  Study INCAGN 1949-201 is a 
Phase 1/2, open-label, nonrandomized study to determine the safety, tolerability, and 
efficacy of INCAGN01949 when given in combination with immune therapies 
(nivolumab and ipilimumab). 
 
In both studies, following a single 30-minute IV infusion of escalating doses (7 to 1400 
mg), the disposition of INCAGN01949 was biphasic with mean plasma half-life values 
ranging from 140 to 391 hours. The estimated mean plasma clearance following single 
dose administration was low, which is typical for a monoclonal antibody. The 
estimated mean volume of distribution ranged from 3240 to 9900 mL, which is also 
consistent with expectations for a monoclonal antibody. Following repeated Q2W 
administration, the preinfusion serum concentrations for the 7, 20, 70, 200, and 700 
mg dose cohorts increased with each subsequent cycle, suggesting lack of any ADA 
effect on the PK of INCAGN01949. 
 
Preliminary data indicate absence of any ADAs in both studies. Analysis of 
proinflammatory cytokines revealed no dose-related changes in plasma cytokines and 
inflammatory proteins in participants infused with doses up to 350 mg consistent with 
the lack of infusion reactions with drug administration. No major changes were 
observed among participants infused with doses up to 1400 mg in the frequency of 
immune cell populations that were evaluated. 
 
In Study INCAGN 1949-101, 84 participants have received INCAGN01949 doses of 
7, 20, 70, 200, 350, 700, or 1400 mg IV Q2W. No DLTs were reported. The most 
common TEAEs (> 10%) for INCAGN01949 monotherapy were fatigue, decreased 

 
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appetite, constipation, cough, nausea, abdominal pain, diarrhea, dyspnea, vomiting, 
and back pain. 
 
In Study INCAGN 1949-201, 36 participants have received INCAGN01949 IV doses 
of 70, 200, 350, or 700 mg Q2W + nivolumab 240 mg Q2W. The most common TEAEs 
(> 10%) for INCAGN01949 + nivolumab were fatigue, pruritus, abdominal pain, back 
pain, cough, peripheral edema, arthralgia, decreased appetite, diarrhea, nausea, 
anemia, vomiting, amylase increased, headache, lipase increased, and pyrexia. 
 
There were no new toxicities observed with the administration of INCAGN0149 in 
combination with nivolumab or ipilimumab nor was the rate of immune-related adverse 
events increased compared with the administration of nivolumab or ipilimumab alone.   
 
There was one objective tumor response in a patient with gallbladder cancer with 
INCAGN01949 alone.  The response rate of the combinations of INCAGN01949 with 
nivolumab was not increased compared with single agent nivolumab or ipilimumab. 
 
The current study will use once a week schedule of administration and will also be the 
first evaluation of INCAGN01949 as an intratumoral injection.  It is not anticipated that 
there will be a major change in toxicity with this approach but subjects will be closely 
monitored for systemic and local reactions. For safety purposes the starting IT dose 
will be only 500mcg/m2 which is less than 10% of the highest dose administered IV. 
 
 
1.1.5 Potential Risks of INCAGN01949 (OX40 agonist) 
The occurrence of DLTs and other toxicities (related or unrelated to INCAGN01949) 
will guide decisions for treatment interruptions and discontinuation for individual 
participants. For management of DLTs or other urgent situations that may arise during 
treatment with INCAGN01949, in all cases, investigators may employ any measures 
or concomitant medications, after discussion with the sponsor (whenever possible), 
necessary to optimally treat the participant. 
 
Participants with potential irAEs should receive appropriate supportive care measures 
as deemed necessary by the treating investigator.  
 
The most frequently reported TEAEs with INCAGN01949 + other agents can be found 
in the INCAGN01949 Investigator Brochure.  
 
 
 
 

 
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2.0 HYPOTHESIS 
 
We hypothesize that activating the innate and adaptive immune systems, via in-situ 
vaccination, will make pancreatic and potentially other cancers recognizable to the 
immune system. Pancreatic cancer has historically not responded well to immuno-
oncology agents but we believe this immunoenhancing technique will induce an 
antitumor T cell response throughout the body, which will attack both local and 
metastatic tumors. 
3.0 OBJECTIVES 
Primary Objective 
Phase IB 
To determine the maximum tolerated dose and tolerance of CMP-001 (TLR9 agonist) 
in combination with INCAGN01949 (an activating antibody against OX40) both given 
intratumorally for patients with previously treated (for their metastatic disease) 
pancreatic ductal adenocarcinoma and other types of cancer except melanoma. 
 
Phase II 
To determine the efficacy (Disease control rate of CR+ PR+SD X 16 weeks) of CMP-
001 (TLR9 agonist) in combination with INCAGN01949 (anti-OX40 antibody) for 
patients with previously treated (for their metastatic disease) pancreatic ductal 
adenocarcinoma.  
 
To determine effects on tumor markers. 
 
Secondary Objective 
• Define the toxicity of the combination of CMP-001 (TLR9) + INCAGN01949 
(OX40) 
 
• Determine progression free survival and overall survival 
 
Exploratory Objectives 
• Using flow cytometry on peripheral blood OX40 expression will be analyzed 
within the lymphocyte subsets (Teff and Treg)  
 
• On tissue samples collected prior to, and during, treatment, we will: 
 

 
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o Use flow cytometry to enumerate CD4+ and CD8+ T cell subsets, and 
the expression of activation/differentiation markers (including CD127, 
HLA-DR, CD45RO, CCR7, CXCR3) on each 
o Use RT-PCR and sequencing to amplify and characterize the TCRa and 
b sequences of tumor-infiltrating T cells, looking for evidence of oligo-
clonal T cell expansion, OX40 expression  
o If there is adequate tumor tissue, perform RNAseq to determine different 
immune cell populations, including T cells and macrophages  
 
 
Primary Endpoints 
• 
Phase IB – Dose and tolerance and recommended Phase II dose 
 
• 
Phase II – Disease control rate (CR+PR+SD x 16 weeks via RECIST and 
iRECIST) and effects on tumor markers 
 
Secondary Endpoints 
• Incidence of toxicities 
 
• Progression free and overall survival 
 
Exploratory Endpoints 
• To determine OX40 expression within the lymphocyte subsets (Teff and Treg) 
 
• On tissue samples collected prior to, and during, treatment, we will: 
 
o Use flow cytometry to enumerate CD4+ and CD8+ T cell subsets, and 
the expression of activation/differentiation markers (including CD127, 
HLA-DR, CD45RO, CCR7, CXCR3) on each 
o Use RT-PCR and sequencing to amplify and characterize the TCRa and 
b sequences of tumor-infiltrating T cells, looking for evidence of oligo-
clonal T cell expansion, OX40 expression 
o If there is adequate tumor tissue, perform RNAseq to determine different 
immune cell populations, including T cells and macrophages  
 
 
 
 

 
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4.0 PATIENT ELIGIBILITY 
 
4.1 Eligibility 
A total of up to 21 patients in Phase IB and up to 21 in Phase II with previously treated 
stage IV pancreatic cancer and other appropriate types of metastatic cancer except 
melanoma will be recruited from up to 4 centers. 
 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and 
exclusion criteria to be registered to the study. Study treatment may not begin until a 
subject is registered. 
 
4.1.1 Inclusion Criteria 
Patients must meet the following criteria to be included in the trial: 
 
1. Be willing and able to provide written informed consent for the trial. 
 
2. Be ≥ 18 years of age. 
 
3. Histologically or cytologically confirmed pancreatic adenocarcinoma with 
metastasis or other locally advanced un-resectable solid tumor malignancies 
(during the phase Ib and pancreatic cancer during phase II) deemed 
appropriate by the Investigator except melanoma. 
 
4. Patients will have had at least 2 prior therapies for locally advanced, un-
resectable and/or metastatic disease. Adjuvant therapy will count as one line 
of therapy if disease progression occurred during treatment or within 6 months 
of completion.  
 
Patients with metastatic pancreatic cancer must have received either 
FOLFIRINOX or a gemcitabine-based regimen as one of their prior lines of 
therapy. Patients with germline BRCA mutations must have received olaparib 
as maintenance therapy. 
 
5. Be willing to undergo an image-guided biopsy of a tumor lesion at baseline, 
after 2 weeks of IT injection and 4 weeks of IT injection (week 4 and 6), unless 
tumor is considered inaccessible or biopsy is otherwise considered not in the 
patient’s best interest. 
 
6. Have a performance status of 0 or 1 on the ECOG performance scale. 
 
7. Subjects must have at least one extra-central nervous system (CNS), non-bone 
tumor lesion amenable for IT injection ≥ 1.5 cm and that is not in close proximity 
or encasing crucial structures such as major blood vessels, trachea, nerve 
bundles etc. Measurable disease is required in a minimum of two lesions and 

 
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there must be at least one measurable lesion in addition to the one being 
injected. 
 
8. Demonstrate adequate organ function as defined below in Table 2.   
 
9. Female participants of childbearing potential should have a negative serum 
pregnancy test within 24 hours prior to receiving first dose of trial medication.   
 
10. A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least one of the following conditions applies: 
 
a. Not a woman of childbearing potential (WOCBP) 
• A female of child-bearing potential is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by 
choice) who meets the following criteria: 
 Has not undergone a hysterectomy or bilateral oophorectomy; or 
 Has not been naturally postmenopausal for at least 12 
consecutive months (i.e., has had menses at any time in the 
preceding 12 consecutive months). 
 
OR 
 
b. A WOCBP who agrees to follow the contraceptive guidance during the 
treatment period and for at least 180 days after the last dose of trial 
treatment. 
 
11. Male participants must agree to use contraception as detailed in the full 
protocol during the treatment period and for at least 120 days after the last 
dose of trial treatment and refrain from donating sperm during this period. 
 
 
 
 
 
 
 
 
 
 
 

 
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Table 4.  Adequate Organ Function Laboratory Values 
 
4.1.2 Exclusion Criteria 
Patients must not meet any of the following criteria in order to be eligible for the 
trial: 
 
 
1. Hypersensitivity to CMP-001 (TLR9 agonist) or INCAGN01949 (anti-OX40) or 
any of its excipients. 
 
2. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to 
Week 1/Day 1, or who has not recovered (i.e., ≤ Grade 1 or to baseline) from 
adverse events due to agents administered more than 4 weeks earlier. 
 
3. Has had prior chemotherapy, investigational agent, targeted small molecule 
therapy, or radiation therapy within 3 weeks (or 5 half-lives whichever is 
shorter) prior to Week 1/ Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent(s). 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1.5 x 10^9/L 
Platelets 
≥100 x 10^9/L 
Hemoglobin 
≥9 g/dL without transfusions within 7 days of assessment 
(transfusions are allowed prior to this period)  
Renal 
Serum creatinine OR 
 
Measured or calculated creatinine 
clearance 
 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) 
 
OR  
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN  
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR 
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  
 
NOTE: Low molecular weight heparin at full dose or 
prophylactic dose is allowed as long as the treating physician 
deems it safe to hold the LMWH on the day before and the 
day of the intra-tumoral injection. No other anti-coagulants 
are permitted. 
a Creatinine clearance should be calculated per institutional standard. 
* Because of the intratumor injections patients cannot be on any anticoagulants other than LMWH. 

 
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Note:  Patients with ≤ Grade 2 neuropathy are an exception to this 
criterion and may qualify for the trial. 
 
Note:  If patient received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention 
prior to starting therapy.   
 
4. Has a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin or squamous 
cell carcinoma of the skin that has undergone potentially curative therapy or in 
situ cervical cancer. Other malignancies which have been treated with curative 
intent, or for which patients are not receiving active therapy, may be considered 
upon discussion with the Investigator. 
 
5. Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.  Patients 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 7 days prior 
to trial treatment. Use of prophylactic anti-epileptic drugs is permitted. This 
exception does not include carcinomatous meningitis, which is excluded 
regardless of clinical stability.   
 
6. Has active autoimmune disease that has required systemic treatment in the 
past 2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment; these 
patients may receive stress steroids orally or IV before the procedure. 
 
7. Has history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
 
8. Has an active bacterial infection requiring systemic therapy. 
 
9. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or is not in the best interest 
of the patient to participate, in the opinion of the treating investigator.   
 
10. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
11. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
 

 
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12. Has a known history of or is positive for Hepatitis B (e.g., HBsAg reactive) or 
untreated Hepatitis C. Treated Hepatitis C with sustained virologic response, 
and patients who are negative for Hepatitis BsAg are not excluded.     
 
13. Current, serious, clinically significant cardiac arrhythmias as determined by the 
treating investigator. 
 
14. Has received a live vaccine within 30 days of planned start of trial therapy. 
 
Note: Seasonal influenza vaccines for injection are generally inactivated 
flu vaccines and are allowed; however intranasal influenza vaccines (e.g., 
Flu-Mist®) are live attenuated vaccines, and are not allowed. 
 
15. Patients must not be receiving any anticoagulation. Low molecular weight 
heparin at full dose or prophylactic dose is allowed as long as the treating 
physician deems it safe to hold the LMWH on the day before and the day of the 
intra-tumoral injection.  
 
16. Patients should not be on aspirin or any anti-platelet agent. Patients may have 
been receiving aspirin 81 mg if deemed safe by the investigator to hold aspirin 
for the duration of the study, starting at least 7 days prior to start of treatment. 
5.0 TRIAL TREATMENTS 
The treatments to be used in this trial are outlined below in Table 3. Full details for 
dose preparation and administration are in the pharmacy manual. 
 
Table 5.  Trial Treatments 
Drug 
Dose/Potency 
Dose 
Frequency 
Route  
Regimen/Treatment Period 
CMP-001 
(TLR9) 
 
A fixed dose of 10mg 
CMP-001 will be used 
for IT injection (5mg will 
be used for the first two 
SC injections).  
Once a 
week for 6 
weeks  
First two 
doses are 
SC and 
remaining 
4 doses 
are IT 
Week 1, Day 1 (SC) 
Week 2, Day 1 (SC) 
Week 3, Day 1 (IT) 
Week 4, Day 1 (IT) 
Week 5, Day 1 (IT) 
Week 6, Day 1 (IT) 
INCAGN01949 
(OX40) 
Up to 6 different dose 
levels (up to 6 patients 
per dose level in Phase 
IB to select dose level 
for Phase II) 
500 mcg/m2** 
1000 mcg/m2 
1670 mcg/m2 
2505 mcg/m2 
3507 mcg/m2 
4559 mcg/m2* 
Once a 
week for 4 
weeks 
All doses 
are IT 
Week 1, Day 1 (none) 
Week 2, Day 1 (none) 
Week 3, Day 1 (IT) 
Week 4, Day 1 (IT) 
Week 5, Day 1 (IT) 
Week 6, Day 1 (IT) 
 
 

 
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5.1.1 Body Surface Area Calculation 
The calculation of the dose of INCAGN01949 (OX40) will be based on the patient’s 
body surface area (BSA) using the Mosteller formula (Verbraeken 2006). The BSA 
will be calculated at baseline and before each new week, based on the actual height 
and weight of the patient. If there has been a ≥10% weight change from baseline, the 
drug doses will be recalculated based on the new BSA value.  The calculated dose 
will be rounded to the nearest whole microgram (mcg).  
 
5.1.2 Dose Escalation in Phase IB 
The dose escalation scheme proposed is a conservative modified Fibonacci method 
(Le Tourneau 2009).  
 
Up to six dose levels of INCAGN01949 (OX40) as detailed in Table 3 are planned in 
order to determine the MTD for dose selection for the Phase II trial.  One patient will 
be entered at each dose level until the occurrence of a grade ≥ 2 treatment related 
toxicity, then a minimum of 3 patients will be entered at each dose level starting at the 
dose level with the grade 2 treatment related toxicity.   
 
The starting dose for intratumoral injection of INCAGN01949 is based on the known 
safety profile of intravenous INCAGN01949 at doses ranging from 7-1400 mg.  The 
proposed starting dose is less than 10% of the intravenous route of administration and 
provides an additional margin for safety in the trial.  There is the potential for OX40 
upregulation following TLR9 agonist administration and its binding could produce 
cytokine release. 
 
One or three patients at a given dose level will then be followed for a minimum of 4 
weeks before initiating dosing at the next level.  If any patient experiences a DLT, up 
to an additional 3 patients will be added at that dose level.  All patients will be followed 
through the first 4 doses (Weeks 1-4 of dosing, including CMP-001 SC alone for 2 
doses, and CMP-001 IT plus INCAGN01949 IT for 2 doses) before further dose 
escalation occurs.  If no more than 1 of 6 develops a DLT, dose escalation will 
continue to the next level for the succeeding patients.  However, if another patient 
experiences a treatment related toxicity qualifying as a DLT, those doses will be 
considered the toxic doses. The MTD will then be defined as the next lower dose level.    
 
If 2 of 6 patients in dose level 1 develop DLTs, further patients will be enrolled into 
dose level -1 for CMP-001 (5mg) and INCAGN01949 of 250mcg/m2. If 2 or more 
patients experience any DLT attributable to the study drugs at dose level -1, study 
accrual will be stopped, and all toxicities will be reviewed.  
 
The design will allow us to determine the MTD. However, the RP2D may be different 
and take into account pharmacodynamics markers such as expression of OX40 on 
the CD4+ T cells.   
 

 
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5.1.3 Dose Modification for Toxicity 
Toxicities will be graded using the NCI-CTCAE V5.0 (appendix 1). If toxicity occurs 
during or after any treatment, the toxicity will be graded and appropriate supportive 
care treatment will be administered to decrease the signs and symptoms (e.g. 
antiemetics, antidiarrheals, antipyretics, antihistamines).  
 
Dose adjustments will be made according to the table below. A maximum of two dose 
reductions will be allowed. Further toxicities requiring dose reduction will result in 
study discontinuation.  
 
In most cases, management of toxicity may require either a temporary or permanent 
discontinuation of both CMP-001 and INCAGN01949. However, if in the opinion of the 
investigator, a toxicity is more clearly related to one drug, the administration of that 
drug may be modified with Sponsor consultation and approval. 
 
Dosing Modifications and Toxicity Management Guidelines 
 
CTC Grade 
Dose Modification 
Toxicity 
Management 
Any Grade 
NOTE: Dose modifications are not required for 
adverse events not deemed to be related to study 
treatment (i.e. events due to underlying disease) or 
laboratory abnormalities not deemed to be clinically 
significant. 
Treat 
accordingly as 
per 
institutional 
standard. 
1 
No dose adjustment. 
2 
Continue treatment and increase monitoring 
frequency to once weekly at a minimum until the 
event returns to ≤ Grade 1. 
3-4 
 
First 
Occurrence 
Hold study treatment until resolution to ≤ Grade 1 or 
baseline. Then resume therapy at one level dose 
reduction.  
 
If patient is receiving the lowest dose level of study 
drug and experiences a treatment-related Grade 3-
4 adverse event, then treatment will be permanently 
discontinued. 
 
For toxicities with adequate supportive care options 
such as nausea, vomiting, diarrhea, the Grade 3 
toxicity must have occurred despite optimal 
supportive care to warrant a dose reduction. 
3-4 
 
Second 
Occurrence 
Discontinue study treatment permanently if patient 
has a recurrent Grade 3-4 toxicity despite optimal 
supportive care.  
 
 

 
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NOTE:  
- For Grade 3-4 electrolyte abnormalities, if easily managed medically and return to 
Grade ≤ 2 within 72 hours, do not require a dose reduction.  
- For Grade 3-4 laboratory abnormalities, the decision to discontinue treatment should 
be based on accompanying clinical signs/symptoms and as per Investigator’s clinical 
judgment and in consultation with the sponsor.  
 
Dose Levels of CMP-001 and INCAGN01949 
 
Dose 
Level 
CMP-001 
(mg) 
INCAGN01949  
(mcg/m2) 
-1 
5 (IT) 
250 (IT) 
1 
10 (IT) 
500 (IT) 
2 
10 (IT) 
1000  (IT) 
3 
10 (IT) 
1670  (IT) 
4 
10 (IT) 
2505  (IT) 
5 
10 (IT) 
3507  (IT) 
6 
10 (IT) 
4559* (IT) 
* If higher dose levels are needed, escalation will be in 50% increments 
 
5.1.4 Injection Site Reactions 
If subjects develop inflammation at the injection site of CMP-001 this may be managed 
using cold compresses and/or acetaminophen or non-steroidal anti-inflammatory 
agents. If flu-like symptoms (i.e., fever, myalgia, and headache) arise, these may be 
managed using acetaminophen or non-steroidal anti-inflammatory agents. 
 
5.1.5 
Required Prophylaxis Before and After CMP-001 Dosing 
 
CMP-001 has been administered as an IT or SC injection. Intratumoral injection of 
CMP-001 provides the most direct approach to activate tumor-associated pDC, and 
thereby may induce a more potent antitumor CD8+ T-cell response. 
 
To reduce the severity of these symptoms associated with CMP-001 treatment, 
prophylaxis is required. Prophylactic regimens already in place at institutions should 
be followed; if not, below is a suggested regimen that has been effective for the 
treatment of CMP-001 induced AEs: 
 
• 
Intravenous fluids (eg, approximately 1000 cc IV normal saline)  
• 
Anti-pyretics (eg, acetaminophen 1000 mg and a non-steroidal anti-
inflammatory agent such as indomethacin 50 mg or ibuprofen 600 to 800 mg)  
• 
Anti-emetics (eg, ondansetron 8 mg) 
• 
Antihistamine: diphenhydramine 50 mg, with or without an H2-antagonist 
• 
Recommended: hydrocortisone 25 mg at the investigator’s discretion.  
 
Subjects with a history of adrenal insufficiency are at increased risk for moderate to 
severe AEs such as hypotension. It is strongly recommended that these subjects 

 
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receive stress dose steroids (ie, 50 to 100 mg hydrocortisone orally every 8 hours) 
prior to or immediately after injection of CMP-001. 
 
Prophylaxis administration should be completed before initiation of CMP-001 
injection. The medications are recommended for oral administration, but IV is 
acceptable at the discretion of the investigator. It is also highly recommended to 
continue to administer fluids immediately following the CMP-001 injection, rather than 
waiting to initiate fluids if hypotension is detected. There is no waiting period between 
the end of prophylaxis and the start of the CMP-001 injection. The following algorithm 
(Figure 2) is provided as guidance for the treatment of symptoms associated with 
CMP-001. 
 
In subjects with hypotension unresponsive to supportive care with intravenous fluids, 
the administration of stress dose steroids is recommended according to institutional 
practices. Additional treatment measures may include the use of anti-cytokine therapy 
per institutional protocol. Prior to dosing an anti-cytokine therapy, it is recommended 
that blood be obtained to determine the cytokine level believed to be responsible for 
the AE. The result of the cytokine assay does not need to be available prior to dosing.   
 
For subjects who previously experienced a CMP-001-related Grade 3 or higher AE, 
prophylaxis with stress dose steroids (50 mg to 100 mg hydrocortisone orally every 8 
hours before or immediately after injection of CMP-001 or institutional standard) is 
recommended for subsequent CMP-001 doses. A minimum dose of corticosteroids of 
25 mg prednisone or equivalent (eg, hydrocortisone, methylprednisolone, 
dexamethasone) is recommended. The selection and dose of corticosteroid should 
be determined by the Investigator based on clinical parameters.

UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR. 
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
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Figure 2: Treatment Algorithm for Management of Adverse Events Associated with CMP-001
 

UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR. 
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
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5.1.6 Dose Limiting Toxicity 
DLT (dose Limiting toxicity): DLT will be assessed in the first 28 days of dosing. To be 
evaluable for DLT, patient must have either experienced a DLT or received all 
scheduled doses of therapy in the first 4 weeks of treatment. Patients who have 
treatment held or discontinued for reasons other than DLT will be replaced. 
 
Definition of DLT for the Phase 1 part of this trial: 
The following AEs will be considered DLTs if deemed related to study drug 
combination: 
 
• Hematologic 
 
o Grade 4 neutropenia 
 
o Febrile neutropenia, defined as absolute neutrophil count (ANC) 
<1000/mm3 with a temperature of ≥ 38.3 degrees C 
 
o Grade ≥ 3 thrombocytopenia with clinically significant bleeding requiring 
medical intervention  
 
o Grade 4 thrombocytopenia 
 
• Non-hematologic: 
 
o Grade ≥ 3 toxicities (non-laboratory); excluding: 
 
 Grade 3 fatigue lasting <7 days 
 
 Grade 3 fever, chills, rigors and hypotension that is responsive to 
standard supportive care measures and returns to baseline within 
24 hours.  
 
 Grade 3 arthralgia or myalgia that downgrades to less or equal to 
grade 2 within 3 days of supportive care 
 
 Grade 3 pain at injection site that downgrades to less than or 
equal to Grade 2 within 3 days of supportive care 
 
 Grade 3 electrolyte abnormalities that are asymptomatic and 
reversed with medical intervention within 3 days 
 
o Grade ≥ 3 nausea, vomiting or diarrhea despite maximal medical 
intervention 
 

 
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o Grade 3 aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) if it represents a 2 grade increase from baseline or if it is 
accompanied by grade 3 bilirubin elevation 
 
o Grade 4 aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT)  
 
• Other (non-AST/ALT) non-hematologic Grade ≥ 3 laboratory value if the 
abnormality leads to overnight hospitalization  
 
• Grade > 2 toxicities possibly or probably related to study procedures 
 
• Any Grade 3 CRS which does not resolve in 7 days to Grade 0 or 1 and is 
considered possibly or probably related to treatment 
 
• Any Grade 2 or higher neurotoxicity (related to CRES/ICANS) that does not 
resolve to Grade 1 within 72 hours 
 
 
5.1.7 Rules for discontinuation of CMP-001 (TLR9) + INCAGN01949 (OX40) 
Patients must be withdrawn from study treatment for the reasons listed below:  
 
• Occurrence of intolerable side effects  
 
• Intercurrent illness which prevents further treatment  
 
• Patient choice 
 
• Patient pregnancy  
 
• Disease progression by RECIST (Version 1.1) if accompanied by medically 
significant clinical deterioration, in the judgment of the Investigator. 
Continuation of treatment through suspected pseudo-progression or 
radiological progression is permitted if in the opinion of the Investigator the 
subject has not clinically progressed.  
• Any alterations in the patient’s condition which justifies the discontinuation of 
treatment in the investigator’s opinion  
 
Unless patients withdraw their consent, disease and survival status data as well as 
details of future anti-cancer treatments will continue to be collected as described in 
the table of assessments. 
  
If a patient permanently discontinues study drug for reasons other than disease 
progression, such as toxicity, the state of disease in terms of progression should be 

 
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noted at this time point. Ideally, formal imaging should occur at this point to document 
the state of disease. Alternatively, the previous scan should be used. Where possible, 
scanning should continue as per normal practice until progression has been reached 
as per protocol. The date of progression of disease should be recorded in the CRF. 
Further treatment is at the treating doctor’s discretion.  
 
5.1.8 Intended Dose Delays 
Intended doses may be delayed for non-toxicity reasons for up to 14 days (for reasons 
such as scheduling conflicts), but only with documentation and explanation in the CRF 
after discussion with the study Principal Investigator. 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial.  If there is a clinical indication for one of these or 
other medications or vaccinations specifically prohibited during the trial, 
discontinuation from trial therapy or vaccination may be required.  The investigator 
should discuss any questions regarding this with the Sponsor.  The final decision on 
any supportive therapy or vaccination rests with the investigator and/or the patient's 
primary physician.  
 
5.1.9 Acceptable Concomitant Medications 
All concomitant medication will be recorded on the case report form (CRF) including 
all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF. 
 
All concomitant medications received within 30 days before the first dose of trial 
treatment and 30 days after the last dose of trial treatment should be recorded.  
Concomitant medications administered more than 30 days after the last dose of trial 
treatment should be recorded for SAEs as defined in Section 9.1.3. 
 
5.1.10 Prohibited Concomitant Medications 
Patients are prohibited from receiving the following therapies during the Screening 
and Treatment Phase (including retreatment for post-complete response relapse) of 
this trial.  Patients who, in the assessment by the investigator, require the use of any 
of the below mentioned treatments for clinical management should be removed from 
the trial.   
 
• 
Antineoplastic systemic chemotherapy or biological therapy  
 
• 
Immunotherapy  
 
• 
Chemotherapy  
 

 
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• 
Investigational agents other than TLR9 + OX40 
 
• Radiation therapy  
 
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain 
may be allowed at the investigator’s discretion and with sponsor 
approval.   
 
Patients may receive other medications (not listed here as prohibited) that the 
investigator deems to be medically necessary. 
 
The Exclusion Criteria describes other medications, which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
Diet/Activity/Other Considerations 
5.1.11 Diet 
Patients should maintain a normal diet unless modifications are required to manage 
an AE such as diarrhea, nausea or vomiting. 
 
5.1.12 Contraception 
CMP-001 and INCAGN01949 may have adverse effects on a fetus in utero.  
Furthermore, it is unknown whether CMP-001 or INCAGN01949 has transient adverse 
effects on the composition of sperm.   
 
For this trial, male patients will be considered to be of non-reproductive potential if 
they have azoospermia (whether due to having had a vasectomy or due to an 
underlying medical condition).   
 
Female patients will be considered of non-reproductive potential if they are either:  
 
1. Postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a 
post-menopausal state in women not using hormonal contraception or 
hormonal replacement therapy. In the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient.);  
 
OR 
 
2. Have had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to 
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OR 
 
3. Has a congenital or acquired condition that prevents childbearing. 
 
Female and male patients of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving study drug and for 
120 days for male patients and 180 days for female patients after the last dose of 
study drug by complying with one of the following: 
   
1. Practice abstinence† from heterosexual activity;  
 
OR 
 
2. Use (or have their partner use) acceptable contraception during heterosexual 
activity.   
 
Acceptable methods of contraception are‡: 
  
Single method (one of the following is acceptable): 
 
• 
intrauterine device (IUD) 
 
• 
vasectomy of a female patient’s male partner  
 
• 
contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 
 
• diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
 
• cervical cap with spermicide (nulliparous women only)   
 
• contraceptive sponge (nulliparous women only)  
 
• male condom or female condom (cannot be used together) 
 
• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
  
†Abstinence (relative to heterosexual activity) can be used as the sole method 
of contraception if it is consistently employed as the patient’s preferred and 
usual lifestyle and if considered acceptable by local regulatory agencies and 
IRBs.  Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-

 
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ovulation methods, etc.) and withdrawal are not acceptable methods of 
contraception.  
  
‡If 
a 
contraceptive 
method 
listed 
above 
is 
restricted 
by 
local 
regulations/guidelines, then it does not qualify as an acceptable method of 
contraception for patients participating at sites in this country/region. 
 
Patients should be informed that taking the study medication might involve unknown 
risks to the fetus (unborn baby) if pregnancy were to occur during the study.  In order 
to participate in the study patients of childbearing potential must adhere to the 
contraception requirement (described above) from the day of study medication 
initiation (or 14 days prior to the initiation of study medication for oral contraception) 
throughout the study period up to 180 days after the last dose of trial therapy.  If there 
is any question that a patient of childbearing potential will not reliably comply with the 
requirements for contraception, that patient should not be entered into the study. 
 
5.1.13 Use in Pregnancy 
If a patient becomes pregnant while on trial treatment, the patient will immediately be 
discontinued from all trial treatment and have end of visit procedures performed and 
will be followed-up throughout the remainder of the pregnancy. The site will contact 
the patient at least monthly and document the patient’s status until the pregnancy has 
been completed or terminated.  The outcome of the pregnancy will be reported to the 
Sponsor without delay and within 2 working days to the Sponsor if the outcome is a 
serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
 
The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor.   If a male patient impregnates his female partner the study personnel at the 
site must be informed immediately and the pregnancy reported to the Sponsor and 
followed as described above and in Section 9.1.3. 
 
5.1.14 Use in Nursing Women 
It is unknown whether CMP-001 or INCAGN01949 is excreted in human milk. Since 
many drugs are known to be excreted in breast milk and because of the potential for 
serious adverse reactions in the nursing infant, patients who are breast-feeding or 
plan to breast feed during the course of the trial are not eligible for enrollment and 
breast feeding is not permitted while taking trial treatment. 
 
Patient Withdrawal/Discontinuation Criteria 
Patients may withdraw consent at any time for any reason or be discontinued from the 
trial at the discretion of the investigator should any untoward effect occur.  In addition, 
a patient may be withdrawn by the investigator or the Sponsor if enrollment into the 

 
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trial is inappropriate, the trial plan is violated, or for administrative and/or other safety 
reasons.  Specific details regarding assessments to be done at an EOT visit at time 
of discontinuation or withdrawal are provided in Table 5. 
 
A patient must be discontinued from the trial for any of the following reasons: 
 
• The patient withdraws consent. 
 
• Confirmed disease progression 
 
• Unacceptable adverse events  
 
• Intercurrent illness that prevents further administration of treatment 
 
• Investigator’s decision to withdraw the patient 
 
• The patient has a confirmed positive serum pregnancy test 
 
• Noncompliance with trial treatment or procedure requirements 
 
• The patient is lost to follow-up 
 
• Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in Section 7.1.5.3 
(End of Treatment and Survival Follow-up).  After the end of treatment, each patient 
will be followed for 30 days for adverse event monitoring after the end of treatment as 
described in Table 5.  Patients who discontinue for reasons other than progressive 
disease will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent or 
becoming lost to follow-up.  After documented disease progression each patient will 
be followed by telephone for overall survival until death, withdrawal of consent, or the 
end of the study, whichever occurs first. 
 
Patient Replacement Strategy 
Patients who discontinue from the study will not be replaced. Patients who discontinue 
treatment without progression will be followed to determine their disease status at 6 
months.  Patients who are enrolled into the trial, but fail to receive CMP-001 (TLR9) + 
INCAGN01949 (OX40) may be replaced. 
 
Clinical Criteria for Early Trial Termination  
Early trial termination will be the result of the criteria specified below: 
 

 
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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 clinical trials 
indicates a potential health hazard to patients 
 

 
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6.0 Study Calendar 
Table 6.  Screening – Treatment Period 
 
SCREENING 
TREATMENT 
STUDY WEEK 
 
1 
2 
3 
4 
5 
6 
8 
Scheduling Window (Days): 
-28 to -1 
± 1 
±2 days 
±2 days 
±2 days 
±2 days 
±2 days 
±1 week 
Informed Consent 
x a 
 
 
 
 
 
 
 
Inclusion/Exclusion  
x 
x 
 
 
 
 
 
 
Demographics and Medical History 
x b 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
x 
x 
x 
x 
x 
x 
x 
 
Review Adverse Events 
 
x 
x 
x 
x 
x 
x 
 
Physical Examination c 
x 
x 
 
x 
x 
x 
x 
 
Vital Signs d 
x 
x 
x 
x 
x 
x 
x 
 
ECG 
x 
 
 
 
 
 
x 
 
ECOG e(see appendix 2) 
x 
x 
x 
x 
x 
x 
x 
 
CBC with Differential 
x 
x 
x 
x 
x 
x 
x 
 
Comprehensive Serum Chemistry 
Panel f 
x 
x 
x 
x 
x 
x 
x 
 
Urinalysis 
x 
x 
x 
x 
x 
x 
x 
 
Serum β HCG Pregnancy Test (if 
applicable) h 
x 
x 
x 
x 
x 
x 
x 
 
PTT/INR and aPTT 
x 
 
 
 
x 
x 
x 
 
Tumor Imaging l, J 
xi 
 
 
 
 
 
 
x 
•CA 19-9 (or CA 125, or CEA if not 
expressers of CA 19-9)k 
x 
x 
 
 
x 
 
x 
 
Tumor Biopsy l  
x 
 
 
 
x 
 
x 
 
Central Blood Samples 3 X 10 mLm 
x 
x 
 
 
x 
 
x 
 
Autoimmune lab panel n 
x 
 
 
 
 
 
 
 
Thyroid Function Tests 
x 
 
 
 
x 
 
x 
 
Hepatitis Testing (HepBsAg, 
HepBcAb, HCV Ab ) 
x 
 
 
 
 
 
 
 
HIV antibody testing 
x 
 
 
 
 
 
 
 
CMP-001 (SC dose is 5mg) 
 
x 
x 
 
 
 
 
 
CMP-001 (IT dose is 10mg) 
 
 
 
x 
x 
x 
x 
 
INCAGN01949 (IT) in mcgo 
 
 
 
x 
x 
x 
x 
 
 
Table 4 Screening through –Treatment Period 
a. Written IRB-approved informed consent must be obtained prior to any screening assessments 
being performed. 
b. Documented medical history to include concurrent baseline conditions (using NCI-CTCAE V5. 
Appendix 1), prior cancer treatment and surgeries. Any events occurring from consent to first dose 
of study medication will be recorded as medical history. 
c. Complete physical exam including height and weight at screening, directed physical exam for 
day 1 of Week 1, 3 and 6 (if clinically indicated) and at the EOT, if deemed necessary. 
d. Vital signs to include: Blood pressure, pulse, pulse oximetry, respiratory rate, weight, and 
temperature. Height will be measured at screening only. 

 
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e. ECOG Performance Status must be 0 or 1 to be eligible for entry to the study. 
f. Refer to Table 8 for details of required labs to be included.  Adequate organ function must be 
demonstrated in accordance with protocol criteria within 10 days of start of study medication as 
defined in Table 2.  The following labs are to be drawn at screening, Week 4, end of treatment 
only and as clinically indicated: LDH, lipase, amylase, magnesium, phosphorous, uric acid. 
h. Negative serum pregnancy test is required for women of child-bearing potential within 72 hours 
of start of study medication; adequate contraception (both males and females) as defined by the 
protocol (refer to Section 5.1.12) should be used throughout the study and for 180 days past the 
last dose for females and 120 days for males.   
i. CT/MRI to document disease status at baseline to include chest abdomen and pelvis and other 
regions as clinically indicated. A screening CT/MRI is not necessary if the patient’s last scan was 
obtained within 28 days before the screening visit. 
j. The same radiographic procedures used to document disease status at baseline must be used 
throughout the study. Tumor assessments will be conducted using CT or MRI, approximately every 
8 weeks (+/- 1 week) until study discontinuation or disease progression, whichever is later. All sites 
of disease must be followed using the same baseline assessment method. Confirmatory 
assessment of complete response (CR) or partial response (PR) must be performed no less than 
4 weeks after the initial documentation of response.   
k. CA19-9 (or other relevant tumor markers) assessments  will be taken at baseline and at weeks 
4 and 6  during the trial treatment period. All CA19-9 assessments must be assayed by the same 
laboratory for each patient. The Investigator is encouraged to obtain radiological assessments and 
tumor marker values earlier if there is a strong clinical suspicion of disease progression, in order to 
confirm or refute the clinical impression. 
l. Baseline biopsy to be obtained during the screening period.  If possible, a biopsy will also be 
collected on day 1 of week 4 and 6.   
m. Each patient will have 3 X 10 mL vials of blood collected at the following time points: Pre-
treatment (0-14 days prior to Week1/day1), prior to treatment on day 1 of Week 4 and 6.  
n. Autoimmune lab panel to be collected at Screening and EOT 
o. Reminder INCAGN01949 is dosed in micrograms (mcg) per m2 and CMP-001 is in milligrams 
(mg) as a flat dose. 
 
 
 
 
 
 
 
 
 
 
 

 
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Table 7.  End of Treatment –Follow-Up 
EOT thru Follow-Up Period 
EOT 
Every 12 
weeks  
Scheduling Window (Days) 
14-28 ± 2 
days of 
last dose 
 
Post-study anticancer therapy status 
 
X 
Survival Status 
 
X 
Tumor imagingb 
 
X 
Directed Physical Examination a  
X 
 
Concomitant Medication Review 
X 
 
Review Adverse Events 
X 
 
Vital Signs 
X 
 
ECG 
X 
 
ECOG (see appendix 2) 
X 
 
Hematology: CBC with Differential 
X 
 
Comprehensive Serum Chemistry Panel 
X 
 
Urinalysis 
X 
 
Tumor Imaging b 
X 
 
Autoimmune lab panel 
X 
 
CA19-9 (or Relevant Tumor Marker)c 
X 
 
Review contraception use as required by protocol Section 5.1.12 
(where applicable) d 
X 
 
Contact Information Reviewe 
X 
 
Footnotes for Table 5. End of Treatment-Survival Follow-up   
a. Directed physical exam at the EOT, if deemed necessary. 
b. The same radiographic procedures used to document disease status at baseline must be 
used throughout the study. Tumor assessments will be conducted using CT or MRI,  every 
8+/- weeks until study discontinuation or disease progression. After the  first 12 months 
on trial, then assessments will be done every 12 +/- 1 weeks. All sites of disease must be 
followed using the same baseline assessment method. Confirmatory assessment of complete 
response (CR) or partial response (PR) must be performed no less than 4 weeks after the 
initial documentation of response.  An EOT CT/MRI is not necessary if the patient’s last scan 
was obtained within 28 days before the EOT visit. 
c. All CA19-9 (or other relevant tumor marker) assessments must be assayed by the same 
laboratory for each patient.  
d. Adequate contraception as defined by the protocol should be used throughout the trial and 
for at least 120 days for males w/WOCBP sexual partner and 180 days for WOCBP from the 
last dose of trial treatment. Refer to Section 5.1.12 for complete details. 
e. Site to confirm contact information for patient and a designated family member and remind 
patient of FU telephone contact that will be conducted every 12 weeks for survival status. 
 
 
 

 
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7.0 TRIAL PROCEDURES 
 
Assessments performed exclusively to determine eligibility for this study will be done 
only after obtaining informed consent. Assessments performed for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values even if 
the studies were done before informed consent was obtained. 
 
7.1 Trial Procedures 
The Trial Flow Chart - Section 6 summarizes the trial procedures to be performed at 
each visit.  Individual trial procedures are described in detail below.  It may be 
necessary to perform these procedures at unscheduled time points if deemed 
clinically necessary by the investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the 
Sponsor for reasons related to patient safety.  
 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential patient prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the patient’s dated signature. A copy of the signed 
and dated consent form should be given to the patient before participation in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent 
form and any written information provided to the patient must receive the IRB’s 
approval/favorable opinion in advance of use.  The patient should be informed in a 
timely manner if new information becomes available that may be relevant to the 
patient’s willingness to continue participation in the trial.  The communication of this 
information will be provided and documented via a revised consent form or addendum 
to the original consent form that captures the patient’s dated signature or by the 
patient’s legally acceptable representative’s dated signature. 
 
Specifics about a trial and the trial population will be added to the consent form 
template at the protocol level.   
 
The informed consent will adhere to IRB requirements, applicable laws and 
regulations and Sponsor requirements. 
 

 
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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified 
designee to ensure that the patient qualifies for the trial.  
 
7.1.1.3 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 patient has enrolled in this study will be recorded 
separately and not listed as medical history.   
 
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 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 
patient within 28 days before starting the trial.  Treatment for the disease for which the 
patient has enrolled in this study will be recorded separately and not listed as a prior 
medication.  
 
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the 
patient during the trial.  All medications related to reportable SAEs should be recorded. 
 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding 
disease status.  
 
7.1.1.5.2 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy 
initiated after the last dose of trial treatment.  If a patient initiates a new anti-cancer 
therapy within 30 days after the last dose of trial treatment, the EOT visit must occur 
before the first dose of the new therapy.  Once new anti-cancer therapy has been 
initiated the patient will move into survival follow-up.  
 
7.1.1.6 Assignment of Screening Number 
A patient will be assigned a screening number once they provide written informed 
consented for the study.  This screening number will be site specific and maintained 
on a Screening log in the Investigator Site File. 
 

 
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7.1.1.7 Assignment of Enrollment Number  
Eligible patients will be assigned an enrollment number that will serve as the patient’s 
number throughout the trial.  This enrollment number will be site specific and 
maintained on an Enrollment log in the Investigator Site File.  
 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each patient to evaluate for potential 
new or worsening AEs as specified in the Trial Flow Chart and more frequently if 
clinically indicated.  Adverse experiences will be graded and recorded throughout the 
study and during the follow-up period according to NCI CTCAE Version 5.0 (Appendix 
1).  Toxicities will be characterized in terms regarding seriousness, causality, toxicity 
grading, and action taken with regard to trial treatment.  
 
Please refer to section 9.0 for detailed information regarding the assessment and 
recording of AEs.   
 
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during 
the screening period.  Clinically significant abnormal findings should be recorded as 
medical history.  A full physical exam should be performed during screening. 
 
7.1.2.3 Directed Physical Exam 
For weeks that do not require a full physical exam per the Trial Flow Chart, the 
investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to trial treatment administration.  
 
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as 
specified in the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, 
pulse, pulse oximetry, respiratory rate, weight and blood pressure.  Height will be 
measured at screening only. 
 
For the first 5 CMP-001 dosing visits (SC W1D1, W2D1 and IT W3D1, W4D1, W5D1) 
vital signs are to be collected prior to CMP-001 dosing, and at 30 (±15) minute 
intervals for 4 hours following CMP-001 dosing. Based upon the discretion of the 
Investigator, observation periods can be reduced to one hour for individual subjects 
who demonstrate mild to no AEs post CMP-001 injection for the first 5 doses (2 SC 
and 3 IT). Reduced observation periods can be implemented starting with the 6th dose 
of CMP-001.  
 
Vital signs should be taken in the supine or seated position, following ≥ 3 minutes of 
rest. 

 
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When vital signs are scheduled at the same time as a blood sample, the vital sign 
measurements may be obtained within 15 minutes before the scheduled blood draw. 
If an indwelling cannula is being used to obtain plasma samples, blood pressure 
should be measured in the arm opposite to the cannula placement. 
 
7.1.2.5 Electrocardiogram 
A single standard, 12-lead ECG will be obtained at Screening for each subject. ECGs 
will also be assessed at the 6th (W6D1) dosing visit and EOT.  
 
Assessed ECG parameters will include heart rate and PR, QRS, QT and QT corrected 
for heart rate (QTc) intervals. QT will be corrected using Fridericia’s (QTcF) formula. 
 
Electrocardiograms will be performed after the subject has been resting in supine or 
semi-supine position for at least 5 minutes. 
 
The ECG results will be interpreted locally at the site by a delegated medically 
qualified person. If indicated, ECG findings may be confirmed by a cardiologist or 
internist. 
 
7.1.2.6 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status at screening, prior to 
the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
 
7.1.2.7 Tumor Imaging and Assessment of Disease  
Assessment of the patient’s pancreatic cancer or other cancer will be evaluated based 
on tumor assessments using RECIST 1.1 and iRECIST (Section 8).   
 
Tumor assessments for evaluation of response will be conducted using contrast 
enhanced multiphase (delayed arterial phase and portal venous phase) CT or MRI. 
Imaging will be obtained  every 8 ± 1 weeks until study discontinuation, disease 
progression.After the end of first 12 months on trial, then assessments will be done 
every 12 +/- 1 weeks. All sites of disease must be followed using the same baseline 
assessment method. Confirmatory assessment of complete response (CR) or partial 
response (PR) must be performed no less than 4 weeks after the initial documentation 
of response.  
 
All target lesions will be measured by consistent imaging techniques for each patient 
throughout the study. Suitable imaging techniques include CT-scan, or MRI. The 
same technique should be used for each evaluation in an individual patient. Copies of 
the scans must be available for review. 
 
CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9) assessments for patients 
with pancreatic cancer will be taken at baseline, week 1, 4 and 6 during the trial 

 
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treatment period. All CA 19-9 assessments must be assayed by the same laboratory 
for each patient. 
 
7.1.3 Blood and Tumor Tissue Collection  
Each patient will have three 10mL vials (total of 30 ml) of blood collected at the 
following time points: Pre-treatment (0-14 days prior to week1/day1), and during the 
trial prior to treatment on W1/D1, W4/D1 and W6/D1. A needle biopsy will be 
performed at the following time points: pre-treatment (0-14 days prior to week1/day1), 
and on treatment prior to IT drug administration on W4/D1 and W6/D1.   
 
Tumor and blood samples will be collected pre-treatment and during treatment. These 
biomarker assessments will potentially aid in understanding the effect of the two 
agents. All patients will be consented for the collection and use of these samples. All 
samples will be linked anonymized and only identified by the trial ID and unique 
sample number allocated by the Sponsor. The results of any exploratory analyses will 
not be included in the clinical study report and may be reported separately from the 
main study results. 
 
• The assays described below may be performed with the material derived from 
each patient (if available). It is likely that not all assays will be performed on 
samples provided by each patient (possibly because of insufficient tumor 
material or inadequate sample quality). Outcome measures may include but 
are not limited to: 
 
• Determine OX40 expression within the lymphocyte subsets (Teff and Treg) 
 
• Flow cytometry performed on pre and post treatment aspirates to quantify T 
cells and tumor cells  
 
• On tissue samples collected prior to, and during, treatment, we will: 
 
o Use flow cytometry to enumerate CD4+ and CD8+ T cell subsets, and the 
expression of activation/differentiation markers (including CD127, HLA-DR, 
CD45RO, CCR7, CXCR3) on each 
 
o Use RT-PCR and sequencing to amplify and characterize the TCRa and b 
sequences of tumor-infiltrating T cells, looking for evidence of oligo-clonal 
T cell expansion 
 
o Perform RNAseq to determine different immune cell populations including 
T cells and macrophages 
 
 

 
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7.1.4 Laboratory Procedures/Assessments 
Safety laboratory tests for hematology, chemistry, urinalyses, and serum or urine 
pregnancy tests (if applicable) will be performed by the local laboratory at each 
investigational site at screening, baseline, and throughout the trial treatment period.  
 
 
 
Table 8.  Laboratory Tests – performed locally 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human 
chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
 PT (INR)  
Platelet count 
Alanine 
aminotransferase (ALT) 
Protein 
aPTT  
WBC (total and 
differential) 
Aspartate 
aminotransferase (AST) 
Specific gravity  
Thyroid Function 
Studies (thyroid 
stimulating hormone 
[TSH], Free T3, Free 
T4] 
Red Blood Cell 
Count 
Lactate dehydrogenase 
(LDH) 
Microscopic exam 
(If abnormal)  
Autoimmune lab panel 
(anti-dsDNA, ANA, 
ANCA, RF, and anti-
RNP) 
Absolute 
Neutrophil Count 
Carbon Dioxide ‡ 
pH 
Serology panel (HIV, 
Hepatitis) 
Absolute 
Lymphocyte Count 
  (CO2 or bicarbonate) 
WBCs 
 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total 
bilirubin is elevated 
above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
 
Vitamin D  
• 
25-Hydroxy D2  
 
 

 
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Hematology 
Chemistry 
Urinalysis 
Other 
• 
25-Hydroxy D3  
• 
25-Hydroxy D 
Total 
 
Amylase 
 
 
 
Lipase 
 
 
 
Creatinine 
 
 
† Perform on women of childbearing potential only.  
‡ If considered standard of care in your region. 

 
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7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-
related details are provided above in Section 7.0 - Trial Procedures. 
 
7.1.5.1 Screening 
Screening of potential patients will be performed only after informed consent is 
obtained and within 28 days prior to first dose of trial medication (unless stated 
otherwise below).  All necessary laboratory values and assessment reports must be 
available prior to week1/ day 1.  
 
 The following will be completed as part of the screening visit: 
 
1. Written informed consent   
 
2. Medical history including concurrent baseline conditions (using NCI CTCAE 
version 5.0; Appendix 1), prior cancer therapy (including documentation of prior 
surgery, adjuvant or neoadjuvant chemotherapy and radiotherapy). 
 
3. Complete physical examination including height (cm) and weight (kg). 
 
4. ECOG Performance Status (see Appendix 2) 
 
5. Vital signs (blood pressure, pulse, pulse oximetry, respiratory rate, weight, and 
temperature). 
 
6. Computed tomography (CT) / magnetic resonance imaging (MRI) scans to 
document disease status (including chest, abdomen, pelvis, and other regions 
as clinically indicated.  In addition, brain scan is required to exclude brain 
metastases if clinically indicated only). If a CT scan was performed within 28 
days prior to first dose, new scans are not necessary. However, if new scans 
are to be done, they should be performed within 5 days prior to starting trial 
medication.  
 
7. Electrocardiogram (ECG) 
 
8. PTT/INR and aPTT 
 
9. Complete blood count (CBC) with differential and platelet count. 
 
10. Comprehensive serum chemistries (refer to Table 6). 
 
11. CA 19-9 (or CA125 or CEA if not expressers of CA19-9) for patients with 
pancreatic cancer 
 
12. Urinalysis (refer to Table 6) 

 
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13. Serum β-HCG pregnancy test for women of child-bearing potential (refer to 
Section 5.1.12 for more details) 
 
14. Concomitant medication notation (to include all medications taken within 30 
days prior to enrollment) 
 
15. Baseline biopsy of the tumor to be injected.  
 
16. Central Blood Samples to be collected at screening and at the time of each 
treatment. Three 10 mL vials (must be collected within 14 days of Week 1/Day 
1) 
 
17. Hepatitis B (using Hep B sAg, Hep B cAb IgG) and Hepatitis C (using HCV Ab 
and HCV RNA if HCV Ab is positive) 
 
18. Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) 
 
19. Thyroid function test 
 
20. Autoimmune lab panel 
 
7.1.5.2 Treatment Period 
 
Patients will be treated at weekly (7day) ± 2 day intervals.  Patient must begin Week 
1/ Day 1 within 28 days of signing the IRB approved informed consent document and 
after the screening assessments.   
 
Treatment will be administered by qualified and trained site personnel in a hospital, 
clinic, or other outpatient setting appropriate for chemotherapeutic infusions. Please 
reference section 7.1.6 for specific guidance on prophylaxis prior to and after CMP-
001 dosing. 
 
For subsequent treatments, all assessments must be conducted within 48 hours 
(except those noted), or if medical or scheduling conditions require a delay.     
 
Screening clinical evaluations and laboratory assessments may be used as the Week 
1 /Day 1 evaluations if they are completed within 48 hours of trial treatment 
administration. 
 
Week 1 Day 1 (except where noted) 
 
• Week 1 only: Inclusion/exclusion review  
 
• Directed physical exam 
 

 
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• Vital signs 
 
• Measurement of weight (kg) and BSA calculation prior to dosing (After Week 
1, the BSA only needs to be changed if there has been a change > 10% in body 
weight from Week 1 /Day 1 
 
• ECOG Performance Status (Appendix 2) 
 
• Hematology: CBC with differential and platelet count 
 
• Serum chemistries (refer to Table 6) 
 
• CA19-9 (or CA 125, or CEA if not expressers of CA 19-9) for patients with 
pancreatic cancer.  
 
• Urinalysis 
 
• Serum β-HCG pregnancy test. Results must be reviewed prior to treatment 
initiation confirming a negative serum β-HCG for women of child-bearing 
potential and documentation of the patient’s confirmation of preferred 
acceptable method of contraception starting from the day of trial treatment 
initiation or 14 days prior to the initiation of trial medication for oral 
contraception (refer to Section 5.1.12 for more details). 
 
• As a precaution and as per protocol, patients must be observed on site for at 
least 4 hours after injection, or until the investigator deems necessary, e.g., 
until any suspected symptoms have spontaneously disappeared or have been 
successfully treated.  
 
• Central Blood Sample, 3 X10 mL vials – collected prior to treatment.  
 
• AEs using the NCI CTCAE 5.0 (Appendix 1) 
 
• Concomitant medication notation 
 
• CMP-001 administration (SC administration) 
 
 
Week 2 Day 1 
 
• Vital signs 
 
• Measurement of weight (kg) and BSA calculation prior to dosing (After Week 
1, the BSA only needs to be changed if there has been a change > 10% in body 
weight from Week 1 /Day 1 
 

 
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• Hematology: CBC with differential and platelet count 
 
• Serum chemistries (refer to Table 6) 
 
• Urinalysis 
 
• As a precaution and as per protocol, patients must be observed on site for at 
least 4 hours after injection, or until the investigator deems necessary, e.g., 
until any suspected symptoms have spontaneously disappeared or have been 
successfully treated. After week 5 this can be reduced based on investigator 
judgment.  
 
• AEs using the NCI CTCAE 5.0 (Appendix 1) 
 
• Concomitant medication notation 
 
• CMP-001 administration (SC administration) 
 
Week 3 and 5, Day 1 
 
• Vital signs 
 
• Measurement of weight (kg) and BSA calculation prior to dosing (After Week 
1, the BSA only needs to be changed if there has been a change > 10% in body 
weight from Week 1 /Day 1 
 
• Hematology: CBC with differential and platelet count 
 
• Serum chemistries (refer to Table 6) 
 
• Urinalysis 
 
• As a precaution and as per protocol, patients must be observed on site for at 
least 4 hours after injection, or until the investigator deems necessary, e.g., 
until any suspected symptoms have spontaneously disappeared or have been 
successfully treated. After week 5 this can be reduced based on investigator 
judgment.  
 
• AEs using the NCI CTCAE 5.0 (Appendix 1) 
 
• Concomitant medication notation 
 
• CMP-001 administration (IT administration) 
 
• 
INCAGN01949 administration (IT administration) 
 

 
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Week 4 and 6, Day 1 
 
• Directed physical exam 
 
• Vital signs 
 
• Week 6 only – Computed tomography (CT) / magnetic resonance imaging 
(MRI) to document disease status (including chest, abdomen, pelvis, and other 
regions as clinically indicated.  In addition, brain scan is required to exclude 
brain metastases if clinically indicated only).  
 
• Measurement of weight (kg) and BSA calculation prior to dosing (After Week 
1, the BSA only needs to be changed if there has been a change > 10% in body 
weight from Week 1 /Day 1 
 
• ECOG Performance Status (Appendix 2) 
 
• Hematology: CBC with differential and platelet count 
 
• Serum chemistries (refer to Table 6) 
 
• PTT/INR and aPTT 
 
• CA19-9 (or CA 125, or CEA if not expressers of CA 19-9) for pancreatic cancer.  
 
• Urinalysis 
 
• Needle biopsy of the injected tumor prior to first intratumor injection  
 
• Serum β-HCG pregnancy test. Results must be reviewed prior to treatment 
initiation confirming a negative serum β-HCG for women of child-bearing 
potential and documentation of the patient’s confirmation of preferred 
acceptable method of contraception starting from the day of trial treatment 
initiation or 14 days prior to the initiation of trial medication for oral 
contraception (refer to Section 5.1.12 for more details). 
 
• As a precaution and as per protocol, patients must be observed on site for at 
least 4 hours after injection (during week 6 observation time can be reduced), 
or until the investigator deems necessary, e.g., until any suspected symptoms 
have spontaneously disappeared or have been successfully treated.  
 
• Central Blood Sample, 3 X10 mL vials – collected prior to treatment.  
 
• AEs using the NCI CTCAE 5.0 (Appendix 1) 
 

 
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• Concomitant medication notation 
 
• Thyroid function tests 
 
• CMP-001 administration (IT administration) 
 
• 
INCAGN01949 administration (IT administration)  
 
• CT/MRI scan in Week 8 to evaluate disease status (using same imaging 
method as Baseline).   
o Every 8 ± 1 week until disease progression or study discontinuation (whichever 
is later), or end of first 12 months on trial, then every 12 +/- 1 weeks, whichever 
comes first 
 
 
Note: In order to more precisely determine time to progression, the investigator is 
encouraged to obtain radiological assessments and CA19-9 values earlier if there is 
a strong clinical suspicion of disease progression. In order to either confirm or refute 
the clinical impression. 
 
7.1.5.3 End of Treatment (EOT) 
The patient will continue on study treatment until there is evidence of clear-cut tumor 
progression, has treatment ending toxicities, withdraws from treatment (refer to 
section 5.1.14) or finishes 6 weeks (6 doses). The following assessments will be 
performed 14-28 (+/- 2) days after completing the last dose of trial medication or 
before the initiation of a new anti-cancer treatment, whichever comes first: 
 
• Directed physical exam, if deemed necessary 
 
• ECOG Performance Status (see Appendix 2) 
 
• Vital signs 
 
• ECG 
 
• Hematology: CBC with differential and platelet count 
 
• Serum chemistries 
 
• CA 19-9 (or CA125 or CEA if not expressers of CA19-9) for pancreatic cancer 
 
• Serum β-HCG pregnancy test.  
 
• Review contraception use as required by protocol Section 5.1.12 (where 
applicable) 

 
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• Urinalysis 
 
• Concomitant medications  
 
• CT/MRI scan to evaluate disease status (using same imaging method as 
Baseline. An EOT CT/MRI is not necessary if the patient’s last scan was 
obtained within 28 days before the EOT visit 
 
• Autoimmune lab panel 
 
• AEs using the NCI CTCAE Version 5.0 (see Appendix 1) 
 
Patients with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 
0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  
SAEs that occur within 30 days of the end of treatment or before initiation of a new 
anti-cancer treatment should also be followed and recorded.   
 
• Confirm contact information for patient and a designated family member and 
remind patient of FU telephone contact that will be conducted every 12 weeks 
for survival status  
 
 
7.1.5.4 Survival Follow-up 
Once a patient experiences confirmed disease progression or starts a new anti-cancer 
therapy, the patient moves into the survival follow-up phase and should be contacted 
by telephone every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first.  
 
7.1.6 Required Prophylaxis Prior to and After CMP-001 Dosing 
CMP-001 has been administered as an IT or SC injection. Intratumoral injection of 
CMP-001 provides the most direct approach to activate tumor-associated pDC, and 
thereby may induce a more potent antitumor CD8+ T-cell response. 
To reduce the severity of these symptoms associated with CMP-001 treatment, 
prophylaxis is required. Prophylactic regimens already in place at institutions should 

 
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be followed; if not, below is a suggested regimen that has been effective for the 
treatment of CMP-001 induced AEs: 
• Intravenous fluids (eg, approximately 1000 cc IV normal saline)  
• Anti-pyretics (eg, acetaminophen 1000 mg and a non-steroidal anti-
inflammatory agent such as indomethacin 50 mg or ibuprofen 600 to 800 mg)  
• Anti-emetics (eg, ondansetron 8 mg) 
• Antihistamine: diphenhydramine 50 mg, with or without an H2-antagonist 
• Recommended: hydrocortisone 25 mg at the investigator’s discretion.  
Subjects with a history of adrenal insufficiency are at increased risk for 
moderate to severe AEs such as hypotension. It is strongly recommended that 
these subjects receive stress dose steroids (ie, 50 to 100 mg hydrocortisone 
orally every 8 hours) prior to or immediately after injection of CMP-001. 
Prophylaxis administration should be completed before initiation of CMP-001 
injection. The medications are recommended for oral administration, but IV is 
acceptable at the discretion of the investigator. It is also highly recommended to 
continue to administer fluids immediately following the CMP-001 injection, rather than 
waiting to initiate fluids if hypotension is detected. There is no waiting period between 
the end of prophylaxis and the start of the CMP-001 injection. The following algorithm 
(Figure 2) is provided as guidance for the treatment of symptoms associated with 
CMP-001. 
In subjects with hypotension unresponsive to supportive care with intravenous fluids, 
the administration of stress dose steroids is recommended according to institutional 
practices. Additional treatment measures may include the use of anti-cytokine therapy 
per institutional protocol. Prior to dosing an anti-cytokine therapy, it is recommended 
that blood be obtained to determine the cytokine level believed to be responsible for 
the AE. The result of the cytokine assay does not need to be available prior to dosing.   
For subjects who previously experienced a CMP-001-related Grade 3 or higher AE, 
prophylaxis with stress dose steroids (50 mg to 100 mg hydrocortisone orally every 8 
hours before or immediately after injection of CMP-001 or institutional standard) is 
recommended for subsequent CMP-001 doses. A minimum dose of corticosteroids of 
25 mg prednisone or equivalent (eg, hydrocortisone, methylprednisolone, 
dexamethasone) is recommended. The selection and dose of corticosteroid should 
be determined by the Investigator based on clinical parameters.  
7.1.7 Subcutaneous Injections with CMP-001 
CMP-001 should be injected using aseptic technique. Use of topical and/or local 
anesthetic is permitted. The injection may be given into any SC site in the body. 
Please refer to Appendix 3 for CMP-001 Injection Guideline. 

 
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7.1.7.1 Preferred Sites for Subcutaneous Injection 
In order to maximize the distribution and exposure to CMP-001, the full volume from 
a single dose should be distributed to as many SC sites as is practical. It is 
recommended that equal amounts of drug be injected at each SC site. Please refer to 
Appendix 3 for CMP-001 Injection Guideline. 
Preferred sites of SC injection include: 
• 
Within the area of lymphatic drainage corresponding to the site of metastatic 
disease. For example, in a subject with a muscle or bone metastasis in the lower leg, 
preferred SC injection sites would be in the same leg, with the expectation that at least 
some of the CMP-001 will drain to lymph nodes that also contain tumor antigens. 
Likewise, in a subject with metastases in an upper lobe of the lung, a preferred SC 
injection site would be in the ipsilateral supraclavicular fossa, where the injection may 
activate pDC in the supraclavicular lymph nodes that also can drain the upper lung.  
• 
Unsuitable sites for injection would include, for example, the palm of the hand 
or the sole of the foot  
 
7.1.7.2 Method of CMP-001 Subcutaneous (SC) Administration 
Using standard aseptic technique, the needle is inserted into the SC tissue. After using 
gentle backward pressure on the syringe plunger to confirm extravascular location of 
the needle tip, the desired volume of CMP-001 is injected and the needle is withdrawn. 
Please refer to Appendix 3 for CMP-001 Injection Guideline. 
 
7.1.8 Intratumoral Injections with CMP-001 and INCAGN01949 
Please refer to Appendix 3 for CMP-001 Injection Guideline. CMP-001 and 
INCAGN01949 should be injected into the same lesion. However, the two drugs 
should not be mixed together since the saline that OX40 is diluted in can interfere with 
CMP-001.  Avoid selecting lesions that may place the subject at undue risk of 
complications such as lesions near large blood vessels or near the subject’s airway. 
If possible, select a single lesion to be injected throughout the study. Clean the 
injection site and surrounding area based on standard procedures at your institution.  
 
Biopsy needle should be removed from the body and a fresh injection needle should 
be used for intratumoral injections. A 25-gauge needle is recommended, however, the 
choice of needle is at the investigator’s discretion. Avoid necrotic or non-solid areas 
of lesion. Give injections via a fanning motion to maximize distribution throughout the 
tumor.  
 
Inject CMP-001 and INCAGN01949 via different needles due to saline’s ability to 
destabilize CMP-001. Inject CMP-001 using the first needle. Then withdraw the first 
needle, and inject INCAGN01949 using the second needle. Do not mix CMP-001 and 

 
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INCAGN01949 together. Try to inject both compounds into the same tumor but in 
different areas.  
 
7.1.9 Observation Period Following CMP-001 and INCAGN01949 Dosing 
Following the first 5 doses of CMP-001 and INCAGN01949 patients must be observed 
for a period of at least four hours for signs and symptoms of reactions to the CMP-
001 and INCAGN01949 injections and other AEs. During the 6-week course of 
treatment patients should be within 20 minutes of the treating clinic. 
 
Based upon the discretion of the Investigator, observation periods can be reduced to 
one hour for individual patients who demonstrate mild to no AEs post CMP-001 and 
INCAGN01949 injection for the first 5 doses. Reduced observation periods can be 
implemented starting with the 6th dose of CMP-001 and INCAGN01949 (W6D1). 
8.0 MEASUREMENT OF EFFECT  
 
8.1 Definitions 
Evaluable for adverse events 
All patients will be evaluable for adverse event evaluation from the time of their first 
treatment. 
8.1.1 
Evaluable for response 
All patients who have received at least one dose of therapy and have their disease 
re-evaluated will be considered evaluable for response (exceptions will be those who 
exhibit objective disease progression prior to the end of Week 1 who will also be 
considered evaluable). Patients on therapy for at least this period and who meet the 
other listed criteria will have their response classified according to the definitions set 
out below. 
 
Response and progression will be evaluated in this study using the revised 
international criteria (1.1) proposed by the RECIST (Response Evaluation Criteria in 
Solid Tumors) committee as well as the modified iRECIST guidelines. Investigators 
should note the different requirements for confirmatory scans as well as follow up for 
the two criteria. 
 
See section 5.1.7 for criteria for continuing treatment past RECIST 1.1 disease 
progression. 

 
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RECIST 1.1 Response and Evaluation Endpoints 
8.1.2 
Measurable Disease.  
Measurable tumor lesions (nodal, subcutaneous, lung parenchyma, solid organ 
metastases) are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥20 mm with chest x-ray and as ≥10 
mm with CT scan or clinical examination. Bone lesions are considered measurable 
only if assessed by CT scan and have an identifiable soft tissue component that meets 
these requirements (soft tissue component ≥10 mm by CT scan). Malignant lymph 
nodes must be ≥15 mm in the short axis to be considered measurable; only the short 
axis will be measured and followed. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). Previously irradiated lesions are not 
considered measurable unless progression has been documented in the lesion. 
 
8.1.3 
Non-measurable Disease.  
All other lesions (or sites of disease), including small lesions are considered non- 
measurable disease. Bone lesions without a measurable soft tissue component, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonis, inflammatory breast disease, lymphangitic involvement of lung or skin 
and abdominal masses followed by clinical examination are all non-measurable. 
Lesions in previously irradiated areas are non-measurable, unless progression has 
been demonstrated. 
 
8.1.4 
Target Lesions.  
When more than one measurable tumor lesion is present at baseline all lesions up to 
a maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements. Note that pathological nodes must meet the criterion of a short axis 
of ≥15 mm by CT scan and only the short axis of these nodes will contribute to the 
baseline sum. All other pathological nodes (those with short axis ≥10 mm but <15 
mm) should be considered non-target lesions. Nodes that have a short axis <10 mm 
are considered non-pathological and should not be recorded or followed. At baseline, 
the sum of the target lesions (longest diameter of tumor lesions plus short axis of 
lymph nodes: overall maximum of 5) is to be recorded. 
 
After baseline, a value should be provided on the CRF for all identified target lesions 
for each assessment, even if very small. If extremely small and faint lesions cannot 
be accurately measured but are deemed to be present, a default value of 5 mm may 
be used. If lesions are too small to measure and indeed are believed to be absent, a 
default value of 0 mm may be used. 
 

 
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8.1.5 
Non-target Lesions.  
All non-measurable lesions (or sites of disease) plus any measurable lesions over and 
above those listed as target lesions are considered non-target lesions. Measurements 
are not required but these lesions should be noted at baseline and should be followed 
as “present” or “absent”. 
 
8.1.6 
Response. 
All patients will have their BEST RESPONSE from the start of study treatment 
until the end of treatment classified as outlined below: 
 
Complete Response (CR): disappearance of target and non-target lesions and 
normalization of tumor markers. Pathological lymph nodes must have short axis 
measures <10 mm (Note: continue to record the measurement even if <10 mm 
and considered CR). Residual lesions (other than nodes <10 mm) thought to be 
non-malignant should be further investigated (by cytology specialized imaging or 
other techniques as appropriate for individual cases before CR can be accepted. 
Confirmation of response is only required in non-randomized studies. 
 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest 
diameter for tumor lesions and short axis measure for nodes) of target lesions, 
taking as reference the baseline sum of diameters. Non-target lesions must be 
non-PD. Confirmation of response is only required in non-randomized studies. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest sum of diameters on 
study. 
 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of 
measured lesions taking as references the smallest sum of diameters recorded 
on study (including baseline) AND an absolute increase of ≥5 mm. Appearance 
of new lesions will also constitute progressive disease (including lesions in 
previously unassessed areas). In exceptional circumstances, unequivocal 
progression of non-target disease may be accepted as evidence of disease 
progression, where the overall tumor burden has increased sufficiently to merit 
discontinuation of treatment or where the tumor burden appears to have 
increased by at least 73% in volume. Modest increases in the size of one or more 
non-target lesions are NOT considered unequivocal progression. If the evidence 
of PD is equivocal (target or non-target), treatment may continue until the next 
assessment, but if confirmed, the earlier date must be used. 
 
Table S1: Integration of target, non-target and new lesions into response 
assessment 
Target Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best 
Response 
for
 
this Category also 
Requires 
Target lesions ± non target lesions 

 
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CR 
CR 
No 
CR 
Normalization of tumor markers, 
tumor nodes <10 mm 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ 
not 
all 
evaluated 
No 
PR 
SD 
Non-PD/ 
not 
all 
evaluated 
No 
SD 
Documented at least once ≥4 wks.  
from baseline 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Yes 
PD 
Non target lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of tumor markers, 
tumor nodes <10 mm 
No Target 
Non-CR/non-PD 
No 
Non- 
CR/non- 
PD 
No Target 
Not all evaluated 
No 
NE 
No Target 
Unequivocal PD 
Any 
PD 
No Target 
Any 
Yes* 
PD 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. This is a reason for stopping therapy, but is NOT objective PD. 
Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
*Investigators should record all new lesions; if the new lesion is felt to be equivocal, treatment may 
be continued pending further assessments. 
 
 
 
 
 
8.1.7 iRECIST Response Assessment 
Overall response will also be assessed using iRECIST. Immunotherapeutics 
may result in infiltration of immune cells leading to transient increase in the size 
in malignant lesions, or undetectable lesions becoming detectable. The criteria 
are identical to those of RECIST 1.1 in many respects but have been adapted to 
account for instances where an increase in tumor burden, or the appearance of 
new lesions, does not reflect true tumor progression. 
 
Key differences are described below. All responses defined using iRECIST 
criteria are designated with a prefix. iRECIST time-point and best overall 
responses will be recorded separately. 
 

 
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8.1.8 Confirming Progression 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses 
the terms iUPD (unconfirmed progression) and iCPD (confirmed progression). 
Confirmatory scans should be performed at least 4 weeks, but no longer than 8 
weeks after iUPD. 
 
iCPD is confirmed if further increase in tumor burden, compared to the last 
assessment, is seen as evidenced by one or more of the following: 
• Continued increase in tumor burden (from iUPD) where RECIST 1.1 
definitions of progression had been met (from nadir) in target, non-target 
disease or new lesions 
o Progression in target disease worsens with an increase of at least 5 mm 
in the absolute value of the sum 
o Continued unequivocal progression in non-target disease with an 
increase in tumor burden 
o Increase in size of previously identified new lesion (s) (an increase of at 
least 5 mm in the absolute value of the sum of those considered to be 
target new lesions) or additional new lesions. 
• RECIST 1.1 criteria are met in lesions types (target or non-target or new 
lesions) where progression was not previously identified, including the 
appearance of additional new lesions. 
 
If iUPD is not confirmed at the next assessment, then the appropriate response 
will be assigned (iUPD if the criteria are still met, but no worsening, or iSD, iPR 
or iCR if those criteria are met compared to baseline). As can be seen in table 
S2, the prior documentation of iUPD does not preclude assigning iCR, iPR, or 
iSD in subsequent time-point assessments or as best overall response (BOR) 
providing that iCPD is not documented at the next assessment after iUPD. 
 
8.1.9 New Lesions 
New lesions should be assessed and measured as they appear using RECIST 
1.1 criteria (maximum of 5 lesions, no more than 2 per site, at least 10 mm in 
long axis (or 15 mm in short axis for nodal lesions), and recorded as New 
Lesions-Target (NLT) and New Lesion-Non-Target (NLNT) to allow clear 
differentiation from baseline target and non-target lesions. 
 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). 
However, the measurements of target lesions should NOT be included in the 
sum of measures of original target lesions identified at baseline. Rather, these 
measurements will be collected on a separate table in the case record form. 
 
PD is confirmed in the New Lesion category if the next imaging assessment, 
conducted at least 4 weeks (but not more than 8 weeks) after iUPD confirms 
further progression from iUPD with either an increase of at least 5 mm in the 
absolute value of the sum of NLT OR an increase (but not necessarily 

 
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unequivocal increase) in the size of NLNT lesions OR the appearance of 
additional new lesions. 
 
Table S2: Time-point (TP) iResponse 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No 
prior 
iUPD** 
Prior iUPD**; *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non- 
iUPD 
No 
iSD 
iSD 
iUPD with 
no 
change 
OR 
decrease 
from last 
TP 
iUPD 
with 
no 
change
 
O
R decrease from 
last TP 
Yes 
NA 
NLs confirms iCPD if NLs were previously identified 
and increase in size (≥5 mm in SOM for NLT or any 
increase for NLNT) or number. If no change in NLs 
(size or number) from last TP, remains iUPD 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based in 
further increase in size of NT disease (need not 
meet RECIST 1.1 criteria for unequivocal PD) 
iUPD 
Non-iCR/Non- 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on: 
o further increase in SOM of at least 5 mm, 
otherwise remains iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on 
further increase in: 
o previously identified T lesion iUPD SOM ≥5 mm 
and / or 
o NT lesion iUPD (prior assessment - need not be 
unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
further increase in: 
o previously identified T lesion iUPD ≥5 mm and / 
or 
o previously identified NT lesion iUPD (need not 
be unequivocal) and /or 
o size or number of new lesions previously 
identified 
Non- 
iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
o increase in size or number of new lesions 
previously identified 

 
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* Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, 
PR and SD would be the same. ** in any lesion category. *** previously identified in assessment 
immediately prior to this TP. 

 
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All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined below. 
 
 Table S3: iRECIST Best Overall Response (iBOR) 
TPR1 
TPR2 
TPR3 
TPR4 
TPR5 
iBOR 
iCR 
iCR, iPR, 
iUPD, NE 
iCR, iPR, iUPD, 
NE 
iUPD 
iCPD 
iCR 
iUPD 
iPR, iSD, NE iCR 
iCR, iPR, iSD, 
iUPD, NE 
iCR, iPR, iSD, iUPD, iCPD, 
NE 
iCR 
iUPD 
iPR 
iPR, iSD, iUPD, 
NE 
iPR, iSD, iUPD, NE, 
iCPD 
iPR, iSD, iUPD, NE, iCPD 
iPR 
iUPD 
iSD, NE 
PR 
iPR, iSD, iUPD, NE iPR, iSD, iUPD, iCPD, NE 
iPR 
iUPD 
iSD 
iSD, iUPD, NE 
iSD, iUPD, iCPD, 
NE 
iSD, iUPD, ICPD, NE 
iSD 
iUPD 
iCPD 
Anything 
Anything 
Anything 
iCPD 
iUPD 
iUPD 
iCPD 
Anything 
Anything 
iCPD 
iUPD 
NE 
NE 
NE 
NE 
iUPD 
1. Table assumes a randomized study where confirmation of CR or PR is not required. 
2. NE = not evaluable that cycle. 
3. Designation “I” for BOR can be used to indicate prior iUPD to aid in data interpretation. 
4. For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be 
assigned at each TPR but is not shown in the table for ease of presentation. 
 
 
8.1.10 Response and Stable Disease Duration (RECIST 1.1 and iRECIST) 
Response duration will be measured from the time measurement criteria for CR/PR 
or iCR/iPR (whichever is first recorded) are first met until the first date that recurrent 
or progressive disease is objectively documented, taking as reference the smallest 
measurements recorded on study (including baseline). 
 
Stable disease duration will be measured from the time of start of treatment until the 
criteria for progression are met, taking as reference the smallest sum on study 
(including baseline). 
 
 
8.1.11 Methods of Measurement 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Assessments should be identified on a calendar schedule and should not be affected 
by delays in therapy. While on study, all lesions recorded at baseline should have 
their actual measurements recorded at each subsequent evaluation, even when very 
small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed 
to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned. For lesions which fragment/split add together the longest 
diameters of the fragmented portions; for lesions which coalesce, measure the 
maximal longest diameter for the “merged lesion”. 

 
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8.1.12 Clinical Lesions.  
Clinical lesions will only be considered measurable when they are superficial 
and ≥10 mm as assessed using calipers (e.g. skin nodules). For the case of 
skin lesions, documentation by color photography including a ruler to estimate 
the size of the lesion is recommended. If feasible, imaging is preferred. 
 
8.1.13 Chest X-ray.  
Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in 
identifying new lesions. However, lesions ≥20 mm on chest X-ray may be 
considered measurable if they are clearly defined and surrounded by aerated 
lung. 
 
8.1.14 CT, MRI.  
CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability 
of lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less. When CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans). Other 
specialized imaging or other techniques may also be appropriate for individual 
case. For example, while PET scans are not considered adequate to measure 
lesions, PET-CT scans may be used providing that the measures are obtained 
from the CT scan and the CT scan is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast). 
 
8.1.15 Ultrasound.  
Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT is advised. 
 
8.1.16 Endoscopy, Laparoscopy.  
The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response or surgical resection is an endpoint. 
 

 
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8.1.17 Tumor Markers.  
Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response. 
 
8.1.18 Cytology, Histology.  
These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types 
such as germ cell tumors, where known residual benign tumors can remain). 
When effusions are known to be a potential adverse effect of treatment (e.g. 
with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or 
stable disease is advised to differentiate between response or stable disease 
and progressive disease. 
9.0 ASSESSING AND REPORTING ADVERSE EVENTS  
 
9.1 Definition of Adverse Event 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation patient administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a 
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 the any of the component of trial treatments, is also 
an adverse event. 
From the time of treatment allocation/randomization through 30 days following cessation 
of treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
9.1.3. The investigator will make every attempt to follow all patients with non-serious 
adverse events for outcome. 
 

 
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9.1.1 Reporting of Pregnancy and Lactation  
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 
patient (spontaneously reported to them) that occurs during the trial. 
 
Pregnancies and lactations that occur after the consent form is signed but before 
treatment allocation/randomization must be reported by the investigator if they cause the 
patient to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.   
 
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through trial treatment or 30 days following cessation of treatment if the patient initiates 
new anticancer therapy, whichever is earlier, must be reported by the investigator.  All 
reported pregnancies 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. 
 
An “Initial Pregnancy Report” or equivalent must be completed in full and emailed to 
SafetyReporting@Incyte.com 
or 
faxed 
to 
(+) 
1-866-981-2057 
and 
to 
cfrench@checkmatepharma.com within 24 hours of discovery of a pregnancy of a subject 
who has taken the Incyte product or the pregnancy of a partner for a subject who has 
taken the Incyte product.  The “Follow-up Pregnancy Report Form” or equivalent must be 
completed and emailed to SafetyReporting@Incyte.com or faxed to (+) 1-866-981-2057 
and to cfrench@checkmatepharma.com within 30 days after delivery, so that Incyte is 
provided with information regarding the outcome of the pregnancy.  If the pregnancy 
results in any events which meet the serious criteria (i.e., miscarriage or termination), the 
SAE reporting process needs to be followed and the timelines associated with a SAE 
should be followed. 
 
 
9.1.2 Immediate Reporting of Adverse Events to the Sponsor  
In addition, all SAEs must be reported promptly to Checkmate Pharmaceuticals 
(SafetyInbox@checkmatepharma.com and cfrench@checkmatepharma.com) after the 
Investigator recognizes/classifies the event as a SAE. The specific reporting time frame 
depends on the type of SAE. For life-threatening or fatal events, the Investigator must 
report initial information on the SAE within 24 hours/1 business day of becoming aware 
of the event, preferably by fax or alternatively by phone or email; at a minimum, a 
description of the event and the Investigator’s judgment of causality must be provided at 
the time of the initial report. Attribution of adverse events specifically to either CMP-001 
or INCAGN01949 may be challenging, but every effort should be made to assign 

 
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attribution to the individual drug rather than the combination of the two drugs. If an SAE 
is reported by phone or by e-mail, the Investigator must fax a completed SAE report form 
to TBD within 1 business days. The Investigator should follow all AEs/SAEs observed 
during the study until they resolve or stabilize, the patient is lost to follow-up, or the events 
are otherwise explained. TBD is responsible for notifying the relevant regulatory 
authorities and study partners of certain Serious Adverse Events. 
 
 
The Principal Investigator (PI) must report all Serious Adverse Events (SAEs) to Incyte 
within 24 hours of learning of an event, regardless of the PI’s causality assessment. This 
notification should be provided on a completed Serious Adverse Event (SAE) form.  SAE 
reporting for each subject begins the day the informed consent is signed by the patient 
and within 30 days after subject has completed or discontinued from the study or has 
taken last dose of the study drug, or as described in the protocol. 
 
SAEs, occurring using Incyte study drug, are reported in accordance with the effective 
protocol.  SAEs occurring with any other commercial drug are reported to the 
manufacturer of that drug in accordance with regulations and protocol.  
 
Initial SAEs and/or subsequent follow-up reports should be reported via email to 
SafetyReporting@Incyte.com 
or 
fax 
(+) 
1-866-981-2057 
and 
cfrench@checkmatepharma.com.  SAE reports should be for a single subject.  SAE forms 
should be sent with a cover sheet and any additional attachments. 
 
All 
adverse 
event 
information 
is 
reported 
to 
Incyte 
on 
the 
Principal 
Investigator’s/Institution’s Adverse Event Report Form, or a CIOMS-I or MedWatch Form 
FDA 3500A, or on an Adverse Event Report Form which may be provided by Incyte upon 
request. The Principal Investigator does not provide medical records (e.g., discharge 
summary) to Incyte, unless specifically requested. 
 
 
9.1.3 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose that: 
 
• Results in death (In this study, deaths that are unequivocally due to Disease 
Progression are not to be reported as SAEs); 
• 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 another important medical event  

 
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For the time period beginning when the consent form is signed until treatment initiation 
any serious adverse event, or follow up to a serious adverse event, including death due 
to any cause other than progression of the cancer under study that occurs to any patient 
must be reported within 24 hours to the Sponsor and within 2 working days if it causes 
the patient to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a 
procedure. 
 
For the time period beginning at treatment initiation through 30 days following cessation 
of treatment, or until the patient initiates new anticancer therapy, whichever is earlier, any 
serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study whether or not related to the 
trial treatment, must be reported within 24 hours to the Sponsor.  
 
Additionally, any serious adverse event, considered by an investigator to be related to 
trial treatment that is brought to the attention of the investigator at any time following 
consent through the end of the specified safety follow-up period specified in the paragraph 
above, or at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor. 
 
The USC NCCC Data and Safety Monitoring Committee (DSMC) must be notified within 
24 hours of submission of such reportable event to the IRB. The patient ID and the study 
number as well as identifier of the SAE report should be submitted to the DSMC 
Coordinator via email or Fax to the attention of the DSMC Coordinator at 323-865-0089. 
 
The FDA should be notified within 7 business days of any unexpected fatal or life-
threatening adverse event with possible relationship to study drug, and 15 business days 
of any event that is considered: 1) serious, 2) unexpected, and 3) at least possibly related 
to study participation. 
 
All patients with serious adverse events must be followed up for outcome. 
 
9.1.4 Evaluating Adverse Events 
An investigator will evaluate all adverse events according to the NCI Common 
Terminology for Adverse Events (CTCAE), version 5.0.  A copy of the CTCAE Version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
website 
at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm 
 
Any adverse event which changes CTCAE grade over the course of a given episode will 
have each change of grade recorded on the adverse event case report forms/worksheets. 
 
Disease Progression is not considered an AE in this study 
 
When flu-like or cytokine release-like symptoms are reported, each individual symptom 
should be recorded as a separate AE in the Electronic Data Capture system. 

 
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When specific adverse events are not listed in the CTCAE they will be graded by the 
investigator according to the following grades and definitions, consistent with the CTCAE 
Version 5.0. 
 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL). Instrumental ADL refer 
to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL. Self-care ADL refer to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden 
 
• Grade 4: Life-threatening consequences; urgent intervention indicated. 
 
• Grade 5: Death related to AE. 
 
Duration 
 
The investigator will record the start and stop dates of the adverse event.  If less than1 
day, this will be indicated in the appropriate length of time in units. 
 
Action Taken 
 
Did the adverse event cause the trial treatment to be discontinued? 
 
Relationship 
 
All adverse events regardless of CTCAE grade must be evaluated for relationship to each 
individual drug. 
 
The determination of the likelihood that trial treatment caused the adverse event will be 
provided by an investigator. 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 trial treatment and the adverse 
event based upon the available information. 
 

 
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The following components are to be used to assess the relationship between trial 
treatment and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely the trial treatment 
caused the adverse event (AE): 
 
Exposure: Is there evidence that the patient was actually exposed to trial treatment such 
as: reliable history, acceptable compliance assessment (pill count, diary, 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 trial treatment?  Is the time of onset of the AE compatible with a drug-induced effect? 
 
Likely Cause: Is the AE not reasonably explained by another etiology such as underlying 
disease, other drug(s)/vaccine(s), or other host or environmental factors? 
 
Dechallenge: Was trial treatment 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 the trial treatment; or 
(3) the trial is a single-dose drug trial); or (4) trial treatment is/are only used one time. 
 
Rechallenge: Was the patient re-exposed to trial treatment 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: If a rechallenge is planned for an adverse event which was serious and which 
may have been caused by either of the trial treatments, or if reexposure to trial 
treatment poses additional potential significant risk to the patient, then the 
rechallenge must be approved in advance by the Sponsor 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 trial treatment or drug class 
pharmacology or toxicology? 
 
Relationship 
Attribution 
Description 
Unrelated to the trial 
treatment/intervention 
Unrelated 
The AE is clearly NOT related to the trial 
treatment/intervention 

 
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Unlikely 
The AE is doubtfully related to the trial 
treatment/intervention 
Related to the trial 
treatment/intervention 
Possible 
The AE may be related to trial 
treatment/intervention 
Definite 
The AE is clearly related to trial 
treatment/intervention 
 
9.1.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB and investigators in 
accordance with all applicable global laws and regulations.  
 
10.0 STATISTICAL CONSIDERATIONS 
 
10.1 Study Design 
This is a phase 1B/II pilot trial.  Up to 21 patients will be enrolled in Phase IB, and up to 
21 patients in Phase II. Eligible patients will be treated with CMP-001 + INCAGN01949. 
The dose of CMP-001 + INCAGN01949 used in the Phase II study will be determined 
from the safety responses occurring in the Phase 1B dose study. 
 
Trial treatment will be administered per the schedule as described in 6.0.  The primary 
endpoint will be response rate, objective response rate (CR+ PR), as well as disease 
control rate (CR+ PR+ SD x 16 weeks). 
 
The secondary endpoint will be incidence of toxicities, percent of patients who normalized 
their CA19-9, progression free survival, and overall survival. 
 
10.2 Sample Size Considerations 
The sample size (estimated to be between 3 and 21 patients) during dose escalation 
(Phase IB) cannot be precisely determined and depends on the observed toxicity. The 
Phase II portion is designed to rule out an ineffective disease control rate of 5% (null 
hypothesis) versus a hypothesized disease control rate of 30% (alternative hypothesis). 
In phase II, we will treat an initial cohort of 10 patients, and if no patient demonstrates 
disease control, defined as a CR, PR, or SD for 16 weeks, the trial will be closed. If there 
are 1 or more patients with disease control, the trial will be expanded to 21 patients (likely 
of a specific tumor type).Four or more out of 21 patients with disease control will be 
sufficient evidence for rejection of the null hypothesis of insufficient activity of the regimen. 
Enrollment will be suspended after the first stage of the phase II portion to assess for 
futility. This Simon two-stage minimax design has a power of 90% at a one-sided Type I 
error rate of 2.5%. 

 
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Statistical Analysis Plan 
10.3 Analysis of the Conduct of the Study 
Enrollment, major protocol violations, and discontinuations for the study will be 
summarized. 
 
10.4 Analysis of Patient Characteristics 
Demographic and baseline characteristics, such as age, race, BSA, duration of pancreatic 
or other cancer, site(s) of metastatic disease, prior cancer treatment, and baseline ECOG 
performance status will be summarized using means (± standard error) or medians 
(range) for continuous variables and proportions for categorical variables. 
 
10.5 Analysis of Trial Treatment Administration 
Trial treatment (CMP-001 + INCAGN01949) administration will be listed and dose 
modifications will be flagged.  Mean and standard deviations will be used to summarize 
the average dose received.   
 
10.6 Analysis of Toxicities 
Incidence of toxicity will be assessed through summaries of adverse events, clinically 
relevant changes in laboratory results, and vital signs.  All patients who receive any 
amount of trial treatment will be included in the analysis. 
 
All adverse events occurring on or after Week 1/day 1 will be summarized by body 
systems and per grade according to NCI-CTC Version 5.  Additionally, all serious adverse 
events as defined in section 9.1.2.1 will be listed separately and tabulated.   
 
10.7 Analysis of Primary Endpoint 
The objective response for each patient (complete response, partial response or 
stabilization of disease) will be assessed at the determined evaluation time points as 
detailed in 6.0.  The duration of objective response as determined by the investigator and 
the time to disease progression and duration of survival will be assessed for each patient.  
 
Progression-free survival is defined as the interval from the date of registration (i.e. 
assignment of patient number) to the earliest date of documented evidence of recurrent 
or progressive disease, or the date of death due to any cause, whichever occurs first. 
Patients who do not progress and remain alive will be censored at their last radiographic 
assessment date. Overall survival will be measured from the date of registration (i.e. 
assignment of patient number) to the date of death due to any cause, or the date of last 
contact (censored observations).  
 
The efficacy analysis will include summaries for the following parameters: complete 
response rate (CR), objective response rate (CR + PR), disease control rate (CR + PR + 

 
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SD at 16 weeks), percent of patients who normalize their CA 19-9 (or CA 125 or CEA if 
these are used to follow the patient disease), progression-free survival (PFS), and overall 
survival (OS). The efficacy analysis will only be conducted on patients who have received 
at least one dose of CMP-001 and INCAGN01949 and have at least one post baseline 
tumor assessment.  All proportions will be estimated using an exact 95% binomial 
confidence interval.  For the estimation of progression-free and overall survival, a Kaplan-
Meier analysis will be performed.  
 
11.0 LABELING, PACKAGING, STORAGE AND RETURN OF 
CLINICAL SUPPLIES 
 
11.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution and 
usage of investigational product in accordance with the protocol and any applicable laws 
and regulations. 
 
The study pharmacist at each participating site will be responsible for maintaining a record 
of shipment, receipt and dispensation of study medication(s). The study pharmacist will 
utilize an NCI drug accountability template for documenting dates, and amounts/doses 
received from the sponsor and dates, patient initials and doses dispensed to the patient.  
 
The study Research Coordinator(s) and Data Manager(s) will be responsible for drug 
accountability of dispensed and returned drug in accordance with the USC CISO SOP. 
 
For the purpose of this trial the term investigational products refer to both TLR9 agonist 
(CMP-001) and OX40 (INCAGN01949). 
 
CMP-001 (TLR9) will be provided by CHECKMATE PHARMACEUTICALS 45 Main 
Street, 2nd Floor Cambridge, MA, 02142 
 
INCAGN01949 (OX40) will be provided by Incyte Corporation 1801 Augustine Cut-off 
Wilmington, DE 19803 
 
11.2 Packaging and Labeling Information 
11.2.1 CMP-001  
CMP-001 drug product is supplied as a 5.0 mg/mL concentration and is described as 
follows: 
 

 
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• CMP-001 5.0 mg/mL is a colorless to pale yellow/brown opalescent liquid 
practically free of particles. Each single use vial contains 1.0 mL of CMP-001 
(extractable volume of 1.0mL=5.0mg) with a 0.1 mL overfill. 
 
The CMP-001 study drug vials and kit cartons will be labeled with the following 
information: 
 
• The protocol number; 
 
• The kit number; 
 
• Number of vials per kit (kit carton only); 
 
• The batch number of the drug; 
 
• The drug name, concentration, and nominal volume per vial; 
 
• The recommended storage conditions of the drug; 
 
• Cautionary statement indicating that the drug is for investigational use only; 
 
• The name and address of the Sponsor.  
 
11.3 Storage and Handling Requirements 
11.3.1 CMP-001  
All CMP-001 will be transported, received, stored, and handled in accordance with the 
container or drug product kit/product label, the instructions supplied to the site and its 
designated pharmacy personnel, the site’s standard operating procedures (SOPs), and 
applicable regulations. 
 
Appropriate storage and transportation conditions will be maintained for the drug product 
vials from the point of manufacture up to delivery of each drug product. All shipments of 
drug product vials will include a temperature monitoring device that records required 
storage conditions for the vials, at regular intervals for the entire time the shipment is in 
transit. 
 
Upon receipt by the site, the designated site personnel will examine the shipment and 
temperature monitoring devices to verify the drug product vials were received in 
acceptable condition. If not received in acceptable condition, the site must notify the CRA 
and the site should quarantine the drug until a decision has been made by Checkmate. 
Once inspected, CMP-001 vials should be stored at the specified temperature (2°C to 
8°C) in a locked area accessible only to designated site personnel until dispensing. Once 

 
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dispensed, drug product vials will be stored in a limited access area under appropriate 
environmental conditions. 
 
The designated site personnel will be responsible for maintaining accurate records of the 
quantity and dates of all study drug supplies received, dispensed, and returned, in 
accordance with applicable regulations and the site’s SOPs. The quantity of study drug 
lost, destroyed, etc. must also be accounted for and documented. 
 
All original vials, whether empty or containing CMP-001 will be kept at the site. Used vials 
will not be dispensed again (even to the same subject) nor will they be relabeled or 
reassigned for use by other subjects. Contents of the drug product vials will not be 
combined. Unused vials will be available for verification by the study monitor. 
 
At the termination of the study, a final drug accountability review and reconciliation must 
be completed, and any discrepancies must be investigated and their resolution 
documented. 
 
All drug product vials will be destroyed onsite as per institutional SOPs, after site close 
out has been completed. 
 
11.3.2 INCAGN01949 
11.3.2.1 
Description and Administration 
The study drug (INCAGN01949) is in liquid form in the formulation buffer of 20 mM 
histidine, 250 mM sorbitol, pH 6.5 to be used for IT infusion.  
 
Study drug will be diluted in acceptable admixture as outlined in the Pharmacy Manual 
and will be administered by qualified personnel as an IT injection on Day 1 of Weeks 3, 
4, 5, and 6. The Pharmacy Manual contains additional information and instructions for 
study drug preparation and injection. Do not mix INCAGN01949 with CMP-001 as 
saline destabilizes this drug.  
 
11.3.2.2 
Supply, Packaging, and Labeling 
Study drug will be supplied as 5 mL of aqueous solution in 10 mL glass vials with 10 
mg/mL of INCAGN01949.  Study drug will be packaged as open-labeled supplies, and 
each vial will be labeled and placed in a carton.  The Pharmacy Manual contains 
additional information regarding supply, packaging, and labeling of study drug. 
 
The investigator will take responsibility for and take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
drug in accordance with the Protocol and any applicable laws and regulations.   
All Incyte investigational product labels will be in the local language and will comply with 
the legal requirements of each country.    
 

 
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11.3.2.3 
Storage 
Study drug must be stored refrigerated (2°C-8°C) and protected from light in a secure, 
limited access location.  Receipt and dispensing of study drug must be recorded by an 
authorized person at the study site.  Study drug may not be used for any purpose other 
than that stated in the Protocol.  The Pharmacy Manual contains additional information 
regarding storage of study drug. 
 
12.0 ADMINISTRATIVE AND REGULATORY DETAILS 
 
12.1 Institutional Review Board/Ethics Committee Approval and Consent Process 
Before trial initiation, this protocol and informed consent form will be submitted for review 
and approval to the IRBs charged with oversight for the clinical sites. In addition, any form 
of proposed advertising and advertising text for patient recruitment must be reviewed and 
approved by the Sponsor prior to submission to the IRB. The Investigator will forward to 
the Sponsor or their nominated designee a copy of the IRB’s approval of this protocol, 
any amendments, informed consent form, and any modifications to the informed consent, 
based on the FDA regulations set forth in 21 CRF 56 of the Code of Federal Regulations, 
as well as those of the applicable regulatory bodies in all other participating countries 
outside of the U.S. 
 
In addition, the Investigator will be responsible for forwarding to the Sponsor or their 
nominated designee a description of the IRB members (including profession and 
affiliation) or a United States (US) Department of Health and Human Services (DHHS) 
General Assurance number and expiration date. If neither of these is available, the 
chairperson must submit a statement indicating that the members of the board 
responsible for the review meet the FDA and other appropriate regulatory requirements. 
In addition, the labeling for all approved trial medications should be submitted to the IRB 
for information purposes. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s) and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing a dated IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person authorized to   obtain the 
informed consent. 

 
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12.2 Investigators Protocol Agreement and Required Documentation 
The Investigator must sign the Investigator’s Protocol Agreement. The original must be 
kept on file at the Sponsor and the Investigator must retain a copy. The completed 
Investigator’s Protocol Agreement signifies agreement to comply with all procedures 
outlined by this protocol by the Investigator. An Investigator’s Protocol Agreement must 
be signed if and when a protocol amendment is issued by the Sponsor. 
 
Before the study can be initiated at any site, the following documentation must be 
provided to the USC Clinical Investigation Support Office (CISO):  
 
• A copy of the official IRB approval letter for the protocol and informed consent 
• IRB membership list 
• CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 
• Protocol signature page with Investigator signature  
• Form FDA 1572 appropriately filled out and signed with appropriate documentation 
• A copy of the IRB-approved consent form 
• CAP and CLIA Laboratory certification numbers and institution lab normal values 
• Executed clinical research contract 
 
12.3 Investigator Obligations 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that 
all the required data will be collected and entered onto the Case Report Forms. 
Periodically, monitoring visits will be conducted and the Principal Investigator will provide 
access to his/her original records to permit verification of proper entry of data. At the 
completion of the study, all case report forms will be reviewed by the Principal Investigator 
and will require his/her final signature to verify the accuracy of the data. 
 
12.4 Registration Procedures 
Multi-Site Registration:  
 
All sites must register all patients with the Café USC database before enrollment to study. 
Prior to registration, eligibility criteria must be confirmed with the CISO Quality Assurance 
Manager. To register a patient, fax the Protocol Eligibility Form, signed IRB approved ICF 

 
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and HIPPA to 323-865-0089 Monday through Friday, 8:00AM-4:00PM PST. At the same 
time, notify the QA Manager of pending registration by calling 323-865-0451 or 323-865-
0420. 
 
After the eligibility is confirmed by the QA manager, site Research coordinator or DM will 
register the patient into USC Norris Cancer Center database “café”, by accessing the 
Registration forms. Likewise, after the patient has completed the study, the Off Study 
forms in cafe will need to be completed, for Off Treatment and Off Study. 
 
USC Registration:  
For patients enrolled at USC, the Research Coordinator must complete the protocol 
eligibility form to ensure that the patient is eligible. The PI will review the patient eligibility 
(with assistance from the Research Coordinator- who will assemble the required source 
documents and do an initial review) prior to registering the patient on study. 
 
The Research Coordinator or data manager will then register the patient into the Cancer 
Center database, Café, by accessing the Registration forms. Likewise, after the patient 
has completed the study, the Off Study forms in Cafe will need to be completed, for Off 
Treatment and Off Study. 
 
12.5 Slot Assignment 
The availability of slots and the assignment of patients to a specific dose level in a specific 
cohort will be done by the phase I committee in the USC Norris Comprehensive Cancer 
Center.   
12.6 Confidentiality 
The Investigator and any other personnel involved in this trial shall not disclose, or use 
for any purposes (other than for the performance of this trial any data, records, or other 
information (hereinafter collectively “information”) disclosed to the Investigator or other 
trial personnel. Such information shall remain the confidential and proprietary property of 
the Sponsor and shall be disclosed only to the Investigator or other designated trial 
personnel. 
 
Patient confidentiality will be ensured by using assigned site-specific Screening and 
numbers (refer to Section 7.1.1.6) throughout the trial.  
 
The original data collection forms will be kept in secure file cabinets. For USC patients, 
forms will be kept in the Clinical Investigations Support Office (CISO). 
 
12.7 Compliance with Financial Disclosure Requirements 
All Investigators will be required to submit written financial disclosure to the Sponsor prior 
to participating in this clinical trial and any changes in disclosures during the course of the 
trial as per 21 CFR part 54. 

 
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All investigators will follow the University conflict of interest policy. Any USC investigator 
who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must complete a “Statement 
of Outside Interests Related to Research” Form. The application is reviewed and 
approved by the Conflict of Interest Review Committee (CIRC) USC conflict of interest 
policy is available at http://ooc.usc.edu/conflict-interest-research. 
 
12.7.1 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and 
the Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is 
solely responsible for determining whether the trial and its results are patient to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  
Information posted will allow patients to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.   
   
12.8 Quality Management System 
All aspects of the study will be carefully monitored by the and/or its authorized 
representative for compliance with applicable government regulations with respect to 
current ICH GCP guidelines as well as other applicable regulations and guidelines. 
 
12.9 Data Monitoring Plan 
The Data Safety Monitoring Committee is an independent body responsible for the safety 
of study subjects through the review of new protocols to ensure an adequate adverse 
event assessment/reporting plan, study stopping rules and through the real-time and 
periodic monitoring of severe adverse events (SAEs) or those AEs that require expedited 
reporting. The DSMC performs quarterly and annual safety reviews as well as interim 
efficacy/futility analyses on institutional trials. DSMC procedures are detailed in USC 
NCCC DSM Plan available on the CISO website. 
 
12.10 Data Management 
12.10.1 
Case Report Forms 
All the clinical data will be captured by the site on electronic case report forms (eCRFs).   
The eCRFs will be used for all consented patients. The investigator and trained trial 
personnel will enter and edit the data via a secure network, with secure identification and 
password requirement.  A complete electronic audit trial will be maintained.  The 
investigator will be required to provide approval of all data to confirm accuracy.   Copies 
of the eCRFs will be provided to the investigator at the conclusion of the trial.    
 

 
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12.10.2 
Patient Consent Form 
At the time of registration, signed and dated copies of the patient Informed Consent with 
the Human Rights and the HIPAA authorization must be given to the patient. Institutional 
policy regarding distribution and location of original consent documents should be 
followed.  When a study is opened at two or more institutions, a copy of the signed 
consent and HIPAA should be sent to USC CISO QA team as soon as possible, and not 
later than within 5 business days of obtaining consent.  For patients consented at 
USC/LAC, institutional policy should be followed: a copy of ICF and HIPAA should be 
uploaded to the USC CRO and CISO QA Team. The original will be kept in the patient 
research chart maintained by the study assigned Data Manager. 
 
12.10.3 
Registration Eligibility Worksheet 
At the time of registration, the completed Eligibility Worksheet will be submitted to the 
QA Monitor at CISO for review of eligibility compliance. 
 
12.10.4 
Data Collection Forms and Submission Schedule 
Protocol data will be entered into eCRFs in iMedidata Rave. 
 
Within two weeks of registration, the data manager will complete the initial set of On Study 
forms and baseline toxicities. 
 
Within two weeks of completion of each course of treatment, the data manager must 
complete the Course Assessment, Toxicities, and if appropriate Response data. 
 
After Off Treatment, within two weeks of each follow up, complete the Follow Up forms. 
 
12.10.5 
Source Documents 
Source documents serve as the evidence of the existence of the patient and the data 
collected for this trial.  Source documents will be the responsibility of the Investigator and 
will be filed at the site and available as needed by the sponsor or assigned clinical monitor. 
 
Data captured on the eCRF is to be transcribed from source document and must be 
consistent with any discrepancies explained and documented. 
 
12.11 Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 

 
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Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator must 
retain all study documentation pertaining to the conduct of a clinical trial. In the case of a 
study with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
 
12.12 Data Management and Monitoring/Auditing 
Adherence to Protocol/Per Patient: It is the responsibility of the USC Principal 
Investigator (PI) to ensure that patient recruitment and enrollment, treatment, follow-up 
for toxicities and response, and documentation and reporting at USC are all performed 
as specified in the protocol. When a study is opened at two or more institutions, the PI at 
each institution will assume the responsibilities for the day-to-day monitoring of the trial, 
as described below. 
Day-to-Day Monitoring – Eligibility:  At USC, the Study Coordinator will assist the 
Investigator in reviewing eligibility and will assemble the required source documents, and 
do a final review by completing an Eligibility Registration Worksheet. When a study is 
opened at two or more institutions, the PI at each institution will review the patient 
eligibility in accordance with that institution’s policy.  For all institutions, the Eligibility 
Registration Worksheet with a copy of Informed Consent and supporting source 
documents will be submitted to CISO QA via email or Fax for verification prior to 
registering the patient on study. 
Day-to-Day Monitoring – Informed Consent: Prior to registering the patient on study, 
the Study Coordinator will review the informed consent, to ensure that the patient has 
signed and dated the most current IRB-approved form, and that the form has been signed 
and dated by the person obtaining the consent as well as appropriate witnesses. A copy 
of the ICF will also be provided to CISO QA for review. CISO SOP 3.3 will be followed.  
Day-to-Day Monitoring – Treatment: The PI and co-investigators are responsible for 
ensuring that treatment is given per protocol. The Study Coordinator will review the 
treatment orders with the treating investigator. Regardless of who the treating physician 
is, there will be only one responsible Study Coordinator for each study at each of the 
hospitals affiliated with the USC Norris Cancer Center. The treating investigator will 
review the status of each patient on-study, with the Study Coordinator and treating 
physicians, on an on-going basis.  When a study is opened at two or more institutions, 
CISO QA will periodically audit medical records for the subjects on study at other 
institutions to ensure compliance and adherence to the protocol. 
Data Management – Patient Charts: When a study is opened at two or more institutions, 
the policy in place at each institution will be followed for maintaining medical and research 
related records. Such policies will be provided to the CISO QA prior to enrolling 1st patient.  

 
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At USC, all written source documents not associated with the study research are 
maintained in the patient chart, which is stored in the Department of Medical Records at 
the appropriate hospital. At the Norris Hospital, the official medical record is Cerner. 
Radiographical images are stored in the Department of Radiology and in an electronic 
system called Synapse. At Los Angeles County General Hospital the official medical 
record is called Power Chart. These are the permanent, official documents for each 
patient on-study. A copy of the signed informed consent, physician’s notes, orders, test 
results and pathology notes are maintained in the patients’ hospital charts. It is the 
responsibility of the research staff to ensure that the patient chart contains the required 
documents and work closely with treating investigators to ensure all protocol-related 
assessments are carefully documented. At Hoag, the official medical record is called Epic.  
Data Management – Research Charts: When a study is opened at two or more 
institutions, the policy in place at each institution will be followed for maintaining medical 
and research related records. Such policies will be provided to the CISO QA prior to 
enrolling 1st patient.  At USC, to facilitate adherence to the protocol schedule and data 
management, research charts are created to collect copies of the relevant notes, orders 
and results, that are in the Patient Chart. In Addition, all source documents related to the 
research, such as original informed consent forms, HIPAA Forms, AE assessment 
worksheets, disease response worksheets and NTFs are maintained in the Research 
Charts. Protocol calendars, worksheets, and checklists, are also kept in the research 
chart. These are maintained in the Clinical Investigation Support Office until the study is 
completed and the results are published and no further need is anticipated. These are 
then stored off-site. It is the responsibility of the Data Manager to ensure that the research 
chart contains all the required documents. 
Data Management – Case Report Forms: It is the responsibility of the Data Manager to 
complete the required case report forms. For in-house trials, case report forms are 
developed for each trial; these are used to finalize the data entry screens in the Cancer 
Center clinical trials database. It is the responsibility of the PI to review the Off-Study 
Summary form which summarizes pertinent toxicity, response and adherence 
information, once the patient has completed treatment. 
 
12.13 Quality Assurance Monitoring Committee (QAMC) Oversight  
The Quality Assurance and Monitoring Committee (QAMC) of the NCCC has the 
responsibility for study auditing and monitoring for protocol compliance, data accuracy, 
performance of audits and monitoring of accrual. QAMC procedures are detailed in the 
NCCC Data Safety and Monitoring Plan available on CISO Website.  
QAMC Annual Patient Audits 
 
The QAMC is responsible for conducting audits and providing the initial review of the 
audits, for all open institutional (i.e. USC initiated), CCCP-sponsored trials, and any trials 
identified by the CIC.  These trials are audited by the QAMC once a year. Faculty and 
staff at the Cancer Center involved in clinical research – but not directly involved in the 
research under evaluation – are asked to serve as auditors. Twenty percent of patients 
accrued during the past 12 months – and a minimum of 2 patients – are selected at 

 
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random; however, additional patients may be selected for audit if there is some indication 
that there might have been a problem or unusual circumstance (possibly related to 
compliance, toxicity, response or some indication of an irregularity). The audit involves a 
review of the research chart, hospital medical record (i.e., source documentation) and 
evaluates the following: documentation of eligibility (including failure to obtain appropriate 
informed consent) and baseline status of the patient; documentation of adherence to 
protocol-specified treatment and follow-up; evaluation of toxicity; and evaluation of 
response or other outcome. In addition, for investigative agents, a drug audit is also 
performed for these patients by the Research Pharmacist. In addition, for Institutional, 
Investigator Initiated Trials, Data in the CAFÉ database are compared to the information 
in the medical record.   
 
QAMC Annual Protocol Review 
 
All open trials are reviewed at least once a year by the QAMC (or more often if stipulated 
by the CIC). This annual review includes the following: evaluation of the current accrual 
relative to the planned total accrual; examination of gender and minority accrual; 
examination of all reported violations; review of past audits and correspondence with the 
PI; review of results of current audit (by an outside agency or by the NCCC QAMC); 
review of previous correspondence between the PI and the QAMC/DSMC. The QAMC 
review process is detailed in USC NCCC DSM Plan available on the CISO website. 
 
12.14 Phase I Committee Oversight 
The USC Norris Comprehensive Cancer Center Phase I DLT committee reviews all open 
institutional phase I studies at regularly scheduled intervals. The committee reviews the 
adverse events, serious adverse events, and treatment administration for each patient 
during the DLT observation period as specified per protocol. The committee will determine 
whether a patient is evaluable for DLT and whether an AE meets the DLT definition or 
not. Decisions regarding dose escalation, de-escalation and cohort expansion are made 
by the committee in coordination with the PI. 
 
12.15 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol.  
 
12.15.1 
Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate 
an immediate hazard(s) to trial subjects without prior IRB approval.  
 

 
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For any such emergency modification implemented, an IRB modification form must be 
completed within five (5) business days of making the change.  
 
12.15.2 
Non-Emergency Departures from Protocol 
A protocol deviation is any variance from an IRB approved protocol.  
 
If the deviation meets all of the following criteria, it is considered a minor protocol deviation 
that:  
• Is generally noted or recognized only after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan or the value 
of the data collected  
• Did not result from willful or knowing misconduct on the part of the investigator(s).  
 
If the deviation meets any of the following criteria, it is considered a protocol violation: 
• Has harmed or increased the risk of harm to one or more research participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the investigator(s). 
• Demonstrates serious noncompliance with federal regulations, State laws, or 
University policies. 
 
Protocol Deviations: Personnel will report to any sponsor or data and safety monitoring 
committee in accordance with their policies.  
 
Protocol Violations: All protocol violations will be entered in the clinical trial database by 
the Research Coordinator. In addition, Research Coordinator and Investigator should 
report all protocol violations within one (1) week of the knowledge of the event using iStar. 
 
12.15.3 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB as well as to all the sponsoring agencies (FDA, NCI, etc.) for review and for approval 
prior to implementation. It is the responsibility of the study PI to ensure that the 
appropriate agencies have been informed of the proposed amendments and that these 
have been reviewed and approved.   
 
12.16 Data Safety and Monitoring Committee 
The Data and Safety Monitoring Committee (DSMC) is an independent body responsible 
for the safety of study subjects through the review of new protocols to ensure an adequate 

 
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adverse event assessment/reporting plan, study stopping rules and through the real-time 
and periodic monitoring of severe adverse events (SAEs) or those AEs that require 
expedited reporting. The DSMC performs quarterly and annual safety reviews as well as 
interim efficacy/futility analyses on institutional trials. DSMC procedures are detailed in 
USC NCCC DSM Plan available on the CISO website. 
 
An independent DSMC will be formed to evaluate the safety and effectiveness of the 
study medication for each subject as well as study conduct of each site. The DSMC will 
also review all SAEs reported by each site. The DSMC will review study data to determine 
if endpoints are being met and if the study can continue with or without changes to the 
protocol or if the study should be terminated immediately due to safety concerns or lack 
of data to support study endpoints. Findings and recommendations of the DSMC will be 
reported to the Sponsor after each meeting. The DSMC will meet at least once annually 
and more frequently as needed if safety concerns are raised. Furthermore, prior to 
opening the Phase II portion of the study a review by the DSMC will be conducted. This 
treatment regimen combines 2 immunotherapeutic agents with known toxicity profiles.  
Because cancer is a life-threatening disease, treatments that result in Grade 3 and 4 
toxicities are considered to have an acceptable risk profile. Data reported to the sponsor 
will be received by sponsor representatives on a regular basis and not less than once a 
month. In addition, SAEs will be reported to the sponsor immediately and reviewed as 
they are received. Any unacceptable toxicities or severe toxicities that occur more 
frequently than expected will be discussed by the sponsor, the site Principal Investigators 
and DSMC members who will decide jointly whether the study should be modified, 
interrupted, or stopped. The statistical group will provide listings of toxicities on a regular 
basis. 
 
 
 
 

 
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REFERENCES 
 
1. Ambuhl PM, Tissot AC, Fulurija A, Maurer P, Nussberger J, Sabat R, Nief V, 
Schellekens C, Sladko K, Roubicek K, Pfister T, Rettenbacher M, Volk HD, Wagner F, 
Muller P, Jennings GT, Bachmann MF (2007) A vaccine for hypertension based on 
virus-like particles: preclinical efficacy and phase I safety and immunogenicity. J 
Hypertens 25(1): 63-72 
2. Ascierto, P. A., Daniele, B., Hammers, H., Hirsh, V., Kim, J., Licitra, L., Nanda, R. & 
Pignata, S. 2017. 'Perspectives in immunotherapy: meeting report from the 
“Immunotherapy Bridge”, Napoli, November 30th 2016.' Journal of Translational 
Medicine, 15:1, 205. 
3. Cornuz J, Zwahlen S, Jungi WF, Osterwalder J, Klingler K, van Melle G, Bangala Y, 
Guessous I, Muller P, Willers J, Maurer P, Bachmann MF, Cerny T (2008) A vaccine 
against nicotine for smoking cessation: a randomized controlled trial. PLoS One 
3(6):e2547 
4. Krieg AM, Efler SM, Wittpoth M, Al Adhami MJ, Davis HL. Induction of systemic TH1-like 
innate immunity in normal volunteers following subcutaneous but not intravenous 
administration of CPG 7909, a synthetic B-class CpG oligodeoxynucleotide TLR9 
agonist. J Immunother. 2004 Nov-Dec;27(6):460-71 
5. Krieg AM. CpG still rocks! Update on an accidental drug. Nucleic acid therapeutics. 
2012;22(2): 77-89. 
6. Krieg, A. M. & Vollmer, J. 2007. Toll-like receptors 7, 8, and 9: linking innate immunity to 
autoimmunity. Immunological Reviews, 220:1, 251-69. 
7. Kundig TM, Senti G, Schnetzler G, Wolf C, Prinz Vavricka BM, Fulurija A, et al. Der p 1 
peptide on virus-like particles is safe and highly immunogenic in healthy adults. The 
Journal of allergy and clinical immunology. 2006;117(6): 1470-6. 
8. Le Tourneau, C., Lee, J. J. & Siu, L. L. 2009. 'Dose Escalation Methods in Phase I 
Cancer Clinical Trials.' JNCI: Journal of the National Cancer Institute, 101:10, 708-20. 
9. Maurer P, Jennings GT, Willers J, Rohner F, Lindman Y, Roubicek K, et al. A 
therapeutic vaccine for nicotine dependence: preclinical efficacy, and Phase I safety and 
immunogenicity. Eur J Immunol 2005;35(7): 2031-40. 
10. Milhelm M, et al. Intratumoral injection of CMP-001, a Toll-like receptor 9 (TLR9) agonist, 
in combination with pembrolizumab reversed programmed death receptor 1 (PD-1) 
blockade resistance in advanced melanoma. Poster 304. SITC, 2020. 
11. Neoptolemos, J. P., Stocken, D. D., Bassi, C. & et al. 2010. 'Adjuvant chemotherapy with 
fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: A 
randomized controlled trial.' JAMA, 304:10, 1073-81. 
12. Oettle, H., Neuhaus, P., Hochhaus, A. & et al. 2013. 'Adjuvant chemotherapy with 
gemcitabine and long-term outcomes among patients with resected pancreatic cancer: 
The conko-001 randomized trial.' JAMA, 310:14, 1473-81. 
13. Rahib, L., Smith, B. D., Aizenberg, R., Rosenzweig, A. B., Fleshman, J. M. & Matrisian, 
L. M. 2014. 'Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden 
of Thyroid, Liver, and Pancreas Cancers in the United States.' Cancer Research, 74:11, 
2913-21. 
14. Sagiv-Barfi, I., Czerwinski, D. K., Levy, S., Alam, I. S., Mayer, A. T., Gambhir, S. S. & 
Levy, R. 2018. 'Eradication of spontaneous malignancy by local immunotherapy.' 
Science Translational Medicine, 10:426. 
15. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019.CA Cancer J Clin. 2019; 69:7–34. 
https://doi.org/10.3322/caac.21551. 

 
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16. Skelton, R. A., Javed, A., Zheng, L. & He, J. 2017. 'Overcoming the resistance of 
pancreatic cancer to immune checkpoint inhibitors.' Journal of Surgical Oncology, 116:1, 
55-62. 
17. Tissot AC, Renhofa R, Schmitz N, Cielens I, Meijerink E, Ose V, , et al. Versatile virus-
like particle carrier for epitope based vaccines. PLoS One. 2010;5(3): e9809. 
18. Verbraecken, J., Van de Heyning, P., De Backer, W. & Van Gaal, L. 2006. 'Body surface 
area in normal-weight, overweight, and obese adults. A comparison study.' Metabolism, 
55:4, 515-24. 
 
 
 
 
 
 
 

 
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APPENDICES 
 
 
 
 

 
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Appendix 1 - NCI CTCAE version 5.0 
 
The CTCAE Version 5.0 can be accessed and downloaded from the CTEP website at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm 
 
 
 
 
 
 

 
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Appendix 2 – ECOG Performance Status 
 
 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
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 
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am 
J Clin Oncol. 1982;5:649-655. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 3 – CMP-001 INJECTION GUIDELINE 
 
Refer to the current Pharmacy Manual for additional information. 
 
Method of CMP-001 Administration 
Intratumoral Injection 
Using standard aseptic technique, the needle should be inserted near the tumor periphery 
(Figure 1 left panel) and advanced into the tumor to the desired depth while maintaining 
gentle backward pressure on the syringe plunger to confirm an extravascular location of 
the needle tip. The syringe and needle should be slowly withdrawn to within a few 
millimeters of the skin or tumor surface while maintaining gentle downward pressure on 
the plunger to inject the desired volume of CMP-001 along the needle track (Figure 1 
middle panel).  
 
With the tip of the needle still under the skin, the syringe should be rotated by ~20o to 40o 
and the process of insertion and injection during needle withdrawal repeated (Figure 1 
right panel). Using this process, CMP-001 is injected IT along multiple tracks through a 
single insertion point as far as the radial reach of the needle allows within the tumor; 2 
insertion points may be used if the tumor is larger than the radial reach of the needle or 
the intended volume cannot be delivered through a single insertion point. If gentle 
injection pressure along 5 needle tracks within the tumor has not succeeded in delivering 
the desired volume, then the remainder of the CMP-001 may be injected peritumorally 
around the same lesion. If the full volume cannot be injected within the tumor, the 
remaining drug volume should be injected into a second accessible tumor, if present; 
otherwise, the remaining volume should be injected SC near an original tumor 
(peritumoral). 
 
Figure 1:  
Method for CMP-001 Intratumoral Injection 

 
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Recommended Intratumoral Injection Volume Based on Lesion Size  
Lesion Size (longest dimension)  
CMP-001 Injection Volume  
< 0.5 cm 
Up to 0.25 mL 
0.5 to 1.5 cm 
Up to 0.5mL  
1.5 to 2.5 cm 
Up to 1 mL 
> 2.5 cm 
2 mL 
Note: If the full 2 mL dose cannot be accommodated within accessible tumor(s), then the remaining 
volume may be injected peritumorally.  
 
Subcutaneous Injection 
SC administration of CMP-001 should only occur when all accessible lesions have 
regressed. CMP-001 SC can be administered within the area of lymphatic drainage 
corresponding to the site of metastatic disease and follow local standards for SC 
injection. 
In order to maximize the distribution and exposure to CMP-001, the full volume from a 
single dose should be distributed to as many SC sites as is practical. It is recommended 
that equal amounts of drug be injected at each SC site. 
Preferred sites of injection include the following: 
• Location of the primary tumor. 
• Within the area of lymphatic drainage corresponding to the site of metastatic 
disease. For example, in a patient with a muscle or bone metastasis in the 
lower leg, preferred SC injection sites would be in the same leg, with the 
expectation that at least some of the CMP-001 will drain to lymph nodes that 
also contain tumor antigens. Likewise, in a patient with metastases in an 
upper lobe of the lung, a preferred SC injection site would be in the ipsilateral 
supraclavicular fossa, where the injection may activate pDC in the 
supraclavicular lymph nodes that also can drain the upper lung.  
• Unsuitable sites for injection would include, for example, the palm of the hand 
or the sole of the foot. 

 
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Figure 2:  
 
Preferred Sites of Subcutaneous Injection