Conditions: Squamous Cell Carcinoma of Head and Neck
Keywords: Head and Neck Cancer Pembrolizumab Carcinoma HNSCC
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
CMP-001-007 is a Phase 2 study of CMP-001 intratumoral (IT) and pembrolizumab intravenous (IV) administered to participants with head and neck squamous cell carcinoma (HNSCC) who have not been previously treated with a programmed cell death protein 1 (PD-1) blocking antibody.

The primary objective of the study is to determine the Investigator-assessed confirmed objective response with CMP-001 in combination with pembrolizumab in subjects with head and neck squamous cell carcinoma (HNSCC)

The secondary objectives are to:

* To evaluate the safety and tolerability of CMP-001 administered by intratumoral (IT) injection in combination with pembrolizumab in subjects with HNSCC
* To evaluate the efficacy of CMP-001 in combination with pembrolizumab in subjects with HNSCC
* To evaluate the effect of human papillomavirus (HPV) infection and programmed death-ligand 1 (PD-L1) expressions on the efficacy of CMP-001 in combination with pembrolizumab

Participants will continue to receive treatment of CMP-001 and pembrolizumab according to the treatment schedule until a reason for treatment discontinuation is reached.

Detailed description:
Former Sponsor Checkmate Pharmaceuticals

Arms:
arm 1: All subjects will receive CMP-001 IT and pembrolizumab IV according to the treatment schedule until a reason for treatment discontinuation is reached.

Interventions: intervention 1: CMP-001 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Subjects will receive CMP-001 10mg weekly for 2 doses after which CMP-001 will be administered every 3 weeks. The first dose of CMP-001 may be administered subcutaneously (SC) or Intratumorally (IT) at the discretion of Investigator. All subsequent doses will be injected intratumorally every 3 weeks (Q3W). intervention 2: Pembrolizumab 200 mg IV is administered Q3W.

Protocol document:
Prot_000.pdf: 
VV-TMF-2406459 - 2.0 - Approved
NCT04633278
Protocol CMP-001-007 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 
14 January 2022 
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Confidential 
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CMP-001-007 
A MULTICENTER, PHASE 2, OPEN-LABEL STUDY 
OF INTRATUMORAL CMP-001 IN COMBINATION 
WITH INTRAVENOUS PEMBROLIZUMAB IN 
SUBJECTS WITH RECURRENT OR METASTATIC 
HEAD AND NECK SQUAMOUS CELL CARCINOMA 
Study Phase: 
Phase 2 
IND Number: 
16695 
Sponsor: 
Checkmate Pharmaceuticals, Inc. 
245 Main Street, 2nd Floor 
Cambridge, MA 02142 United States 
Responsible Medical Officer: 
 
Issue Date: 
Original Protocol 11 June 2020 
Amendment 2 (Version 3.0) 14 January 2022 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that is 
privileged or confidential and may not be disclosed, unless disclosure is required by 
applicable laws and regulations. In any event, persons to whom the information is disclosed 
must be informed that the information is privileged or confidential and may not be further 
disclosed by them. These restrictions on disclosure will apply equally to all future 
information supplied to you indicated as privileged or confidential. 


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INVESTIGATOR’S AGREEMENT 
 
A MULTICENTER, PHASE 2, OPEN-LABEL STUDY OF INTRATUMORAL CMP- 
001 IN COMBINATION WITH INTRAVENOUS PEMBROLIZUMAB IN SUBJECTS 
WITH RECURRENT OR METASTATIC HEAD AND NECK SQUAMOUS CELL 
CARCINOMA 
 
Protocol Number: CMP-001-007 
I have read this protocol and agree to the following: 
• I am thoroughly familiar with the appropriate use of the investigational drug, as 
described in this protocol, and any other information provided by the Sponsor 
including, but not limited to, the current Investigator’s Brochure (IB) provided by the 
Sponsor. 
• I will conduct the study in compliance with this protocol, with any future 
amendments, and with any other written study conduct procedures provided and 
reviewed and approved by the Sponsor or its representatives. 
• I will conduct the study in accordance with the current US Food and Drug 
Administration (FDA)/applicable local regulations; International Council for 
Harmonisation (ICH) guidelines and any other applicable regulatory requirements; as 
well as Good Clinical Practice (GCP) standards (CPMP/ICH/135/95); the ethical 
principles that have their origin in the Declaration of Helsinki, and that are consistent 
with the principles of GCP; all local ethical and legal requirements; and will complete 
the study within the time designated. 
• I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material 
with them to ensure they are fully informed regarding the drug and the conduct of the 
study. 
• I agree that the Sponsor or its representatives shall have access to any source 
documents from which electronic case report form information may have been 
generated. 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
Signature of Investigator 
Date 


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SPONSOR PROTOCOL APPROVAL 
 
I have read this protocol and approve the design of this study: 
 
 
 
 
 
 
 
 
 
Checkmate Pharmaceuticals, Inc. 
20-Jan-2022 | 5:55 AM PST 
 
Date 


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Amendment 2 (Version 3.0) 
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PROCEDURES IN CASE OF EMERGENCY 
Emergency Contact Information 
 
Name 
Role in Study 
Address and Telephone Number 
Checkmate Pharmaceuticals, 
Inc. 
Sponsor 
245 Main Street, 2nd Floor 
Cambridge, MA, USA 02142 
Phone: 617-682-3625 
IQVIA Biotech 
Medical Monitor 
24-Hour emergency 
contact 
Email: 
 
Serious adverse events (SAEs) should be recorded on an SAE Report Form 
and completed and submitted to IQVIA Biotech Safety preferably via email to: 
 or by fax to 
 as back up 
within 24 hours of awareness. Information including a detailed description 
of the event; date and time (24-hour clock) of event onset and resolution. 


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SYNOPSIS 
 
Name of Sponsor/Company: Checkmate Pharmaceuticals, Inc. 
Name of Investigational Product: CMP-001 
Name of Active Ingredient: QbG10, a virus-like particle (VLP) that encapsulates G10, a cytosine 
linked to a guanine by a phosphate bond (CpG) oligodeoxynucleotide 
Title of Study: A Multicenter, Phase 2, Open-Label Study of Intratumoral CMP-001 in 
Combination with Intravenous Pembrolizumab in Subjects with Recurrent or Metastatic Head and 
Neck Squamous Cell Carcinoma 
Study Center(s): The study will be conducted at clinical sites in the United States 
Phase of Development: Phase 2 
Study Objectives: 
Primary Objective: 
• 
To determine the Investigator-assessed confirmed objective response with CMP-001 in 
combination with pembrolizumab in subjects with head and neck squamous cell 
carcinoma (HNSCC) 
Secondary Objectives: 
• 
To evaluate the safety and tolerability of CMP-001 administered by intratumoral (IT) 
injection in combination with pembrolizumab in subjects with HNSCC 
• 
To evaluate the efficacy of CMP-001 in combination with pembrolizumab in subjects 
with HNSCC 
• 
To evaluate the effect of human papillomavirus (HPV) infection and programmed death- 
ligand 1 (PD-L1) expressions on the efficacy of CMP-001 in combination with 
pembrolizumab 
Exploratory Objective: 
• 
To evaluate the pharmacodynamic and pharmacokinetic effects of CMP-001 
administered in combination with pembrolizumab 
Study Endpoints: 
Primary Endpoint: 
• 
Objective response rate (ORR), defined as the proportion of subjects with a confirmed 
objective response of complete response (CR) or partial response (PR) based on 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as determined 
by Investigator assessment 
Secondary Endpoints: 
• 
Adverse events (AEs), serious adverse events (SAEs), and AEs leading to 
discontinuation or death, and severity of AEs as assessed by the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0 
• 
Duration of response (DOR), defined as the time from date of first documented response 
(CR or PR) to date of documented progressive disease (PD), based on RECIST v1.1 by 
Investigator assessment 


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• 
Progression-free survival (PFS), defined as the time from date of first dose of study drug 
to date of documented PD based on RECIST v1.1 by Investigator assessment or death, 
whichever occurs first 
• 
Overall survival (OS), defined as the time from the date of first dose of study drug to the 
date of death 
• 
Immune objective response rate (iORR), defined as the proportion of subjects with a 
best overall response (BOR) of immune complete response (iCR) or immune partial 
response (iPR) based on the immunotherapy Response Evaluation Criteria in Solid 
Tumors (iRECIST) by Investigator assessment 
• 
Immune duration of response (iDOR), defined as the time from the date of the first 
immune response (iCR or iPR) to the date of immune confirmed progressive disease 
(iCPD) by Investigator assessment 
• 
Immune progression-free survival (iPFS), defined as the time from date of first dose of 
study drug to date of iCPD by Investigator assessment or death, whichever occurs first 
• 
ORR, DOR, and PFS based on HPV status and PD-L1 expressions (combined positive 
score [CPS] ≥ 1 and CPS ≥ 20) 
Exploratory Endpoints: 
• 
Response in injected and noninjected target lesions per intratumoral Response 
Evaluation Criteria in Solid Tumors (itRECIST) by Investigator assessment 
• 
Baseline, and change from Baseline, in tumor or blood measurements of biomarkers 
related to TLR9, immune checkpoints, and potential markers of resistance or response to 
immunotherapy 
• 
Change from Baseline in blood concentrations of C-X-C motif chemokine 10 (CXCL10) 
(IP-10) and other cytokines after treatment with CMP-001 
• 
Blood concentrations of CMP-001 or its metabolites 
Methodology: 
This is a multicenter, open-label, Phase 2 clinical trial of CMP-001 administered by IT injection in 
combination with intravenous (IV) pembrolizumab in subjects with recurrent or metastatic head and 
neck squamous cell carcinoma (HNSCC) not previously treated with a PD-1 blocking antibody. This 
will be a Phase 2 study, with response and DOR assessments using RECIST v1.1 and iRECIST 
criteria according to Investigator assessment. All subjects will receive CMP-001 IT and 
pembrolizumab IV according to the treatment schedule until a reason for treatment discontinuation 
is reached. 
Number of subjects (planned): 
A total of 43 subjects is planned for this study. This is based on the following assumptions: 
• 
A historical ORR of 19% with pembrolizumab monotherapy in subjects with HNSCC 
who have a CPS ≥1 and were not previously treated with a PD-1 blocking antibody (null 
hypothesis) 
• 
An anticipated ORR of 35% with CMP-001 and pembrolizumab (alternative 
hypothesis). 
• 
Power of 80% and one-sided alpha level of 0.05. 


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Diagnosis and main criteria for inclusion: 
Inclusion criteria: 
Subjects enrolled in the study must meet all of the following inclusion criteria to be eligible: 
1. Subjects with histologically- or cytologically-confirmed recurrent or metastatic HNSCC 
considered incurable by local therapies, and subjects with T4 or N3 disease who are 
ineligible for or refusing local therapies. 
2. No prior systemic therapy in the recurrent or metastatic setting. Systemic therapy as part of 
multi-modal treatment for locally advanced disease is allowed. 
3. Primary tumor locations of oropharynx, oral cavity, hypopharynx, larynx, paranasal sinus, or 
HNSCC of unknown primary origin. Participants may not have a primary tumor site of 
nasopharynx (any histology). 
4. Able to provide tissue from a core or excisional biopsy (fine needle aspirate is not 
sufficient). A newly obtained biopsy (within 90 days before the start of study treatment) is 
preferred but an archival sample is acceptable. 
5. CPS ≥1 for PD-L1 on immunohistochemistry (IHC) of tumor tissue. 
6. Have results of tumor HPV p16 by IHC for oropharyngeal or for unknown primary cancer. 
7. Measurable disease as defined by RECIST v1.1, and both of the following: 
a. At least 1 lesion amenable to repeated IT injection. 
b. Documented disease progression in any lesion that was previously radiated in order to 
serve as a target lesion. 
8. Adequate organ function based on most recent laboratory values within 3 weeks before the 
first dose of study drug on Week 1 Day 1 (W1D1): 
a. Bone marrow function: 
- 
neutrophil count ≥ 1,500/mm3 
- 
platelet count ≥ 100,000/mm3 
- 
hemoglobin concentration ≥ 9 g/dL 
b. Liver function: 
- 
total bilirubin ≤ 1.5 times the upper limit of normal (ULN) with the following 
exception: subjects with Gilbert Disease serum bilirubin ≤ 3 times ULN 
- 
aspartate aminotransferase and alanine aminotransferase ≤ 3 times the ULN or 
≤ 5 times the ULN for subjects with active liver metastases 
c. Renal function: estimated (Cockroft-Gault) or measured CrCl ≥30 mL/min 
d. Coagulation 
- 
International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 times ULN 
unless subject is receiving anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants 
- 
Activated Partial Thromboplastin Time (aPTT) or partial thromboplastin time (PTT) 
≤ 1.5 times ULN unless subject is receiving anticoagulant therapy as long as PT or 
PTT is within therapeutic range of intended use of anticoagulants 
9. Age ≥ 18 years at time of consent. 
10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 at Screening. 
11. Capable of understanding and complying with protocol requirements. 
12. Women of childbearing potential must have negative serum pregnancy test during Screening 
and be willing to use an adequate method of contraception (Section 4.3.2) from the time of 
consent until at least 120 days after the last dose of study drug. 


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13. Able and willing to provide written informed consent and to follow study instructions. 
Subjects unable to provide written informed consent on their own behalf will not be eligible 
for the study. 
Exclusion criteria: 
Subjects presenting with any of the following will not qualify for entry into the study: 
1. Disease suitable for local therapy administered with curative intent. 
2. Has PD within 3 months of completion of curatively intent systemic treatment for 
locoregionally advanced HNSCC. 
3. Radiation therapy (or other non-systemic therapy) within 2 weeks before the first dose of 
study drug on W1D1. 
4. Received prior therapy with PD-1 or PD-L1 blocking antibody therapy in the 
recurrent/metastatic setting. If PD-1 or PD-L1 blocking antibody therapy was given as part 
of curative intent therapy, it must be at least 1 year since receipt of PD-1 or PD-L1 blocking 
antibody. 
5. Not fully recovered from adverse events (to Grade 1 or less [per CTCAE v 5.0]) with the 
exception of persistent alopecia, neuropathy, ototoxicity, hypothyroidism, pain, xerostomia, 
or dysphagia, due to prior treatment. 
6. Received systemic pharmacologic doses of corticosteroids ≥ 10 mg/day prednisone within 
30 days before the first dose of study drug on W1D1. 
a. Subjects who are currently receiving steroids at a prednisone-equivalent dose of 
≤ 10 mg/day do not need to discontinue steroids prior to enrollment. 
b. Replacement doses, topical, ophthalmologic, and inhalational steroids are permitted. 
c. Stress-dose corticosteroids will be required in subjects with adrenal insufficiency (see 
Section 5.1.2.1.1.). 
7. Active pneumonitis or history of noninfectious pneumonitis that required steroids. 
8. Severe uncontrolled cardiac disease within 6 months of Screening, including but not limited 
to poorly controlled hypertension, unstable angina, myocardial infarction, congestive heart 
failure (New York Heart Association Class II or greater), pericarditis within the previous 
6 months, cerebrovascular accident, implanted or continuous use of a pacemaker or 
defibrillator. 
9. Known history of immunodeficiency. 
10. Known additional malignancy that is progressing or required active treatment within the past 
3 years. Exceptions include cancers that have undergone potentially curative therapy, e.g., 
basal cell carcinoma of the skin, squamous cell carcinoma of the skin, localized prostate 
cancer with prostate-specific antigen level below 4.0 ng/mL, in situ cervical cancer on 
biopsy or a squamous intraepithelial lesion on Papanicolaou smear, thyroid cancer (except 
anaplastic), in situ breast cancer, and adjuvant hormonal therapy for breast cancer > 3 years 
from curative-intent surgical resection. 
11. Active autoimmune disease that has required systemic treatment in past 2 years; replacement 
therapy is not considered a form of systemic treatment. 
12. Untreated, symptomatic, or enlarging central nervous system (CNS) metastases or 
carcinomatous meningitis. 


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13. Prior allogenic tissue/solid organ transplant. 
14. Active infection requiring systemic therapy. 
15. Known or suspected active infection with SARS-CoV-2 virus. 
16. Known or suspected active infection with human immunodeficiency virus, hepatitis B virus, 
or hepatitis C virus (testing is not required unless suspected). 
17. Received a live virus/attenuated vaccination within 30 days before the start of study drug on 
W1D1. 
18. Received blood products (including platelets or red blood cells) or colony stimulating 
factors (including GCSF, GMCSF, or recombinant erythropoietin) within 14 days before the 
start of W1D1. 
19. Any concurrent uncontrolled illness, including mental illness or substance abuse, which in 
the opinion of the Investigator, would make the subject unable to cooperate or participate in 
the trial. 
20. Participation in another clinical trial of an investigational anticancer therapy or device 
within 30 days before the first dose of study drug on W1D1 
NOTE: Participation in the follow-up phase (receiving no study treatment) of a prior study is 
allowed. 
21. Requires prohibited treatment (i.e., non-protocol specified anticancer pharmacotherapy, 
surgery, or conventional radiotherapy) for treatment of malignant tumor. 
22. Has a life expectancy of less than 3 months and/or has rapidly progressing disease (e.g., 
tumor bleeding, uncontrolled tumor pain) in the opinion of the treating Investigator. 
23. Received previous CMP-001 treatment. 
24. Pregnant or breast-feeding or expecting to conceive or father children within the projected 
duration of the study, from the time of consent until at least 120 days after the last dose of 
study drug. 
Investigational product, dosage, and mode of administration: 
Subjects will receive CMP-001 10 mg weekly for 2 doses (W1D1 and Week 2 Day 1 [W2D1 (-2/+5 
days)]), after which CMP-001 will be administered every 3 weeks (Q3W) (beginning on Week 4 
Day 1 [W4D1], then on Week 7 Day 1 [W7D1], etc.). The first dose of CMP-001 may be 
administered subcutaneously (SC) or by IT injection at the discretion of the Investigator; all 
subsequent doses are planned to be administered by IT injection. See Section 5.1.2.5 for treatment 
modifications for CMP-001. 
Subjects will receive pembrolizumab 200 mg IV over 30 minutes following CMP-001 injection at 
W1D1 and every 3 weeks thereafter according to the KEYTRUDA® (pembrolizumab) United States 
Prescribing Information. Pembrolizumab should be administered until the subject satisfies a 
condition for study treatment discontinuation. See protocol for treatment modifications for 
pembrolizumab. 
Duration of treatment: 
Subjects will continue study treatment until they reach a reason for treatment or study 
discontinuation. Clinically stable subjects may continue study treatment beyond RECIST v1.1 
progression based upon Investigator judgement of potential benefit. Study treatment may not 
continue beyond 2 years from initial dose of study treatment. 


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If a subject achieves and maintains a confirmed CR or iCR by Investigator review, treatment with 
CMP-001 or the combination of CMP-001 and pembrolizumab may be discontinued at the 
Investigator’s discretion once they meet both of the following criteria: 
• 
Subject has been treated with both study drugs for at least 24 weeks 
• 
Subject has received at least 3 doses of both study drugs beyond the date of the initial 
CR/iCR 
NOTE: 3 doses are required only if medically feasible in the Investigator’s opinion – 
less than 3 doses are acceptable if the Investigator is not medically able to inject. 
Subjects who discontinue study treatment should complete an end of treatment (EOT) visit and 
30-day safety follow-up. Subjects who are posttreatment but have not met criteria for study 
discontinuation should remain on study for posttreatment follow-up (PTFU) and long-term survival 
follow-up (LTSFU) and receive study evaluations for efficacy according to the Schedule of 
Assessments. 
Subjects who discontinue CMP-001 and/or pembrolizumab treatment may not be retreated on this 
study. 
Criteria for evaluation: 
Efficacy: 
Disease status will be assessed by computed tomography (CT) or magnetic resonance imaging 
(MRI) and other appropriate measures beginning pre-dose at Week 10 Day 1 and will be repeated 
every 9 weeks (e.g., Week 19 Day 1). Responses (CR, PR, iCR, or iPR) will be confirmed by 
follow-up disease assessment performed at least 4 weeks after the date of initial response and should 
be at least 2 weeks after the last CMP-001 injection. Imaging should not be delayed for delays in 
treatment. 
Objective responses will be assessed by the Investigator according to RECIST v1.1 and iRECIST. 
Subjects who continue study treatment beyond PD according to RECIST v1.1 will be assessed by 
the Investigator according to iRECIST. 
Translational Assessments: 
• 
Quantification of the concentration of cytokines and chemokines from blood of subjects 
obtained at time points specified in the Schedule of Assessments 
• 
Analysis of CD3+CD8+ T-cell infiltrates or other multi-parameter assessment of the 
tumor microenvironment in tumor tissue obtained via fresh biopsy or from archival 
tumor tissue, and correlation with antitumor activity. 
• 
Intra-subject changes in immune status from pretreatment to posttreatment may be 
evaluated by technologies such as RNA profiling, flow cytometry, or IHC using tumor 
biopsies of injected or non-injected lesions, collected before treatment and starting at 
4 weeks after initiation of weekly CMP-001 treatment. 
Safety: 
Safety and tolerability will be assessed by evaluating the following: 
• 
Treatment-emergent adverse events, which will be evaluated and assigned a grade using 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
• 
Vital signs (oral temperature, respiratory rate, pulse, systolic and diastolic blood 
pressure), and physical examination (including weight and body mass index) 
• 
Clinical laboratory parameters (chemistry, hematology, urinalysis, coagulation, and 
thyroid function tests) 


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• 
12-Lead electrocardiograms (ECGs) 
Statistical methods: 
Study analysis sets for safety and efficacy will include: 
• 
Intent-to-Treat (ITT) Analysis Set: all subjects who receive at least 1 dose of study drug 
• 
Safety Analysis Set: all subjects who receive at least 1 dose of study drug 
• 
Pharmacodynamic Analysis Set: all subjects who receive at least 1 dose of CMP-001 
and have at least 1 measurable biomarker at Baseline and after CMP-001 injection 
• 
Pharmacokinetic Analysis Set: all subjects who receive CMP-001 and have evaluable 
samples at Baseline and after CMP-001 injection 
Categorical variables will be summarized as the number and percentage of subjects within each 
category (with a category for missing data, if applicable). Continuous variables will be presented as 
number (n), mean, median, standard deviation, and range (minimum and maximum). 
Data from all investigational sites will be pooled in the analyses. 
A detailed statistical analysis plan (SAP) will be finalized before database lock and will document 
the analysis methods, data handling procedures, and other statistical analysis issues. Statistical 
analyses will be performed using SAS® software version 9.4 or higher. 
Safety data, including vital signs, ECGs, laboratory test results, physical examinations, and AEs, 
will be summarized by assessment time points, as appropriate. Change from Baseline will be 
included in summary tables for laboratory, ECG, and vital sign parameters. 
The primary efficacy analysis of confirmed ORR will be assessed according to RECIST (Version 
1.1) by the Investigator for the ITT Analysis Set. Secondary efficacy analyses will include PFS, 
BOR, DOR, OS, iORR, iPFS, iDOR; efficacy in relation to PD-L1 expression CPS ≥ 1 and 
CPS ≥ 20, and HPV status will also be assessed and summarized for the ITT Analysis Set. 


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Table 1: 
Schedule of Assessments 
 
Procedure or Assessment 
Screening 
(Day -30 to 
Day -1) 
W1D1 
W2D1 
W4D1 
W4D2 
Q3W 
(W7D1, 
W10D1, 
etc.) 
End of 
Treatment 
(EOT)a 
30-Day 
Safety 
Follow-up 
(30DFU)b 
Posttreatment 
Follow-up 
(PTFU)c 
(Q3mo) 
Long-Term 
Survival 
Follow-up 
(LTSFU)d 
(Q3mo) 
Visit Windows 
n/a 
n/a 
-2/+5d 
+3d 
n/a 
± 3d 
+7d 
+7d 
± 2 weeks 
± 4 weeks 
CMP-001 Injection 
(Dose Number)e 
1 
SC/IT 
2 
3 
4+ 
Pembrolizumab Dosing 
(Dose Number)f 
1 
2 
3+ 
Informed Consent 
X 
Eligibility Criteria 
Assessment 
X 
Demographics 
X 
Head and Neck Cancer 
History 
X 
Prior Cancer Treatments 
X 
Medical History 
X 
Alcohol and Tobacco Use 
History 
X 
Physical Examinationg 
X 
X 
X 
X 
X 
X 
Vital Signsh 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
Adverse Event Monitoringi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medicationsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGk 
X 
X 
X 
Clinical Laboratory Tests 
(hematology, serum 
chemistry, urinalysis)l 
X 
X 
X 
X 
X 
X 
Coagulation Testsl 
X 
X 
X 
X 


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Table 1: 
Schedule of Assessments (Continued) 
 
Procedure or Assessment 
Screening 
(Day -30 to 
Day -1) 
W1D1 
W2D1 
W4D1 
W4D2 
Q3W 
(W7D1, 
W10D1, 
etc.) 
End of 
Treatment 
(EOT)a 
30-Day 
Safety 
Follow-up 
(30DFU)b 
Posttreatment 
Follow-up 
(PTFU) c 
(Q3mo) 
Long-Term 
Survival 
Follow-up 
(LTSFU)d 
(Q3mo) 
Visit Windows 
n/a 
n/a 
-2/+5d 
+3d 
n/a 
± 3d 
+7d 
+7d 
± 2 weeks 
± 4 weeks 
CMP-001 Injection 
(Dose Number)e 
1 
SC/IT 
2 
3 
4+ 
Pembrolizumab Dosing 
(Dose Number)f 
1 
2 
3+ 
Thyroid Function Testsl 
X 
X 
X 
X 
Autoimmune Laboratory 
Panell 
X 
X 
Pregnancy Test and Follicle 
Stimulating Hormonel 
X 
X 
X 
X 
X 
Exploratory Biomarker 
Samplingm 
X 
X 
X 
W7D1 
Exploratory Sampling for 
Pharmacokineticsm 
X 
X 
X 
W7D1 
Tumor Biopsy (known PD- 
L1 status)n 
X 
W7D1 
Blood Sampling for Cytokine 
and Complemento 
X 
X 
W7D1 
Disease Assessment 
(Radiographic Imaging)p 
X 
W10D1 
Q9W 
X 
X 
Disease Assessment (CNS 
Imaging)p 
X 
W10D1 
Q9W 
X 
X 
Photographic Imagingq 
X 
W10D1 
Q9W 
X 
X 
30-Day Follow-Up 
(Office or Phone Call) 
X 
Long-Term Survival Follow- 
up Phone Call 
X 
Abbreviations: 30DFU = 30-day follow-up; CNS = central nervous system; CPS = combined positive score; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of 
treatment; FSH = follicle stimulating hormone; HPV = human papillomavirus; iRECIST = immunotherapy Response Evaluation Criteria in Solid Tumors; LTSFU = long-term survival follow-up; MRI = magnetic 
resonance imaging; PTFU = posttreatment follow-up; RECIST = Response Evaluation Criteria in Solid Tumors; Q3W = every 3 weeks; W = week; WOCBP = women of child bearing potential. 
a. EOT assessments to be performed within 7 days following subject discontinuation from study treatment. Removal of a subject from CMP-001 treatment is defined as the time in which the Investigator decides to 
discontinue study treatment. If a subject has CMP-001 dosing withheld for more than 3 consecutive doses for any reason during the Q3W dosing period, resumption of treatment must be discussed with the Medical 


VV-TMF-2406459 - 2.0 - Approved 
Protocol CMP-001-007 
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Amendment 2 (Version 3.0) 
14 January 2022 
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VV-RIM-00380641-1.0 Approved - 21 Nov 2024 GMT-5:00 
Confidential 
 
 
Monitor; otherwise, the subject will be discontinued from study treatment and will have all EOT assessments performed. End of Treatment occurs once the subject discontinues administration of CMP-001. Subjects 
can continue to receive pembrolizumab as standard of care but will no longer be considered in study treatment. 
b. The 30-Day Follow-up is a safety follow-up visit that may be conducted in the study clinic OR via phone. This visit should occur 30 days (+7) after the EOT visit. 
c. PTFU will be conducted every 3 months (± 2 weeks) for all subjects who discontinue study treatment but have not met criteria for study discontinuation. These subjects should remain on study and receive disease 
assessments every 3 months, until discontinuation. 
d. LTSFU will be conducted every 3 months (± 4 weeks) after the EOT visit or the last disease assessment date in PTFU and may occur by phone call. 
e. CMP-001 Injection Visits: Weekly Dosing (W1D1 and W2D1): The first dose of CMP-001 may be administered SC or IT, at the discretion of the Investigator; all subsequent doses are planned to be administered IT 
until no injectable lesions remain. A window of -2/+5 days is permitted for CMP-001 dosing on W2D1. Q3W Dosing (W4D1+): A window of ±3 days is permitted for CMP-001 dosing from W4D1 throughout the 
trial. When pembrolizumab is permanently discontinued, CMP-001 must also be permanently discontinued. Refer to Section 5.4 for Treatment Compliance. 
f. Pembrolizumab dosing will begin on W1D1 and continue Q3W throughout the study. When CMP-001 injection and pembrolizumab dosing fall on the same day, the CMP-001 injection will be given before 
pembrolizumab dosing. Refer to Section 5.1.1 for Pembrolizumab Dosing. 
g. A full PE will be conducted at Screening and EOT. If the Screening full PE is performed > 72 hours before the W1D1 visit, then a brief (symptom directed) PE must be performed within 72 hours before the first 
injection of CMP-001. Brief PEs focused on areas of disease or AEs must be performed at every CMP-001 injection visit, and at any other time as clinically indicated. Height will be obtained at Screening only and 
weight at all PE assessments. 
h. Vital signs include measurement of blood pressure (systolic and diastolic blood pressure), respiratory rate, heart rate, and body temperature. Blood pressure and heart rate should be taken in the seated position 
following ≥ 3 minutes of rest. For the first 4 CMP-001 dosing visits (W1D1, W2D1, W4D1, and W7D1), vital signs must be collected before the CMP-001 injection and at 30 (± 15)-minute intervals for 4 hours after 
CMP-001 injection. Starting at W10D1, observation periods may be reduced to a minimum of 1 hour following CMP-001 injection at the Investigator’s discretion based on the AE profile of the individual subject. 
When vital signs are scheduled at the same time as collection of a blood sample, the vital sign measurements should be obtained before the scheduled phlebotomy. If a study visit occurs where only pembrolizumab 
is administered, vital signs must be collected before the start of the pembrolizumab infusion. 
NOTE: Oxygen saturation is not a required parameter to be collected. Sites are to capture oxygen saturation every time an AE of hypoxia or cytokine release syndrome is reported for a subject. 
i. Adverse events will be assessed continually from time of consent through 30 days after the last dose of study drug for all subjects. Subjects who discontinue CMP-001 but remain on treatment with pembrolizumab 
will continue to have AEs collected according to this schedule until 30 days after the last dose of pembrolizumab. 
j. Concomitant medications will be assessed continually from time of consent through 30 days after the last dose of study drug. Treatment medications for study-related AEs that occur through 30 days after the last 
dose of study drug will be collected during the 30-Day Safety Follow-Up period. 
k. 12-lead ECGs will be obtained at Screening, before the W1D1 CMP-001 injection, and at EOT. ECG parameters will include heart rate and PR, QRS, QT, and QT corrected for heart rate (QTc) intervals. ECGs will 
be performed after the subject has been resting in supine or semi-supine position for at least 5 minutes. When an ECG is scheduled at the same time as a blood sampling, the ECG reading should be obtained before 
the scheduled blood sampling. 
l. Clinical laboratory assessments may be performed up to 72 hours before CMP-001 injection. When clinical laboratory assessments are done the same day as CMP-001 injection, vital signs should, if 
feasible/possible per site standard process, be performed before collection of clinical laboratory tests. Refer to Section 7.1.13 for Clinical Laboratory Assessments. 
NOTE: For WOCBP, a serum pregnancy test and FSH are completed at Screening. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human 
chorionic gonadotropin) within 24 hours before the start of study treatment. An extension up to 72 hours before the start of study treatment is permissible in situations where results cannot be obtained within the 
standard 24-hour window. Serum or urine pregnancy tests are also to be completed before CMP-001 injection on W1D1 and Q3W thereafter and EOT. Refer to Section 7.1.14 for Pregnancy Testing. An FSH test 
is required to confirm menopause in women with less than 12 months of amenorrhea (see Section 4.3.1). If fertility is unclear and a menstrual cycle cannot be confirmed before the first dose of study treatment 
(W1D1), subject should be considered of childbearing potential and applicable pregnancy tests completed. 
NOTE: Coagulation samples (PT, INR, and PTT) to be collected and results reviewed before CMP-001 injection at the W1D1 visit. Subsequent results are to be reviewed before every CMP-001 injection 
continuing Q3W thereafter beginning on W4D1 until EOT. 
m. Exploratory biomarker and pharmacokinetic blood samples are to be collected at the following time points: pre-dose and 4 to 6 hours after CMP-001 injection on W1D1, W4D1, and W7D1. Optional collection 24 
hours after CMP-001 injection on W4D1. 
NOTE: For sample collection on W1D1, W4D1, and W7D1, preference should be given to the later collection time point (i.e., 6 hours). Refer to Section 7.3.1 Collection of Blood for Translational Biomarker and 
Pharmacokinetics Analyses. 
n. Fresh tumor biopsy samples are mandatory, if safe and medically feasible, at Screening or within 90 days (before W1D1) and W7D1 before CMP-001 IT injection. If the Investigator believes it is unsafe to perform a 
biopsy, the subject may be considered eligible after discussion with the Medical Monitor if tissue and/or prior assessments are available to determine PD-L1 expression and HPV status. Refer to Section 7.3.2 for 
Tumor Biopsies. 
NOTE: PD-L1 status is mandatory, and the combined CPS value must be recorded in the electronic case report form. 
o. Blood samples for cytokine and complement assessment are to be collected at the following time points: 1) -2 to 0 hours before CMP-001 injection on W1D1, W4D1, and W7D1; 2) 4 hours (±30 minutes) after 
CMP-001 injection on W1D1, W4D1, and W7D1; and 3) if any AEs of cytokine release syndrome are experienced. Refer to Section 7.3.1 Collection of Blood for Translational Biomarker and Pharmacokinetics 
Analyses. 
p. Disease assessment methods include radiographic imaging (CT or MRI) and CNS imaging by contrast-enhanced CT or MRI (per site local standards). The same modality used at Screening must be used throughout 
the study. Baseline CNS imaging should be provided for subjects with known or suspected brain metastases; on-study CNS imaging is required if symptoms or history of CNS disease is present at Baseline. Disease 


VV-TMF-2406459 - 2.0 - Approved 
Protocol CMP-001-007 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 
14 January 2022 
15 
VV-RIM-00380641-1.0 Approved - 21 Nov 2024 GMT-5:00 
Confidential 
 
 
assessments will be performed pre-dose beginning at W10D1 (-7 days) and repeated every 9 weeks (-7 days) (e.g., W19D1, W28D1). A response (CR, PR, iCR or iPR [per RECIST v1.1 or iRECIST]) will be 
confirmed with follow-up disease assessments performed at least 4 weeks after the date of initial response. Disease assessments will continue every 9 weeks after the confirmatory scans. Disease assessments may be 
performed every 12 weeks for subjects with a response continuing more than 1 year. All scans should be performed at least 2 weeks after the previous CMP-001 IT injection to prevent injection-related 
pseudoprogression. Refer to Section 7.2 for Disease Assessments. 
q. If a subject has a visible lesion, digital photographs of CMP-001-injected and non-injected skin lesions should be taken at Baseline and if a clinically relevant change occurs. As part of disease assessment, photos 
should be taken at the same intervals as the radiographic imaging. Refer to Section 7.2.2 for Photographic Imaging. 


VV-TMF-2406459 - 2.0 - Approved 
Protocol CMP-001-007 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 
14 January 2022 
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Confidential 
VV-RIM-00380641-1.0 Approved - 21 Nov 2024 GMT-5:00 
 
 
TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ............................................................................ 2 
SPONSOR PROTOCOL APPROVAL ......................................................................... 3 
PROCEDURES IN CASE OF EMERGENCY ............................................................. 4 
SYNOPSIS .................................................................................................................... 5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................. 22 
1. 
INTRODUCTION ................................................................................... 25 
1.1. 
Background .............................................................................................. 25 
1.2. 
CMP-001 .................................................................................................. 26 
1.2.1. 
Previous Clinical Studies With CMP-001 ................................................ 27 
1.3. 
Study Rationale ........................................................................................ 27 
1.3.1. 
Rationale for Combining a TLR9 Agonist With an PD-1 Blocking 
Antibody .................................................................................................. 27 
1.3.2. 
Rationale for Intratumoral Administration of TLR9 Agonists................. 28 
1.3.3. 
Rationale for CMP-001 Dose and Schedule ............................................ 29 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................... 30 
2.1. 
Study Objectives ...................................................................................... 30 
2.1.1. 
Primary Objective .................................................................................... 30 
2.1.2. 
Secondary Objectives ............................................................................... 30 
2.1.3. 
Exploratory Objective .............................................................................. 30 
2.2. 
Study Endpoints ....................................................................................... 30 
2.2.1. 
Primary Endpoint ..................................................................................... 30 
2.2.2. 
Secondary Endpoints ................................................................................ 30 
2.2.3. 
Exploratory Endpoints ............................................................................. 31 
3. 
INVESTIGATIONAL PLAN .................................................................. 32 
3.1. 
Overall Study Design ............................................................................... 32 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................... 34 
4.1. 
Subject Inclusion Criteria ......................................................................... 34 
4.2. 
Subject Exclusion Criteria ....................................................................... 35 
4.3. 
Women of Childbearing Potential ............................................................ 36 
4.3.1. 
Women of Non-Childbearing Potential ................................................... 37 
4.3.2. 
Acceptable Methods of Contraception ..................................................... 37 
4.4. 
Prohibited Treatments .............................................................................. 38 
4.4.1. 
Vaccinations ............................................................................................. 38 
4.4.2. 
Concomitant Procedures .......................................................................... 38 


VV-TMF-2406459 - 2.0 - Approved 
Protocol CMP-001-007 
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Amendment 2 (Version 3.0) 
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4.5. 
Treatment Discontinuation ....................................................................... 38 
4.6. 
Study Withdrawal .................................................................................... 39 
4.7. 
End of Clinical Trial................................................................................. 40 
5. 
TREATMENT OF SUBJECTS ............................................................... 41 
5.1. 
Administration of Study Drug .................................................................. 41 
5.1.1. 
Pembrolizumab ........................................................................................ 41 
5.1.2. 
CMP-001 .................................................................................................. 41 
5.1.2.1. 
Required Prophylaxis Before and After CMP-001 Injection ................... 41 
5.1.2.2. 
Observation Following CMP-001 Dosing ............................................... 42 
5.1.2.3. 
CMP-001 Injections ................................................................................. 42 
5.1.2.4. 
Dose Modifications for CMP-001 ............................................................ 43 
5.1.2.5. 
Management of Adverse Events Associated with CMP-001 ................... 43 
5.1.3. 
Adverse Events Associated with Pembrolizumab and Dose Modifications 
for Pembrolizumab ................................................................................... 45 
5.1.4. 
Method of Assigning Subjects ................................................................. 45 
5.2. 
Blinding and Unblinding Process ............................................................ 45 
5.3. 
Prior and Concomitant Medications ......................................................... 45 
5.4. 
Treatment Compliance ............................................................................. 45 
6. 
STUDY TREATMENT MATERIALS AND MANAGEMENT ............ 47 
6.1. 
Study Treatment ....................................................................................... 47 
6.2. 
Study Treatment Packaging and Labeling ............................................... 47 
6.3. 
Study Treatment Handling, Storage, Accountability ............................... 47 
6.4. 
Study Drug Dispensing ............................................................................ 48 
7. 
STUDY ASSESSMENTS AND PROCEDURES ................................... 49 
7.1. 
Procedures and Assessments .................................................................... 49 
7.1.1. 
Informed Consent ..................................................................................... 49 
7.1.2. 
Eligibility Criteria .................................................................................... 49 
7.1.3. 
Demographics .......................................................................................... 49 
7.1.4. 
Head and Neck Cancer History ................................................................ 49 
7.1.5. 
Prior Cancer Treatments .......................................................................... 49 
7.1.6. 
Medical History ....................................................................................... 49 
7.1.7. 
Alcohol and Tobacco Use History ........................................................... 49 
7.1.8. 
Concomitant Medications ........................................................................ 50 
7.1.9. 
Physical Examination ............................................................................... 50 
7.1.10. 
Vital Signs ................................................................................................ 50 


VV-TMF-2406459 - 2.0 - Approved 
Protocol CMP-001-007 
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Amendment 2 (Version 3.0) 
14 January 2022 
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Confidential 
VV-RIM-00380641-1.0 Approved - 21 Nov 2024 GMT-5:00 
 
 
7.1.11. 
Eastern Cooperative Oncology Group Performance Status ..................... 50 
7.1.12. 
Electrocardiogram .................................................................................... 50 
7.1.13. 
Clinical Laboratory Assessments ............................................................. 51 
7.1.14. 
Pregnancy Testing .................................................................................... 52 
7.2. 
Disease Assessments ................................................................................ 53 
7.2.1. 
Radiographic Imaging .............................................................................. 53 
7.2.2. 
Photographic Imaging .............................................................................. 53 
7.2.3. 
Central Nervous System Imaging ............................................................ 53 
7.2.4. 
On-Treatment Disease Assessment .......................................................... 54 
7.2.5. 
Treatment and Disease Assessment Beyond Progressive Disease ........... 54 
7.2.6. 
Confirmation of Response ....................................................................... 54 
7.3. 
Translational Assessments ....................................................................... 54 
7.3.1. 
Collection of Blood for Translational Biomarker and Pharmacokinetics 
Analyses ................................................................................................... 54 
7.3.2. 
Collection of Tumor Biopsies for Translational Assessments Analyses . 55 
7.3.3. 
Collection of Blood Samples for Cytokine and Complement Assessment 
. ................................................................................................................ 55 
7.4. 
Safety Assessments .................................................................................. 55 
7.4.1. 
Adverse Events ........................................................................................ 56 
7.5. 
30-Day Follow-Up Contact ...................................................................... 56 
7.6. 
Posttreatment Follow-Up ......................................................................... 56 
7.7. 
Long-Term Survival Follow-Up .............................................................. 56 
8. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING. 57 
8.1. 
Adverse Events ........................................................................................ 57 
8.1.1. 
Definition of an Adverse Event................................................................ 57 
8.1.2. 
Definition of a Serious Adverse Event ..................................................... 57 
8.1.3. 
Definition of a Treatment-Emergent Adverse Events .............................. 58 
8.2. 
Evaluation of Adverse Events and Serious Adverse Events .................... 58 
8.2.1. 
Adverse Event Severity/Grade ................................................................. 59 
8.2.2. 
Relationship to Study Drug ...................................................................... 59 
8.2.3. 
Classification of Adverse Event Outcome ............................................... 60 
8.2.4. 
Action Taken Related to Study Drug Administration Regarding the 
Adverse Event .......................................................................................... 60 
8.3. 
Procedures for Recording and Reporting Adverse Events....................... 61 
8.3.1. 
Reporting Serious Adverse Events .......................................................... 61 
8.3.2. 
Reporting Pregnancies ............................................................................. 62 


VV-TMF-2406459 - 2.0 - Approved 
Protocol CMP-001-007 
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Amendment 2 (Version 3.0) 
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VV-RIM-00380641-1.0 Approved - 21 Nov 2024 GMT-5:00 
 
 
8.3.3. 
Reporting to IRBs and Regulatory Authorities ........................................ 63 
8.3.4. 
Follow-up of Adverse Events/Serious Adverse Events ........................... 63 
9. 
STATISTICAL METHODS .................................................................... 65 
9.1. 
Sample Size Calculation .......................................................................... 65 
9.2. 
Analysis Sets ............................................................................................ 65 
9.2.1. 
Intent-to-Treat Analysis Set ..................................................................... 65 
9.2.2. 
Safety Analysis Set .................................................................................. 65 
9.2.3. 
Pharmacodynamic Analysis Set ............................................................... 65 
9.2.4. 
Pharmacokinetic Analysis Set .................................................................. 65 
9.3. 
Background Characteristics...................................................................... 66 
9.3.1. 
Disposition ............................................................................................... 66 
9.3.2. 
Demographics and Other Baseline Characteristics .................................. 66 
9.3.3. 
Eastern Cooperative Oncology Group Performance Status ..................... 66 
9.3.4. 
Head and Neck Squamous Cell Carcinoma History ................................ 66 
9.3.5. 
Prior Cancer Treatments .......................................................................... 66 
9.3.6. 
Medical and Surgical History .................................................................. 66 
9.3.7. 
Protocol Deviations .................................................................................. 66 
9.3.8. 
Prior and Concomitant Medications ......................................................... 66 
9.4. 
Study Drug Exposure and Compliance .................................................... 67 
9.5. 
Efficacy Analyses .................................................................................... 67 
9.5.1. 
Confirmed Objective Response Rate ....................................................... 67 
9.5.2. 
Disease Control Rate ................................................................................ 67 
9.5.3. 
Duration of Response ............................................................................... 68 
9.5.4. 
Progression-Free Survival ........................................................................ 68 
9.5.5. 
Overall Survival ....................................................................................... 68 
9.5.6. 
Post-progression Disease Response ......................................................... 68 
9.6. 
Safety Analyses ........................................................................................ 68 
9.6.1. 
Adverse Events ........................................................................................ 68 
9.6.2. 
Clinical Laboratory Assessments ............................................................. 69 
9.6.3. 
Vital Signs ................................................................................................ 69 
9.6.4. 
Physical Examinations ............................................................................. 69 
9.6.5. 
Electrocardiograms ................................................................................... 69 
9.7. 
Pharmacokinetic Analyses ....................................................................... 69 
9.8. 
Pharmacodynamic Analyses .................................................................... 70 
9.9. 
Exploratory Tumor Biopsy Analyses ....................................................... 70 


VV-TMF-2406459 - 2.0 - Approved 
Protocol CMP-001-007 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 
14 January 2022 
20 
Confidential 
VV-RIM-00380641-1.0 Approved - 21 Nov 2024 GMT-5:00 
 
 
9.10. 
Appropriateness of Measures ................................................................... 70 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ...................... 71 
10.1. 
Study Monitoring ..................................................................................... 71 
10.2. 
Case Report Forms ................................................................................... 71 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ....................... 72 
11.1. 
Data Quality Assurance ........................................................................... 72 
11.2. 
Quality Assurance Audits ........................................................................ 72 
11.3. 
Audits and Inspections by Regulatory Authorities .................................. 72 
11.4. 
Retention of Records ................................................................................ 72 
12. 
ETHICS.................................................................................................... 73 
12.1. 
Ethics Review .......................................................................................... 73 
12.2. 
Ethical Conduct of the Study ................................................................... 73 
12.3. 
Written Informed Consent ....................................................................... 73 
13. 
PUBLICATION POLICY ........................................................................ 75 
14. 
LIST OF REFERENCES ......................................................................... 76 
15. 
APPENDICES ......................................................................................... 79 
APPENDIX A. ECOG PERFORMANCE STATUS ............................................... 80 
APPENDIX B. APPROXIMATE MAXIMUM AMOUNT OF BLOOD DRAWN 
FOR 1 YEAR OF STUDY PARTICIPATION ....................................... 81 
APPENDIX C. COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS (CTCAE) VERSION 5.0 ......................................................... 82 
APPENDIX D. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) VERSION 1.1 ......................................................................... 83 
APPENDIX E. IMMUNOTHERAPY RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS (IRECIST).................................................................. 88 
APPENDIX F. INTRATUMORAL RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS (ITRECIST) VERSION 1.1 ....................................... 92 
APPENDIX G. CMP-001 INJECTION GUIDELINE ........................................... 100 


VV-TMF-2406459 - 2.0 - Approved 
Protocol CMP-001-007 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 
14 January 2022 
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LIST OF TABLES 
Table 1: 
Schedule of Assessments ......................................................................... 12 
Table 2: 
Clinical Laboratory Assessments ............................................................. 52 
Table 3: 
Criteria for Determination of Serious Adverse Events ............................ 58 
Table 4: 
CTCAE Adverse Event Grades ................................................................ 59 
Table 5: 
Classification for Adverse Event Causality ............................................. 60 
Table 6: 
Classifications for Adverse Event Outcomes ........................................... 60 
Table 7: 
Classifications for Actions Taken Related to Study Drug Administration 
Regarding an Adverse Event .................................................................... 61 
Table 8: 
Response for Lesion Category ................................................................. 96 
 
LIST OF FIGURES 
Figure 1: 
CMP-001-007 Study Schema .................................................................. 33 
Figure 2: 
Prophylaxis and Treatment for Adverse Events Associated with 
CMP-001 .................................................................................................. 44 
Figure 3: 
Method for CMP-001 Intratumoral Injection ......................................... 100 
Figure 4: 
Preferred Sites of Subcutaneous Injection ............................................. 102 


VV-TMF-2406459 - 2.0 - Approved 
Protocol CMP-001-007 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 
14 January 2022 
22 
Confidential 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or Specialist Term 
Explanation 
5-FU 
5-fluorouracil 
30DFU 
30-Day Follow-Up 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
BOR 
best overall response 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CpG 
cytosine linked to a guanine by a phosphate bond 
CPS 
combined positive score 
CR 
complete response 
CRA 
Clinical Research Associate 
CT 
computed tomography 
CTL 
cytotoxic T lymphocyte 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
CTA 
Clinical Trial Agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
CXCL10 
C-X-C motif chemokine 10 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HCC 
hepatocellular carcinoma 
HNSCC 
head and neck squamous cell carcinoma 
HPV 
human papillomavirus 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 


VV-TMF-2406459 - 2.0 - Approved 
Protocol CMP-001-007 
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Amendment 2 (Version 3.0) 
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VV-RIM-00380641-1.0 Approved - 21 Nov 2024 GMT-5:00 
 
 
 
Abbreviation or Specialist Term 
Explanation 
ID 
identification 
IEC 
Independent Ethics Committee 
IFN 
interferon 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
iCPD 
immune confirmed progressive disease 
iCR 
immune complete response 
iORR 
immune objective response rate 
iPFS 
immune progression-free survival 
iPR 
immune partial response 
iRECIST 
immunotherapy Response Evaluation Criteria in Solid 
Tumors 
itRECIST 
intratumoral Response Evaluation Criteria in Solid 
Tumors 
iSD 
immune stable disease 
IT 
intratumoral(ly) 
ITT 
intent-to-treat 
iUPD 
immune unconfirmed progressive disease 
IV 
intravenous 
LTSFU 
long-term survival follow-up 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
ODN 
oligodeoxynucleotide 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
pDC 
plasmacytoid dendritic cell 
PD-L1 
programmed death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PTFU 
Posttreatment Follow-Up 
PR 
partial response 
PS20 
polysorbate 20 
PT 
protime 
PTT 
partial thromboplastin time 


VV-TMF-2406459 - 2.0 - Approved 
Protocol CMP-001-007 
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Amendment 2 (Version 3.0) 
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Abbreviation or Specialist Term 
Explanation 
Q3mo 
every 3 months 
Q3W 
every 3 weeks 
Qb 
Qbeta 
QTc 
QT corrected 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SD 
stable disease 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TLR9 
toll-like receptor 9 
ULN 
upper limit of normal 
UPD 
unconfirmed progressive disease 
US 
United States 
USPI 
United States Prescribing Information 
VLP 
virus-like particle 
WBC 
white blood cell 
WNL 
within normal limits 


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1. 
INTRODUCTION 
1.1. 
Background 
This is a Phase 2 study to evaluate the safety and efficacy of intratumoral (IT) CMP-001 in 
combination with intravenous (IV) pembrolizumab in subjects with head and neck squamous 
cell carcinoma (HNSCC) with tumors that have a programmed death-ligand 1 (PD-L1) 
combined positive score (CPS) ≥ 1. 
Head and neck cancer is the seventh leading cancer by incidence worldwide with 
approximately 890,000 new cases and 450,000 deaths each year (Bray et al 2018). Squamous 
cell carcinomas of the head and neck constitute 90% of all head and neck cancers and are the 
ninth leading cancer by incidence worldwide (Jemal et al 2007; Gupta et al 2016). Head and 
neck cancers include cancers of the lip, oral cavity, oropharynx, hypopharynx, nasopharynx, 
larynx, as well as paranasal tumors, ethmoid sinus tumors, maxillary sinus tumors, salivary 
gland tumors, and mucosal melanoma head or neck tumors. In the United States, it is 
estimated that approximately 65,630 new cases of oral cavity, pharyngeal, and laryngeal 
cancers will occur in 2020, which account for approximately 3.6% of new cancers. An 
estimated 14,500 deaths from head and neck cancers will occur in the United States in the 
same time period (Siegel et al 2020). 
Heavy use of alcohol and tobacco are typical etiologic factors in older patients. Human 
papillomavirus (HPV) infection, a well-accepted cause of squamous cancers of the 
oropharynx, has become more common, particularly in younger patients in North America 
and northern Europe (Chow 2020). The incidence of HPV-negative cancer has decreased; 
however, the overall incidence of HPV-positive head and neck cancers has increased in the 
United States, with the proportion of head and neck cancers diagnosed as HPV-positive rising 
from 16.3% in the 1980s to 72.7% in the 2000s (Chaturvedi et al 2008; Chow 2020). While 
oral HPV type 16 infection is the primary cause (Agalliu et al 2016; Gillison et al 2000; 
Gillison et al 2012; Ndiaye et al 2014), HPV types 18, 31, and 33 are responsible for the 
remaining HPV-related head and neck HPV-positive cancer (Snow and Laudadio 2010) and 
these primarily occur in younger patients. Two methods are used to detect HPV, polymerase 
chain reaction and p16 immunohistochemistry (IHC), with International Council for 
Harmonisation (ICH) testing being the more accessible established method (Duncan et al 
2013). 
NCCN guidelines on head and neck cancers (NCCN 2020) focused on head and neck cancers 
recommends participation in clinical trials for all patients with very advanced head and neck 
cancers. All combined chemoradiotherapy regimens are associated with mucosal toxicities. 
For patients with an ECOG Performance Status of 0 or 1, the NCCN guidelines on head and 
neck cancers (NCCN 2020) for newly diagnosed, very advanced disease is concurrent 
systemic/radiation therapy (with high-dose cisplatin and 5 fluorouracil [5-FU]) being a 
Category 1 option. 
Response rates to systemic therapies range from 15% to 35% in patients with metastatic 
disease at initial presentation. In many circumstances, combination regimens result in a 
doubling of response rates compared to single agents but the median survival with systemic 
therapy is short (approximately 6 months) and a low 1-year survival rate of approximately 
20% (NCCN 2020). 
In KEYNOTE-048, pembrolizumab was evaluated as a first-line systemic treatment for 
patients with untreated, locally incurable recurrent or metastatic HNSCC (Burtness et al 
2019). In this study, patients were randomized to receive pembrolizumab 200 mg every 3 


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weeks (Q3W) as a single agent (n = 300, monotherapy), the combination of pembrolizumab 
and chemotherapy consisting of a platinum and 5-FU (n = 276), or the combination of 
cetuximab, platinum, and 5-FU (n = 287, referred to as the EXTREME regimen). There was 
an overall survival (OS) advantage observed in the arm treated with the combination of 
pembrolizumab and chemotherapy with a median OS of 13 months compared to the 
EXTREME regimen with a median OS of 10.7 months (KEYTRUDA United States 
Prescribing Information [USPI]). Importantly, an OS advantage was also observed in patients 
with a PD-L1 CPS of both ≥ 20 and ≥ 1 for patients who received pembrolizumab 
monotherapy with a median OS of 14.9 months compared to those receiving the EXTREME 
regimen, where a median OS of 10.7 months was observed. The ORR for pembrolizumab 
monotherapy was 19% and 23% for the CPS ≥ 1 and CPS ≥ 20 groups, respectively, which 
was lower than the ORR observed with the EXTREME regimen of 35% and 36%, 
respectively. However, pembrolizumab monotherapy led to durable responses with a median 
duration of response (DOR) of 20.9 months for both CPS groups, which was longer than the 
4.5 months and 4.2 months for the CPS ≥ 1 and CPS ≥ 20 groups in the EXTREME group, 
respectively. 
In KEYNOTE-048, pembrolizumab was discontinued for adverse reactions in 12% of 
patients in the pembrolizumab monotherapy arm. The most common adverse reactions 
resulting in permanent discontinuation of pembrolizumab were sepsis (1.7%) and pneumonia 
(1.3%). Adverse reactions leading to the interruption of pembrolizumab occurred in 31% of 
patients. The most common adverse reactions leading to interruption of pembrolizumab 
(≥ 2%) were pneumonia (2.3%), pneumonitis (2.3%), and hyponatremia (2%). Based upon 
these safety and efficacy data, FDA approved pembrolizumab as first-line treatment for 
recurrent, unresectable, or metastatic HNSCC as monotherapy in patients with PD-L1 
positive expressed tumors or when combined with a platinum and 5-FU. Despite this 
important advance, the majority of patients who received pembrolizumab did not achieve a 
response, and significant unmet need remains for new agents and combinations that achieve 
durable responses and prolong survival. 
1.2. 
CMP-001 
CMP-001 is a Toll-like receptor 9 (TLR9) agonist comprised of QbG10, a virus-like particle 
(VLP) that encapsulates G10, a cytosine linked to a guanine by a phosphate bond (CpG) 
oligodeoxynucleotide (ODN). The VLP is composed of a capsid protein derived from 
bacteriophage Qbeta. G10 is an ODN that contains CpG, and contains poly-G tails that allow 
it to form G-quadruplexes. Once administered to a subject, an antidrug antibody response to 
the VLP (anti-Qbeta antibodies) develops. Antibody coated QbG10 is taken up by cells 
through Fc receptors into the endosome. In plasmacytoid dendritic cells (pDCs), 
antibody-coated QbG10 is taken up via FcgRII into endosomes where the G10 is released and 
activates TLR9 (Lemke Miltner et al 2020). 
TLR9 is found in pDCs and B cells, but Type A CpG compounds have little effect on B cells. 
The pDCs primarily reside in blood but can also be found in tumors and lymph nodes. 
Unactivated tumor-infiltrating pDCs contribute to tumor growth and are associated with an 
adverse prognosis in subjects with cancer (Lombardi et al 2015; Demoulin et al 2013). 
Activation and maturation of pDCs through TLR9 agonism induces Type I interferons (IFN), 
which in turn mediate the release of IFN-inducible chemokines such as C-X-C motif 
chemokine 9 (CXCL9) and C-X-C motif chemokine 10 (CXCL10) (Swiecki and Colonna 
2015). Activated pDCs also take up tumor specific antigens for presentation to T cells and 
other immune cells, facilitating the development of an antigen-specific, antitumor T cell 


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response. Together, the Type I IFNs, IFN inducible chemokines, and antigen presentation 
promote the activation and differentiation of CD8+ T cells into cytotoxic T lymphocytes 
(CTL) capable of circulating throughout the body and attacking distant tumor cells. 
Therefore, administration of CMP-001 IT is hypothesized to change the pDC functional 
phenotype from tumor promoting to one that promotes an antigen-specific, antitumor CD8+ T 
cell response. 
1.2.1. 
Previous Clinical Studies With CMP-001 
Safety and efficacy data demonstrating the clinical benefit of CMP-001 IT in combination 
with pembrolizumab IV in subjects with melanoma refractory to PD-1 blockade was obtained 
in an ongoing clinical trial, Study CMP-001-001, which is described in detail in the 
Investigator’s Brochure (IB). In the 61 subjects who initiated treated with pembrolizumab 
according to the KEYTRUDA® (pembrolizumab) USPI in combination with CMP-001 10 
mg IT QW × 7 and Q3W (Schedule A) thereafter with a preparation containing PS20 0.01%, 
the confirmed objective response Rate (ORR) was 23.1% (95% CI 5.0%, 53.8%) (Wong et al. 
2021). A comparable response rate was observed in the 13 subjects treated with 
pembrolizumab in combination with CMP-001 10 mg IT QW × 2 and Q3W thereafter 
(Schedule B; Milhem et al. 2020; Kirkwood et al. 2021). This ORR is substantially higher 
than the 4% to 7% rate of pseudoprogression observed with continued PD-1 blockade after 
disease progression in other studies, and the recommended 6% to 7% for use as the null 
hypothesis for trials in this population (Hodi et al 2016; Ribas et al 2018). The clinical benefit 
of this combination treatment includes durable CRs and PRs in injected and non-injected 
target and non-target lesions of the skin, lymph nodes, and viscera. The current Kaplan-Meier 
estimate for median DOR for the 14/61 responders is 14 months (95% Confidence Interval = 
6 months, not reached), which is described in detail in the IB. 
1.3. 
Study Rationale 
1.3.1. 
Rationale for Combining a TLR9 Agonist With an PD-1 Blocking Antibody 
PD-1 blockade is an effective and important therapy for the treatment of HNSCC, however, 
more than 80% of patients do not respond to monotherapy treatment with an anti-PD-1 
antibody. PD-1 negatively regulates T cell function when it interacts with its ligand PD-L1, 
which is commonly expressed on tumors (Chen and Mellman 2013). A major mechanism of 
resistance to PD-1 blockade is the absence of activated effector T cells in the tumor. 
Therefore, TLR9-mediated T cell activation and trafficking to tumor has the potential to 
improve the response to PD-1 blockade, particularly in non-inflamed tumors. 
In prior clinical trials, TLR9 agonism resulted in strong induction of CTL responses; 
however, very few objective responses were observed, and the T cell responses were not 
sustained, especially within tumors (Appay et al 2006). This may be because TLR9-mediated 
T cell activation induces PD-1 expression on activated T cells (Fourcade et al 2014). TLR9 
agonists are capable of inducing tumor-specific CD8+ T cells in cancer subjects, but the 
expression of PD-1 on these T cells blocks their function. Therefore, PD-1 blockade may 
facilitate and sustain the TLR9-mediated activation of tumor-specific T cells. 
Several nonclinical and clinical reports support the hypothesis that TLR9 agonism may 
enhance the antitumor response to PD-1 blockade. 
The ex vivo addition of an anti-PD-1 antibody to CD8+ T cells from melanoma subjects who 
had been treated with a TLR9 agonist significantly increased the T cell function for cytokine 


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secretion (Fourcade et al 2014), providing a strong rationale for the use of the combination of 
TLR9 agonists and anti-PD-1 antibodies in cancer therapy. 
Several TLR9 agonists have shown antitumor efficacy in mouse tumor models in 
combination with PD-1 blockade. In mice with MB49 bladder cancer, a CpG-B ODN in 
combination with anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) or 
anti-PD-1 increased survival, and PD-1 blockade plus CpG treatment was superior to either 
agent alone. CpG plus anti-CTLA-4 or anti-PD-1 increased the numbers of circulating tumor- 
specific CD107a-expressing, CD8+ T cells as well as activated (CD25+FoxP3-) CD4 
splenocytes. Furthermore, regulatory T cells were decreased in the tumor area of treated 
animals after anti-CTLA-4 or anti-PD-1 plus CpG therapy (Mangsbo et al 2010). 
Additionally, mice treated with a CpG-B TLR9 agonist in combination with PD-1 blockade 
in an ovarian cancer model also had improved survival (Duraiswamy et al 2013). Mechanistic 
studies in the PD-L1 resistant mouse tumor models including CT26 and MCA38 colon 
carcinoma and TSA mammary adenocarcinoma demonstrated that IT injection of a CpG-C 
ODN reversed resistance to PD-1 blockade by inducing the infiltration of activated CD8+ T 
cells expressing IFN-g (Wang et al 2016). Finally, injection of CMP-001 IT in a mouse A20 
lymphoma model reduced the growth of both injected and noninjected tumors and improved 
survival, and these antitumor effects were enhanced by combination with systemic anti-PD-1 
therapy (Lemke Miltner et al 2020). The VLP appeared to contribute to the antitumor 
efficacy of CpG-A therapy, since a reduced antitumor effect was seen if the CpG-A TLR9 
agonist was administered without the VLP. 
Several studies evaluating the addition of TLR9 agonism to immune checkpoint inhibition 
have been conducted, and data with CMP-001 in combination with pembrolizumab in 
subjects with PD-1 refractory melanoma is described above. Presently, only one study has 
been reported in subjects with HNSCC. A Phase 2 study (SYNERGY-001/KEYNOTE-184, 
NCT02521870) with SD-101, a synthetic class-C CpG-ODN TLR9 agonist, administered IT 
in combination with pembrolizumab in subjects with advanced/metastatic HNSCC, 
demonstrated acceptable safety and clinical efficacy (Cohen et al 2019). Responses (PR) and 
disease control were observed in subjects with low PD-L1 status at Baseline (CPS ≥1–20); 2 
subjects with unknown PD-L1 status achieved a best response of CR. ORR was 35% in 
subjects with HPV-positive tumors and 11% in subjects with HPV-negative tumors. The best 
ORR across all subjects and doses was 24.0% (13.1, 38.2), and DOR was immature. 
1.3.2. 
Rationale for Intratumoral Administration of TLR9 Agonists 
CMP-001 is intended to activate pDCs via TLR9 agonism, which causes the pDCs to release 
Type I IFN and take up and present tumor antigens to T cells, culminating in the generation 
of an antigen -specific, antitumor T cell response. Administration of CMP-001 IT is intended 
to activate pDCs, and subsequently T cells, within the tumor and tumor-draining lymph nodes 
where tumor-specific antigen is most likely to exist. Systemic administration of TLR9 
agonists is expected to result in uptake by the liver, spleen, and reticuloendothelial system, 
which may lead to suboptimal activation of pDCs in tumor and tumor-draining lymph nodes. 
IT administration of CMP-001 is expected to activate resting pDCs thereby overcoming their 
tumor-promoting phenotype and ultimately inducing an antitumor CD8+ T cell response in 
the tumor microenvironment. In preclinical models, IT dosing of TLR9 agonists was more 
effective than distant subcutaneous (SC) dosing, and induced regression not only in the 
directly injected tumor lesion, but also distant metastases (Heckelsmiller et al 2002; Shirota et 
al 2012; Lemke Miltner et al 2020). 


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1.3.3. 
Rationale for CMP-001 Dose and Schedule 
In the Phase 1b study CMP-001-001, CMP-001 IT was evaluated at doses of 1 mg to 10 mg 
using 2 dosing schedules and with preparations containing 2 different concentrations of the 
excipient polysorbate 20 (PS20) (0.01% and 0.00167%) in combination with pembrolizumab 
IV and as monotherapy in subjects with PD-1 refractory melanoma. The safety profile was 
similar and manageable across CMP-001 doses of 1 to 10 mg. Clinical activity, including 
durable complete and partial responses, was observed with CMP-001 10 mg (PS20 0.01%) IT 
weekly for 7 doses, followed by administration Q3W in combination with pembrolizumab IV 
(Schedule A) at the FDA-approved dose and schedule until treatment discontinuation. 
Comparable clinical activity was observed with an alternative schedule of CMP-001 
administration in combination with pembrolizumab Q3W (Schedule B; Milhem et al. 2020; 
Kirkwood et al. 2021). The Schedule A dosing schedule and dose were selected for further 
development in refractory melanoma. As subjects with HNSCC often require radiology- 
assisted IT injections, the administration per modified Schedule B is introduced in this proof- 
of-concept study. Further details can be found in the IB. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
The primary objective of the study is to determine Investigator-assessed confirmed objective 
response with CMP-001 in combination with pembrolizumab in subjects with HNSCC. 
2.1.2. 
Secondary Objectives 
The secondary objectives of the study are to: 
• Evaluate the safety and tolerability of CMP-001 administered by IT injection in 
combination with pembrolizumab in subjects with HNSCC 
• Evaluate the efficacy of CMP-001 in combination with pembrolizumab in subjects 
with HNSCC 
• Evaluate the effect of HPV infection and PD-L1 expressions on the efficacy of 
CMP-001 in combination with pembrolizumab 
2.1.3. 
Exploratory Objective 
The exploratory objective of the study is to evaluate the pharmacodynamic and 
pharmacokinetic effects of CMP-001 administered in combination with pembrolizumab. 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoint 
The primary endpoint is ORR, defined as the proportion of subjects with a confirmed 
objective response of complete response (CR) or partial response (PR) based on Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as determined by Investigator 
assessment 
2.2.2. 
Secondary Endpoints 
The secondary endpoints are as follows: 
• Adverse events (AEs), serious adverse events (SAEs), and AEs leading to 
discontinuation or death, and severity of AEs as assessed by the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
version 5.0 
• DOR, defined as the time from date of first documented response (CR or PR) to 
date of documented PD, based on RECIST v1.1 by Investigator assessment 
• Progression-free survival (PFS), defined as the time from date of first dose of 
study drug to date of documented PD based on RECIST v1.1 by Investigator 
assessment or death, whichever occurs first 
• OS, defined as the time from the date of first dose of study drug to the date of 
death 
• Immune objective response rate (iORR), defined as the proportion of subjects with 
a best overall response (BOR) of immune complete response (iCR) or immune 


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partial response (iPR) based on immunotherapy Response Evaluation Criteria in 
Solid Tumors (iRECIST) by Investigator assessment 
• Immune duration of response (iDOR), defined as the time from the date of the 
first immune response (iCR or iPR) to the date of immune confirmed progressive 
disease (iCPD) by Investigator assessment 
• Immune progression-free survival PFS (iPFS), defined as the time from date of 
first dose of study drug to date of iCPD by Investigator assessment or death, 
whichever occurs first 
• ORR, DOR, and PFS based on HPV and PD-L1 expressions (CPS ≥ 1 and CPS ≥ 
20) 
2.2.3. 
Exploratory Endpoints 
The exploratory endpoints of the study are as follows: 
• Response in injected and noninjected target lesions per intratumoral Response 
Evaluation Criteria in Solid Tumors (itRECIST) by Investigator assessment 
(Appendix F) 
• Baseline, and change from Baseline, in tumor or blood measurements of 
biomarkers related to TLR9, immune checkpoints, and potential markers of 
resistance or response to immunotherapy 
• Change from Baseline in blood concentrations of C-X-C motif chemokine 10 
(CXCL10) (IP-10) and other cytokines after treatment with CMP-001 
• Blood concentrations of CMP-001 or its metabolites 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, open-label, Phase 2 clinical trial of CMP-001 IT in combination with 
pembrolizumab IV in subjects with recurrent or metastatic HNSCC. Eligible subjects must 
have histologically- or cytologically-confirmed recurrent or metastatic HNSCC considered 
incurable by local therapies, and subjects with T4 or N3 disease who are ineligible for or 
refusing local therapies. All subjects will receive CMP-001 IT and pembrolizumab IV 
according to the treatment schedule until a reason for treatment discontinuation is reached. 
CMP-001 10 mg will be administered weekly for 2 doses, after which CMP-001 will be 
administered Q3W along with pembrolizumab, beginning from the next pembrolizumab dose 
on W4 until the subject meets a condition for discontinuation of study treatment or up to 2 
years. The first dose of CMP-001 may be administered SC or by IT injection, at the discretion 
of the Investigator; all subsequent doses are planned to be administered IT (Figure 1). 
If all injectable tumors regress, CMP-001 may be injected SC in the region of prior tumors or 
draining lymph node bed, at the Investigator’s discretion (see Appendix G). On visits where 
both study drugs are administered, CMP-001 IT should be administered before 
pembrolizumab. CMP-001 should be administered until a reason for treatment 
discontinuation is reached. See Section 5.1.2.5 for treatment modifications for CMP-001. 
Pembrolizumab 200 mg IV will be administered following CMP-001 10 mg IT injection at 
W1D1 and Q3W thereafter according to the KEYTRUDA® USPI. Pembrolizumab treatment 
during this study will continue until the subject meets a condition for discontinuation of study 
treatment. 
Objective responses will be assessed by the Investigator according to RECIST v1.1 and 
iRECIST. Disease status will be assessed by computed tomography (CT) or magnetic 
resonance imaging (MRI) and other appropriate measures beginning pre-dose at Week 10 
Day 1 (W10D1) and will be repeated every 9 weeks (e.g., Week 19 Day 1). Responses (CR, 
PR, iCR or iPR) will be confirmed by a follow-up disease assessment performed at least 4 
weeks after the initial response date, and at least 2 weeks after the last CMP-001 injection. 
Disease assessments will continue every 9 weeks while the subject is on treatment. 
Progressive disease (PD) will be assessed by the Investigator according to RECIST v1.1 
criteria. Subjects who continue study treatment beyond PD according to RECIST v1.1 will be 
assessed by the Investigator according to iRECIST. 
All scans should be performed at least 2 weeks after the previous CMP-001 IT injection to 
prevent injection-related pseudoprogression. Imaging should not be delayed for delays in 
treatment. 
Subjects who discontinue study treatment should complete the end of treatment (EOT) visit 
and 30-day safety follow-up. Subjects who are posttreatment but have not met criteria for 
study discontinuation should remain on study for posttreatment follow-up (PTFU) and long- 
term survival follow-up (LTSFU) and receive study evaluations for efficacy according to the 
Schedule of Assessments (Table 1). 
There is no planned study extension beyond the 2 years of treatment. 


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Figure 1: 
CMP-001-007 Study Schema 
 
Abbreviations: 30DFU = 30-Day Follow-up; EOT = End of Treatment; LTSFU = Long-term Survival Follow- 
Up; IT = intratumoral; IV = intravenous; PTFU = Posttreatment Follow-up; Q3W = every 3 weeks; Q12W = 
every 12 weeks; QW = every week; SC = subcutaneous. 
NOTE: The first dose of CMP-001 may be administered by SC or IT injection, per Investigator discretion. All 
subsequent doses of CMP-001 are planned to be administered IT. 


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4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects will be eligible for this study if they meet all of the specified inclusion and none of 
the exclusion criteria. 
4.1. 
Subject Inclusion Criteria 
Subjects enrolled into this study must meet the following inclusion criteria to be eligible. 
1. Subjects with histologically- or cytologically-confirmed recurrent or metastatic 
HNSCC considered incurable by local therapies, and subjects with T4 or N3 disease 
who are ineligible for or refusing local therapies. 
2. No prior systemic therapy in the recurrent or metastatic setting. Systemic therapy as 
part of multi-modal treatment for locally advanced disease is allowed. 
3. Primary tumor locations of oropharynx, oral cavity, hypopharynx, larynx, paranasal 
sinus, or HNSCC of unknown primary origin. Participants may not have a primary 
tumor site of nasopharynx (any histology). 
4. Able to provide tissue from a core or excisional biopsy (fine needle aspirate is not 
sufficient). A newly obtained biopsy (within 90 days before the start of study 
treatment) is preferred but an archival sample is acceptable. 
5. CPS ≥1 for PD-L1 on immunohistochemistry (IHC) of tumor tissue. 
6. Have results of tumor HPV p16 by IHC for oropharyngeal or for unknown primary 
cancer. 
7. Measurable disease as defined by RECIST v1.1, and both of the following: 
a. At least 1 lesion amenable to repeated IT injection. 
b. Documented disease progression in any lesion that was previously radiated in 
order to serve as a target lesion. 
8. Adequate organ function based on most recent laboratory values within 3 weeks 
before the first dose of study drug on Week 1 Day 1 (W1D1): 
a. Bone marrow function: 
- 
neutrophil count ≥ 1,500/mm3 
- 
platelet count ≥ 100,000/mm3 
- 
hemoglobin concentration ≥ 9 g/dL 
b. Liver function: 
- 
total bilirubin ≤ 1.5 times the upper limit of normal (ULN) with the following 
exception: subjects with Gilbert Disease serum bilirubin ≤ 3 times ULN 
- 
aspartate aminotransferase and alanine aminotransferase ≤ 3 times the ULN or 
≤ 5 times the ULN for subjects with active liver metastases 
c. Renal function: estimated (Cockroft-Gault) or measured CrCl ≥30 mL/min 
d. Coagulation 
- 
International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 times 
ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of anticoagulants 
- 
Activated Partial Thromboplastin Time (aPTT) or partial thromboplastin time 
(PTT) ≤ 1.5 times ULN unless subject is receiving anticoagulant therapy as 
long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 


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9. Age ≥ 18 years at time of consent. 
10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 at 
Screening. 
11. Capable of understanding and complying with protocol requirements. 
12. Women of childbearing potential must have negative serum pregnancy test during 
Screening and be willing to use an adequate method of contraception (Section 4.3.2) 
from the time of consent until at least 120 days after the last dose of study drug. 
13. Able and willing to provide written informed consent and to follow study instructions. 
Subjects unable to provide written informed consent on their own behalf will not be 
eligible for the study. 
4.2. 
Subject Exclusion Criteria 
Subjects presenting with any of the following will not qualify for entry into the study: 
1. Disease suitable for local therapy administered with curative intent. 
2. Has PD within 3 months of completion of curatively intent systemic treatment for 
locoregionally advanced HNSCC. 
3. Radiation therapy (or other non-systemic therapy) within 2 weeks before the first dose 
of study drug on W1D1. 
4. Received prior therapy with PD-1 or PD-L1 blocking antibody therapy in the 
recurrent/metastatic setting. If PD-1 or PD-L1 blocking antibody therapy was given as 
part of curative intent therapy, it must be at least 1 year since receipt of PD-1 or PD- 
L1 blocking antibody. 
5. Not fully recovered from adverse events (to Grade 1 or less [per CTCAE v 5.0]) with 
the exception of persistent alopecia, neuropathy, ototoxicity, hypothyroidism, pain, 
xerostomia, or dysphagia, due to prior treatment. 
6. Received systemic pharmacologic doses of corticosteroids ≥ 10 mg/day prednisone 
within 30 days before the first dose of study drug on W1D1. 
a. Subjects who are currently receiving steroids at a prednisone-equivalent dose of 
≤ 10 mg/day do not need to discontinue steroids prior to enrollment. 
b. Replacement doses, topical, ophthalmologic, and inhalational steroids are 
permitted. 
c. Stress-dose corticosteroids will be required in subjects with adrenal insufficiency 
(see Section 5.1.2.1.1). 
7. Active pneumonitis or history of noninfectious pneumonitis that required steroids. 
8. Severe uncontrolled cardiac disease within 6 months of Screening, including but not 
limited to poorly controlled hypertension, unstable angina, myocardial infarction, 
congestive heart failure (New York Heart Association Class II or greater), pericarditis 
within the previous 6 months, cerebrovascular accident, implanted or continuous use 
of a pacemaker or defibrillator. 
9. Known history of immunodeficiency. 
10. Known additional malignancy that is progressing or required active treatment within 
the past 3 years. Exceptions include cancers that have undergone potentially curative 
therapy, e.g., basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 


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localized prostate cancer with prostate-specific antigen level below 4.0 ng/mL, in situ 
cervical cancer on biopsy or a squamous intraepithelial lesion on Papanicolaou smear, 
thyroid cancer (except anaplastic), in situ breast cancer, and adjuvant hormonal 
therapy for breast cancer > 3 years from curative-intent surgical resection. 
11. Active autoimmune disease that has required systemic treatment in past 2 years; 
replacement therapy is not considered a form of systemic treatment. 
12. Untreated, symptomatic, or enlarging central nervous system (CNS) metastases or 
carcinomatous meningitis. 
13. Prior allogenic tissue/solid organ transplant. 
14. Active infection requiring systemic therapy. 
15. Known or suspected active infection with SARS-CoV-2 virus. 
16. Known or suspected active infection with human immunodeficiency virus, hepatitis B 
virus, or hepatitis C virus (testing is not required unless suspected). 
17. Received a live virus/attenuated vaccination within 30 days before the start of study 
drug on W1D1. 
18. Received blood products (including platelets or red blood cells) or colony stimulating 
factors (including GCSF, GMCSF, or recombinant erythropoietin) within 14 days 
before the start of W1D1. 
19. Any concurrent uncontrolled illness, including mental illness or substance abuse, 
which in the opinion of the Investigator, would make the subject unable to cooperate 
or participate in the trial. 
20. Participation in another clinical trial of an investigational anticancer therapy or device 
within 30 days before the first dose of study drug on W1D1 
NOTE: Participation in the follow-up phase (receiving no study treatment) of a prior 
study is allowed. 
21. Requires prohibited treatment (i.e., non-protocol specified anticancer 
pharmacotherapy, surgery, or conventional radiotherapy) for treatment of malignant 
tumor. 
22. Has a life expectancy of less than 3 months and/or has rapidly progressing disease 
(e.g., tumor bleeding, uncontrolled tumor pain) in the opinion of the treating 
Investigator. 
23. Received previous CMP-001 treatment. 
24. Pregnant or breast-feeding or expecting to conceive or father children within the 
projected duration of the study, from the time of consent until at least 120 days after 
the last dose of study drug. 
4.3. 
Women of Childbearing Potential 
A woman of childbearing potential (WOCBP) is considered fertile following menarche and 
until becoming post-menopausal unless permanently sterile (Section 4.3.1). If fertility is 
unclear and a menstrual cycle cannot be confirmed before the first study drug dose (W1D1), 
subject should be considered of childbearing potential and applicable pregnancy tests 
completed. 


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A WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L 
or equivalent units of human chorionic gonadotropin) within 24 hours before the start of 
study treatment. An extension up to 72 hours before the start of study treatment is permissible 
in situations where results cannot be obtained within the standard 24-hour window. 
4.3.1. 
Women of Non-Childbearing Potential 
Female subjects must meet 1 of the following criteria to be considered of non-childbearing 
potential: 
• Have undergone hysterectomy or bilateral salpingectomy/oophorectomy or 
bilateral tubal occlusion/ligation at least 1 month before Informed Consent. 
• Are medically confirmed to be post-menopausal (cessation of regular menses for 
at least 12 consecutive months before W1D1 with no alternative pathological or 
physiological cause). 
Females with less than 12 months of amenorrhea must have a serum follicle 
stimulating hormone (FSH) level > 40 mIU/mL on 2 measurements performed 
2 months apart 
If fertility is unclear and a menstrual cycle cannot be confirmed before the first dose of study 
treatment (W1D1), subject should be considered of childbearing potential and applicable 
pregnancy tests completed. 
4.3.2. 
Acceptable Methods of Contraception 
Heterosexually active female subjects of childbearing potential must agree to use at least 2 
forms of highly effective methods of contraception, including at least 1 barrier method for the 
duration of the study and at least 120 days after the last dose of study drug. Women should 
not donate eggs during this posttreatment period. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of < 1% per year when used consistently and correctly (i.e., perfect use) and 
include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
o Oral 
o Intravaginal 
o Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral 
o Injectable 
o Implantable 
• Intrauterine Device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence 


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4.4. 
Prohibited Treatments 
Medications intended solely for supportive care are allowed (i.e., antiemetics, analgesics, 
megestrol acetate for anorexia). 
The following concomitant medications are prohibited: 
• Concurrent anticancer therapy with agents other than the combination study drug 
therapy (CMP-001 + pembrolizumab) is not allowed at any time during the study. 
• Agents known to have TLR9 antagonist activity are prohibited throughout the 
study. The current known antagonists are chloroquine, hydroxychloroquine, and 
quinacrine. 
• Systemic pharmacologic doses of corticosteroids > 10 mg/day of prednisone 
equivalent are not permitted at the time of study enrollment. However, 
corticosteroid administration is allowed in the following circumstances: 
− In the treatment of subjects with known adrenal insufficiency (see 
Section 5.1.2.1.1. Consultation with the Medical Monitor is required before 
enrollment of subjects with adrenal insufficiency 
− For the management of immune-mediated toxicities 
− For palliation of pain, brain metastases, or other disorders (consultation with 
the Medical Monitor is required) 
• Complementary medications to treat the disease under study (e.g., herbal 
supplements or traditional Chinese medicines). 
4.4.1. 
Vaccinations 
Given the potential for injection site reactions and flu-like symptoms, vaccination with a viral 
vector or mRNA vaccine should not be performed within 1 week of CMP-001 injection. 
4.4.2. 
Concomitant Procedures 
Palliative radiotherapy or palliative surgery may be allowed after Medical Monitor 
consultation to ascertain whether clinical progression has occurred. If the lesion(s) targeted 
for palliation are target lesions, then the anatomic site requiring palliation must be assessed 
for disease status. 
4.5. 
Treatment Discontinuation 
Study treatment should continue until 1 of the following occurs: 
• Unacceptable adverse event that precludes further study treatment (see 
Section 5.1.2.5.4 and Section 5.1.3) 
• 2 years of study treatment 
• PD per RECIST v1.1; continuation of treatment through suspected 
pseudo-progression is permitted at the Investigator’s discretion until 
confirmed PD per iRECIST (Section 7.2.5) 
• Upon request of the Sponsor or regulatory agency 
• Clinical disease progression 


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• If medically necessary in the opinion of the Investigator 
• Subject withdraws consent for treatment (note that a subject who withdraws 
consent for additional study treatment and procedures but not for antitumor 
response will continue to be followed) 
• Subject becomes pregnant or begins breastfeeding 
• Subject is lost to follow-up 
• Death 
• End of Clinical Trial 
Subjects who permanently discontinue treatment with pembrolizumab because of immune- 
mediated AEs must also permanently discontinue treatment with CMP-001. 
Subjects will continue study treatment until they reach a reason for treatment or study 
discontinuation. Clinically stable subjects may continue study treatment beyond RECIST 
v1.1 progression based upon Investigator judgement of potential benefit. Study treatment 
may not continue beyond 2 years from initial dose of study treatment. 
If a subject achieves and maintains a confirmed CR or iCR by Investigator review, treatment 
with CMP-001 or the combination of CMP-001 and pembrolizumab may be discontinued at 
the Investigator’s discretion once they meet both of the following criteria: 
• Subject has been treated with both study drugs for at least 24 weeks 
• Subject has received at least 3 doses of both study drugs beyond the date of the 
initial CR/iCR 
NOTE: 3 doses are required only if medically feasible in the Investigator’s 
opinion – less than 3 doses are acceptable if the Investigator is not medically able 
to inject. 
Subjects who discontinue study treatment should undergo the EOT assessments per Table 1. 
Subjects who discontinue study treatment for reasons other than disease progression (per 
RECIST v1.1 or iRECIST by Investigator, or clinical PD per Investigator) should remain on 
study for PTFU (Section 7.6) and LTSFU (Section 7.7) and receive disease assessments 
according to the Schedule of Assessments (Table 1). 
4.6. 
Study Withdrawal 
Subjects may withdraw from the study at any time and without penalty or loss of future 
medical care, or any other benefits to which they are otherwise entitled. Subjects will be 
withdrawn from the study for any of the following reasons: 
• Subject withdraws consent for the study 
• Subject lost to follow-up 
• Death 
• End of clinical trial 
For subjects who withdraw consent from overall study participation (not only study 
treatment) will not have the EOT visit, safety follow-up visits, or further evaluations 
performed. 


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4.7. 
End of Clinical Trial 
The End of Clinical Trial (EOT) is defined as the last visit for the last subject on the trial. All 
data collection will cease in all subjects when End of Clinical Trial is reached. 


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5. 
TREATMENT OF SUBJECTS 
5.1. 
Administration of Study Drug 
5.1.1. 
Pembrolizumab 
Subjects will receive CMP-001 10 mg IT injection followed by pembrolizumab 200 mg IV at 
W1D1 and every 3 weeks thereafter according to the KEYTRUDA® USPI. Pembrolizumab 
should be administered until the subject satisfies a condition for study treatment 
discontinuation (Section 4.5). On visits where both study drugs are administered, CMP-001 
should be administered first followed by administration of pembrolizumab. There is no 
specified waiting period between the end of CMP-001 injection and the initiation of 
pembrolizumab infusion. 
5.1.2. 
CMP-001 
Subjects will receive CMP-001 10 mg weekly for 2 doses (W1D1 and W2D1), after which 
CMP-001 will be administered by IT injection Q3W (beginning on W4D1, then on W7D1, 
etc.). The first dose of CMP-001 may be administered SC or by IT injection, at the discretion 
of the Investigator; all subsequent doses are planned to be administered IT. On visits where 
both study drugs are administered, CMP-001 should be administered before pembrolizumab. 
There is no specified waiting period between the end of CMP-001 injection and the initiation 
of pembrolizumab infusion. CMP-001 should be administered until a reason for treatment 
discontinuation is reached (Section 4.5). See Section 5.1.2.5 for dose modifications for CMP- 
001. 
5.1.2.1. 
Required Prophylaxis Before and After CMP-001 Injection 
To reduce the incidence and severity of symptoms associated with CMP-001 injection, 
prophylaxis is required. All recommended prophylaxis should be administered before 
initiation of the CMP-001 injection. The medications are recommended for oral 
administration, but IV is acceptable at the discretion of the Investigator. There is no waiting 
period between the end of prophylaxis and the start of the CMP-001 injection. 
The optimal recommended regimen that has been effective for the treatment of 
CMP-001-associated AEs, should include all the following components: 
• Intravenous fluids (e.g., approximately 1000 cc IV normal saline). The rate, 
volume, and substation fluids are at the Investigator’s discretion 
• Antipyretics (e.g., acetaminophen 1000 mg and a non-steroidal anti-inflammatory 
agent such as indomethacin 50 mg or ibuprofen 600 to 800 mg) 
• Antiemetics (e.g., ondansetron 8 mg) 
• Antihistamine (e.g., diphenhydramine 50 mg, with or without an H2-antagonist) 
• Recommended hydrocortisone 25 mg at the Investigator’s discretion. Subjects 
with adrenal insufficiency should be treated with stress dose steroids as described 
in Section 5.1.2.1.1. 
It is also highly recommended to continue to administer IV fluids during the observation 
period immediately following the CMP-001 injection, rather than waiting to initiate fluids if 
hypotension is detected. Antipyretics, antiemetics, and antihistamines may be repeated at the 
Investigator’s discretion. 


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Each medication given prophylactically before and after CMP-001 dosing must be recorded 
separately and for each visit. 
5.1.2.1.1. Prophylaxis for Subjects with a History of Adrenal Insufficiency 
Subjects with a history of adrenal insufficiency are at increased risk for moderate to severe 
AEs such as hypotension, which may occur within 1 to 4 hours after CMP-001 injection but 
may also occur outside this window. Subjects with known adrenal insufficiency may be 
allowed in the study. 
At Screening, subjects previously treated with a CTLA-4 blocking antibody, subjects with 
clinical symptoms and/or laboratory findings suggesting risk for adrenal insufficiency, or 
subjects receiving corticosteroids with daily doses > 5 mg and ≤ 10 mg of prednisone 
equivalent for > 2 weeks should undergo diagnostic tests for adrenocorticotropic hormone 
(ACTH) and morning cortisol, and/or high-dose ACTH stimulation test (preferred testing 
method), if clinically indicated, via local laboratory, unless the diagnosis of adrenal 
insufficiency had been previously established. 
All subjects with adrenal insufficiency must receive prophylactic stress-dose steroids (e.g., 50 
to 100 mg hydrocortisone or equivalent orally every 8 hours) before and for 24 to 48 hours 
after each CMP-001 injection. 
5.1.2.2. 
Observation Following CMP-001 Dosing 
Subjects must be observed for at least 4 hours following each of the first 4 CMP-001 
injections (W1D1 to W7D1). Beginning with the fifth CMP-001 injection (W10D1), the 
observation period may be reduced to a minimum of 1 hour following CMP-001 injection at 
the Investigator’s discretion based on the AE profile of the individual subject. 
5.1.2.3. 
CMP-001 Injections 
5.1.2.3.1. Tumor Selection 
Cutaneous, SC, and/or nodal tumors that are visible, palpable, or detectable by ultrasound 
guidance are acceptable for IT injection. Refer to Appendix G for CMP-001 injection 
guidelines. 
Vigilance should be used when selecting lesions for injection that are in close proximity to 
critical structures (e.g., major airways). 
Special attention and judgement should be exercised before injection of a lesion in the 
following areas: the “mask areas” of the face (central face, eyelids, eyebrows, periorbital 
nose, lips [cutaneous and vermilion], chin, mandible, preauricular and postauricular 
skin/sulci, temple, ear, genitalia, hands, and feet). 
Tumors should be at least 0.5 cm in longest diameter and need not be the largest lesion. A 
visceral tumor may be injected with or without the use of interventional radiology if, in the 
opinion of the Investigator and after discussion with the Medical Monitor, it is the most 
appropriate site for IT injection. A preferred tumor for IT injection is an accessible lesion that 
is most rapidly progressing in the judgment of the Investigator. 
When more than 1 tumor is amenable to IT injection, the Investigator may inject up to 
3 tumors per CMP-001 treatment visit. The total dose of CMP-001 may be divided across the 
tumors at the Investigator’s discretion, and the volume injected into each tumor must be 
recorded. The same tumor(s) should be injected each week during therapy, if possible. If an 


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injected tumor is clearly decreasing in size and another accessible non-injected tumor is not, 
then the Investigator may divide the CMP-001 dose between the 2 tumors or switch from 
injecting the regressing tumor to injecting the non-responding (or growing) tumor. 
Subjects with metastatic disease who have regression of all injectable lesions, or who have an 
injection site reaction that precludes injection of the tumor, should receive CMP-001 SC near 
an original tumor (peritumoral) or in the area of the draining lymph nodes (see Appendix G). 
5.1.2.3.2. Method of CMP-001 Administration 
Topical or local anesthesia may be used at the Investigator’s discretion. 
See the Pharmacy Manual for guidance on selection of syringe and needles for CMP-001 IT 
and CMP-001 SC injection. For methods of CMP-001 administration see Appendix G. 
5.1.2.4. 
Dose Modifications for CMP-001 
The CMP-001 dose should remain unchanged during the study. 
If a planned dose cannot be given on schedule due to a CMP-001 related toxicity, the 
injection should be delayed until the toxicity has improved or resolved. If a subject has CMP- 
001 dosing withheld for more than 3 consecutive doses for any reason during the Q3W 
dosing period, resumption of treatment must be discussed with the Medical Monitor; 
otherwise, the subject will be discontinued from study treatment and will have all EOT 
assessments performed. 
If a planned pembrolizumab dose is delayed, the CMP-001 dosing may be delayed. 
5.1.2.5. 
Management of Adverse Events Associated with CMP-001 
Based on observations in earlier studies, CMP-001 has been associated with AEs such as 
injection site reactions (see Section 5.1.2.5.1) and flu-like symptoms. Flu-like symptoms 
could include fever, nausea, vomiting, chills, rigors, and/or hypotension. Additional 
symptoms may occur, such as headache, tachycardia, rash, and hypoxia. Symptoms should be 
expected within 1 to 4 hours following the injection but may also occur outside this window. 
Sites are to capture oxygen saturation every time an AE of hypoxia or cytokine release 
syndrome is reported for a subject. 
Required prophylaxis is designed to prevent or minimize the severity of these symptoms (see 
Section 5.1.2.1). 
For additional safety information see the CMP-001 IB. 
The following algorithm (Figure 2) is provided as guidance for prophylaxis and treatment of 
AEs associated with CMP-001. 


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Figure 2: 
Prophylaxis and Treatment for Adverse Events Associated with CMP-001 
 
Abbreviations: IV = intravenous(ly); NSAID = non-steroidal anti-inflammatory drug; po = orally; Q4-6H = 
every 4 to 6 hours. 
 
5.1.2.5.1. Allergic Reactions 
Allergic reactions of an immediate type, including anaphylaxis, have been observed after 
CMP-001 administration. Please refer to the CMP-001 IB for a detailed description of a 
single case of anaphylaxis Grade 4. 
Investigators must be vigilant in identifying and managing these disorders according to 
institutional guidelines. Precautionary measures consisting of pre-treatment prophylaxis and 
post-injection observation are in place to mitigate the risk of known adverse events associated 
with CMP-001, and these measures may prevent or lessen the potential for allergic reactions. 
Each site should have appropriate emergency equipment, medication, and skills necessary to 
diagnose and treat anaphylaxis and allergic reactions. CMP-001 should not be readministered 
to a subject who developed a suspected clinically significant allergic reaction without 
discussion with the Sponsor. The diagnosis and management of anaphylaxis should follow 
institutional guidelines. 
5.1.2.5.2. Injection Site Reactions 
Injection site inflammation is expected following the second and subsequent injections. If a 
subject develops inflammation at the injection site, this may be managed using cold 
compresses and medications for pain and inflammation, such as acetaminophen or non- 
steroidal anti-inflammatory agents. If, in the Investigator’s opinion, a tumor cannot be 
injected due to injection site reaction or pain, refer to Section 5.1.2.3.1 on changing the site of 
injection. 
5.1.2.5.3. Hypotension 
If hypotension is unresponsive to IV fluids, stress dose steroids should be administered 
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5.1.2.5.4. Grade 3 or Higher Adverse Events Related to CMP-001 
For subjects who, despite optimal prophylaxis, experienced a Grade 3 or higher AE deemed 
related to CMP-001, prophylaxis with prednisone 25 mg or equivalent (at the Investigator’s 
discretion) is required for subsequent CMP-001 doses. If treatment-related Grade 3 or higher 
hypotension, hypoxia, or cytokine release syndrome, or any treatment-related Grade 4 AE 
occurs despite premedication with 25 mg prednisone or equivalent, CMP-001 should be 
discontinued. 
5.1.3. 
Adverse Events Associated with Pembrolizumab and Dose Modifications for 
Pembrolizumab 
Pembrolizumab has been associated with a variety of AEs. The current KEYTRUDA® USPI 
should be consulted for treatment guidance on dose modifications. No dose reductions of 
pembrolizumab are recommended and specific treatment guidance is provided on 
withholding or discontinuing pembrolizumab to manage AEs. When pembrolizumab is 
permanently discontinued for an AE, CMP-001 must also be permanently discontinued. 
5.1.4. 
Method of Assigning Subjects 
Each enrolled subject will be assigned a unique Subject ID number using an Interactive Web 
Response System (IWRS). This number will be recorded on the subject’s eCRF pages and 
used to identify the subject throughout the study. Once a subject number is assigned, it cannot 
be reassigned to any other subject. Subjects who discontinue the study before receiving the 
first dose of CMP-001 may be replaced to ensure at least 43 enrolled subjects. 
5.2. 
Blinding and Unblinding Process 
This is an open-label study. Investigator review will be used for assessment of the primary 
efficacy endpoint. 
5.3. 
Prior and Concomitant Medications 
IMPORTANT: Please refer to Section 5.1.2.1.1 for required prophylaxis before CMP-001 
injection. Prophylaxis administered before and after CMP-001 dosing will be collected in the 
EDC for each visit. 
Please refer to Section 4.4 for prohibited treatments. 
Concomitant medications will be assessed continually from 30 days before the first dose of 
study drug (W1D1) through 30 days after the last dose of study drug. Treatment medications 
for study related AEs that occur through 30 days after the last dose of study drug will be 
collected. Subjects who discontinue CMP-001 but remain on treatment with pembrolizumab 
will continue to have concomitant medications/treatment medications collected according the 
Schedule of Assessments (Table 1). 
In addition, at each LTSFU contact, an inquiry will be made regarding the start of any new 
cancer treatments since the date of the last contact. Prior cancer treatments will be 
documented on a separate eCRF. 
5.4. 
Treatment Compliance 
CMP-001 injections must be performed by qualified, trained, site personnel. Any deviations 
in planned dosing, including fully missed study visits, will be documented in the source 


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documents, verified by the Clinical Research Associate (CRA), and recorded as a protocol 
deviation as appropriate. 
Pembrolizumab will be administered by trained site personnel at the clinic site according to 
the dosing instructions provided in the KEYTRUDA® USPI. 


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6. 
STUDY TREATMENT MATERIALS AND MANAGEMENT 
6.1. 
Study Treatment 
Pembrolizumab is an FDA approved drug product for the treatment of patients with 
metastatic or unresectable, recurrent HNSCC whose tumors express PD-L1 [CPS ≥1] as 
determined by an FDA-approved test, and as a single agent for the treatment of patients with 
recurrent or metastatic HNSCC with disease progression on or after platinum-containing 
chemotherapy; therefore, subjects will be treated with commercial product of KEYTRUDA®. 
The physical characteristics of pembrolizumab are found in the KEYTRUDA® USPI. 
CMP-001 is an investigational study drug. CMP-001 will be provided by the Sponsor as a 
5 mg/mL solution in a single-use vial. Each single use vial will contain either 1 mL 
extractable volume, for a 5-mg dose of CMP-001, or 2 mL extractable volume, for a 10-mg 
dose of CMP-001. The physical characteristics and other details about the CMP-001 drug 
product are found in the current IB and the Pharmacy Manual. 
At the end of the treatment period, study treatment will no longer be provided to 
subjects/investigators unless the Sponsor chooses to extend the study. The Investigator should 
ensure that the subject receives appropriate standard of care to treat the condition under 
study. 
6.2. 
Study Treatment Packaging and Labeling 
Details of the study drug labeling and packaging are provided in the CMP-001 Pharmacy 
Manual. The CMP-001 carton and CMP-001 study drug vials will be labeled with the 
following information: 
• The protocol number 
• The kit number 
• Number of vials per kit (CMP-001 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 to keep away from children 
• Cautionary statement indicating that the drug is for investigational use only 
• The name and address of the Sponsor 
6.3. 
Study Treatment Handling, Storage, Accountability 
All CMP-001 drug product vials will be transported, received, stored, and handled in 
accordance with the drug product carton and vial labels, the Pharmacy Manual, the 
instructions, and training provided to the site and relevant personnel, the site’s standard 
operating procedures (SOPs), and applicable regulations. Appropriate storage and 
transportation conditions will be maintained for the CMP-001 drug product vials from the 
point of manufacture up to delivery of CMP-001. All shipments of CMP-001 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. 


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Upon receipt by the site, the designated site personnel will examine the shipment and 
temperature monitoring devices to verify the CMP-001 drug product vials were received in 
acceptable condition. Vials received in acceptable condition should be stored at the specified 
temperature (2°C to 8°C) in a locked area accessible only to designated site personnel until 
dispensed. Dispensed CMP-001 drug product vials will be stored in a limited access area 
under appropriate environmental conditions as defined in the Pharmacy Manual. Vials not 
received in acceptable condition should be immediately quarantined at the appropriate 
temperature (2°C to 8°C), and the site personnel must immediately notify the CRA. Such 
study drug material may not be used until the Sponsor, or its representative (e.g., CRA) has 
conveyed a determination about these specific CMP-001 drug product vials. 
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, or 
otherwise unaccounted for must also be accounted for and documented. 
All original CMP-001 drug product vials, whether empty or containing CMP-001 drug 
product, will be kept at the site. CMP-001 vials are single-use only; therefore, contents of 
partially used CMP-001 drug product vials may not be dispensed again, even to the same 
subject, nor relabeled or reassigned for use by other subjects. Unused CMP-001 drug product 
vials will be available for verification by the study monitor. Used vials will be destroyed 
onsite according to institutional SOPs after agreement with the Sponsor or its representatives. 
At each site closeout visit, a final drug accountability review and reconciliation must be 
completed, and any discrepancies must be investigated by site and Sponsor representatives, 
and their resolution documented. All remaining CMP-001 drug product vials will be 
destroyed onsite according to institutional SOPs, after discussion with the Sponsor or its 
representatives following the completion of site close out. 
Refer to the pembrolizumab USPI for information on handling and storage (KEYTRUDA® 
USPI). 
6.4. 
Study Drug Dispensing 
CMP-001 will be dispensed, prepared, and administered according to applicable study- 
specific Pharmacy Manual and site SOPs. Details regarding the preparation, dilution, and 
administration of the CMP-001 is outlined in the Pharmacy Manual. Only eligible subjects 
participating in the study may receive CMP-001. Only authorized and qualified site staff may 
dispense, prepare, or administer CMP-001. 
Pembrolizumab will be dispensed, prepared, and administered according to the 
KEYTRUDA® USPI and site SOPs. 


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7. 
STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Procedures and Assessments 
Assessments to be performed at Screening and throughout the study are specified in the 
Schedule of Assessments Table 1. 
7.1.1. 
Informed Consent 
Subjects must sign a written informed consent form (ICF) before the initiation of any study 
procedures and thereafter if there are any ICF changes. Subjects will be given a signed copy 
of the ICF to take home. Subjects unable to provide written informed consent on their own 
behalf will not be eligible for the study. 
7.1.2. 
Eligibility Criteria 
Subjects must meet all inclusion and exclusion criteria to be eligible for the study. Refer to 
Section 4. 
7.1.3. 
Demographics 
Demographic data will be collected during Screening. Demographic data will include date of 
birth, sex, ethnicity, and race (i.e., white, black, or African American, Asian, American 
Indian/Alaskan Native, Native Hawaiian/other Pacific Islander, or other). 
7.1.4. 
Head and Neck Cancer History 
Eligible subjects must have been diagnosed with a histologically- or cytologically-confirmed 
diagnosis of recurrent or metastatic HNSCC with primary tumor locations of oropharynx, 
oral cavity, hypopharynx, larynx, or paranasal sinus. Participants may not have a primary 
tumor site of nasopharynx (any histology). American Joint Committee on Cancer (AJCC) 
staging at the time of study entry is required. 
7.1.5. 
Prior Cancer Treatments 
Details regarding all prior cancer treatments, including drug generic name, dose (if available), 
route of administration, start date, end date, best response, and last response to prior therapy, 
will be documented on a separate page in the EDC. Combination treatments should be 
considered as a single regimen and recorded as such in the EDC. Data on prior surgical 
procedures related to HNSCC will be captured on the same eCRF. 
7.1.6. 
Medical History 
At Screening, a general medical history will be obtained, including chronic conditions and 
co-morbidities, relevant acute conditions, or infections; surgical procedures unrelated to 
HNSCC, and any reported conditions affecting major body systems during the 10 years 
before Screening. 
7.1.7. 
Alcohol and Tobacco Use History 
At Screening, a history and current use of alcohol and tobacco or nicotine products (e.g., 
cigarettes, vaping, chewing tobacco, etc.) will be obtained. Subjects should be asked for 
details about the type, quantity, and frequency of alcohol and tobacco or nicotine use. 


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7.1.8. 
Concomitant Medications 
All medications (Section 5.3) administered to the subject from 30 days before the first dose of 
study drug (W1D1) until 30 days after discontinuation of both CMP-001 and pembrolizumab 
will be recorded in EDC. Documentation for each medication will include the generic name 
of the medication, total daily dose, route of administration, dates of administration, and 
indication for use. Combination drugs must be listed separately by each component product 
and dose. Prior cancer treatment will be recorded separately. 
7.1.9. 
Physical Examination 
Physical examinations, including height and weight, will be conducted as specified in the 
Schedule of Assessments (Table 1). A full physical examination will be conducted at 
Screening and EOT. If the Screening full physical examination is performed > 72 hours 
before the W1D1 visit, then a brief (symptom directed) physical examination must be 
performed within 72 hours before the first injection of CMP-001. Brief physical examinations 
focused on areas of disease or AEs may be performed at any clinically indicated time but 
must be obtained before each CMP-001 injection visit. Height will be obtained at Screening 
only and weight at all physical examination assessments. 
7.1.10. 
Vital Signs 
Vital signs will be conducted as specified in the Schedule of Assessments (Table 1). Vital 
signs include measurement of blood pressure (systolic and diastolic blood pressure), 
respiratory rate, heart rate, and body temperature. Blood pressure and heart rate should be 
taken in the seated position following ≥ 3 minutes of rest. When vital signs are scheduled at 
the same time as collection of a blood sample, the vital sign measurements should be 
obtained before the scheduled phlebotomy. If a study visit occurs where only pembrolizumab 
is administered, vital signs must be collected before the start of the pembrolizumab infusion. 
If an indwelling cannula is being used to obtain blood, blood pressure should be measured in 
the arm opposite to the cannula placement. 
Oxygen saturation is not a required parameter to be collected. Sites are to capture oxygen 
saturation every time an AE of hypoxia or cytokine release syndrome is reported for a 
subject. 
7.1.11. 
Eastern Cooperative Oncology Group Performance Status 
At Screening, the ECOG Performance Status (Appendix A) will be assessed and must be 
either 0 or 1 for the subject to be eligible. The ECOG Performance Status will be assessed as 
specified in the Schedule of Assessments (Table 1). 
7.1.12. 
Electrocardiogram 
A single standard, 12-lead electrocardiogram (ECG) will be obtained as specified in the 
Schedule of Assessments (Table 1). 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. ECGs will be performed after the subject has been resting in 
supine or semi-supine position for at least 5 minutes. When an ECG is scheduled at the same 
time as a blood sampling, the ECG reading should be obtained before the scheduled blood 
sampling. The ECG results will be interpreted at the site by a medically qualified person. If 
indicated, the ECG must be evaluated by a cardiologist or qualified internist. 


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7.1.13. 
Clinical Laboratory Assessments 
Clinical laboratory tests will be performed as specified in the Schedule of Assessments 
(Table 1). Additional tests may be performed as clinically indicated. 
Clinical laboratory parameters (Table 2) to be obtained include: 
• Hematology, chemistry, and urinalysis assessments 
• Coagulation (Partial thromboplastin time, Prothrombin time, and INR) 
assessments 
• Thyroid function tests (thyroid stimulating hormone, free triiodothyronine, and 
free thyroxine) for clinical signs and symptoms of thyroid disorder 
• Autoimmune panel 
• Adrenal function tests, if indicated 
NOTE: At Screening, subjects assessed as at risk for adrenal insufficiency should 
undergo diagnostic tests for ACTH and morning cortisol, and/or high-dose ACTH 
stimulation test (preferred testing method), if clinically indicated, via local 
laboratory. 
• HIV, Hepatitis C/B, if indicated 
A central laboratory will be used for clinical laboratory safety assessments; local laboratories 
may be used for eligibility and treatment decisions. The central laboratory will provide 
collection supplies and perform analysis of clinical laboratory evaluations. Specimens will be 
appropriately processed, and laboratory reports will be provided to the Investigator. A 
summary of the number and volume of laboratory specimens collected at each study visit is 
provided in Appendix B. 
The Investigator is responsible for reviewing central laboratory results and assessing all out- 
of-range findings as either clinically significant or non-clinically significant. Clinically 
significant laboratory results should be recorded in the eCRF as medical history if before 
CMP-001 dosing at W1D1, or as AEs following CMP-001 dosing at W1D1. 


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Table 2: 
Clinical Laboratory Assessments 
 
Hematology 
Serum Chemistry 
Urinalysis 
Other Laboratory Tests 
Red blood cells (RBCs) 
White blood cells 
(WBCs) 
Alanine 
aminotransferase 
Albumin 
Blood 
Glucose 
Nitrites 
pH 
Protein 
Specific gravity 
WBCs 
Microscopic Battery: 
RBCs, WBCs, 
epithelial cells, casts 
(only if significant 
positive findings on 
urinalysis) 
Coagulation: 
PTT 
PT 
INR 
Thyroid Function Studies: 
Thyroid stimulating hormone, 
Free T3, Free T4 
Autoimmune Laboratory 
Panel: 
Anti-dsDNA, anti-nuclear 
antibody, anti-neutrophil 
cytoplasmic antibody, 
rheumatoid factor, and 
antibodies to ribonucleoprotein 
(anti-RNP) 
Tests to be performed as 
clinically indicated: 
Human immunodeficiency virus 
Hepatitis B and C 
Differential WBC count 
Alkaline phosphatase 
Hemoglobin 
Amylase 
Hematocrit 
Platelets 
Aspartate 
aminotransferase 
Bilirubin 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Lipase 
Phosphorous 
Potassium 
Sodium 
Total protein 
Abbreviations: dsDNA = double-stranded DNA; INR = international normalized ratio; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; RNP = ribonucleoprotein; T3 = triiodothyronine; T4 = thyroxine; WBC = 
white blood cell. 
NOTE: Refer to the Study Laboratory Manual for additional information. 
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory 
value). Laboratory parameters and/or assessments that are included in the Schedule of 
Assessments (Table 1) may be repeated in an effort to find all possible well-qualified 
participants. Consultation with the Medical Monitor may be needed to identify whether 
repeat testing of any particular parameter is clinically relevant. 
7.1.14. 
Pregnancy Testing 
Pregnancy testing will be performed on WOCBP at the time points specified in the Schedule 
of Assessments (Table 1). A serum pregnancy test is required during screening. A serum or 
urine pregnancy testing will be completed for time points after Screening. 
A WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L 
or equivalent units of human chorionic gonadotropin) within 24 hours before the start of 
study treatment. An extension up to 72 hours before the start of study treatment is permissible 
in situations where results cannot be obtained within the standard 24-hour window. 
If a urine pregnancy test is positive at any time point, the test must be confirmed with a serum 
sample. If a serum pregnancy test is required based on a positive urine pregnancy test, serum 
test results must be confirmed as negative before enrollment or subsequent treatment of the 
subject. If the serum test confirms the subject is pregnant, they must have the EOT visit, and 
the pregnancy must be reported to the Medical Monitor. 


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7.2. 
Disease Assessments 
Disease assessments (radiographic and CNS imaging) will be collected according to the 
Schedule of Assessments (Table 1). Acceptable assessment methods, definition of 
measurable disease, and selection of target and non-target lesions will be defined by RECIST 
v1.1 (see Appendix D). 
The same disease assessment method(s) used to confirm eligibility during Screening (CT, 
MRI) should be used throughout the study for all disease assessments. Changes in imaging 
modalities may be acceptable with Medical Monitor approval if required for the subject’s 
safety. All scans should be performed at least 2 weeks after the previous CMP-001 IT 
injection to prevent detection of injection-related pseudoprogression. 
Photographic and/or radiographic images demonstrating disease progression on prior PD-1– 
blocking antibody treatment will be collected whenever available. 
All disease assessments will be evaluated by the Investigator according to RECIST v1.1 
(Appendix D) and iRECIST (Appendix E). 
7.2.1. 
Radiographic Imaging 
Contrast-enhanced CT and MRI are the only acceptable radiographic imaging modalities for 
disease assessment. Contrast-enhanced CT imaging is required when contraindications are 
not present. Contrast-enhanced CT assessments may be combined with positron emission 
tomography (PET) as long as disease status can be thoroughly assessed. Ultrasound imaging 
may be used for measurement of lesions for itRECIST (Appendix F). 
A target lesion(s) not intended for intratumoral (IT) injections should be clearly labeled in the 
Baseline imaging. 
7.2.2. 
Photographic Imaging 
Digital photographs of visible CMP-001-injected and non-injected skin lesions should be 
taken at Baseline and if a clinically relevant change occurs. As part of disease assessment, 
photos should be taken at the same intervals as the radiographic imaging. These photographs 
will be utilized to demonstrate response in visible tumors. Photos should be taken with a 
digital camera of adequate resolution. To clearly capture the morphology of the tumor, both 
the skin lesion and the surrounding tissue should be included in the field of view. Care should 
be taken to ensure subject privacy. Each lesion should be clearly labeled with a unique 
identifier which must be used throughout the trial. A metric ruler must also be included in the 
photograph field of view as a size reference. Photographic imaging will be collected by the 
site staff and uploaded to the central image repository. 
A target lesion(s) not intended for IT injections should be clearly labeled in the Baseline 
imaging. 
If a CR is observed, sites should continue to obtain confirmation photographs according to 
the Schedule of Assessments (Table 1). 
Refer to the photographic imaging guideline for further guidance. 
7.2.3. 
Central Nervous System Imaging 
Baseline brain imaging by contrast-enhanced CT or MRI (per site local standards) should be 
provided at Screening for subjects with known or suspected brain metastases. On-study brain 


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imaging is only required for subjects with current or prior history of brain metastases or 
clinical signs or symptoms of CNS disease. 
The same modality of brain imaging should be utilized throughout the study for an individual 
subject. 
7.2.4. 
On-Treatment Disease Assessment 
On-treatment disease assessments will be collected per the time points specified in the 
Schedule of Assessments (Table 1). 
Because the volume from the IT injection of CMP-001 and related inflammation may cause a 
tumor to transiently enlarge leading to an inaccurate assessment, disease imaging that 
includes a lesion injected with CMP-001 should not be performed within 2 weeks after the 
injection unless medically necessary. 
7.2.5. 
Treatment and Disease Assessment Beyond Progressive Disease 
Clinically stable subjects may continue to be treated beyond RECIST v1.1 progression at the 
Investigator’s discretion. Subjects who receive study treatment beyond PD per RECIST v1.1 
will have subsequent disease assessments evaluated using iRECIST by the Investigator. 
Clinically stable subjects may continue to be treated beyond RECIST v1.1 progression at the 
Investigator’s discretion until PD is confirmed according to iRECIST. Treatment beyond 
progression is permitted only in subjects who are clinically stable (Seymour, 2017). An 
assignment of clinical stability requires that no worsening of performance status has 
occurred, that no clinically relevant increases in disease-related symptoms such as pain or 
dyspnoea occur that are thought to be associated with disease progression, and that no 
requirement for intensified management of disease-related symptoms exists, including 
increased analgesia, radiotherapy, or other palliative care. Disease assessments should 
continue according to the Schedule of Assessments (Table 1). 
7.2.6. 
Confirmation of Response 
Subjects with a CR or PR per RECIST v1.1 or iCR or iPR per iRECIST must have a 
confirmatory assessment performed at least 4 weeks after the initial response. All scans 
should be performed at least 2 weeks after the previous CMP-001 IT injection to prevent 
injection-related pseudoprogression. 
Subjects with an iCR or iPR per iRECIST must also have a confirmatory assessment 
performed at least 4 weeks after the initial assessment where response was declared by the 
Investigator. 
Once confirmed, subsequent assessments should continue according to the Schedule of 
Assessments (Table 1). 
7.3. 
Translational Assessments 
7.3.1. 
Collection of Blood for Translational Biomarker and Pharmacokinetics 
Analyses 
Blood samples, including serum and/or plasma will be collected for 
exploratory biomarker and pharmacokinetic assessments as specified in the Schedule of 
Assessments (Table 1). The procedures for sample collection, processing, storage, and 
shipment are provided in the Laboratory Manual. Blood samples will be tested to determine 
concentration of CXCL10 and other cytokines before and during treatment with CMP-001 to 


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evaluate association with the observed clinical responses to study treatment. Samples may be 
used for additional exploratory analysis of biomarkers thought to play a role in head and neck 
cancer, cancer immunotherapy, or TLR9, including but not limited to concentration of 
serum/plasma analytes. These findings may be analyzed for association with observed 
clinical responses to the combination of CMP-001 and pembrolizumab, and subsequent 
exploration of factors associated with response or resistance to CMP-001 in combination with 
pembrolizumab. These samples may be also used for research to develop methods, assays, 
prognostics and/or companion diagnostics related to TLR9 agonism and cancer 
immunotherapy. 
7.3.2. 
Collection of Tumor Biopsies for Translational Assessments Analyses 
Fresh tumor biopsy samples are mandatory, if safe and medically feasible, at Screening or 
within 90 days (before W1D1) and W7D1 before CMP-001 IT injection, as specified in the 
Schedule of Assessments (Table 1). If the Investigator believes it is unsafe to perform a 
biopsy, the subject may be considered eligible for study enrollment after discussion with the 
Medical Monitor. The decision and rationale to forego biopsy samples should be clearly 
documented. Archival tumor biopsy samples should also be collected during Screening, if 
available. 
Tumor biopsies will be used to assess PD-L1 expression and may be used to analyze tumor 
immune cell infiltrates, such as CD3+CD8+ T-cells. Biopsies may be used for additional 
exploratory analysis of biomarkers thought to play a role in head and neck cancer, cancer 
immunotherapy, or TLR9, including but not limited to techniques such as the Nanostring 
IO360 panel evaluating 46 RNA gene expression signatures, and may be used to determine 
the presence of DNA mutations associated with tumor resistance. These findings may be 
analyzed for association with observed clinical response, resistance and/or adverse events to 
the combination of CMP-001 and pembrolizumab. 
Determination of PD-L1 status is mandatory. If tumor PD-L1 status has been obtained before 
study entry, this value and method (detection antibody) will be recorded in the eCRF. If 
tumor PD-L1 status has not been obtained before study entry and archival tissue is available, 
it should be obtained from the archival biopsy sample at Screening. The PD-L1 value will be 
recorded in the EDC. 
Additional tumor biopsies may be collected at other time points at the discretion of the 
Investigator. 
7.3.3. 
Collection of Blood Samples for Cytokine and Complement Assessment 
Blood samples are to be collected at the time points specified in the Schedule of Assessments 
(Table 1). When possible, samples should be collected at the time that any AEs of cytokine 
release syndrome are experienced. 
7.4. 
Safety Assessments 
Safety will be assessed on an ongoing basis throughout this study. All safety assessments and 
AEs will be recorded on the appropriate eCRF and reported to the Sponsor or its 
representatives (as applicable). Medical occurrences that begin before the start of study 
treatment administration but after obtaining informed consent will be recorded on the 
Medical History/Current Medical Conditions section of the eCRF, not the AE section. All 
treatment-emergent adverse events (TEAEs), defined as an AE that started or worsened in 
severity on or after the date of Informed Consent, will be graded according to CTCAE 


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version 5.0 (Appendix C) and coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Worsening TEAEs (i.e., increase to higher severity/grade) should be recorded as 
new AEs. Ongoing AEs with a decrease in severity/grade do not need to be captured as new 
AEs. 
Abnormal vital sign measurements, clinical laboratory test results, and/or physical 
examination findings deemed clinically significant by the Investigator may be repeated, until 
the value returns to Baseline, within normal limits (WNL), or reaches a clinically stable 
endpoint, as determined by the Investigator. Any post-Baseline abnormal findings that are 
considered clinically significant by the Investigator will be recorded on the AE page of the 
eCRF. The Investigator is responsible for reviewing all clinical laboratory results. 
7.4.1. 
Adverse Events 
AEs should be monitored from the time of consent through 30 days after the last dose of 
study drug (both CMP-001 and pembrolizumab). Pretreatment AEs related to study 
procedures will be monitored from informed consent until the first dose of study drug 
(W1D1). After the subject is enrolled, all AEs will be captured on the eCRF. 
See Section 8.3 for a full description of the collection and reporting of AEs during this study. 
7.5. 
30-Day Follow-Up Contact 
The 30-Day Follow-up contact is a safety follow-up visit that should be conducted in the 
study clinic or via phone. The subject should be questioned for any new AEs, resolution of 
prior AEs, and use of concomitant medications, including other cancer treatments. No other 
safety assessments are required unless the Investigator identifies a new safety concern that 
requires further follow-up. 
7.6. 
Posttreatment Follow-Up 
Subjects who discontinue study treatment and transition into PTFU will continue to have 
assessments collected per the time points specified in the Schedule of Assessments (Table 1). 
Post treatment follow-up disease assessments will continue until disease progression, 
initiation of another cancer treatment, death, lost to follow-up, withdrawal of consent, or End 
of Clinical Trial. 
7.7. 
Long-Term Survival Follow-Up 
Subjects who discontinue study treatment and PTFU, will be contacted by the site according 
to the Schedule of Assessments (Table 1) for LTSFU, which will continue until death, 
withdrawal of consent, lost to follow-up, or End of Clinical Trial. 


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8. 
SAFETY DATA COLLECTION, RECORDING, AND 
REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definition of an Adverse Event 
An AE is an untoward or medical occurrence associated with the use of study drug (active or 
placebo drug, biologic, or device) in clinical investigation subjects, which does not 
necessarily have a causal relationship with the study drug. An AE can therefore be any 
unfavorable and unintended symptom, sign, disease, condition, or test abnormality whether or 
not considered related to study drug (Appendix C). Adverse events that do not meet the 
definition for an SAE are considered non-SAEs. 
Adverse events should be recorded upon first occurrence and followed until resolution. A 
persistent AE is continuous and does not resolve between Q3W dosing visits. The AE is 
documented only once unless the grade becomes more severe. If the grade becomes more 
severe the AE must be reported again with the new grade. Any recurrent AE should be 
reported as new AE. 
Adverse events include: 
• Changes in health status described by the subject or signs observed by the 
Investigator or medical staff. 
• Test abnormalities (e.g., laboratory tests) that result in an alteration in medical 
care (diagnostic or therapeutic) and/or are considered clinically significant by the 
Investigator. 
Disease progression, and associated hospitalizations, are not considered an AE or SAE in this 
study. 
Abnormalities present at Baseline will be recorded as medical history and will only be 
considered AEs if they reoccur after resolution or worsen during the study. 
8.1.2. 
Definition of a Serious Adverse Event 
An SAE is any AE that fulfills 1 of the criteria outlined in Section 8.1.2. 


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Table 3: 
Criteria for Determination of Serious Adverse Events 
 
Death 
An adverse event (AE) that results in death. 
NOTE: In this study, deaths due to Disease Progression are not to be 
reported as SAEs. 
Life-threatening AE 
An AE that places the subject, in the view of the Investigator, at 
immediate risk of death from the AE as it occurred (i.e., does not include 
an AE that had it occurred in a more severe form, might have caused 
death). 
Required or prolonged 
inpatient 
hospitalizationa 
An AE that results in an initial inpatient hospitalization or prolongs an 
existing hospitalization of the subject. If a subject is hospitalized as part 
of the clinical use of the study drug, a period of normal hospitalization 
will be outlined in the protocol or by the judgment of the Investigator. 
Hospitalizations longer than this period will be prolonged 
hospitalizations. 
Persistent or 
significant 
disability/incapacity 
An AE that results in a substantial disruption of a subject’s ability to 
conduct normal life functions. 
Congenital 
anomaly/birth defect 
A congenital anomaly/birth defect that occurs in the offspring of a subject 
exposed to the study drug. 
Important medical 
event 
An AE which may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the subject and may require 
medical or surgical intervention to prevent 1 of the outcomes listed above, 
in the opinion of the Investigator. 
a. Planned hospital admissions or surgical procedures for elective procedures or for an illness or disease that 
existed before the W1D1 visit will not be captured as SAEs. If planned admissions or procedures occur at a time 
other than what was planned (i.e., due to an exacerbation in the preexisting illness or disease), they should be 
reported as SAEs. 
Appendix C: CTCAE version 5.0 
Examples of “important medical events” include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as with important medical events described above. 
Events that meet SAE criteria must be recorded and reported regardless of expectedness or 
assessed association with study drug. 
Hospitalization due solely to the progression of underlying HNSCC should not be reported as 
an SAE. 
8.1.3. 
Definition of a Treatment-Emergent Adverse Events 
A TEAE is defined as an AE that started or worsened in severity on or after the date that 
study drug was first administered (W1D1) until 30 days after the last dose of study treatment. 
8.2. 
Evaluation of Adverse Events and Serious Adverse Events 
The Investigator or designee is responsible for making an assessment as to the severity 
(CTCAE Grade), causality/relationship to CMP-001 and pembrolizumab separately, and 
outcome of AEs and SAEs (as defined in Section 8.2.3). Every attempt should be made to 


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provide the causality/relationship at the time at the time of reporting the SAE. In addition, the 
Investigator or designee must report any actions taken as a result of an AE or SAE separately 
for CMP-001 and pembrolizumab. 
8.2.1. 
Adverse Event Severity/Grade 
For each recorded AE or SAE, the Investigator or designee must provide an assessment of 
Severity/Grade using the CTCAE version 5.0 (Appendix C). 
Note that severity is not the same as “seriousness” (defined in Section 8.1.2). Seriousness 
(not severity) serves as a guide for defining regulatory reporting obligations. 
Worsening of an ongoing TEAE (i.e., an increase to higher grade) should be recorded as a 
new AE. Ongoing AEs that decrease in severity/grade should not be captured as new AEs. 
Table 4: 
CTCAE Adverse Event Grades 
 
Classification 
Definition 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2 
Moderate; minimal, local, or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limited 
self-care activities of daily living 
Grade 4 
Life-threatening consequences: urgent intervention indicated 
Grade 5 
Death related to adverse event 
Appendix C: CTCAE version 5.0 
 
8.2.2. 
Relationship to Study Drug 
For each AE or SAE, the Investigator will determine whether there is a reasonable possibility 
demonstrated by evidence that suggests a causal relationship between the study treatment and 
each AE according to the categories provided in Table 5 (see Appendix C). Attribution of 
AEs will be determined for each of the individual components (CMP-001 and 
pembrolizumab) of the study treatment. The Investigator may change their opinion of 
causality in light of follow-up information; if this occurs, the Investigator must amend the AE 
or SAE information in the EDC and on the paper SAE form accordingly. 


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Table 5: 
Classification for Adverse Event Causality 
 
Classification 
Definition 
Unrelated 
There is no suspicion of a causal relationship between exposure to the study 
drug regimen and the AE; another cause of the AE has been identified, no 
temporal association with study drug has been identified, or the study drug 
cannot be implicated 
Possibly related 
There is some evidence supporting the possibility of a causal relationship 
between study drug regimen exposure and the AE; an alternative 
explanation (i.e., concomitant drug or concomitant disease) is inconclusive, 
the temporal association with study drug is reasonable, and the causal 
relationship cannot be excluded 
Probably related 
An AE that has a timely relationship to the administrative of the 
investigational drug regimen and follows a known pattern of response, but 
for which a potential alternative cause may be present 
Definitely related 
There is strong evidence that there is a causal relationship between study 
drug regimen and the AE; the AE cannot be reasonably explained by an 
alternate explanation (i.e., concomitant drug or concomitant disease) and the 
temporal association with study drug is suggestive of a causal relationship 
Abbreviations: AE = adverse event. 
NOTE: CMP-001 and pembrolizumab must be assessed separately. An AE is considered related to treatment if 
the attribution is “possibly related”, “probably related”, or “definitely related.” 
Appendix C: CTCAE version 5.0 
 
8.2.3. 
Classification of Adverse Event Outcome 
Adverse event outcome describes the status of the AE at the last observation. The 
Investigator will document the outcomes of each AE using the categories provided in below 
Table 6. 
Table 6: 
Classifications for Adverse Event Outcomes 
 
Classification 
Definition 
Fatal 
Termination of life as a result of an AE 
Not recovered/not resolved 
Subject has not recuperated, or the AE has not improved 
Recovered/resolved 
Subject has recuperated, the AE resolved, or returned to 
Baseline status / stabilized 
Recovered/resolved with sequelae 
Adverse event has resolved, but the subject has been left 
with symptoms or pathology 
Unknown 
Not known, not observed, not recorded, or refused 
Appendix C: CTCAE version 5.0 
 
8.2.4. 
Action Taken Related to Study Drug Administration Regarding the Adverse 
Event 
The Investigator will provide the action taken regarding study treatment separately for CMP- 
001 and pembrolizumab in response to the AE. Refer to Section 5.1.2.5 and Section 5.1.3 for 
CMP-001 and pembrolizumab allowed dose modifications. Classification for each of the 
potential actions taken are provided in Table 7. 


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Table 7: 
Classifications for Actions Taken Related to Study Drug Administration 
Regarding an Adverse Event 
 
Classification 
Definition 
No change 
No change in administration of study drug 
Study drug delayed 
Temporary delay in administration of the study drug 
Study drug withheld 
One or more planned doses of study drug completely withheld 
(skipped) 
Study drug permanently 
withdrawn 
Administration of the study drug terminated (no further dosing) 
Not applicable 
Determination of a value is not relevant in the current context 
8.3. 
Procedures for Recording and Reporting Adverse Events 
The Investigator is required to report to the Sponsor or its representatives all AEs that occur 
during the clinical trial (Title 21 Code of Federal Regulations [CFR] Part 312.64[b] and ICH 
E6 entitled “Guideline to Good Clinical Practice”) (ICH E6). At each study visit, subjects 
will be evaluated for new AEs and the status of existing AEs. TEAEs observed from the time 
of consent until 30 days after the last dose of study drug (both CMP-001 and pembrolizumab) 
are to be recorded on the AE page of the eCRF. 
The date, time of onset, resolution, determination of seriousness, severity, action taken, 
outcome and relationship to CMP-001 and pembrolizumab will be recorded for all AEs. AEs 
starting more than 30 days after the last dose of study drug should not be recorded on the AE 
eCRF unless they are considered to be related to study treatment. 
All AEs and SAEs experienced by a subject will be recorded on the appropriate eCRF. In 
addition, for all SAEs a paper SAE Report Form will be completed and submitted to IQVIA 
Biotech Safety preferably via email to: 
or by fax to 
 as back up within 24 hours of awareness. Information including a detailed 
description of the event; date and time (24-hour clock) of event onset and resolution; 
determination of seriousness, severity, corrective treatment, outcome, relationship to study 
drug; and action taken regarding the study drug will be recorded. Vital signs, laboratory 
results, and other safety assessments noted in Section 7.4 will be recorded as AEs if they are 
determined to be clinically significant findings in the opinion of the Investigator. When 
possible, a diagnosis should be recorded as an AE, rather than symptoms or isolated 
laboratory abnormalities related to the diagnosis. A medical or surgical procedure is not an 
AE; rather the condition leading to the procedure should be recorded as the AE. If the 
condition is not known, the procedure must be recorded as an AE instead. Similarly, death is 
not an AE, but is rather the outcome of the AE(s) that resulted in death. If the AE(s) leading 
to death are not known, then death must be reported as an AE. 
8.3.1. 
Reporting Serious Adverse Events 
All SAEs and associated source documents must be reported in written or typed English via 
completion of the eCRF AE page and accompanying paper SAE Report Form to IQVIA 
Biotech Safety (following the same reporting process outlined in Section 8.3) within 24 hours 
of first knowledge of the event regardless of relationship to the study procedures or individual 
study drugs. The paper SAE Report form should be used to record pertinent information, 


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regarding the SAE. The Investigator is requested to supply as much detailed information as 
possible regarding the event at the time of the initial report. 
SAEs will be collected from the time of consent until 30 days after the last dose of any study 
allowed drug treatment. 
If at any time after the subject has completed participation in the study, the Investigator or 
study staff becomes aware of an SAE during the study reporting period that they believe is 
possibly, probably, or definitely related to either study drug (see Section 8.2.2), then the 
event and any known details must be reported promptly to the Sponsor or its representatives. 
The following reporting instructions must be followed. 
At minimum, the Investigator will be asked to provide the following information: 
• For the initial SAE notification, the Investigator must provide, at a minimum, 
basic information such as the protocol number, subject’s year of birth or age at 
onset, subject identification (ID) number, period of study drug intake, event term, 
nature of the event, detailed description of the clinical course of the event, 
seriousness criteria, causality of the event to CMP-001 and pembrolizumab 
separately, and severity. 
• In addition, the initial SAE information entered on the eCRF and paper SAE 
Report Form should include all pertinent known information about the SAE and 
the affected subject, such as the following: subject sex; description of the AE 
including reason for assessment as serious, and individual study drug information 
including doses, dates of dosing, and action taken with individual study drugs. 
Follow-up information must be entered or uploaded into the eCRF system and paper SAE 
Report Form and sent to IQVIA Biotech Safety (following the same reporting process 
outlined in Section 8.3.1) within 24 hours of the Investigator’s first knowledge of the new 
information. Follow-up SAE reports may describe the evolution of the reported events and 
any new assessment of their outcome and/or relationship to individual study drugs. 
Supporting documentation may be solicited from the site even if the SAE occurred at another 
institution. Such documentation may include copies of relevant subject/hospital records, and 
pathology or autopsy reports. For subject deaths, the cause of death is to be recorded as the 
SAE term. A death certificate and an autopsy report, if performed, should be submitted. 
The Sponsor designee contact information is available for SAE reporting on a 24-hour basis 
and is reviewed during normal business hours. A paper SAE Report Form should be 
completed and submitted to IQVIA Biotech Safety within 24 hours of awareness. 
8.3.2. 
Reporting Pregnancies 
Female subjects or the partners of male subjects who become pregnant within 1 year of their 
last CMP-001 dose will be instructed to notify the Investigator immediately. 
If the Investigator learns of a report of pregnancy at any time after the W1D1 visit, the 
Investigator must complete and submit a paper Pregnancy Report Form and report the 
pregnancy to the IQVIA Biotech Safety within 24 hours of awareness (following the same 
reporting process outlined in Section 8.3.1). 
The Investigator will inform the subject that the Sponsor or its representatives is required to 
gather information regarding the course and outcome of a pregnancy that has occurred after 
exposure to a study drug. The progress of the pregnancy must be followed until the outcome 
of the pregnancy is known (i.e., delivery, elective termination, or spontaneous abortion). If 


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the pregnancy results in the birth of a child, additional follow-up information may be 
requested. 
The Investigator will be asked to obtain follow-up information no later than 2 months after 
the gestational period to obtain maternal/fetal/neonatal outcome and any other relevant 
information. 
Follow-up information may be requested at additional time points. All study-related contacts 
involving a known pregnancy should include pregnancy status assessment until pregnancy 
outcome is known. 
Please note that pregnancy in and of itself is not an AE or an SAE. Pregnancy should not be 
entered into the eCRF as an AE unless the Investigator suspects an interaction between the 
study drug and the contraceptive method. Additionally, all information received will be 
assessed for any AEs and SAEs and processed per study guidelines. If the subject is 
discontinued because of pregnancy, pregnancy will be documented as the reason for study 
discontinuation. Spontaneous abortions and stillbirths will be reported as SAEs. 
8.3.3. 
Reporting to IRBs and Regulatory Authorities 
Investigators will receive initial, and follow-up expedited safety reports (ESR) (unexpected 
SAEs that are determined to be associated with the use of study drug) from the Sponsor or its 
representatives. The Investigator is responsible for fulfilling applicable local reporting 
requirements to their Institutional Review Board (IRB). Investigators must forward copies of 
the IRB notification to the Sponsor or its representatives. 
In the US, the Sponsor will be responsible for notifying the FDA of any serious unexpected 
suspected adverse reaction that is determined to be associated with the use of study drug. The 
Sponsor’s assessment of attribution and expectedness will determine regulatory reporting. 
8.3.4. 
Follow-up of Adverse Events/Serious Adverse Events 
All AEs and SAEs documented at a previous visit that are designated as not 
recovered/resolved, will be reviewed by the Investigator at subsequent visits. 
All AEs will be followed until resolution of AE, completion of the subject’s study 
participation, or study termination, whichever occurs first. 
Serious AEs and AEs resulting in discontinuation will be followed until 1 of the following 
occurs: 
• The event resolves. 
• The event stabilizes. 
• The event returns to a Baseline value if a Baseline value is available. 
• The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct. 
• The Investigator and Medical Monitor agree that follow-up is no longer necessary. 
Follow-up reports from the Investigator must be provided via completion of the eCRF AE 
page and accompanying paper SAE page within 24 hours of the Investigator’s first 
knowledge of the new information. Additional information (i.e., hospital records, laboratory, 
or other diagnostic test results) should be provided if requested and/or indicated. In addition, 
for SAEs, the follow-up information should be added using the same form the initial SAE 


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was reported on. It should be completed and submitted to IQVIA Biotech Safety via email: 
 
Rules for AE/SAE follow up apply to all subjects, including those who withdraw consent 
before study completion (to the extent allowed). The Investigator will ensure that follow up 
includes further investigations to elucidate the nature and/or causality of the AE/SAE. These 
investigations must be consistent with appropriate medical management and subject consent. 
Investigators are not obligated to actively seek AEs or SAEs in former study subjects that 
occur pursuant to the follow-up period. However, if the Investigator or designee learns of any 
AE or SAE at any time after a subject has been discharged from the study and the event is 
considered as reasonably related to the study drug, the Investigator will notify the Sponsor or 
its representatives. 


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9. 
STATISTICAL METHODS 
Categorical variables will be summarized as the number and percentage of subjects within 
each category (with a category for missing data, if applicable). Continuous variables will be 
presented as number (n), mean, median, standard deviation, and range (minimum and 
maximum). 
Data from all investigational sites will be pooled in the analyses. 
A detailed statistical analysis plan (SAP) will be finalized before database lock and will 
document the analysis methods, data handling procedures, and other statistical analysis 
issues. Statistical analyses will be performed using SAS® software version 9.4 or higher. 
9.1. 
Sample Size Calculation 
The number of subjects planned for inclusion in this study is 43. Subjects who have provided 
written informed consent once the enrollment goal is reached may be allowed to complete 
Screening and enter study treatment if they meet all eligibility criteria, at the discretion of the 
Sponsor or its representatives. Subjects who discontinue the study before receiving the first 
dose of CMP-001 may be replaced to ensure at least 43 enrolled subjects. 
A sample size of 43 achieves 
 power to detect a difference of 
 using normal 
approximation method at one-sided alpha level of 0.05, assuming that the null hypothesis for 
ORR is 
, and the alternative hypothesis for ORR is 
. The sample size calculation is 
performed in PASS 2020 using the normal approximation to the binomial distribution. 
9.2. 
Analysis Sets 
The main analysis sets are defined in this section. Additional analysis sets may be defined in 
the SAP. 
9.2.1. 
Intent-to-Treat Analysis Set 
The Intent-to-Treat (ITT) Analysis Set is defined as all subjects who receive at least 1 dose of 
study drug. This analysis set will be the primary analysis set for all efficacy endpoints. 
9.2.2. 
Safety Analysis Set 
The Safety Analysis Set is defined as all subjects who receive at least 1 dose of study drug. 
This analysis set will be the primary analysis set for all safety endpoints. 
9.2.3. 
Pharmacodynamic Analysis Set 
The Pharmacodynamic Analysis Set is defined as all subjects who receive at least 1 dose of 
CMP-001 and have at least 1 measurable biomarker at Baseline and after CMP-001 injection. 
9.2.4. 
Pharmacokinetic Analysis Set 
The Pharmacokinetic Analysis Set is defined as all subjects who receive CMP-001 and have 
evaluable samples at Baseline and after CMP-001 injection. 


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9.3. 
Background Characteristics 
9.3.1. 
Disposition 
The number and percentage of subjects who screen fail, enroll in the study (receive their first 
dose of study drug), discontinue study treatment, and who discontinue the study will be 
summarized. The primary reason for treatment and study discontinuation will also be 
summarized. 
Subject disposition will be presented in a by-subject data listing. 
9.3.2. 
Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics (age, sex, race, ethnicity, body weight, 
height, and BMI) will be summarized using descriptive statistics for the ITT Analysis Set and 
listed by subject. 
9.3.3. 
Eastern Cooperative Oncology Group Performance Status 
ECOG data will be presented in a by-subject data listing. Change from Baseline in ECOG 
Performance Status will be summarized for the ITT Analysis Set. 
9.3.4. 
Head and Neck Squamous Cell Carcinoma History 
Head and neck squamous cell carcinoma history (time since diagnosis, tumor stage, nodal 
status, and metastatic disease status at time of diagnosis) will be summarized using 
descriptive statistics for the ITT Analysis Set and listed by subject. HNSCC history will be 
captured on a separate eCRF in the EDC system. All prior HNSCC treatments will be 
captured on a Prior Cancer Treatment eCRF. Prior cancer treatments will be presented in the 
data listings. 
9.3.5. 
Prior Cancer Treatments 
All prior treatments for HNSCC will be captured in the EDC separately from other prior 
medications. A summary of the number of prior lines of cancer therapy, best response on 
prior PD-1, and last response on prior PD-1 will be generated for the ITT Analysis Set. Prior 
cancer treatment details will be presented in the data listings. 
9.3.6. 
Medical and Surgical History 
Medical and surgical history will be listed by subject. Medical history will be coded using 
MedDRA. 
9.3.7. 
Protocol Deviations 
All protocol deviations will be captured electronically and presented in a by-subject data 
listing. All deviations will be reviewed on an ongoing basis and classified as major or minor. 
9.3.8. 
Prior and Concomitant Medications 
Prior medications are those taken within 30 days of the first dose of study drug and 
discontinued before the first dose of study drug. 
Concomitant medications will be assessed continually from 30 days before the first dose of 
study drug (W1D1) through 30 days after the last dose of study drug (both CMP-001 and 


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pembrolizumab). Treatment medications for study-related AEs that occur more than 30 days 
after the last dose of study drug will be collected. 
Medications will be coded using the most recent version of the World Health Organization 
drug dictionary and summarized according to the Anatomical Therapeutic Chemical (ATC) 
classes, and preferred term for each dose group for the Safety Analysis Set. Subjects will be 
counted only once for a given concomitant medication for each ATC class and preferred term 
in the summary tables. 
Concomitant medications will be presented in a by-subject data listing. 
9.4. 
Study Drug Exposure and Compliance 
The number of CMP-001 and pembrolizumab doses received by each subject will be 
summarized descriptively for the Safety Analysis Set. The duration of each treatment, dose 
intensity and relative dose intensity will also be summarized. 
CMP-001 dosing, including date and time of each dose, route of administration, dose 
administered, location of each injection, and the volume injected into each tumor at each 
dosing visit will be presented in a by-subject data listing. 
Pembrolizumab dosing, including date, time, and dose administered, will be presented in a 
by-subject data listing. 
9.5. 
Efficacy Analyses 
9.5.1. 
Confirmed Objective Response Rate 
The primary efficacy endpoint for the study is the confirmed ORR based on RECIST v1.1 as 
determined by the Investigator. 
The confirmed ORR is defined as the proportion of the subjects in the analysis set who have 
confirmed best response as CR or PR. The confirmed ORR will be calculated as the number 
of subjects with a confirmed CR or PR divided by the number of subjects in the analysis 
population [ORR = (cCR + cPR)/# subjects] for the ITT Analysis Set. For the ORR, 95% 
Clopper-Pearson confidence intervals will be calculated. 
Subjects who discontinue due to death due to disease progression or disease progression, 
before having a post-Baseline tumor assessment will be classified as having a best response 
of PD. Subjects who discontinue before having a post-Baseline scan for other reasons will be 
counted as non-responders in the ITT analyses. 
The primary efficacy analysis of confirmed ORR will be assessed according to RECIST v 1.1 
by the Investigator for the ITT Analysis Set. 
9.5.2. 
Disease Control Rate 
The confirmed disease control rate is defined as the proportion of subjects in the analysis set 
who have a confirmed best response of CR, PR, or SD. Per RECIST v1.1, CR or PR must be 
confirmed by a confirmatory assessment performed at least 4 weeks after the initial response. 
In the case of stable disease, measurements must have met the SD criteria at least once after 
study entry at a minimum interval of 6 weeks. 


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9.5.3. 
Duration of Response 
DOR will be based on RECIST v1.1 responses as determined by the Investigator and 
calculated for responders in the ITT Analysis Set. The DOR will be measured from the time 
at which criteria are first met for CR or PR (whichever is first recorded) until the first date 
that recurrence or PD is objectively documented (taking as reference for PD the smallest 
measurements recorded on study). The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease is 
objectively documented. Censoring details will be described in the SAP, including handling 
of subjects who continue to be followed for PTFU disease assessments. 
9.5.4. 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the time from first CMP-001 injection to disease 
progression or death from any cause. PFS will be calculated based on RECIST v1.1 as 
determined by the Investigator. Subjects who are alive and progression-free at the time of 
analyses will be censored in the analyses. Additional censoring rules may be defined in the 
SAP. Median PFS will be calculated using the Kaplan-Meier method for ITT Analysis Set. A 
Kaplan-Meier plot will also be generated for PFS. 
An additional iPFS analysis based on Investigator assessments using iRECIST will be also be 
performed. 
9.5.5. 
Overall Survival 
OS will be calculated as the time from first CMP-001 injection to death due to any cause. 
Subjects who are alive at the time of analyses will be censored in the analyses at the time of 
last study contact. Median OS will be calculated using the Kaplan-Meier method for the ITT 
Analysis Set. A Kaplan-Meier plot will also be generated for OS. 
9.5.6. 
Post-progression Disease Response 
Post-progression disease assessments of tumor response based on iRECIST evaluated by the 
Investigator will be summarized in a similar way to the RECIST v1.1 assessment, and will 
include the calculation of iORR, iDOR, and iPFS for the ITT Analysis Set. 
9.6. 
Safety Analyses 
The assessment of safety will be based on the following assessments: AEs, clinical laboratory 
tests, vital sign measurements, ECGs, and physical examinations. 
9.6.1. 
Adverse Events 
TEAEs will be coded using MedDRA and data will be summarized for the Safety Analysis 
Set. The number and percent of subjects reporting each TEAE will be summarized, as well as 
the number of TEAEs. A subject with 2 or more TEAEs within the same level of 
summarization (i.e., system organ class [SOC] or preferred term) will be counted only once in 
that level using the most severe event or most related (for the relationship to study treatment 
tables). 
Additional summary tables will be generated for Grade 3 or higher TEAEs, TEAEs 
considered related to treatment (possibly + probably + definitely), TEAEs by maximum grade 
and relationship, TEAEs resulting in death, SAEs, and TEAEs leading to treatment 
discontinuation. 


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A by-subject AE data listing, including verbatim term, SOC, preferred term, treatment, grade 
outcome, and relationship to treatment for CMP-001 and pembrolizumab, will be generated. 
Separate listings will also be generated for TEAEs ≥ Grade 3, TEAEs considered related to 
study treatment (possibly, probably, or definitely), TEAEs resulting in death, SAEs, and 
TEAEs leading to treatment discontinuation. 
9.6.2. 
Clinical Laboratory Assessments 
Safety central laboratory data will be summarized using descriptive statistics (mean, standard 
deviation, median, minimum, and maximum), and presented for each time point, including 
change from Baseline, for the Safety Analysis Set. Shift from Baseline tables will also be 
created. The categories in the shift tables will be WNL, Low, and High. WNL and Normal 
will be used when appropriate for urinalysis parameters. Clinically significant post-Baseline 
laboratory values will be reported as AEs. By-subject data listings of all central laboratory 
data will be generated and all values outside the normal range will be flagged as High or 
Low. Listings of all clinically significant post-Baseline laboratory values from central 
laboratory assessments will be presented in the data listings. 
9.6.3. 
Vital Signs 
Vital signs will be summarized using descriptive statistics (mean, standard deviation, median, 
minimum, and maximum) and presented for each time point, including change from Baseline, 
for the Safety Analysis Set. Clinically significant post-Baseline vital sign findings will be 
reported as AEs. A by-subject data listing of all vital sign data will be generated. 
9.6.4. 
Physical Examinations 
Detailed information on the physical examinations will be listed by subject. Clinically 
significant post-Baseline physical examination findings will be reported as AEs. 
9.6.5. 
Electrocardiograms 
Heart rate, PR interval, QRS interval, QT interval, and QTcF interval will be summarized 
using descriptive statistics (mean, standard deviation, median, minimum, and maximum) and 
presented for each time point, including change from Baseline, for the Safety Analysis Set. 
Clinically significant post-Baseline ECG findings will be reported as AEs. A by-subject data 
listing of all ECG data will be generated. 
9.7. 
Pharmacokinetic Analyses 
Blood samples obtained at predetermined time points may be analyzed for CMP-001 
concentrations and metabolites for the Pharmacokinetic Analysis Set according the Schedule 
of Assessments (Table 1). PK parameters based on the actual sample collection times will be 
determined using standard noncompartmental methods. The PK parameters that may be 
assessed include, but are not necessarily limited to, maximum observed serum concentration 
(Cmax), time of maximum observed serum concentration (tmax), area under the serum 
concentration-time curve from time zero to the last quantifiable time point (AUC0-last), area 
under the serum concentration-time curve from time zero extrapolated to infinity (AUC0-∞), 
terminal elimination half-life (t1/2). 
Additional details on the PK analyses will be provided in the SAP. 


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9.8. 
Pharmacodynamic Analyses 
Concentrations of CXCL10 and other chemokine or cytokine biomarkers will be summarized 
using descriptive statistics for all time points for the Pharmacodynamic Analysis Set. 
9.9. 
Exploratory Tumor Biopsy Analyses 
Tumor biopsy obtained at predetermined time points, according the Schedule of Assessments 
(Table 1), may be analyzed for protein, RNA, DNA, or other biomarkers related to TLR9, 
immune checkpoints, and potential markers of resistance or response to immunotherapy for 
the Pharmacodynamic Analysis Set. 
9.10. 
Appropriateness of Measures 
The safety assessments in this protocol (i.e., physical examination, vital signs, hematology, 
serum chemistry, urinalysis, coagulation, thyroid function, AEs, ECGs, and concomitant 
medications) are widely used and generally recognized as reliable, accurate, and relevant for 
an early phase oncology study. The safety assessments are adequate to protect the subjects’ 
safety. 


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10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
10.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of the 
Sponsor will determine the adequacy of the facilities and discuss with the Investigator(s) and 
other site personnel their responsibilities with regard to protocol adherence, and the 
responsibilities of the Sponsor or its representatives. This will be documented in a Clinical 
Study Agreement between the Sponsor and the Investigator. 
During the study, a monitor from the Sponsor or its representatives will have regular contacts 
with the investigational site, for the following: 
• Provide information and support the Investigator(s) 
• Confirm that the facilities remain acceptable 
• Confirm that the study team is adhering to the protocol, data are being accurately 
recorded in the eCRFs, and the investigational product is being properly 
maintained and accountability records are current 
• Perform source data verification with access to all original clinical records for 
each patient 
Additional details regarding monitoring procedures and responsibilities are provided in the 
Clinical Monitoring Plan. 
10.2. 
Case Report Forms 
Electronic case report form (eCRF) will be used in this study. An eCRF is required and 
should be completed for each screened and enrolled subject. The completed eCRFs are the 
sole property of Checkmate Pharmaceuticals, Inc. and should not be made available in any 
form to third parties without written permission from Checkmate Pharmaceuticals, Inc. 
Limited data will be collected for Screen Failures. 
The Investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the eCRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required. The 
eCRFs must be electronically signed by the Investigator to attest that the data contained on 
the eCRF is true. Any corrections to entries made in the source documents must be dated, 
initialed, and explained (if necessary) and should not obscure the original entry. 
In most cases, the source documents are the hospital’s or physician’s subject chart. In these 
cases, data collected on the eCRFs must match the data in those charts. 


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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. 
Data Quality Assurance 
Steps will be taken to ensure the accuracy and reliability of data. Such steps will include the 
selection of qualified Investigators and appropriate sites, review of protocol procedures with 
Investigators and associated personnel before study start, and periodic site monitoring visits 
by the Sponsor or its representatives. Before study initiation, Investigators and site personnel 
will receive specific training with regards to study procedures and systems as required. 
Training will include use of clinical laboratory kits and central laboratory operations. 
Data management representatives will be available to provide assistance to study center 
personnel regarding entering subject data. The Sponsor or its representatives will review data 
contained within eCRFs for accuracy and completeness during remote and/or on-site 
monitoring visits and after entry into the database. Identified discrepancies will be queried 
and resolved with the Investigator (or designee) as indicated. 
11.2. 
Quality Assurance Audits 
To ensure compliance with Good Clinical Practice (GCP) and all applicable regulatory 
requirements, the Sponsor and/or designee may also conduct a quality assurance audit. The 
purpose of a Sponsor audit or inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted, 
and data were recorded, analyzed, and accurately reported according to the protocol, GCP 
guidelines of the ICH, and any applicable regulatory requirements. 
11.3. 
Audits and Inspections by Regulatory Authorities 
A regulatory authority or an IRB may visit the site to perform audits or inspections. The 
Investigator should contact the Sponsor immediately if contacted by a regulatory agency 
about an inspection. 
11.4. 
Retention of Records 
The Investigator must maintain all documentation relating to the study for a period of 2 years 
after a marketing application is approved for the test article, or if not approved, or if no 
application is to be filed, 2 years following the discontinuance of the test article for 
investigation [21 CFR 312.6I)]. If it becomes necessary for the Sponsor or a Regulatory 
Authority to review any documentation relating to the study, the Investigator must permit 
access to such records. 


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12. 
ETHICS 
12.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate. The 
Investigator must submit written approval to Sponsor or its representatives before he or she 
can enroll any patient/subject into the study. Initial IRB approval and all materials approved 
by the IRB for this study, including the ICF and recruitment materials, must be maintained by 
the Investigator and made available for inspection. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to 
the protocol in accordance with local requirements. No changes will be made in the study 
without IRB approval, except when required to eliminate apparent immediate hazards to 
human subjects. In addition, the IRB or IEC must approve all advertising used to recruit 
subjects for the study. The protocol must be re-approved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the 
investigational product. Sponsor or its representatives will provide this information to the 
Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB or IEC according to local regulations and guidelines. 
Notification of the End of Clinical Trial will be sent to the IRB within 90 days after 
completion of follow-up for the last subject or per local regulations and guidelines. 
In case the study is ended prematurely, the IRB will be notified within 15 days or per local 
regulations and guidelines, including the reasons for the premature termination. 
The Clinical Study Report will be sent to the sites, and IRB where appropriate per local 
regulations and guidance, within one year after the End of Clinical Trial. 
12.2. 
Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol and in accordance with current 
US FDA regulations. This study is also designed to comply with ICH E6 Guideline for GCP 
(CPMP/ICH/135/95), the European Union Clinical Trials Directive 2001/20/EC, as well as 
the ethical principles that have their origin in the Declaration of Helsinki, adopted by the 18th 
World Medical Assembly Helsinki, Finland, June 1964 and subsequent amendments. 
12.3. 
Written Informed Consent 
The ICF should be written in accordance with the current revision of the Declaration of 
Helsinki and current ICH and GCP guidelines. The Sponsor or its representatives will provide 
template ICF to the Investigator. The final ICF must be approved by the Sponsor or 
representatives before being reviewed and approved by the IRB. The final IRB approved 
ICFs must be provided to the Sponsor or its representatives for regulatory purposes. 
The Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study. Subjects must 
also be notified that they are free to discontinue from the study at any time. The subject 


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should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
Each subject must provide voluntary written informed consent (and sign other locally 
required documents) according to local requirements after the nature of the study has been 
fully explained. Each subject must sign an ICF before any study-related activities are 
performed and before participation in the study. A copy of the signed ICF must be provided 
to the subject, and the original signed ICF must remain in each subject’s study file and must 
be available for verification by the study monitor at any time. The Investigator will also 
ensure each subject follows the proper re-consenting procedures for all applicable or 
additional versions of the ICF that become effective while they are enrolled in the study. 


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13. 
PUBLICATION POLICY 
All information concerning CMP-001, Sponsor operations, patent application, formulas, 
manufacturing processes, basic scientific data, and formulation information, supplied by the 
Sponsor or its representatives to the Investigator and not previously published, is confidential 
and remains the sole property of the Sponsor. The Investigator agrees to use this information 
only to complete this study and not for other purposes without the Sponsor written consent. 
The institution and Investigator understand that the information developed in this study will 
be used by the Sponsor in connection with the continued development of CMP-001, and thus 
may be disclosed as required to other Investigators, government regulatory agencies, or other 
scientific groups. To permit the information derived from this study to be used, the 
Investigator is obligated to provide the Sponsor with all data obtained in the study. 


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14. 
LIST OF REFERENCES 
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types with risk of incident head and neck cancer. JAMA Oncol. 2016;2(5):599‐606. 
Appay V, Jandus C, Voelter V, et al. New generation vaccine induces effective melanoma- 
specific CD8+ T cells in the circulation but not in the tumor site. J Immunol. 2006 Aug 
1;177(3):1670-8. 
Bray F, Global Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: Globocan 
estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J 
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Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus 
cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the 
head and neck (KEYNOTE-048)a randomised, open-label, phase 3 study [published 
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Lancet. 2020 Feb 22;395(10224):564]. Lancet. 2019;394(10212):1915‐28. 
Chaturvedi AK, Engels EA, Anderson WF, et al. Incidence trends for human papillomavirus- 
related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 
2008;26(4):612‐9. 
Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 
2013 Jul 25;39(1):1-10. 
Chow LQM. Head and neck cancer. N Engl J Med. 2020;382(1):60‐72. 
Cohen E, Nabell L, Wong D, et al. Phase 1b/2, open label, multicenter study of intratumoral 
SD-101 in combination with pembrolizumab in anti-PD-1 treatment naïve patients with 
recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Journal of Clinical 
Oncology 37, no. 15_suppl (May 20, 2019) 6039-6039. 
Demoulin S, Herfs M, Delvenne P, et al. Tumor microenvironment converts plasmacytoid 
dendritic cells into immunosuppressive/tolerogenic cells: insight into the molecular 
mechanisms. J Leukoc Biol 2013;93:343-52. 
Duncan LD, Winkler M, Carlson ER, et al. p16 immunohistochemistry can be used to detect 
human papillomavirus in oral cavity squamous cell carcinoma. J Oral Maxillofac Surg. 
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Duraiswamy J, Freeman GJ, Coukos G. Therapeutic PD-1 pathway blockade augments with 
other modalities of immunotherapy T-cell function to prevent immune decline in ovarian 
cancer. Cancer Res. 2013;73(23):6900-12. 
Fourcade J, Sun Z, Pagliano O, et al. PD-1 and Tim-3 regulate the expansion of tumor 
antigen-specific CD8+ T cells induced by melanoma vaccines. Cancer Res. 2014 Feb 
15;74(4):1045-55. 
Gillison ML, Alemany L, Snijders PJ, et al. Human papillomavirus and diseases of the upper 
airway: head and neck cancer and respiratory papillomatosis. Vaccine. 2012;30 Suppl 5:F34‐ 
F54. 
Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human 
papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92(9):709‐20. 
Gupta B, Johnson NW, Kumar N. Global Epidemiology of Head and Neck Cancers: A 
Continuing Challenge. Oncology. 2016;91(1):13‐23. 


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Heckelsmiller K, Rall K, Beck S, et al. Peritumoral CpG DNA elicits a coordinated response 
of CD8 T cells and innate effectors to cure established tumors in a murine colon carcinoma 
model. J Immunol. 2002;169:3892-9. 
Hodi FS, Hwu WJ, Kefford R, et al. Evaluation of immune-related response criteria and 
RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin 
Oncol. 2016 May 1;34(13):1510-7. 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH). Integrated Addendum to ICH E6(R1): Guideline for Good Clinical 
Practice E6(R2). Available from: 
https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf (accessed 13 March 2020) 
Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J 
Clin. 2007;57(1):43‐66. 
KEYTRUDA® United States Prescribing Information: Merck & Co., Inc. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s066lbl.pdf. (Accessed 
13 March 2020) 
Kirkwood J, Zakharia Y, Davar D, et al. 950 Final analysis: phase 1b study investigating 
intratumoral injection of toll-like receptor 9 agonist vidutolimod ± pembrolizumab in patients 
with PD-1 blockade–refractory melanoma. JImmunother Cancer. 2021;9. 
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containing virus-like particle enhances in situ immunization. J Immunol. 2020 Mar 
1;204(5):1386-94. 
Lombardi VC, Khaiboullina SF, Rizvanov AA. Plasmacytoid dendritic cells, a role in 
neoplastic prevention and progression. Eur J Clin Invest. 2015 Jan;45 Suppl 1:1-8. 
Mangsbo SM, Sandin LC, Anger K, et al. Enhanced tumor eradication by combining CTLA- 
4 or PD-1 blockade with CpG therapy. J Immunother. 2010;33(3):225-35. 
Milhem MM, Zakharia Y, Davar D, 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. J Immunother Cancer. 2020; 
8(Suppl 3):A331-A331. 
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(NCCN). Cutaneous Melanoma. Version 1; 2020. 
Ndiaye C, Mena M, Alemany L, et al. HPV DNA, E6/E7 mRNA, and p16INK4a detection in 
head and neck cancers: a systematic review and meta-analysis [published correction appears 
in Lancet Oncol. 2015 Jun;16(6):e262]. Lancet Oncol. 2014;15(12):1319‐1331. 
Oken M, Creech RH, Tormey DC, et al. Toxicity and response criteria of the eastern 
cooperative oncology group. Am J Clin Oncol. (CCT) 1982; 5:649-55. 
Power Analysis & Sample Size (PASS). Version 20.0.1 software 2020. 
Ribas, A, Kirkwood, JM, Flaherty, KT. Anti-PD-1 antibody treatment for melanoma. Lancet 
Oncol. 2018 May;19(5):e219. 
Shirota Y, Shirota H, Klinman DM. Intratumoral injection of CpG oligonucleotides induces 
the differentiation and reduces the immunosuppressive activity of myeloid-derived 
suppressor cells. J Immunol. 2012 Feb 15;188(4):1592-9. 


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Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2020. CA Cancer J Clin, 2020;70(1):7-30 
Snow AN, Laudadio J. Human papillomavirus detection in head and neck squamous cell 
carcinomas. Adv Anat Pathol. 2010;17(6):394‐403. 
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Immunol. 2015 Aug;15(8):471-85. 
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resistance to PD-1 blockade by expanding multifunctional CD8+ T cells. Proc Natl Acad Sci 
USA. 2016 Nov 15;113(46):E7240-9. 
Wong DJL, Panwar A, Rosenberg A, et al. CMP-001-007: Open-label, phase 2 study of 
intratumoral CMP-001 + pembrolizumab in patients with recurrent or metastatic head and 
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15. 
APPENDICES 


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APPENDIX A.  ECOG PERFORMANCE STATUS 
 
Grade 
Eastern Cooperative Oncology Group (ECOG)a 
0 
Fully active, able to carry on all predisease-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 housework, office work. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Death 
a. 
Oken et al 1982 


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APPENDIX B. APPROXIMATE MAXIMUM AMOUNT OF BLOOD 
DRAWN FOR 1 YEAR OF STUDY PARTICIPATION 
 
Study Phase 
Estimated Blood Volume 
Screening/Baseline 
25 mL 
Weekly Dosing 
(2 doses every week) 
50 mL 
Q3 Week Visits 
(~16 visits over 1 year) 
400 mL 
End of Treatment 
25 mL 
Total Blood Volume Estimate for 1 year of study 
participation 
500 mL 
(approximately 2 cups) 


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APPENDIX C. COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS (CTCAE) VERSION 5.0 
Common Terminology Criteria for Adverse Events Terms 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical treatment or procedure. An AE is a 
term that is a unique representation of a specific event used for medical documentation and 
scientific analyses. Each CTCAE version 5.0 term is a MedDRA Lowest Level Term. 
Definitions 
A brief definition is provided to clarify the meaning of each AE term. A single dash (-) 
indicates a definition is not available. Grade refers to the severity of the AE. The CTCAE 
displays Grade 1 to Grade 5 with unique clinical descriptions of severity for each AE based 
on this general guideline: 
• 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)*. 
• Grade 3 Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
selfcare ADL**. 
• Grade 4 Life-threatening consequences; urgent intervention indicated. 
• Grade 5 Death related to AE. 
A Semi-colon indicates “or” within the description of the grade. 
A single dash (-) indicates a grade is not available. Not all Grades are appropriate for all AEs. 
Therefore, some AEs are listed with fewer than 5options for Grade selection. 
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Selfcare ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
*Version 5.0 Publish date 27 November 2017 (v5.0: 27 November 2017) 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick 
_Reference_8.5x11.pdf 


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APPENDIX D. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) VERSION 1.1 
Response criteria were adapted from: RECIST Criteria; Version 1.1, 2009 
(https://project.eortc.org/recist/wp-content/uploads/sites/4/2015/03/RECISTGuidelines.pdf) 
These criteria are provided as reference; any discrepancy should be resolved by consulting 
the original publication. 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response, it is necessary to estimate the overall tumor burden at Baseline 
and use this as a comparator for subsequent measurements. Only subjects with measurable 
disease at Baseline should be included in protocols where objective tumor response is an 
endpoint. Measurable disease is defined by the presence of at least 1 measurable lesion. 
A measurable lesion is defined as one that can be accurately measured in at least 1 dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of: 
• 1 cm by CT scan (CT scan slice thickness no greater than 0.5 cm) 
• 1 cm caliper measurement by clinical examination (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 2 cm by chest X-ray 
Non-measurable lesions are defined as all other lesions, including small lesions (longest 
diameter < 1.0 cm or pathological lymph nodes with ≥ 10 to < 1.5 cm short axis) as well as 
truly non-measurable lesions. Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, and abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging 
techniques. 
Special Considerations Regarding Lesion Measurability: 
Bone lesions: 
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. Lytic bone lesions or mixed lytic-blastic lesions, with 
identifiable soft tissue components, that can be evaluated by cross-sectional imaging 
techniques such as contrast-enhanced CT or MRI can be conserved as measurable lesions if 
the soft tissue component meets the definition of measurability described above. Blastic bone 
lesions are non-measurable. 
Cystic lesions: 
Lesions that meet the criteria for radiographically-defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability described 
above. However, if noncystic lesions are present in the same subject, these are preferred for 
selection as target lesions. 
Lesions with prior local treatment: 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 


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loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
Baseline Documentation of Target and Non-Target Lesions 
Baseline documentation of tumor sites may include imaging assessment of disease in the 
chest, abdomen, and pelvis. A Baseline CNS image is required for all subjects within 3 
months of Screening. All Baseline tumor measurements must be documented within 4 weeks 
before start of therapy. 
Target Lesions 
All measurable 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 (this means in instances where subjects have only 1 or 
2 organ sites involved a maximum of 2 and 4 lesions, respectively, will be recorded). 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. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest 
lesion that can be measured reproducibility should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the Baseline sum diameters. If lymph nodes are to be included in 
the sum, then as noted above, only the short axis is added into the sum. The Baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
Non-target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at Baseline. Measurements are not required, 
and these lesions should be followed as ‘present,’ ‘absent,’ or in rare cases ‘unequivocal 
progression.’ In addition, it is possible to record multiple non-target lesions involving the 
same organ as a single item on the case record form (i.e., ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
Tumor Response Criteria 
Evaluation of Target Lesions 
Complete response: Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 1 cm. 
Partial response: At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the Baseline sum diameters. 
Progressive disease: At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the Baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 0.5 cm (NOTE: the appearance of 1 or more new lesions is also 
considered progression). 
Stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 


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Evaluation of Non-Target Lesions 
Complete response: Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 1 cm short axis). 
Non-complete response/Non-progressive disease: Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits. 
Progressive disease: Unequivocal progression of existing non-target lesions (NOTE: the 
appearance of 1 or more new lesions is also considered progression). 
Evaluation of Best Overall Response 
The best overall response (BOR) is recorded from the start of the study treatment until the 
End of Clinical Trial, taking into account any requirement for confirmation. The subject’s 
BOR assignment will depend on the findings of both target and non-target disease and will 
also take into consideration the appearance of new lesions. In non-randomized studies where 
response is the primary endpoint, confirmation of PR or CR is needed to deem either one the 
‘BOR.’ 
Determination of Tumor Response 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Response Assessment 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not Evaluated 
No 
PR 
PR 
Non-PD or Not All 
Evaluated 
No 
PR 
SD 
Non-PD or Not All 
Evaluated 
No 
SD 
Not All Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable 
disease. 
NOTE: Subjects 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.” Every effort should be made to document the objective 
progression, even after discontinuation of treatment. Conditions that may define “early 
progression, early death, and inevaluability” are study-specific and should be clearly defined 
in each protocol (depending on treatment duration and treatment periodicity). In some 
circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of CR depends upon this determination, it is recommended that the residual lesion 
be investigated (fine needle aspiration/biopsy) before confirming the CR status. 
Best Overall Response When Confirmation of CR or PR Are Required 
When confirmation of response is required, CRs or PRs may be claimed only if the criteria 
for each are met at a subsequent time point as speciﬁed in the protocol (generally 4 weeks 
later). 


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Confirmation of CR and PR 
Overall 
Response 
First Time Point 
Overall Response 
Subsequent Time 
Point 
BOR 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise 
PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise 
PD 
CR 
NE 
SD provided minimum criteria for SD duration met, otherwise 
NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise 
PD 
PR 
NE 
SD provided minimum criteria for SD duration met, otherwise 
NE 
NE 
NE 
NE 
Abbreviations: BOR = best overall response; CR = complete response; NE = not evaluable; PD = progressive 
disease; PR = partial response; SD = stable disease. 
a. If a CR is truly met at the first time point, any disease seen at a subsequent time point, even disease meeting 
PR criteria relative to Baseline, makes the disease PD at that time point (because disease must have reappeared 
after CR). Best response would depend on whether minimum duration for SD was met. However, “CR” may 
be claimed when subsequent scans suggest small lesions were likely still present and in fact the subject had 
PR, not CR at the first time point. Under these circumstances, the original CR should be changed to PR and 
the best response PR. 
 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation using a ruler or calipers. All 
Baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of treatment. 
NOTE: Tumor lesions in a previously irradiated area are not optimally considered measurable 
disease. If the Investigator thinks it appropriate to include them, the conditions under which 
such lesions should be considered must be defined in the protocol. 
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. Imaging-based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical examination. 
Clinical lesions will only be considered measurable when they are superficial and 1 cm 
diameter as assessed using calipers (i.e., skin nodules). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
suggested. 
For chest lesions, 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 


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lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
Cross-sectional imaging: Computed tomography 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 0.5 cm or less. When CT scans have slice thickness greater than 0.5 cm, the minimum size 
for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (i.e., for body scans). 
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 contrast-enhanced CT or MRI is advised. If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). The 
duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the Baseline sum is the smallest, this is 
the reference for calculation of PD). 
Time to Disease Progression 
Defined as the time from the date of first day of enrollment to progression, as assessed by the 
conventional response criteria, death, or the start of further antitumor therapy. Subjects lost to 
follow-up will be censored at their last known alive date. 


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APPENDIX E. IMMUNOTHERAPY RESPONSE EVALUATION 
CRITERIA IN SOLID TUMORS (IRECIST) 
Response criteria were adapted from: Response Evaluation Criteria in Solid Tumors 
(RECIST) for use in trials testing immunotherapeutics; published in final edited form as: 
Lancet Oncol. 2017 March; 18(3): e143–e152. doi:10.1016/S1470-2045(17)30074-8. These 
criteria are provided as reference; any discrepancy should be resolved by consulting the 
original publication. 
iRECIST 
The basic principles of defining tumor lesions as measurable or non-measurable and 
assessing tumor responses used in iRECIST remain unchanged from RECIST v1.1. The most 
important change is in the introduction of an additional follow-up to confirm or withdraw an 
‘unconfirmed’ tumor progression after initial increase in size. Similar to RECIST v1.1, 
iRECIST is primarily based on the use of contrast-enhanced CT and MRI, while inclusion of 
clinically visible superficial lesions in malignant melanoma is possible as well. 
Baseline Evaluation 
At Baseline, iRECIST is used similarly to RECIST v1.1 to determine the total tumor burden 
by defining target and non-target lesions. For that purpose, a distinction is made between 
measurable and non-measurable lesions (target lesions and non-target lesions). 
Target Lesions 
All measurable solid tumor manifestations with a minimum long axis diameter ≥ 10 mm (or 
at least double slice thickness), nodal lesions with a short axis diameter ≥ 15 mm and clinical 
measurements of superficially localized tumor lesions ≥ 10 mm (documented 
photographically using a tape measure) can be defined as target lesions. 
Of these potential target lesions, analogous to RECIST v1.1, up to 5 lesions per subject can 
be determined within iRECIST, of which a maximum of 2 lesions per organ can be defined as 
target lesions. Paired organs, such as lung or kidneys, and organ systems, such as the skeletal 
or lymphatic systems, are understood as an organ group for which a maximum of 2 target 
lesions can be defined. The individual quantitative measurement results of the selected target 
lesions are noted and documented as a Baseline target sum. This Baseline sum diameters are 
used as reference to further characterize any objective tumor regression or progression in the 
measurable dimension of the disease. 
Non-Target Lesions 
Non-target lesions are lesions that may not be measured with a sufficient amount of 
reproducibility, e.g., solid tumor lesions < 10 mm, lymph node metastases with a short axis 
diameter ranging between 10 and 14 mm and tumor manifestations without clear borders like 
infiltrative organ metastases, lymphangitis carcinomatosa, or lesions with highly variable 
distribution patterns, such as malignant pleural and pericardial effusion or ascites. In addition 
to these non-target lesions, all other potential measurable target lesions which have not been 
selected for the category target lesions are also added to the non-target lesions category. 
Several tumor lesions of 1 organ could be combined into 1 organ group, such as ‘multiple 
lung metastases’ or ‘diffuse liver metastasis.’ Non-target lesions are qualitatively documented 
as ‘present’ and do not require a specific indication of quantitative size or absolute number. 


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This procedure is intended to warrant complete lesion documentation in case of uncountable 
metastases. 
Bone and Cystic Lesions 
According to RECIST v1.1, there are specific recommendations regarding bone lesions, 
cystic lesions, and lesions previously treated with local therapy. First, osteolytic bone lesions 
or mixed lytic-blastic lesions with a measurable soft tissue component ≥ 10 mm could be 
considered as a target lesion. However, osteoblastic bone lesions represent non-target lesions. 
Second, cystic metastatic lesions ≥ 10 mm could be considered as target lesions. However, if 
noncystic target lesions are present in the same subject, these should be preferred. Finally, 
lesions with prior local treatment, e.g., radiation therapy or biopsy, should usually not be 
considered as target lesions unless there has been demonstrated clear tumor progression 
afterwards. 
Follow-up 
Regular follow-up response assessment every 6 to 12 weeks is recommended for iRECIST. 
During iRECIST follow-up monitoring, in line with RECIST v1.1, all target lesions defined 
at Baseline must be quantitatively re-measured and all non-target lesions must be 
qualitatively re-evaluated. The measurement of the maximum diameter of the target lesion at 
the new follow-up is independent of the previous direction of the measurement within the 
lesion or slice position, but always in identical slice orientation. In case a target lesion is 
reported as too small to measure but still visible, a default value of 5 mm could be used. In 
the rare case if a target lesion splits into 2 separate lesions, the separate measurements of the 
lesions should be added together for the target lesion sum. In case target lesions coalesce and 
are radiologically no longer separable, the maximum longest diameter for the coalesced 
lesion should be provided and the other lesion should be noted with 0 mm. Lymph node 
metastases are handled specifically. Even under a highly effective treatment, in most cases 
they will never fully disappear and will only shrink to their physiological size. Lymph nodes 
are considered as tumor-free once their short axis diameter is < 10 mm, but the measurements 
should be recorded in all subsequent follow-ups in order not to overstate progression in case 
of a minor increase in size, e.g., from 9 mm to 11 mm. This means that when lymph node 
metastases are target lesions, the tumor burden will mostly not become ‘zero’ even in the case 
of a CR. Please notice that a target lesion defined at Baseline assessment always remains a 
target lesion, even if it shows a size reduction to less than 10 mm. Similarly, a non-target 
lesion yielding a size increase of more than 10 mm at follow-up remains a non-target lesion 
but could qualify for ‘unequivocal progression’ in case of an overall level of substantial 
worsening in non-target disease. 
With regards to the measurable target lesion, the proportional change of the sum of the target 
lesion can be calculated with the formula: Change in (%) = ([∑Follow-up - ∑Baseline/ 
∑Nadir]/ ∑Baseline/ ∑Nadir) * 100. This formula takes as reference the smallest target sum 
in the study, the so-called Nadir, which could be the Baseline target sum if that is the smallest 
sum in the study. 
Non-target lesions are assessed qualitatively, i.e., visually, as ‘present,’ ‘disappeared,’ or 
‘unequivocal progression.’ When considering determining an ‘unequivocal progression’ of a 
non-target lesion, the total tumor load should always be taken into account in proportion and 
carefully weighed, as this would necessarily imply classification of ‘PD,’ even if all other 
lesions have responded strongly or even completely. In case of doubt, the responsible 
oncologist should be consulted. 


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In contrast to RECIST v1.1, where new tumor lesions are considered qualitatively and 
directly denote ‘PD’ and end of study, within iRECIST they are differentiated into new 
measurable and non-measurable lesions. Although new tumor lesions within iRECIST will 
also be classified as tumor progression, this progression initially counts as an immune 
unconfirmed progressive disease (iUPD), which should be re-assessed in a dedicated earlier 
follow-up after 4 to 8 weeks. For classification as new measurable or non-measurable tumor 
lesions, criteria applied are the same as for the Baseline examination with a maximum of 5 
measurable new target lesions per subject and 2 per organ, respectively, which are measured 
as a separate group at the time of the first occurrence while the sum product of all new 
measurable target lesions is determined. The new non-measurable lesions are documented 
qualitatively, similarly to the non-target lesions at Baseline. Tumor lesions diagnosed for the 
first time in a previously unexamined body region are also classified as ‘new lesions’ in line 
with RECIST v1.1. The rationale behind this procedure is that the extension of imaging to a 
previously unexamined region, which leads to the detection of new tumor lesions, is usually 
triggered by the occurrence of new clinical symptoms. 
In case of a new unclear lesion, e.g., because of its small size, this lesion should be preferably 
noted as a ‘finding,’ therapy should be continued, and follow-up evaluation could clarify if it 
represents truly new disease. If repeat examination confirms a new tumor lesion, then 
progression should be declared using the date of the initial scan when the lesion was first 
detected. 
Tumor Response Criteria 
The overall response according to iRECIST results from the combination of changes in target 
lesion and non-target lesion, as well as the possible detection and change of new measurable 
and non-measurable tumor lesions. The objective response in the context of immunotherapy 
(with the prefix ‘i’ for immune-related) is differentiated into: 
• iCR, which describes the complete disappearance of target lesion and non-target 
lesion. All lymph nodes must be non-pathological in size (< 10 mm in short axis 
diameter). 
• iPR, which occurs when the tumor load of the target lesion is reduced by ≥ 30% 
compared to the Baseline, or in the case of complete remission of the target lesion, 
when 1 or more non-target lesions can still be distinguished 
• Immune stable disease (iSD), which is to be determined if the criteria of iCR or 
iPR are not met and no tumor progression is present 
In case of a tumor progression and in order to facilitate differentiation of true tumor 
progression from pseudoprogression in clinically stable subjects, iRECIST proposes to 
determine first: 
• Unconfirmed progressive disease due to an increase in the sum of all target lesions 
by at least 20% (but at least ≥ 5 mm) compared with the time point with the lowest 
target lesion sum (Nadir), or an unequivocal progression of non-target lesions, or 
by the occurrence of new measurable and/or non-measurable target lesions 
• This initially unconfirmed tumor progression might be confirmed by a subsequent 
follow-up where: 
- 
Immune confirmed progressive disease is present if further progress of 
the target sum (≥ 5 mm), or any further progress of the non-target lesion, 


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and/or progress of the new measurable and non-measurable lesions either 
in number or in size (sum ≥ 5 mm) 
In case of iUPD, the follow-up for re-evaluation and diagnosis of potential pseudoprogression 
should be carried out earlier after 4 to 8 weeks, in contrast to the regularly recommended time 
interval of 6 to 12 weeks. In case tumor progression is not confirmed and target lesions, non- 
target lesions, and new lesions remain unchanged, iUPD status should be kept and subsequent 
follow-up should be performed according to the regular schedule, e.g., after 8, 16, and 24 
weeks. Moreover, if the tumor burden decreases more than 20%, this should be considered 
iSD; if it decreases more than 30%, this should be considered iPR. If tumor lesions 
completely disappear, there is iCR even after iUPD. 
However, in iRECIST it is clearly recommended to carefully consider the continuation of 
immunotherapy at the first stage of iUPD. This decision should be thoroughly discussed with 
both subject and referring physicians and made only in case of subjective stable tumor 
disease or clinically suspected pseudoprogression. New lesions in a potentially curative 
therapy approach could be biopsied in order to enable a more reliable differentiation of rare 
pseudoprogression from more frequent PD and to be able to initiate an early modification of 
the tumor therapy before the subject may no longer tolerate it due to a physical deterioration. 
In the case that a biopsy is not technically feasible or only feasible with a significantly 
increased risk, the confirmation of the less probable delayed therapy response can be 
represented by a follow-up after 4 to 8 weeks in subjectively stable tumor subjects during this 
period. 
According to RECIST v1.1, the RECIST working group did not believed that there were 
sufficient data available to recommend implementation of a metabolic and/or functional 
imaging response parameter. An exception is the use of fluorodeoxyglucose (FDG)-PET 
imaging as an adjunct to determination of progression if a positive FDG-PET at follow-up 
corresponds to a new site of disease confirmed by CT. However, the actual literature does not 
support the non-invasive differentiation of true progression from pseudoprogression by 
PET/CT. 
Evaluation of Best Overall Response 
For iRECIST, the BOR is the best time point response recorded from the start of 
immunotherapy until the end of treatment. Immune unconfirmed disease progression will not 
override a subsequent BOR of iSD, iPR, or iCR. 


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APPENDIX F. INTRATUMORAL RESPONSE EVALUATION 
CRITERIA IN SOLID TUMORS (ITRECIST) VERSION 
1.1 
Response criteria were adapted from: itRECIST Criteria as described in Goldmacher GV, 
Khilnani AD, Andtbacka R, Luke RJ, F. Hodi S, et al. Response criteria for intratumoral 
immunotherapy in solid tumors: itRECIST. J Clin Oncol. 2020; 38:15_suppl, 3141 
(Goldmacher-2020). These criteria are provided as reference; any discrepancy should be 
resolved by consulting the original publication. 
INTRODUCTION 
Intratumoral (IT) immunotherapy is approved for stage IIIB to IV melanoma and under 
evaluation in other malignancies with novel immune-stimulatory products. Standardized 
efﬁcacy evaluation is essential for drug development. Current oncology response criteria, 
such as Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and 
guidelines for immunotherapeutic trials (iRECIST), were designed only to assess response to 
systemic therapy. 
RECIST is an evolving standardized framework for evaluating changes in tumor size, that is 
used in clinical trials to deﬁne treatment responses and disease progression. RECIST 1.1 and 
iRECIST are unsuitable for IT immunotherapy trials for several reasons. Because they were 
designed for systemic therapy, focal intervention renders treated lesions nonevaluable. 
RECIST 1.1 does not allow separate response assessment in injected and noninjected lesions, 
which is critical for IT immunotherapy trials. Moreover, there is no consensus on injected 
lesion assessment when lesions chosen for injection may change during treatment because of 
regression, loss of accessibility, or growth of other lesions. iRECIST has limited usefulness 
because the purpose of assessment after initial progression is solely to exclude 
pseudoprogression; it does not consider that the lesions selected for injection may change at 
progression. 
Nevertheless, the experience of developing iRECIST by revising RECIST 1.1 for 
immunotherapy provides valuable guidance. Before the consensus effort of the RECIST 
Working Group, stakeholders devised divergent approaches to RECIST modiﬁcation for 
immunotherapy, resulting in confusion and incomparability among trials. Without 
standardization, these issues may recur for IT therapy. 
The goal of IT RECIST (itRECIST) is to create guidelines for capturing data and assessing 
response in IT immunotherapy trials. As with iRECIST, the standardized data collection and 
initial suggestions for response assessment of itRECIST will be reﬁned based on collected 
data. We anticipate itRECIST will initially be used for exploratory analyses, with primary 
and secondary end points based on RECIST 1.1, until evidence indicates that itRECIST 
improves efﬁcacy assessment. 
itRECIST 
itRECIST is designed to address the unique needs of IT immunotherapy trials but, where 
possible, aligns with RECIST 1.1 and iRECIST. It does not dictate which lesions to inject at 
each visit, but rather provides guidelines for assessing responses as treatment evolves. The 
key questions, and the approaches to answering them, are as follows: 


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1. What is the overall response? Overall response is determined as per RECIST 1.1 (or 
per iRECIST, after initial progression). 
2. What is the maximal effect of IT therapy (with or without systemic therapy) on 
noninjected lesions? The smallest (nadir) total size of predesignated noninjected 
lesions is compared with pretreatment size. 
3. What is the effect of therapy on injected lesions? During treatment, an iterative 
assessment accounts for changes in lesions selected for injection. After treatment, a 
combined response compares the smallest size achieved by each injected target lesion 
with its size before injection. 
It is important to deﬁne a lexicon of precise and simple terms for these criteria; novel, 
nonintuitive terminology hinders understanding and adoption. Therefore, lesions are 
classiﬁed as injected or noninjected, and the terms injected response and noninjected 
response describe response in injected and noninjected lesions, respectively. The choice not 
to use the term abscopal effect was deliberate, because this implies causality: injecting lesion 
A causes a response in lesion B. Many IT immunotherapies are administered with systemic 
immunotherapies; hence, noninjected lesions may be affected by systemic therapy alone. 
LESION MEASUREMENT 
Lesion measurements should be performed per RECIST 1.1, with one exception. Brieﬂy, 
either computed tomography (CT) or magnetic resonance imaging should be used to measure 
target lesions. For skin lesions, RECIST 1.1 recommends color photography documentation, 
including a size standard or caliper for scale. 
RECIST 1.1 does not allow ultrasound for lesion measurement because of operator 
dependence and difﬁculty with standardization. However, in practice, ultrasound may be the 
only practical choice for some subcutaneous lesions. Therefore, itRECIST permits ultrasound 
measurement if no other lesions are available for quantitative assessment (Data Supplement). 
When feasible, the same operator should perform the ultrasound at all visits using the same 
equipment and acquisition parameters, capturing lesion images in a similar orientation, with 
anatomic landmarks to align with preceding scans. Standard RECIST 1.1 thresholds apply to 
consider a lesion measurable (≥ 10-mm longest diameter for extranodal lesions, ≥ 15-mm 
short axis for lymph nodes). 
Most importantly, investigators should use the same imaging technique for a given target 
lesion at each assessment to evaluate changes over time. For instance, if a patient underwent 
CT at Baseline and ultrasound-guided IT immunotherapy for liver metastasis, response 
assessments should be based on repeat CT. Although pre-IT injection ultrasound assessments 
might yield information about the kinetics of response, ultrasound should not be used in 
itRECIST calculations in this speciﬁc example. 
The intent with itRECIST is to capture both systemic and local effects of IT therapy. Thus, 
unlike in RECIST 1.1, injected lesions remain evaluable for overall response assessment even 
after local procedures, such as electroporation or low-dose irradiation, as long as these are 
integral to the IT regimen to support or enhance the injection effect. Although intralesional 
administration techniques and intrinsic tumor factors add variability to changes resulting 
from injection, no obvious adjustment to measurement methods would improve response 
assessment. Tumor biopsies are often performed as part of a clinical trial. Excisional biopsy 


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renders a lesion nonevaluable in itRECIST. Although core needle biopsy would not 
automatically make a lesion nonevaluable, its use is discouraged for target lesions. When 
feasible, biopsies should be restricted to nontarget lesions. 
BASELINE DOCUMENTATION OF TUMOR BURDEN 
At Baseline, lesions are classiﬁed as measurable (eligible for selection as target lesions) or 
nonmeasurable per RECIST 1.1 guidelines on size and reproducibility. Baseline lesions are 
categorized as target injected (T-I), target noninjected (T-NI), nontarget injected (NT-I), and 
nontarget noninjected (NT-NI) according to an algorithm (see Figure 1A as found in the 
primary publication Goldmacher-2020). As in RECIST 1.1, target refers strictly to lesions 
that are selected for measurement; it has no relationship to lesions selected for injection. One 
to 5 measurable lesions are designated as T-I and are used to evaluate the injected lesion 
response. One to 5 measurable lesions are designated as T-NI and remain noninjected for as 
long as possible to allow assessment of the maximal noninjected lesion response, as discussed 
in a later section. A sum of diameters (SOD; longest diameters for extranodal lesions and 
short axis for lymph nodes) is calculated for all target lesions combined, and separately for T- 
I and T-NI lesions (see Figure 1A as found in the primary publication Goldmacher-2020). 
If only 1 lesion is measurable, although others are accessible for injection but not suitable for 
reproducible quantiﬁcation, the measurable lesion should be designated as T-NI, because it 
may be more important to detect objective responses in noninjected lesions than in injected 
lesions as a means of assessing treatment efﬁcacy. This suggestion must, of course, be 
considered in light of other clinically signiﬁcant factors, such as whether the measurable 
lesion should be injected to palliate symptoms and whether the other injectable lesions offer 
sufﬁciently attractive injection targets to achieve the overall treatment goals. 
RECLASSIFICATION OF LESIONS AFTER BASELINE 
Injected lesions may change if those initially injected regress or become inaccessible, or if 
others enlarge. Nevertheless, target lesions always remain target, and nontarget lesions 
remain nontarget, regardless of whether they receive injections (see Figure 1B as found in the 
primary publication Goldmacher-2020). If initially noninjected lesions enlarge, the treating 
physician may decide the enlarging T-NI lesions can be controlled by injection (especially if 
injected lesions are regressing). Once injected, these lesions are recategorized as T-I lesions. 
T-NI lesions can also be injected when previously injected lesions regress or become 
noninjectable, particularly when initially selected T-NI lesions are not regressing (maximal 
noninjected effect has been achieved). NT-NI lesions may be recategorized as NT-I and 
injected when the original NT-I lesions can no longer be injected because of regression, 
inaccessibility, injection-site reaction, patient intolerance, or need for more aggressive 
anesthesia. 
Guidelines for Prioritization of Lesion Injection for IT Therapy 
Selection and prioritization of lesions for IT injection is a complex set of decisions made at 
each treatment visit and is ultimately based on clinical judgment. A complete description of 
the process is beyond the scope of this guidance, which is focused on response assessment, 
but a set of guiding principles follows. 
The ﬁrst priority is patient safety. Lesions are selected to minimize the potential for 
procedural complications and operational complexity. One important safety concern is 


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vascularity within and adjacent to a lesion. To minimize systemic administration, injection 
into tumor vasculature should be avoided. To minimize bleeding risk, vessels adjacent to a 
tumor should not be traversed, and areas of vascular encasement should be avoided in high- 
risk locations (e.g., inferior vena cava encasement for liver lesions, great vessel encasement 
for head and neck tumors). 
The next priority is accessibility. Preference is given to visible cutaneous lesions, and 
superﬁcial subcutaneous lesions and lymph nodes which are easily palpable. Deeper lesions, 
including nonpalpable lymph nodes and extranodal lesions in viscera or body cavities, are 
more difﬁcult to access and typically require imaging guidance, increasing procedural 
complexity. Deciding to inject a lesion based on accessibility must be balanced against 
potential clinical beneﬁts such as symptom relief. 
At initiation of therapy, other factors guiding lesion prioritization include size and amount of 
viable tumor tissue. Other factors being equal, larger lesions are preferred because of the 
greater amount of tissue and because the likely older age of the lesion may indicate the 
potential to release a wider breadth of tumor-speciﬁc antigens to stimulate a broader 
repertoire of antigen-speciﬁc T cells. Very large lesions should be approached cautiously 
because of possible central necrosis, increased bleeding risk, and difﬁculty dispersing 
immunotherapeutics. Radiographically visible necrosis should be avoided, with IT therapy 
directed at viable portions of lesions. A larger lesion that is predominantly necrotic may have 
lower priority than a smaller lesion with little or no radiographic necrosis. Lesions with 
radiographic evidence of aggressiveness (e.g., local invasiveness) should have higher priority. 
If additional lesions are injected after therapy begins, new or enlarging lesions should be 
given priority over lesions selected based on size or imaging features, but safety and 
accessibility are still paramount. These lesions contain actively dividing cells and therefore 
may be more responsive to injection. In addition, new or enlarging lesions may contain 
cancer cells that represent the vanguard of the disease as it attempts to evolve under the 
selective pressure of immunotherapy. These lesions could harbor new tumor antigens not 
strongly represented in previously injected lesions. Although some lesion types or anatomic 
locations may be better for stimulating systemic immune responses, evidence is insufﬁcient 
to use such information for lesion prioritization. Nonetheless, data related to lesion response 
by disease site will inform such choices in the future. 
Response Assessment Before Radiographic Progression 
Overall response. The principle that target lesions remain target and that nontarget lesions 
remain nontarget regardless of injection status allows an overall assessment for each imaging 
visit similar to that for RECIST 1.1 (different only in allowing more target lesions, in injected 
lesions not becoming nonevaluable, and allowing ultrasound). Target lesion response, 
nontarget lesion response, and new lesion appearance are deﬁned as they are for RECIST 1.1 
and combined similarly to determine overall response for each visit (see Figure 2 as found in 
the primary publication Goldmacher-2020). The overall response should include all lesions 
classiﬁed as target at Baseline (SOD of T-I and T-NI combined v SOD at Baseline and at 
nadir) and all nontarget lesions (NT-I and NT-NI) combined (classiﬁed as absent, present, or 
collectively showing unequivocal progression). Of note, the rare instances of seeding along a 
needle track should not be reported as new lesions unless they show growth on subsequent 
imaging. 


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The role of ﬂuorodeoxyglucose (FDG)–positron emission tomography and biopsy in 
assessing response must be further evaluated. Because radiographic assessment might not 
correlate with tissue response and loss of FDG uptake in injected lesions may represent 
necrosis, biopsy may provide additional information in case of doubt. 
In the neoadjuvant setting, IT immunotherapy may yield pathologic complete response (pCR) 
rates surpassing clinical response rates (which include radiographic objective response and 
clinical assessment). For example, after 12 weeks of neoadjuvant talimogene laherparepvec 
in resectable stage IIIB to IVM1a melanoma, 3 patients achieved clinical CR and all achieved 
pCR. Additionally, 1 of 7 patients with clinical partial response (PR) achieved pCR, 6 of 21 
patients with clinical stable disease (SD) achieved pCR, and even 2 of 35 patients with 
clinical progressive disease (PD) achieved pCR. Subanalysis of noninjected response may not 
apply in the neoadjuvant setting if only a single lesion is present initially. 
Noninjected response. Noninjected response is based entirely on T-NI lesions. The SOD for 
these lesions at each time point is compared with those at Baseline and nadir, similar to target 
lesion response assessments in RECIST 1.1 (Table 8). Lesions designated T-NI at Baseline 
should remain noninjected for as long as possible to allow assessment of maximal systemic 
response to IT therapy in noninjected lesions. The treating physician may choose to inject T- 
NI lesions when they enlarge (systemic therapy alone is not restraining their growth) or when 
previously injected lesions have become noninjectable, especially if the T-NI lesions are not 
regressing. Once any T-NI lesion is injected, the noninjected response becomes nonevaluable. 
Table 8: 
Response for Lesion Category 
 
Responses 
Definition 
T-I lesions 
CR 
All nonnodal lesions gone, nodal lesions < 10 mm 
PR 
≥ 30% decrease in SOD from last imaging assessment 
PD 
≥ 20% increase in SOD from last imaging assessment (≥ 5 mm 
absolute) 
SD 
Not enough growth for PD 
Not enough shrinkage for PR 
NE 
≥ 1 lesion cannot be measured 
T-NI lesions 
CR 
All nonnodal lesions gone, nodal lesions < 10 mm 
 
PR 
≥ 30% decrease in SOD from last imaging assessment 
PD 
≥ 20% increase in SOD from last imaging assessment (≥ 5 mm 
absolute) 
SD 
Not enough growth for PD 
Not enough growth for PD 
NE 
≥ 1 lesion cannot be measured or has been injected 
Abbreviations: CR, complete response; NE, nonevaluable; PD, progressive disease; PR, partial response; SD, 
stable disease; SOD, sum of diameters; T-I, target injected; T-NI, target noninjected. 


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Overall response, however, remains evaluable because it is based on all target lesions 
together. As discussed below in the section on end points, the best noninjected response and 
maximal tumor shrinkage are determined based on assessments before injection of any T-NI 
lesion. 
Injected response. Lesions selected for injection may change at each treatment visit, so there 
is no stable Baseline for comparison. Therefore, during treatment, the response assessment 
for injected lesions is iterative. At each assessment, the current SOD for all target lesions 
injected during the preceding treatment visit (whether originally classiﬁed or reclassiﬁed as 
T-I) should be compared with their SOD at the preceding assessment (see Figure 3 as found 
in the primary publication Goldmacher-2020). The injected response is based on SOD change 
from the previous assessment (Table 8). The decision about which lesions to inject should be 
made at this time, based on the guidelines for lesion prioritization outlined here. The new T-I 
SOD should be calculated and used as the comparator for the next assessment. After 
treatment discontinuation or during an interim analysis, the best response for injected lesions 
is determined by comparing the size of each injected lesion at its smallest with its size before 
ﬁrst injection, as discussed in the section on end points. 
Decisions at RECIST Progression 
At the time of PD as deﬁned in RECIST 1.1, clinical assessment should determine whether 
continued IT immunotherapy is warranted. If clinical progression is rapid, the decision may 
be made to discontinue study treatment. If the patient’s condition is clinically stable as 
deﬁned in iRECIST, it may be appropriate to continue treatment. 
Continuing treatment in the setting of RECIST 1.1 PD is particularly relevant with a mixed 
response, when injected lesions regress or disappear but a new lesion develops or when 
existing noninjected lesions enlarge. In such a case, as discussed, the treating physician may 
reprioritize which lesions to inject, favoring new or enlarging lesions, if they are deemed safe 
and accessible for injection. 
The challenge for IT immunotherapy assessment is not only to avoid misclassiﬁcation of 
inﬂammatory reactions (pseudoprogression) as disease progression but also to account for 
injection of new or previously noninjected lesions. Additionally, the interval to conﬁrmatory 
reassessment should allow sufﬁcient time for IT therapy to produce an effect on these lesions; 
we recommend allowing 4 to 12 weeks (rather than 4 to 8 weeks per iRECIST). 
Management at initial radiographic progression (overall response) depends on whether new 
lesions appear. For clinically stable subjects without new lesions, lesions should be injected if 
they are progressing or were previously injected, and consideration should be given to 
additional noninjected lesions according to the prioritization guidelines (see Figure 4A as 
found in the primary publication Goldmacher-2020). 
New lesions, if present, should be categorized as new target or new nontarget lesions (per 
iRECIST), and the SOD of the new lesions should be calculated for future overall response 
assessment. If the new lesions are inaccessible, only existing lesions should continue to be 
injected, including those that are enlarging and those not yet injected. If the new lesions are 
accessible, they should be injected according to the principles previously outlined (see Figure 
4B as found in the primary publication Goldmacher-2020). Again, the decision to inject 
should be based on prioritization rules and clinician discretion (described in Guidelines for 


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Prioritization of Lesion Injection for IT Therapy). Regardless of the presence or absence of 
new lesions, treatment should be discontinued in subjects with clinically unstable disease. 
Response Assessment After RECIST Progression 
Overall response for visits after RECIST progression is determined using a process similar to 
iRECIST, taking into account target lesions (injected and noninjected combined), nontarget 
lesions (injected and noninjected combined), and new lesions, to produce overall response 
categories that include immunotherapeutic CR, immunotherapeutic PR, immunotherapeutic 
SD, immune unconﬁrmed PD (iUPD), and immune conﬁrmed PD (iCPD). An additional 
response category is described in the next section. 
Injected lesion assessment after RECIST 1.1 progression uses the same iterative process as 
before. At each assessment, the current SOD of all target lesions injected at the previous visit 
(including any new lesions classiﬁed as new lesion targets and selected for injection) should 
be compared with the immediately preceding SOD of the same lesions. Then, based on 
prioritization rules and clinician discretion, the physician determines which lesions to inject 
at this visit, and the SOD of these is the new comparator for the next assessment. 
Noninjected response after overall progression is also assessed as it was before. As long as 
the T-NI lesions remain noninjected, the T-NI SOD is compared with Baseline and nadir 
values to determine the noninjected lesion response. If any T-NI lesion must be injected (e.g., 
because of enlargement or because of inaccessibility of other lesions), the maximal 
noninjected response has been achieved and any subsequent noninjected response is 
considered nonevaluable. 
Management and Response After Conﬁrmed Progression 
If RECIST 1.1 PD has been observed and a conﬁrmatory scan shows conﬁrmed PD per 
iRECIST, it may be appropriate to continue therapy and modify the lesions for injection. As 
discussed, these are typically mixed responses: injected lesions are responding, but new 
lesions have appeared or noninjected lesions have enlarged. 
For example, if Baseline lesions are responding but a new lesion appears, this would be 
RECIST 1.1 PD (and iUPD by itRECIST). If the new lesion is injected and the next scan 
shows that this lesion, along with other injected lesions, has responded favorably but an 
additional new lesion has appeared, this would be considered iCPD by iRECIST, and therapy 
would be stopped. However, because the injected lesions are responding, the treating 
physician may decide (if the patient remains clinically stable) that the patient is deriving 
beneﬁt from continued IT immunotherapy, inject the new lesion, and obtain another 
conﬁrmatory scan (4-12 weeks later, based on clinical judgment). 
We propose a novel response category to describe such situations, designated iTPD (with T 
representing therapy, which will continue for these subjects). This category encompasses 
situations in which the iRECIST response would have been iCPD (worsening of an existing 
cause of PD or appearance of a new cause, after an overall response of iUPD) despite the fact 
that the injected lesions are stable or responding, and the treating physician reprioritizes 
lesions for injection and continues IT immunotherapy. The response may be designated 
iTPD, and IT immunotherapy may continue, with imaging every 4 to 12 weeks, until any of 
the following occurs (at which point the response would become iCPD per itRECIST): 
clinical progression with worsening signs, symptoms, or performance status; physician and/or 


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patient decision to discontinue therapy because of intolerance; or radiographic progression, 
particularly in injected lesions (indicating that injection is failing to prevent growth) or 
physician determines another treatment is clinically indicated (e.g., a lesion is impinging on 
the spinal cord, necessitating urgent intervention). 


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APPENDIX G. CMP-001 INJECTION GUIDELINE 
Syringe size is at the discretion of the Investigator or qualified designated staff for 
administering the CMP-001 study drug according to institutional guidelines or SOPs. 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 3 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 3 middle panel). 
Vigilance should be used when selecting lesions for injection that are in close proximity to 
critical structures (e.g., major airways). 
With the tip of the needle still under the skin, the syringe should be rotated by ~20 o to 40o 
and the process of insertion and injection during needle withdrawal repeated (Figure 3 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 3: 
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: 2 mL is the maximum CMP-001 injection volume allowed in up to 3 accessible lesion(s) regardless of 
the lesion size. If the accessible lesion(s) cannot accommodate the full 2 mL volume, then the remaining volume 
may be injected peritumorally. 
Subcutaneous Injection 
Subcutaneous 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 (see Figure 4): 
• Location of the primary tumor 
• 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. 


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Figure 4: 
Preferred Sites of Subcutaneous Injection 
 

SAP_001.pdf: 
Statistical Analysis Plan  
NCT04633278
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-007 
IQVIA Biotech (Confidential) Project # SZA56629 
Template No.: NVA_TP_CR694 Revision 3
CONFIDENTIAL
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
Page 1 of 40 
Regeneron Pharmaceuticals, Inc. 
Protocol #: CMP-001-007 
A MULTICENTER, PHASE 2, OPEN-LABEL STUDY OF 
INTRATUMORAL CMP-001IN COMBINATION WITH 
INTRAVENOUS PEMBROLIZUMAB IN SUBJECTS WITH 
RECURRENT ORMETASTATIC HEAD AND NECK SQUAMOUS 
CELL CARCINOMA 
Protocol Amendment 2 14 January 2022 
Statistical Analysis Plan 
Version 1.0 
Document last saved: 11-Oct-2022 4:11 PM 
Prepared by: 
IQVIA Biotech 
1700 Perimeter Park Dr. 
Morrisville, NC 27560 
VV-RIM-00350887-1.0 Approved - 15 May 2024 GMT-5:00


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Statistical Analysis Plan  
  
 
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Page 3 of 40 
TABLE of CONTENTS 
ABBREVIATIONS ................................................................................................................. 5 
I.Introduction ........................................................................................................................... 6 
A. Background ............................................................................................................ 6 
B. Protocol and Amendment History ......................................................................... 6 
II.Study Design ........................................................................................................................ 7 
A. Design Overview ................................................................................................... 7 
B. Study Population .................................................................................................... 8 
C. Sample Size Status ................................................................................................. 9 
D. Treatment Randomization ...................................................................................... 9 
E. Assessment Schedule ............................................................................................. 9 
F. End of Study .......................................................................................................... 9 
III.Protocol Objectives ............................................................................................................. 9 
A. Primary ................................................................................................................. 10 
B. Secondary ............................................................................................................. 10 
C. Exploratory .......................................................................................................... 10 
IV.Study Endpoints ................................................................................................................ 10 
A. Primary ................................................................................................................. 10 
B. Secondary ............................................................................................................. 10 
C. Exploratory .......................................................................................................... 11 
V.Interventions....................................................................................................................... 12 
A. Clinical Trial Material.......................................................................................... 12 
VI.General Analytical Considerations ................................................................................... 12 
A. Data Sources ........................................................................................................ 13 
B. Definition of Baseline and Study Day ................................................................. 13 
C. Missing Data ........................................................................................................ 13 
D. Multiple Study Centers ........................................................................................ 14 
E. Covariate Adjustment in Primary Analysis ......................................................... 14 
F. Sample Size Reassessment .................................................................................. 14 
G. Ad-hoc Analyses .................................................................................................. 15 
H. Multiple Comparisons .......................................................................................... 15 
I. Analysis Sets ........................................................................................................ 15 
J. Subgroups of Analysis Populations ..................................................................... 16 
K. Data Display Characteristics ................................................................................ 17 
VII.Subject Accountability .................................................................................................... 18 
A. Subject Characteristics ......................................................................................... 18 
B. Disposition ........................................................................................................... 20 
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Page 4 of 40 
C. Protocol Deviations and Population Inclusions ................................................... 21 
VIII.Efficacy Analyses .......................................................................................................... 21 
A. Efficacy Endpoints ............................................................................................... 22 
B. Primary Efficacy Analysis ................................................................................... 27 
C. Secondary Efficacy Analyses .............................................................................. 28 
D. Exploratory Efficacy Analysis ............................................................................. 29 
IX.Safety Analyses ................................................................................................................ 29 
A. Exposure .............................................................................................................. 29 
B. Adverse Events .................................................................................................... 31 
C. Deaths .................................................................................................................. 34 
D. Clinical Laboratory Results ................................................................................. 34 
E. Vital Signs ............................................................................................................ 35 
F. Physical Examination........................................................................................... 36 
G. Prior and Concomitant Medications .................................................................... 36 
H. Prior and Concomitant Procedures ...................................................................... 37 
I. Electrocardiograms (ECGs) ................................................................................. 37 
J. Eastern Cooperative Oncology Group Performance (ECOG) ............................. 38 
X.Pharmacokinetic Analyses ................................................................................................. 38 
XI.Pharmacodynamic Analyses ............................................................................................. 38 
XII.Exploratory Tumor Biopsy Analyses .............................................................................. 38 
XIII.References ...................................................................................................................... 40 
 
 
 
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Statistical Analysis Plan  
  
 
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Page 5 of 40 
ABBREVIATIONS 
 
Abbreviation 
Term 
AEs 
Adverse Events 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CR 
Complete Response 
DOR 
Duration of Overall Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture system 
eCRFs 
Electronic Case Report Forms 
ITT 
Intent to Treat 
iCR 
immune complete response 
iCPD 
immune confirmed progressive disease 
iDOR 
immune Duration of Response 
iORR 
immune Objective Response Rate 
iPR 
immune partial response 
iPFS 
Immune Progression-Free Survival 
iRECIST 
immunotherapy Response Evaluation Criteria in Solid Tumors 
MedDRA 
Medical Dictionary for Regulatory Activities  
ORR 
Objective Response Rate 
PD 
Progressive Disease 
PFS 
Progression-free Survival 
PR 
Partial Response 
QTcF 
QT corrected according to Fridericia 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Stable Disease 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 
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Page 6 of 40 
I. Introduction 
 
A. Background 
 
Head and neck cancer are the seventh leading cancer by incidence worldwide with 
approximately 890,000 new cases and 450,000 deaths each year. Squamous cell 
carcinomas of the head and neck constitute 90% of all head and neck cancers and 
are the ninth leading cancer by incidence worldwide. PD-1 blockade is an effective 
and important therapy for the treatment of HNSCC, however, more than 80% of 
patients do not respond to monotherapy treatment with an anti-PD-1 antibody. PD-
1 negatively regulates T cell function when it interacts with its ligand PD-L1, 
which is commonly expressed on tumors. A major mechanism of resistance to PD-
1 blockade is the absence of activated effector T cells in the tumor. Therefore, 
TLR9-mediated T cell activation and trafficking to tumor has the potential to 
improve the response to PD-1 blockade, particularly in non-inflamed tumors.  
 
CMP-001 is intended to activate pDCs via TLR9 agonism, which causes the pDCs 
to release Type I IFN and take up and present tumor antigens to T cells, 
culminating in the generation of an antigen-specific, antitumor T cell response. 
Safety and efficacy data demonstrating the clinical benefit of CMP-001 IT in 
combination with pembrolizumab IV in patients with melanoma refractory to PD-
1 blockade was obtained in an ongoing clinical trial, Study CMP-001-001. 
 
This is a Phase 2 exploratory study to evaluate the safety and efficacy of 
intratumoral (IT) CMP-001 in combination with intravenous (IV) pembrolizumab 
in subjects with head and neck squamous cell carcinoma (HNSCC) with tumors 
that have a programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 
1. The protocol for Study CMP-001-007 describes the general approach to analysis 
of data from the study. This analysis plan describes additional details needed to 
complete such an analysis. 
 
B. Protocol and Amendment History 
   
This Statistical Analysis Plan (SAP) is based on the Amendment 2 (version 3.0) of 
the Protocol CMP-001-007.   
 
Version 
Approval Date 
Salient Changes, if any* 
Initial 
11 June 2020 
 
Amendment 1 
03 August 2021 
 
Amendment 2 
14 January 2022 
Change in Schedule of Assessments 
*  Changes expected to require accommodation in analysis plan. 
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Per Sponsor’s decision, site activation and study enrollment were stopped earlier 
for any subjects who had not signed informed consent yet, and analyses were made 
exploratory. Consequently, the SAP will not necessarily be consistent with the 
protocol. In case of any discrepancies, this SAP will govern the analysis of data 
from this study.   
 
 
II. Study Design 
 
A. Design Overview  
 
This is a multicenter, open-label, exploratory Phase 2 clinical trial of CMP-001 IT in 
combination with pembrolizumab IV in subjects with recurrent or metastatic HNSCC. 
Eligible subjects must have histologically- or cytologically-confirmed recurrent or 
metastatic HNSCC considered incurable by local therapies. All subjects will receive 
CMP-001 IT and pembrolizumab IV according to the treatment schedule until a reason 
for treatment discontinuation is reached. 
 
CMP-001 10 mg will be administered weekly for 7 doses, after which it will be 
administered Q3W until the subject meets a condition for discontinuation of study 
treatment. The treatment will be given for a maximum of 2 years from the start of the 
study treatment. The first dose of CMP-001 may be administered SC or by IT injection, 
at the discretion of the Investigator; all subsequent doses are planned to be administered 
IT. The initial 7 CMP-001 doses on a weekly schedule must be completed before 
moving on to the Q3W CMP-001 dosing schedule. 
 
If all injectable tumors regress, CMP-001 may be injected SC in the region of prior 
tumors or draining lymph node bed, at the Investigator’s discretion (see Protocol 
Appendix F). On visits where both study drugs are administered, CMP-001 IT should 
be administered before pembrolizumab. CMP-001 should be administered until a reason 
for treatment discontinuation is reached, or for a maximum of 2 years from the start of 
the study treatment. See Protocol Section 5.1.2.4 for treatment modifications for CMP-
001. Pembrolizumab 200 mg IV will be administered following CMP-001 10 mg IT 
injection at W1D1 and Q3W thereafter according to the KEYTRUDA® USPI. 
Pembrolizumab treatment during this study will continue until the subject meets a 
condition for discontinuation of study treatment. 
 
Objective responses will be assessed by the Investigator according to RECIST v1.1 and 
iRECIST. Disease status will be assessed by computed tomography (CT) or magnetic 
resonance imaging (MRI) and other appropriate measures beginning pre-dose at Week 
10 Day 1 (W10D1) and will be repeated every 9 weeks (e.g., Week 19 Day 1). 
Responses (CR, PR, iCR or iPR) will be confirmed by a follow-up disease assessment 
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performed at least 4 weeks after the initial response date, and at least 2 weeks after the 
last CMP-001 injection. Disease assessments will continue every 9 weeks while the 
subject is on treatment. Disease assessments may continue every 12 weeks for subjects 
with a response lasting more than one year. Subjects who discontinue study treatment and 
transition into PTFU will continue to have assessments collected per the timepoints 
defined in the schedule of assessments. 
 
Progressive disease (PD) will be assessed by the Investigator according to RECIST v1.1 
criterion. Subjects who continue study treatment beyond PD according to RECIST v1.1 
will be assessed by the Investigator according to iRECIST. 
 
All scans should be performed at least 2 weeks after the previous CMP-001 IT injection 
to prevent injection-related pseudo progression. Imaging should not be delayed for 
delays in treatment. 
 
Subjects who discontinue study treatment should complete the end of treatment (EOT) 
visit and 30-day safety follow-up. Subjects who are posttreatment but have not met 
criteria for study discontinuation should remain on study for posttreatment follow-up 
(PTFU) and long-term survival follow-up (LTSF) and receive study evaluations for 
efficacy according to the Schedule of Assessments. 
 
Figure 1: CMP-001-007 Study Schema 
 
Abbreviations: 30DFU = 30-Day Follow-up; EOT = End of Treatment; LTSFU = Long-term 
Survival Follow-Up; IT = intratumoral; IV = intravenous; PTFU = Posttreatment Follow-up; Q3W 
= every 3 weeks; Q12W = every 12 weeks; QW = every week; SC = subcutaneous. 
Note: The first dose of CMP-001 may be administered by SC or IT injection, per Investigator 
discretion. All subsequent doses of CMP-001 are planned to be administered IT. 
 
B. Study Population 
 
See Protocol Section 4.1 and 4.2 for a complete list of the inclusion/exclusion 
criteria. 
 
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C. Sample Size Status 
 
Given the early termination of site activation and study enrollment since 24Jun2022 
per Sponsor’s decision, all the analyses will be descriptive and exploratory. The 
number of subjects included in this study is 24. Subjects who have provided written 
informed consent once the enrollment goal is reached may be allowed to complete 
Screening and enter study treatment if they meet all eligibility criteria, at the 
discretion of the Sponsor or its representatives. As enrollment is terminated, 
subjects who discontinue the study before receiving the first dose of CMP-001 will 
not be replaced. 
 
With the enrollment of the last subject on 22Jun2022, the subject status of this study 
is as follows: 
x 39 subjects were screened 
x 15 subjects were screen failures 
x 24 subjects started the treatment 
 
D. Treatment Randomization 
 
No randomization will be performed in this study. 
 
E. Assessment Schedule 
 
See Protocol Table 1 for the study schedule of assessments.    
 
F. End of Study 
 
Per Sponsor’s decision, site activation and study enrollment were terminated 
officially on 24Jun2022. All subjects previously enrolled in the study may continue 
receiving up to 2 years of study treatment per the current protocol.  
 
The end of study is defined as the date of the last dose of study treatment for the 
last ongoing subject, plus 30 days of safety follow-up. 
 
 
III. 
Protocol Objectives 
 
Per Sponsor’s decision, enrollment was stopped before reaching the sample size 
planned for the analyses described in the Protocol. All analyses will be exploratory. 
The performance of the statistical analysis for the protocol objectives and endpoints of 
the exploratory phase 2 study is contingent on the availability of the data source. 
Detailed information will be provided in the corresponding sections to follow. 
 
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A. Primary 
 
x To determine the Investigator-assessed confirmed objective response with 
CMP-001 in combination with pembrolizumab in subjects with head and 
neck squamous cell carcinoma (HNSCC). 
 
B. Secondary 
 
x To evaluate the safety and tolerability of CMP-001 administered by 
intratumoral (IT) injection in combination with pembrolizumab in subjects 
with HNSCC. 
x To evaluate the efficacy of CMP-001 in combination with pembrolizumab 
in subjects with HNSCC. 
x To evaluate the effect of human papillomavirus (HPV) infection and 
programmed death-ligand 1 (PD-L1) expressions on the efficacy of CMP-
001 in combination with pembrolizumab. 
 
C. Exploratory 
 
x To evaluate the effect of CMP-001 in combination with pembrolizumab on 
injected and noninjected target lesions in subjects with HNSCC 
x To evaluate the pharmacodynamic and pharmacokinetic effects of CMP-
001 administered in combination with pembrolizumab 
 
 
IV. 
Study Endpoints 
 
A. Primary 
 
x Objective response rate (ORR), defined as the proportion of subjects with a 
confirmed objective response of complete response (CR) or partial response 
(PR) based on Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST v1.1) as determined by Investigator assessment. 
 
B. Secondary 
 
x Adverse events (AEs), serious adverse events (SAEs), and AEs leading to 
discontinuation or death, and severity of AEs as assessed by the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE), version 5.0. 
x Duration of response (DOR), defined as the time from date of first 
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documented response (CR or PR) to date of documented progressive 
disease (PD), based on RECIST v1.1 by Investigator assessment. 
x Progression-free survival (PFS), defined as the time from date of first dose 
of study drug to date of documented PD based on RECIST v1.1 by 
Investigator assessment or death, whichever occurs first. 
x Overall survival (OS), defined as the time from the date of first dose of 
study drug to the date of death. 
x Immune objective response rate (iORR), defined as the proportion of 
subjects with a best overall response (BOR) of immune complete response 
(iCR) or immune partial response (iPR) based on the immunotherapy 
Response Evaluation Criteria in Solid Tumors (iRECIST) by Investigator 
assessment. 
x Immune duration of response (iDOR), defined as the time from the date of 
the first immune response (iCR or iPR) to the date of immune confirmed 
progressive disease (iCPD) by Investigator assessment. 
x Immune progression-free survival (iPFS), defined as the time from date of 
first dose of study drug to date of iCPD by Investigator assessment or death, 
whichever occurs first. 
x ORR, DOR, and PFS based on HPV status and PD-L1 expressions 
(combined positive score [CPS] ≥ 1 and CPS ≥ 20). 
 
C. Exploratory 
 
x Response in injected and noninjected target lesions per intratumoral 
Response Evaluation Criteria in Solid Tumors (itRECIST) by Investigator 
assessment 
x Baseline, and change from baseline, in tumor or blood measurements of 
biomarkers related to TLR9, immune checkpoints, and potential markers of 
resistance or response to immunotherapy 
x Change from baseline in blood concentrations of C-X-C motif chemokine 
10 (CXCL10) (IP-10) after treatment with CMP-001 
x Blood concentrations of CMP-001 or its metabolites 
 
 
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V. Interventions 
 
A. Clinical Trial Material 
 
Pembrolizumab is an FDA approved drug product for the treatment of patients with 
metastatic or unresectable, recurrent HNSCC whose tumors express PD-L1 [CPS ≥1] 
as determined by an FDA-approved test, and as a single agent for the treatment of 
patients with recurrent or metastatic HNSCC with disease progression on or after 
platinum-containing chemotherapy; therefore, subjects will be treated with 
commercial 
product 
of 
KEYTRUDA®. 
The 
physical 
characteristics 
of 
pembrolizumab are found in the KEYTRUDA® USPI. 
 
CMP-001 is an investigational drug product and will be provided by the Sponsor. CMP-
001 is provided as a 5 mg/mL solution in a single-use vial. The physical characteristics 
and other details about the CMP-001 drug product are found in the current 
Investigator’s Brochure and the Pharmacy Manual. 
 
At each site closeout visit, a final drug accountability review and reconciliation must 
be completed, and any discrepancies must be investigated by site and Sponsor 
representatives, and their resolution documented. All remaining CMP-001 drug 
product vials will be destroyed onsite according to institutional SOPs, after discussion 
with the Sponsor or its representatives following the completion of site close out. 
 
The protocol provides additional product details in Protocol Section 6.   
 
 
VI. 
General Analytical Considerations 
 
Data analyses will be primarily descriptive and exploratory. Categorical variables will 
be summarized as the number and percentage of subjects within each category of the 
parameter (with a category for missing data, if applicable). Continuous variables will 
be presented as number (n), mean, median, standard deviation, and range (minimum 
and maximum). Discrete variables will be presented as frequencies or proportions. 
 
Statistical analyses will be performed using SAS® software version 9.4 or higher. 
MedDRA version 23.1 will be used for the coding of Medical History and Adverse 
Events.  AEs are graded using Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0.  World Health Organization Drug Dictionary (WHO-DD) version 
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B3 Global September 2020 (or later) will be used to code the Prior and Concomitant 
Medications, and Prior Cancer Systemic Treatments.   
 
A. Data Sources 
 
Data are recorded on electronic case report forms (eCRFs).  Central laboratory data 
will be provided via electronic data transfers.  Protocol Section 11 and the study 
Data Management Plan provide additional details regarding data recording and 
handling. 
 
B. Definition of Baseline and Study Day 
 
Baseline is defined as the last non-missing observation prior to the first 
administration of study drugs (CMP-001 or Pembrolizumab). Study Day 1 will be 
designated as the first day a subject receives either study drug (i.e., Week 1 Day 
1).    
 
C. Missing Data 
 
Unless stated otherwise, missing data will not be replaced with imputed values. 
When relevant, sections below will address how missing data will be handled for 
the analyses.  
 
Missing or Partial Death Dates 
A death date missing the month and day will be imputed as Jan 1st of the year or 
the date after the date of last known alive, whichever comes last. 
 
A death date missing the day will be imputed as the 1st of the month or the day 
after the date of last contact, whichever comes last.  
 
Missing Dates in Adverse Events/Concomitant Medications 
Every effort will be made to avoid missing/partial dates in on-study data including 
AE and medication start and stop dates.  
 
Start dates of AEs/ Concomitant medications will be imputed as follows: 
x Completely missing start date will not be imputed.  
x Start date missing both the month and day will be imputed as:  
o The date of the first dose if the year of the start date is the same as the 
date of first dose.  
o Otherwise, Jan 1st of the year of the start date will be used. 
x Start date missing the day will be imputed as: 
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o The date of first dose if the year and month of the start date are the same 
as the date of first dose. 
o Otherwise, the 1st of the month of the start date will be used. 
 
Stop dates of AEs / Concomitant Medications will be imputed as follows: 
x Completely missing stop date will not be imputed. 
x Stop date missing both the month and day will be imputed as Dec 31st of 
the year of stop date.  
x Stop date missing the day will be imputed as the last date of the month of 
the stop date. 
x After imputation, the imputed date will be compared against the date of 
death, if available. If the planned imputed date is later than the date of 
death, the date of death will be used as the imputed date instead. If there is 
no date of death in the EDC for a subject and the planned imputed date is 
later than the End-of-Treatment (the last drug received) date + 30 days, 
then the End-of-Treatment (EOT of the last study drug received) date + 30 
days will be used for the stop date. 
 
Missing Dates in Prior Medications 
Start or Stop dates of Prior Medications will be imputed as follows: 
x Completely missing start or stop date will not be imputed. 
x Start or stop date with missing both the month and day will be imputed as 
Dec 31st of the year of stop date. 
x Start date missing the day will be imputed as the 1st of the month of the 
start date. 
x Stop date missing the day will be imputed as the last date of the month of 
the stop date or the study first dose date, whichever comes earlier. 
 
D. Multiple Study Centers 
 
No adjustment for study center is planned.    
 
E. Covariate Adjustment in Primary Analysis 
 
No covariate adjustments are planned.    
 
F. Sample Size Reassessment 
 
Not applicable. 
 
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G. Ad-hoc Analyses 
 
There will be an ad-hoc analysis planned with the trigger event being two disease 
assessments after the enrollment of the last subject. The ad-hoc analysis of the 
endpoints will follow the efficacy analysis methods described in Section Error! 
Reference source not found. below as well as the safety analysis methods detailed 
in Section Error! Reference source not found. below for the exploratory Phase 
2 study. 
 
The following unblinded subject information, efficacy-related and safety-related 
data displays will be produced for the purpose of the ad-hoc analysis. Unless stated 
otherwise, these displays are summary tables that summarize data for the 
corresponding analysis set: 
x Subject information 
o Demographics 
o Baseline characteristics 
o Disposition 
o Medical history 
o Cancer history 
o ECOG 
x Efficacy 
o ORR, DOR, TTR, PFS per RECIST v1.1 by Investigator 
o OS 
o Selected subgroup analysis 
x Safety 
o Study drug exposure: CMP-001 and pembrolizumab 
o Prior and concomitant medications 
o Prior and concomitant procedures 
o All TEAEs (SAE, AESI) 
o Summary of clinical laboratory results 
o Summary of ECG results 
 
H. Multiple Comparisons 
 
No control for the effect of multiple comparisons is planned.  
 
I. Analysis Sets  
 
Three analysis sets will be defined for use with various analyses. The following 
table illustrates the relationship between each population and the analyses for 
which the data from the population will be used. 
 
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Analysis Set 
Analysis 
Baseline 
Subject 
Disposition 
Efficacy 
Safety 
PD 
Tumor 
Biopsy 
Treated 
X 
X 
X 
X 
 
 
Pharmacodynamic 
 
 
 
 
X 
X 
All Screened 
 
X 
 
 
 
 
 
1. Treated Analysis Set 
 
The Treated Analysis Set is defined as all subjects who receive at least 1 dose 
of study treatment. 
 
2. Pharmacodynamic Analysis Set 
 
The Pharmacodynamic Analysis Set is defined as all subjects who receive at 
least 1 dose of CMP-001 and have at least 1 measurable sample at Baseline 
and at least 1 evaluable biomarker sample after CMP-001 administration. 
 
3. All-Screened Analysis Set 
 
The All-Screened Analysis Set is defined as all subjects who was screened 
including subjects who were screen failure. 
 
J. Subgroups of Analysis Populations     
 
1. HPV Status 
x Negative 
x Positive 
 
2. PD-L1 Expression (Combined Positive Score, CPS) 
x 1 ≤ CPS < 20 
x CPS ≥ 20 
 
3. Schedule  
x A: Subjects under Schedule A are those who consented to protocol v1.0 
and v2.0. 
o Per Protocol, subjects will receive CMP-001 10 mg weekly for 7 
doses, after which CMP-001 will be administered every 3 weeks 
(Q3W), beginning on Week 10 Day 1 (W10D1), then on Week 13 
Day 1 (W13D1), etc. 
o Subjects will receive Pembrolizumab 200 mg IV over 30 minutes 
following CMP-001 injection at Week 1 Day 1 (W1D1) and every 
3 weeks thereafter (W4D1, W7D1, etc.) according to the 
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KEYTRUDA® (pembrolizumab) United States Prescribing 
Information. Pembrolizumab should be administered until the 
subject satisfies a condition for study treatment discontinuation. 
x B: Subjects under Schedule B are those who consented to protocol v3.0, 
including those who reconsented to v3.0 from v2.0. 
o Per Protocol, subjects will receive CMP-001 10 mg weekly for 2 
doses, after which CMP-001 will be administered every 3 weeks 
(Q3W), beginning on Week 4 Day 1 (W4D1), then on Week 7 Day 
1 (W7D1), etc.  
o Subjects will receive Pembrolizumab 200 mg IV over 30 minutes 
following CMP-001 injection at Week 1 Day 1 (W1D1) and every 
3 weeks thereafter (W4D1, W7D1, etc.) according to the 
KEYTRUDA® (pembrolizumab) United States Prescribing 
Information. Pembrolizumab should be administered until the 
subject satisfies a condition for study treatment discontinuation. 
 
Efficacy in relation to HPV status and PD-L1 expression will be assessed and 
summarized for the Treated Analysis Set. Subgroup analysis based on Schedule 
will be performed where applicable. 
 
K. Data Display Characteristics 
 
Data displays produced for this study will include three types—summary tables, 
data listings, and figures. Unless stated otherwise, data listings will be produced 
for all recorded data. Summary tables will be produced as specified in following 
sections.  Additional data listings may be produced for outcome measures that 
involve extensive procedures to derive the analyzed outcomes, if appropriate. 
Figures will be produced when specified in sections to follow. 
 
Data listings will simply list the data recorded on the CRF or derived for each 
subject.  They will be ordered by site, subject number, and time of assessment (i.e., 
visit). When expedient, additional levels of ordering hierarchy may reflect subsets 
of assessments within subject.   
 
The summary statistics displayed will be a function of the type of data associated 
with the summarized assessment. Unless stated otherwise in relevant sections to 
follow, continuous data will be summarized with the number of non-missing 
values, mean, standard deviation, minimum, median, and maximum. Categorical 
data will be summarized as the number of subjects within each category (with a 
category for missing data, if applicable). Percentages of subjects within each of the 
categories will be calculated from the number of subjects in the corresponding 
analysis population, unless stated otherwise. Some continuous variables may also 
be grouped into categorical levels and evaluated in frequency tables. 
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Summary tables, listings and figures will follow IQVIA Biotech display standard 
including the following: 
x Program source (e.g., SAS program name) 
x Database extraction date (e.g., database lock date or data cut date or data 
extract date) 
x SAS output generation date and time 
The purpose of the database extraction date is to link the output to a specific 
database cut, either active or locked database. Individual data listings will display 
all the relative values supporting corresponding table and figures. 
 
 
VII. Subject Accountability 
 
A. Subject Characteristics 
 
Demography.  Data collected about the following subject characteristics at the 
screening visit will be summarized for the Treated Analysis Set: 
x Age.  Age will be calculated as the number of years elapsed between birth 
date and the date of the ICF signature, adjusted for whether the birthday has 
passed as of the day of the screening visit. (This corresponds to the typical 
calculation of age a person would use in conversation.) 
x 
Sex  
o Childbearing potential yes/no 
o Non-childbearing potential criteria, Follicle Stimulating Hormone 
(FSH) Result and Luteinizing Hormone (LH) Result 
x Race 
x Ethnicity 
Additionally, subgroup analysis of demographics by schedule will also be 
performed. All demography data including informed consent date will be listed. 
 
Baseline Characteristics.  Height, baseline weight, baseline body mass index 
(BMI), and substance history will be summarized for the Treated Analysis Set and 
presented in a listing. Additionally, subgroup analysis of baseline characteristics 
by schedule will also be performed. 
 
Baseline Disease Characteristics. Time since Initial Diagnosis of Primary Cancer 
to First Dose (Months), ECOG Performance Status at Baseline, Disease Type at 
Enrollment, Tumor Burden at Baseline, Measurable Disease at Baseline, and other 
key baseline information will be summarized for Treated Analysis Set and 
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presented in a listing. Additionally, subgroup analysis of baseline disease 
characteristics by schedule will also be performed. 
 
Medical History Other Than Head/Neck Cancer.  Medical history will be 
summarized in a table and listed by subject for the Treated Analysis Set. Medical 
history will be coded using MedDRA, associating lower-level terms with preferred 
terms and system organ classes by the primary hierarchy.   
 
Head/Neck Cancer History.  Listings of all collected data related to Head/Neck 
cancer history will be provided for Treated Analysis Set. A summary table of the 
following elements (but not limited to) will also be provided.  
x Primary Site 
x AJCC Version used at time of diagnosis 
x Tissue Diagnosis Confirmed by 
x p53 mutation 
x EGFR status 
x kRAS 
x Cyclin d1 
x Grade at diagnosis 
x Clinical staging 
o Clinical staging at diagnosis 
o Tumor status 
o Nodal status 
o Metastatic disease status 
x Pathologic staging 
o Pathologic staging at diagnosis 
o Tumor status 
o Nodal status 
o Metastatic disease status 
x PD-L1 status 
  
Prior Cancer Treatments.  The following information will be summarized for the 
Treated Analysis Set for the prior head/neck cancer treatments: 
x Number of Lines of Prior Systemic Therapies 
o Continuously (mean [SD], median, Q1, Q3, min and max) 
o Categorically (0, 1, 2, ≥ 3) 
x Most Recent Prior Therapy 
o Prior Systemic Therapy 
o Prior Radiotherapy 
o Prior Cancer-related Surgery 
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x Any Prior Therapy 
o Prior Systemic Therapy 
o Prior Radiotherapy 
o Prior Cancer-related Surgery 
x Reason for Discontinuation from Any Prior Systemic Therapy 
x Regimen Best Response on the Most Recent Prior Systemic Therapy 
x Regimen Best Response on Any Prior Systemic Therapy 
x Duration of Exposure to Any Prior Systemic Therapy (months), 
summarized continuously 
x Administrative Setting of Prior Systemic Therapy 
x Time since Completion of Prior Adjuvant Systemic Therapy to First Dose 
Date (< 6 months, ≥ 6 months) 
 
All prior head/neck treatments will be captured in the EDC separately from other 
prior medications. Combination treatments should be considered as a single 
regimen and recorded as such in the EDC. Details regarding all prior head/neck 
treatments, including drug generic name, start date, end date, regimen best 
response to prior therapy, and administrative setting, as well as key data related to 
prior melanoma treatments, will be listed by subject for Treated Analysis Set.  
 
Data on Prior Cancer Radiation and Prior Cancer Surgery will be captured on 
different pages of eCRF and presented in separate by-subject data listings.  
 
B. Disposition 
 
As of the data cutoff date, the number and percentage of subjects who screen fail 
and enroll in the study (receive at least one dose of study treatment), discontinue 
study treatment, and discontinue the study will be summarized for all screened 
subjects. The primary reason for treatment(s) and study discontinuation will also 
be summarized for Treated Analysis Set. Additionally, subgroup analysis of 
disposition by schedule will also be performed. Subject disposition will be 
presented in a by-subject data listing. 
 
Study treatment (CMP-001 only or both CMP-001 and Pembrolizumab) may be 
discontinued for any of the following occurrences: 
x Adverse Event 
x PD per RECIST v1.1 
x Subject Achieved and Maintained a Confirmed CR or iCR (and has been 
treated for at least 24 weeks, and has received at least 2 doses of both study 
treatments beyond the date of initial CR/iCR) 
x Upon Request of the Sponsor or Regulatory Agency 
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x Clinical Disease Progression 
x Medically Necessary in the Opinion of the Investigator 
x Subject Withdrew Consent for Treatment 
x Subject Became Pregnant or Began Breastfeeding 
x Subject Lost to Follow-up 
x Death 
x Subject Completed 2 Years of Study Treatment 
x End of Clinical Trial 
x Other 
 
Study Participation may be discontinued for any of the following occurrences: 
x Completed 
x Adverse Event 
x Subject Withdrew Consent 
x Lost to Follow-Up 
x Death 
x Study Terminated by Sponsor 
x End of Clinical Trial 
x Other 
 
Percentages of subjects who withdrew for each of these reasons will be calculated 
using all members of the relevant analysis set for the denominator. 
 
C. Protocol Deviations and Population Inclusions 
 
All protocol deviations will be captured electronically outside of the Electronic 
Data Capture (EDC) system in the IQVIA Biotech IL-2 system and presented in a 
by-subject data listing. All deviations will be reviewed on an ongoing basis and 
classified as major or minor following study review process. 
 
 
VIII. Efficacy Analyses  
 
Efficacy analyses will use data from the Treated Analysis set. Disease status will be 
assessed by computed tomography (CT) or magnetic resonance imaging (MRI) and 
other appropriate measures beginning pre-dose at Week 10 Day 1 and will be repeated 
every 9 weeks (e.g., Week 19 Day 1). Responses (CR, PR, iCR, or iPR) will be 
confirmed by follow-up disease assessment performed at least 4 weeks after the date 
of initial response and should be at least 2 weeks after the last CMP-001 injection. 
Imaging should not be delayed for delays in treatment. 
 
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A. Efficacy Endpoints 
 
Confirmed Objective Response Rate (ORR).  The confirmed ORR is defined as the 
proportion of subjects in the analysis set who have confirmed best response as CR 
or PR based on RECIST v1.1 as assessed by the Investigator. Per RECIST v1.1, 
CR or PR must be confirmed by a confirmatory assessment performed at least 4 
weeks after the initial response. 
 
The confirmed ORR will be calculated as the number of subjects with a confirmed 
CR or PR divided by the number of subjects in the analysis population [ORR = 
(confirmed CR + confirmed PR)/number of subjects] for the Treated Analysis Set.  
 
Subjects who discontinue due to death or disease progression, prior to having a 
post-Baseline tumor assessment will be classified as having a best response of PD. 
Subjects who discontinue prior to having a post-Baseline scan for other reasons 
will be counted as non-responders in the ITT analyses (i.e., these subjects will 
contribute to the denominator, but not the numerator). Objective Response 
assessment evaluated after new anti-cancer treatment will not be considered for 
ORR calculation. 
 
Best Overall Response (BOR).  The best response based on RECIST v1.1 as 
assessed by the Investigator recorded from the date of first study drug until PD or 
death was be considered the BOR for a subject. The number and percentage of 
subjects within each BOR category (confirmed CR, confirmed PR, stable disease 
(SD), PD, or not evaluable) will be summarized for the Treated Analysis Set. 
Objective Response assessment evaluated after new anti-cancer treatment will not 
be considered for BOR calculation. 
 
The best overall response (BOR) will be derived as below: 
CR > PR > SD> PD > NE 
 
Disease Control Rate (DCR).  The confirmed disease control rate is defined as the 
proportion of subjects in the analysis set who have a confirmed best response of 
CR, PR, or SD per RECIST v1.1 as assessed by the Investigator. Per RECIST v1.1, 
CR or PR must be confirmed by a confirmatory assessment performed at least 4 
weeks after the initial response. In the case of SD, measurements must have met 
the SD criteria at least once after study entry at a minimum interval of 6 weeks. 
Confirmation of SD is not required. OR assessment evaluated after new anti-cancer 
treatment will not be considered for DCR calculation. 
 
Duration of Response (DOR).  Duration of response will be based on RECIST v1.1 
as determined by Investigator and calculated for confirmed responders. The DOR 
will be measured from the time at which criteria are first met for CR or PR 
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(whichever is first recorded) until the first date that recurrence or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on 
study).   
 
DOR is only defined for subjects who have a confirmed BOR of CR or PR. 
Subjects with an overall response of CR or PR must have a repeat tumor 
assessment performed no less than 4 weeks after the criteria for response are first 
met. The first date at which a CR or PR response was noted will be used to 
calculate DOR, not the date of the confirmatory tumor assessment. Subjects who 
did not have PD or death will be censored at the date of their last disease 
assessment. For subjects who started a subsequent anti-cancer therapy before 
having a documented PD, the last disease assessment prior to the start of the 
subsequent therapy will be used. Censoring rules are detailed in Table 1a. 
 
DOR will be calculated as follows: 
DOR (months) = (Event/Censoring Date – Response Start Date + 1) / 30.4375 
 
Progression-Free Survival (PFS).  Progression-free survival is defined as the time 
from first dose of study treatment to the date of documented PD based on RECIST 
v1.1 by Investigator or death from any cause, whichever occurs first.  
 
PFS will be calculated as follows: 
PFS (months) = (Event or Censoring Date – First Dose Date + 1) / 30.4375 
 
All events of RECIST v1.1 disease progression or death will be counted regardless 
of whether the event occurred while the subject was on study drug or had 
previously discontinued treatment. Subjects who do not experience disease 
progression or death before the analysis cutoff date will be censored at the date of 
last adequate tumor assessment. Date of censoring for these subjects will be based 
on the last tumor assessment prior to missing the assessments. For subjects who 
started a subsequent anti-cancer therapy before having a documented PD, the 
overall response assessment evaluated after new anti-cancer treatment will not be 
considered for PFS calculation, and the last disease assessment prior to the start of 
the subsequent therapy will be used. Censoring rules are summarized in Table 1a. 
If a subject meets the criteria for more than one censoring rule, PFS will be 
censored at the earliest censoring date. 
 
Overall Survival (OS). Overall survival will be calculated as the time from first 
dose of study treatment to the date of death due to any cause. Subjects who are 
alive at the time of analyses will be censored at the time of last known alive date, 
or at data cutoff date, whichever occurs first. Censoring rules are detailed in Table 
1c. The last contact date will be derived as Table 2.  
 
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OS will be calculated as follows: 
OS (months) = (Death or Censoring Date – First Dose Date + 1) / 30.4375 
 
Immune Objective Response Rate (iORR).  iORR is defined as the proportion of 
subjects with a best overall immune response (iBOR) of confirmed immune 
complete response (iCR) or confirmed immune partial response (iPR) based on 
immunotherapy Response Evaluation Criteria in Solid Tumors (iRECIST) by 
Investigator assessment. 
 
Subjects who continue study treatment beyond PD per RECIST v1.1 will be 
assessed by the Investigator according to iRECIST. Subjects with an iCR or iPR 
per iRECIST must have a confirmatory assessment performed at least 4 weeks 
after the initial assessment where response was declared by the Investigator and 
all scans should be performed at least 2 weeks after the previous CMP-001 IT 
injection to prevent injection-related pseudo-progression. 
 
The confirmed iORR will be calculated as the number of subjects with a confirmed 
iCR or iPR divided by the number of subjects in the analysis population [iORR = 
(confirmed iCR + confirmed iPR)/number of subjects]. The two-sided 95% 
Clopper-Pearson CIs will be calculated for the iORR. 
 
The best overall immune response (iBOR) will be derived as below: 
iCR > iPR > iSD > iCPD > iUPD > NE 
 
If assessments are not performed or cannot be assessed following iUPD, and there 
is no subsequent iCPD, iSD, iPR or iCR, iUPD will continue to be used and the 
subject will be censored at the date of iUPD.   
 
Immune Progression-Free Survival (iPFS).  iPFS is defined as the time from date 
of first dose of study drug to date of iCPD per iRECIST as assessed by Investigator 
or death, whichever occurs first. Censoring rules are detailed in Table 1b. 
 
Immune Duration of Response (iDOR).  iDOR is defined as the time from the date 
of the first immune response (iCR or iPR) to the date of immune confirmed 
progressive disease (iCPD) per iRECIST by Investigator assessment. 
 
iDOR is only defined for Subjects who have a confirmed iBOR of iCR or iPR. 
Subjects with a response of iCR or iPR must have a repeat tumor assessment 
performed no less than 4 weeks after the criteria for response are first met. The 
first date at which an iCR or iPR response was noted will be used to calculate 
iDOR, not the date of the confirmatory tumor assessment. Subjects who did not 
have iCPD or death will be censored at the date of their last disease assessment. 
Censoring rules are detailed in Table 1b. 
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Table 1a: Censoring Rules for the PFS/DOR 
Situation 
Outcome 
Date 
Event Description/ 
Censoring Reason 
PD per RECIST v1.1 on/before new 
anticancer therapy or data cutoff date, 
whichever is earlier  
Event 
Earliest date of tumor 
assessment documenting 
PD 
PD per RECIST v1.1 
Death without PD per RECIST v1.1 and 
not receiving new anticancer therapy 
on/before data cutoff date 
Event 
Date of death 
Death without PD per 
RECIST v1.1 
[PFS only]  
Subjects with no post-baseline assessments 
Censored 
Date of First Dose of 
Study Drug 
No Adequate Disease 
Assessment per RECIST 
v1.1 
No PD per RECIST v1.1 or Death as of 
data cutoff date and subject not received 
new anticancer therapy or received it after 
the data cutoff date 
Censored 
Date of last disease 
assessment on/before 
data cutoff date 
Alive without Documented 
PD 
No PD per RECIST v1.1 or Death as of 
data cutoff date and new anticancer 
therapy started before the data cutoff date 
Censored 
Date of last disease 
assessment prior to new 
anticancer therapy  
Subsequent Anti-cancer 
Therapy without 
Documented PD 
PD per RECIST v1.1 or Death after new 
anticancer therapy and the new anticancer 
started before data cutoff date 
Censored 
Date of last disease 
assessment prior to new 
anticancer therapy  
Documented PD or Death 
after Subsequent Anti-cancer 
Therapy 
PD per RECIST v1.1 or Death after new 
anticancer therapy and the new anticancer 
started after data cutoff date 
Censored 
Date of last disease 
assessment on/before 
data cutoff date 
Documented PD or Death 
after Subsequent Anti-cancer 
Therapy 
PD per RECIST v1.1 or Death 
immediately following two or more 
consecutive disease assessments 
missed since the last adequate 
disease assessment 
Censored 
Date of last adequate 
tumor assessment 
prior to missing 
assessments 
PD or Death after Missing 
>= 2 Consecutive Disease 
Assessments 
Withdrew consent or lost to follow-
up before PD per RECIST v1.1 or 
Death 
Censored 
Date of last adequate 
disease assessment 
Discontinued from Study 
without Documented PD 
or Death 
 
Table 1b: Censoring Rules for the iPFS/iDOR 
Situation 
Outcome 
Date 
Event Description/ 
Censoring Reason 
iCPD per iRECIST between scheduled 
disease assessments on/before new 
anticancer therapy or data cutoff date, 
Event 
Earliest date of tumor 
assessment documenting 
iUPD 
iCPD per iRECIST 
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whichever is earlier  
Death without iCPD per iRECIST and not 
receiving new anticancer therapy 
on/before data cutoff date 
Event 
Date of death 
Death without iCPD per 
iRECIST 
[iPFS only] 
iUPD per iRECIST at the time of PD 
per RECIST v1.1, continued study 
treatment without further tumor 
assessments as of data cutoff date 
Censored 
Date of the last tumor 
assessment on/before 
data cutoff date 
No Adequate Disease 
Assessment per iRECIST 
iUPD per iRECIST, continued study 
treatment with subsequent disease 
assessments but no confirmed PD (i.e., 
iCPD not assigned) or Death as of data 
cutoff date and subject not received 
new anticancer therapy or received it 
after the data cutoff date 
Censored 
Date of the last tumor 
assessment as of data 
cutoff date 
Alive without Documented 
iCPD 
iUPD per iRECIST, continued study 
treatment, but started a new anti-cancer 
therapy before data cutoff date without 
evidence of iCPD or Death 
Censored 
Date of the last tumor 
assessment prior to new 
anti-cancer therapy  
Subsequent Anti-cancer 
Therapy without 
Documented iCPD 
iCPD per iRECIST or Death after new 
anticancer therapy and the new 
anticancer started before data cutoff date 
Censored 
Date of last disease 
assessment prior to new 
anticancer therapy 
iCPD or Death after 
Subsequent Anti-cancer 
Therapy 
iCPD per iRECIST or Death after new 
anticancer therapy and the new 
anticancer started after data cutoff date 
Censored 
Date of last disease 
assessment on/before 
data cutoff date 
iCPD or Death after 
Subsequent Anti-cancer 
Therapy 
iUPD per iRECIST, continued study 
treatment, iCPD or Death immediately 
following two or more consecutive 
disease assessments since the last 
adequate disease assessment 
Censored 
Date of last adequate 
tumor assessment prior 
to the first missed 
assessment 
iCPD or Death after Missing 
>= 2 Consecutive Disease 
Assessments 
Withdrew consent or lost to follow-up 
before iCPD per iRECIST or death 
Censored 
Date of last adequate 
disease assessment 
Discontinued from Study 
without Documented iCPD 
or Death 
 
Table 1c: Censoring Rules for the OS 
Situation 
Outcome 
Date 
Event Description/ 
Censoring Reason 
Death on/before data cutoff date  
Event 
Date of death 
Death 
Alive with study completed before data 
cutoff date 
Censored 
Study completion 
date 
Alive on or before study 
completion date 
Alive or death after data cutoff date 
with study continuing on/till after data 
cutoff date 
Censored 
Data cutoff date 
Alive on or before data 
cutoff date 
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Lost to follow-up prior to data cutoff 
date 
Censored 
Last known alive 
date  
Discontinued from study 
Discontinued study without death and 
not lost to follow-up on/prior to data 
cutoff date 
Censored 
Date of study 
discontinuation 
Discontinued from study 
 
Table 2: Last Contact Date for the Overall Survival 
Source Data 
Conditions 
Last date patient known to be alive from Long-
Term Follow-Up eCRF 
Use if patient status is reported to be alive. 
Do not use if patient status is not reported unknown 
Post-treatment follow-up eCRF questions 
 Use if record selected 
End of study 
Not lost to follow up 
Start/end dates from drug administration record 
Nonmissing dose. Doses of 0 are allowed 
Dosing prophylaxis eCRF 
Prophylaxis given marked as yes 
End of treatment date from the End of 
Treatment eCRFs 
No condition 
Tumor assessment (RECIST v1.1 or iRECIST) date 
Evaluation is marked as done 
Laboratory/PK collection dates 
Sample collection marked as done 
Vital signs date 
At least 1 nonmissing parameter value 
Physical examination 
Evaluation performed marked as yes 
12-Lead ECG 
Evaluation performed marked as yes 
ECOG performance status date 
Nonmissing ECOG performance status 
Start/end dates of adverse events 
Nonmissing verbatim term 
Start/end dates of concomitant medications and 
procedures 
Nonmissing verbatim term 
 
B. Primary Efficacy Analysis 
 
The primary efficacy endpoint of ORR: The two-sided 95% CIs for the point 
estimates will be provided using Clopper-Pearson method. 
 
A table summarizing the number and percentage of subjects with a Best Overall 
Response (BOR) of CR, PR, SD, PD, or Not Evaluable will be presented. This 
table will also include the ORR and DCR, with their two-sided 95% CI calculated 
using the Clopper-Pearson method.  
 
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C. Secondary Efficacy Analyses 
 
The secondary efficacy endpoints include PFS, DOR, iORR, iPFS, iDOR and OS.  
 
iORR.  The two-sided 95% CIs for the point estimates will be provided using 
Clopper-Pearson method. 
 
PFS, DOR, iPFS, iDOR, and OS.  Estimates of median with 95% CIs will be 
computed using the Kaplan-Meier method. Kaplan-Meier curves will be plotted. 
Median Time-to-Event will be estimated at the 50th percentile of the 
corresponding Kaplan-Meier estimates. The event-free rate with the two-sided 
95% CIs using Greenwood’s formula will be calculated for 3-month interval 
timepoints (e.g., 6, 9, 12 and 18 months). The reasons for censoring will be 
summarized categorically with the number and percentage of subjects tabulated. 
 
Subgroup analysis for ORR, DOR, and PFS based on HPV status (Positive vs. 
Negative) and PD-L1 expressions (combined positive score [CPS] ≥ 1 vs. CPS ≥ 
20) for the Treated Analysis Set will be performed using the same approach for the 
main analysis. Additionally, subgroup analysis of ORR, DOR and OS by schedule 
will also be performed. 
 
The following efficacy figures will be generated using the Investigator reported 
RECIST v1.1 assessments on the Treated Analysis set. Additional figures for the 
iRECIST by Investigator assessments may be produced. 
 
x A waterfall plot of best percent change in the tumor burden of injected and 
non-injected target lesions from the Screening/Baseline target lesion 
assessment for each subject.  
o Tumor burden as reflected by the sum of the diameters (SOD) of all 
target lesions, concerning longest diameters for extranodal lesions 
and short axis for lymph nodes, will be assessed at baseline and at 
each disease assessment after the first dose of CMP-001. 
o Tumor burden change will be calculated as the percentage change 
in SOD of target lesions from baseline for each efficacy evaluable 
subject at each disease assessment. 
o The waterfall plot will display each BOR category as a separate 
color. 
 
x A spider plot of the percent changes in the tumor burden of target lesion 
measruments (including the sum of diameters (SOD) of all target lesions, 
the longest diameters for extranodal lesions, and the short axis for lymph 
nodes) from the Screening/Baseline target lesion assessment over time.   
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o The spider plot will display each BOR category as a separate color. 
 
x A swimmer plot delineating the occurrence of the clinical outcomes of 
interest over time, including the following information: 
o Duration on study treatment  
o Time to BOR based on RECIST v1.1 as assessed by Investigator, 
except that PD will be the first occurrence of PD. The swimmer plot 
will display each Confirmed BOR category as a separate color. 
o Time to death 
o The swimmer plot will display each BOR category as a separate 
color. 
 
x Kaplan-Meier plots displaying time-to-event on TTR, DOR, PFS, OS per 
RECIST v1.1 as assessed by Investigator: 
o Estimate of median and the corresponding two-sided 95% CIs for 
median 
o Event-free rates at selected timepoints  
 
D. Exploratory Efficacy Analysis 
 
The performance of the statistical analysis for the exploratory efficacy endpoint is 
contingent on the availability of the data source. Given the response assessment 
based on itRECIST3 by Investigator has not been collected, and that the RECIST 
v1.1 and iRECIST were deemed sufficient for the purpose of the response 
assessment in the study from the Medical’s perspective, no exploratory efficacy 
analyses will be carried out for the exploratory phase 2 study. 
 
 
IX. 
Safety Analyses 
 
Safety analyses will use data from the Treated Analysis Set. Subjects will be analyzed 
according to the actual study treatment received. 
 
A. Exposure 
 
Exposure to CMP-001 and Pembrolizumab will be summarized separately for the 
Treated Analysis Set with descriptive statistics for  the number of doses received, 
the average number of volumes injected per dosing visit, the duration of treatment 
for each treatment (weeks), the planned dose intensity, the actual dose intensity, 
the relative dose intensity (%), and the treatment compliance. 
 
1. Duration of Treatment 
 
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Duration of treatment (DoT) of CMP-001 and Pembrolizumab will be summarized 
in a descriptive manner, respectively. DoT will be calculated as follows: 
DoT (weeks) = [min(last dose date + 21 days, discontinuation/completion date)  
– first dose date] / 7 
 
2. Dosing Intensities 
 
(1) Actual dose intensity (mg/week) will be calculated as the total actual cumulative 
dose received divided by duration of treatment (weeks) for CMP-001 and 
Pembrolizumab, respectively. 
 
(2) Planned dose intensity (mg/week) will be calculated as the total planned 
cumulative dose to be received divided by the planned duration of treatment 
(weeks) based on the protocol schedule. 
Planned Duration of Treatment (weeks) = number of planned treatments  
* 3 weeks 
 
(3) Relative dose intensity (%) will be calculated based on the actual cumulative 
dose received relative to the planned cumulative dose throughout the duration of 
treatment as follows: 
Relative dose intensity (%) = (actual dose intensity / planned dose intensity) * 
100% 
 
3. Treatment Compliance 
 
Treatment compliance is calculated as the number of CMP-001/Pembrolizumab 
doses received/expected doses within the treatment period defined as time from 
first dose to last dose. 
 
4. Dosage Modifications 
 
The number of subjects with dose modifications (e.g., Drug Delayed, Drug 
Withheld, Drug interrupted, Dose Reduced, Drug Permanently Withdrawn) with 
the reasons will also be summarized by study drug. 
 
Additionally, subgroup analysis of drug dosing and intensities for subjects by 
schedule will also be performed. Listings will be provided with the information 
from the study drug administration eCRFs for CMP-001 and Pembrolizumab, 
including date and time of each dose, route of administration, dose administered, 
location of each injection, and the volume injected into each tumor at each dosing 
visit.  
 
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B. Adverse Events 
 
Adverse events should be recorded upon first occurrence and followed until 
resolution. A persistent AE is continuous and does not resolve between Q3W 
dosing visits; and should be documented only once unless the grade becomes more 
severe. If the grade becomes more severe, the AE must be reported again with the 
new grade. Any recurrent AE should be reported as new AE each time the AE 
occurs. Worsening of an ongoing TEAE (i.e., an increase to higher grade) should 
be recorded as a new AE. Ongoing AEs that decrease in severity/grade should not 
be captured as new AEs. 
 
According to Protocol section 8.1.1, disease progression, and associated 
hospitalizations and deaths, are not considered an AE or SAE in this study. 
 
Medical occurrences that begin before start of study treatment should be recorded 
on the Medical History/Current Medical Conditions section of the eCRF, not the 
AE section.  
 
Adverse events starting more than 30 days after the last dose of study treatment 
should not be recorded on the AE eCRF unless they are related to study treatment. 
 
Serious adverse events and AEs resulting in discontinuation will be followed until 
1 of the following occurs: 
x The event resolves 
x The event stabilizes 
x The event returns to a Baseline value if a Baseline value is available 
x The event can be attributed to agents other than the study treatment or to 
factors unrelated to study conduct 
x The Investigator and Medical Monitor agree that follow-up is no longer 
necessary 
 
Adverse event (AE) data are available to the Sponsor from two sources, the eCRFs 
and the Serious Adverse Event (SAE) paper forms and corresponding SAE 
narratives. While reconciliation will be performed to ensure consistency between 
the two types of data, the production of data summaries and listings will be based 
on the data collected on the eCRF.   
 
Treatment-emergent adverse event (TEAE) 
 
Pretreatment AEs are AEs that occur from the time of informed consent up to the 
first dose of study treatment (W1D1). A treatment-emergent adverse event (TEAE) 
is defined as an AE that started or worsened in severity on or after the date that 
study treatment was first administered (W1D1) until 30 days after the last dose of 
                                        VV-RIM-00350887-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan  
  
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-007 
IQVIA Biotech (Confidential) Project # SZA56629 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 32 of 40 
study treatment. AE data collection also ceases at the time a new cancer treatment 
is started per protocol section 8.3, whichever occurs first. 
 
Treatment-emergent adverse events will be coded using MedDRA (version 23.1) 
and data will be summarized for the Treated Analysis Set. The number and percent 
of subjects reporting each TEAE will be summarized, as well as the number of 
TEAEs. A subject with 2 or more TEAEs within the same level of summarization 
(i.e., system organ class or preferred term) will be counted only once in that level 
using the most severe event or most related (for the relationship to study treatment 
tables). 
 
AEs are graded using Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0. AE summaries may include summaries for all AEs and by 
the maximum CTCAE grade for the item being summarized (i.e., SOC or PT). In 
these cases, the outputs will include a row for All Grades as well as rows for the 5 
potential CTCAE grades: Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), 
Grade 4 (Life threatening or disabling), or Grade 5 (Death).  
 
If grade is missing for a TEAE, the event will be counted as grade 3=severe in the 
TEAE summary tables. If relationship is missing for a TEAE, the event will be 
counted as related in the TEAE summary tables. Therefore, related AEs include 
those which are definitely, probably and possible related and those with missing 
relationship. 
 
A TEAE summary table will be generated including the following (N (%)): 
x Subjects with TEAEs 
x Subjects with TEAEs of grade 3 or higher 
x Subjects with TEAEs Related to CMP-001 and/or Pembrolizumab 
x Subjects with CMP-001-related TEAEs 
x Subjects with pembrolizumab-related TEAEs 
x Subjects with grade 3 or higher TEAEs Related to CMP-001 and/or 
Pembrolizumab 
x Subjects with grade 3 or higher CMP-001-related TEAEs 
x Subjects with grade 3 or higher pembrolizumab-related TEAEs 
x Subjects with treatment-emergent Serious AEs (SAEs) 
x Subjects with SAE Related to CMP-001 and/or Pembrolizumab 
x Subjects with CMP-001-related SAEs 
x Subjects with pembrolizumab-related SAEs 
x Subjects with AE of Special Interest 
                                        VV-RIM-00350887-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan  
  
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-007 
IQVIA Biotech (Confidential) Project # SZA56629 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 33 of 40 
x Subjects with TEAEs leading to CMP-001 and/or Pembrolizumab 
Treatment Discontinuation 
x Subjects with TEAEs leading to CMP-001 treatment discontinuation 
x Subjects 
with 
TEAEs 
leading 
to 
Pembrolizumab 
Treatment 
Discontinuation 
x  Subjects with TEAEs leading to study discontinuation 
x Subjects with TEAEs resulting in death 
 
In addition, the following TEAE summaries tables will be generated. Percentages 
will be based upon the number of subjects in the Treated Analysis Set.   
x All TEAEs, by MedDRA SOC and preferred term  
x Grade 3 or higher TEAEs, by MedDRA SOC and preferred term  
x TEAEs by maximum severity, by MedDRA SOC and preferred term 
x TEAEs Related CMP-001 and/or pembrolizumab by maximum severity, 
by MedDRA SOC and preferred term 
x TEAEs Related CMP-001 by maximum severity, by MedDRA SOC and 
preferred term 
x TEAEs Related Pembrolizumab by maximum severity, by MedDRA SOC 
and preferred term TEAEs by highest relationship to CMP-001 and/or 
Pembrolizumab, by MedDRA SOC and preferred term  
x Grade 3 or higher TEAEs Related to CMP-001 and/or pembrolizumab by 
MedDRA SOC and preferred term 
x Grade 3 or higher CMP-001-related TEAEs, by MedDRA SOC and 
preferred term  
x Grade 3 or higher pembrolizumab-related TEAEs, by MedDRA SOC and 
preferred term 
x Death due to TEAEs, by MedDRA SOC and preferred term  
x Serious AEs (SAEs), by MedDRA SOC and preferred term  
x Grade 3 or higher SAEs, by MedDRA SOC and preferred term 
x Grade 3 or higher CMP-001-related SAEs, by MedDRA SOC and 
preferred term 
x Grade 3 or higher pembrolizumab-related SAEs, by MedDRA SOC and 
preferred term 
x SAEs related to treatment (possibly + probably + definitely), by MedDRA 
SOC and preferred term  
x SAEs related to CMP-001 by MedDRA SOC and preferred term 
x SAEs related to pembrolizumab by MedDRA SOC and preferred term 
x TEAEs 
leading 
to 
CMP-001 
and/or 
Pembrolizumab 
treatment 
discontinuation 
                                        VV-RIM-00350887-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan  
  
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-007 
IQVIA Biotech (Confidential) Project # SZA56629 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 34 of 40 
x TEAEs leading to CMP-001 treatment discontinuation 
x TEAEs leading to pembrolizumab treatment discontinuation 
x TEAEs leading to study discontinuation by SOC and preferred term 
 
Additionally, subgroup analysis for the overall summary of adverse events by 
schedule will also be performed. A by-subject AE data listing, including verbatim 
term, SOC, preferred term, severity, outcome, and relationship to treatment, will 
be provided. Listed terms will be ordered alphabetically within subject. Separate 
listings will be generated for deaths, SAEs and AEs leading to treatment and study 
discontinuation. 
 
C. Deaths 
 
All deaths that occur during the study or within the protocol-specified follow-up 
period after the last dose of the study drug will be reported.  
 
Death information to be included in the summary table concerns the incidence of 
deaths, along with the primary cause of death for the Treated Analysis Set. All 
deaths including deaths that occur within 30 days after the last dose of the study 
treatment or the initiation of an alternative new anti-cancer therapy, whichever is 
earlier, will be tabulated and presented in a by-subject listing, involving the 
primary cause of death, duration of treatment and the number of days between the 
last dose date of the study drug and death. Additionally, subgroup analysis for 
deaths by schedule will also be performed. 
 
D. Clinical Laboratory Results 
 
Gradable laboratory values will be evaluated and assigned toxicity grades 
according to the NCI CTCAE v5.0. Clinically significant post-baseline laboratory 
values will be reported as AEs. When possible, a diagnosis should be recorded as 
an AE, rather than the symptoms or isolated laboratory abnormalities related to the 
diagnosis. 
 
Safety central laboratory data, including hematology, coagulation, serum 
chemistry, autoimmune lab panel and thyroid function tests (see Table 3 below), 
will be summarized using descriptive statistics (mean, standard deviation, median, 
minimum, and maximum) and presented for each time point, including change 
from Baseline, for the Treated Analysis Set. Shift tables from Baseline to the Min 
and Max Post-Baseline, the categories in the shift tables will be WNL, Low, and 
High. Within normal limits and Normal will be used when appropriate for 
urinalysis parameters.  
 
                                        VV-RIM-00350887-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan  
  
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-007 
IQVIA Biotech (Confidential) Project # SZA56629 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 35 of 40 
By-subject data listings of all central laboratory data will be generated and all 
values outside the normal range will be flagged as High or Low. Listings of all 
clinically significant post-Baseline laboratory values from local and central 
laboratory assessments will be presented in the data listings. 
 
Table 3: Clinical Laboratory Assessments 
Hematology 
Serum Chemistry 
Urinalysis 
Other Laboratory 
Tests 
Red blood cells (RBCs) 
White blood cells 
(WBCs) 
Differential WBC count 
Hemoglobin 
Hematocrit 
Platelets 
Alanine aminotransferase 
(ALT) 
Albumin 
Alkaline phosphatase 
(ALP) 
Amylase 
Aspartate 
aminotransferase (AST) 
Bilirubin 
Blood urea nitrogen 
Calcium  
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
(LDH) 
Lipase 
Phosphorous 
Potassium 
Sodium  
Total protein 
Blood 
Glucose 
Nitrites 
pH 
Protein 
Specific gravity 
WBCs 
 
Microscopic battery: 
RBCs, WBCs, epithelial 
cells, casts (only if 
significant positive 
findings on urinalysis) 
Coagulation: 
PTT 
PT 
INR 
 
Thyroid Function 
Studies: 
Thyroid Stimulating 
Hormone, Free T3, Free 
T4 
 
Autoimmune laboratory 
Panel: 
Anti-dsDNA 
Antinuclear 
Antibody 
Antineutrophil 
cytoplasmic antibody 
Rheumatoid factor 
Antibodies to 
ribonucleoprotein (anti-
RNP) 
 
Tests to be performed as 
clinically indicated: 
Human 
immunodeficiency virus 
Hepatitis B and C 
Abbreviations: Anti-dsDNA = anti-double stranded DNA; RBC = red blood cell; T3 = triiodothyronine; T4 = 
thyroxine; WBC = white blood cell. 
Note: Refer to the Study Laboratory Manual for additional information. 
 
E. Vital Signs 
 
Vital signs include measurement of blood pressure (systolic and diastolic blood 
pressure), respiratory rate, heart rate, and body temperature. Summaries of actual 
values and changes from baseline will be presented for each assessment time point, 
beginning with the first post-baseline assessment.  
 
Moreover, each of these vital signs will be summarized in a descriptive manner for 
the following values that will be derived per unique subject: 
                                        VV-RIM-00350887-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan  
  
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-007 
IQVIA Biotech (Confidential) Project # SZA56629 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 36 of 40 
x Baseline value  
x Minimum post-baseline value and corresponding change from baseline 
x Maximum post-baseline value and corresponding change from baseline 
x Last post-baseline value and corresponding change from baseline 
 
A by-subject data listing of all vital sign data will be generated. 
 
F. Physical Examination 
 
Detailed information on the physical examinations (height, weight, and BMI) will 
be listed by subject. Clinically significant post-baseline physical examination 
findings will be reported as AEs. 
 
G. Prior and Concomitant Medications 
 
All medications administered to the subject from 30 days prior to first dose of 
study treatment (W1D1) until 30 days after discontinuation of both CMP-001 and 
Pembrolizumab will be recorded in the EDC. Treatment medications for AEs 
related to study treatment that occur more than 30 days after the last dose of study 
treatment will also be collected.  
 
Documentation for each medication will include the generic name of the 
medication, dose per administration, route of administration, dates of 
administration, and indication for use. Combination drugs must be listed separately 
by each component study treatment and dose, when possible. Prior cancer 
treatments will be recorded separately. 
 
Prior medications are those taken within 30 days of the first dose of study treatment 
and discontinued before the first dose of study treatment. 
 
Concomitant medications are defined as medications which are taken during study 
treatment and within 30 days of the last dose of study treatment. Additionally, 
medications started prior to the first dose of study treatment, but with a stop date 
after the first dose of study treatment and within 30 days of the last dose of study 
treatment will be considered concomitant medications. 
 
Medications will be coded using the B3 Global September 2020 of World Health 
Organization drug dictionary and summarized according to the Anatomical 
Therapeutic Chemical (ATC) class II and preferred term for subjects in the Treated 
Analysis Set. Subjects will be counted only once for a given concomitant 
medication for each Anatomical Therapeutic Chemical class and preferred term in 
the summary tables. 
 
                                        VV-RIM-00350887-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan  
  
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-007 
IQVIA Biotech (Confidential) Project # SZA56629 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 37 of 40 
Prior and Concomitant medications will be presented in a by-subject data listing. 
The listing will contain both prior and concomitant medications with an indication 
of whether the medication is a prior or concomitant medication. The listing will 
display entries from the Concomitant Medications form, ordered within subject by 
the “Start Date of Medication”.  
 
A second hierarchical listing will display WHO Drug Anatomical Therapeutic 
Chemical class represented in the data. Within each anatomical class, the listing 
will display each preferred term. Within each preferred term, the listing will 
display each unique verbatim (recorded) term. Listed terms will be ordered 
alphabetically.  
 
H. Prior and Concomitant Procedures 
 
All procedures within 30 days of Week 1, Day 1 and through 100 days after last 
study treatment must be recorded in the EDC.   
 
Prior procedures are defined as procedures with a procedure date that is prior to 
the first dose of study drug. Concomitant procedures are defined as procedures 
with a procedure date on or after the first dose of study drug, and within 30 days 
of the last dose of study drug. 
 
Prior and Concomitant procedures will be presented in a by-subject data listing.  
The listing will contain both prior and concomitant procedures with an indication 
of whether the procedure is a prior or concomitant procedure. The listing will 
display entries from the Concomitant Procedures form, ordered within subject by 
the “Procedure Start Date”. 
 
I. Electrocardiograms (ECGs)  
 
ECG results (Heart Rate, PR Interval, QRS Interval, QT Interval, QTcF Interval), 
and classification of “Normal”, “Abnormal, Not Clinically Significant”, and 
“Abnormal, Clinically Significant” will be presented in data listings.    
 
Summaries of actual values and changes from baseline will be presented for each 
assessment visit. Additionally, each ECG parameter will be summarized in a 
descriptive manner using the Treated Analysis Set for the following values that are 
derived per unique subject and ECG parameter: 
x Baseline value 
x Minimum post-baseline value and corresponding change from baseline 
x Maximum post-baseline value and corresponding change from baseline 
x Last post-baseline value and corresponding change from baseline   
 
                                        VV-RIM-00350887-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan  
  
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-007 
IQVIA Biotech (Confidential) Project # SZA56629 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 38 of 40 
For the overall ECG result (“Normal”, “Abnormal, Not Clinically Significant”, 
and “Abnormal, Clinically Significant”) summaries will be provided for baseline 
and each post-baseline assessment visit.   
 
J. Eastern Cooperative Oncology Group Performance (ECOG) 
 
Eastern Cooperative Oncology Group performance status (ECOG) results will be 
presented in data listings. ECOG PS at baseline will be presented in summary table 
of baseline characteristics. Shift table analysis of baseline vs. worst and last post-
baseline score will be presented. Change from baseline in ECOG Performance 
Status will be summarized for the Treated Analysis Set. 
 
 
X. Pharmacokinetic Analyses 
 
Per Sponsor’s decision, no Pharmacokinetic analyses will be performed. The following 
exposes the root cause of this decision. 
 
Section 9.7 of the protocol states the PK parameters that may be assessed include, but 
are not necessarily limited to, maximum observed serum concentration, time of 
maximum observed serum concentration, area under the serum concentration-time 
curve from time zero to the last quantifiable time point, area under the serum 
concentration-time curve from time zero extrapolated to infinity, and terminal 
elimination half-life. 
 
Even though section 9.7 of the protocol indicates that PK parameters will be assessed 
in serum, the study lab manual instructs sites to collect PK using K2EDTA plasma 
tubes.  Plasma PK samples cannot be utilized to determine PK of CMP-001 as the data 
will not be valid for any future assessments. 
 
 
XI. 
Pharmacodynamic Analyses 
 
Concentrations of CXCL10 and other chemokine or cytokine biomarkers will be 
summarized using descriptive statistics and listed for all time points for the 
Pharmacodynamic Analysis Set. Changes from Baseline will be included. 
 
 
XII. Exploratory Tumor Biopsy Analyses 
 
Tumor biopsy obtained at baseline and specified time points during the study will be 
summarized and listed for protein, RNA, DNA, or other biomarkers related to TLR9, 
                                        VV-RIM-00350887-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan  
  
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-007 
IQVIA Biotech (Confidential) Project # SZA56629 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 39 of 40 
immune checkpoints, and potential markers of resistance or response to 
immunotherapy, for the Pharmacodynamic Analysis Set. 
 
                                        VV-RIM-00350887-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan  
  
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-007 
IQVIA Biotech (Confidential) Project # SZA56629 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 40 of 40 
XIII. References 
 
None.  
                                        VV-RIM-00350887-1.0 Approved - 15 May 2024 GMT-5:00


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