Conditions: Melanoma Advanced Melanoma Metastatic Melanoma Unresectable Melanoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 44
Healthy volunteers: no

Brief summary:
CMP-001-010 is a Phase 2 study of CMP-001 intratumoral (IT) and nivolumab intravenous (IV) administered to participants with refractory unresectable or metastatic melanoma.

The primary objective of the study is to determine confirmed objective response with CMP-001 in combination with nivolumab in subjects with refractory unresectable or metastatic melanoma.

The secondary objectives are to:

* To evaluate the safety and tolerability of CMP-001 administered by intratumoral (IT) injection in combination with nivolumab in subjects with refractory unresectable or metastatic melanoma.
* To evaluate the efficacy of CMP-001 in combination with nivolumab in subjects with refractory unresectable or metastatic melanoma.
* To assess the pharmacokinetic (PK) profile of CMP-001 in combination with nivolumab in subjects with refractory unresectable or metastatic melanoma.
* To assess and describe the immunogenicity of CMP-001 in combination with nivolumab in subjects with refractory unresectable or metastatic melanoma.

Detailed description:
Former Sponsor Checkmate Pharmaceuticals

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

Interventions: intervention 1: CMP-001 intervention 2: Nivolumab
Intervention descriptions: intervention 1: Subjects will receive CMP-001 10 mg IT weekly for 7 doses after which CMP-001 will be administered every 3 weeks (Q3W). intervention 2: Nivolumab 360 mg IV is administered Q3W.

Protocol document:
Prot_000.pdf: 
Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 1 
Confidential 
VV-RIM-00381493-1.0 Approved - 27 Nov 2024 GMT-5:00
CMP-001-010 
A MULTICENTER, OPEN-LABEL, PHASE 2 STUDY 
OF INTRATUMORAL CMP-001 IN COMBINATION 
WITH INTRAVENOUS NIVOLUMAB IN SUBJECTS 
WITH REFRACTORY UNRESECTABLE OR 
METASTATIC MELANOMA 
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 31 August 2020 
Amendment 1 (Version 2.0) 04 February 2021 
Amendment 2 (Version 3.0) 26 August 2021 
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. 
Complion Document ID: 3328737
NCT04698187


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 2 
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INVESTIGATOR’S AGREEMENT 
A MULTICENTER, OPEN-LABEL, PHASE 2 STUDY OF INTRATUMORAL CMP- 
001 IN COMBINATION WITH INTRAVENOUS NIVOLUMAB IN SUBJECTS 
WITH REFRACTORY UNRESECTABLE OR METASTATIC MELANOMA 
 
Protocol Number: CMP-001-010 
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, 
reviewed, and approved by the Sponsor or its representatives. 
• I will conduct the study in accordance with the current United States (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 (eCRF) information may have 
been generated. 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
Signature of Investigator 
Date 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 3 
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SPONSOR PROTOCOL APPROVAL 
 
I have read this protocol and approve the design of this study: 
 
 
 
 
 
 
 
31-Aug-2021 | 7:06 AM PDT 
 
Checkmate Pharmaceuticals, Inc 
Date 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 4 
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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, 02142 United States 
Phone: 617-682-3625 
IQVIA Biotech 
Medical Monitor 
24-Hour emergency 
contact 
IQVIA Biotech 
Email: CMP-001-010@novellaclinical.com 
Serious adverse events (SAEs) should be recorded on the SAE Report Form 
and completed and submitted to IQVIA Biotech Safety preferably via email to: 
Safety-Inbox.Biotech@IQVIA.com or by fax to +1-866-761-1274 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. 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 5 
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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 that encapsulates G10, a cytosine linked 
to a guanine by a phosphate bond oligodeoxynucleotide 
Title of Study: A multicenter, open-label, phase 2 study of intratumoral CMP-001 in combination 
with intravenous nivolumab in subjects with refractory unresectable or metastatic melanoma 
Study Center(s): This study will be conducted at clinical sites in regions including (but not limited 
to) North America and Asia Pacific. 
Phase of Development: Phase 2 
Objectives: 
Primary: 
• 
To determine confirmed objective response with CMP-001 in combination with 
nivolumab in subjects with refractory unresectable or metastatic melanoma 
Secondary: 
• 
To evaluate the safety and tolerability of CMP-001 administered by intratumoral (IT) 
injection in combination with nivolumab in subjects with refractory unresectable or 
metastatic melanoma 
• 
To evaluate the efficacy of CMP-001 in combination with nivolumab in subjects with 
refractory unresectable or metastatic melanoma 
• 
To assess the pharmacokinetic (PK) profile of CMP-001 in combination with 
nivolumab in subjects with refractory unresectable or metastatic melanoma 
• 
To assess and describe the immunogenicity of CMP-001 in combination with 
nivolumab in subjects with refractory unresectable or metastatic melanoma 
Exploratory: 
• 
To evaluate the effect of CMP-001 in combination with nivolumab on injected and 
noninjected target lesions in subjects with unresectable or metastatic melanoma 
• 
To evaluate the pharmacodynamic effects of CMP-001 administered in combination 
with nivolumab 
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 Blinded Independent Central Review (BICR) 
Secondary Endpoints: 
• 
Adverse events (AEs), serious adverse events, and AEs leading to discontinuation or 
death, and severity of AEs as assessed by the National Cancer Institute Common 
Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 6 
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• 
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 BICR 
• 
Treatment response in non-injected target lesions based on RECIST v1.1 by BICR 
• 
Progression-free survival (PFS), defined as the time from date of first dose of study 
treatment to date of documented PD based on RECIST v1.1 by BICR or death, 
whichever occurs first 
• 
Overall survival, defined as the time from date of first dose of study treatment to date 
of death 
• 
ORR, DOR, and PFS based on RECIST v1.1 and immune objective response rate 
(iORR), immune duration of response (iDOR), and immune progression-free survival 
(iPFS) based on immunotherapy Response Evaluation Criteria in Solid Tumors 
(iRECIST) by Investigator assessment 
• 
Blood concentrations of CMP-001 or its metabolites 
• 
Development of anti-Qbeta (Qb) antibodies 
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 Toll-like receptor 9, immune checkpoints, and potential markers of 
resistance or response to immunotherapy 
• 
Change from Baseline in blood concentrations of C-X-C motif chemokine 10 
(interferon gamma-induced protein 10) and other cytokines after treatment with CMP- 
001 
Methodology: 
This is a multicenter, open-label, Phase 2 clinical study of CMP-001 administered by IT injection 
in combination with intravenous (IV) nivolumab in subjects with unresectable or metastatic 
melanoma refractory to prior programmed cell death protein 1 (PD-1) blockade. 
Response and DOR will be evaluated using RECIST v1.1 criteria by BICR and Investigator 
assessments and using iRECIST criteria by Investigator assessment. All enrolled subjects will 
receive CMP-001 IT and nivolumab IV according to the treatment schedule until a reason for 
treatment discontinuation is reached. 
Number of subjects (planned): 
The number of subjects planned for this study is 100. 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 7 
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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. Histopathologically-confirmed diagnosis of malignant melanoma that is metastatic or 
unresectable at Screening. 
2. Known BRAF mutation status; if BRAF V600 mutation positive, must have had prior 
treatment with a local Health Authority approved BRAF inhibitor, with or without 
mitogen-activated protein kinase inhibitor. Patients with BRAF V600 mutations who 
refuse a BRAF inhibitor will not be eligible. 
3. Refractory to PD-1 blockade either as monotherapy or in combination with other therapies, 
as defined by the following criteria: 
a. Received treatment with a Food and Drug Administration approved PD-1 blocking 
antibody for 12 weeks or longer. 
b. Have PD (according to RECIST v1.1) within 12 weeks of the last dose of a PD-1 
blocking antibody, either as monotherapy or in combination with other agents. 
− 
Evidence of confirmed PD must be established by Investigator assessment at least 
4 weeks after the initial date of PD. The confirmatory assessment may serve as the 
Baseline for this study if completed within 30 days before the start of study 
treatment. 
NOTE: in subjects with histologically confirmed recurrence on or after adjuvant 
PD-1 blocking antibody, confirmatory imaging is not required. 
4. Measurable disease, as defined by RECIST v1.1 and all of the following: 
a. At least 1 accessible lesion amenable to repeated IT injection. 
b. One or more measurable lesions at least 1 cm in diameter that are not intended for 
CMP-001 injection and can be followed as target lesions per RECIST v1.1. 
c. Documented disease progression in any lesion that was previously radiated in order to 
serve as a target lesion. 
5. Able to provide tissue from a core or excisional/incisional biopsy (fine needle aspirate is 
not sufficient). A fresh tissue biopsy (within 90 days before the start of study treatment) is 
preferred but an archival sample is acceptable (as a substitute) if no intervening therapy 
was received. 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 programmed death-ligand 1 expression. 
6. NOTE: for tissue sampling details, please refer to the laboratory manual. 
7. Adequate organ function based on most recent laboratory values within 3 weeks before 
first dose of study treatment on Week 1 Day 1 (W1D1): 
a. Bone marrow function: 
− 
neutrophil count ≥ 1500/mm3 
− 
platelet count ≥ 100,000/mm3 
− 
hemoglobin concentration ≥ 9 g/dL 
− 
white blood cells ≥ 2000/mm3 
b. Liver function: 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 8 
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− 
total bilirubin ≤ 1.5 times the upper limit of normal (ULN) with the following 
exception: subjects with Gilbert Disease total serum bilirubin ≤ 3 times ULN 
− 
aspartate aminotransferase and alanine aminotransferase ≤ 3 times the ULN 
c. Lactate dehydrogenase ≤ 2 times the ULN 
d. Renal function: estimated (Cockcroft-Gault) or measured creatinine clearance 
≥ 30 mL/min. 
e. Coagulation: 
− 
International normalized ratio or prothrombin time (PT) ≤ 1.5 times ULN, unless 
subject is receiving anticoagulant therapy, as long as PT or partial thromboplastin 
time (PTT) is within therapeutic range of intended use of anticoagulants 
− 
Activated partial thromboplastin time or 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 
8. Age ≥ 18 years at time of consent. 
9. Eastern Cooperative Oncology Group Performance Status of 0 to 1 at Screening. 
10. Capable of understanding and complying with protocol requirements. 
11. Women of childbearing potential must have negative serum pregnancy test before dosing 
at W1D1 and be willing to use an adequate method of contraception (Section 4.3.2.) from 
the time of consent until at least 150 days after last dose of study treatment. 
12. 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. Uveal, acral, or mucosal melanoma. 
2. Received radiation therapy (or other nonsystemic therapy) within 2 weeks before first dose 
of study treatment on W1D1. Subjects should have recovered (ie, Grade ≤1 or at Baseline) 
from radiation-related toxicities. 
3. Treatment with complementary medications (eg, herbal supplements or traditional Chinese 
medicines) to treat the disease under study within 2 weeks before start of study treatment. 
Refer to Section 4.4. for prohibited therapies. 
4. Received systemic pharmacologic doses of corticosteroids > 10 mg/day prednisone within 
30 days before first dose of study treatment on W1D1. 
a. Subjects who are currently receiving steroids at a prednisone-equivalent dose of 
≤ 10 mg/day do not need to discontinue steroids before 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.). 
5. History of immune-related AE that required permanent discontinuation of PD-1 blocking 
antibody. 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 9 
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6. Not fully recovered from AEs (to Grade 1 or less [per CTCAE v5.0], with the exception of 
persistent adverse events or sequelae, eg, vitiligo, alopecia, hypothyroidism, diabetes 
mellitus, and adrenal and/or pituitary insufficiency) due to prior treatment. 
NOTE: Subjects previously treated with a CTLA-4–blocking antibody, subjects receiving 
corticosteroids with daily doses > 5 mg and ≤ 10 mg of prednisone equivalent for > 2 
weeks, and subjects with clinical symptoms and/or laboratory findings suggesting risk for 
adrenal insufficiency should undergo diagnostic tests for adrenal insufficiency via local 
laboratory. 
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, or 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, 
eg, 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, and 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 metastases or carcinomatous 
meningitis (including leptomeningeal metastases from solid tumors). 
13. Prior allogenic tissue/solid organ transplant. 
14. Active infection requiring systemic therapy. 
15. Known or suspected active infection with severe acute respiratory syndrome coronavirus 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 first dose of study 
treatment on W1D1. 
18. Received blood products (including platelets or red blood cells) or colony stimulating 
factors (including granulocyte colony stimulating factor, granulocyte/macrophage colony 
stimulating factor, or recombinant erythropoietin) within 30 days before the start of 
Screening. 
19. History of permanent discontinuation of nivolumab due to infusion reactions. 
20. 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 study. 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 10 
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21. Participation in another clinical study of an investigational anticancer therapy or device 
within 30 days before first dose of study treatment on W1D1. 
NOTE: Participation in the follow-up phase (receiving no study treatment) of a prior study 
is allowed. 
22. Requires prohibited treatment (ie, non-protocol specified anticancer pharmacotherapy, 
surgery, or radiotherapy) for treatment of malignant tumor. 
23. Has a life expectancy of less than 3 months and/or has rapidly progressing disease (eg, 
tumor bleeding, uncontrolled tumor pain) in the opinion of the treating Investigator. 
24. Received previous CMP-001 treatment. 
25. Pregnant or breastfeeding or expecting to conceive or donate eggs within the projected 
duration of the study, from the time of consent until at least 150 days after last dose of 
study treatment for women. 
Investigational product, dosage, and mode of administration: 
Subjects will receive CMP-001 10 mg weekly for 7 doses (W1D1 to W7D1), after which CMP-001 
will be administered every 3 weeks (Q3W) (W10D1, W13D1, etc.) until the subject meets a 
condition for discontinuation of study treatment. 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. The initial 7 CMP-001 weekly dose schedule must 
be completed before starting the Q3W CMP-001 dosing schedule. 
Subjects will receive nivolumab 360 mg IV over 30 minutes at W1D1 and Q3W thereafter until the 
subject satisfies a condition for study treatment discontinuation. Please refer to the nivolumab 
Investigator’s Brochure. The subjects will be first dosed with CMP-001 followed by nivolumab. 
Duration of treatment: 
Subjects will continue study treatment until they reach a reason for treatment or study 
discontinuation (Section 4.5. and Section 4.6.). Subjects may continue study treatment beyond 
progression based upon Investigator judgment of potential benefit. Treatment will be given for a 
maximum of 2 years from the start of study treatment. 
If a subject achieves and maintains a confirmed CR or immune complete response (iCR) by 
investigator review, treatment with CMP-001 or the combination of CMP-001 and nivolumab may 
be discontinued at the Investigator’s discretion once they meet both of the following criteria: 
• 
Subject has been treated with both study treatments for at least 48 weeks 
• 
Subject has received at least 3 doses of both study treatments beyond the date of the 
initial CR/iCR 
Subjects who discontinue study treatment should complete the end of treatment visit and 100-day 
safety follow-up. Subjects who are posttreatment but have not met criteria for study discontinuation 
should remain on study for posttreatment follow-up and long-term survival follow-up and receive 
study evaluations for efficacy according to the Schedule of Assessments. 
Subjects who permanently discontinue treatment with nivolumab due to an immune related AE 
must also permanently discontinue treatment with CMP-001. 
Subjects who discontinue CMP-001 or both CMP-001 and nivolumab treatment may not be 
retreated on this study. 
Complion Document ID: 3328737 


Protocol CMP-001-010 
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Criteria for evaluation: 
Efficacy: 
Disease status will be assessed by computed tomography or magnetic resonance imaging and other 
appropriate measures according to the Schedule of Assessments (Table 1). Calipers and 
photographs containing a ruler may be used to facilitate measurement of superficial cutaneous 
tumors. Objective responses will be assessed by a BICR and the Investigator according to RECIST 
v1.1. Subjects who experience PD according to RECIST v1.1 will be assessed by the Investigator 
according to iRECIST. Other endpoints include PFS, best overall response (BOR), and DOR. 
Pharmacokinetics: 
Pharmacokinetic assessment will be performed in order to assess serum CMP-001 levels following 
IT injection and potentially SC administration in the first 20 subjects enrolled. Samples will be 
collected according to the Schedule of Assessments (Table 1). 
Immunogenicity: 
Plasma will be obtained at time points described in the Schedule of Assessments (Table 1), for the 
presence of anti-Qb antibodies. 
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 DNA or RNA profiling, gene expression, flow 
cytometry, or immunohistochemistry using tumor biopsies of injected or non-injected 
target lesions, collected before treatment and during 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 CTCAE v5.0 
• 
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) 
• 
12-lead electrocardiograms (ECGs) 
Statistical methods: 
Sample size calculation: 
The study will enroll approximately 100 subjects. A subject is enrolled in the study when they have 
received the first dose of study treatment. 
A sample size of 69 subjects achieves at least 90% power to detect a difference of 13% using a 
2-sided exact test with a significance level of 0.05, assuming that the null hypothesis for ORR is 
7% (Hodi-2016; Ribas-2018), and the study ORR is 20%. The sample size was increased to 
100 subjects to adjust for an early discontinuation rate of 15%, and to allow for a robust assessment 
of safety. A sample size of 100 subjects with an ORR of 20% produces a 95% Clopper-Pearson CI 
for the ORR of 12.7% to 29.2% (PASS 2020). 
Statistical analysis methods: 
Analysis sets for safety and efficacy will include: 
Complion Document ID: 3328737 


Protocol CMP-001-010 
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• 
Intent-to-Treat (ITT) Analysis Set: all subjects who receive at least 1 dose of study 
treatment 
• 
Safety Analysis Set: all subjects who receive at least 1 dose of study treatment 
• 
Per Protocol Analysis Set: all subjects who receive at least 1 dose of study treatment 
and are without major protocol deviations 
• 
Pharmacodynamic Analysis Set: 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 injection 
• 
Pharmacokinetic Analysis Set: all subjects who receive CMP-001 and have evaluable 
samples at Baseline and after CMP-001 injection 
• 
Immunogenicity Analysis Set: all subjects who receive CMP-001 and have evaluable 
samples for immunogenicity 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, 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 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 v9.4 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 v1.1 by 
BICR for the ITT Analysis Set. Secondary efficacy analyses will include ORR, PFS, BOR, and 
DOR according to RECIST v1.1 by BICR. Additional secondary efficacy analyses will include 
ORR, DOR, and PFS according to RECIST v1.1, and iORR, iDOR, and iPFS according to 
iRECIST by Investigator assessment. 
Blood concentrations of CMP-001 will be summarized using appropriate descriptive statistics by 
visit/time point for the PK Analysis Set. 
Immunogenicity endpoints will be summarized using appropriate descriptive statistics for the 
Immunogenicity Analysis Set. 
Complion Document ID: 3328737 


Protocol CMP-001-010 
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Table 1: 
Schedule of Assessments 
 
Procedure or 
Assessment 
Screening 
(Day -30 
to Day -1) 
W1D1 
W2D1 
W3D1 
W4D1 
W5D1 
W6D1 
W6D2 
W7D1 
Q3W 
(W10, W13, etc.) 
End of 
Treatment 
(EOT)a 
100-Day 
Follow-up 
(100DFU)b 
Posttreatment 
Follow-up 
(PTFU)c 
(Q3mo) 
Long-Term 
Survival 
Follow-up 
(LTSFU)d 
(Q3mo) 
Visit Windows 
n/a 
n/a 
± 2d 
± 2d 
± 2d 
±2d 
±2d 
n/a 
±2d 
± 3d 
+7d 
+7d 
± 2weeks 
± 4weeks 
CMP-001 
Injection 
(Dose Number)e 
1 
SC/IT 
2 
3 
4 
5 
6 
7 
8+ 
Nivolumab 
Dosing 
(Dose Number)f 
1 
2 
3 
4+ 
Informed Consent 
X 
Eligibility 
Criteria 
Assessment 
X 
Demographics 
X 
Medical History 
X 
Melanoma 
History 
X 
Prior Cancer 
Treatment 
X 
Physical 
Examinationg 
X 
X 
X 
X 
X 
X 
Vital Signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
Performance 
Status 
X 
X 
X 
X 
X 
X 
Adverse Event 
Monitoringi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medicationsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 
14 
Confidential 
VV-RIM-00381493-1.0 Approved - 27 Nov 2024 GMT-5:00 
 
 
Table 1: 
Schedule of Assessments (Continued) 
 
Procedure or 
Assessment 
Screening 
(Day -30 
to Day -1) 
W1D1 
W2D1 
W3D1 
W4D1 
W5D1 
W6D1 
W6D2 
W7D1 
Q3W 
(W10, W13, etc.) 
End of 
Treatment 
(EOT)a 
100-Day 
Follow-up 
(100DFU)b 
Posttreatment 
Follow-up 
(PTFU)c 
(Q3mo) 
Long-Term 
Survival 
Follow-up 
(LTSFU)d 
(Q3mo) 
Visit Windows 
n/a 
n/a 
± 2d 
± 2d 
± 2d 
±2d 
±2d 
n/a 
±2d 
± 3d 
+7d 
+7d 
± 2weeks 
± 4weeks 
CMP-001 
Injection 
(Dose Number)e 
1 
SC/IT 
2 
3 
4 
5 
6 
7 
8+ 
Nivolumab 
Dosing 
(Dose Number)f 
1 
2 
3 
4+ 
12-Lead ECGk 
X 
X 
X 
X 
X 
Clinical 
Laboratory Tests 
(hematology, 
serum chemistry, 
urinalysis)l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
Testsl 
X 
X 
X 
X 
Thyroid Function 
Testsl 
X 
X 
X 
X 
X 
Autoimmune 
Laboratory Panell 
X 
X 
X 
Pregnancy Test 
and Follicle 
Stimulating 
Hormonel 
X 
X 
X 
X 
X 
X 
Exploratory 
Biomarker 
Samplingm 
X 
X 
X 
X 
X 
Pharmacokinetic 
Samplingn 
X 
X 
X 
X 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 
15 
Confidential 
VV-RIM-00381493-1.0 Approved - 27 Nov 2024 GMT-5:00 
 
 
Table 1: 
Schedule of Assessments (Continued) 
 
Procedure or 
Assessment 
Screening 
(Day -30 
to Day -1) 
W1D1 
W2D1 
W3D1 
W4D1 
W5D1 
W6D1 
W6D2 
W7D1 
Q3W 
(W10, W13, etc.) 
End of 
Treatment 
(EOT)a 
100-Day 
Follow-up 
(100DFU)b 
Posttreatment 
Follow-up 
(PTFU)c 
(Q3mo) 
Long-Term 
Survival 
Follow-up 
(LTSFU)d 
(Q3mo) 
Visit Windows 
n/a 
n/a 
± 2d 
± 2d 
± 2d 
±2d 
±2d 
n/a 
±2d 
± 3d 
+7d 
+7d 
± 2weeks 
± 4weeks 
CMP-001 
Injection 
(Dose Number)e 
1 
SC/IT 
2 
3 
4 
5 
6 
7 
8+ 
Nivolumab 
Dosing 
(Dose Number)f 
1 
2 
3 
4+ 
Blood Sampling 
for Cytokine and 
Complemento 
X 
X 
X 
Immunogenicity 
Samplingp 
X 
X 
X 
X 
Tumor Biopsyq 
X 
X 
Disease 
Assessment 
(radiographic 
imaging)r 
Xs 
W13u; Q9W 
X 
X 
Disease 
Assessment 
(CNS Imaging)r 
Xs, t 
W13u; Q9W 
X 
X 
Disease 
Assessment 
(photographic 
imaging)r 
Xs 
X 
W13u; Q9W 
X 
X 
100-Day 
Follow-up 
(Office or Phone 
Call) 
X 
Long-Term 
Survival 
Follow-Up 
Phone Call 
X 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 
16 
Confidential 
VV-RIM-00381493-1.0 Approved - 27 Nov 2024 GMT-5:00 
 
 
Abbreviations: 100DFU = 100-Day Follow-up; AE = adverse event; BICR = Blinded Independent Central Review; CNS = central nervous system; CRS = cytokine release syndrome; d = day; CT = computed 
tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; IT = intratumorally; LTSFU = long-term survival follow-up; MRI = magnetic resonance imaging; 
n/a = not applicable; PD = progressive disease; PE = physical examination; PTFU = posttreatment follow-up; Q3W = every 3 weeks; Q3mo = every 3 months; Qb = Qbeta; RECIST = Response Evaluation Criteria in 
Solid Tumors; SC = subcutaneously; W = week. 
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 at which the Investigator decides to 
discontinue study treatment. If a subject has CMP-001 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. 
b. The 100DFU is a safety follow-up visit that may be conducted at the study site or via phone. This visit should occur 100 days (+7) after the EOT. 
NOTE: If a subject’s 100DFU, PTFU, and LTSFU visits overlap, then the visits can be combined into 1 study site visit. 
c. Posttreatment follow-up will be conducted Q3mo (± 2 weeks) for all subjects who discontinue study treatment for reasons other than disease progression (either per RECIST v1.1, iRECIST, or clinical PD per 
Investigator) but have not met criteria for study discontinuation. These subjects should remain on study and receive disease assessments Q3mo, until discontinuation. 
d. LTSFU will be conducted Q3mo (± 4 weeks) after the EOT visit or the last disease assessment date in PTFU and may occur via phone. 
e. CMP-001 dosing will begin on W1D1. Weekly dosing: A window of ± 2 days is permitted for CMP-001 dosing from W1D1 to W7D1. 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. Subjects must complete all 7 weekly CMP-001 doses before moving to the Q3W dosing schedule. Q3W 
dosing (W10D1+): A window of ±3 days is permitted for CMP-001 dosing from W10D1 throughout the study. When nivolumab is permanently discontinued due to an immune related AE, CMP-001 must also be 
permanently discontinued. Refer to Section 5.3 for Treatment Compliance. 
f. Nivolumab dosing will begin on W1D1 and continue Q3W throughout the study. When CMP-001 injection and nivolumab dosing fall on the same day, CMP-001 injection will be given before nivolumab dosing. 
Refer to Section 5.1.1 for Nivolumab 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 the W1D1, W3D1, and W7D1 CMP-001 injection visits, at every CMP-001 injection visit thereafter, 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 6 CMP-001 dosing visits (W1D1 to W6D1), vital signs must be collected before the CMP-001 injection and at 30-minute (± 15 minutes) intervals for 4 hours after CMP- 
001 injection. Starting at W7D1, 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 nivolumab is 
administered, vital signs must be collected before the start of the nivolumab infusion. 
NOTE: Oxygen saturation is not a required parameter to be collected for all subjects. Sites are to capture oxygen saturation (and FiO2, if available) at every time point only for subjects in whom an AE of hypoxia or 
CRS is reported. 
i. AEs will be assessed continually from the time of informed consent through 100 days after the last dose of study treatment or until an alternative cancer treatment is initiated, whichever occurs first, for all subjects. 
Subjects who discontinue CMP-001 but remain on treatment with nivolumab will continue to have AEs collected according to this schedule until 100 days after the last dose of nivolumab. 
j. Concomitant medications will be assessed continually from 30 days before the first dose of study treatment through 100 days after the last dose of study treatment or until an alternative cancer treatment is initiated, 
whichever occurs first. Treatment medications for study-related AEs that occur through 100 days after the last dose of study treatment will be collected during the 100DFU period. 
k. 12-lead ECGs will be obtained at Screening, before the W1D1, W3D1, and W7D1 CMP-001 injections, and at EOT. Electrocardiogram parameters will include heart rate and PR interval, QRS, QT, and QT 
corrected intervals. Electrocardiograms 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 the CMP-001 injection. When clinical laboratory assessments are done the same day as CMP-001 injection, vital signs should be performed 
before collection of clinical laboratory tests. Refer to Section 7.1.12. for Clinical Laboratory Assessments. 
NOTE: For women of childbearing potential, a serum pregnancy test should be done at Screening. Serum or urine pregnancy tests should be done before first CMP-001 injection on W1D1, W4D1, W7D1, and 
Q3W thereafter and EOT. Refer to Section 7.1.13. for Pregnancy Testing. A follicle stimulating hormone 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: Screening coagulation samples (prothrombin time, international normalized ratio, and partial prothrombin time) are 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 beginning at W7D1 and continuing Q3W thereafter. 
NOTE: Free T3 and Free T4 will be drawn at each thyroid function timepoint (Screening, W3D1, W7D1, then Q3W, and at EOT). 
m. Exploratory biomarker blood samples are to be collected at the following time points: W1D1 within 2 hours before CMP-001 injection; W5D1 (same day as tumor biopsy) before CMP-001 injection; W6D1 within 2 
hours before CMP-001 injection, 4 hours (± 30 minutes) after CMP-001 injection, and 24 hours (± 4 hours) after CMP-001 injection (W6D2); and W7D1 within 2 hours before CMP-001 injection. Refer to 
Section 7.3.1. Collection of Blood for Translational Biomarker Analyses. 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 
17 
Confidential 
VV-RIM-00381493-1.0 Approved - 27 Nov 2024 GMT-5:00 
 
 
n. For the first 20 subjects enrolled, pharmacokinetic blood samples are to be collected at the following time points: 1) -2 to 0 hours before CMP-001 injection on W1D1, W6D1, and W7D1; 2) 4 hours (± 30 minutes) 
after CMP-001 injection on W1D1 and W6D1; and 3) 24 hours (± 4 hours) after CMP-001 injection on W6D2. Refer to Section 7.4. for additional details. 
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, W3D1, and W6D1; 2) 4 hours (± 30 minutes) after 
CMP-001 injection on W1D1, W3D1, and W6D1; and 3) if any AEs of CRS are experienced. 
p. Immunogenicity blood samples to assess anti-Qb antibodies are to be collected at the following time points: 1) before CMP-001 injection on W1D1 and W7D1; 2) at W58 and W103 for active subjects who are 
continuing study treatment or PTFU subjects who have discontinued study treatment, and at EOT. 
q. Fresh tumor tissue biopsy (within 90 days before the start of study treatment) samples are preferred (an archival sample is acceptable as a substitute if no intervening therapy was received), if safe and medically 
feasible, at Screening and W5D1 (± 1 week) 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 programmed death-ligand 1 expression. Archival tumor biopsy samples should also be collected during Screening, if available. Refer to 
Section 7.3.2. for Tumor Biopsies. 
r. Disease Assessment methods include radiographic (contrast-enhanced CT or MRI), photographic, 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 imaging should be performed within 30 days (+ 5 days) of W1D1. 
s. To be eligible, subjects must have progressive disease according to RECIST v1.1 within 12 weeks of the last dose of a PD-1 blocking antibody (either monotherapy or combination therapy). Disease progression on 
PD-1 blocking antibody must be confirmed by PI assessment using baseline imaging or imaging at the time of response and 2 consecutive scans 4 weeks apart demonstrating sustained progression. The confirmatory 
scan may serve as the Baseline for this study if completed within 30 days before the start of study treatment. Radiographic and/or photographic imaging must be submitted for BICR eligibility verification. If 
available, historic photographic imaging collected at screening may be used to verify subject eligibility. Subjects must have a minimum of one target lesion not intended for IT injections identified at baseline. 
t. Baseline CNS imaging by contrast-enhanced CT or MRI must be provided at Screening; on-study CNS imaging is required in presence of clinical symptoms or if CNS disease was present at Baseline. 
u. Disease assessments will be performed predose beginning at W13D1 (-7 days) and repeated every 9 weeks (-7 days) (eg, W22D1, W31D1, etc.). A response (complete response, partial response, immune complete 
response, or immune partial response [per RECIST v1.1 or immunotherapy Response Evaluation Criteria in Solid Tumors]) 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. All scans should be performed at least 2 weeks after the most recent CMP-001 IT injection to account for 
injection-related pseudoprogression. Disease assessments may be performed every 12 weeks for subjects with a response continuing more than 1 year. Refer to Section 7.2. for Disease Assessments. If a CR is 
observed in a subject, sites should continue to obtain confirmation photographs at subsequent assessments. 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 18 
Confidential 
VV-RIM-00381493-1.0 Approved - 27 Nov 2024 GMT-5:00 
 
 
 
TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ............................................................................ 2 
SPONSOR PROTOCOL APPROVAL ......................................................................... 3 
PROCEDURES IN CASE OF EMERGENCY ............................................................. 4 
SYNOPSIS5 
LIST OF TABLES ...................................................................................................... 24 
LIST OF FIGURES ..................................................................................................... 24 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................. 25 
1. 
INTRODUCTION ................................................................................... 28 
1.1. 
Background .............................................................................................. 28 
1.2. 
CMP-001 .................................................................................................. 29 
1.2.1. 
Previous Clinical Studies With CMP-001 ................................................ 29 
1.3. 
Nivolumab ................................................................................................ 30 
1.3.1. 
Nivolumab Mechanism of Action ............................................................ 30 
1.3.2. 
Nivolumab Clinical Activity .................................................................... 30 
1.3.3. 
Benefit/Risk Assessment .......................................................................... 30 
1.4. 
Study Rationale ........................................................................................ 31 
1.4.1. 
Rationale for Combining a TLR9 Agonist with a PD-1 Blocking 
Antibody .................................................................................................. 31 
1.4.2. 
Rationale for Intratumoral Administration of TLR9 Agonists ................. 32 
1.4.3. 
Rationale for CMP-001 Dose and Schedule ............................................. 32 
1.4.4. 
Rationale for Nivolumab Dose and Schedule .......................................... 32 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................... 33 
2.1. 
Study Objectives ...................................................................................... 33 
2.1.1. 
Primary Objective .................................................................................... 33 
2.1.2. 
Secondary Objectives ............................................................................... 33 
2.1.3. 
Exploratory Objective .............................................................................. 33 
2.2. 
Study Endpoints ....................................................................................... 33 
2.2.1. 
Primary Endpoint ..................................................................................... 33 
2.2.2. 
Secondary Endpoints ................................................................................ 33 
2.2.3. 
Exploratory Endpoints.............................................................................. 34 
3. 
INVESTIGATIONAL PLAN .................................................................. 35 
3.1. 
Overall Study Design ............................................................................... 35 
3.2. 
Duration of Treatment with Nivolumab ................................................... 36 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................... 38 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 19 
Confidential 
VV-RIM-00381493-1.0 Approved - 27 Nov 2024 GMT-5:00 
 
 
4.1. 
Inclusion Criteria ...................................................................................... 38 
4.2. 
Exclusion Criteria .................................................................................... 39 
4.3. 
Women of Childbearing Potential ............................................................ 41 
4.3.1. 
Women of Non-Childbearing Potential .................................................... 41 
4.3.2. 
Acceptable Methods of Contraception ..................................................... 42 
4.4. 
Prohibited Concomitant Medications ....................................................... 42 
4.4.1. 
Vaccinations ............................................................................................. 43 
4.5. 
Treatment Discontinuation ....................................................................... 43 
4.6. 
Study Discontinuation .............................................................................. 44 
4.7. 
End of Clinical Trial ................................................................................. 44 
5. 
TREATMENT OF SUBJECTS ............................................................... 45 
5.1. 
Administration of Study Treatment .......................................................... 45 
5.1.1. 
Nivolumab ................................................................................................ 45 
5.1.1.1. 
Nivolumab Dose Selection ....................................................................... 45 
5.1.1.2. 
Clinical Pharmacology Summary ............................................................. 46 
5.1.2. 
CMP-001 .................................................................................................. 47 
5.1.2.1. 
Required Prophylaxis Before and After CMP-001 Injection ................... 47 
5.1.2.2. 
Observation Following CMP-001 Dosing ................................................ 48 
5.1.2.3. 
CMP-001 Injections ................................................................................. 49 
5.1.3. 
Dose Modifications for CMP-001 ............................................................ 49 
5.1.4. 
Management of Adverse Events Associated with CMP-001 ................... 50 
5.1.4.1. 
Allergic Reactions .................................................................................... 50 
5.1.4.2. 
Injection Site Reactions ............................................................................ 51 
5.1.4.3. 
Hypotension ............................................................................................. 51 
5.1.4.4. 
Grade 3 or Higher Adverse Events Related to CMP-001 ......................... 51 
5.1.5. 
Dose Modifications and Management of Adverse Events Associated with 
Nivolumab ................................................................................................ 51 
5.1.5.1. 
Criteria to Resume Nivolumab Treatment ............................................... 56 
5.1.5.2. 
Treatment of Nivolumab-related Infusion Reactions ............................... 56 
5.1.5.3. 
Nivolumab Treatment Beyond Disease Progression ................................ 57 
5.1.6. 
Method of Assigning Subjects ................................................................. 58 
5.1.7. 
Blinding and Unblinding Process ............................................................. 58 
5.2. 
Prior and Concomitant Medications ......................................................... 58 
5.3. 
Treatment Compliance ............................................................................. 58 
6. 
STUDY TREATMENT MATERIALS AND MANAGEMENT ............ 59 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 20 
Confidential 
VV-RIM-00381493-1.0 Approved - 27 Nov 2024 GMT-5:00 
 
 
6.1. 
Study Treatments ..................................................................................... 59 
6.2. 
Study Drug Labeling and Packaging ........................................................ 59 
6.3. 
Study Drug Handling, Storage, Accountability ........................................ 59 
6.4. 
Study Drug Dispensing ............................................................................ 60 
7. 
STUDY ASSESSMENTS AND PROCEDURES ................................... 61 
7.1. 
Procedures and Assessments .................................................................... 61 
7.1.1. 
Informed Consent ..................................................................................... 61 
7.1.2. 
Eligibility Criteria .................................................................................... 61 
7.1.3. 
Demographics .......................................................................................... 61 
7.1.4. 
Melanoma History .................................................................................... 61 
7.1.5. 
Prior Cancer Treatments ........................................................................... 62 
7.1.6. 
Medical History ........................................................................................ 62 
7.1.7. 
Medication History................................................................................... 62 
7.1.8. 
Vital Signs ................................................................................................ 62 
7.1.9. 
Eastern Cooperative Oncology Group Performance Status ..................... 62 
7.1.10. 
Physical Examination ............................................................................... 62 
7.1.11. 
Electrocardiogram .................................................................................... 63 
7.1.12. 
Clinical Laboratory Assessments ............................................................. 63 
7.1.13. 
Pregnancy Testing .................................................................................... 65 
7.2. 
Disease Assessments ................................................................................ 65 
7.2.1. 
Radiographic Imaging .............................................................................. 65 
7.2.2. 
Photographic Imaging .............................................................................. 66 
7.2.3. 
Eligibility Disease Assessment ................................................................ 66 
7.2.3.1. 
Confirmation of Disease Progression on Prior PD 1-blocking antibody 66 
7.2.3.2. 
Central Nervous System Imaging ............................................................ 67 
7.2.4. 
On-Treatment Disease Assessment .......................................................... 67 
7.2.4.1. 
Disease Assessment Beyond Progressive Disease ................................... 67 
7.2.4.2. 
Confirmation of Response ........................................................................ 67 
7.3. 
Translational Assessments ....................................................................... 67 
7.3.1. 
Collection of Blood for Translational Biomarker Analyses ..................... 67 
7.3.2. 
Collection of Tumor Biopsies for PD-L1 Staining and Translational 
Analyses ................................................................................................... 68 
7.4. 
Pharmacokinetic Assessments .................................................................. 68 
7.4.1. 
Collection of Blood Samples for Measurement of CMP-001 
Concentration in Serum ............................................................................ 68 
7.4.2. 
Measurement of CMP-001 Concentration in Blood Samples .................. 68 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 21 
Confidential 
VV-RIM-00381493-1.0 Approved - 27 Nov 2024 GMT-5:00 
 
 
7.4.3. 
Collection of Blood Samples for Cytokine and Complement 
Assessment ............................................................................................... 69 
7.5. 
Immunogenicity Sampling ....................................................................... 69 
7.6. 
Safety Assessments .................................................................................. 69 
7.6.1. 
Adverse Events ........................................................................................ 70 
7.7. 
100-Day Follow-up Contact ..................................................................... 70 
7.8. 
Posttreatment Follow-up .......................................................................... 70 
7.9. 
Long-Term Survival Follow-up ............................................................... 71 
8. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING.72 
8.1. 
Adverse Events ........................................................................................ 72 
8.1.1. 
Definition of an Adverse Event ................................................................ 72 
8.1.2. 
Definition of a Serious Adverse Event ..................................................... 72 
8.1.3. 
Definition of a Treatment-Emergent Adverse Event ................................ 73 
8.2. 
Evaluation of Adverse Events and Serious Adverse Events .................... 73 
8.2.1. 
Adverse Event Severity/Grade ................................................................. 74 
8.2.2. 
Relationship to Study Treatment .............................................................. 74 
8.2.3. 
Classification of Adverse Event Outcome ............................................... 75 
8.2.4. 
Action Taken Related to Study Treatment Administration Regarding the 
Adverse Event .......................................................................................... 75 
8.3. 
Procedures for Recording and Reporting Adverse Events ....................... 76 
8.3.1. 
Reporting Serious Adverse Events ........................................................... 77 
8.3.2. 
Reporting Pregnancies .............................................................................. 78 
8.3.3. 
Reporting to IRBs and Regulatory Authorities ........................................ 78 
8.3.4. 
Follow-up of Adverse Events/Serious Adverse Events ............................ 78 
9. 
STATISTICAL METHODS .................................................................... 80 
9.1. 
Sample Size Calculation .......................................................................... 80 
9.2. 
Analysis Sets ............................................................................................ 80 
9.2.1. 
Intent-to-Treat Analysis Set ..................................................................... 80 
9.2.2. 
Safety Analysis Set .................................................................................. 80 
9.2.3. 
Per Protocol Analysis Set ......................................................................... 80 
9.2.4. 
Pharmacodynamic Analysis Set ............................................................... 80 
9.2.5. 
Pharmacokinetic Analysis Set .................................................................. 81 
9.2.6. 
Immunogenicity Analysis Set .................................................................. 81 
9.3. 
Background Characteristics ...................................................................... 81 
9.3.1. 
Disposition ............................................................................................... 81 
9.3.2. 
Demographics and Other Baseline Characteristics ................................... 81 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021 22 
Confidential 
VV-RIM-00381493-1.0 Approved - 27 Nov 2024 GMT-5:00 
 
 
9.3.3. 
ECOG Performance Status ....................................................................... 81 
9.3.4. 
Melanoma History .................................................................................... 81 
9.3.5. 
Prior Cancer Treatments ........................................................................... 81 
9.3.6. 
Medical and Surgical History ................................................................... 81 
9.3.7. 
Protocol Deviations .................................................................................. 81 
9.3.8. 
Prior and Concomitant Medications ......................................................... 82 
9.4. 
Study Treatment Exposure and Compliance ............................................ 82 
9.5. 
Efficacy Analyses ..................................................................................... 82 
9.5.1. 
Confirmed Objective Response Rate ....................................................... 82 
9.5.2. 
Disease Control Rate ................................................................................ 83 
9.5.3. 
Treatment Effect in Non-injected Target Lesions .................................... 83 
9.5.4. 
Duration of Response ............................................................................... 83 
9.5.5. 
Progression-Free Survival ........................................................................ 83 
9.5.6. 
Overall Survival ....................................................................................... 83 
9.5.7. 
Post-Progression Disease Response ......................................................... 83 
9.5.8. 
Exploratory Efficacy Analyses ................................................................. 84 
9.6. 
Safety Analyses ........................................................................................ 84 
9.6.1. 
Adverse Events ........................................................................................ 84 
9.6.2. 
Clinical Laboratory Assessments ............................................................. 84 
9.6.3. 
Vital Signs ................................................................................................ 84 
9.6.4. 
Physical Examinations ............................................................................. 85 
9.6.5. 
Electrocardiograms ................................................................................... 85 
9.7. 
Pharmacokinetic Analyses ....................................................................... 85 
9.8. 
Pharmacodynamic Analyses .................................................................... 85 
9.9. 
Immunogenicity Analyses ........................................................................ 85 
9.10. 
Exploratory Tumor Biopsy Analyses ....................................................... 85 
9.11. 
Appropriateness of Measures ................................................................... 85 
9.11.1. 
Blinded Independent Central Review Committee .................................... 86 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ...................... 87 
10.1. 
Study Monitoring ..................................................................................... 87 
10.2. 
Case Report Forms ................................................................................... 87 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ....................... 88 
11.1. 
Data Quality Assurance ............................................................................ 88 
11.2. 
Quality Assurance Audits ........................................................................ 88 
11.3. 
Audits and Inspections by Regulatory Authorities ................................... 88 
 
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11.4. 
Retention of Records ................................................................................ 88 
12. 
ETHICS.................................................................................................... 89 
12.1. 
Ethics Review .......................................................................................... 89 
12.2. 
Ethical Conduct of the Study ................................................................... 89 
12.3. 
Written Informed Consent ........................................................................ 89 
13. 
PUBLICATION POLICY ........................................................................ 91 
14. 
LIST OF REFERENCES ......................................................................... 92 
15. 
APPENDICES ......................................................................................... 95 
APPENDIX A. ..................................................................................................... ECOG 
PERFORMANCE STATUS .................................................................... 96 
APPENDIX B. ...... APPROXIMATE MAXIMUM AMOUNT OF BLOOD DRAWN 
FOR ONE YEAR OF STUDY PARTICIPATION ................................. 97 
APPENDIX C.COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE) VERSION 5.0 .......................................................................... 98 
APPENDIX D. .......... RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) VERSION 1.1 ......................................................................... 99 
APPENDIX E. ..... IMMUNOTHERAPY RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS (IRECIST) ................................................................ 104 
APPENDIX F. ........ INTRATUMORAL RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS (ITRECIST) VERSION 1.1 ..................................... 108 
APPENDIX G. ........................................................................... CMP-001 INJECTION 
GUIDELINE .......................................................................................... 116 
APPENDIX H. ....................................................................... NIVOLUMAB SAFETY 
ALGORITHM ........................................................................................ 119 
APPENDIX I. ....... COUNTRY-SPECIFIC REQUIREMENTS FOR HIV TESTING / 
EXCLUSION ......................................................................................... 128 
APPENDIX J. .... WOMEN OF CHILDBEARING POTENTIAL DEFINITION AND 
METHODS OF CONTRACEPTION .................................................... 129 
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LIST OF TABLES 
Table 1: 
Schedule of Assessments ......................................................................... 13 
Table 2: 
Dose Modifications and Management of Adverse Events Associated with 
Nivolumab ................................................................................................ 51 
Table 3: 
Clinical Laboratory Assessments ............................................................. 64 
Table 4: 
Criteria for Determination of Serious Adverse Events ............................. 73 
Table 5: 
CTCAE Adverse Event Grades ................................................................ 74 
Table 6: 
Classification for Adverse Event Causality .............................................. 75 
Table 7: 
Classifications for Adverse Event Outcomes ........................................... 75 
Table 8: 
Classifications for Actions Taken Related to Study Treatment 
Administration Regarding an Adverse Event ........................................... 76 
Table 9: 
Response for Lesion Category ............................................................... 112 
 
 
 
 
LIST OF FIGURES 
Figure 1: 
CMP-001-010 Study Schema ................................................................... 36 
Figure 2: 
Prophylaxis and Treatment for Adverse Events Associated with 
CMP-001 .................................................................................................. 50 
Figure 3: 
Method for CMP-001 Intratumoral Injection ......................................... 116 
Figure 4: 
Preferred Sites of Subcutaneous Injection .............................................. 118 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
Abbreviation or Specialist Term 
Explanation 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibody 
ADL 
activities of daily living 
AE 
adverse event 
AJCC 
American Joint Committee on Cancer 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BICR 
Blinded Independent Central Review 
BMI 
body mass index 
BOR 
best overall response 
Cavg28 
average serum concentration at Day 28 
CFR 
Code of Federal Regulations 
cHL 
classical Hodgkin lymphoma 
CLss 
steady-state clearance 
Cmax 
maximum serum concentration 
Cmin28 
trough serum concentration at Day 28 
CMP-001 
investigational product 
CNS 
central nervous system 
CpG 
cytosine linked to a guanine by a phosphate bond 
CR 
complete response 
CRA 
Clinical Research Associate 
CRC 
colorectal cancer 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
CV 
coefficient of variation 
CXCL 
C-X-C motif chemokine 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
ER 
exposure-response 
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Abbreviation or Specialist Term 
Explanation 
EU 
European Union 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
GCP 
Good Clinical Practice 
HCC 
hepatocellular carcinoma 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
iCR 
immune complete response 
ID 
identification 
iDOR 
immune duration of response 
IEC 
Independent Ethics Committee 
IFN 
interferon 
INR 
international normalized ratio 
iORR 
immune objective response rate 
iPFS 
immune progression-free survival 
iPR 
immune partial response 
IRB 
Institutional Review Board 
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 
MEK 
mitogen-activated protein/extracellular signal-regulated 
kinase 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NSCLC 
non-small cell lung cancer 
ODN 
oligodeoxynucleotide 
ORR 
objective response rate 
OS 
overall survival 
pCR 
pathological complete response 
PD 
progressive disease 
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Abbreviation or Specialist Term 
Explanation 
pDC 
plasmacytoid dendritic cell 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
pMR 
pathological major response 
PPK 
population pharmacokinetics 
pPR 
pathological partial response 
PR 
partial response 
PT 
prothrombin time 
PTFU 
posttreatment follow-up 
PTT 
partial thromboplastin time 
Q3W 
every 3 weeks 
Qb 
Qbeta 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RVT 
residual viable tumor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SOP 
standard operating procedure 
TB 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TLR9 
Toll-like receptor 9 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
VLP 
virus-like particle 
W 
week 
W1D1 
Week 1 Day 1 
WNL 
within normal limits 
WOCBP 
woman of childbearing potential 
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1. 
INTRODUCTION 
1.1. 
Background 
Melanoma remains the most common cause of skin cancer death in the United States (US), 
Europe, and Australia. Despite an evolving understanding of the molecular aberrations and 
clinical factors that impact outcomes as well as improvements in the therapeutic paradigm, 
including immunotherapy, metastatic melanoma remains essentially incurable in view of the 
limited efficacy and the toxicity of the currently available agents. Despite the improved 
outcomes with programmed cell death protein 1 (PD-1) blockade, more than 60% of patients 
do not respond to single-agent nivolumab or pembrolizumab. Therefore, there remains a 
critical need for innovative anticancer therapy in this condition. 
There are several preferred Category 1 regimens (based upon high-level evidence and 
National Comprehensive Cancer Network consensus) available for the first-line treatment of 
patients with unresectable or metastatic melanoma, including PD-1 blockade monotherapy or, 
if a BRAF V600-activating mutation is present, a combination of agents targeted at BRAF 
and mitogen-activated protein/extracellular signal-regulated kinase (MEK) (NCCN-2020). In 
certain circumstances, nivolumab combined with ipilimumab may be another option. There 
are no Category 1 options for subsequent therapy once disease progression occurs on a 
preferred regimen (NCCN-2020). Treatments that may be considered after disease 
progression due to PD-1 blockade include ipilimumab or chemotherapy; however, response 
rates are low and both are accompanied by greater toxicity than PD-1 blocking antibody 
administration (Ribas-2015; Robert-2015; da Silva -2020; Davar -2015). 
Some patients treated with PD-1 blockade achieve a complete response (CR) or partial 
response (PR) with continued treatment beyond Response Evaluation Criteria in Solid 
Tumors (RECIST) progressive disease (PD); however, the frequency is very low. Hodi-2016 
evaluated the relationship between overall survival (OS) and response using RECIST and 
immunotherapy Response Evaluation Criteria in Solid Tumors (iRECIST) in patients with 
advanced melanoma previously treated with pembrolizumab. Of the 327 subjects who had at 
least 28 weeks of imaging follow-up, 24 (7%) had PD by RECIST that was not confirmed on 
subsequent assessment by iRECIST. Of these subjects with pseudoprogression, 13 subjects 
went on to achieve a CR or PR. Ribas-2018 recommended that single arm studies in the 
setting of continued PD-1 blockade beyond PD should rule out a null hypothesis of 6% to 
7%. Given that a minority of patients achieve an objective response with initial nivolumab or 
pembrolizumab treatment, and there are limited treatment options post-PD-1 blockade, there 
is significant unmet medical need for the treatment of patients with melanoma who do not 
respond or who progress following treatment with PD-1 blockade. 
This unmet need is even more compelling in patients with confirmed progressive disease to 
PD-1 blockade. The Society for the Immunotherapy of Cancer convened an Immunotherapy 
Resistance Task Force to provide expert guidance on the selection of patients for clinical 
trials with a scientific objective to address resistance to PD-1 blockade (Kluger-2020). Key 
elements of the guidance from this group focused on the need to ensure adequate exposure to 
PD-1 blockade (minimum of 6 weeks in the case of primary resistance) and to confirm 
progressive disease with two assessments at least 4 weeks apart, unless disease recurrence 
occurred during adjuvant therapy. This guidance provides the foundation for the intended 
patient population in this clinical trial. 
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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 (Qb). G10 is an ODN that contains CpG and also contains poly-G tails 
that allow it to form G-quadruplexes. Once administered to a patient, an antidrug antibody 
response to the VLP (anti-Qb 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-2020). 
Toll-like receptor 9 is found in pDCs and B cells, but Type A CpG compounds have little 
effect on B cells. Plasmacytoid dendritic cells 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 patients with cancer (Lombardi-2015; 
Demoulin-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 (CXCL)9 and CXCL10 (Swiecki-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 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 capable of circulating 
throughout the body and attacking distant tumor cells. Therefore, administration of CMP-001 
intratumorally (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 
The safety and efficacy data demonstrating the clinical benefit of CMP-001 IT in 
combination with pembrolizumab intravenous (IV) in patients with melanoma refractory to 
PD-1 blockade were obtained in an ongoing clinical study, Study CMP-001-001 (Milhem - 
2020). In the 98 subjects treated with pembrolizumab according to the KEYTRUDA® 
(pembrolizumab) United States Prescribing Information (KEYTRUDA® USPI) in 
combination with CMP-001 10 mg IT every week for 7 weeks and every 3 weeks (Q3W) 
thereafter, the objective response rate (ORR) was 27.6% (27/98; 95% confidence interval 
[CI], 19.0%, 37.6%), including patients with responses after initial progressive disease and 
the best ORR by RECIST v1.1 was 23.5% (23/98; 95% CI, 15.5%, 33.1%), including 7 
complete responses and 16 partial responses. This ORR is substantially higher than the 7.7% 
response rate observed in the 6 of 78 patients who received treatment beyond progression 
with pembrolizumab in the Keynote-002 study (Ahmed-2020). The clinical benefit of this 
combination treatment includes durable CRs and PRs in injected and non-injected target 
lesions and non-target lesions of the skin, lymph nodes, and viscera. The Kaplan-Meier 
estimate for median duration of response (DOR) for both RECIST v1.1 responders and 
RECIST v1.1 responders plus post-progressive disease responders was 19.9 months (95% CI, 
6 months, 19.9 months). Most treatment related adverse events (TRAEs) were Grade 1 or 2 
and included flu-like symptoms, including chills, fever, fatigue, nausea, vomiting, and 
headache, and injection site pain. The most common treatment-related Grade 3 or 4 adverse 
events were hypotension (6.3%) and hypertension (5.0%). No Grade 5 treatment-related 
adverse events were reported. Additional information is provided in the CMP-001 
Investigator’s Brochure (IB). 
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Preliminary safety and efficacy data from an ongoing Phase 2 Investigator Sponsored Trial of 
CMP-001 IT in combination with nivolumab in subjects with high-risk resectable melanoma 
(Study HCC 17-169) demonstrated clinical activity and a tolerable safety profile (Davar - 
2020). Pathological responses, defined as ≤ 50% residual viable tumor (RVT), were reported 
in 70% of subjects (21/30) and included pathological complete response (pCR), defined as 
0% RVT, in 50% (15/30) of subjects, pathological major response (pMR), defined as 1% to 
10% RVT, in 10% (3/30) of subjects, and pathological partial response (pPR), defined as 
11% to 50% RVT, in 10% (3/30) of subjects. In the 31 subjects evaluable for safety, CMP- 
001 in combination with nivolumab was generally well tolerated with an acute toxicity 
profile consisting predominantly of Grade 1 or 2 TRAEs. The only treatment-related Grade 3 
adverse event in more than 1 subject was hypertension (n = 3, 9.7%). No Grade 4/5 TRAEs 
were reported. There were no dose limiting toxicities or delays in surgery related to 
neoadjuvant treatment. One-year recurrence free survival was 89% in patients with major 
pathological response (pCR and pMR) and 90% in patients with any pathological response 
(pCR, pMR, and pPR). 
1.3. 
Nivolumab 
1.3.1. 
Nivolumab Mechanism of Action 
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human 
monoclonal antibody (HuMAb; immunoglobulin G4-S228P) that targets the PD-1 cluster of 
differentiation 279 cell surface membrane receptor. PD-1 is a negative regulatory molecule 
expressed by activated T and B lymphocytes (Schadendorf-2017). Binding of PD-1 to its 
ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation 
of lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes 
immune responses and antigen-specific T-cell responses to both foreign antigens as well as 
self-antigens. Nivolumab is expressed in Chinese hamster ovary cells and is produced using 
standard mammalian cell cultivation and chromatographic purification technologies. The 
clinical study product is a sterile solution for parenteral administration. 
Nivolumab is approved for the treatment of several types of cancer in multiple regions 
including the US (Dec-2014), the European Union (EU, Jun-2015), and Japan (Jul-2014). 
1.3.2. 
Nivolumab Clinical Activity 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy in 
several tumor types, including non-small cell lung cancer (NSCLC), melanoma, renal cell 
carcinoma (RCC), classical Hodgkin lymphoma (cHL), small cell lung cancer, gastric cancer, 
squamous cell carcinoma of the head and neck (SCCHN), urothelial cancer, hepatocellular 
carcinoma (HCC), and colorectal cancer (CRC). In confirmatory trials, nivolumab as 
monotherapy demonstrated a statistically significant improvement in OS as compared with 
the current standard of care in patients with advanced or metastatic NSCLC, unresectable or 
metastatic melanoma, advanced RCC, or SCCHN. Details of the clinical activity in these 
various malignancies are provided in the nivolumab Investigator’s Brochure. 
1.3.3. 
Benefit/Risk Assessment 
Extensive details on the safety profile of nivolumab are available in the nivolumab 
Investigator’s Brochure and will not be repeated herein. 
Overall, the safety profile of nivolumab monotherapy is manageable and generally consistent 
across completed and ongoing clinical trials with no maximum tolerated dose reached at any 
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dose tested up to 10 mg/kg. Most AEs were low-grade (Grade 1 to 2) with relatively few 
related high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, severity, or 
causality of AEs with respect to nivolumab dose level. 
A pattern of immune-related AEs has been defined, for which management algorithms have 
been developed; these are provided in Appendix H. Most high-grade events were manageable 
with the use of corticosteroids or hormone replacement therapy (endocrinopathies) as 
instructed in these algorithms. 
Additional details on the safety profile of nivolumab, including results from other clinical 
studies, are also available in the nivolumab Investigator’s Brochure. 
1.4. 
Study Rationale 
1.4.1. 
Rationale for Combining a TLR9 Agonist with a PD-1 Blocking Antibody 
PD-1 blockade is an effective and important therapy for the treatment of melanoma; however, 
more than 60% 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-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 studies, TLR9 agonism resulted in strong induction of cytotoxic T 
lymphocyte responses; however, very few objective responses were observed and the T cell 
responses were not sustained, especially within tumors (Appay-2006). This may be because 
TLR9-mediated T cell activation induces PD-1 expression on activated T cells (Fourcade- 
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 of melanoma 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 
secretion (Fourcade-2014), providing a 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-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-2013). Mechanistic studies in the PD- 
L1 resistant mouse tumor models including CT26 and MCA38 colon carcinoma and TS/A 
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 
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IFN-g (Wang-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-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. 
1.4.2. 
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. 
Intratumoral 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 in distant metastases (Heckelsmiller- 
2002; Shirota-2012). 
1.4.3. 
Rationale for CMP-001 Dose and Schedule 
In the Phase 1b clinical study, CMP-001-001, CMP-001 IT was evaluated at doses of 1 to 
10 mg using 2 dosing schedules and with preparations containing 2 different concentrations 
of the excipient polysorbate 20 (0.01% and 0.00167%) in combination with 
pembrolizumab IV in subjects with PD-1 refractory melanoma. The safety profile was similar 
and manageable across the CMP-001 doses of 1 to 10 mg. Antitumor activity, including 
durable CRs and PRs, with a predictable/manageable safety profile was observed in 23% of 
subjects who initiated treatment with the proposed dose and schedule for this study: CMP- 
001 10 mg (polysorbate 20 0.01%) IT QW for 7 doses, followed by administration Q3W in 
combination with pembrolizumab 200 mg IV Q3W. This dose and schedule were selected for 
further development. Further details can be found in the IB for CMP-001. 
1.4.4. 
Rationale for Nivolumab Dose and Schedule 
The rationale for administering nivolumab Q3W is to align with the schedule of CMP-001 
evaluated in Study CMP-001-001. Population pharmacokinetic (PK) analyses have shown 
that the PK of nivolumab is linear with proportional exposures over a dose range of 0.1 to 10 
mg/kg. The benefit-risk profiles of nivolumab 240 mg Q2W, 360 mg Q3W and 480 mg 
Q4W are predicted to be comparable to 3 mg/kg Q2W. This is further discussed in 
Section 5.1.1.1. 
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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 confirmed objective response 
with CMP-001 in combination with nivolumab in subjects with refractory unresectable or 
metastatic melanoma. 
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 nivolumab in subjects with refractory unresectable or metastatic 
melanoma 
• Evaluate the efficacy of CMP-001 in combination with nivolumab in subjects with 
refractory unresectable or metastatic melanoma 
• Assess the PK profile of CMP-001 in combination with nivolumab in subjects 
with refractory unresectable or metastatic melanoma 
• Assess and describe the immunogenicity of CMP-001 in combination with 
nivolumab in subjects with refractory unresectable or metastatic melanoma 
2.1.3. 
Exploratory Objective 
The exploratory objective of the study is to: 
• Evaluate the effect of CMP-001 in combination with nivolumab on injected and 
noninjected target lesions in subjects with unresectable or metastatic melanoma 
• Evaluate the pharmacodynamic effects of CMP-001 administered in combination 
with nivolumab 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoint 
The primary endpoint of the study is the ORR, defined as the proportion of subjects with a 
confirmed objective response of CR or PR based on RECIST v1.1 as determined by Blinded 
Independent Central Review (BICR). 
2.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are: 
• AEs, serious adverse events (SAEs), and AEs leading to discontinuation or death, 
and severity of AEs as assessed by the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) 
• Duration of response, defined as the time from date of first documented response 
(CR or PR) to date of documented PD, based on RECIST v1.1 by BICR 
• Treatment response in non-injected target lesions based on RECIST v1.1 by BICR 
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• Progression-free survival (PFS), defined as the time from date of first dose of 
study treatment to date of documented PD based on RECIST v1.1 by BICR or 
death, whichever occurs first 
• Overall survival, defined as the time from date of first dose of study treatment to 
date of death 
• ORR, DOR, and PFS based on RECIST v1.1 and immune objective response rate, 
immune duration of response (iDOR), and immune progression-free survival 
(iPFS) based on iRECIST by Investigator assessment 
• Blood concentrations of CMP-001 or its metabolites 
• Development of anti-Qb antibodies 
2.2.3. 
Exploratory Endpoints 
The exploratory endpoints of the study are: 
• Response in injected and noninjected target lesions per intratumoral Response 
Evaluation Criteria in Solid Tumors (itRECIST, Appendix F, Goldmacher-2020) 
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 CXCL10 (interferon gamma- 
induced protein 10) and other cytokines after treatment with CMP-001 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, open-label, Phase 2 clinical study of CMP-001 IT in combination with 
nivolumab IV in subjects with unresectable or metastatic melanoma refractory to PD-1 
blockade. Eligible subjects must have confirmed disease progression during or within 12 
weeks of their last dose of therapy containing a PD-1 blocking antibody for the treatment of 
unresectable cutaneous melanoma before enrollment. All subjects will receive CMP-001 IT 
and nivolumab IV according to the Schedule of Assessments (Table 1) until a reason for 
treatment discontinuation is reached. 
Tumor tissue collection will be obtained as per instructions in the laboratory manual. 
CMP-001 10 mg IT 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 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 Appendix G). On visits where 
both study treatments are administered, CMP-001 IT should be administered before 
nivolumab. CMP-001 should be administered until a reason for treatment discontinuation is 
reached. See Section 5.1.3. for treatment modifications for CMP-001. 
Objective responses will be assessed by BICR and Investigator assessment according to 
RECIST v1.1. Subjects who experience PD according to RECIST v1.1 may continue study 
treatment at the discretion of the Investigator and will be evaluated by the Investigator 
according to iRECIST. Disease status will be assessed by computed tomography (CT) or 
magnetic resonance imaging (MRI) and other appropriate measures beginning predose at 
Week 13 Day 1 (W13D1) and will be repeated every 9 weeks (eg, W22D1). Responses (CR, 
PR, immune complete response [iCR], or immune partial response [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. Disease assessments may continue every 12 
weeks for subjects with a response lasting more than 1 year. All scans should be performed at 
least 2 weeks after the most recent CMP-001 IT injection to account for injection-related 
pseudoprogression. Imaging should not be delayed in cases where treatment is delayed. 
Subjects who discontinue study treatment should complete an end of treatment (EOT) visit 
and 100-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). 
At the end of the treatment period (2 years), the Sponsor will not continue to provide supplied 
study treatment to subjects/investigators unless the Sponsor chooses to extend the study. The 
Investigator should ensure that the subjects receive appropriate standard of care to treat the 
condition under study. 
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Figure 1: 
CMP-001-010 Study Schema 
 
Abbreviations: 100DFU = 100-Day Follow-up; EOT = End of Treatment; IT = intratumoral; IV = intravenous; LTSFU = 
long-term survival follow-up; PTFU = posttreatment follow-up; Q3W = every 3 weeks; Q9W = every 9 weeks; Q12W = 
every 12 weeks; QW = every week. 
a. Disease assessments performed predose beginning at W13D1 (- 7 days). 
 
3.2. 
Duration of Treatment with Nivolumab 
The optimal duration of immunotherapy is an important question and continues to be 
investigated. Clinical trials across different tumors types in the nivolumab and ipilimumab 
development program indicate that most of the responses occur early, with a median time to 
response of 2 to 4 months, and emerging data suggest that benefit can be maintained in the 
absence of continued treatment. A retrospective pooled analysis of 2 melanoma studies 
suggest the majority of patients who discontinue nivolumab and/or ipilimumab for toxicity 
maintain disease control in the absence of further treatment (Schadendorf-2017). 
Furthermore, a limited duration of ipilimumab, including only 4 induction doses, resulted in 
long-term survival in patients with metastatic melanoma, with a sustained plateau in survival 
starting around 2 years after the start of treatment (Schadendorf-2015). 
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be 
sufficient for long-term benefit. CA209003, a dose-escalation cohort expansion trial 
evaluating the safety and clinical activity of nivolumab in patients with previously treated 
advanced solid tumors (including 129 subjects with NSCLC), specified a maximum treatment 
duration of 2 years. Among 16 subjects with NSCLC who discontinued nivolumab after 
completing 2 years of treatment, 12 subjects were alive > 5 years and remained progression- 
free without any subsequent therapy. In the CA209003 NSCLC cohort, the OS curve begins 
to plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years (Brahmer- 
2017). These survival outcomes are similar to phase 3 studies in previously treated NSCLC, 
in which nivolumab treatment was continued until progression or unacceptable toxicity 
(2-year OS rates of 23% and 29%, and 3-year OS rates of 16%-18% for squamous and non- 
squamous NSCLC respectively) (Felip-2017). 
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer 
additional clinically meaningful benefit and that the risk of progression after discontinuing 
treatment at 2 years is low. 
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk 
of progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 
year is likely needed. In CA209153, patients with previously treated advanced NSCLC who 
completed 1 year of nivolumab therapy were randomized to either continue or stop treatment, 
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with the option of retreatment upon progression. Among 163 patients still on treatment at 
1 year and without progression, those who were randomized to continue nivolumab had 
significant improvement in PFS compared with those who were randomized to stop 
treatment, with median PFS (post-randomization) not reached vs 10.3 months, respectively; 
hazard ratio (HR) = 0.42 (95% CI, 0.25 to 0.71). With a median follow-up of 14.9 months 
post-randomization, there also was a trend for patients on continued treatment to live longer 
(OS HR = 0.63 [95% CI, 0.33, 1.20]). Of note, the PFS curves in both groups plateau 
approximately 1 year after randomization (ie, 2 years after treatment initiation), suggesting 
that there may be minimal benefit in extending treatment beyond a total of 2 years (Spigel- 
2017). 
Collectively, these data suggest that there is minimal if any benefit derived from continuing 
immuno-oncology treatment beyond 2 years in advanced tumors. Even though 
immunotherapy is well tolerated, patients will be at risk for additional toxicity with longer- 
term treatment. Therefore, in this study, treatment will be given for a maximum of 2 years 
from the start of study treatment. 
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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. 
Inclusion Criteria 
Subjects enrolled in the study must meet all of the following inclusion criteria to be eligible. 
1. Histopathologically-confirmed diagnosis of malignant melanoma that is metastatic or 
unresectable at Screening. 
2. Known BRAF mutation status; if BRAF V600 mutation positive, must have had prior 
treatment with a local Health Authority approved BRAF inhibitor, with or without 
MEK inhibitor. Patients with BRAF V600 mutations who refuse a BRAF inhibitor 
will not be eligible. 
3. Refractory to PD-1 blockade either as monotherapy or in combination with other 
therapies, as defined by the following criteria: 
a. Received treatment with a Food and Drug Administration approved PD-1 
blocking antibody for 12 weeks or longer. 
b. Have PD (according to RECIST v1.1) within 12 weeks of the last dose of a PD-1 
blocking antibody, either as monotherapy or in combination with other agents. 
− Evidence of confirmed PD must be established by Investigator assessment at 
least 4 weeks after the initial date of PD. The confirmatory assessment may 
serve as the Baseline for this study if completed within 30 days before the start 
of study treatment. 
NOTE: in subjects with histologically confirmed recurrence on or after 
adjuvant PD-1 blocking antibody, confirmatory imaging is not required. 
4. Measurable disease, as defined by RECIST v1.1 and all of the following: 
a. At least 1 accessible lesion amenable to repeated IT injection. 
b. One or more measurable lesions at least 1 cm in diameter that are not intended for 
CMP-001 injection and can be followed as target lesions per RECIST v1.1. 
c. Documented disease progression in any lesion that was previously radiated in 
order to serve as a target lesion. 
5. Able to provide tissue from a core or excisional/incisional biopsy (fine needle aspirate 
is not sufficient). A fresh tissue biopsy (within 90 days before the start of study 
treatment) is preferred but an archival sample is acceptable (as a substitute) if no 
intervening therapy was received. 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 programmed 
death-ligand 1 expression. 
6. NOTE: for tissue sampling details, please refer to the laboratory manual. 
7. Adequate organ function based on most recent laboratory values within 3 weeks 
before first dose of study treatment on Week 1 Day 1 (W1D1): 
a. Bone marrow function: 
− neutrophil count ≥ 1500/mm3 
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− platelet count ≥ 100,000/mm3 
− hemoglobin concentration ≥ 9 g/dL 
− white blood cells ≥ 2000/mm3 
b. Liver function: 
− total bilirubin ≤ 1.5 times the upper limit of normal (ULN) with the following 
exception: subjects with Gilbert Disease total serum bilirubin ≤ 3 times ULN 
− aspartate aminotransferase and alanine aminotransferase ≤ 3 times the ULN 
c. Lactate dehydrogenase ≤ 2 times the ULN 
d. Renal function: estimated (Cockcroft-Gault) or measured creatinine clearance 
≥ 30 mL/min. 
e. Coagulation: 
− International normalized ratio or prothrombin time (PT) ≤ 1.5 times ULN, 
unless subject is receiving anticoagulant therapy, as long as PT or partial 
thromboplastin time (PTT) is within therapeutic range of intended use of 
anticoagulants 
− Activated partial thromboplastin time or 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 
8. Age ≥ 18 years at time of consent. 
9. Eastern Cooperative Oncology Group Performance Status of 0 to 1 at Screening. 
10. Capable of understanding and complying with protocol requirements. 
11. Women of childbearing potential must have negative serum pregnancy test before 
dosing at W1D1 and be willing to use an adequate method of contraception 
(Section 4.3.2.) from the time of consent until at least 150 days after last dose of study 
treatment. 
12. 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. 
Exclusion Criteria 
Subjects presenting with any of the following will not qualify for entry into the study: 
1. Uveal, acral, or mucosal melanoma. 
2. Received radiation therapy (or other nonsystemic therapy) within 2 weeks before first 
dose of study treatment on W1D1. Subjects should have recovered (ie, Grade ≤1 or at 
Baseline) from radiation-related toxicities. 
3. Treatment with complementary medications (eg, herbal supplements or traditional 
Chinese medicines) to treat the disease under study within 2 weeks before start of 
study treatment. Refer to Section 4.4. for prohibited therapies. 
4. Received systemic pharmacologic doses of corticosteroids > 10 mg/day prednisone 
within 30 days before first dose of study treatment on W1D1. 
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a. Subjects who are currently receiving steroids at a prednisone-equivalent dose of 
≤ 10 mg/day do not need to discontinue steroids before 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.). 
5. History of immune-related AE that required permanent discontinuation of PD-1 
blocking antibody. 
6. Not fully recovered from AEs (to Grade 1 or less [per CTCAE v5.0], with the 
exception of persistent adverse events or sequelae, eg, vitiligo, alopecia, 
hypothyroidism, diabetes mellitus, and adrenal and/or pituitary insufficiency) due to 
prior treatment. 
NOTE: Subjects previously treated with a CTLA-4–blocking antibody, subjects 
receiving corticosteroids with daily doses > 5 mg and ≤ 10 mg of prednisone 
equivalent for > 2 weeks, and subjects with clinical symptoms and/or laboratory 
findings suggesting risk for adrenal insufficiency should undergo diagnostic tests for 
adrenal insufficiency via local laboratory. 
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, or 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, eg, 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, 
and 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 metastases or 
carcinomatous meningitis (including leptomeningeal metastases from solid tumors). 
13. Prior allogenic tissue/solid organ transplant. 
14. Active infection requiring systemic therapy. 
15. Known or suspected active infection with severe acute respiratory syndrome 
coronavirus 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 first dose of study 
treatment on W1D1. 
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18. Received blood products (including platelets or red blood cells) or colony stimulating 
factors (including granulocyte colony stimulating factor, granulocyte/macrophage 
colony stimulating factor, or recombinant erythropoietin) within 30 days before the 
start of Screening. 
19. History of permanent discontinuation of nivolumab due to infusion reactions. 
20. 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 study. 
21. Participation in another clinical study of an investigational anticancer therapy or 
device within 30 days before first dose of study treatment on W1D1. 
NOTE: Participation in the follow-up phase (receiving no study treatment) of a prior 
study is allowed. 
22. Requires prohibited treatment (ie, non-protocol specified anticancer pharmacotherapy, 
surgery, or radiotherapy) for treatment of malignant tumor. 
23. Has a life expectancy of less than 3 months and/or has rapidly progressing disease 
(eg, tumor bleeding, uncontrolled tumor pain) in the opinion of the treating 
Investigator. 
24. Received previous CMP-001 treatment. 
25. Pregnant or breastfeeding or expecting to conceive or donate eggs within the 
projected duration of the study, from the time of consent until at least 150 days after 
last dose of study treatment for women. 
4.3. 
Women of Childbearing Potential 
A woman of childbearing potential (WOCBP) is considered fertile following menarche and 
until becoming postmenopausal unless permanently sterile (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. 
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 
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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 150 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 (ie, 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 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence 
4.4. 
Prohibited Concomitant Medications 
The following medications are prohibited during the study (unless utilized to treat a drug- 
related AE): 
• Immunosuppressive agents 
• Any concurrent systemic anti-neoplastic therapy (ie, chemotherapy, hormonal 
therapy, immunotherapy, or standard or investigational agents for treatment of 
unresectable or metastatic melanoma) other than the current study treatment. 
• Any non-palliative radiation therapy. 
• Any complementary medications (eg, herbal supplements or traditional Chinese 
medicines) intended to treat the disease under study. 
• Any live / attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral 
polio and measles, mumps, rubella [MMR]) during treatment and until 100 days 
post last dose. 
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• Concurrent anticancer therapy with agents other than the combination drug 
therapy (CMP-001 + nivolumab) 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) 
Medications intended solely for supportive care (ie, antiemetics, analgesics, megestrol acetate 
for anorexia) are allowed. 
Palliative radiotherapy or palliative surgery (ie, for pain, bleeding, spinal cord compression, 
brain metastasis, new or impending pathologic fracture, superior vena-cava syndrome, or 
obstruction) 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. 
4.4.1. 
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. 
4.5. 
Treatment Discontinuation 
Treatment discontinuation is defined as any subject who stops receiving study treatment and 
does not restart within 12 weeks. Subjects who permanently discontinue (> 12 weeks) 
CMP-001 or nivolumab, may not be retreated with the discontinued study treatment in this 
study. 
Study treatment should continue until 1 of the following occurs: 
• Unacceptable AE that precludes further study treatment 
• 2 years of study treatment 
• Progressive disease per RECIST v1.1; continuation of treatment through 
suspected pseudoprogression is permitted at the Investigator’s discretion until 
confirmed PD per iRECIST 
• Upon request of the Sponsor or regulatory agency 
• Clinical disease progression in the opinion of the Investigator 
• If medically necessary in the opinion of the Investigator 
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• 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 nivolumab due to an immune related 
AE must also permanently discontinue treatment with CMP-001. 
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 nivolumab may be discontinued at the 
Investigator’s discretion once they meet both of the following criteria: 
• Subject has been treated with both study treatments for at least 48 weeks 
• Subject has received at least 3 doses of both study treatments beyond the date of 
the initial CR/iCR 
Subjects who discontinue study treatment should complete an EOT visit and 100-day safety 
follow-up assessments per Table 1. Subjects who discontinue study treatment for reasons 
other than disease progression (either per RECIST v1.1, iRECIST, or clinical PD per 
Investigator) should remain on study for PTFU (Section 7.8.) and receive disease assessments 
according to the Schedule of Assessments (Table 1). 
4.6. 
Study Discontinuation 
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 
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. 
4.7. 
End of Clinical Trial 
The End of Clinical Trial is defined as the last visit for the last subject on the study. 
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5. 
TREATMENT OF SUBJECTS 
5.1. 
Administration of Study Treatment 
5.1.1. 
Nivolumab 
Subjects will receive CMP-001 10 mg IT injection followed by nivolumab 360 mg IV at 
W1D1 and Q3W thereafter until the subject satisfies a condition for study treatment 
discontinuation. Nivolumab should be administered to the subject according to the nivolumab 
Investigator’s Brochure. Nivolumab should be administered until the subject satisfies a 
condition for study treatment discontinuation (Section 4.5.). On visits where both study 
treatments are administered, nivolumab should be administered after CMP-001. There is no 
specified waiting period between the end of CMP-001 injection and the initiation of 
nivolumab infusion. 
Participants should receive nivolumab at a dose of 360 mg as a 30-minute infusion each 
treatment cycle until progression, unacceptable toxicity, withdrawal of consent, or the study 
ends, whichever occurs first. 
There will be no dose escalations or reductions of nivolumab allowed. Participants should be 
dosed in accordance with the Schedule of Assessments (Table 1). 
Participants should be carefully monitored for infusion reactions during nivolumab 
administration. If an acute infusion reaction is noted, participants should be managed 
according to Section 5.1.5. 
Doses of study treatment(s) may be interrupted, delayed, or discontinued depending on how 
well the participant tolerates the treatment. Dosing visits are not skipped, only delayed. 
The assessment for discontinuation of nivolumab should be made separately from the 
assessment made for discontinuation of CMP-001. If discontinuation criteria are met for 
CMP-001 but not for nivolumab, treatment with nivolumab may continue if CMP-001 is 
discontinued. 
Please refer to the current nivolumab Investigator’s Brochure and/or Pharmacy Manual for 
further details regarding storage, preparation, and administration of nivolumab. 
Care must be taken to assure sterility of the prepared solution as the product does not contain 
any antimicrobial preservative or bacteriostatic agent. 
5.1.1.1. 
Nivolumab Dose Selection 
The nivolumab dose of 360 mg Q3W was selected based on clinical data and modeling and 
simulation approaches using population pharmacokinetics (PPK) and exposure-response (ER) 
analyses of data from studies in multiple tumor types (melanoma, NSCLC, and RCC) where 
body weight normalized dosing (mg/kg) was used. 
Nivolumab PK has been extensively studied in multiple tumor types, including melanoma, 
NSCLC, RCC, cHL, SCCHN, CRC, and urothelial carcinoma and has been safely 
administered at doses up to 10 mg/kg Q2W. Nivolumab monotherapy was originally 
approved as a body-weight based dose of 3 mg/kg Q2W and was updated to 240 mg Q2W or 
480 mg Q4W in multiple indications (nivolumab Investigator’s Brochure). Nivolumab 
360 mg Q3W is also under evaluation in monotherapy and in combination therapy studies. 
Less frequent 360 mg Q3W and 480 mg Q4W dosing regimens can reduce the burden to 
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patients of frequent, lengthy IV treatments and allow combination of nivolumab with other 
agents using alternative dosing regimens. 
The benefit-risk profiles of nivolumab 240 mg Q2W, 360 mg Q3W, and 480 mg Q4W are 
predicted to be comparable to 3 mg/kg Q2W. This assessment is based on a comprehensive 
characterization of nivolumab PK, safety, efficacy, and ER relationships across indications. 
Population PK analyses have shown that the PK of nivolumab is linear with proportional 
exposures over a dose range of 0.1 to 10 mg/kg; no clinically meaningful differences in PK 
across ethnicities and tumor types were observed. Using the PPK model, the exposures 
following administration of several dosing regimens of nivolumab administered as a flat dose 
were simulated, including 240 mg Q2W, 360 mg Q3W, and 480 mg Q4W. The simulated 
average serum concentration at steady state following administration of nivolumab 360 mg 
Q3W and 480 mg Q4W are predicted to be similar to those following administration of 
nivolumab 240 mg Q2W and nivolumab 3 mg/kg Q2W administered to participants over a 
wide body weight range (34 to 180 kg) across tumor types. 
Nivolumab ER relationships for efficacy and safety were evaluated for IV nivolumab 
administered as monotherapy at the dose range of 1 mg/kg Q2W to 10 mg/kg Q2W. 
Generally, a flat ER relationship was observed over this dose range in melanoma, RCC, and 
NSCLC subjects between nivolumab exposure and clinical endpoints such as the hazard of 
death, probability of overall response, AE leading to discontinuation or death, Grade 3+ AEs, 
and/or Grade 2+ immune-mediated AEs. Therefore, 3 mg/kg IV Q2W was approved in 
melanoma, RCC, NSCLC, and also studied and approved in other indications. For NSCLC, 
there was a trend of additional benefit (especially in ORR) at 3 mg/kg IV Q2W, when 
compared with 1 mg/kg IV Q2W, which had a small sample size. Therefore, a flat ER 
relationship could only be confirmed from 3 mg/kg IV Q2W to 10 mg/kg IV Q2W for 
NSCLC. Flat doses of 240 mg IV Q2W nivolumab, 360 mg IV Q3W nivolumab, and 480 mg 
IV Q4W nivolumab have been incorporated in monotherapy and combination oncology 
studies, and the 240 mg IV Q2W and 480 mg IV Q4W nivolumab dose regimens are now 
approved in multiple indications. Q4W dosing regimens can reduce the burden to patients of 
frequent, lengthy IV treatments and allow combination of nivolumab with other agents using 
alternative dosing regimens. 
Extensive ER analyses using multiple PK measures (maximum serum concentration in Cycle 
1 [Cmax1], average serum concentration at Day 28 [Cavg28], and trough serum concentration at 
Day 28 [Cmin28]) and efficacy and safety endpoints indicated that the efficacy of the flat-dose 
480 mg IV regimen is similar to that of 3 mg/kg IV Q2W. In ER efficacy analyses for OS and 
ORR conducted in melanoma, RCC, and NSCLC using Cavg28 as the driver of efficacy, 
probabilities of achieving a response and survival probabilities at 1 year and 2 years for 
480 mg IV Q4W were similar to that of 3 mg/kg IV Q2W. 
Similar analyses conducted in different tumor types using the Cmin28 as the worst-case 
scenario for the potential loss of efficacy also showed benefit risk profiles of 480 mg IV 
Q4W were comparable to 3 mg/kg IV Q2W. 
5.1.1.2. 
Clinical Pharmacology Summary 
Nivolumab PK was assessed using a PPK approach for both single-agent nivolumab and 
nivolumab with ipilimumab. 
Nivolumab as a single agent: The PK of single-agent nivolumab was studied in patients over 
a dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of 
nivolumab as a 60-minute intravenous infusion every 2 or 3 weeks. Nivolumab clearance 
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decreases over time, with a mean maximal reduction (% coefficient of variation [CV%]) from 
baseline values of 24.5% (47.6%) resulting in a geometric mean steady-state clearance (CLss) 
(CV%) of 8.2 mL/h (53.9%) in patients with metastatic tumors; the decrease in CLss is not 
considered clinically relevant. Nivolumab clearance does not decrease over time in patients 
with completely resected melanoma, as the geometric mean population clearance is 24% 
lower in this patient population compared with patients with metastatic melanoma at steady 
state. The geometric mean volume of distribution at steady state (CV%) is 6.8 L (27.3%), and 
geometric mean elimination half-life is 25 days (77.5%). Steady-state concentrations of 
nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and 
systemic accumulation was 3.7-fold. The exposure to nivolumab increases dose 
proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. The 
predicted exposure (Cavg and Cmax) of nivolumab after a 30-minute infusion is comparable to 
that observed with a 60-minute infusion. 
Specific Populations: The PPK analysis suggested that the following factors had no clinically 
important effect on the clearance of nivolumab: age (29 to 87 years), weight (35 to 160 kg), 
gender, race, baseline lactate dehydrogenase, PD-L1 expression, solid tumor type, tumor size, 
renal impairment, and mild hepatic impairment. 
Renal Impairment: The effect of renal impairment on the clearance of nivolumab was 
evaluated by a PPK analysis in patients with mild (eGFR 60 to 89 mL/min/1.73 m2), 
moderate (eGFR 30 to 59 mL/min/1.73 m2), or severe (eGFR 15 to 29 mL/min/1.73 m2) renal 
impairment. No clinically important differences in the clearance of nivolumab were found 
between patients with renal impairment and patients with normal renal function. 
Hepatic Impairment: The effect of hepatic impairment on the clearance of nivolumab was 
evaluated by PPK analyses in patients with HCC and in patients with other tumors with mild 
hepatic impairment (total bilirubin [TB] less than or equal to the ULN and aspartate 
aminotransferase (AST) greater than ULN or TB greater than 1 to 1.5 times ULN and any 
AST) and in HCC patients with moderate hepatic impairment (TB greater than 1.5 to 3 times 
ULN and any AST). No clinically important differences in the clearance of nivolumab were 
found between patients with mild/moderate hepatic impairment. 
Details on the clinical pharmacology of nivolumab can be found in the nivolumab 
Investigator’s Brochure. 
5.1.2. 
CMP-001 
Subjects will receive CMP-001 10 mg weekly for 7 doses (W1D1 to W7D1), after which 
CMP-001 will be administered by IT injection Q3W (W10D1, W13D1, 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 treatments 
are administered, CMP-001 should be administered before nivolumab. There is no specified 
waiting period between the end of CMP-001 injection and the initiation of nivolumab 
infusion. CMP-001 should be administered until a reason for treatment discontinuation is 
reached (Section 4.5.). If treatment with nivolumab is permanently discontinued due to an 
immune related AE, treatment with CMP-001 must be discontinued. See Section 5.1.3. 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 
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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 of the following components: 
• Intravenous fluids (eg, approximately 1000 cc IV normal saline). The rate, 
volume, and substitution fluids are at the Investigator’s discretion 
• Antipyretics (eg, acetaminophen 1000 mg and a non-steroidal anti-inflammatory 
agent such as indomethacin 50 mg or ibuprofen 600 to 800 mg) 
• Antiemetics (eg, ondansetron 8 mg) 
• Antihistamine (eg, 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. 
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 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 (eg, 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 6 CMP-001 
injections (W1D1 to W6D1). Beginning with the 7th CMP-001 injection (W7D1), 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. 
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5.1.2.3. 
CMP-001 Injections 
5.1.2.3.1. Selection of Lesion for Injection 
All Screening disease assessments (radiological and photographic images) must be submitted 
to a BICR in order to verify disease progression. The same disease assessment method (eg, 
CT, MRI) used during Screening should be used throughout the study for all disease 
assessments, whenever possible. 
Eligible subjects must have at least 1 accessible lesion amenable to repeated IT injection. 
Cutaneous, SC, and/or nodal tumors that are visible, palpable, or detectable by ultrasound 
guidance are acceptable for IT injection. 
Vigilance should be used when selecting lesions for injection that are in close proximity to 
critical structures (eg, major airways, major blood vessels). 
Tumors should be at least 0.5 cm in longest diameter and need not be the largest measurable 
lesion. A visceral tumor may be injected with or without the use of interventional radiology 
if, in the opinion of the Investigator after discussion with the Medical Monitor, it is an 
appropriate additional site for IT injection. The 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. If an 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. However, there should always be at least 1 target lesion that will not be 
injected for each subject. These lesions not intended for injection may be located in any 
metastatic site. 
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). 
NOTE: Subjects must have a minimum of one target lesion not intended for IT injections 
identified at baseline. 
5.1.2.3.2. Method of CMP-001 Administration 
Topical or local anesthesia may be used at the Investigator’s discretion. 
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 standard 
operating procedures (SOPs). For methods of CMP-001 administration, see Appendix G. 
5.1.3. 
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 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 
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subject will be discontinued from study treatment and will have all EOT assessments 
performed. 
If a planned nivolumab dose is delayed, the CMP-001 dosing may be delayed. 
5.1.4. 
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 5.1.4.1.), hypotension (see Section 5.1.4.3.), and flu-like 
symptoms. Flu-like symptoms may 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 (and FiO2, if available) every time an AE of hypoxia or 
cytokine release syndrome (CRS) is reported for a subject. 
Required prophylaxis is designed to prevent or minimize the severity of these symptoms (see 
Section 5.1.2.1.). 
The following algorithm (Figure 2) is provided as guidance for prophylaxis and treatment of 
AEs associated with CMP-001. 
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. 
 
5.1.4.1. 
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. 
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 
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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. 
5.1.4.2. 
Injection Site Reactions 
Injection site inflammation is expected following the second and subsequent injections. If 
subjects develop 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. 
5.1.4.3. 
Hypotension 
If hypotension is unresponsive to IV fluids, stress dose steroids should be administered 
(Figure 2). 
5.1.4.4. 
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 CRS, or any related Grade 4 AE occurs despite premedication with 
25 mg prednisone or equivalent, CMP-001 should be discontinued. 
5.1.5. 
Dose Modifications and Management of Adverse Events Associated with 
Nivolumab 
Nivolumab has been associated with a variety of AEs. The current nivolumab Investigator’s 
Brochure should be consulted for treatment guidance. 
If a planned nivolumab dosing is delayed, the CMP-001 dosing may be delayed. When 
nivolumab is permanently discontinued for an immune-related AE, CMP-001 must also be 
permanently discontinued. 
A pattern of immune-related AEs has been defined for nivolumab, for which management 
algorithms have been developed; these are provided in Appendix H. Most high-grade events 
were manageable with the use of corticosteroids or hormone replacement therapy 
(endocrinopathies) as instructed in these algorithms. 
Nivolumab administration should be delayed or discontinued as below: 
Table 2: 
Dose Modifications and Management of Adverse Events Associated with 
Nivolumab 
 
Drug-Related 
Adverse Event 
Severitya 
Action Taken 
Clarifications, Exceptions, and 
Resume Criteria 
Colitis or diarrhea 
Grade 2 
Delay doseb 
Dosing may resume when AE 
resolves to Baseline. 
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Drug-Related 
Adverse Event 
Severitya 
Action Taken 
Clarifications, Exceptions, and 
Resume Criteria 
Grade 3 
Delay doseb 
when 
administered 
as a single 
agent 
Dosing may resume when AE 
resolves to Baseline. 
Grade 4 
Permanently 
discontinue 
Serum Creatinine 
Increased 
Grade 2 or 3 
Delay doseb 
Dosing may resume when AE 
resolves to Grade ≤ 1 or Baseline 
value. 
Grade 4 
Permanently 
discontinue 
Pneumonitis 
Grade 2 
Delay doseb 
Dosing may resume after 
pneumonitis resolves to Grade ≤ 1 
or Baseline value. 
Grade 3 or 4 
Permanently 
discontinue 
Aspartate 
aminotransferase 
(AST), alanine 
aminotransferase 
(ALT), or total 
bilirubin (TB) 
increasedc 
AST or ALT > 3x 
and ≤ 5 x upper 
limit of normal 
(ULN) or TB > 1.5 
x and ≤ 3 x ULN, 
regardless of 
Baseline value 
Delay doseb 
Dosing may resume when 
laboratory values return to 
Baseline. 
AST or ALT > 5 x 
ULN or TB > 3 x 
ULN, regardless of 
Baseline value 
Delay doseb or 
permanently 
discontinue 
(see 
clarification) 
In most cases of AST or ALT > 5 x 
ULN, study treatment will be 
permanently discontinued. If the 
Investigator determines a possible 
favorable benefit/risk ratio that 
warrants continuation of study 
treatment, a discussion between the 
Investigator and the Medical 
Monitor/ designee must occur and 
approval from Medical Monitor 
before resuming therapy. 
Adrenal 
Insufficiency 
Grade 2 adrenal 
insufficiency 
Delay doseb 
Dosing may resume after 
adequately controlled with 
hormone replacement. 
Grade 3 or 4 adrenal 
insufficiency or 
adrenal crisis 
Delay doseb or 
permanently 
discontinue 
Mandatory discussion with and 
approval from the Medical Monitor 
needed before resuming therapy. If 
adrenal insufficiency resolves or is 
adequately controlled with 
physiologic hormone replacement, 
participant may not require 
discontinuation of study drug. 
Hyperglycemia 
Grade 2 or 3 
(Hyperglycemia 
requiring initiation 
Delay doseb 
Dosing may resume if 
hyperglycemia resolves to Grade 
≤ 1 or Baseline value, or is 
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Drug-Related 
Adverse Event 
Severitya 
Action Taken 
Clarifications, Exceptions, and 
Resume Criteria 
or change in daily 
management) 
adequately controlled with 
glucose-controlling agents. 
Grade 4 
Permanently 
discontinue 
Mandatory discussion with and 
approval from the Medical Monitor 
needed before resuming therapy. If 
hyperglycemia resolves, or is 
adequately controlled with 
glucose-controlling agents, 
participant may not require 
discontinuation of study drug. 
Hypophysitis/ 
Hypopituitarism 
Symptomatic Grade 
1 to 3 that is also 
associated with 
corresponding 
abnormal lab and/or 
pituitary scan 
Delay doseb 
Dosing may resume if 
endocrinopathy resolves to be 
asymptomatic, or is adequately 
controlled with only physiologic 
hormone replacement. 
Grade 4 
Delay doseb or 
permanently 
discontinue 
Mandatory discussion with and 
approval from the Medical Monitor 
needed before resuming therapy. If 
endocrinopathy resolves or is 
adequately controlled with 
physiologic hormone replacement, 
participant may not require 
discontinuation of study drug. 
Hyperthyroidism or 
Hypothyroidism 
Grade 2 or 3 
Delay doseb 
Dosing may resume if 
endocrinopathy resolves to be 
asymptomatic, or is adequately 
controlled with only physiologic 
hormone replacement or other 
medical management. 
Grade 4 
Delay doseb or 
permanently 
discontinue 
Mandatory discussion with and 
approval from the Medical Monitor 
needed before resuming therapy. If 
endocrinopathy resolves or is 
adequately controlled with 
physiologic hormone replacement 
or other medical management, 
participant may not require 
discontinuation of study drug. 
Rash 
Grade 2 rash 
covering > 30% 
body surface area or 
Grade 3 rash or 
suspected SJS, 
TEN, or DRESS 
Delay doseb 
Dosing may resume when rash 
reduces to ≤ 10% body surface 
area. Dosing may resume if SJS, 
TEN, or DRESS is ruled out and 
rash reduces to ≤ 10% body surface 
area. 
Grade 4 rash or 
confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
Guillain-Barre 
Syndrome (GBS) 
Any Grade 
Permanently 
discontinue 
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Drug-Related 
Adverse Event 
Severitya 
Action Taken 
Clarifications, Exceptions, and 
Resume Criteria 
Myasthenia Gravis 
(MG) 
Any Grade 
Permanently 
discontinue 
Encephalitis 
Any Grade 
encephalitis 
Delay doseb 
After workup for differential 
diagnosis, (ie, infection, tumor- 
related), if encephalitis is not drug 
related, then dosing may resume 
when AE resolves. 
Any Grade drug- 
related encephalitis 
Permanently 
discontinue 
Myelitis 
Any Grade myelitis 
Delay doseb 
After workup for differential 
diagnosis, (ie, infection, tumor- 
related), if myelitis is not drug 
related, then dosing may resume 
when AE resolves. 
Any Grade drug- 
related myelitis 
Permanently 
discontinue 
Neurological (other 
than GBS, MG, 
encephalitis, or 
myelitis) 
Grade 2 
Delay doseb 
Dosing may resume when AE 
resolves to Baseline. 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Symptoms induced 
from mild to 
moderate activity or 
exertion 
Delay doseb 
Dosing may resume after 
myocarditis has resolved. 
Severe or life 
threatening, with 
symptoms at rest or 
with minimal 
activity or exertion, 
and/or where 
intervention 
indicated. 
Permanently 
discontinue 
Pancreatitis: 
Amylase or Lipase 
increased 
Grade 3 with 
symptoms 
Delay doseb 
NOTE: Grade 3 increased amylase 
or lipase without signs or 
symptoms of pancreatitis does not 
require dose delay. Dosing may 
resume when subject becomes 
asymptomatic. 
Grade 4 
Permanently 
discontinue 
Uveitis 
Grade 2 uveitis 
Delay doseb 
Dosing may resume if uveitis 
responds to topical therapy (eye 
drops) and after uveitis resolves to 
Grade ≤ 1 or Baseline. If subject 
requires oral steroids for uveitis, 
then permanently discontinue study 
drug. 
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Drug-Related 
Adverse Event 
Severitya 
Action Taken 
Clarifications, Exceptions, and 
Resume Criteria 
Grade 3 or 4 uveitis 
Permanently 
discontinue 
Other drug-related 
AE (not listed 
above) 
Grade 2 non-skin 
AE, except fatigue 
Delay doseb 
Dosing may resume when AE 
resolves to Grade ≤ 1 or Baseline 
value. 
Grade 3 AE - First 
occurrence lasting ≤ 
7 days 
Delay doseb 
Dosing may resume when AE 
resolves to Grade ≤ 1 or Baseline 
value. 
Grade 3 AE- First 
occurrence lasting > 
7 days 
Permanently 
discontinue 
Recurrence of 
Grade 3 AE of any 
duration 
Permanently 
discontinue 
Grade 4 or Life- 
threatening adverse 
reaction 
Permanently 
discontinue 
Other drug-related 
laboratory 
abnormality (not 
listed above) 
Grade 3 
Delay doseb 
Exceptions: 
No delay required for: Grade 3 
lymphopenia 
Permanent Discontinuation for: 
Grade 3 thrombocytopenia > 7 
days or associated with bleeding. 
Grade 4 
Permanently 
discontinue 
Exceptions: The following events 
do not require discontinuation of 
study drug: 
• Grade 4 neutropenia ≤ 7 days 
• Grade 4 lymphopenia or 
leukopenia 
• Grade 4 isolated electrolyte 
imbalances/abnormalities that are 
not associated with clinical 
sequelae and are responding to 
supplementation/appropriate 
management within 72 hours of 
their onset 
Hypersensitivity 
reaction or infusion 
reaction 
(manifested by 
fever, chills, rigors, 
headache, rash, 
pruritus, 
arthralgia, 
hypotension, 
hypertension, 
bronchospasm, or 
other allergic-like 
reactions) 
Grade 3 or 4 
Permanently 
discontinue 
Refer to Section 5.1.5.2. on 
Treatment of Related Infusion 
Reactions 
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Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; DRESS = drug reaction 
with eosinophilia and systemic symptoms; SJS = Stevens-Johnson syndrome; TB = total bilirubin; TEN = 
toxic epidermal necrolysis; ULN = upper limit of normal. 
a Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 
5.0. 
b Resume treatment when adverse reaction improves to Grade 0 or 1. 
c Resume treatment when AST/ALT returns to Baseline. 
 
 
Nivolumab dosing should also be delayed for any AE, laboratory abnormality, or intercurrent 
illness which, in the judgment of the Investigator, warrants delaying the dose of study 
medication. 
Any event that leads to delay in dosing lasting > 12 weeks from the previous dose requires 
discontinuation, with the following exceptions: 
• Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs 
are allowed. 
• Dosing delays lasting > 12 weeks from the previous dose that occur for non-drug- 
related reasons may be allowed if approved by the Medical Monitor (or designee). 
Participants who require delay of nivolumab should be re-evaluated weekly or more 
frequently if clinically indicated and resume nivolumab dosing when re-treatment criteria are 
met (see Section 5.1.5.1.). Tumor assessments should continue as per protocol even if dosing 
is delayed. 
5.1.5.1. 
Criteria to Resume Nivolumab Treatment 
Please see Table 2 in Section 5.1.5. for guidance on resuming treatment. 
Before re-initiating treatment in a participant with a dosing delay lasting > 12 weeks, the 
Medical Monitor (or designee) must be consulted. Tumor assessments should continue as per 
protocol even if dosing is delayed. Periodic study visits to assess safety and laboratory studies 
should also continue every 6 weeks or more frequently if clinically indicated during such 
dosing delays. 
5.1.5.2. 
Treatment of Nivolumab-related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction 
were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the study Medical Monitor/designee 
and reported as an SAE if it meets the criteria. Infusion reactions should be graded according 
to NCI CTCAE v5.0 guidelines. 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines, as appropriate: 
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
• Remain at bedside and monitor participant until recovery from symptoms. The 
following prophylactic premedication are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg at least 30 minutes before additional nivolumab administrations. 
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For Grade 2 symptoms (therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, narcotics, 
IV fluids]; prophylactic medications indicated for ≤ 24 hours): 
• Stop the study drug infusion, begin an IV infusion of normal saline, and treat the 
participant with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor 
participant until resolution of symptoms. Corticosteroid and/or bronchodilator 
therapy may also be administered as appropriate. If the infusion is interrupted, 
then restart the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor participant closely. If 
symptoms recur, then no further study medication will be administered at that 
visit. 
• For future infusions, the following prophylactic premedication are recommended: 
• diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 
325 to 1000 mg should be administered at least 30 minutes before nivolumab 
and/or ipilimumab infusions. If necessary, corticosteroids (up to 25 mg of 
hydrocortisone or equivalent) may be used. 
For Grade 3 or 4 symptoms (severe reaction, Grade 3: Prolonged [eg, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for clinical sequelae. 
Grade 4: Life-threatening consequences; urgent intervention indicated): 
• Immediately discontinue infusion of study drug. Begin an IV infusion of normal 
saline and treat the participant as follows: Recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1000 solution for subcutaneous administration or 
0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or 
diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), 
as needed. Participant should be monitored until the Investigator is comfortable 
that the symptoms will not recur. Study drug will be permanently discontinued. 
Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms. 
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (eg, 
oral antihistamine or corticosteroids). 
5.1.5.3. 
Nivolumab Treatment Beyond Disease Progression 
Reasons for treatment discontinuation are described in Section 4.5. These include 
discontinuation for progressive disease per RECIST v1.1 and clinical disease progression in 
the opinion of the Investigator. 
However, accumulating evidence indicates a minority of participants treated with 
immunotherapy may derive clinical benefit despite initial evidence of PD (Spigel-2017). 
Participants treated with nivolumab will be permitted to continue nivolumab treatment 
beyond initial RECIST 1.1 defined PD, assessed by the Investigator up to a maximum of 
24 months from date of first dose as long as they meet the following criteria: 
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• Investigator-assessed clinical benefit 
• Tolerance of study treatment 
• Stable performance status 
5.1.6. 
Method of Assigning Subjects 
Each subject will be assigned a unique subject identification (ID) number using an Interactive 
Web Response System. This number will be recorded on the subject’s electronic case report 
form (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. 
5.1.7. 
Blinding and Unblinding Process 
This is an open-label study. A BICR will be used for assessment of the primary efficacy 
endpoint. 
5.2. 
Prior and Concomitant Medications 
IMPORTANT: Please refer to Section 5.1.2.1. for required prophylaxis before CMP-001 
injection. Prophylaxis administered before and after CMP-001 dosing will be collected in the 
electronic data capture (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 treatment (W1D1) through 100 days after the last dose of study treatment or until an 
alternative cancer treatment is initiated, whichever occurs first. Treatment medications for 
AEs related to study treatment that occur more than 100 days after the last dose of study 
treatment or until an alternative cancer treatment is initiated, whichever occurs first, will be 
collected. Subjects who discontinue CMP-001 but remain on treatment with nivolumab will 
continue to have concomitant medications/treatment medications collected according to 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. 
5.3. 
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 
documents, verified by the Clinical Research Associate (CRA), and recorded as a protocol 
deviation as appropriate. Nivolumab will be administered by trained site personnel at the 
clinic site according to the dosing instructions provided in the nivolumab Investigator’s 
Brochure. 
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6. 
STUDY TREATMENT MATERIALS AND MANAGEMENT 
6.1. 
Study Treatments 
Nivolumab is an FDA approved drug product for the treatment of several types of cancer in 
multiple regions including the US (Dec-2014), the EU (Jun-2015), and Japan (Jul-2014). The 
physical characteristics of nivolumab are found in the nivolumab Investigator’s Brochure. 
CMP-001 is an investigational study drug and will be provided by the Sponsor. CMP-001 is 
provided 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 
study drug are found in the 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 Drug Labeling and Packaging 
Details of the study drug labeling and packaging are provided in the Pharmacy Manual. The 
study drug vials will be labeled with the following information: 
• The protocol number 
• The kit number 
• Number of vials per kit (carton only) 
• The batch number of the drug 
• The drug name, concentration, and nominal volume per vial 
• The recommended storage conditions of the drug 
• Cautionary statement 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 Drug Handling, Storage, Accountability 
All study drug vials will be transported, received, stored, and handled in accordance with the 
carton and vial labels and instructions provided to the site and relevant personnel. The site’s 
SOPs, and applicable regulations will be followed. 
Appropriate storage and transportation conditions will be maintained for the study drug vials 
from the point of manufacture up to delivery. All shipments of study drug vials will include a 
temperature-monitoring device that records required storage conditions for the vials at regular 
intervals for the entire time the shipment is in transit. 
Upon receipt by the site, the designated site personnel will examine the shipment and 
temperature-monitoring devices to verify the study drug 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 study drug vials will be stored in a limited access area under 
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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 IQVIA CRA. Such study 
drug vials may not be used until IQVIA representatives (eg, IQVIA CRA) has conveyed a 
determination about these specific study drug 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 study drug product, whether empty or containing study drug, will be kept at the 
site. Study drug vials are single-use only; therefore, contents of partially used study drug vials 
may not be dispensed again, even to the same subject, nor relabeled or reassigned for use by 
other subjects. Unused study drug vials will be available for verification by the study 
monitor. Once dispensed, used study drug vials will be stored in a limited access area under 
appropriate environmental conditions. 
At each investigational site closeout visit and end of clinical trial, a final study drug vial 
accountability review and reconciliation must be completed by the Sponsor or its 
representatives and any discrepancies must be investigated and their resolution documented. 
All study drug product vials will be destroyed at the investigational site as per institutional 
SOPs, after site closeout has been completed or if approved by the Sponsor or its 
representative as required by the site (ie, space limitations, policy) once drug accountability is 
conducted by the IQVIA Biotech CRA. A copy of the site destruction SOP must be 
maintained on file and available for the IQVIA Biotech CRA. If unable to destroy on site, 
please inform the IQVIA Biotech CRA. 
Details of the study drug storage and handling are provided in the Pharmacy Manual. 
6.4. 
Study Drug Dispensing 
CMP-001 will be dispensed, prepared, and administered according to the 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. CMP-001 study drug is dedicated to each study and is labeled specifically 
for each CMP-001 study. Only authorized and qualified site staff may dispense, prepare, or 
administer CMP-001. 
Nivolumab will be dispensed, prepared, and administered according to the Pharmacy Manual 
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(s) (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 (ie, white, black or African American, Asian, American 
Indian/Alaskan Native, Native Hawaiian/other Pacific Islander, or other). 
7.1.4. 
Melanoma History 
Eligible subjects must have been diagnosed with a histopathologically-confirmed diagnosis of 
metastatic malignant or unresectable melanoma. Subjects with uveal, acral, or mucosal 
melanoma are not eligible. 
Documentation, including radiographic and/or photographic images at baseline or at the time 
of response and from 2 consecutive scans separated by at least 4 weeks that demonstrate 
confirmed disease progression during or within 12 weeks of prior treatment that included 
PD-1 blockade with an FDA-approved PD-1 blocking antibody, must be reviewed by the 
investigator at Screening to meet eligibility (see Section 7.2.). These images should be 
sent/uploaded for central review for post-enrollment verification and endpoint assessment. If 
necessary, additional prior images may be requested for central review. 
For subjects with relapse/recurrence on or after adjuvant PD-1 blocking antibody, a 
histological confirmation of recurrence is required. In such cases required images include 
imaging at initiation of adjuvant therapy demonstrating no evidence of disease and images 
demonstrating relapse/recurrence; images are not required for confirmation of progression. 
These images should be sent/uploaded for central review. 
At Screening, a detailed melanoma history will be obtained, including date of initial 
diagnosis, American Joint Committee on Cancer (AJCC) melanoma cancer staging at 
diagnosis, and BRAF mutation status including treatment with a kinase inhibitor targeted for 
BRAF mutation (with or without a MEK inhibitor). BRAF mutation status must be assessed 
with an FDA-approved test. Sites should refer to the Eighth Edition AJCC Cancer Staging 
Manual (Amin-2017) for cancer staging. 
Programmed death-ligand 1 expression status from prior biopsies, if available, will be 
recorded in the EDC. 
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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. Data on prior surgical procedures related 
to melanoma will also be captured in the EDC. 
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 
melanoma, and any reported conditions affecting major body systems during the 10 years 
before Screening. 
7.1.7. 
Medication History 
All medications (see Section 5.2.) administered to the subject from 30 days before first dose 
of study treatment (W1D1) until 100 days after discontinuation of both CMP-001 and 
nivolumab will be recorded in EDC. Treatment medications for AEs related to study 
treatment that occur more than 100 days after the last dose of study treatment will also be 
collected. 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 study treatment and 
dose. Prior cancer treatment will be recorded separately. 
7.1.8. 
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 nivolumab is 
administered, vital signs must be collected before the start of the nivolumab 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 for all subjects. Sites are, 
however, to capture oxygen saturation (and FiO2, if available) at every time point only for 
subjects in whom an AE of hypoxia or CRS is reported. 
7.1.9. 
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). 
7.1.10. 
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 exams 
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focused on areas of disease or AEs may be performed at any clinically indicated time but 
must be obtained before the 1st, 3rd, and 7th weekly CMP-001 injections (W1D1, W3D1, 
W7D1), and at each CMP-001 injection visit thereafter. Height will be obtained at Screening 
only and weight at all physical examination assessments. Body mass index (BMI) will be 
calculated by the EDC system each time weight is entered. 
7.1.11. 
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 
interval, QRS, QT, and QT corrected heart rate intervals. QT will be corrected using 
Fridericia’s (QTcF) formula. Electrocardiograms will be performed after the subject has been 
resting in supine or semi-supine position for at least 5 minutes. 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. 
7.1.12. 
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 3) to be obtained include: 
• Hematology, chemistry, and urinalysis assessments 
• Coagulation (PTT, PT, and INR) assessments 
• Thyroid function tests (thyroid stimulating hormone, Free T3, and Free T4) for 
clinical signs and symptoms of thyroid disorder 
• Autoimmune panel 
• Adrenal function tests, if indicated 
− NOTE: At Screening, patients 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 B/C, 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 local and 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 as medical history if before CMP- 
001 dosing at W1D1, or AEs following CMP-001 dosing at W1D1 in the eCRF. 
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Table 3: 
Clinical Laboratory Assessments 
 
Hematology 
Serum Chemistry 
Urinalysis 
Other Laboratory 
Tests 
RBCs 
WBCs 
Differential WBC count 
Total leukocyte count, 
including differential 
Hemoglobin 
Hematocrit 
Platelets 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate 
aminotransferase 
Bilirubin 
Blood urea nitrogen or 
serum urea 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
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: 
TSH, Free T3, Free T4 
(at Screening) 
Autoimmune 
laboratory panel: 
Anti-dsDNA, antinuclear 
antibody, antineutrophil 
cytoplasmic antibody, 
rheumatoid factor, and 
antibodies to 
ribonucleoprotein (anti- 
RNP) 
Tests to be performed 
as clinically indicated: 
Adrenal function tests 
NOTE: At Screening, 
patients 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. 
Human 
immunodeficiency virus 
Hepatitis B and C 
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; TSH = 
thyroid stimulating hormone; WBC = white blood cell. 
NOTE: Refer to the 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. 
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7.1.13. 
Pregnancy Testing 
Pregnancy testing will be performed on women of childbearing potential at the time points 
specified in the Schedule of Assessments (Table 1). A central serum pregnancy test is 
required during Screening. 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. Women of childbearing potential must have a negative serum or urine pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) 
before dosing at W1D1 as specified in Table 1. Urine pregnancy testing will be completed for 
time points after Screening. 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. 
7.2. 
Disease Assessments 
Disease assessments (radiographic, photographic, and CNS imaging) will be collected 
according to the Schedule of Assessments (Table 1). Imaging that demonstrates confirmed 
disease progression must be reviewed by Investigator to define eligibility and should be 
provided for post-enrollment review by a BICR to verify subject eligibility and endpoint 
assessment (see Section 7.2.3.). Baseline imaging should be performed within 30 days of 
W1D1. On-study disease assessments (radiographic, photographic, 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 per RECIST v1.1 (see Appendix D). 
The same disease assessment method(s) (ie, CT, MRI, photographs) used during Screening 
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. 
Baseline CNS imaging by contrast-enhanced CT or MRI must be provided at Screening; on- 
study CNS imaging is required in presence of clinical symptoms or if CNS disease was 
present at Baseline. 
All disease assessments will be evaluated by BICR according to RECIST v1.1, and by 
Investigator according to RECIST v1.1 (see Appendix D), iRECIST (see Appendix E), and 
itRECIST (Appendix F). 
All scans should be performed at least 2 weeks after the most recent CMP-001 IT injection to 
account for an injection-related pseudoprogression. 
All radiographic and photographic images should be uploaded into the imaging portal within 
1 week of completion to enable BICR (see imaging guidelines). 
7.2.1. 
Radiographic Imaging 
Contrast-enhanced CT and MRI are the preferred 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 
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tomography (PET) as long as disease status can be thoroughly assessed. Ultrasound imaging 
may be used for measurement of lesions for itRECIST. 
Any additional imaging that may demonstrate tumor response or progression (including scans 
performed at unscheduled timepoints and/or at an outside institution) should be collected for 
RECIST 1.1 tumor assessment and submitted to the BICR. 
A target lesion(s) not intended for intratumoral injections should be clearly labeled in the 
baseline imaging. 
7.2.2. 
Photographic Imaging 
Digital photographic images of CMP-001 target and non-target skin lesions, including caliper 
measurements of superficial cutaneous lesions, will be obtained per the time points specified 
in the Schedule of Assessments (Table 1). These photos will be utilized for response 
assessment by the BICR. If available, historic photos collected at screening may be used by 
the BICR to verify subject eligibility post enrollment. Photos should be taken with a digital 
camera of adequate resolution according to the imaging guideline. To clearly capture the 
morphology of the tumor, both the skin lesion and the surrounding tissue must be included in 
the field of view. Each lesion should be clearly labeled with a unique identifier which must 
be used throughout the study. A metric ruler must also be included in the photograph field of 
view as a size reference. 
A target lesion(s) not intended for intratumoral 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 imaging guidelines for further guidance. 
7.2.3. 
Eligibility Disease Assessment 
7.2.3.1. 
Confirmation of Disease Progression on Prior PD-1-blocking antibody 
Investigator must review and confirm subject eligibility before initiation of study treatment. 
Disease assessments (radiographic and/or photographic imaging) at 3 timepoints at minimum 
must be reviewed by Investigator to verify eligibility. Subjects must have a baseline image or 
images at the time of response to prior PD-1-blocking antibody AND images at the time of 
progression AND confirmatory images of progression performed consecutively at least 4 
weeks apart. PD according to RECIST v1.1 should be established during or within 12 weeks 
of the last dose of a PD-1 blocking antibody (either monotherapy or combination therapy). 
The confirmatory scan may serve as the Baseline for this study if completed within 30 days 
before the start of study treatment. A target lesion(s) not intended for intratumoral injections 
should be clearly labeled in the baseline imaging. 
In subjects with recurrence on or within 12 weeks of completion of an adjuvant PD-1- 
blocking antibody a histological confirmation of recurrence is required. In subjects with 
histologically confirmed recurrence, confirmatory image is not required. 
All images used to define subject eligibility must be submitted to BICR for post-enrollment 
eligibility verification. 
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7.2.3.2. 
Central Nervous System Imaging 
Baseline brain imaging by contrast-enhanced CT or MRI (per site local standards) must be 
provided and reviewed by BICR to verify subject eligibility post enrollment. 
Subsequent brain 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). 
The volume and inflammation from an IT injection of CMP-001 may cause a tumor to 
transiently enlarge leading to an inaccurate assessment. All scans should be performed 
predose and at least 2 weeks after the most recent CMP-001 IT injection to account for 
injection-related pseudoprogression. 
7.2.4.1. 
Disease Assessment Beyond Progressive Disease 
Subjects with PD per RECIST v1.1 as determined by Investigator assessment who are 
clinically stable should remain on treatment and have a follow-up scan performed at least 
4 weeks after the initial date of PD to confirm progression per RECIST v1.1. Subjects who 
receive study treatment beyond PD per RECIST v1.1 will have subsequent disease 
assessments evaluated using iRECIST by the Investigator. Disease assessments should 
continue according to the Schedule of Assessments (Table 1). 
7.2.4.2. 
Confirmation of Response 
Subjects with a CR or PR per RECIST v1.1 or iCR or iPR per iRECIST as determined by 
Investigator assessment must have a confirmatory assessment at least 4 weeks after the initial 
response. All scans should be performed at least 2 weeks after the most recent CMP-001 IT 
injection to account for injection-related pseudoprogression. 
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 Analyses 
Blood samples, including serum and/or plasma, will be collected for exploratory 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 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 melanoma, 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 nivolumab, and subsequent 
exploration of factors associated with response or resistance to CMP-001 in combination with 
nivolumab. These samples may also be used for research to develop methods, assays, 
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prognostics, and/or companion diagnostics related to TLR9 agonism and cancer 
immunotherapy. 
7.3.2. 
Collection of Tumor Biopsies for PD-L1 Staining and Translational Analyses 
Fresh tumor tissue biopsy samples are preferred, if safe and medically feasible, as specified in 
the Schedule of Assessments (Table 1). If in the Investigator’s opinion it is unsafe to perform 
a new biopsy, archival material can be used as a substitute for analysis of PD-L1 expression 
if no intervening therapy was received. 
The decision and rationale to forego biopsy samples at screening or during the treatment 
period 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 melanoma, cancer 
immunotherapy, or TLR9, including but not limited to RNA analyses to monitor gene 
expression and DNA analyses to identify mutations associated with cancer. These findings 
may be analyzed for association with observed clinical response, resistance, and/or AEs to 
the combination of CMP-001 and nivolumab. 
Additional tumor biopsies may be collected during the study at the discretion of the 
Investigator. 
7.4. 
Pharmacokinetic Assessments 
7.4.1. 
Collection of Blood Samples for Measurement of CMP-001 Concentration in 
Serum 
Venous blood samples will be collected in the first 20 subjects enrolled for measurement of 
CMP-001 concentrations. 
If the CMP-001 dose is divided across multiple tumors, sample collection times will be 
relative to the time of the first tumor injection. 
Blood will be obtained by either direct venipuncture or from an indwelling cannula inserted 
in a forearm vein, whenever possible. Samples collected on the same day of dose 
administration should be collected in the contralateral (opposite) side of the body from the 
one where CMP-001 is administered (if administered into a tumor on the extremities). Refer 
to Table 1 for acceptable collection windows. 
Additional detailed instructions for the blood collection, processing, storage, and shipment to 
the bioanalytical laboratory will be detailed in the Laboratory Manual. 
Blood will be collected before CMP-001 injection at Weeks 1, 6, and 7. Blood will be 
collected following CMP-001 dosing at Weeks 1 and 6. Samples will continue to be collected 
according to the Schedule of Assessments (Table 1). 
7.4.2. 
Measurement of CMP-001 Concentration in Blood Samples 
Samples for the determination of CMP-001 concentrations in blood will be analyzed by a 
bioanalytical laboratory under the responsibility of the Sponsor using appropriate validated 
bioanalytical methods. 
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Samples that meet the criteria of the bioanalytical laboratory’s SOPs (ie, condition upon 
receipt, stability, etc.) will be analyzed in accordance with the bioanalytical laboratory’s 
SOP(s), the validated method, and the bioanalytical sample analysis plan. Full details of the 
bioanalytical methods and batch performance will be described in a separate Bioanalytical 
Report. 
Remaining blood samples may be subjected to further analysis by the Sponsor or its 
representatives for the development of additional bioanalytical assays and/or for further 
investigation of CMP-001 stability/degradation. Samples collected for analyses of CMP-001 
concentration may also be used to evaluate safety or efficacy aspects related to concerns 
arising during or after the study. 
7.4.3. 
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 CRS are 
experienced. 
7.5. 
Immunogenicity Sampling 
Blood samples will be collected for immunogenicity (anti-Qb antibodies) at the time points 
specified in the Schedule of Assessments (Table 1). 
Samples for nivolumab immunogenicity may be evaluated for development of anti-drug 
antibody (ADA). Samples may also be analyzed for neutralizing antibodies. If applicable and 
within the same matrix, PK samples may be used for ADA analysis in the event of 
insufficient volume, to complete immunogenicity assessment, or to follow-up on suspected 
immunogenicity-related AEs. 
The procedures for sample collection, processing, storage, and shipment are provided in the 
Laboratory Manual. 
7.6. 
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). All AEs/SAEs will be captured from the time of ICF and 
recorded on the eCRF as AEs. All other medical occurrences (non-adverse events) 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. All AEs reported on or after the date that 
study treatment was first administered (W1D1), will be recorded on the eCRF and will be 
considered treatment-emergent adverse events (TEAEs). All TEAEs, defined as an AE that 
started or worsened in severity on or after the date that study treatment was first administered 
(W1D1), will be graded according to CTCAE v5.0 (Appendix C) and coded using Medical 
Dictionary for Regulatory Activities (MedDRA). Worsening TEAEs (ie, 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 
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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. 
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected 
drug induced liver enzyme evaluations) will be monitored during the follow-up phase via on- 
site/local labs until all study treatment-related toxicities resolve, return to Baseline, or are 
deemed irreversible. 
If a participant shows cardiac or pulmonary-related signs (hypoxia, abnormal heart rate, or 
changes from Baseline) or symptoms (eg, dyspnea, cough, chest pain, fatigue, palpitations), 
the participant should be immediately evaluated to rule out cardiac or pulmonary toxicity. 
Some of the assessments referred to in this section may not be captured as data in the eCRF. 
They are intended to be used as safety monitoring by the treating physician. Additional 
testing or assessments may be performed as clinically necessary or where required by 
institutional or local regulations. 
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
7.6.1. 
Adverse Events 
AEs should be monitored from the time that the informed consent is signed through 100 days 
after the last dose of study treatment (both CMP-001 and nivolumab) or until an alternative 
cancer treatment is initiated, whichever occurs first, for all subjects. All AEs from the time 
that the informed consent is signed will be captured on the eCRF. Subjects who discontinue 
CMP-001 but remain on treatment with nivolumab will continue to have AEs collected 
according to this schedule until 100 days after the last dose of nivolumab or until an 
alternative cancer treatment is initiated, whichever occurs first. 
Treatment-related SAEs starting more than 100 days after the last dose of study treatment 
will be recorded on the AE eCRF. 
Immune-mediated AEs are AEs consistent with an immune-mediated mechanism or immune- 
mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. Immune-mediated AEs can include events with an alternate 
etiology that were exacerbated by the induction of autoimmunity. Information supporting the 
assessment will be collected on the participant’s case report form. 
See Section 8.3 for a full description of the collection and reporting of AEs during this study. 
7.7. 
100-Day Follow-up Contact 
The 100-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. 
7.8. 
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). 
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Posttreatment follow-up disease assessments will continue until disease progression, 
initiation of another cancer treatment, death, loss to follow-up, withdrawal of consent, or End 
of Clinical Trial. 
7.9. 
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. 
In this study, OS is a key endpoint of the study. Post-study follow-up is of critical importance 
and is essential to preserving participant safety and the integrity of the study. Participants 
who discontinue study treatment must continue to be followed for collection of outcome 
and/or survival follow-up data as required until death or the conclusion of the study. 
The Sponsor may request that survival data be collected on all treated participants outside of 
the protocol defined window (Schedule of Assessments, Table 1). At the time of this request, 
each participant will be contacted to determine their survival status unless the participant has 
withdrawn consent for all contacts or is lost to follow-up. 
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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 treatment 
(active or placebo drug, biologic, or device) in clinical investigation subjects, which does not 
necessarily have a causal relationship with the study treatment. An AE can therefore be any 
unfavorable and unintended symptom, sign, disease, condition, or test abnormality whether or 
not considered related to study treatment (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 (eg, laboratory tests) that result in an alteration in medical care 
(diagnostic or therapeutic) and/or are considered clinically significant by the 
Investigator 
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism 
or immune-mediated component for which non-inflammatory etiologies (eg, infection or 
tumor progression) have been ruled out. Immune-mediated AEs can include events with an 
alternate etiology that were exacerbated by the induction of autoimmunity. Information 
supporting the assessment will be collected on the participant’s case report form. 
Every adverse event must be assessed by the Investigator with regard to whether it is 
considered immune-mediated. For events which are potentially immune-mediated, additional 
information will be collected on the participant’s case report form. 
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 Table 4. 
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Table 4: 
Criteria for Determination of Serious Adverse Events 
 
Death 
An 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 (ie, 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 treatment, 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 treatment. 
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. 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; SAE = serious adverse 
event; W1D1 = Week 1 Day 1. 
a. Planned hospital admissions or surgical procedures for elective procedures or an illness or disease that existed before the 
time of consent will not be captured as SAEs. If there was a change in medical condition it may be an SAE. 
Appendix C: CTCAE v5.0 
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 treatment. 
Hospitalization due solely to the progression of underlying melanoma should not be reported 
as an SAE. 
8.1.3. 
Definition of a Treatment-Emergent Adverse Event 
A 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 100 days after the last dose of study 
treatment or until an alternative cancer treatment is initiated, whichever occurs first 
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 v5.0), causality/relationship to CMP-001 and to nivolumab separately, and outcome 
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of AEs and SAEs (as defined in Section 8.2.3.). Every attempt should be made to provide the 
causality/relationship 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 for nivolumab. 
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 v5.0 (Appendix C). 
Note that severity is not the same as seriousness (defined in Table 4). Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations. 
Worsening of an ongoing TEAE (ie, 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 5: 
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 AE 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events. 
Appendix C: CTCAE version 5.0 
 
8.2.2. 
Relationship to Study Treatment 
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 6 (see Appendix C). Attribution of 
AEs will be determined for each of the individual components (CMP-001 and nivolumab) 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 6: 
Classification for Adverse Event Causality 
 
Classification 
Definition 
Unrelated 
There is no suspicion of a causal relationship between exposure to the study 
treatment regimen and the AE; another cause of the AE has been identified, 
no temporal association with study treatment has been identified, or the 
study treatment cannot be implicated 
Possibly related 
There is some evidence supporting the possibility of a causal relationship 
between study treatment regimen exposure and the AE; an alternative 
explanation (ie, concomitant drug or concomitant disease) is inconclusive, 
the temporal association with study treatment is reasonable, and the causal 
relationship cannot be excluded 
Probably related 
An AE that has a timely relationship to the administration 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 
treatment regimen and the AE; the AE cannot be reasonably explained by an 
alternate explanation (ie, concomitant drug or concomitant disease) and the 
temporal association with study treatment is suggestive of a causal 
relationship 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events. 
NOTE: CMP-001 and nivolumab 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 
 
Every AE must be assessed by the Investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional 
information will be collected on the participant’s case report form. 
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 
Table 7. 
Table 7: 
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 
AE has resolved, but the subject has been left with symptoms 
or pathology 
Unknown 
Not known, not observed, not recorded, or refused 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events. 
Appendix C: CTCAE version 5.0 
 
8.2.4. 
Action Taken Related to Study Treatment Administration Regarding the 
Adverse Event 
The Investigator will provide the action taken regarding study treatment separately for 
CMP-001 and nivolumab in response to the AE. Refer to Section 5.1.3. and Section 5.1.5. for 
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CMP-001 and nivolumab allowed dose modifications. Classifications for each of the potential 
actions taken are provided in Table 8. 
Table 8: 
Classifications for Actions Taken Related to Study Treatment 
Administration Regarding an Adverse Event 
 
Classification 
Definition 
No change 
No change in administration of study treatment 
Study treatment delayed 
Temporary delay in administration of the study treatment 
Study treatment withheld 
1 or more planned doses of study treatment completely withheld 
(skipped) 
Study treatment permanently 
withdrawn 
Administration of the study treatment 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 study (Title 21 Code of Federal Regulations [CFR] Part 312.64[b] and 
International Council for Harmonisation [ICH] E6 entitled “Guideline to Good Clinical 
Practice”). At each study visit, subjects will be evaluated for new AEs and the status of 
existing AEs. All AEs/SAEs will be captured from the time of ICF and recorded on the eCRF 
as AEs. All other medical occurrences (non-adverse events) 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. All AEs reported on or after the date that study treatment was 
first administered (W1D1), will be recorded on the eCRF and will be considered TEAEs. 
Treatment-emergent adverse events observed until 100 days after the last dose of study 
treatment (both CMP-001 and nivolumab) or until an alternative cancer treatment is initiated, 
whichever occurs first, 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 nivolumab will be recorded for all AEs. Adverse 
events starting more than 100 days after the last dose of study treatment should not be 
recorded on the AE eCRF unless they are serious and 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: Safety-Inbox.Biotech@IQVIA.com or by fax to: 
+1 866-761-1274 as backup 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 the individual components (CMP-001 and nivolumab) of the study 
treatment; and action taken regarding the study treatment will be recorded. Vital signs, 
laboratory results, and other safety assessments noted in Section 7.1.8. 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 
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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 treatments. The paper SAE Report form should be used to record pertinent 
information 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. 
Serious adverse events will be collected from the time of ICF until 100 days after the last 
dose of study treatment or until an alternative cancer treatment is initiated, whichever occurs 
first. Any SAE considered to have at least possible relationship to the study treatment and 
discovered by the Investigator at any time period after EOT should be reported throughout 
the study period. 
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 treatment (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 ID number, period of study treatment intake, event term, nature of 
the event, detailed description of the event, seriousness criteria, causality of the 
event to CMP-001 and to nivolumab 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 treatment 
information including doses, dates of dosing, and action taken with individual 
study treatments 
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 treatments. 
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 representative 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. 
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8.3.2. 
Reporting Pregnancies 
Female subjects or the partners of male subjects who become pregnant within 1 year of their 
last dose of study treatment 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 treatment. The progress of the pregnancy must be followed until the 
outcome of the pregnancy is known (ie, delivery, elective termination, or spontaneous 
abortion). If 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 SAE. Pregnancy should not be 
entered into the eCRF as an AE unless the Investigator suspects an interaction between the 
study treatment 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 (unexpected SAEs 
that are determined to be associated with the use of study treatment) 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 United States, 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 treatment. 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 adverse events and AEs resulting in discontinuation will be followed until 1 of the 
following occurs: 
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• 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 treatment 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 (ie, 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 was 
reported on. It should be completed and submitted to IQVIA Biotech Safety via email: 
Safety-Inbox.Biotech@IQVIA.com. 
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 treatment, 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, 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 v9.4 or higher. 
9.1. 
Sample Size Calculation 
This study will enroll approximately 100 subjects. A subject is enrolled in the study when 
they have received the first dose of study treatment. 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. 
A sample size of 69 subjects achieves at least 90% power to detect a difference of 13% using 
a 2-sided exact test with a significance level of 0.05, assuming that the null hypothesis for 
ORR is 7% (Hodi-2016; Ribas-2018), and the study ORR is 20%. The sample size was 
increased to 100 subjects to adjust for an early discontinuation rate of 15% and to allow for a 
robust assessment of safety. A sample size of 100 subjects with an ORR of 20% produces a 
95% Clopper-Pearson CI for the ORR of 12.7% to 29.2% (PASS 2020). 
Blood samples for PK analysis will be collected from approximately 20 subjects. 
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 treatment. 
9.2.2. 
Safety Analysis Set 
The Safety Analysis Set is defined as all subjects who receive at least 1 dose of study 
treatment. 
9.2.3. 
Per Protocol Analysis Set 
The Per Protocol Analysis Set is defined as all subjects who receive at least 1 dose of study 
treatment and are without major protocol deviations. 
9.2.4. 
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 injection. 
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9.2.5. 
Pharmacokinetic Analysis Set 
The PK Analysis Set is defined as all subjects who receive CMP-001 and have evaluable 
samples at Baseline and after CMP-001 injection. 
9.2.6. 
Immunogenicity Analysis Set 
The Immunogenicity Analysis Set is defined as all subjects who receive CMP-001 and have 
evaluable samples for immunogenicity at Baseline and after CMP-001 injection. 
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 treatment), discontinue study treatment, and 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. 
ECOG Performance Status 
Eastern Cooperative Oncology Group 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. 
Melanoma History 
Melanoma history (time since initial diagnosis, tumor stage, nodal status, and metastatic 
disease status at time of initial diagnosis) will be summarized using descriptive statistics for 
the ITT Analysis Set and listed by subject. Melanoma history will be captured on a separate 
eCRF in the EDC system. 
9.3.5. 
Prior Cancer Treatments 
All prior melanoma treatments 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. 
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9.3.8. 
Prior and Concomitant Medications 
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 will be assessed continually from 30 days before the first dose of 
study treatment (W1D1) through 100 days after the last dose of study treatment (both 
CMP-001 and nivolumab) or until an alternative cancer treatment is initiated, whichever 
occurs first. Treatment medications for study-related AEs that occur more than 100 days after 
the last dose of study treatment will be collected. 
Medications will be coded using the World Health Organization drug dictionary and 
summarized according to the Anatomical Therapeutic Chemical 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 Anatomical Therapeutic Chemical class and preferred 
term in the summary tables. 
Concomitant medications will be presented in a by-subject data listing. 
9.4. 
Study Treatment Exposure and Compliance 
The number of CMP-001 and nivolumab 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. 
Nivolumab dosing, including date, time, and dose administered, will be presented in a by 
subject data listing. 
9.5. 
Efficacy Analyses 
The efficacy analyses will be based on the ITT Analysis Set and may also be performed for 
the Per Protocol Analysis Set if deemed appropriate. 
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 BICR. 
The confirmed ORR is defined as the proportion of 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 = (confirmed CR + confirmed PR)/number of subjects] for the ITT 
Analysis Set. Ninety-five percent Clopper-Pearson CIs for the ORR 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 analyses will be the comparison of the study BICR RECIST v1.1 
confirmed ORR to a 7% ORR assumed under the null hypothesis (Hodi-2016) using a 2-sided 
exact test for the ITT Analysis Set. 
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The objective response rate per RECIST v1.1, iRECIST, and itRECIST by Investigator 
assessments will also be summarized. 
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 stable disease (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 SD, measurements must have met the SD criteria at least once 
after study entry at a minimum interval of 6 weeks. 
9.5.3. 
Treatment Effect in Non-injected Target Lesions 
The treatment effect in non-injected target lesions will be assessed separately from the overall 
effect. The confirmed ORR in non-injected target lesions based the RECIST v1.1 BICR 
measurements will be summarized. 
9.5.4. 
Duration of Response 
Duration of response will be based on RECIST v1.1 as determined by BICR and calculated 
for responders. 
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. 
Duration of response and iDOR will also be determined by Investigator assessment per 
RECIST and iRECIST. 
9.5.5. 
Progression-Free Survival 
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 BICR or death from any cause, whichever 
occurs first. 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. 
Analysis of PFS and iPFS based on RECIST v1.1 and iRECIST determined by Investigator 
assessment will also be performed. 
9.5.6. 
Overall Survival 
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 study contact. Median OS will be calculated using the Kaplan-Meier method. 
9.5.7. 
Post-Progression Disease Response 
Post-progression disease assessments of tumor response based on iRECIST by Investigator 
assessment will be summarized. 
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9.5.8. 
Exploratory Efficacy Analyses 
Exploratory efficacy analyses may also be performed to evaluate the effect of CMP-001 in 
combination with nivolumab on injected and noninjected target lesions. These analyses will 
be based on itRECIST (Goldmacher-2020) (Appendix F) by Investigator assessment and may 
include ORR in noninjected target lesions, the maximal size reduction for each injected target 
lesion, the time until IT therapy is determined to stop providing benefit to the injected target 
lesions, and the time until the first instance of PD in the injected target lesions. 
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 
Treatment-emergent adverse events 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 (ie, 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). 
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, related SAEs, and TEAEs leading to 
treatment discontinuation. 
A by-subject AE data listing, including verbatim term, system organ class, preferred term, 
treatment, grade, outcome, and relationship to treatment for CMP-001 and nivolumab 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. Within normal limits 
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 local 
and 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. 
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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 PK Analysis Set. Pharmacokinetic 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, 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. 
Additional details on the PK analyses will be provided in the SAP. 
9.8. 
Pharmacodynamic Analyses 
Concentrations of CXCL10 and other biomarkers will be summarized using descriptive 
statistics for all time points for the Pharmacodynamic Analysis Set. 
9.9. 
Immunogenicity Analyses 
Immunogenicity data based on anti-Qb antibodies will be summarized descriptively for the 
Immunogenicity Analysis Set. 
9.10. 
Exploratory Tumor Biopsy Analyses 
Tumor biopsy obtained at Baseline and specified time points during the study 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. 
9.11. 
Appropriateness of Measures 
The safety assessments in this protocol (ie, physical examination, vital signs, hematology, 
serum chemistry, urinalysis, coagulation, thyroid function, AEs, 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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9.11.1. 
Blinded Independent Central Review Committee 
Blinded Independent Central Review will be used for the primary efficacy assessments of 
tumor response. A detailed charter for the BICR will be created before the first BICR 
assessment. 
Blinded Independent Central Review responsibilities include verification of disease 
progression. 
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10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
10.1. 
Study Monitoring 
Before an investigational site can enter a subject 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 to the Investigator(s) 
• Confirm that the facilities remain acceptable 
• Confirm that the study team is adhering to the protocol, that data are being accurately 
recorded in the eCRFs, and the study treatment is being properly maintained and 
accountability records are current 
• Perform source data verification with access to all original clinical records for each 
subject 
Additional details regarding monitoring procedures and responsibilities are provided in the 
Clinical Monitoring Plan. 
10.2. 
Case Report Forms 
Electronic Case Report Forms 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 site 
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 or its representatives 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 ICF, must be approved or given a 
favorable opinion in writing by an IRB or Independent Ethics Committee (IEC) as 
appropriate. The Investigator must submit written approval to the Sponsor or its 
representatives before he or she can enroll any 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. The 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 the event 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 1 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 
a template ICF to the Investigator. The final ICF must be approved by the Sponsor or its 
representatives before being reviewed and approved by the IRB. The final IRB-approved ICF 
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 be 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, including 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’s 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 
Ahmed FS, Dercle L, Goldmacher GV, et al. Comparing RECIST 1.1 and iRECIST in 
advanced melanoma patients treated with pembrolizumab in a phase II clinical trial. Eur 
Radiol. 2020 Sep 30; online ahead of print. 
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Felip E et al. Three-year follow-up from Checkmate 017/057: Nivolumab versus docetaxel in 
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Madrid, Spain. Poster 1301PD 
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Heckelsmiller K, Rall K, Beck S, Schlamp A, Seiderer J, Jahrsdörfer B, et al. Peritumoral 
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Schadendorf D, et al. Efficacy and Safety Outcomes in Patients With Advanced Melanoma 
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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, eg, 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-1982 
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APPENDIX B. APPROXIMATE MAXIMUM AMOUNT OF BLOOD 
DRAWN FOR ONE YEAR OF STUDY 
PARTICIPATION 
 
Study Phase 
Estimated Blood Volume 
Screening/Baseline 
35 mL 
Weekly Dosing 
(7 doses every week) 
260 mL 
Q3W Visits 
(~15 visits over 1 year) 
375 mL 
EOT 
45 mL 
PTFU 
10 mL 
Total Blood Volume Estimate for 1 year of 
study participation 
725 mL 
(approximately 3 cups) 
Abbreviations: EOT = End of Treatment; Q3W = every 3 weeks. 
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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 v5.0 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 5 options for Grade selection. 
Activities of Daily Living 
*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 (ie, ‘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 (ie, 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 (ie, 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, eg, 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, eg, 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, eg, 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, ie, 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, eg, 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, eg, 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). 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 ﬁve measurable 
lesions are designated as T-I and are used to evaluate the injected lesion response. One to ﬁve 
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). 
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). 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 
vascularity within and adjacent to a lesion. To minimize systemic administration, injection 
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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 (eg, 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 (eg, 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). 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 9). 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 9: 
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). The injected response is based on SOD change from the previous 
assessment (Table 9). 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 patients 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). 
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). Again, the decision to inject should be based on 
prioritization rules and clinician discretion (described in Guidelines for Prioritization of 
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Lesion Injection for IT Therapy). Regardless of the presence or absence of new lesions, 
treatment should be discontinued in patients 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 (eg, 
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 patients). 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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Protocol CMP-001-010 
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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 (eg, a lesion is impinging on 
the spinal cord, necessitating urgent intervention). 
Complion Document ID: 3328737 


Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021116  
Confidential 
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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 mm 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 (eg, major airways, major blood vessels). 
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 
 
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Protocol CMP-001-010 
Checkmate Pharmaceuticals, Inc. 
Amendment 2 (Version 3.0) 26 August 2021119  
Confidential 
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APPENDIX H. NIVOLUMAB SAFETY ALGORITHM 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens. 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and 
appropriately treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into 
account when switching to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially before an invasive diagnostic or 
therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used. 
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28-Sep-2020 
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28-Sep-2020 
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28-Sep-2020 
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Protocol CMP-001-010 
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Amendment 2 (Version 3.0) 26 August 2021128  
Confidential 
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APPENDIX I. COUNTRY-SPECIFIC REQUIREMENTS FOR HIV 
TESTING / EXCLUSION 
Certain countries may require additional parameters for exclusion of HIV-positive 
participants which are locally mandated. 
As needed, the following table can be used to identify the changes needed to adapt the 
protocol to suit these local requirements. 
 
Original language 
Country-specific language 
Section 4.1 Exclusion Criterion #16 
TBD 
Section 7.1.12 Clinical Laboratory 
Assessments, Table 3 
TBD 
Table 1, Schedule of Assessments 
TBD 
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APPENDIX J. WOMEN OF CHILDBEARING POTENTIAL 
DEFINITION AND METHODS OF CONTRACEPTION 
 
 
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Protocol CMP-001-010 
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VV-RIM-00381493-1.0 Approved - 27 Nov 2024 GMT-5:00 
 
 
COLLECTION OF PREGNANCY INFORMATION 
Guidance for collection of Pregnancy Information and outcome of pregnancy is provided in 
Section 7.1.13. and Section 8.3.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amendment 2 (Version 3.0) 26 August 2021 131 
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SAP_001.pdf: 
Regeneron Pharmaceuticals, Inc. 
Protocol #: CMP-001-010 
A MULTICENTER, OPEN-LABEL, PHASE 2 STUDY OF INTRATUMORAL  
CMP-001 IN COMBINATION WITH INTRAVENOUS NIVOLUMAB IN SUBJECTS 
WITH REFRACTORY UNRESECTABLE OR METASTATIC MELANOMA  
Amendment 2 (Version 3.0) 26 August 2021 
Statistical Analysis Plan 
Version 1.0 
Document last saved: 11-Oct-2022 4:00 PM 
Prepared by: 
IQVIA Biotech 
1700 Perimeter Park Dr. 
Morrisville, NC 27560 
VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00
NCT04698187


Statistical Analysis Plan 
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-010 
IQVIA Biotech (Confidential) Project # RZA44091 
 
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CONFIDENTIAL 
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Reference: SOPCR008, WPCR013 
 
Page 2 of 43 
The approval signatures below indicate that these individuals have reviewed the 
Statistical Analysis Plan (SAP) and agreed on the planned analysis defined in this 
document for reporting. 
Regeneron Pharmaceuticals 
______________________________________ 
Regeneron Pharmaceuticals 
______________________________________ 
Regeneron Pharmaceuticals 
________________________________ 
Regeneron Pharmaceuticals 
_________________________________ 
                                        VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan 
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-010 
IQVIA Biotech (Confidential) Project # RZA44091 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 3 of 43 
CONTENTS 
Abbreviations ..........................................................................................................................5 
I.Introduction ..........................................................................................................................6 
A. Background and Rationale ....................................................................................6 
B. Protocol and Amendment History ........................................................................6 
II.Study Design .......................................................................................................................7 
A. Design Overview ..................................................................................................7 
B. Study Population ...................................................................................................9 
C. Sample Size Status ................................................................................................9 
D. Treatment Randomization .....................................................................................9 
E. Assessment Schedule ............................................................................................9 
F. End of Study .........................................................................................................9 
III.Interventions ....................................................................................................................10 
A. Clinical Trial Material.........................................................................................10 
IV.Protocol Objectives ..........................................................................................................10 
A. Primary ................................................................................................................10 
B. Secondary ............................................................................................................10 
C. Exploratory .........................................................................................................11 
V.Study Endpoints ................................................................................................................11 
A. Primary ................................................................................................................11 
B. Secondary ............................................................................................................11 
C. Exploratory .........................................................................................................12 
VI.General Analytical Considerations ..................................................................................12 
A. Data Sources .......................................................................................................12 
B. Definition of Baseline and Study Day ................................................................12 
C. Missing Data .......................................................................................................13 
D. Multiple Study Centers .......................................................................................14 
E. Covariate Adjustment in Primary Analysis ........................................................14 
F. Sample Size Reassessment .................................................................................14 
G. Ad-hoc Analysis..................................................................................................14 
H. Test Sizes ............................................................................................................15 
I. Multiple Comparisons .........................................................................................15 
J. Analysis Sets .......................................................................................................15 
K. Subgroups of Analysis Populations ....................................................................16 
L. Data Display Characteristics ...............................................................................16 
M. Blinded Review of Data ......................................................................................17 
VII.Subject Accountability ...................................................................................................18 
                                        VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan 
 
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A. Subject Characteristics ........................................................................................18 
B. Disposition ..........................................................................................................20 
C. Protocol Deviations and Population Inclusions ..................................................21 
VIII.Efficacy Analyses .........................................................................................................21 
A. Efficacy Endpoints ..............................................................................................21 
B. Primary Efficacy Analysis ..................................................................................28 
C. Secondary Efficacy Analyses .............................................................................29 
D. Efficacy Analysis on Subgroups of Subjects ......................................................31 
E. Exploratory Efficacy Analysis ............................................................................31 
IX.Safety Analyses ...............................................................................................................32 
A. Exposure .............................................................................................................32 
B. Adverse Events ...................................................................................................33 
C. Clinical Laboratory Results ................................................................................37 
D. Vital Signs ...........................................................................................................38 
E. Physical Examination..........................................................................................38 
F. Prior and Concomitant Medications ...................................................................39 
G. Prior and Concomitant Procedures .....................................................................40 
H. Electrocardiograms (ECGs) ................................................................................40 
I. Eastern Cooperative Oncology Group Performance (ECOG) ............................40 
X.Pharmacokinetic Analyses ................................................................................................41 
XI.Pharmacodynamic Analyses ............................................................................................41 
XII.Immunogenicity Analyses ..............................................................................................41 
XIII.Exploratory Tumor Biopsy Analyses ............................................................................41 
XIV.References .....................................................................................................................43 
 
                                        VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan 
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-010 
IQVIA Biotech (Confidential) Project # RZA44091 
 
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Page 5 of 43 
 
 
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 
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 
 
                                        VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan 
 
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I. Introduction 
 
A. Background and Rationale 
 
Melanoma remains the most common cause of skin cancer death in the United 
States (US), Europe, and Australia. Despite an evolving understanding of the 
molecular aberrations and clinical factors that impact outcomes as well as 
improvements in the therapeutic paradigm, including immunotherapy, metastatic 
melanoma remains essentially incurable in view of the limited efficacy and the 
toxicity of the currently available agents. Despite the improved outcomes with 
programmed cell death protein 1 (PD-1) blockade, more than 60% of patients do 
not respond to single-agent Nivolumab or pembrolizumab. Therefore, there 
remains a critical need for innovative anticancer therapy in this condition.  
 
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 (Qb). G10 is an ODN that 
contains CpG and also contains poly-G tails that allow it to form G-quadruplexes. 
Once administered to a patient, an antidrug antibody response to the VLP (anti-Qb 
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 TLR91. 
 
Several nonclinical and clinical reports support the hypothesis that TLR9 agonism 
may enhance the antitumor response of melanoma 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 secretion (Fourcade-2014), providing a rationale for the use of the 
combination of TLR9 agonists and anti-PD-1 antibodies in cancer therapy. 
 
The protocol for Study CMP-001-010 describes the general approach to analysis 
of data from the study. This analysis plan describes additional details needed to 
complete such an analysis which will be conducted for the clinical study report 
(CSR). 
 
B. Protocol and Amendment History 
   
This Statistical Analysis Plan (SAP) is based on initial version of Protocol CMP-
001-010.  
 
                                        VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan 
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-010 
IQVIA Biotech (Confidential) Project # RZA44091 
 
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Version 
Approval Date 
Salient Changes, if 
any* 
Description of 
change and 
rationale 
Initial 
31 August 2020 
 
 
Amendment 1 
04 February 2021 
 
 
Amendment 2 
26 August 2021 
 
 
*  This table notes changes that require accommodation in analysis plan. Further details of all 
changes in protocol amendments are included in the protocol. 
 
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 study of CMP-001 
IT in combination with Nivolumab IV in subjects with unresectable or metastatic 
melanoma refractory to PD-1 blockade. Eligible subjects must have confirmed 
disease progression during or within 12 weeks of their last dose of therapy 
containing a PD-1 blocking antibody for the treatment of unresectable cutaneous 
melanoma prior to enrollment. All subjects will receive CMP-001 IT and 
Nivolumab IV according to the Schedule of Assessments (Protocol Table 1) until 
a reason for treatment discontinuation is reached. 
 
CMP-001 10 mg IT 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 
Appendix F). On visits where both study treatments are administered, CMP-001 
IT should be administered before Nivolumab. CMP-001 should be administered 
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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 5.1.3. for treatment 
modifications for CMP-001. 
 
Objective responses will be assessed by BICR and Investigator assessment 
according to RECIST v1.1. Subjects who continue study treatment beyond PD 
according to RECIST v1.1 at the discretion of the Investigator will be evaluated 
by the Investigator according to iRECIST.  
 
Disease status will be assessed by computed tomography (CT) or magnetic 
resonance imaging (MRI) and other appropriate measures beginning predose at 
Week 13 Day 1 (W13D1) and repeated every 9 weeks (eg, W22D1) while the 
subject is on treatment. 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. Disease assessments may 
continue every 12 weeks for subjects with a response lasting more than 1 year. 
 
Responses (CR, PR, immune complete response [iCR], or immune partial response 
[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. 
 
Subjects who discontinue study treatment should complete an end of treatment 
(EOT) visit and 100-day safety follow-up. Subjects who have stopped all study 
treatment but have not met criteria for study discontinuation should remain on 
study for post-treatment follow-up (PTFU) and long-term survival follow-up 
(LTSFU) and receive study evaluations for efficacy according to the Schedule of 
Assessments. 
 
Figure 1: CMP-001-010 Study Schema 
 
Note: 100DFU = 100-Day Follow-up; EOT = End of Treatment; IT = intratumoral; IV = 
intravenous; LTSFU = long-term survival follow-up; PTFU = posttreatment follow-up; Q3W = 
every 3 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; QW = every week. 
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a. Disease assessments performed predose beginning at W13D1 (- 7 days). 
 
B. Study Population 
 
See Protocol Section 4.1 and 4.2 for a complete list of the inclusion/exclusion 
criteria. 
 
C. Sample Size Status 
 
Given the early termination of site activation and study enrollment since 
exploratory. This study has enrolled 44 subjects. A subject is enrolled in the study 
when they have received the first dose (partial or complete) of study treatment. 
Subjects who have provided written informed consent may be allowed to complete 
Screening and enter study treatment if they meet all eligibility criteria, at the 
discretion of the Sponsor or their representatives. 
 
With the enrollment of the last subject on 30Jun2022, the subject status of this 
study is as follows: 
 67 subjects were screened 
 23 subjects were screen failures 
 44 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 
 
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 100 days of safety follow-up. 
 
 
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III. 
Interventions 
 
A. Clinical Trial Material 
 
Nivolumab is an FDA approved drug product for the treatment of several types of 
cancer in multiple regions including the US (Dec-2014), the EU (Jun-2015), and Japan 
(Jul-2014). The physical characteristics of Nivolumab are found in the OPDIVO® 
(Nivolumab) Prescribing Information. Nivolumab will be provided by the sponsor. 
 
CMP-001 is an investigational study drug 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 study drug are found in the 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.  
 
The protocol provides additional product details in Section 6.   
 
 
IV. 
Protocol Objectives 
 
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. 
 
A. Primary 
 
The protocol lists the following primary objective:  
 To determine confirmed objective response with CMP-001 in combination 
with Nivolumab in subjects with refractory unresectable or metastatic 
melanoma. 
 
B. Secondary 
 
The protocol lists the following secondary objective: 
 To evaluate the safety and tolerability of CMP-001 administered by 
intratumoral (IT) injection in combination with Nivolumab in subjects with 
refractory unresectable or metastatic melanoma. 
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 To evaluate the efficacy of CMP-001 in combination with Nivolumab in 
subjects with refractory unresectable or metastatic melanoma. 
 To assess the pharmacokinetic (PK) profile of CMP-001 in combination 
with Nivolumab in subjects with refractory unresectable or metastatic 
melanoma.  
 To assess and describe the immunogenicity of CMP-001 in combination 
with Nivolumab in subjects with refractory unresectable or metastatic 
melanoma. 
 
 
C. Exploratory 
 
The protocol (Section 2.1.3) lists the following exploratory objective: 
 Evaluate the effect of CMP-001 in combination with Nivolumab on 
injected and non-injected target lesions in subjects with unresectable or 
metastatic melanoma. 
 Evaluate the pharmacodynamic effects of CMP-001 administered in 
combination with Nivolumab. 
 
V. Study Endpoints 
 
A. Primary 
The primary endpoint is the ORR, defined as the proportion of subjects with a 
confirmed objective response of CR or PR based on Response Evaluation Criteria 
in Solid Tumors version 1.1 (RECIST v1.1) as determined by Blinded Independent 
Central Review (BICR). 
 
B. Secondary 
 
The protocol describes as secondary endpoints the following: 
 AEs, serious adverse events (SAEs), and AEs leading to discontinuation or 
death, and severity of AEs as assessed by the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events version 5.0 
(CTCAE v5.0) 
 Duration of response (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 BICR 
 Treatment response in non-injected target lesions based on RECIST v1.1 
by BICR 
 Progression-free survival (PFS), defined as the time from date of first dose 
of study treatment to date of documented PD based on RECIST v1.1 by 
BICR or death, whichever occurs first 
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 Overall survival, defined as the time from date of first dose of study 
treatment to date of death 
 ORR, DOR, and PFS based on RECIST v1.1 and immune objective 
response rate, immune duration of response (iDOR), and immune 
progression-free survival (iPFS) based on immunotherapy Response 
Evaluation Criteria in Solid Tumors (iRECIST) by Investigator assessment 
 Blood concentrations of CMP-001 or its metabolites 
 Development of anti-Qb antibodies 
 
C. Exploratory 
 
In addition to the endpoints described above, the following endpoints will be 
evaluated: 
 Response in injected and non-injected target lesions per intra-tumoral 
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 CXCL10 (interferon 
gamma-induced protein 10) after treatment with CMP-001 
 
 
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. 
 
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 
 
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Baseline is defined as the last non-missing observation prior to the first 
administration of study drugs (CMP-001 or Nivolumab). Study Day 1 will be 
designated as the first day a patient 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 contact, 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: 
 Completely missing start date will not be imputed.  
 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. 
 Start date missing the day will be imputed as: 
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: 
 Completely missing stop date will not be imputed. 
 Stop date missing both the month and day will be imputed as Dec 31st of 
the year of stop date.  
 Stop date missing the day will be imputed as the last date of the month of 
the stop date. 
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 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 + 100 days, 
then the End-of-Treatment (the last drug received) date + 100 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: 
 Completely missing start or stop date will not be imputed. 
 Start or stop date with missing both the month and day will not be imputed. 
 Start date missing the day will be imputed as the 1st of the month of the 
start date. 
 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. 
 
G. Ad-hoc Analysis 
 
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 VIII 
below as well as the safety analysis methods detailed in Section IX below for the 
exploratory Phase 2 study. 
 
The following subject information, efficacy-related and safety related data 
displays will be produced for the purpose of the ad-hoc analysis. Unless stated 
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otherwise, these displays are summary tables that summarize data for the 
corresponding analysis set: 
 Subject information 
o Demographics 
o Baseline characteristics 
o Disposition 
o Medical history 
o Cancer history 
o ECOG 
 Efficacy 
o ORR, DOR, TTR, PFS per RECIST v1.1 by BICR and Investigator 
o OS 
o Selected subgroup analysis 
 Safety 
o Study drug exposure: CMP-001 and nivolumab 
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. Test Sizes 
 
Not Applicable. 
 
I. Multiple Comparisons 
 
No control for the effect of multiple comparisons is planned.  
 
J. Analysis Sets  
 
Five analysis sets will be defined for use with various analyses, provided that there 
are data available for the analysis set to be defined and analysis to be performed. 
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 
Immuno
genicity 
Tumor 
Biopsy 
Intent-to-Treat 
X 
X 
X 
 
 
 
 
Safety 
 
 
 
X 
 
 
 
Per Protocol  
 
 
X* 
 
 
 
 
Pharmacodynamic 
 
 
 
 
X 
 
X 
Immunogenicity 
 
 
 
 
 
X 
 
* The efficacy analyses may also be performed for the Per Protocol Analysis Set if deemed appropriate. 
 
1. Intent-to-Treat Analysis Set 
 
The Intent-to-Treat (ITT) Analysis Set is defined as all subjects who receive 
at least 1 (partial or full) dose of study treatment. 
 
2. Safety Analysis Set 
 
The Safety Analysis Set is defined as all subjects who receive at least 1 dose 
of study treatment. 
 
3. Per Protocol Analysis Set 
 
The Per Protocol Analysis Set is defined as all subjects who receive at least 1 
dose of study treatment and are without major protocol deviations. 
 
4. 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. 
 
5. Immunogenicity Analysis Set 
 
The Immunogenicity Analysis Set is defined as all subjects who receive at 
least 1 dose of CMP-001 and have at least 1 non-missing ADA result after 
CMP-001 administration. 
 
K. Subgroups of Analysis Populations     
 
Not applicable. 
 
L. Data Display Characteristics 
 
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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 subjects. Summary tables will be produced as specified in following 
sections. Additional data listings will be produced for outcome measures that 
involve extensive procedures to derive the analyzed outcomes such as efficacy 
measures. 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 
possible 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. 
 
Summary tables, listings and figures will include a 
that will indicate, at a minimum, the following: 
 Program source (e.g., SAS program name) 
 Database extraction date (e.g., database lock date or data cut date or data 
extract date) 
 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, that is write-protected for replication 
and future reference. Individual data listings will display all the relative values 
supporting corresponding table and figures. 
 
M. Blinded Review of Data 
 
Blinded Independent Central Review (BICR) RECIST v1.1 assessment will be 
used for the primary efficacy assessments of tumor response. A detailed charter 
for the BICR will be created prior to the first BICR assessment. 
 
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Blinded Independent Central Review responsibilities also include confirmation of 
disease progression prior to study entry, in addition to the primary efficacy 
assessment of the study. 
 
 
VII. 
Subject Accountability 
 
A. Subject Characteristics 
 
Demography and Baseline Characteristics.  Data collected about the following 
subject characteristics at the screening visit will be summarized: 
 Age  
o Age will be calculated as the number of years elapsed between birth 
date and the date of the ICF date, 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.) 
 Sex  
o Childbearing potential yes/no 
o Non-childbearing potential, and confirmation by site  
 Race 
 Ethnicity 
 Height 
 Baseline Weight 
 Baseline Body Mass Index 
 
All demography data including informed consent date will be listed. 
 
Baseline Disease Characteristics. Time since Initial Diagnosis of Primary Cancer 
to First Dose (Months), Disease Type at Enrollment, Tumor Burden at Baseline, 
Measurable Disease at Baseline, Baseline ECOG, and other key baseline 
information will be summarized for ITT Analysis Set and presented in a listing. 
 
Medical History Other Than Melanoma Cancer.  Medical history including CNS 
screening will be summarized in a table and listed by subject. Medical history will 
be coded using MedDRA, associating lower-level terms with preferred terms and 
system organ classes by the primary hierarchy.   
 
Melanoma Cancer History.  Listings of all collected data related to Melanoma 
history will be provided for ITT Analysis Set. A summary of the following 
elements will also be provided: 
 PD-L1 status 
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 Clinical staging 
o Clinical staging at diagnosis 
o Tumor status 
o Nodal status 
o Metastatic disease status 
 Pathologic staging 
o Pathologic staging at diagnosis 
o Tumor status 
o Nodal status 
o Metastatic disease status 
 
Prior Primary Cancer Treatments.  Listings of key data related to prior melanoma 
treatments will be provided for ITT Analysis Set, and include the following 
information: 
 Number of Lines of Prior Systemic Therapies: summarized categorically 
 
 Any Prior Therapy 
o Prior Systemic Therapy 
o Prior Radiotherapy 
o Prior Cancer-related Surgery 
 Reason for Discontinuation from Any Prior Systemic Therapy 
 Regimen Best Response on Any Prior Systemic Therapy 
 Duration of Exposure to Any Prior Systemic Therapy (months), 
summarized continuously 
 Administrative Setting of Prior Systemic Therapy 
 Time since Completion of Prior Adjuvant Systemic Therapy to First Dose 
Date (< 6 months
) 
 
All prior melanoma 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 melanoma 
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 ITT 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.  
 
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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. The primary reason 
for treatment(s) and study discontinuation and follow-up status will also be 
summarized for the ITT Analysis Set. 
 
Study treatment (CMP-001 only or both CMP-001 and Nivolumab) may be 
discontinued for any of the following occurrences: 
 Adverse Event 
 PD per RECIST v1.1 
 Subject Achieved and Maintained a Confirmed CR or iCR (and has been 
treated for at least 48 weeks, and has received at least 3 doses of both study 
treatments beyond the date of initial CR/iCR) 
 Upon Request of the Sponsor or Regulatory Agency 
 Clinical Disease Progression 
 Medically Necessary in the Opinion of the Investigator 
 Subject Withdrew Consent for Treatment 
 Subject Became Pregnant or Began Breastfeeding 
 Subject Lost to Follow-up 
 Death 
 Subject Completed 2 Years of Study Treatment 
 End of Clinical Trial 
 Other 
 
Study Participation may be discontinued for any of the following occurrences: 
 Completed 
 Adverse Event 
 Subject Withdrew Consent 
 Lost to Follow-Up 
 Death 
 Study Terminated by Sponsor  
 End of Clinical Trial 
 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. 
 
Time on Study (TOS) will be summarized descriptively. For subjects who are still 
on study as of the data cutoff date, TOS will be calculated as follows: 
TOS (months) = (Data Cutoff Date  First Dose Date + 1) / 30.4375 
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As for subjects who exited the study on or prior to the data cutoff date, TOS will 
be calculated as: 
TOS (months) = (Study End Date  First Dose Date + 1) / 30.4375 
 
Subject disposition will be presented in a by-subject data listing. 
 
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. 
 
 
VIII. Efficacy Analyses  
 
The primary efficacy analyses will use data from the ITT population. Analyses of data 
from the Per-protocol population may accompany ITT population analyses if 
substantial number of ITT population subjects are excluded from the Per-protocol 
population.    
 
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 per RECIST v1.1 as assessed by BICR. 
  
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 ITT Analysis Set. 
95% Clopper-Pearson CIs for the ORR will be calculated. 
 
Subjects who discontinue due to death as a result of disease progression, 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. Objective Response assessment evaluated after new anti-cancer 
treatment will not be considered for BOR calculation. 
 
Confirmed Best Overall Response (BOR)   
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The Best Overall Response for a subject is the best response designation as 
assessed by BICR, recorded between the date of the first dose of study treatment 
and the date of objectively documented progression per RECIST v1.1, or the date 
of treatment discontinuation, whichever occurs first.  
 
Per RECIST v1.1, CR or PR must be confirmed by a confirmatory response 
assessment performed at least 4 weeks after the initial response. Objective 
Response assessment evaluated after new anti-cancer treatment will not be 
considered for BOR calculation. 
 
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 Overall Response of CR, PR, or stable 
disease (SD) per RECIST v1.1 by BICR.  
 
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. OR assessment evaluated after new anti-cancer 
treatment will not be considered for DCR calculation. 
 
Treatment Effect in Non-injected Target Lesions   
The treatment effect in non-injected target lesions will be assessed separately from 
the overall effect. The confirmed ORR in non-injected target lesions based on the 
RECIST v1.1 per BICR measurements will be derived using the same approach as 
ORR. 
 
Data for the injected target and non-injected target lesions will be analyzed as a 
secondary efficacy analysis using the following definitions (Goldmacher, 2020). 
 
1.  Injected Target Lesions 
The baseline for each individual injected target lesion is defined as the 
measurement prior to the first injection of that lesion. Specifically: 
 For target lesions injected at W1D1, the baseline is defined as the 
measurement obtained prior to W1D1. 
 For the injection of other accessible non-injected lesions when an injected 
tumor is clearly decreasing in size, the baseline measurement for these 
newly injected lesions is defined as the preceding measurement obtained 
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prior to the initial injection of these lesions and the baseline for these 
lesions will not be the measurement prior to W1D1. 
 Baseline SOD is defined as the sum of diameters of the individual lesion at 
its respective baseline; thus, if a lesion is not injected until post W1D1, 
then the baseline for the injected SOD will take the data from different time 
points into consideration. 
 Best change in tumor burden (i.e., maximal percentage reduction in SOD) 
will also incorporate measurement data from different time points, 
regardless of whether a lesion was injected after W1D1. However, only 
measurements taken after the initial injection can be considered for best 
response. 
 
2.  Non-injected Target Lesions 
 As long as the non-injected target lesions remain non-injected, the SOD for 
the non-injected target lesions will be compared against the measurement 
obtained prior to W1D1.  
 If any non-injected target lesions are decided to be injected, then the 
maximal non-injected effect has been achieved and any subsequent non-
injected response is considered non-evaluable. 
 
The injection status of a target lesion will be determined based on the response to 
the Type of Injection question of the CMP-
is selected at a specific time point, then the lesion is considered injected from that 
time point onwards and deemed non-injected prior to that injection time point. 
Once injected, the lesion will be considered an injected target lesion for all 
subsequent time points, even if not injected later on. 
 
Duration of Response (DOR) 
Duration of response will be based on RECIST v1.1 as determined by BICR and 
calculated for confirmed responders of 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). 
 
DOR is only defined for subjects who have a confirmed BOR of CR or PR. Per the 
BOR definition, 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 
do 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 
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subsequent therapy will be used. Details of the censoring rules are provided 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 BICR or death from any 
cause, whichever occurs first. Subjects who are alive and progression-free at the 
time of analyses will be censored in the analyses at the date of their last disease 
assessment. 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. Details 
of the censoring rules are provided in Table 1a.  
 
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. Censoring rules are 
summarized in Table 1a. If a subject meets the criteria for more than 1 censoring 
rule, PFS will be censored at the earliest censoring date. 
 
Secondary Efficacy Assessments by Investigator   
The secondary efficacy endpoints of ORR, BOR, DCR, DOR and PFS by 
investigator assessments will be derived using the same approach as above. 
 
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 or lost to follow-up at 
the time of the analysis data cutoff 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, and the last contact date will be derived as shown in Table 2.  
 
OS will be calculated as follows: 
OS (months) = (Death or Censoring Date  First Dose Date + 1) / 30.4375 
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Immune Objective Response Rate (iORR)   
iORR is defined as the proportion of subjects with an immune best overall 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 pseudoprogression. 
 
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 immune best overall 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 be continue be used and the 
subject will be censored at the date of iUPD.   
 
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) 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. 
 
Immune Progression-Free Survival (iPFS).   
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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. 
 
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 
 
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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, 
whichever is earlier  
Event 
Earliest date of tumor 
assessment documenting 
iUPD 
iCPD per iRECIST 
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 
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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 
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 Known Alive 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 
End of study 
Not lost to follow up 
Start/end dates from drug administration record 
Non missing 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 non missing parameter value 
Physical examination 
Evaluation performed marked as yes 
12-Lead ECG 
Evaluation performed marked as yes 
ECOG performance status date 
Non missing ECOG performance status 
Start/end dates of adverse events 
Non missing verbatim term 
Start/end dates of concomitant medications and 
procedures 
Non missing verbatim term 
 
B. Primary Efficacy Analysis 
 
The primary efficacy analysis will be the confirmed ORR as assessed by BICR per 
RECIST v1.1, and its 2-sided 95% confidence interval, calculated using Clopper-
Pearson
. 
 
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Page 29 of 43 
ment early, the sample size necessary 
to ensure a 95% level of confidence and a power of 90% will not be reached. 
Therefore, the test will be exploratory, and interpreted as such. 
 
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. 
 
C. Secondary Efficacy Analyses 
 
Methodology for DOR, PFS, OS, iPFS, iDOR.  Estimates of median with 95% CIs 
will be computed using the Kaplan-Meier method. Kaplan-Meier graphs will be 
visually displayed. Median Time-to-Event will be estimated at the 50th percentile 
of the corresponding Kaplan-Meier estimates. The event-free rate with the two-
-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. 
 
DOR by BICR.  A table summarizing the secondary endpoint of DOR by BICR 
will be produced for subjects with a confirmed BOR of CR or PR only, following 
the methodology presented above. 
 
PFS by BICR.  The secondary endpoint of PFS by BICR will be summarized 
following the methodology presented above. 
 
Treatment Effect in Non-injected Target Lesions.  The confirmed ORR in non-
injected target lesions per RECIST v1.1 assessed by BICR measurements will be 
evaluated using the same approach as the primary efficacy analysis ORR. 
 
Efficacy Assessments per RECIST v1.1 by Investigator.  Analysis of ORR, BOR, 
DCR, DOR, and PFS based on RECIST v1.1 by Investigator assessment will be 
performed using the same methods described in the previous sections. 
 
OS.  The secondary endpoint of OS will be summarized following the 
methodology presented above. 
 
iORR, iDOR, iPFS.  Post-progression disease assessments of tumor response based 
on iRECIST by Investigator assessment will also be summarized. Analysis of 
immune objective response rate (iORR), immune duration of response (iDOR), 
and immune progression-free survival (iPFS) based on iRECIST by Investigator 
assessment will be performed using the same methods described in the previous 
sections. 
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The following efficacy figures will be generated using the confirmed BICR 
RECIST v1.1 BORs for subject level classification for the ITT Analysis set. 
Additional figures for the Investigator assessment and iRECIST assessments may 
be produced. 
 
 A waterfall plot will be generated summarizing the best percent change in 
tumor burden of injected and non-injected target lesions from the 
Screening/Baseline target lesion assessment for each subject, for 
responders only:  
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 Each BOR category will be displayed in different colors. 
 
 A Spider plot of the percent changes in tumor burden for target lesion 
measurements (including the sum of the 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.  
o Each BOR category will be displayed in different colors 
 
 A Swimmer plot delineating the occurrence of the clinical outcomes of 
interest over time, including the following information: 
o Duration of study treatment  
o Treatment ongoing 
o Time to BOR based on RECIST v1.1 as assessed by BICR, 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 
 
 Kaplan-Meier plots displaying time-to-event on DOR, PFS, OS, per 
RECIST v1.1 as assessed by BICR, and by Investigator: 
o Estimate of median and the corresponding two-sided 95% CIs for 
median 
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o Event-free rates at selected timepoints  
 
 A Forest plot suggesting ORR and the associated two-sided 95% CI  
 
 For the analysis of the potential difference in tumor shrinkage in injected 
and non-injected target lesions within the same subject, a waterfall plot 
delineating the maximal percentage reduction in SOD from baseline for 
injected and non-injected target lesions, respectively, will be provided. 
 
Listings of efficacy-related data (by BICR or by Investigator) will include the 
following: 
 All lesion assessments (target lesion, non-target lesion, new lesion). 
 Response assessments. 
 Time to events (DOR, PFS, OS) 
 
D. Efficacy Analysis on Subgroups of Subjects 
 
The below subgroup analysis (not limited to) for efficacy will be explored using 
forest plots of the calculated ORRs with their 95% CIs. 
 Serum LDH at diagnosis (Elevated, Normal) 
 BRAF mutation (Yes, No) 
 Number of Lines of Prior Therapies 
. Note the categories can be 
modified based on the data). 
 Best Response to Prior Anti-PD-L1 (CR, PR, SD, PD, NE, NA, Unknown) 
 Clinical Disease Stage at diagnosis (M0/M1a/M1b, M1c/M1d) 
 
E. 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 Med
analyses will be carried out for the exploratory phase 2 study. 
 
 
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IX. 
Safety Analyses 
 
Safety analyses will use data from the Safety Analysis Set. Subjects will be analyzed 
according to the actual study treatment received (i.e., the actual treatment arm 
variable(s) in SDTM/ADaM). 
 
A. Exposure 
 
Exposure to CMP-001 and Nivolumab will be summarized separately with 
descriptive statistics for the number of doses received, the duration of treatment to 
each drug (weeks), the planned dose intensity, the actual dose intensity, and the 
relative dose intensity (%). 
 
1. Duration of Treatment 
 
Duration of Treatment (DoT) of CMP-001 and Nivolumab 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 
Nivolumab, 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. Dosage Modifications 
 
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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. 
 
Listings will be provided with the information from the study drug administration 
eCRFs for CMP-001 and Nivolumab, 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. 
 
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 AE (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. 
 
Immune-mediated AEs can include events with an alternate etiology that were 
exacerbated by the induction of autoimmunity. In the EDC system, each AE is 
classified as immune-mediated or not by the Investigator. 
 
Per 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 100 days after the last dose of study treatment 
should not be recorded on the AE eCRF unless they are considered to be related to 
study treatment. 
 
Serious adverse events and AEs resulting in discontinuation will be followed until 
one 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 treatment or to 
factors unrelated to study conduct 
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 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 100 days after the last dose 
of study treatment or a new cancer treatment is initiated, whichever occurs first.  
 
Treatment-emergent adverse events will be coded using MedDRA (version 23.1 
or later) 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 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.  
 
An AE preferred term reported by a subject more than once will be represented in 
the most severe category or most related (for the relationship to study treatment 
tables). 
 
A TEAE summary table will be generated including the following (N (%)): 
 Subjects with one or more TEAEs 
 Subjects with TEAEs of grade 3 or higher 
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 Subjects with CMP-001 treatment-related TEAEs (includes TEAEs which 
are definitely, probably and possibly related and those with missing 
relationship) 
 Subjects with Nivolumab treatment-related TEAEs (includes TEAEs 
which are definitely, probably and possibly related and those with missing 
relationship) 
 Subjects with grade 3 or higher CMP-001 treatment-related TEAEs  
(includes TEAEs which are definitely, probably and possibly related and 
those with missing relationship) 
 Subjects with grade 3 and higher Nivolumab treatment-related TEAEs 
(includes TEAEs which are definitely, probably and possibly related and 
those with missing relationship) 
 Subjects with Serious AEs (SAEs) 
 Subjects with CMP-001 treatment-related SAEs (includes TEAEs which 
are definitely, probably and possibly related and those with missing 
relationship) 
 Subjects with Nivolumab treatment-related SAEs (includes TEAEs which 
are definitely, probably and possibly related and those with missing 
relationship) 
 Subjects with TEAEs leading to CMP-001 treatment discontinuation 
 Subjects with TEAEs leading to Nivolumab treatment discontinuation 
 Subjects with immune-mediated AEs as assessed by the Investigator 
 Subjects with TEAEs resulting in death 
 
The following additional AE summaries by SOC/PT will be produced: 
 All TEAEs 
 Grade 3 or higher TEAEs 
 TEAEs by maximum grade and maximum relationship 
o TEAEs related to any study drug (includes TEAEs which are 
definitely, probably and possibly related and those with missing 
relationship) 
o TEAEs related to CMP-001 (includes TEAEs which are definitely, 
probably and possibly related and those with missing relationship) 
o TEAEs related to Nivolumab (includes TEAEs which are definitely, 
probably and possibly related and those with missing relationship) 
 TEAEs by maximum grade  
 TEAEs by maximum relationship to CMP-001 
 TEAEs by maximum relationship to Nivolumab 
                                        VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan 
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-010 
IQVIA Biotech (Confidential) Project # RZA44091 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 36 of 43 
o Grade 3 or higher TEAEs related to CMP-001 (includes TEAEs 
which are definitely, probably and possibly related and those with 
missing relationship) 
o Grade 3 or higher TEAEs related to Nivolumab (includes TEAEs 
which are definitely, probably and possibly related and those with 
missing relationship) 
 TEAEs of Special Interest 
 TEAEs resulting in death 
 All SAEs 
o SAEs related to any study drug (includes TEAEs which are 
definitely, probably and possibly related and those with missing 
relationship) 
o SAEs related to CMP-001 (includes TEAEs which are definitely, 
probably and possibly related and those with missing relationship) 
o SAEs related to Nivolumab (includes TEAEs which are definitely, 
probably and possibly related and those with missing relationship) 
 TEAEs leading to treatment discontinuation of any study drug 
 TEAEs leading to CMP-001 treatment discontinuation 
 TEAEs leading to Nivolumab treatment discontinuation 
 
A hierarchical listing will display the MedDRA system organ classes represented 
in the data. Within each system organ class, the listing will display each unique 
preferred term. Within each preferred term, the listing will display each unique 
verbatim (recorded) term. Listed terms will be ordered alphabetically.  
 
The following AE listings will be produced: 
 All TEAEs 
 Grade 3 or higher TEAEs 
 TEAEs considered related to study treatment (includes TEAEs which are 
definitely, probably and possibly related and those with missing 
relationship)  
 TEAEs resulting in death 
 SAEs 
 Related SAEs. This listing will include serious TEAEs with a drug 
relationships.   
 TEAEs leading to treatment discontinuation 
                                        VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan 
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-010 
IQVIA Biotech (Confidential) Project # RZA44091 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 37 of 43 
 
C. 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), 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 tables from Baseline to the Max 
Post-Baseline Grade will also be created. Within normal limits and Normal will be 
used when appropriate for urinalysis parameters.  
 
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. 
 
Results from pregnancy tests will be provided in data listings. 
 
Table 3: Clinical Laboratory Assessments 
 
Hematology 
Serum Chemistry 
Urinalysis 
Other Laboratory 
Tests 
RBCs 
WBCs 
Differential WBC count 
Total leukocyte count, 
including differential 
Hemoglobin 
Hematocrit 
Platelets 
Alanine aminotransferase 
(ALT) 
Albumin 
Alkaline phosphatase 
(ALP) 
Amylase 
Aspartate 
aminotransferase (AST) 
Bilirubin 
Blood urea nitrogen or 
serum urea 
Calcium  
Chloride 
Creatinine 
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: 
TSH, Free T3, Free T4 (at 
Screening) 
 
Autoimmune laboratory 
Panel: 
Anti-dsDNA 
Antinuclear 
                                        VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan 
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-010 
IQVIA Biotech (Confidential) Project # RZA44091 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 38 of 43 
Glucose 
Lactate dehydrogenase 
(LDH) 
Lipase 
Phosphorous 
Potassium 
Sodium Total protein 
Antibody 
Antineutrophil 
cytoplasmic antibody 
Rheumatoid factor 
Antibodies to 
ribonucleoprotein (anti-
RNP) 
 
Tests to be performed as 
clinically indicated: 
Adrenal function tests 
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. 
 
D. 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: 
 Baseline value  
 Minimum post-baseline value and corresponding change from baseline 
 Maximum post-baseline value and corresponding change from baseline 
 Last post-baseline value and corresponding change from baseline 
 
A by-subject data listing of all vital sign data will be generated. 
 
E. 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. 
 
                                        VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan 
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-010 
IQVIA Biotech (Confidential) Project # RZA44091 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 39 of 43 
F. Prior and Concomitant Medications 
 
All medications administered to the subject from 30 days prior to first dose of 
study treatment (W1D1) until 100 days after discontinuation of both CMP-001 and 
Nivolumab will be recorded in the EDC. Treatment medications for AEs related 
to study treatment that occur more than 100 days after the last dose of study 
treatment will also be collected.  
 
Documentation for each medication will include the generic name of the 
medication, 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 the 
course of study treatment and within 100 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 100 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 (or later) and might be up-versioned by the end of 
the study. Medications will be summarized according to the Anatomical 
Therapeutic Chemical class II and preferred term. Subjects will be counted only 
once for a given concomitant medication for each Anatomical Therapeutic 
Chemical class and preferred term in the summary tables. Prior medications will 
be summarized for ITT Analysis Set. Concomitant medications will be 
summarized for the Safety Analysis Set. 
 
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 
 
 
 
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.  
 
                                        VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan 
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-010 
IQVIA Biotech (Confidential) Project # RZA44091 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 40 of 43 
G. 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 100 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 eCRF, ordered within subject by 
 
 
H. Electrocardiograms (ECGs)  
 
ECG results (Heart Rate, PR Interval, QRS Interval, QT Interval, QTcF Interval), 
 
 
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 Safety Analysis Set for the following values that are 
derived per unique subject and ECG parameter: 
 Baseline value 
 Minimum post-baseline value and corresponding change from baseline 
 Maximum post-baseline value and corresponding change from baseline 
 Last post-baseline value and corresponding change from baseline   
 
for baseline 
and each post-baseline assessment visit.   
 
I. Eastern Cooperative Oncology Group Performance (ECOG) 
 
Eastern Cooperative Oncology Group performance status (ECOG) results will be 
presented in data listings. ECOG 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 Safety Analysis Set. 
 
                                        VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan 
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-010 
IQVIA Biotech (Confidential) Project # RZA44091 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 41 of 43 
 
X. Pharmacokinetic Analyses 
 
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.  
 
A method to determine the concentration of CMP-001 in serum was developed at Pace 
Labs. Samples (K2EDTA plasma samples) from this study were shipped and analyzed 
in March 2022 as an exploratory assessment. At the time, this analysis occurred since 
the samples were assumed to be human serum. Thus, the analysis results could not be 
interpreted since the method is specifically developed for serum. 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 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. 
Immunogenicity Analyses 
 
Immunogenicity data based on anti-Qb antibodies will be summarized descriptively 
and listed for the Immunogenicity Analysis Set and Changes from Baseline will be 
included, provided that there are data available for the analysis set to be defined and 
analysis to be performed. 
 
 
XIII. Exploratory Tumor Biopsy Analyses 
 
                                        VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan 
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-010 
IQVIA Biotech (Confidential) Project # RZA44091 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 42 of 43 
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, 
immune checkpoints, and potential markers of resistance or response to 
immunotherapy for the Pharmacodynamic Analysis Set, provided that there are data 
available for the analysis set to be defined and analysis to be performed. 
 
 
 
 
 
                                        VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00


Statistical Analysis Plan 
 
Regeneron Pharmaceuticals Inc. / Protocol: CMP-001-010 
IQVIA Biotech (Confidential) Project # RZA44091 
 
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 43 of 43 
XIV. References 
 
1. Lemke-Miltner CD, Blackwell SE, Yin C, Krug AE, Morris AJ, Krieg AM, 
et al. Antibody opsonization of a TRL9 agonist-containing virus-like particle 
enhances in situ immunization. J Immunol. 2020 Mar 1;204(5):1386-1394. 
 
2. Hodi FS, Hwu WJ, Kefford R, Weber JS, Daud A, Hamid O, 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. 
 
3. Goldmacher GV, Khilnani AD, Andtbacka R, Luke RJ, F. Hodi S, et al. 
Response criteria for intratumoral immunotherapy in solid tumors: itRECIST. 
Journal of Clinical Oncology.2020;38:15_suppl, 3141. 
 
                                        VV-RIM-00350888-1.0 Approved - 15 May 2024 GMT-5:00


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