Conditions: Melanoma Lymph Node Cancer
Keywords: Stage IIIB/C/D
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 34
Healthy volunteers: no

Brief summary:
The purpose this research study is to determine if the combination of nivolumab and CMP-001 improves the likelihood of eradicating (destroying) disease in the lymph node (pathologic response rate).

Detailed description:
Patients are being asked to take part in this clinical research study because they have stage IIIB, IIIC or IIID cutaneous (or unknown primary) melanoma with lymph node disease and have yet to undergo surgery. There are two phases, Prime Phase and a Boost Phase. If they participate they will receive nivolumab in combination with CMP-001 for a total of 7 weeks (Prime Phase) prior to surgery. Surgery will be performed approximately 2-4 weeks after completion of the Prime Phase. After recovery from surgery patients will receive additional nivolumab in combination with CMP-001 for approximately 46 additional weeks (Boost Phase).

The main goal of this research study to determine if the combination of nivolumab and CMP-001 improves the likelihood of eradicating (destroying) disease in the lymph node (pathologic response rate). Pathologic responses are associated with improved relapse-free and overall survival in melanoma.

Prior to surgery (Prime Phase) Nivolumab 240mg, will be administered as a 30-minute IV infusion on an outpatient basis. During the Prime Phase, 3 cycles of Nivolumab will be administered every 2 weeks over a 6 week period starting with cycle 2, cycle 4 and then cycle 6.

Prior to surgery (Prime Phase) CMP-001 will be given as an injection from a syringe weekly for a total of 7 weeks. The first injection (week 1), 5mg, will be applied directly into the skin and the remaining injections, 10mg will be administered, will be given intra-tumorally for weeks 2-7.

Surgery will be performed to the cancerous lymph node 2-4 weeks after the Prime Phase is completed.

After recovery from surgery (Boost Phase) Nivolumab will be administered at 240mg every 2 weeks or 480 mg every 4 weeks depending on the physician's preference. CMP-001, 5mg, will be administered by injections intra-tumorally every 4 weeks for up to 54 weeks.

Patients will be followed to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs first. This will be done every 3 months.

Arms:
arm 1: Prime Phase -Nivolumab 240mg, IV Infusion, every two weeks starting with Cycle 2 ( Cycles 2, 4, 6) for 6 weeks in combination with CMP-001, 5mg, Injection, at Week 1 and the remaining injections, 10 mg will be administered Weeks 2 -7.

Boost Phase -Nivolumab 240mg, IV Infusion, every two weeks, over a 46 week period in combination with CMP-001, 5mg, administered every 4 weeks for 1 year.

Interventions: intervention 1: CMP-001 intervention 2: Nivolumab
Intervention descriptions: intervention 1: A molecule comprised of a 30 nucleotide strand, flanked by 10 guanines on either end. The nucleotide strand is surrounded by a Qβ viral-like protein. The intended mechanism of action of CMP-001 in oncology is the activation of TLR9 in pDC within the tumor or the tumor-draining lymph nodes (tumor-associated pDC). intervention 2: A fully human Ig G4 antibody that blocks PD-1. Nivolumab was initially approved by the FDA for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Nivolumab has also been FDA approved to treat patients with advanced (metastatic) squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy, as well as advanced renal cell carcinoma.

Protocol document:
Prot_SAP_001.pdf: 
TITLE: Neoadjuvant Phase II Study of TLR9 Agonist CMP-001 in Combination with 
Nivolumab in Stage IIIB/C/D Melanoma Patients with Clinically Apparent Lymph Node 
Disease 
 
 
 
 
 
 
 
 
 
 
SPONSOR: 
  
Diwakar Davar, MD 
 
IND NUMBER: 
  
18193 
 
PI: 
  
Diwakar Davar, MD 
 
Source of Support: 
Checkmate Pharmaceuticals 
 
  
NIH – UPCI SPORE, RO1 CA257265 
 
  
Melanoma Research Foundation 
 
Version: 
   
11 (08/18/2022) 


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SUMMARY OF CHANGES 
PROTOCOL 
• First Page, Protocol version and date change from v10 01/26/2022 to v11 
08/18/2022 
• First Page, added Funding sources 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


HCC 17-169  
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Table of Contents 
1. Trial Summary 
2. Trial Design 
2.1.1. Trial Design 
2.1.2. Trial Diagram 
3. Objective(s) and Hypothesis(es) 
3.1. Primary Objective and Hypothesis 
3.2. Secondary Objectives 
4. Background and Rationale 
4.1. Background 
4.1.1. Pharmaceutical and Therapeutic Background 
4.1.2. Preclinical and Clinical Trial Data 
4.2. Rationale 
4.2.1. Rationale for Dose Selection/Regimen/Modification 
5. Methodology 
5.1. Entry Criteria 
5.1.1. Diagnosis/Conditions for Study Entry 
5.1.2. Subject Inclusion Criteria 
5.1.3. Subject Exclusion Criteria 
5.2. Trial Treatments 
5.2.1. Nivolumab Dose Selection 
5.2.2. CMP-001 Dose Selection 
5.3. Treatment Allocation 
5.4. Stratification 
5.5. Concomitant Medications 
5.6. Rescue Medications and Supportive Care 
5.6.1. Supportive Care Guidelines 
5.7. Subject Withdrawal/Discontinuation Criteria 
5.8. Subject Replacement Strategy 
5.9. Clinical Criteria for Early Trial Termination 
5.10. 
Surgical Considerations 
5.10.1. 
Primary excision or primary cutaneous melanoma 
5.10.2. 
Regional lymphadenectomy 
5.10.3. 
Lymphadenectomy for nodal recurrence 
6. Trial Flow Chart 
6.1.1. Study Flow Chart 
7. Trial Procedures 
7.1. Trial Procedures 
7.1.1. Administrative Procedures 
7.1.2. Clinical Procedures/Assessments 
7.1.3. Laboratory Procedures/Assessments 
7.1.4. Other Procedures 
7.1.5. Visit Requirements 
7.2. Adverse and Serious Adverse Events 
7.2.1. Definitions 
7.2.2. Evaluation of Adverse Events and Serious Adverse Events 
7.2.3. Timeframe for Adverse Event/Serious Adverse Event Collection 


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7.2.4. Recording Adverse Events/Serious Adverse Events 
7.2.5. Reporting Serious Adverse Events and Serious Unexpected Adverse Events 
7.2.6. IND Safety Report 
7.2.7. Follow-up of Adverse Events/Serious Adverse Events 
8. Statistical Analysis Plan 
8.1. Study Design 
8.2. Safety Monitoring 
8.3. Sample Size 
8.4. Efficacy Analysis 
8.5. Safety Analysis 
8.6. Biomarker Analysis 
8.7. Data Safety and Monitoring Plan 
9. Labeling, Packaging, Storage and Return of Clinical Supplies 
9.1. Investigational Product 
9.2. Packaging and Labeling Information 
9.3. Handling, Storage and Accountability 
9.4. Dispensing 
10. List of References 
Appendix 1 Dietary History Questionnaire for Microbiome Sampling 
Appendix 2 Pathologic Response Assessment (irPRC Criteria) 
 
 
 
 
 
 


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1 Trial Summary 
Trial Phase 
Non-randomized phase II single arm Simon two-stage 
Clinical Indication 
PD-1 naïve stage IIIB/C/D melanoma 
Trial Type 
Neoadjuvant study 
Type of control 
Not applicable 
Route of administration 
CMP-001 pre-operatively (intra-tumoral) and post-operatively 
(subcutaneous) 
Nivolumab pre- and post- operatively (intravenous)  
Trial Blinding 
N/A 
Treatment Groups  
N/A 
Number of trial subjects 
Total sample size: 33 (1st stage 14; 2nd stage 16; 3 additional 
allowing for dropout) 
Estimated enrollment period 
15-20 months 
Estimated duration of trial 
24 months 
Duration of Participation 
24 months 
Estimated average length of 
treatment per patient 
52 weeks 
 
 
2. Trial Design 
 
2.1 
Trial Design 
This is a phase II single arm Simon two-stage single-center study of nivolumab in combination with 
Toll-like receptor 9 (TLR9) agonist CMP-001 in patients with PD-1 naïve stage IIIB-IIID cutaneous 
(or unknown primary) melanoma with clinically apparent lymph node (LN) and/or in-transit and/or 
satellite disease. The study will be conducted over a 52-week period. 
Patients with stage IIIB-IIID cutaneous (or unknown primary) melanoma with palpable nodal disease 
and/or in-transit disease who have yet to undergo definitive surgery are eligible to enroll. Patients 
with nodal and/or in-transit relapse including those who have received prior adjuvant IFN and/or 
ipilimumab are eligible to enroll. However, patients who have received either nivolumab or 
pembrolizumab or ipilimumab/nivolumab are NOT eligible. Other eligibility criteria include, but are 
not limited to, absence of CNS disease and presence of disease amenable to biopsy. 
Suitable patients will be identified pre-operatively. Patients will undergo a rapid (preferred 21 days, 
up to 28 days) screening evaluation consisting of systemic/CNS staging scans, tumor biopsy, and 
correlative blood studies to confirm suitability. Eligible patients will receive nivolumab/CMP-001 
combination (prime phase) peri-operatively for a total of 7 weeks. In the peri-operative period, CMP-
001 will be administered weekly via sub-cutaneous injection (week 1) then intra-tumorally (weeks 2-
7). Following peri-operative therapy and restaging systemic scans, patients will undergo surgical 
resection. Post-operatively, patients will continue to receive nivolumab/CMP-001 combination (boost 
phase) every 2 (or 4) weeks (nivolumab) and 4 weeks (CMP-001) to complete 1 year (52 weeks) of 
therapy. In the post-operative period, CMP-001 will be administered subcutaneously. 
  


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2.2  Trial Diagram 
 
Figure 1: Trial Diagram 
3. Objective(s) and Hypothesis(es) 
 
3.1 
Primary Objective and Hypothesis 
Objective: To evaluate major pathologic response rate (MPR rate) in patients with stage IIIB/C 
melanoma following 7 weeks of nivolumab and injected CMP-001. 
 
Hypothesis: That the combination of nivolumab and injected CMP-001 improves MPR rate in 
patients with stage IIIB/C melanoma. 
 
3.2 
Secondary Objectives 
Objective: To evaluate safety, relapse-free survival (RFS) and overall survival (OS) in patients with 
stage IIIB/C melanoma following 52 weeks of nivolumab/CMP-001 combination. 
 
Hypothesis: Nivolumab/CMP-001 combination is safe and improves RFS and OS in patients with 
stage IIIB/C/D melanoma. 
 
3.3 
Exploratory Objectives 
Objective: To evaluate circulating and intra-tumoral immune cells, including T-cells (CD8, CD4, 
Tregs) and antigen-presenting cells (monocytes, macrophages, MDSCs), for the expression of 
inhibitory and activating receptors and ligands including functional analyses. To evaluate TCR 
clonality/diversity analyses of circulating and intra-tumoral CD8+ T-cells before and after nivolumab 
and CMP-001 combination. To evaluate genetic and transcriptomic signatures of response/non-
response. To evaluate novel imaging characteristics in responders and non-responders. 
Hypothesis: Nivolumab/CMP-001 combination improves T-cell functionality by augmenting antigen 
presentation and increasing T-cell infiltrate. Nivolumab/CMP-001 combination improves T-cell 
infiltrate by genetic, transcriptomic and imaging analyses. 


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4. Background and Rationale 
 
4.1 
Background 
 
4.1.1 
Pharmaceutical and Therapeutic Background: Nivolumab 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation 
has been known for decades (Disis 2010). The inability of the immune system to control tumor growth 
does not appear to result from an inability to recognize the tumor as foreign. Tumor cells have been 
shown to evade immune destruction despite displaying recognizable antigens on their surface and 
despite the presence of high-avidity T cells that are specific for these antigens (Boon and van der 
Bruggen 1996; Boon and Old 1997; Boon et al. 2006; Ercolini et al. 2005). Histologic evaluation of 
many human cancers show extensive infiltration by inflammatory and immune cells (Galon et al. 
2006; Galon et al. 2012), suggesting that the immune system responds less effectively to 
malignancy. These observations have led to the hypothesis that dominant mechanisms of immune 
tolerance or immune suppression are responsible for the immune system's inability to effectively 
respond in a way that consistently results in rejection. 
There are a number of inhibitory mechanisms that have been identified to be involved in tumor-
mediated immune suppression and include expression of the programmed death ligand-1 (PD-L1), 
which can engage the inhibitory receptor PD-1 on activated T cells; the presence of the tryptophan-
catabolizing enzyme IDO1, which exploits the exquisite sensitivity of T cells to tryptophan depletion 
and tryptophan metabolites; and infiltration with FoxP3+ regulatory T cells (Treg), which can mediate 
extrinsic suppression of effector T-cell function. Therefore, agents that target these negative 
regulatory pathways and thereby allow the expansion of effector T cells present in the tumor may be 
beneficial in the clinic. 
The PD-1 receptor-ligand interaction is a major pathway stimulated by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T cells under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune 
reactions. Programmed death receptor-1 (encoded by the gene Pdcd1) is an Ig superfamily member 
related to CD28 and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), which has been shown 
to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-
L2) (Freeman et al. 2000; Latchman et al. 2001; Liang et al. 2003). The mechanism by which PD-1 
down modulates T-cell responses is similar to but distinct from that of CTLA-4, as both molecules 
regulate an overlapping set of signaling proteins (Parry et al. 2005; Hiraoka 2010). 
Programmed death receptor-1 has been shown to be expressed on activated lymphocytes including 
peripheral CD4+ and CD8+ T cells, B cells, Tregs, and natural killer cells (Hodi et al. 2008). 
Expression has also been shown during thymic development on CD4-CD8- (double negative) T cells 
as well as subsets of macrophages and dendritic cells (DCs). The ligands for PD-1 (PD-L1 and PD-
L2) are constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors (Latchman et al. 2001; Loke and Allison 2003; 
Liang et al. 2003; Francisco et al. 2009; Taube et al. 2014). Binding of either PD-1 ligand to PD-1 
inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low levels on 
various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein 
is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments. Programmed death ligand-2 is thought to control immune T-cell 
activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues. Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor. Programmed death receptor-1 has 


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been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (Liotta et al 
2010). This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
Nivolumab is a fully human Ig G4 antibody that blocks PD-1. Nivolumab was initially approved by the 
FDA on December 22, 2014 for the treatment of patients with unresectable or metastatic melanoma 
and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
Nivolumab was also approved on March 4, 2015 to treat patients with advanced (metastatic) 
squamous non–small cell lung cancer (NSCLC) with progression on or after platinum-based 
chemotherapy. Additionally, FDA approved nivolumab on November 23, 2015 for advanced renal 
cell carcinoma. In Europe, it was approved on June 19, 2015 as a single agent (monotherapy) for 
the treatment of advanced (unresectable or metastatic) melanoma in adults. Another extension of 
indication was approved on October 28, 2015 to treat the advanced stages of squamous NSCLC 
after prior chemotherapy in adults. On February 25, 2016, it was also approved for advanced renal 
cell carcinoma after previous therapy in adults. 
More 
recently, 
nivolumab 
was 
approved 
by 
the 
FDA 
(https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm590004.htm) for the adjuvant 
treatment of resected stage IIIB-IVC melanoma patients on the basis of the data from the 
CheckMate-238 study (Weber et al. 2017). In this study, compared to ipilimumab, adjuvant therapy 
with nivolumab for 1 year resulted in significantly longer recurrence-free survival and overall survival. 
Compared to ipilimumab adjuvant therapy, nivolumab adjuvant therapy had a lower rate of grade 3 
or 4 adverse events.  
4.1.2 
Pharmaceutical and Therapeutic Background: CMP-001 
CMP-001 is a molecule comprised of a 30 nucleotide strand, flanked by 10 guanines on either end. 
The nucleotide strand is surrounded by a Qβ viral-like protein. The intended mechanism of action of 
CMP-001 in oncology is the activation of TLR9 in pDC within the tumor or the tumor-draining lymph 
nodes (tumor-associated pDC). Tumor-associated pDC activated by CMP-001 are expected to 
release large amounts of type I interferons (IFN), and increase their expression of costimulatory 
molecules and tumor antigen presentation to T cells, culminating in the generation of a clinically 
effective anti-tumor T cell response. In order for this response to be specific for the tumor, the pDC 
should have taken up the tumor antigens already, which requires them to be activated either within 
the tumor, or in the draining lymph nodes, which in turn requires the subcutaneous route of 
administration to reach a locally effective concentration of CMP-001. Systemic administration of 
TLR9 agonists results primarily in liver, spleen, and RES uptake with little specific activation of pDC 
in peripheral lymph nodes. Immature tumor-associated pDC contribute to tumor growth and an 
adverse prognosis in patients with cancer (Lombardi et al. 2015; Demoulin et al. 2013). Activating 
and maturing these pDC through either subcutaneous or intratumoral administration of CMP-001 is 
expected to reverse the pDC functional effects from promoting to antagonizing tumor growth, and 
from supporting immune tolerance to inducing an anti-tumor CD8+ T cell response in the tumor 
microenvironment.  
CMP-001 is composed of (i) a virus-like particle (VLP) comprised of capsid proteins derived from 
bacteriophage Qbeta, which encapsulate (ii) a cytosine linked to a guanine by a phosphate bond 
(CpG) oligodeoxynucleotide (ODN) known as G10, which is a Toll-like receptor 9 (TLR9) agonist 
designed to induce high levels of type I interferon production and an anti-tumor CD8+ T cell response 
through activation of TLR9 in plasmacytoid dendritic cells (pDC). The therapeutic agent is a VLP 
referred to as QbG10. QbG10 has been previously studied in clinical trials under the name CYT003. 
In this protocol the name CYT003 will refer to historical data using the product in non-oncology 
settings. The name CMP-001 will refer to Checkmate Pharmaceuticals’ plans for the agent. 


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4.1.3 
Preclinical and Clinical Trial Data: Nivolumab 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.1.4 
Preclinical and Clinical Trial Data: CMP-001 
Preliminary Safety and Efficacy in Asthma 
QbG10, currently known as CMP-001, has been previously studied in clinical trials under the name 
CYT003. CYT003 has been administered to 732 humans (volunteers or patients with non-cancer 
diagnoses) either alone or in combination with various allergens. CYT003 has been administered at 
doses as high as 2 mg weekly for seven doses by SC administration. CYT003 has reproducibly 
demonstrated evidence of TLR9 agonist activity with intended immune stimulatory effects. It has 
generally been well tolerated, with mild to moderate flu-like symptoms and/or injection site reactions 
noted in the majority of treated patients. 
Preliminary Safety and Efficacy in PD-1 primary Refractory Melanoma 
Intratumoral administration of CMP-001 is currently being evaluated in combination with 
pembrolizumab in subjects with metastatic melanoma resistant to checkpoint inhibitors. In study 
CMP-001-001, A Multicenter, Open-label Phase 1b clinical Study of CMP-001 in Combination with 
Pembrolizumab in Subjects with Advanced Melanoma, CMP-001 is being administered 
intratumorally on a weekly (Schedule A) and Q3W schedule (Schedule B) across a dose range of 1-
10 mg. To date, approximately 45 subjects have been treated in the CMP-001-001 study. Preliminary 
analysis of safety demonstrates an acute toxicity profile that predominantly consists of Grade 1-2 
adverse events including mild fever, chills, rigors, nausea, vomiting and occasional hypotension. In 
some subjects the severity of this adverse event profile is increased. These AEs typically present 
after the third CMP-001 dose and generally resolve within a few hours with standard supportive care. 
The mechanism of action associated with the acute toxicity profile appears to resemble symptoms 
associated with cytokine release. A treatment algorithm has been developed for the management of 
these reactions and can be found in Section 5.2.2.7. CMP-001-001 adverse event summary in 
Cohort 2 of the Dose Escalation Phase are presented in Table 4.1.4-1. 
Table 4.1.4-1: Related AEs Reported in More than One Subject in CMP-001-001 Study 
CMP001-001 Protocol 
Related AEs Reported in More than One Subject* 
 
N (%) of Subjects 
Schedule A^ 
(N=28) 
Schedule B^^ 
(n=11) 
Anemia 
4 (14.3%) 
- 
Chills 
15 (53.6%) 
- 
Constipation 
2 (7.1%) 
- 
Cough 
2 (7.1%) 
- 
Diarrhea 
3 (10.7%) 
- 


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Fatigue 
7 (25.0%) 
2 (18.2%) 
Fever 
16 (57.1%) 
- 
Flushing 
2 (7.1%) 
- 
Headache 
6 (21.4%) 
2 (18.2%) 
Hypertension 
2 (7.1%) 
- 
Hypotension 
8 (28.6%) 
- 
Injection Site Pain 
2 (7.1%) 
3 (27.3%) 
Nausea 
8 (28.6%) 
- 
Pruritus 
3 (10.7%) 
- 
Rigors 
6 (21.4%) 
- 
Tachycardia 
2 (7.1%) 
- 
Vomiting 
8 (28.6%) 
2 (18.2%) 
*Based on EDC data as of 30 May 2017 
^ Schedule A includes Cohort 1 (1 mg, n=3); Cohort 2 (3 mg, n=12); Cohort 4 (5 mg, n=6); Cohort 6 (10 
mg, n=3); Cohort 8 (10 mg, n=4) 
^^ Schedule B includes Cohort 3 (3 mg, n=4); Cohort 5 (5 mg, n=3); Cohort 7 (10 mg, n=3), Cohort 9 
(10 mg, n=1) 
 
Preliminary efficacy data, based upon RECIST investigator reads, from the ITT population across 
both schedules from the 1, 3 and 5 mg cohorts (N=28) demonstrated on ORR of 21.4% (5 PRs, 1 
CR). The ORR in subjects treated on Schedule A (N=21) was 24% (5/21; 95% CI 8.2%-47.2%) and 
on Schedule B (N=7) was 14.3% (1/7; 95 % CI 0.4-57.9%). All responses seen were evidenced at 
the subject’s first follow up scan (12 weeks). Durability or all responses have been seen beyond 24 
weeks with some responses being maintained beyond 1 year. 
4.2 
Rationale 
 
4.2.1 
Rationale for Dose Selection/Regimen/Modification: Nivolumab 
Refer to the eIB and the nivolumab SmPC or USPI for preclinical and clinical study data. 
 
Nivolumab at a dose of 3 mg/kg has been approved as monotherapy in melanoma and NSCLC 
patients. In the current study, nivolumab will be administered at 240 mg Q2W during the Prime Phase. 
During the Boost Phase, nivolumab will be administered at either 240 mg Q2W or 480mg Q4W 
depending on physician discretion. The choice of the 240 mg Q2W (or 480mg Q4W) as an 
appropriate dose for the switch to fixed dosing is based on simulations performed using the 
population PK model of nivolumab showing that the fixed dose of 240 mg every 2 weeks (and 480mg 
Q4W) will provide exposures that 1) are optimally consistent with those obtained with the 2 mg/kg 
dose every 2 weeks, 2) will maintain individual patient exposures in the exposure range established 
in melanoma as associated with maximal efficacy response and 3) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe 
(Freshwater et al. 2017; Long et al. 2018).  


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A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to 
reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in the logistical 
chain at treatment facilities and reduce wastage. 
4.2.2 
Rationale for Dose Selection/Regimen/Modification: CMP-001 
During the peri-operative period (Prime Phase), CMP-001 5mg will be administered subcutaneously 
for the first dose (week 1). Thereafter, CMP-001 will be administered intra-tumorally at 10mg weekly 
(weeks 2-7). 
During the post-surgical period (Boost Phase), CMP-001 5mg weekly will be administered 
subcutaneously every 4 weeks for up to 54 weeks.  
Upon initial exposure to CMP-001, antibodies against the Q-beta capsid protein are formed. 
Thereafter the FC portion of the antibody bind to the FCR-γ on the pDC. These antibodies are 
necessary to facilitate the binding of the VLP to the FC. After the first dose approximately 100% of 
the subjects exposed to CMP-001 demonstrate the presence of these antibodies. Therefore, to 
maximize the therapeutic potential of CMP-001 and minimize the number of intratumoral injections, 
the first dose of CMP-001 will be administered subcutaneously.  
The rationale for the weekly schedule is primarily based upon the safety and efficacy results from 
the ongoing study in metastatic melanoma noted above. A comparison of the weekly and Q3weekly 
schedule in that study demonstrated a trend towards improved efficacy in the weekly schedule. 
During the initial safety run-in of this study, a variety of doses were explored based on tumor size. 
The rationale for the fixed dose during Prime Phase weeks 2-7 is based on the safety and efficacy 
results from the initial safety run-in that showed no increased incidence of adverse events in patients 
treated with higher doses of CMP-001. 
4.2.3 
Rationale for Combining TLR9 Agonist with an Anti PD-1/PD-L1 Antibody 
Toll-like receptors (TLRs) are part of the innate immune system where they recognize and bind 
conserved pathogen-associated molecular patterns (PAMPs) (Murad and Clay 2009). TLR9 
recognizes unmethylated cytosine guanosine dinucleotides (CpG) oligodinucleotides (ODN); and 
TLR9 agonism activates plasmacytoid dendritic cells (pDC) and B cells, and results in potent T 
helper-1 (Th-1)-type immune and anti-tumor responses in mouse tumor models and in patients with 
human cancer (Fourcade et al. 2008). However, while CpG administration strongly induces tumor-
specific CD8+ T cell responses, objective responses are rare and T cell responses are not sustained 
(Fourcade et al. 2008; Appay, Speiser, et al. 2006; Appay, Jandus, et al. 2006). There are 3 classes 
of CpG ODN: type A which strongly stimulate pDC IFN-α secretion and minimal B cell activation; 
type B which strongly stimulate B cell proliferation/differentiation and NF-κβ activation; and type C 
which stimulate B cell proliferation/differentiation and moderately stimulate pDC IFN-α secretion 
(Krieg 2007). Pre-clinically, intra-tumoral CpG synergizes with anti-PD-1 therapy by promoting 
infiltration of activated TA-specific CD8+ T cells expressing IFN-γ and TNF-α (Wang et al. 2016). In 
patients with advanced melanoma, the combination of type C TLR9 agonist SD-101 and PD-1 
inhibitor pembrolizumab is associated with significant responses with minimal additional toxicity 
(Ribas et al. 2018). 
5 Methodology 
 
5.1 
Entry Criteria 
 
5.1.1 
Diagnosis/Conditions for Study Entry 


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Patients eligible for this study should have locally and/or regionally advanced melanoma that is 
considered potentially surgically resectable and with biopsy-amemable tumor at baseline. 
5.1.2 
Subject Inclusion Criteria 
A patient must meet all of the following criteria to be eligible to participate in this study: 
1. Be willing and able to provide written informed consent for the study. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Diagnosis of histologically or cytologically confirmed diagnosis of cutaneous melanoma 
belonging to one of the following AJCC TNM stages: 
a. Tx or T1-4 and 
b. N1b, or N1c, or N2b, or N2c, or N3b, or N3c and 
c. M0 
Patients are eligible for this trial either at presentation for primary melanoma with concurrent 
regional nodal and/or in-transit metastasis; or at the time of clinical detected nodal and/or in-
transit recurrence; and may belong to any of the following groups: 
• 
Primary cutaneous melanoma with clinically apparent regional lymph node 
metastases. 
• 
Clinically detected recurrent melanoma at the proximal regional lymph node(s) basin. 
• 
Clinically detected primary cutaneous melanoma involving multiple regional nodal 
groups. 
• 
Clinical detected nodal melanoma (if single site) arising from an unknown primary. 
• 
In-transit and/or satellite metastases with or without regional lymph node involved 
permitted if considered potentially surgically resectable at baseline. 
• 
NOTE: Determination of potential resectability must be made at baseline to be 
eligible for this neoadjuvant study. 
• 
NOTE: Patients with mucosal and/or uveal melanoma are not permitted to 
enroll. Patients with melanomas of unknown primary may be enrolled at the 
discretion of the treating investigator in discussion with Principal Investigator. 
 
4. Presence of injectable and measureable disease based on RECIST 1.1. 
 
5. Willing to undergo tumor biopsy (core, punch, incisional or excisional). Patients must undergo 
biopsy (core, punch) or open biopsy (incisional, excisional) within 4 weeks of registration on 
the study. 
 
6. Performance status of 0 or 1 on the ECOG Performance Scale. 
 
7. Demonstrate adequate organ function as defined in Table 5.1.2-1. performed on screening 
labs obtained within 4 weeks of registration. 
 
Table 5.1.2-1: Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC)  
≥1,500 /mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L 
Platelets 
≥100,000 / mcL 
Renal 
Serum creatinine OR  
Measured or calculateda creatinine clearance 
(GFR can also be used in place of creatinine or 
≤1.5 X upper limit of normal (ULN) OR  
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 


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9 
CrCl)  
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with 
total bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN 
Coagulation 
International 
Normalized 
Ratio 
(INR) 
or 
Prothrombin Time (PT)  
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
Activated Partial Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
 
 
8. Female subject of childbearing potential should have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study medication. If the urine test is positive 
or cannot be confirmed as negative, a serum pregnancy test will be required.  
 
9. Female subjects of childbearing potential should be willing to use 2 methods of birth control 
or be surgically sterile, or abstain from heterosexual activity for the course of the study 
through 26 weeks after the last dose of study medication (Section 5.7.2). Subjects of 
childbearing potential are those who have not been surgically sterilized or have not been free 
from menses for > 1 year. 
 
10. Male subjects should agree to use an adequate method of contraception starting with the first 
dose of study therapy through 26 weeks after the last dose of study therapy.  
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 
5.1.3 
Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. History of uveal or mucosal melanoma. 
2. Is currently participating in or has participated in a study of an investigational agent or using 
an investigational device within 4 weeks of the first dose of treatment. 
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered agent. 
- 
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 
- 
Note: If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy. 
- 
Note: Subjects with autoimmune disorders of Grade 4 while on prior immunotherapy 
will be excluded. Subjects who developed autoimmune disorders of Grade ≤ 3 may 


HCC 17-169  
10 
enroll if the disorder has resolved to Grade ≤1 and the subject has been off systemic 
steroids at doses >10 mg/d for at least 2 weeks. 
 
5. Active (i.e., symptomatic or growing) central nervous system (CNS) metastases. 
6. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or 
in situ cervical cancer that has undergone potentially curative therapy. 
7. Has a systemic disease that requires systemic pharmacologic doses of corticosteroids 
greater than 10mg daily prednisone (or equivalent). Subjects who are currently receiving 
steroids at a dose of ≤10mg daily do not need to discontinue steroids prior to enrollment 
Subjects that require topical, ophthalmologic and inhalational steroids would not be excluded 
from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren’s 
syndrome will not be excluded from the study. Subjects who require active 
immunosuppression (greater than steroid dose discussed above) for any reason are 
excluded. 
8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 
 
9. Has an active infection requiring systemic therapy. 
 
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator. 
 
11. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 26 weeks after 
the last dose of trial treatment. 
 
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137. Prior 
treatment with ipilimumab or interferon alfa is allowed. Patients with history of allergic or 
hypersensitivity reaction to interferon alfa or ipilimumab are also excluded. 
 
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected. Patients with treated Hepatitis B/C with no evidence of active 
infection may be enrolled. 
 
 
5.2 
Trial Treatments 
This is a neoadjuvant biotherapy study testing nivolumab with CMP-001 in patients with 
locally/regionally advanced/recurrent melanoma. Subjects will receive combination nivolumab/CMP-
001 for 7 weeks (Prime Phase) prior to surgery. Surgery will be scheduled approximately 2 – 4 weeks 
after completion of Prime Phase depending on recovery. After recovery from surgery subjects will 
receive additional nivolumab/CMP-001 for approximately 46 additional weeks of study drug(s) 


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11 
administration (Boost Phase). The treatment to be used in this trial is outlined below. Trial treatment 
should 
begin 
within 
4 
weeks 
of 
study 
registration. 
 
 
Figure 2: Trial Diagram 
Allocation of study treatment arm: Up to 40 evaluable patients will be enrolled to receive 
nivolumab/CMP-001 combination. 
 
5.2.1 
Nivolumab Dose Selection/Modification 
 
5.2.1.1 
Nivolumab dose selection 
Rationale is provided in Section 4.2.1 – Rationale for Dose Selection/Regimen/Modification: 
Nivolumab. 
5.2.1.2 
Nivolumab dose modification 
Nivolumab will be withheld for drug-related Grade 4 hematologic toxicities, non-hematological toxicity 
≥ Grade 3 including laboratory abnormalities, and severe or life-threatening AEs as per Table 
5.2.1.2-1 below. 
Table 5.2.1.2-1: Dose Modification Guidelines for Drug-related Adverse Events. 


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12 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or 
equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, 
ALT, 
or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) 
or 
Hyperglycemia 
T1DM or 
3-4 
Hold nivolumab and CMP-001 for new 
onset Type 1 diabetes mellitus or Grade 3-
4 hyperglycemia associated with evidence 
of beta cell failure 
Resume nivolumab when patients are clinically and metabolically 
stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with nivolumab and CMP-001 can be 
continued while endocrine replacement 
therapy is instituted 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or 
equivalent per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or 
equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with nivolumab and CMP-001 can 
be continued while thyroid replacement 
therapy is instituted 
Therapy with nivolumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate 
premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or 
equivalent per day within 12 weeks 
Permanently discontinue for recurrent Grade 2 pneumonitis 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or 
equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 
or 
Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. Exceptions may be sought for 
neuropathy or other AE following discussion with Principle 
Investigator. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative 
to baseline and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate   (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be premedicated for the next scheduled dose 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study 
drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks 
of the last dose. 
 
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment 
should be discontinued after consultation with the Sponsor. With investigator and Sponsor 
agreement, subjects with a laboratory adverse event still at Grade 2 after 12 weeks may continue 
treatment in the trial only if asymptomatic and controlled. For information on the management of 
adverse events, see Section 5.6.1. 
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of nivolumab should be discontinued from trial treatment. 


HCC 17-169  
13 
5.2.1.3 
Nivolumab timing of dose administration 
Trial treatment should be administered after all procedures/assessments have been completed as 
detailed on the Trial Flow Chart in Section 6.0. Trial treatment may be administered up to +/- 2 days 
before or after the scheduled Day 1 due to administrative reasons. 
 
All trial treatments will be administered on an outpatient basis. 
 
Nivolumab will be administered as a 30 minute IV infusion (treatment intervals may be increased due 
to toxicity as described). Sites should make every effort to target infusion timing to be as close to 30 
minutes as possible. However, given the variability of infusion pumps from site to site, a window of -
5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
The Procedures Manual contains specific instructions for nivolumab dose calculation, reconstitution, 
preparation 
of 
the 
infusion 
fluid, 
and 
administration. 
 
5.2.1.4 
Nivolumab duration of administration 
During the Prime Phase (Weeks 1-7), nivolumab 240mg will be administered every 2 weeks (W2D1, 
W4D1, 
W6D1). 
During 
this 
period, 
missed 
doses 
will 
not 
be 
made 
up. 
 
During the Boost Phase (Weeks 12-56), nivolumab will be administered at either 240mg every 2 
weeks or 480mg every 4 weeks. 12 doses (if Q4W) or 23 doses (if Q2W) of nivolumab will be 
administered over this period. During this period, missed doses will be made up. The choice of Q2W 
versus Q4W administration of nivolumab will be physician dependent.  
5.2.2 
CMP-001 Dose Selection/Modification 
During the Prime Phase, the first dose of CMP-001 (week 1) is fixed at 5mg subcutaneously. 
Subsequent doses of CMP-001 administered during the Prime Phase (weeks 2-7) will be at 10mg 
administered intra-tumorally. Should patients develop side effects, intra-tumoral doses during this 
period of the Prime Phase (weeks 2-7) may be reduced (see Table 5.2.2.3-1). 
Following resection, during the Boost Phase, the CMP-001 dose is fixed at 5mg injected 
subcutaneously at the site of the resected tumor. 
Rationale for dose selection is provided in Section 4.2.2 – Rationale for Dose 
Selection/Regimen/Modification: CMP-001. 
5.2.2.1 
Recommended prophylaxis 
To reduce the severity of symptoms associated with CMP-001 induced cytokines, prophylaxis is 
strongly recommended. Prophylactic regimens already in place at institutions should be followed, if 
not, below is a suggested regimen that has been effective for the treatment of CMP-001 induced 
adverse events: 
• 
Fluids (e.g. 1000 cc IV normal saline) 
• 
NSAIDS (e.g. 1000 mg acetaminophen and 50 mg Indomethacin) 
• 
Anti-emetics (e.g.8 mg Zofran PO) 
• 
Hydrocortisone prophylaxis (50-100mg hydrocortisone – only for patients with prior G2-3 
CRS-like reaction) 
 


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14 
If an Investigator incorporates prophylaxis, administration should occur 30 minutes prior to intra-
tumoral injection of CMP-001. It is also highly recommended to continue to run additional fluids 
immediately following the CMP-001 injection, rather than waiting to initiate fluids when hypotension 
is detected. There is no waiting period between the end of prophylaxis and the start of CMP-001 
intra-tumoral injection. All treatments given prophylactically pre-and post CMP-001 dosing should be 
recorded on the Prior and Concomitant Medications eCRF separately for each visit where it is given. 
 
IMPORTANT: Subjects with a history of adrenal insufficiency are at increased risk for moderate to 
severe adverse events such as hypotension which may occur with 1-4 hours after injection. It is 
strongly recommended that these subjects receive stress dose steroids (eg. 50-100 mg 
hydrocortisone PO q 8 hours) prior to, or immediately after injection of CMP-001. 
5.2.2.2 
Timing of CMP-001 and nivolumab dosing 
Initial study dose of nivolumab must be within 1 week of W1D1 (i.e., first CMP-001 injection). When 
CMP-001 and nivolumab dosing fall on the same day, it is recommended that CMP-001 dosing 
precede nivolumab dosing. There is no specified waiting period between the end of CMP-001 
administration and the initiation of nivolumab infusion. When a study visit occurs where only 
nivolumab is given, pre-infusion vital signs should be collected and recorded on the eCRF. 
5.2.2.3 
Guidance of CMP-001 Injection 
Intra-tumoral injections 
Tumors selected for CMP-001 intra-tumoral injection should be at least 0.5cm in diameter and may 
be cutaneous, subcutaneous, and/or nodal tumors that are visible, palpable, or detectable 
by ultrasound guidance. Patients with visceral tumors are not candidates for this study. Patient 
candidates for CMP-001 injection may have more than one accessible tumor as a candidate for intra-
tumoral injection. 
• 
If 1 accessible tumor is present: 
o This should be selected as a candidate for intra-tumoral injection.  
o CMP-001 dose selection is outlined as in Table 5.2.2.3-1.  
o Total CMP-001 dose administered should not exceed 10mg/day. 
• 
If >1 accessible tumors are present:  
o 1 or more accessible lesions can be injected (preferably all). 
o CMP-001 dose selection is outlined as in Table 5.2.2.3-1.  
o CMP-001 dose may be split at the discretion of the treating investigator (or designee). 
o Total CMP-001 dose administered across all tumors should not exceed 10mg/day. 
 
Table 5.2.2.3-1: CMP-001 Injection Volume Guidelines Based on Tumor Size (Doses 2-6 in 
Prime Phase) 
Dose 
Level 
CMP-001 Dose (6mg/mL 
concentration) 
Total Volume 
Injected 
1 
10mg 
~2.0 mL 
-1 
7.5mg 
~1.5 mL 
-2 
5mg 
~1.0 mL 
-3 
2.5mg 
~0.5 mL 
 
 
Subcutaneous injections 
CMP-001 should be injected using aseptic technique. Use of topical and/or local anesthetic is 
permitted. The injection may be given into any SC site in the body. 


HCC 17-169  
15 
• 
Preferred Sites for Subcutaneous Injection 
o In principle, the injection may be given into any SC site in the body. Unsuitable sites 
for injection would include, for example, the palm of the hand or the sole of the foot.  
o The injection site should be within the area of lymphatic drainage associated with a 
site of metastatic disease or primary disease. For example, in a patient with a muscle 
or bone metastasis in the lower leg, the preferred SC injection site would be in the 
same leg, with the expectation that at least some of the CMP-001 will drain to lymph 
nodes that also contain tumor antigens. Likewise, in a patient with metastases in an 
upper lobe of the lung, a preferred SC injection site would be in the ipsilateral 
supraclavicular fossa, where the injection may activate pDC in the supraclavicular 
lymph nodes that also can drain the upper lung. 
• 
Method of CMP-001 Subcutaneous Administration 
o Using standard aseptic technique, the needle is inserted into the subcutaneous 
tissue. After using gentle backward pressure on the syringe plunger to confirm 
extravascular location of the needle tip, the desired volume of CMP-001 is injected 
and the needle is withdrawn. 
At Screening, the selected tumor(s) should be large enough to allow intratumoral injection of 
the intended volume of CMP-001 (Table 5.2.2.3-1). Initial administration of CMP-001 (W1D1) will be 
subcutaneous to allow for development of antibodies to the virus like particle which is necessary for 
uptake of CMP into the dendritic cell. Subsequent administrations of CMP-001 during the prime 
phase will be intra-tumoral. The same tumor(s) should be injected each week during therapy, if 
possible, except as outlined below to involuting tumors. 
If the full volume cannot be injected within the tumor, then the remaining drug volume should 
be injected into a second accessible tumor, if present. If the full volume still cannot be 
administered into the tumor, peri-tumoral injection of any remaining volume is acceptable. 
 
Following surgical resection, during the post-operative boost phase, CMP-001 will be administered 
subcutaneously 
at 
the 
resection 
site. 
 
5.2.2.4 
CMP-001 Dose Modification 
CMP-001 will be dose-reduced in patients who develop CMP-001 related DLT and resume study 
therapy with Nivolumab/CMP-001 combination if Investigator determines that continued treatment 
with CMP-001 is in the subject’s best interest. In this event, CMP-001 will be dose reduced as in 
Table 5.2.2.3-1. 
CMP-001 will be withheld for CMP-001 related Grade 4 hematologic toxicities, non-hematological 
toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-threatening AEs.  
If CMP-001 is permanently discontinued for, subjects may continue to receive Nivolumab. 
5.2.2.5 
Method of CMP-001 Administration 
Topical or local anesthesia may be given as appropriate in the Investigators’ judgment. Using 
standard aseptic technique, the needle is inserted near the tumor periphery and is advanced into the 
tumor to the desired depth (usually to the needle hub, if the tumor size permits) while maintaining 


HCC 17-169  
16 
gentle backward pressure on the syringe plunger to confirm extravascular location of the needle tip. 
The syringe and needle are then slowly withdrawn to within a few millimeters of the skin or tumor 
surface while maintaining gentle downward pressure on the plunger to inject the desired volume of 
CMP-001 along the needle track (Figure 3, middle panel). With the tip of the needle still within the 
skin, the syringe is then rotated by ~20-40o and the process of insertion and injection during needle 
withdrawal is repeated (Figure 3, right panel). Using this process, CMP-001 is injected along 
multiple tracks through a single insertion point as far as the radial reach of the needle allows within 
the tumor; two insertion points can be used if the tumor is larger than the radial reach of the needle 
and the intended CMP-001 volume cannot be delivered from 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 peri-tumorally, around the same lesion.  
 
 
 
Essentially the same process is performed for cutaneous, subcutaneous, and nodal injections, but 
for deeper injections, the tip of the needle may be kept within the tumor and a longer needle may be 
used. 
5.2.2.6 
Observation periods 
During the Prime Phase, subjects must be observed for a period of at least four hours following each 
of the first three CMP-001 injections (W1D1, W2D1, W3D1) for signs and symptoms of reactions to 
the injection and other adverse events. Beginning with the fourth CMP-001 injection (W4D1) the 
observation period may be reduced to 1 hour following CMP-001 injection or per the discretion of the 
Investigator and agreement by Sponsor. 
 
During the Boost Phase, subjects must be observed for a minimum of 1 hour following each CMP-
001 injection for signs and symptoms of reactions to the injection and other adverse events. 
Observation periods longer than 1 hour during the Boost Phase should be based on the adverse 
event profile of the individual subject and be performed at the discretion of the Investigator. 
 
5.2.2.7 
Management of CMP-001 toxicity 
CMP-001 Associated Adverse Events 
If subjects develop inflammation at the injection site this may be managed using cold compresses 
and/or acetaminophen or non-steroidal anti-inflammatory agents. If flu-like symptoms (i.e., fever, 
myalgia, and headache) arise, these may be managed using acetaminophen or non-steroidal anti-
inflammatory agents.  
Figure 3: Method for CMP-001 Intra-Tumoral Injection 


HCC 17-169  
17 
It is expected that symptoms associated with a large release in cytokines at the time of injection 
could present 1-4 hours after the injection. These symptoms could include: fever, nausea/vomiting, 
chills/rigors, and hypotension. Subjects must remain in observation until all of these symptoms have 
resolved to ≤ Grade 1. Refer to Table 4.1.4-1 for current CMP-001 safety profile in the ongoing CMP-
001-001 clinical study. 
Subjects who experience a DLT will have dosing of CMP-001 withheld until the toxicity has returned 
to ≤ Grade 1. If the Investigator determines that continued treatment with CMP-001 is in the subject’s 
best interest, treatment may resume at a reduced dose of CMP-001. Only one dose reduction is 
allowed. Subjects who still experiences DLTs at Dose Level-1 must come off study. 
CMP-001 Associated Cytokine Release-like Syndrome 
As noted in Section 4.2.2, CMP-001 has been associated with symptoms associated with cytokine 
release. Most notable severe cases of hypotension have been noted, most often in subjects with a 
prior medical history of adrenal insufficiency secondary to ipilimumab. The backbone of the 
recommended treatment algorithm is the use of stress dose steroids and the IL6 antagonist 
tocilizumab (Maude et al. 2014; Lee et al. 2014; Tanaka et al. 2016; Brudno and Kochenderfer 2018). 
The recommended algorithm for the treatment of symptoms associated with cytokine release below 
has been adapted for the treatment of cytokine release syndrome resulting from other 
immunotherapies such as CAR-T cell therapy (Lee et al. 2014) and is depicted in Figure 4. However, 
its effectiveness in treating symptoms associated with cytokine release resulting from CMP-001 has 
not been previously studied. The first line of treatment for hypotension unresponsive to supportive 
care such as fluids, is stress dose steroids as outlined below.  Additional treatment measures include 
the use of drugs targeting specific cytokines believed to be involved in the development of cytokine 
release syndrome-induced hypotension. It is recommended that the treatment algorithm be 
implemented in subjects who present with acute hypotension following injection of CMP-001. 
 
Figure 4: Management of CMP-001 Associated Cytokine Release-like Syndrome 


HCC 17-169  
18 
 
5.2.2.8 
Changing the selected tumor 
Therapy of a selected lesion generally should continue per protocol unless the tumor is EITHER 
dramatically responding clinically OR dramatically progressing clinically. Inflammation of the injected 
tumor is expected following the 2nd and subsequent injections, but should not be mistaken for anti-
tumor response or clinical progression. 
 
If during therapy the injected tumor is clearly involuting and shrinking, and if a different eligible 
accessible tumor is progressing, then the Investigator should change the selection to the progressing 
tumor, injecting the full dose of CMP-001 into that tumor(s), and continuing to inject the new tumor(s) 
until EOT (or that tumor shows involution, in which case a third progressing tumor may be 
selected). If during therapy the injected tumor is clearly involuting and shrinking, and no other lesions 
are present, CMP-001 may be omitted or injected subcutaneously at the discretion of the treating 
investigator 
in 
consultation 
with 
the 
Principle 
Investigator. 
 
If during therapy the injected tumor progresses, the treating investigator in consultation with the 
Principle Investigator may elect to continue therapy or transition to surgery directly. Every effort 
should be made to complete 7 weeks of perioperative therapy. The decision to proceed with surgery 
should be made (in consultation with the initial evaluating surgical oncologist) only if there is a danger 
of the subject being rendered inoperable. 
 
5.3 
Treatment Allocation 
During the Prime Phase, patients will receive nivolumab 240mg every 2 weeks in combination with 
CMP-001 5mg (week 1), and CMP-001 10mg intra-tumorally (weeks 2-7). Subsequently patients will 
undergo surgical resection.  
 
During the Boost Phase, patients will receive nivolumab either 240mg every 2 weeks (or 480mg 
every 4 weeks) at Investigator’s discretion along with CMP-001 5mg every 4 weeks. 
 
5.4 
Stratification 
None. 
5.5 
Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing trial. If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be 
required. The investigator should discuss any questions regarding this with the principal investigator. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or the 
subject's primary physician. However, the decision to continue the subject on trial therapy or 
vaccination schedule requires the mutual agreement of the treating physician investigator, the 
principal investigator, and the subject.  
 
5.5.1 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care. All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, 
over-the-counter (OTC), herbal supplements, and IV medications and fluids. If changes occur during 


HCC 17-169  
19 
the trial period, documentation of drug dosage, frequency, route, and date may also be included on 
the CRF.  
  
All concomitant medications received within 28 days before the first dose of trial treatment and 30 
days after the last dose of trial treatment should be recorded. Concomitant medications administered 
after 30 days after the last dose of trial treatment should be recorded for SAEs and ECIs as defined 
in Section 7.2.  
 
5.5.2 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial:  
• 
Anti-cancer systemic chemotherapy or biological therapy  
• 
Immunotherapy not specified in this protocol  
• 
Chemotherapy not specified in this protocol  
• 
Investigational agents other than CMP-001 
• 
Radiation therapy  
 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. 
Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however intranasal influenza vaccines 
(e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed.  
 
Glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest 
of suspected immunologic etiology. The use of physiologic doses of corticosteroids may be approved 
after consultation with the Principle Investigator.  
 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial. Subjects may receive other 
medications that the investigator deems to be medically necessary.  
 
The Exclusion Criteria describes other medications which are prohibited in this trial.  
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase.  
 
Agents known to have TLR9 antagonist activity are prohibited throughout the study. The known 
antagonists are chloroquine, hydroxychloroquine, and quinacrine. 
 
Medications intended solely for supportive care (i.e., antiemetics, analgesics, megestrol acetate for 
anorexia) are allowed. 
 
5.6 
Rescue Medications and Supportive Care 
 
5.6.1 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below. Where appropriate, these guidelines include the 
use of oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory 
agents if symptoms do not improve with administration of corticosteroids.   Note that several courses 
of steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. 


HCC 17-169  
20 
For each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment guidelines 
are intended to be applied when the investigator determines the events to be related to nivolumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does not need 
to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
• 
Pneumonitis 
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer additional 
anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
• 
Diarrhea/Colitis 
o Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion.  For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose 
oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
▪ 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
▪ 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
• 
Hypophysitis 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 


HCC 17-169  
21 
• 
Hyperthyroidism or Hypothyroidism 
o Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
▪ 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
▪ 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
▪ 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate hormones may be required 
as the steroid dose is tapered. 
• 
Hepatic 
o For Grade 2 events, monitor liver function tests more frequently until returned to baseline 
values (consider weekly). 
▪ 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Nephritis 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
• 
Management of infusion reactions 
• 
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion.  
Table 5.6.1-1 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of nivolumab. 
Table 5.6.1-1: Infusion Reaction Management Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication 
at 
Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
nivolumab with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 


HCC 17-169  
22 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued 
from 
further 
trial 
treatment 
administration. 
Acetaminophen 500-1000 mg po (or 
equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged 
(i.e., 
not 
rapidly 
responsive 
to 
symptomatic 
medication 
and/or 
brief 
interruption 
of 
infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated 
for 
other 
clinical 
sequelae (e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; 
pressor 
or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of 
drug administration 
 
5.7 
Subject Withdrawal/Discontinuation Criteria 
Subjects are free to 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 may discontinue study 
medication for any of the following conditions: 
• 
Dose-limiting or other unacceptable toxicity considered to be related to either study 
medication; 
o Patients who develop unacceptable toxicity deemed related to CMP-001 but not 
Nivolumab may continue Nivolumab after CMP-001 discontinuation for duration as 
defined in Section 5.2.2.4. 
o Patients who develop unacceptable toxicity deemed related to Nivolumab but not 
CMP-001 must discontinue both CMP-001 and Nivolumab. 
• 
PD by RECIST (Version 1.1) if accompanied by medically significant clinical deterioration, in 
the judgment of the Investigator. (Continuation of treatment through suspected pseudo-
progression is permitted.); 
• 
If, in the opinion of the Investigator, it is medically necessary; 
• 
Subject withdraws consent for the study (note that subjects who withdraw consent 
for additional study treatment and procedures will continue to be followed for long-term 
• 
survival unless they explicitly withdraw consent for any follow-up); 
• 
Subject develops an intercurrent illness or adverse event that precludes further participation, 
or requires a prohibited concomitant treatment; 
• 
Subject becomes pregnant or begins breastfeeding; 


HCC 17-169  
23 
• 
Subject is lost to follow-up. 
 
Subjects discontinuing study medication earlier than planned or withdrawing from the study should 
undergo the subsequent End of Treatment (EOT) clinical and laboratory assessments as soon as 
possible after study medication is stopped and the requisite safety follow-up period of 30 days should 
also be followed. The reason for withdrawal will be recorded in the electronic case report form 
(eCRF) and the subject’s source medical record. All subjects will continue to be followed every three 
months after the last CMP-001 treatment for long-term survival follow-up until death, loss to follow-
up, or withdrawal of consent for follow-up. 
 
5.8 
Subject Replacement Strategy 
Subjects who receive at least 1 dose of CMP-001 and nivolumab are evaluable for safety. Patients 
who complete pre-operative therapy and receive surgery will be evaluable for pathologic response 
rate and other efficacy endpoints. Patients who did not undergo surgery for reasons of disease 
progression precluding surgery (rapid disease progression) will be deemed non-evaluable. Non-
evaluable subjects may be replaced. 
If in the opinion of the treating investigator and treating surgical oncologist in consultation with 
Principle Investigator, subject’s disease is rapidly progressing to the point that window to intervene 
surgically is narrowing, treatment may be discontinued to permit surgery. These patients are 
evaluable for pathological response rate and other efficacy endpoints. These patients are eligible to 
receive CMP-001/nivolumab during “Boost” phase. 
5.9 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below:  
• 
Quality or quantity of data recording is inaccurate or incomplete  
• 
Poor adherence to protocol and regulatory requirements 
• 
Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects  
• 
Plans to modify or discontinue the development of the study drugs. In the event of CheckMate 
decision to no longer supply study drug, ample notification will be provided so that appropriate 
adjustments to subject treatment can be made.  
 
5.10 Surgical Considerations 
The team members will make every effort to comply with the surgical procedures within the time 
windows allowed in this study protocol. However, under certain circumstances and as discussed 
between the sub-investigator(s) and the principal investigator, an alteration in the surgical 
schedule/timing is allowed. These include (but are not limited to) the following: 
• 
A 4 week window between the baseline biopsy and the first dose of nivolumab is allowed.  
• 
The definitive surgery may be a lymphadenectomy or resection of lymphatic metastases as 
clinically indicated. The definitive surgery may be divided into more than one surgical 
procedure, scheduled at different time points as clinically/surgically indicated. Under certain 
circumstances, the definitive surgery may be done after completion of additional therapy 
(e.g., after the forth dose of nivolumab) or earlier if nivolumab was discontinued due to 
adverse events or other reasons. Tissue from any of these surgical procedures may be 
banked under this protocol following the same protocol procedures for tissue handling and 
banking. The tissue for banking may be digested, frozen or handled in another alternative 
method as discussed with the investigator. 


HCC 17-169  
24 
• 
If for some reason, the baseline biopsy or definitive surgery could not be completed due to 
un-anticipated factors such as patient refusal, this will be documented.  
 
NOTE: The surgical guidelines are general and may be followed or modified at the discretion of the 
expert surgical oncologist on the case as clinically indicated and depending on the specifics of the 
individual surgical case.  
 
For the baseline biopsy required on this study, patients will undergo a core needle, punch biopsy, 
open surgical biopsy, or other technique at the discretion of the sub-investigator/investigator. The 
choice of specific surgical technique will be at the discretion of the surgeon or medical oncologist 
and actual techniques will be the same as those used as therapeutically or diagnostically indicated 
to surgically treat or confirm the clinical suspicion of recurrent or metastatic disease in any patient 
undergoing conventional evaluation and treatment (standard of care) within 21 days (preferred; and 
up 
to 
4 
weeks) 
prior 
to 
entry 
to 
the 
study.  
 
5.10.1 Primary Excision or Primary Cutaneous Melanoma 
All patients with initial presentation of melanoma T1-4 will be treated by wide excision of the primary. 
Definitive surgery will include wide excision of the primary and sentinel lymph node assessment. For 
patients with known primary cutaneous melanoma lesion and no history of wide local excision of that 
primary lesion, an adequate wide excision of the primary lesion (minimum margin 1 cm) is 
recommended. The wide local excision will be done at the time of complete lymphadenectomy. 
Patients with nodal relapse after an inadequate primary excision will undergo wide excision at the 
time of complete lymphadenectomy. The recommendation for adequate wide excision is the same 
for patients enrolled at the time of lymph node recurrence as for those enrolled at the time of initial 
treatment of the primary. For lesions whose Breslow's thickness is > 1 mm, a 2 cm minimum margin 
is preferred when anatomically feasible (i.e., for lesions of the trunk and proximal extremities). For 
subungual melanoma, a distal interphalangeal amputation with histologically negative margins 
constitutes an adequate wide excision. The specimen shall be excised to include skin and all 
subcutaneous tissue down to the muscular fascia. Fascia may be included at the discretion of the 
operating surgeon. Closure of the defect may be via primary closure, split thickness skin graft, or 
rotation-flap 
at 
the 
discretion 
of 
the 
surgeon. 
 
5.10.2 Regional Lymphadenectomy 
Note: For patients undergoing sentinel node mapping and lymphoscintigraphic and dye 
lymphographic identification of regional nodal drainage, the minimum number of nodes may be less 
than the mandatory minimum numbers of 5/groin, 10/axilla, and 15/cervical node dissection. 
 
All patients should undergo one of the following staging lymphadenectomies, as found surgically 
applicable by the treating surgical oncologist. 
 
5.10.2.1 Head and neck lesions 
Face, ear and anterior scalp: Modified radical neck or radical neck dissection. Parotidectomy to be 
included if lymphoscintogram indicates flow to the area.  
 
Submandibular and anterior neck: Modified radical or radical neck dissection. 
 
Posterior scalp, posterior neck and uppermost trunk (areas that drain to posterior cervical triangle): 
Modified posterior triangle neck dissection with suboccipital nodes. 
 


HCC 17-169  
25 
At all times, the number of  
 
5.10.2.2 Upper extremity 
Axillary node dissection to include at least 10 nodes taken from levels I and II. Level III nodes should 
be dissected if they are clinically involved. The pectoralis minor muscle may be divided or sacrificed 
at the surgeon's discretion. 
5.10.2.3 Lower extremity 
Superficial inguinal node dissection or deep inguinal node dissection will be performed at the 
discretion of the surgeon. Inguinal node dissection to include at least 5 nodes. 
5.10.3 Lymphadenectomy for Nodal Recurrence 
Regional node recurrences will be treated using the appropriate lymphadenectomy procedure. 
Whenever possible, diagnosis of regional node recurrence will be made using punch or open biopsy 
technique (if done as part of a clinically indicated baseline diagnostic procedure) to provide baseline 
pathologic material needed for evaluation of treatment effect. At the time of the definitive 
lymphadenectomy, the biopsy site will be included in the operative specimen. 
 
6 Trial Flow Chart 
The Investigator/Sub-Investigators are expected to make every reasonable effort to comply with the 
study calendar. However, if a treatment is missed or a subject's study treatment and/or testing days 
need to be rescheduled due to the subject’s inability to comply with the study calendar (i.e., 
hospitalizations, business and vacation travel plans, illness, transportation issues, holidays, family 
emergencies, etc.), a window of ± one week is available for rescheduling of study treatment and 
procedures per the discretion of the Sub- Investigator, and as discussed with the Investigator. For 
the baseline biopsy, a 4 week window is allowed before the first dose of nivolumab and/or CMP-001. 
 


HCC 17-169  
26 
6.1 Study Flow Chart 
Procedure/ 
Assessment 
Screening 
(Day -28 to 
-1)A 
Prime Phase (Weeks 1-7) 
Surgery 
Boost 
Phase 
(Weeks 12-
56) 
End of 
Treat
mentB 
30 Day 
Follow-
UpO 
 
 
Post-
treatm
ent 
surveill
anceN 
W1 
D1 
W2 
D1 
W3 
D1 
W4 
D1 
W5 
D1 
W6 
D1 
W7 
D1 
W7 D2 
W8-W10 
Every 
4 
weeksD 
starting 
3 
weeks after 
surgery 
Visit Windows 
 
+/- 2 days 
+/- 5 days 
 
+/- 3 days 
+/- 
7 
days 
+/- 
7 
days 
+/- 
14 
days 
CMP-001 
dose 
numberC 
N/A 
1 
2 
3 
4 
5 
6 
7 
N/A 
N/A 
1-12 
(12 
doses) 
 
 
 
Nivolumab 
dose 
numberD 
N/A 
 
1 
 
2 
 
3 
 
N/A 
N/A 
D1-23 
(23 
doses – if q2) 
D1-12 
(12 
doses – if q4) 
 
 
 
Tumor BiopsyE 
X 
 
 
 
 
 
 
 
 
 
 
XB 
 
 
Planned 
Surgical 
Evaluation 
and 
ResectionF 
X 
(evaluation) 
 
 
 
 
 
 
 
X 
(evaluation) 
X 
(resection) 
 
 
 
 
Exploratory 
Biomarker 
AnalysesG 
 
X 
 
X 
 
 
 
X 
 
 
X (every 8 
weeks 
starting with 
Week 12) 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Criteria 
Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History, 
Demographics, 
Cancer 
History 
including 
Prior 
Cancer 
Medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical ExamH 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Electrocardiogram 
(ECG)I 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
Autoimmune 
lab 
panelJ 
X 
 
 
 
 
 
 
 
 
 
 
X  
 
 


HCC 17-169  
27 
Clinical laboratory 
tests (hematology, 
serum 
chemistry, 
other 
chemistry, 
urinalysis, 
coagulation 
tests 
and 
thyroid 
function)J 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
(CBC, 
CMP, 
LDH 
only) 
X 
(CBC, 
CMP, 
LDH 
only) 
Urine 
Pregnancy 
TestK 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease 
Assessment 
(CT/MRI)L 
X 
 
 
 
 
 
 
 
X 
 
X (every 8 
weeks 
starting with 
Week 20) 
 
 
 
Stool samplingM 
X 
 
 
X  
 
 
 
X  
 
 
X (every 8 
weeks 
starting with 
Week 12) 
 
 
 
Dietary 
history 
questionnaireN 
X 
 
 
X 
 
 
 
X 
 
 
X (every 8 
weeks 
starting with 
Week 12) 
 
 
 
Adverse 
Event 
Monitoring 
Assessed continually from informed consent through EOT + 30 days 
 
Concomitant 
Medications 
Assessed continually from first CMP-001 dose through EOT + 30 days 
 
30 Day Follow UpO 
 
X 
 
 
 
 


HCC 17-169  
28 
Study Calendar Notes: 
A≤4 weeks prior to first dose; magnetic resonance imaging (MRI)/computed tomography (CT) scans may be performed ≤4 weeks prior to first CMP-001 dose. 
• 
During Screening, MRI brain with contrast (or CT equivalent) should be performed to exclude CNS metastatic disease. CNS imaging need not be repeated on 
study unless patient is symptomatic. 
BEnd-of-treatment (EOT) assessments to be performed within 7 days following removal of subject from CMP-001 treatment. Removal of a subject from CMP-001 treatment 
is defined as the time in which the Investigator decides to discontinue CMP-001 treatment for a subject. 
• 
Management of patients who develop unacceptable toxicity is defined in Section 5.6. 
o 
Patients who develop unacceptable toxicity deemed related to CMP-001 but not Nivolumab may continue Nivolumab after CMP-001 discontinuation for 
duration as defined in Section 5.2.2.4. 
o 
Patients who develop unacceptable toxicity deemed related to Nivolumab but not CMP-001 must discontinue both CMP-001 and Nivolumab. 
• 
Patients who progress will undergo an optional biopsy to confirm progression at the time of RECIST v1.1 confirmed progression. This biopsy should be done 
within 14 days of RECIST v1.1 confirmed progression determination. 
CCMP-001 is dosed weekly during the Prime Phase and q4 weekly during the Boost Phase of this study. 
• 
Vital sign monitoring.  
o 
Weeks 1-3 (Prime Phase): vital signs are to be collected within 15 minutes prior to CMP-001 injection, and at 30 (±15) minute intervals for 4 hours 
following each of the first three CMP-001 injections. 
o 
Weeks 4-7 (Prime Phase): vital signs are to be collected within 15 minutes prior to CMP-001 injection, and at 30 (±15) minute intervals for 1 hour 
following each of the first three CMP-001 injections. 
o 
Boost Phase (all doses): vital signs are to be collected within 15 minutes prior to CMP-001 injection, and at 30 (±15) minute intervals for 1 hour following 
each of the first three CMP-001 injections. 
DNivolumab dosing schedule is q2 weekly during the Prime Phase and either q2 weekly or q4 weekly during the Boost. 
• 
During the Boost Phase of this study, Nivolumab can be dosed q2 or q4 weekly at the discretion of the treating investigator. 
• 
If Nivolumab is dosed at q2 weeks during Boost phase, the patient will receive 23 doses of Nivolumab (doses 1-23; weeks 12-56). 
• 
If Nivolumab is dosed at q4 weeks during Boost phase, the patient will receive 12 doses of Nivolumab (doses 1-12; weeks 12-56). 
ETumor biopsy must be performed prior to commencing CMP-001/nivolumab treatment. Tumor biopsy must be of lesion that is planned for resection. Punch, core (>4 
18gauge) and/or surgical biopsies are acceptable. 
• 
If core biopsy is performed, pathology confirmation is required to ensure adequate tissue is obtained. 
FAssessment of planned resectability must be made DURING screening. Planned surgery after Prime Phase must be with surgeon who initially made determination of 
planned resectability. 
• 
Extent of surgery to follow guidelines based on location of involved lymph node as delineated in Section 5.10. 
GExploratory biomarker blood samples are to be collected at the following times: 
• 
Prior to administration of the 1st, 3rd, and 7th CMP-001 doses (W1D1, W3D1, W7D1) respectively. 
• 
Every 8 weeks prior to administration of nivolumab following surgery starting with Week 12. 
HA full physical exam will be conducted at screening, each treatment visit and EOT.  
• 
Screening physical exam may be performed up to 72 hours prior to the Week 1 Day 1 visit. If the full physical exam is performed >72 hours prior to the Week 1 
Day 1 (W1D1) visit, then a brief (symptom directed) physical exam must be performed within 72 hours prior to initiation of CMP-001.  
• 
Brief physical exams focused on areas of disease or adverse events are performed at the 1st, 3rd, 5th and 7th CMP-001 doses at W1D1, W3D1, W5D1, W7D1 
and at any other time as clinically indicated. 
• 
Both full and brief physical exams should include assessment of ECOG performance status. 
• 
Full physical exams should include height and weight. 
IElectrocardiograms (ECGs) should be obtained at Screening and prior to administration of CMP-001 at the 1st, 3rd, and 7th CMP-001 dosing visits (on W1D1, W3D1, 
and W7D1. 
• 
ECG testing is not required during Boost Phase 
JClinical laboratory tests may be performed up to 72 hours prior to administration of CMP-001. 
• 
Laboratory tests to be obtained are delineated in Table 7.1.5.1-1. 


HCC 17-169  
29 
• 
Autoimmune lab panel to be collected at Screening and EOT only. 
KPregnancy testing should be performed in women of childbearing potential and at Screening only. 
• 
This should be done within 7 days prior to receiving the first dose of study drug).  
• 
Any method (urine pregnancy test; serum β-human chorionic gonadotropin) can be utilized for this purpose.  
LCT or MRI scans to assess tumor status will be obtained at Screening (baseline value should be performed ≤4 weeks prior to first CMP-001 dose). 
• 
Screening:  
o 
Scans should be performed ≤4 weeks prior to first CMP-001 dose). 
• 
Prime Phase: 
o 
CT (or PET/CT) scans should be repeated prior to surgery (+/- 2 week window). 
• 
During Boost Phase, CT or MRI scans will be repeated every 8 weeks starting with week 20 (or after 2 doses of CMP-001 administered during the Boost Phase whichever 
is sooner). 
o 
If Nivolumab is dosed at q2 weeks during Boost phase, 1st restaging scan will occur after 4 doses of nivolumab at Week 20 and be repeated q8 weeks. 
o 
If Nivolumab is dosed at q4 weeks during Boost phase, 1st restaging scan will occur after 2 doses of nivolumab at Week 20 and be repeated q8 weeks. 
MStool sampling will be performed at Screening and at W3D1 and W7D1 during Prime Phase. During Boost Phase, these will be repeated every 8 weeks starting Week 
12. 
NDietary history questionnaire will be performed concordantly with stool sampling at Screening and at W3D1 and W7D1 during Prime Phase. During Boost Phase, these 
will 
be 
repeated 
every 
4 
weeks 
starting 
with 
Week 
12. 
Dietary 
questionnaire 
is 
detailed 
in 
Appendix 
1. 
O30 day follow up 
o 
This begins +30 days following completion of Cycle 12 Boost Phase. 
o 
Procedures to be followed during this phase are outlined in Section 7.1.7.3 and will include a visit, bs (CBC, CMP, LDH, TSH, free T4) and any other 
studied deemed necessary at the discretion of the treating physicians and according to established Standard of Care. 
NPost-treatment surveillance (for patients that have completed treatment or removed due to toxicity): 
• 
This phase begins upon completion of 30 day follow up for patients who have completed treatment or come off study due to toxicity. 
• 
Procedures to be followed during this phase are outlined in Section 7.1.7.2 and will include imaging (CT or PET/CT), labs (CBC, CMP, LDH, TSH, free T4) and 
any other studied deemed necessary at the discretion of the treating physicians and according to established Standard of Care. 
 


HCC 17-169  
30 
 
7 Trial Procedures 
 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each visit. 
Individual trial procedures are described in detail below. It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator.  
 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
CheckMate for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require 
that additional informed consent be obtained from the subject. In these cases, such 
evaluations/testing 
will 
be 
performed 
in 
accordance 
with 
those 
regulations.  
 
7.1.1 
Treatment period 
The study consists of 3 main phases: 
• 
Prime Phase (Weeks 1-7):  
o Nivolumab (240 mg) I.V. infusion every 2 weeks for 3 doses (starting 2nd week of 
CMP-001 administration – W2D1) given concurrently with CMP-001.  
o CMP-001 will be administered subcutaneously (week 1), then intra-tumorally (weeks 
2-7) on a weekly schedule.  
• 
Definitive Surgery: Follows completion of prime phase. 
• 
Boost Phase (following recovery from surgery) (Weeks 12-56):  
o Nivolumab (240 mg I.V. infusion every 2 weeks; or 480 mg I.V infusion every 4 weeks) 
given concurrently with CMP-001 5mg every 4 weeks.  
o CMP-001 will be administered subcutaneously (peri-tumoral resection site).  
o Total of 12 doses of CMP-001 will be administered.  
o Total of 46 weeks of Nivolumab will be administered (every 2 weeks - 23 doses; every 
4 weeks – 12 doses). 
 
7.1.2 
Administrative Procedures 
Informed consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of the 
person conducting the consent discussion prior to enrollment. 
During initial enrollment visit, study investigator (or designee) must discuss the following with 
patients: 
• 
Inclusion and exclusion criteria 
• 
Medical history – pertinently any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator. 
• 
Prior and concomitant medications. All medications related to reportable SAEs and ECIs 
should be recorded as defined in Section 7.2. 
• 
Disease details and treatments. 
 
7.1.3 
Clinical Procedures/Assessments 
7.1.3.1 
Adverse event (AE) monitoring 


HCC 17-169  
31 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated. Adverse 
experiences will be graded and recorded throughout the study and during the follow-up period 
according to NCI CTCAE Version 4.0 (see Section 12.2). Toxicities will be characterized in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to trial treatment. 
 
All AEs of unknown etiology associated with nivolumab exposure should be evaluated to determine 
if it is possibly an event of clinical interest (ECI) of a potentially immunologic etiology (irAE). See 
Section 5.6.1.1 regarding the identification, evaluation and management of AEs of a potential 
immunological etiology. 
 
Related and clinically significant AEs occurring within 30 days after the last dose of study drug should 
be recorded. Patients who are discontinued from the study due to an unacceptable drug-related AE 
will be followed until the resolution of the AE to Grade 0-1 or stabilization or until initiation of a new 
therapy for their cancer, whichever occurs first. Related SAEs that occur within 90 days of the end 
of treatment or before initiation of a new antineoplastic treatment should also be followed and 
recorded. 
 
Please refer to section 7.2 for detailed information regarding the assessment and recording of AEs. 
 
7.1.3.2 
Full physical exam 
The investigator or qualified designee will perform a complete physical exam during the screening 
period. Clinically significant abnormal findings should be recorded as medical history. A full physical 
exam should be performed during screening. 
 
7.1.3.3 
Directed physical exam 
For visits that do not require a full physical exam per the Trial Flow Chart, the investigator or qualified 
designee will perform a directed physical exam as clinically indicated prior to trial treatment 
administration. 
 
7.1.3.4 
Vital signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration of 
each dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart 
(Section 6.1). Vital signs should include temperature, pulse, respiratory rate, weight and blood 
pressure. Height will be measured at screening only. 
 
7.1.3.5 
Eastern Cooperative Oncology Group (ECOG) performance scale 
The investigator or qualified designee will assess ECOG status (see Section 12.4) at screening, prior 
to the administration of each dose of trial treatment and discontinuation of trial treatment as specified 
in the Trial Flow Chart. 
 
7.1.3.6 
Tumor imaging and assessment of disease 
Response and progression will be evaluated in this study using the international criteria proposed by 
the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) Committee [Eisenhauer. Eur J 
Cancer 2009; (45):228-47]. 
  
Acceptable imaging studies to evaluate disease at baseline include: 


HCC 17-169  
32 
• 
Whole body PET-CT scan (except brain) 
• 
Contrast-enhanced CT scan of neck, chest, abdomen and pelvis (and affected body part if 
needed).  
• 
Brain imaging is to done only at Screening and need not be repeated. For brain imaging an 
contrast enhanced MRI is ideal. If an MRI of the brain cannot be done (or is contraindicated) 
a contrast enhanced CT of the brain is acceptable.  
 
A restaging PET-CT (preferred if possible, or CT) is required after completion of Prime Phase (+/- 2 
weeks) and prior to definitive surgery (i.e. after the completion of induction doses of nivolumab and 
CMP-001). MRI brain is not required for follow up studies unless clinically indicated. Additional 
staging studies will be done as clinically indicated at the discretion of the treating physician. During 
the maintenance phase imaging studies will be done every 8 weeks (-/+ 2 weeks). 
7.1.4 
Tumor Tissue Collection and Correlative Studies  
Planned correlative analyses will include flow cytometric analyses of tumor samples, TIL and 
peripheral blood mononuclear cells (PBMC), IHC analyses of pre-/post- treatment tumor samples, 
tumor whole exome/RNA sequencing. Single-cell RNA sequencing will be performed on a subset of 
treated patients. Studies will be performed under the direction of the Principle Investigator along with 
co-Investigator Hassane Zarour in Dr. Zarour’s lab. 
 
Tumor tissue 
Patients must undergo biopsy (e.g. punch or open biopsy) within 21 days (preferred; and up to 4 
weeks) of entry to the study (baseline biopsy). Definitive surgery will be performed after 2 weeks of 
the third dose of nivolumab and any clinically indicated variation from this schedule should be 
discussed between the investigator, treating sub-investigator and surgical oncologist. Tumor tissue 
will be processed as described in the lab manual: 
 
Primary melanoma (if available) 
FFPE tissue block(s) or 10 unstained slides (air dried) from patients’ originally resected primary 
melanoma will be requested as well. 
 
Blood biospecimens 
Blood biospecimens will be collected at baseline, and per the schedule outlined in Study Chart in 
Section 6.1. 
 
At EACH time point please submit the following: 
• 
One (1) 10mL RED top tube 
• 
One (1) 8.5mL YELLOW top tube 
• 
Eight (8) 10mL GREEN top tubes 
• 
One (1) 2.5mL PAXgene DNA tube 
• 
One (1) 2.5mL PAXgene RNA tube 
At Baseline and Week 12 ONLY please submit the following: 
• 
One (1) 2mL BD™ P100.  
Each tube must be clearly labeled to include:  
• 
Protocol number  
• 
Patient sequence number  


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33 
• 
Patient initials  
• 
Originating institution/investigator name  
• 
Date and time drawn  
• 
Collection time point 
Stool specimens 
Stool biospecimens will be collected at baseline,  and per the schedule outlined in Study Chart in 
Section 6.1. 
 
Dietary questionnaire 
DHQ-3 questionnaire may be administered electronically or on paper. Electronic administration is 
preferred. Data will be entered into DHQ-3 online per instructions as outlined in Appendix 1. 
 
7.1.5 
Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of the trial 
(from pre-trial to post-trial visits), including approximate blood/tissue volumes drawn/collected by visit 
and by sample type per subject can be found in the Procedures Manual.  
7.1.5.1 
Laboratory safety evaluations 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 7.1.5.1-1. 
 
Table 7.1.5.1-1: Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Hemoglobin 
Platelet count 
WBC 
(total 
and 
differential 
including 
absolute 
neutrophil 
count) 
Albumin 
Alkaline phosphatase 
Alanine 
aminotransferase 
(ALT)  
Aspartate 
aminotransferase 
(AST) 
Bilirubin (total; directly only if 
total is elevated above ULN) 
Total protein 
Blood urea nitrogen 
Bicarbonate 
Calcium 
Chloride 
Creatinine 
Glucose 
Phosphorus 
Potassium 
Magnesium 
Sodium 
Lactate dehydrogenase (LDH) 
Uric acid 
pH 
Specific gravity 
Glucose 
Protein 
Blood 
Nitrites 
WBCs 
Microscopic battery 
(RBCs, 
WBCs, 
epithelial cells, casts) 
- only if significant 
positive findings on 
urinalysis 
aPTT 
PT (INR) 
Serum or urine pregnancy test 
(β-human 
chorionic 
gonadotropin)+ 
Thyroid function studies 
(thyroid stimulating 
hormone [TSH], Free T3, 
Free T4)# 
Autoimmune lab panel 
(anti-dsDNA, ANA, 
ANCA, RF, and anti- 
RNP) 
HIV$ 
Hepatitis 
B 
surface 
antigen 
(HBsAg) and surface antibody 
HBsAb) $ 
Hepatitis C RNA (HCV RNA)$ 
+Perform on women of childbearing potential and at Screening only. If urine pregnancy results cannot be confirmed as 
negative, serum β-human chorionic gonadotropin will be required.  
#Autoimmune lab panel will be performed at Screening and EOT only. 
$HIV, hepatitis B and C studies will be performed at Screening only in patients as clinically indicated. 
 
Laboratory tests for screening should be performed within 28 days of registration. After W1D1, pre-
dose laboratory procedures can be conducted up to 72 hours prior to dosing at the frequency 


HCC 17-169  
34 
delineated in Section 6.1. Results must be reviewed by the investigator or qualified designee and 
found to be acceptable prior to each dose of trial treatment. 
 
7.1.6 
Other Procedures 
 
7.1.6.1 
Withdrawal and discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled 
for the final trial visit should be performed at the time of discontinuation. Any adverse events which 
are present at the time of discontinuation/withdrawal should be followed in accordance with the safety 
requirements outlined in Section 7.2 - Assessing and Recording Adverse Events. The schedule 
for Post-Treatment Visits including Safety Follow-up Visits are delineated in Section 7.1.7.2. 
Following completion of treatment, patients will enter the Follow-Up Period of the study (described 
in Section 7.1.7.2.2). 
 
7.1.6.2 
Blinding and unblinding 
Not applicable. 
7.1.7 
Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related details 
are provided above in Section 7.1 - Trial Procedures. 
7.1.7.1 
Screening 
Screening period 
Screening starts with the subject’s provision of a written informed consent and should be completed 
within 21 days (preferred; and up to 4 weeks) of initiation of study drug(s).  
 
7.1.7.2 
Post-treatment surveillance  
Follow up period will start 12 weeks after the last on-treatment time point for patients have completed 
study treatments or discontinued study therapy for toxicity and have no disease progression. These 
patients are evaluated per the standard follow-up schedule including imaging (CT vs. CT/PET vs. 
PET at the discretion of the treating physician) at the intervals directed below. Every 3 months (±2 
weeks) if patient is < 2 years from start of follow up period, every 6 months (±4 weeks) if patient is 
2-5 years from start of follow up period, and every 12 months (±4 weeks) if patient is > 5 years from 
start of follow up period for up to 15 years. Patients who develop recurrent melanoma will be followed 
for information on survival and for information on salvage patterns. The schedule of clinical follow up 
for these patients will be at the discretion of the treating physicians and according to established 
Standard of Care. Adverse Events Assessment on the study will continue for all patients until 30 
days after the last study drug administration.  
 
7.1.7.3 Safety follow up visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes first. 
All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Subjects with an AE of 
Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a new 
anti-neoplastic therapy, whichever occurs first. SAEs that occur within 90 days of the end of 


HCC 17-169  
35 
treatment or before initiation of a new anti-cancer treatment should also be followed and recorded. 
 
7.1.7.4 Follow up visit 
Subjects who discontinue trial treatment for a reason other than disease progression will move into 
the Follow-Up Phase and should be assessed by radiologic imaging to monitor disease status. Every 
effort should be made to collect information regarding disease status until the start of new anti-
neoplastic therapy, disease progression, death, end of the study or if the subject begins retreatment 
with nivolumab as detailed in Section 7.1.5.2.1. Information regarding post-study anti-neoplastic 
treatment will be collected if new treatment is initiated. 
 
7.1.7.5 Survival follow up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted to assess for survival status 
until death, withdrawal of consent, or the end of the study, whichever occurs first. This will be done 
every 3 months. 
 
7.2 
Adverse and Serious Adverse Events 
 
7.2.1 
Definitions 
 
7.2.1.1 
Adverse events (AE) 
An AE is an untoward or medical occurrence associated with the use of study drug (active or placebo 
drug, biologic, or device) in clinical investigation subjects, which does not necessarily have a causal 
relationship with the study drug. An AE can therefore be any unfavorable and unintended symptom, 
sign, disease or condition, or test abnormality whether or not considered related to study drug. AEs 
that do not meet the definition for an SAE are considered non-serious AEs. 
 
AEs include: 
• 
Changes described by the subject or signs observed by the Investigator or medical staff.  
• 
Test abnormalities (i.e., laboratory tests, ECGs) that result in an alteration in medical care 
(diagnostic or therapeutic). 
 
Disease Progression is not considered an AE in this study. 
  
Abnormalities present at baseline are considered AEs only if they reoccur after resolution or they 
worsen during the study. 
7.2.1.2 
Serious adverse events (SAE) and serious unexpected adverse 
events (SUSAR) 
An SAE is any AE that fulfills one of the criteria outlined in Table 7.2.1.2-1. 
Table 7.2.1.2-1: Criteria for Determination of Serious Adverse Events 
Death 
An AE that results in death.  
*In this study, deaths that are unequivocally due to Disease Progression are not to be 
reported as SAEs. 


HCC 17-169  
36 
Life-threatening AE 
An AE that places the subject, in the view of the Investigator, at immediate risk of death 
from the AE as it occurred (i.e., does not include an AE that had it occurred in a more 
severe form, might have caused death). 
Required 
or 
prolonged 
inpatient hospitalization 
An AE that results in an initial inpatient hospitalization or prolongs an existing 
hospitalization of the subject. If a subject is hospitalized as part of the clinical use of the 
study drug, a period of normal hospitalization will be outlined in the protocol or by the 
judgment of the Investigator. Hospitalizations longer than this period will be prolonged 
hospitalizations. 
Persistent 
or 
significant 
disability/incapacity 
An AE that results in a substantial disruption of a subject’s ability to conduct normal life 
functions. 
Congenital 
anomaly/birth 
defect 
A congenital anomaly/birth defect that occurs in the offspring of a subject exposed to the 
study drug. 
Important medical event 
An AE that 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. 
 
Examples of such “important medical events” include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as with important medical events described above.  
Events that meet SAE criteria must be recorded and reported regardless of expectedness or 
assessed association with study drug.  
Note: Planned hospital admissions or surgical procedures for elective procedures or for an illness 
or disease that existed before the signing of the ICF or before the subject was enrolled in the study 
will not be captured as SAEs. If planned admissions or procedures occur at a time other than what 
was planned (i.e., due to an exacerbation in the preexisting illness or disease), they should be 
reported as SAEs. 
7.2.1.3 
Unexpected AE 
An unexpected AE is any AE that is not consistent in specificity or severity with the current 
Investigator’s Brochure (IB). 
 
7.2.2 
Evaluation of Adverse Events and Serious Adverse Events 
The Investigator or designee is responsible for making an assessment as to the severity/grade (as 
defined in Section 10.18.2.1, below), causality/relationship (as defined in Section 10.18.2.2, below), 
and outcome of AEs and SAEs (as defined in Section 10.18.2.3, below). In addition, the Investigator 
or 
designee 
must 
report 
any 
actions 
taken 
as 
a 
result 
of 
an 
AE 
or 
SAE. 
 
7.2.2.1 
AE severity/grade 
For each recorded AE or SAE, the Investigator or designee must make an assessment of Grade 
using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade refers to 
the severity of the AE. Note that severity is not the same as “seriousness”. Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 
 


HCC 17-169  
37 
7.2.2.2 
Causality and relationship to study drug(s) 
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 drug regimen 
(CMP-001 pus nivolumab), and the AE according to the categories provided in Table 7.2.2.2-1. 
Attribution of adverse events specifically to either CMP-001 or nivolumab is challenging, therefore, 
the relationship to study drug should be based on attribution to the combination of the two drugs, not 
a single drug. 
 
An AE with causal relationship not initially determined will require follow-up to assign causality which 
must be made by the Investigator prior to completion of the study. The Investigator may change 
his/her opinion of causality in light of follow-up information; if this occurs, the Investigator must amend 
the AE or SAE information accordingly. 
 
Table 7.2.2.2-1: Classifications for Adverse Event Causality/Relationship 
Classification 
Definition 
Unrelated 
There is no suspicion of a causal relationship between exposure to 
the study drug regimen and the AE; another cause of the AE has 
been identified, no temporal association with study drug has been 
identified, or the study drug cannot be implicated.  
Possibly related 
There is some evidence supporting the possibility of a causal 
relationship between study drug regimen exposure and the AE; an 
alternative explanation (i.e., concomitant drug or concomitant 
disease) is inconclusive, the temporal association with study drug is 
reasonable, and the causal relationship cannot be excluded. 
Probably related 
An adverse event 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 drug regimen and the AE; the AE cannot be reasonably 
explained by an alternative explanation (i.e., concomitant drug or 
concomitant disease) and the temporal association with study drug 
is suggestive of a causal relationship. 
 
An AE is considered related to treatment if the attribution is “possibly related”, “probably related”, or 
“definitely related.” 
 
7.2.2.3 
Classification of AE outcome 
Adverse event outcome describes the status of the AE at the last observation. The Investigator will 
document the outcome of each AE or SAE using the categories provided in Table 7.2.2.3-1. 
 
Table 7.2.2.3-1: Classifications for Adverse Event Outcome 
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. 
Recovering/resolving 
Subject is recuperating or the AE is improving. 
Recovered/resolved 
Subject has recuperated, the AE resolved, or returned to baseline status / 
stabilized. 
Recovered/resolved 
with 
sequelae 
Adverse event has resolved, but the subject has been left with symptoms or 
pathology. 
Unknown 
Not known, not observed, not recorded, or refused. 
 


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38 
7.2.2.4 
Action taken regarding AE 
The Investigator will provide the action taken regarding study drug in response to the AE. 
Classifications for each of the potential actions taken are provided in Table 7.2.2.4-1. More than one 
option may apply to a single AE/SAE. For example, study drug may be delayed and the dose reduced 
in response to an AE. Action related to CMP-001 and nivolumab will be assessed and recorded 
separately in the EDC. 
 
Table 7.2.2.4-1: Classifications for Actions Taken Regarding an Adverse Event 
Classification 
Definition 
Dose not changed 
No change in administration of study drug 
Dose reduced1 
Reduction in the amount of study drug administered 
Study drug interrupted 
Temporary interruption (termination) in administration of the study 
drug 
Study drug withdrawn 
Administration of the study drug terminated (no further dosing) 
Not applicable 
Determination of a value is not relevant in the current context  
Unknown 
Not known, not observed, not recorded, or refused 
1Refer to Section 5.2.1. and 5.2.3. regarding dose reductions of either Nivolumab or CMP-001 due 
to dose-limiting toxicities. 
 
7.2.3 
Timeframe for Adverse Event/Serious Adverse Event Collection 
The Investigator is required to record all AEs occurring during the clinical study (21 CFR 312.64[b] 
and ICH E6 [R1]) starting from the time the subject signs the ICF until 30 days after the last dose of 
CMP-001 on the AE page of the eCRF. SAEs that occur within 90 days of the end of treatment or 
before initiation of a new anti-cancer treatment should also be followed and recorded. SAEs as 
defined in Section 7.2.1.2. must also be reported to the Sponsor or its representative within 24 hours 
of knowledge of their occurrence, in accordance with Section 7.2.5. 
 
7.2.3.1 
Treatment-related AE 
Treatment-related AE/SAE is defined as an AE that started or worsened in severity on or after the 
date the study drug was first administered. TEAE information will be collected from the time of the 
subject’s first receipt of CMP-001 until 30 days after the last dose of CMP-001. 
 
7.2.3.2 
SAE 
SAE information will be collected from the point the subject starts study treatment until 30 days after 
the last dose of CMP-001. If, at any time after the subject has completed participation in the study, 
the Investigator or study staff becomes aware of an SAE that they believe is possibly related or 
related to CMP-001 (see Section 7.2.1.2), then the event and any known details must be reported 
promptly to the Sponsor or its designee. The reporting instructions described in Section 7.2.5 must 
be followed. 
 
7.2.4 
Recording Adverse Events/Serious Adverse Events 
All AEs and SAEs experienced by a subject will be recorded on the appropriate eCRF. Information 
including a concise description of the event; date and time of event onset and resolution; 
determination of seriousness, severity, corrective treatment, outcome, relationship to study drug; and 
action taken regarding the study drug will be recorded. Vital signs, laboratory results, and other safety 


HCC 17-169  
39 
assessments noted in Section 7.1.2 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 that diagnosis. 
However, when flu-like or cytokine release-like symptoms are reported, each individual symptom 
should be recorded as a separate AE in the Electronic Data Capture (EDC) system. A medical or 
surgical procedure is not an AE; rather the condition leading to the procedure should be recorded as 
the AE. If the condition is not known, the procedure must be recorded as an AE instead. Similarly, 
death is not an AE, but is rather the outcome of the AE(s) that resulted in death. If the AE(s) leading 
to death are not known, then death must be reported as an AE.  
 
All SAEs experienced by the subject will be entered into the CTMA and reported to the Sponsor or 
designee, in accordance with Section 7.2.5.1. 
 
7.2.5 
Reporting Serious Adverse Events and Serious Unexpected Adverse Events 
7.2.5.1 
SAE and SUAE Reporting 
All events meeting the definition of a serious adverse event should be recorded on a MedWatch 
3500AForm 
(http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf) 
or 
departmental SAE form. Copies should be sent to: 
• 
Principle Investigator (and Sponsor) 
• 
The Checkmate Drug Safety contact information is available for SAE reporting on a 24-hour 
basis and is reviewed during normal business hours. The contact information is as follows: 
Email: cfrench@checkmatepharma.com 
• 
The Bristol-Myers Squibb Drug Safety contact information is available for SAE reporting on 
a 24-hour basis and is reviewed during normal business hours. The contact information is as 
follows: 
Email:  Worldwide.Safety@BMS.com 
• 
UPMC Institutional Review Board per institutional reporting requirements 
• 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include as applicable the following information that is available 
at the time of report within the Event Description (section 5) of the MedWatch 3500A form or 
departmental SAE form: 
o CTCAE term(s) and grade(s) 
o Current status of study drug 
o Intervention(s) to address the AE (testing and result, treatment and response)  
o Hospitalization and/or discharge dates  
o Event 
relationship 
to 
study 
drug 
combination 
 
7.2.5.2 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) 
and must be reported within 24 hours to the Sponsor and within 2 working days to Checkmate Drug 
Safety Contact (see Section 7.2.5.1.).  
For the time period beginning when the consent form is signed until treatment initiation, any ECI, or 
follow up to an ECI, that occurs to any subject must be reported within 24 hours to the Sponsor and 
within 2 working days to Checkmate Drug Safety Contact if it causes the subject to be excluded from 
the trial, or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.  


HCC 17-169  
40 
For the time period beginning at treatment initiation through 90 days following cessation of treatment, 
or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever 
is earlier, any ECI, or follow up to an ECI, whether or not related to Checkmate product, must be 
reported within 24 hours to the Sponsor and within 24 hours to Checkmate Drug Safety Contact.  
Events of clinical interest for this trial include: 
• 
An overdose of Checkmate product 
• 
Cutaneous adverse events at  the injection site 
 
7.2.5.3 
Pregnancies 
Female subjects or the partners of male subjects who discover they are pregnant within a year of 
their last CMP-001 dose will be instructed to notify the Investigator immediately.  
If the Investigator learns of a report of pregnancy at any time after signing the ICF, the Investigator 
must complete a Pregnancy Form and report the pregnancy to Checkmate Pharmaceuticals Drug 
Safety within 24 hours (following the same reporting process outlined in Section 7.2.5.1). 
The Investigator will inform the subject that the Sponsor or its designee is required to gather 
information regarding the course and outcome of a pregnancy that has occurred after exposure to a 
study drug. The progress of the pregnancy must be followed until the outcome of the pregnancy is 
known (i.e., delivery, elective termination, or spontaneous abortion). If the pregnancy results in the 
birth of a child, additional follow-up information may be requested. 
The Investigator will be asked to obtain follow-up information no later than 2 months after the 
gestational period to obtain maternal/fetal/neonatal outcome and any other relevant information. 
Follow-up information may be requested at additional time points. All study-related contacts involving 
a known pregnancy should include pregnancy status assessment until pregnancy outcome is known. 
Please note that pregnancy in and of itself is not an AE or an SAE. Pregnancy should not be entered 
into the eCRF as an AE unless the Investigator suspects an interaction between the study drug and 
the contraceptive method. Additionally, all information received will be assessed for any AEs and 
SAEs and processed per study guidelines. If the subject is discontinued because of pregnancy, 
pregnancy will be documented as the reason for study discontinuation. Spontaneous abortions and 
stillbirths will be reported as SAEs. 
7.2.6 
IND Safety Report 
The sponsor must notify FDA and all participating investigators (i.e., all investigators to whom the 
sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case 
later than 15 calendar days after the sponsor determines that the information qualifies for reporting 
under Sections 7.2.6.1. to 7.2.6.3. below. In each IND safety report, the sponsor must identify all 
IND safety reports previously submitted to FDA concerning a similar suspected adverse reaction, 
and must analyze the significance of the suspected adverse reaction in light of previous, similar 
reports or any other relevant information. 
7.2.6.1 Serious and unexpected adverse reaction 


HCC 17-169  
41 
The sponsor must report any suspected adverse reaction that is both serious and unexpected. The 
sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to 
suggest a causal relationship between the drug and the adverse event, such as: 
• 
A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome);  
• 
One or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture); 
• 
An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events that 
commonly occur in the study population independent of drug therapy) that indicates those 
events occur more frequently in the drug treatment group than in a concurrent or historical 
control group. 
7.2.6.2 Findings from other studies 
The sponsor must report any findings from epidemiological studies, pooled analysis of multiple 
studies, or clinical studies (other than those reported under section 7.2.6.1), whether or not 
conducted under an IND, and whether or not conducted by the sponsor, that suggest a significant 
risk in humans exposed to the drug. Ordinarily, such a finding would result in a safety-related change 
in the protocol, informed consent, investigator brochure (excluding routine updates of these 
documents), or other aspects of the overall conduct of the clinical investigation. 
7.2.6.3 Findings from animal or in vitro testing 
The sponsor must report any findings from animal or in vitro testing, whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug, such as reports of 
mutagenicity, teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the 
expected human exposure. Ordinarily, any such findings would result in a safety-related change in 
the protocol, informed consent, investigator brochure (excluding routine updates of these 
documents), or other aspects of the overall conduct of the clinical investigation. 
7.2.6.4 Increase rate of occurrence of serious suspected adverse reactions 
The sponsor must report any clinically important increase in the rate of a serious suspected adverse 
reaction over that listed in the protocol or investigator brochure. 
7.2.6.5 Submission of IND safety reports 
The sponsor must submit each IND safety report in a narrative format or on FDA Form 3500A or in 
an electronic format that FDA can process, review, and archive. FDA will periodically issue guidance 
on how to provide the electronic submission (e.g., method of transmission, media, file formats, 
preparation and organization of files). The sponsor may submit foreign suspected adverse reactions 
on a Council for International Organizations of Medical Sciences (CIOMS) I Form instead of a FDA 
Form 3500A. Reports of overall findings or pooled analyses from published and unpublished in vitro, 
animal, epidemiological, or clinical studies must be submitted in a narrative format. Each notification 
to FDA must bear prominent identification of its contents, i.e., "IND Safety Report," and must be 
transmitted to the review division in the Center for Drug Evaluation and Research or in the Center 
for Biologics Evaluation and Research that has responsibility for review of the IND. Upon request 
from FDA, the sponsor must submit to FDA any additional data or information that the agency deems 
necessary, as soon as possible, but in no case later than 15 calendar days after receiving the 
request. 


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7.2.6.5.1 Unexpected fatal or life-threatining suspected adverse reaction 
reports 
The sponsor must also notify FDA of any unexpected fatal or life-threatening suspected adverse 
reaction as soon as possible but in no case later than 7 calendar days after the sponsor's initial 
receipt of the information. 
7.2.6.5.2 Reporting format or frequency 
FDA may require a sponsor to submit IND safety reports in a format or at a frequency different than 
that required under this paragraph. The sponsor may also propose and adopt a different reporting 
format or frequency if the change is agreed to in advance by the director of the FDA review division 
that has responsibility for review of the IND. 
7.2.6.5.3 Investigations of marketed drugs 
A sponsor of a clinical study of a drug marketed or approved in the United States that is conducted 
under an IND is required to submit IND safety reports for suspected adverse reactions that are 
observed in the clinical study, at domestic or foreign study sites. The sponsor must also submit safety 
information from the clinical study as prescribed by the post marketing safety reporting requirements. 
7.2.6.5.4 Reporting study endpoints 
Study endpoints (e.g., mortality or major morbidity) must be reported to FDA by the sponsor as 
described in the protocol and ordinarily would not be reported under Section 7.4.6. However, if a 
serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the drug and the event (e.g., death from anaphylaxis), the event must be 
reported under Serious and unexpected suspected adverse reaction as a serious and unexpected 
suspected adverse reaction even if it is a component of the study endpoint (e.g., all-cause mortality). 
 
7.2.7. 
Follow-up of Adverse Events/Serious Adverse Events  
 
All AEs and SAEs documented at a previous visit that are designated as either recovering/resolving 
or 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 participation, or study 
termination, whichever occurs first. 
 
Serious AEs 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 drug or to factors unrelated to 
study conduct. 
• 
The Investigator agrees that follow-up is no longer necessary. 
 
Follow-up reports from the Investigator must be provided as indicated using the SAE report form 
within 24 hours of the Investigator’s first knowledge of the new information. Additional information 
(i.e., hospital records, laboratory, or other diagnostic test results) should be provided if requested 
and/or indicated. 
 


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Rules for AE/SAE follow up apply to all subjects, including those who withdraw consent prior to study 
completion (to the extent allowed). The Investigator will ensure that follow up includes further 
investigations to elucidate the nature and/or causality of the AE/SAE. These investigations must be 
consistent with appropriate medical management and subject consent. 
 
Investigators are not obligated to actively seek AEs or SAEs in former study subjects that occur 
pursuant to the follow-up period. However, if the Investigator or designee learns of any AE or SAE 
at any time after a subject has been discharged from the study and the event is considered as 
reasonably related to the study drug, the Investigator will notify the Sponsor. 
 
8 Statistical Analysis Plan 
 
8.1 
Study Design 
This is a non-randomized phase II single arm Simon’s minimax two-stage study of neoadjuvant 
nivolumab and CMP-001. Nivolumab (I.V.) and CMP-001 (intra-tumorally) will be administered for 7 
weeks pre-operatively (weeks 1-7) followed by planned surgical resection at week 8-10. Following 
recovery from surgery, nivolumab (I.V.) and CMP-001 (S.C. or peri-tumoral resection site) will 
commence and continue for 48 weeks. Details for the two-stage design are in Section 8.3. 
8.2 
Safety Monitoring 
The PD-1/CMP-001 combination has been tested in the PD-1 refractory setting in melanoma 
including in a phase I study that evaluated multiple doses of CMP-001 including 5mg, 7.5mg and 
10mg. The safety profile observed thus far suggests that the risk of additive toxicities are unlikely 
to be significantly increased in the neoadjuvant setting. Further, the dose being tested in this study 
(5mg) is 50% the ceiling dose tested in other CMP-001 studies in combination with PD-1 inhibitors, 
none of which reported a toxicity rate >33%.  
However, in the context of this neoadjuvant trial, we will monitor dose limiting toxicities (DLTs) for 4 
weeks for the 1st 3 patients accrued. DLT is defined as any adverse event(s) (AEs) considered 
possibly, probably, or definitely related to the CMP-001 plus nivolumab regimen, which occur during 
the first 15 days of therapy (i.e. following 3 doses of CMP-001; W1D1, W2D1, W3D1) IN the Prime 
phase only. Attribution of AEs specifically to either CMP-001 or nivolumab is challenging, therefore, 
the relationship to CMP-001 should be based on attribution to the combination of the two drugs. 
During DLT monitoring period, no further accrual will be permitted. Any patient who has started the 
studied treatment will be evaluable for safety.  
The following AEs will be considered DLTs if deemed related to study therapy: 
• 
Hematologic 
o Grade 4 neutropenia 
o Febrile neutropenia, defined as absolute neutrophil count (ANC) ≤1000/mm3 with a 
temperature of ≥ 38.3 degrees °C 
o Grade ≥ 3 neutropenic infection 
o Grade ≥ 3 thrombocytopenia with bleeding 
o Grade 4 thrombocytopenia 
• 
Non-hematologic 
o Grade ≥ 3 toxicities (non-laboratory) 
o Grade ≥ 3 nausea, vomiting or diarrhea despite maximal medical intervention 
o Grade 4 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 


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44 
• 
Other (non AST/ALT) non-hematologic Grade ≥ 3 laboratory value if the abnormality leads to 
overnight hospitalization 
IMPORTANT: CMP-001 is designed to specifically bind to Toll like receptor 9 (TLR9) which is 
expressed in the endosomes of pDCs. Upon activation through TLR9, pDCs will secrete large 
amounts of type 1 interferons and associated Th1-promoting cytokines.  Given this mechanism of 
action, it is expected that the adverse event profile associated with intratumoral injection of CMP-
001 may be similar to that seen after administration of interferons (e.g. flu-like symptoms such as 
fever, rigors, nausea & vomiting). In addition, given the release of IFN-inducible chemokines and 
cytokines, symptoms associated with cytokine release, such as chills/rigors, fever, nausea/vomiting 
and hypotension, may occur within hours of a CMP-001 intratumoral injection. Recommended 
prophylaxis, outlined above in Section 5.2.2.1. may help to minimize the severity of these reactions. 
An AE believed to be caused by tumor flare or pseudoprogression does not necessarily need to be 
considered a DLT. Any such cases that would otherwise meet DLT criteria must be discussed 
immediately with the Principle Investigator. If the Principle Investigator and Sponsor agree that tumor 
flare is a likely explanation for the AE, treatment with CMP-001 may continue so long as the subject 
is closely monitored by the Principle Investigator or study staff while on study. 
Subjects who experience a DLT will have CMP-001 and nivolumab dosing withheld until the toxicity 
has returned to ≤ Grade 1. If the Investigator determines that continued treatment with CMP-001 is 
in the subject’s best interest, treatment may resume at a reduced dose (2.5mg weekly or every 4 
weeks; 1 dose level lower) at the same schedule after consultation with the Principle Investigator. If 
a CMP-001 injection is delayed due to toxicity it should be given as soon as possible once the toxicity 
has resolved. If a subject experiences DLT on a reduced dose of CMP-001, further accrual will be 
halted. 
Subjects may remain on the same dose of nivolumab. Any dose modification should follow the 
approved nivolumab label. 
The Investigator may escalate the subject back to the original CMP-001 dose level if: 1) the lower 
dose level was tolerated without any DLTs; 2) Sponsor approval is given. 
8.3 
Sample Size 
Several of the agents being utilized in the melanoma armamentarium have been evaluated in the 
neoadjuvant context including: HDI (Moschos et al. 2006), ipilimumab (Tarhini et al. 2014), 
pembrolizumab (Forde et al. 2018) and nivolumab/ipilimumab combination (Blank et al. 2018; Amaria 
et al. 2018). In earlier studies, response was typically assessed using chemotherapy criteria and 
reported as pathologic complete response (pCR) rates. Cognizant of the different mechanism of 
action of immuno-oncologic agents, more recent studies have utilized alternative means of assessing 
response using novel immuno-oncologic agent-specific criteria (major pathologic response or MPR 
rate) as delineated in Section 8.4. In the latter studies, MPR rates reported with PD-1 inhibitors 
range from 28% (Nivolumab, melanoma) to 45% (Nivolumab/Ipilimumab, melanoma) (Huang et al. 
2019; Blank et al. 2018; Amaria et al. 2018). 
However, the PD-1/CMP-001 combination has not been evaluated in the neoadjuvant setting and 
the MPR rate for this combination is unknown. To balance efficacy while minimizing exposure of 
patients to a potentially ineffective combination, we utilize Simon’s minimax two-stage design with 
MPR as the primary endpoint. 


HCC 17-169  
45 
In this study, we will test the null hypothesis of 28% MPR versus the alternative hypothesis of 55% 
MPR. In the 1st stage, we will enroll 14 evaluable patients (defined in Section 5.8). If we see at least 
5/14 major pathologic responses, we will enroll a further 16 patients to the 2nd stage. The combination 
will be considered worthy of further evaluation if ≥13 responses are observed in both stages in 30 
evaluable patients. The Simon’s minimax two-stage design and sample size of 30 evaluable patients 
provides a type I error rate of 5%, with a power of 0.91. Allowing for 10% drop out rate, we set a total 
sample size of 33 patients. 
8.4 
Efficacy Analysis 
Definition of evaluable patient 
See Section 5.8. 
 
Determination of residual volume of tumor (RVT) 
Early neoadjuvant studies in melanoma reported pCR utilizing criteria to define the residual volume 
of tumor (RVT) derived from neoadjuvant studies of chemotherapy in select tumors including lung 
cancer (Hellmann et al. 2014) 
 
Neoadjuvant use of immuno-oncologic agents results in distinct histopathologic features compared 
to neoadjuvant chemotherapy. Specifically, neoadjuvant PD-1 therapy produces unusual features 
beyond CD8+ T cell infiltrate and tumor necrosis previously associated with response (Tumeh et al. 
2014) including features in areas adjacent to the actual tumor – a location termed “the regression 
bed”. Histopathologic features associated with response herein include neovascularization; 
proliferative fibrosis; presence of cholesterol clefts; development of tertiary lymphoid structures; 
presence of plasma cells, giant cells, foamy macrophages and granulomas (Cottrell et al. 2018; 
Tetzlaff et al. 2018). 
 
This observations have led investigators to propose new criteria – immune related pathologic 
response criteria (irPRC) – wherein immune related RVT (% irRVT) is defined as the total surface 
area of RVT divided by the total tumor bed area (comprising regression bed area + RVT area + areas 
of necrosis) (Cottrell et al. 2018; Tetzlaff et al. 2018). Compared to standard methods, irPRC had 
lower inter-observer variability better correlated with imaging assessments. The neoadjuvant 
administration of PD-1 and/or CTLA-4 inhibitors is associated with high PRR; ranging from 25-30% 
pCR (nivolumab monotherapy) to 45% pCR (ipilimumab/nivolumab combination) (Amaria et al. 2018; 
Blank et al. 2018). Primary endpoint of this study is MPR rate, where MPR is defined as ≤10% RVT 
remaining in post-therapy specimen using immunotherapy-specific criteria based on residual volume 
of tumor  (RVT) (Cottrell et al. 2018; Tetzlaff et al. 2018). 
 
Residual tumor will be determined in each resection specimen as outlined in Appendix 2. All tumors 
will be macroscopically localized after correlation with radiologic findings. Specimens were sectioned 
in 5 mm-thick slices. In patients with multiple metastases, each lesion will be extensively sampled 
from the center to the periphery to include multiple sections of tumor and non-neoplastic 
parenchyma. Sampling of the tumor nodules in the pathology suite will be directed at the most viable 
section of the tumor nodule. More than one section per centimeter will be reviewed from each tumor 
nodule. The number of hematoxylin-eosin slides reviewed per tumor nodule will be at least four 
(range, 1 to 14 slides). Hematoxylin-eosin stained sections will be reviewed by two melanoma 
pathologists  blinded with respect to clinical information and treatment regimen.  
 
Definition of major pathologic response (MPR) 
MPR is defined as ≤10% RVT remaining in post-therapy specimen using immunotherapy-specific 
pathologic response criteria (irRPRC) (Cottrell et al. 2018; Tetzlaff et al. 2018). MPR rate will be 


HCC 17-169  
46 
calculated along with its exact 95% confidence interval. Other categories of response based on 
%RVT are given below: 
• 
Pathologic complete response (pCR): 0% RVT 
• 
Major pathologic response (irMPR): ≤10% RVT 
• 
Partial pathologic response: <10% but ≤50% RVT 
• 
Pathologic non-response: >50% RVT. 
 
Definition of other endpoints 
RFS is defined as the time from initiation of treatment till melanoma relapse or death. All suspected 
relapse should be biopsied to confirm relapse. In the event where this is difficult and/or dangerous, 
imaging may be used as a surrogate. OS is defined as the time from initiation of treatment till death. 
Kaplan-Meier estimates of RFS and OS will be provided. The corresponding median survival time 
(with 95% confidence intervals) will be determined, along with survival estimates at selected time 
points (e.g. 6 months, 1 years, and 2 years). 
8.5 
Safety Analysis 
As per NCI CTCAE Version 4.0, the term toxicity is defined as adverse events that are classified as 
either possibly, probably, or definitely related to study treatment. The maximum grade for each type 
of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine 
toxicity patterns.  
As CMP-001 has previously been dose-escalated in combination with PD-1 inhibitors 
pembrolizumab and nivolumab with minimal additional toxicities, no “dose-escalation” will be 
performed in this study. However, to accurately capture toxicities for this novel combination, we will 
be monitoring toxicities closely. The detailed data and safety monitoring plan is in Section 8.7. 
8.6 
Biomarker Analysis 
To search for potential prognostic biomarkers (and toxicity marker) for the investigation regimen, 
logistic regression will be used to assess the association between each marker and clinical response 
(and occurrence of SAEs). The Cox proportional hazards model will be used to assess the 
association of each marker and survival endpoints (i.e. RFS and OS).  
 
8.7 
Data Safety and Monitoring Plan 
All enrolled patients will be reviewed weekly to discuss AEs, in particular during DLT period. 
 
Principle 
Investigator/Sub-investigators, 
regulatory, 
CRS 
management, 
clinical 
research 
coordinators, clinical research associates, data managers, and clinic staff meet monthly in disease 
center Data Safety Monitoring Boards (DSMB) to review and discuss study data to include, but not 
limited to, the following:  
• 
serious adverse events  
• 
subject safety issues  
• 
recruitment issues  
• 
accrual  
• 
protocol deviations  
• 
unanticipated problems  
• 
breaches of confidentiality 
 


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47 
All toxicities encountered during the study will be evaluated on an ongoing basis according to the 
NCI Common Toxicity Criteria version 4.0. All study treatment associated adverse events that are 
serious, at least possibly related and unexpected will be reported to the IRB. Any modifications 
necessary to ensure subject safety and decisions to continue, or close the trial to accrual are also 
discussed during these meetings. If any literature becomes available which changes the risk/benefit 
ratio or suggests that conducting the trial is no longer ethical, the IRB will be notified in the form of 
an Unanticipated Problem submission and the study may be terminated. 
 
All study data reviewed and discussed during these meetings will be kept confidential. Any breach 
in subject confidentiality will be reported to the IRB in the form of an Unanticipated Problem 
submission. The summaries of these meetings are forwarded to the UPCI DSMC which also meets 
monthly following a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies for reporting 
unanticipated problems involving risk to subjects or others (including adverse events). DSMC 
progress reports, to include a summary of all serious adverse events and modifications, and approval 
will be submitted to the IRB at the time of renewal. 
 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will be 
reviewed twice a year rather than monthly by the disease center DSMB. 
 
Both the UPCI DSMC as well as the individual disease center DSMB have the authority to suspend 
accrual or further investigate treatment on any trial based on information discussed at these 
meetings. 
 
All records related to this research study will be stored in a double locked environment. Only the 
researchers affiliated with the research study and their staff will have access to the research records. 
 
 
9 Labeling, Packaging, Storage and Return of Clinical Supplies 
 
9.1 
Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution and usage of investigational product 
in accordance with the protocol and any applicable laws and regulations. 
Clinical supplies provided by Checkmate are summarized in Table 9.1-1. 
Table 9.1-1: Product Descriptions 
Product 
Name 
and 
Potency 
Dosage Form 
CMP-001 
Working concentration: 5.0 mg/mL.  
CMP-001 is a clear, colorless to pale yellow/brown liquid solution, 
essentially free of particles. Each single use vial contains 1.0 mL of 
CMP-001 (extractable volume of 1.0 mL = 5.0 mg dose) with a 0.1 
mL overfill. 
 
9.2 
Packaging and Labeling Information 
The CMP-001drug product vials will be labeled with the following information:  


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48 
• 
The protocol number;  
• 
The kit number;  
• 
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;  
• 
The route of administration;  
• 
Cautionary statement indicating that the drug is for investigational use only;  
• 
The name and address of the Sponsor;  
 
The CMP-001 kit carton will be labeled with the following information:  
• 
The protocol number;  
• 
The kit number;  
• 
Number of vials per kit;  
• 
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;  
• 
The route of administration;  
• 
Cautionary statement indicating that the drug is for investigational use only;  
• 
The name and address of the Sponsor; 
 
9.3 
Handling, Storage and Accountability 
All CMP-001 drug product vials will be transported, received, stored, and handled in accordance with 
the container or drug product kit/vial label, the instructions supplied to the site and its designated 
pharmacy personnel, the site’s standard operating procedures (SOPs), and applicable regulations. 
 
Appropriate storage and transportation conditions will be maintained for the CMP-001 drug product 
vials from the point of manufacture up to delivery of CMP-001. All shipments of CMP-001 drug 
product vials will include a temperature monitoring device that records required storage conditions 
for the vials, at regular intervals for the entire time the shipment is in transit. 
 
Upon receipt by the site, the designated site personnel will examine the shipment and temperature 
monitoring devices to verify the CMP-001 drug product vials were received in acceptable condition. 
If not received in acceptable condition, the site must notify the CRA and the site should quarantine 
the drug until a decision has been made by Checkmate. Once inspected, vials should be stored at 
the specified temperature (2°C to 8°C) in a locked area accessible only to designated site personnel 
until dispensing. Once dispensed, CMP-001 drug product vials will be stored in a limited access area 
under 
appropriate 
environmental 
conditions. 
 
The designated site personnel will be responsible for maintaining accurate records of the quantity 
and dates of all study drug supplies received, dispensed, and returned, in accordance with applicable 
regulations and the site’s SOPs. The quantity of study drug lost, destroyed, etc. must also be 
accounted 
for 
and 
documented. 
 
All original vials, whether empty or containing CMP-001 will be kept at the site and destroyed 
according to the site’s drug destruction standard operating procedures. Used CMP-001 vials will not 
be dispensed again (even to the same subject) nor will they be relabeled or reassigned for use by 
other subjects. Contents of the CMP-001 drug product vials will not be combined. At the termination 


HCC 17-169  
49 
of the study, a final drug accountability review and reconciliation must be completed and any 
discrepancies 
must 
be 
investigated 
and 
their 
resolution 
documented. 
 
All CMP-001 drug product vials will be destroyed onsite as per institutional standard operating 
procedures, after site close out has been completed.  
 
9.4 
Dispensing 
The CMP-001 drug product vials will be dispensed and CMP-001 drug product will be administered 
according to applicable site SOPs. Details regarding the preparation and administration of the study 
drug will be outlined in a study-specific pharmacy manual. Only eligible subjects participating in the 
study will receive CMP-001. Only authorized and qualified site staff may supply or administer CMP-
001. 
 
 


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Appendix 1: Dietary History Questionnaire for Microbiome Sampling 
Dietary history questionnaire will be administered either on paper or electronically and data 
entered and stored securely electronically. Instrument will be administered by PI or designee. 
 
Detailed information for study staff: 
1. Please obtain patient’s username and password from study PI. 
2. Please provide instructions (see below) to patients. 
3. Patients are to be instructed to provide detailed dietary information either during visit 
(preferred) or at home. 
4. The instrument that will be utilized is the DHQ-3 “past month with portion size” obtained from 
https://epi.grants.cancer.gov/dhq3/ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Detailed information for patients: 
• 
Thank you for participating in this study. We are interested in evaluating your dietary history. 
To do this we are using a validated questionnaire termed the “Diet History Questionnaire 
(DHQ-3)”. 
• 
This questionnaire takes approximately 30 minutes to complete. You can do this either while 
receiving your therapy or at home. 
• 
After completing the questionnaire, you will receive a Respondent Nutrition Report. This 
report shows estimated daily nutrient and food group intakes based on questionnaire 
responses. Recommended values are only available for some nutrients and food groups. 
• 
Please feel free to discuss this with your study doctor. 
 
 
 
Dietary study login URL: https://epi.grants.cancer.gov/dhq3/ 
Your username (case sensitive): __________ 
Your study password (case sensitive): __________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2: Pathologic Response Assessment (irPRC Criteria) 
Study ID: 
 
Background and Demographic Information: 
• 
Sex/Age: 
 
Pre-Treatment Pathology 
• 
Location of tumor 
• 
Nature of tumor: 
• 
Initial pathologic stage: 
• 
Date of initial diagnosis: 
• 
Pre-treatment imaging findings: 
• 
Pre-treatment biopsy: 
o Date: 
o Nature of biopsy: 
o Location/anatomic site: 
o Tumor present/absence: 
 
Neoadjuvant Therapy 
• 
Nature of therapy 
• 
Duration of therapy 
• 
Location of injection 
 
Surgical Resection: 
• 
Date: 
• 
Type of surgery: 
• 
Location/anatomic site: 
• 
Post-treatment imaging findings 
 
Post-Treatment Pathological Response Assessment 
• 
Lymph node or In-transit nodule: 
• 
Number of lymph nodes/nodule: 
• 
Largest positive LN/nodule size: 
• 
Sizes of other lymph nodes/nodules: 
• 
Grossly positive: 
• 
Block number of positive LN/nodules: 
• 
Tissue banked (if any): 
• 
Treatment response evaluation metrics: 
o Size of tumor bed: 
o Gross/microscopy: 
▪ 
Percentage of viable tumor: 
▪ 
Percentage of stromal fibrosis: 
▪ 
Percentage of necrosis: 
▪ 
Percentage of tumoral melanosis: 
▪ 
Extra-capsular extension 
• 
Y/N 
• 
Viable/regressed 
• 
Response assessment (immune related pathologic response rate; based on %RVT): 
o Pathologic NR (pNR; %RVT>50%) 
o Partial PR (pPR; 10%<%RVT<50%) 


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o Major PR (MPR; %RVT≤10%) 
o Pathologic CR (pCR; %RVT=0%)