A Randomized Phase 3 Comparison of IMO-2125 With Ipilimumab Versus Ipilimumab Alone in Subjects With Anti-PD-1 Refractory Melanoma (ILLUMINATE-301)
Phase: PHASE3
Conditions: Metastatic Melanoma
Sponsor: Idera Pharmaceuticals, Inc.

IMO-2125 
 
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PROTOCOL 2125-MEL-301 
Study Title 
A Randomized Phase 3 Comparison of IMO-2125 with 
Ipilimumab versus Ipilimumab Alone in Subjects with 
Anti-PD-1 Refractory Melanoma 
Investigational Drug: 
IMO-2125 (tilsotolimod) 
IND Number: 
125515 
EUDRACT Number: 
2017-002454-36 
Sponsor: 
Idera Pharmaceuticals, Inc. 
505 Eagleview Boulevard 
Suite 212 
Exton, PA, 19341, USA 
Protocol Number: 
2125-MEL-301 
Protocol Version: 
4.0 
Date: 
4 June 2020 
Statement of Confidentiality 
This document contains Idera Pharmaceuticals’ privileged or confidential information and 
is provided to you as an Investigator, potential Investigator, or consultant, solely for review 
by you, your staff, and applicable institutional review board(s). The information is not to 
be disclosed to others without written authorization from Idera Pharmaceuticals, Inc. 

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INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices and the Investigator’s Brochure, and I agree 
that it contains all necessary details for me and my staff to conduct this study as described.  I will 
personally oversee the conduct of this study as outlined herein and will make a reasonable effort 
to complete the study within the time designated. 
I will provide all study personnel under my supervision with copies of the protocol and access to 
all information provided by Idera Pharmaceuticals, Inc.  I will discuss this material with them to 
ensure that they are fully informed about IMO-2125, the safety parameters, and the conduct of 
the study in general.  I am aware that, before commencement of this study, the institutional 
review board responsible for such matters must approve this protocol in the clinical facility 
where it will be conducted.  I agree to make all reasonable efforts to adhere to the attached 
protocol. 
I, or my designee, agree to be present at all site-initiation visits and Investigator meetings.  In 
addition, I will ensure the presence of all relevant study personnel under my supervision at these 
visits and meetings. 
I agree to provide all subjects with informed consent forms, as required by government and 
International Council for Harmonisation regulations.  I further agree to conduct the study and 
report to Idera Pharmaceuticals, Inc. any adverse experiences in accordance with the terms of 
this protocol and Good Clinical Practices (GCP). 
 
 
Principal Investigator Name (print) 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 

IMO-2125
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Confidential
Protocol Approval Page
Study Title
A Randomized Phase 3 Comparison of IMO-2125 with Ipilimumab versus 
Ipilimumab Alone in Subjects with Anti-PD-1 Refractory Melanoma
Protocol Number: 2125-MEL-301
Protocol Version:
4.0
Date:
4 June 2020
I, the undersigned, have read and approve this protocol and agree on its content.
Shah Rahimian, MD
Vice President, Medical Lead (Oncology) 
Idera Sponsor Representative
Date
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Version History 
Ver. No.  Approval Date 
Comment 
1.0 
05 July 2017 
Draft 
1.1 
10 July 2017 
Draft 2 
1.2 
31 July 2017 
Initial submission (submitted to one ex-US Health Authority (Australia TGA) 
2.0 
05 Feb 2018 
Revises inclusion criteria for prior BRAF inhibitor treatment and adjuvant anti-
PD-1 
Adds a stratification factor for BRAF mutation status and prior treatment 
Updates the analysis methodology 
Adds secondary endpoint for time to response 
Revises the disease assessment schedule during the first year 
Adds PRO assessment at Week 7 (Arm A) and Week 8 (Arm B) 
Clarifies dosing and assessment procedures  
Updated RECIST v1/1 appendix 
3.0 
10 July 2019 
Updated Medical Monitor Information 
Investigator Statement Updated 
Study Period Updated from 36 to 56 months 
Addition of PD-1 inhibitor as a clarification to nivolumab or pembrolizumab 
Sample Size increase from approximately 308 to approximately 454 
Clarification that IDMC will be performing safety and benefit:risk assessments 
throughout the study 
Clarification to Exclusion #7 language 
Removal of subcutaneous injections where complete tumor regression occurs in 
visceral lesions 
Clarification that a range from 1-4mL of IMO-2125 can be injected into the tumor 
or tumor bed 
IMO-2125 dose modification instruction table updated 
Modified irRECIST updated to irRECIST 
Update to clinically relevant target effect size and clinical assumptions for OS 
Addition of serum samples for anti-drug antibodies for ipilimumab 
Clarification of timing for Active Follow-up 
Clarification on ECG Monitoring for Arm B 
Clarification on AE Reporting 90-day post-last study treatment dose and thereafter 
Administrative changes 

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Version History 
Ver. No.  Approval Date 
Comment 
4.0 
4 June 2020 
Clarified process for reporting serious adverse events (SAEs) 
Updated Medical Monitor information 
Clarified disease staging is per AJCC 7 criteria 
Removed irRECIST assessment from secondary endpoints 
Added duration of response as a secondary endpoint 
Modified planned statistical analyses to re-allocate alpha between the primary 
endpoint family of objective response rate (ORR) followed by overall survival 
(OS), to include hierarchical testing for ORR followed by OS using the fallback 
method, to remove interim analysis for OS, and to allow for analysis of final OS at 
approximately 36 months if the required number of events have not yet been 
reached 
Clarified requirements related to corticosteroid use 
Modified procedures for assessment of subjects with changes in complement 
levels 
Included several additional adverse events that should be reported as immune-
related in the absence of another etiology 
 

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EMERGENCY CONTACT INFORMATION 
 
Reporting of Serious Adverse Events (SAEs) 
 
Any SAE must be reported within 24 hours via SAE form.  See Section 10.1 (Adverse Events) 
for definition and reporting procedure for SAEs. 
 
SAEs must be captured on the paper SAE form and reported by email within 24 hours to:  
Role in Study 
Name, Title, Address 
Telephone / fax / email 
 
Sponsor Medical Monitor 
Shah Rahimian, MD 
Medical Lead (Oncology) 
505 Eagleview Blvd., Suite 212 
Exton, PA 19341 
Tel: +1 484-348-1642 
Mobile: +1 814-691-7377 
Email: 
srahimian@iderapharma.com 
 
24-Hour SAE Reporting 
TMC PharmaLodge Farm Barn 
Elvetham Park Estate 
Fleet Road, Hartley Wintney 
Hants, RG27 8AS, UK 
 
 
Email: Idera@TMCPharma.com 
Fax:  
Australia: (02) 8569 0673 
Canada: +1 800 364 8501 
Czech Republic, France,  
Germany, Italy, Netherlands, Spain, 
Sweden, United Kingdom:  
+44 (0)1189 195 200 
Israel: +972 (0) 3761 8089 
United States of America: (617) 663 
6222 
 
 
 
 

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1. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................7 
2. 
SYNOPSIS .................................................................................................................12 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................25 
4. 
BACKGROUND INFORMATION AND RATIONALE..........................................28 
4.1. 
Refractory Melanoma: The Disease Under Study ......................................................28 
4.2. 
Toll-like Receptor Agonists in the Treatment of Cancer ............................................28 
4.3. 
IMO-2125 ...................................................................................................................29 
4.3.1. 
Nonclinical Experience with IMO-2125 ....................................................................29 
4.3.1.1. 
Nonclinical Pharmacology ..........................................................................................29 
4.3.1.2. 
Nonclinical Toxicology ..............................................................................................29 
4.3.2. 
Clinical Experience with IMO-2125 ..........................................................................30 
4.3.2.1. 
IMO-2125 in Combination with Checkpoint Inhibitors (Study 2125-204) ................30 
4.3.2.2. 
IMO-2125 in Refractory Solid Tumors (Study 2125-RST-101) ................................31 
4.4. 
Rationale for Study Design .........................................................................................31 
4.4.1. 
Rationale for Population .............................................................................................31 
4.4.2. 
Rationale for Ipilimumab Comparator ........................................................................31 
4.4.3. 
Rationale for Combining IMO-2125 with Ipilimumab ..............................................31 
4.4.4. 
Rationale for Dose ......................................................................................................32 
5. 
STUDY OBJECTIVES ..............................................................................................34 
5.1. 
Primary Objective .......................................................................................................34 
5.2. 
Secondary Objectives .................................................................................................34 
5.3. 
Exploratory Objectives ...............................................................................................34 
6. 
STUDY ENDPOINTS ................................................................................................35 
6.1. 
Primary Endpoint Family ...........................................................................................35 
6.2. 
Secondary Endpoints ..................................................................................................35 
6.3. 
Exploratory Endpoints ................................................................................................35 
7. 
SUBJECTS TO BE RECRUITED .............................................................................36 
7.1. 
Subject Recruitment ....................................................................................................36 
7.2. 
Inclusion Criteria ........................................................................................................36 

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7.3. 
Exclusion Criteria .......................................................................................................37 
8. 
STUDY DESIGN .......................................................................................................39 
8.1. 
Overview .....................................................................................................................39 
8.1.1. 
Independent Review Facility ......................................................................................39 
8.1.2. 
Independent Data Monitoring Committee ..................................................................39 
8.2. 
Duration of Study .......................................................................................................39 
8.2.1. 
Treatment Duration .....................................................................................................39 
8.2.2. 
Study Duration ............................................................................................................39 
8.3. 
Study Drug Discontinuation and Study Withdrawal ..................................................40 
8.3.1. 
Subject Discontinuation of Study Drug ......................................................................40 
8.3.2. 
Subject Withdrawal from the Study ...........................................................................40 
8.3.3. 
Study and Subject Completion ...................................................................................40 
8.3.4. 
Lost to Follow-up .......................................................................................................40 
8.4. 
Number of Subjects ....................................................................................................40 
8.5. 
Benefits and Risk Assessment ....................................................................................41 
9. 
STUDY TREATMENTS............................................................................................42 
9.1. 
IMO-2125 ...................................................................................................................42 
9.2. 
Ipilimumab ..................................................................................................................42 
9.3. 
Drug Handling and Administration ............................................................................42 
9.3.1. 
Drug Delivery to Site ..................................................................................................42 
9.3.2. 
Drug Storage ...............................................................................................................42 
9.3.2.1. 
IMO-2125 Storage ......................................................................................................42 
9.3.2.2. 
Ipilimumab Storage ....................................................................................................42 
9.3.3. 
Administration ............................................................................................................42 
9.3.3.1. 
Ipilimumab- Arm A ....................................................................................................43 
9.3.3.2. 
IMO-2125 + Ipilimumab- Arm B ...............................................................................43 
9.3.4. 
Dose Modification ......................................................................................................43 
9.3.4.1. 
Dose Modifications for Ipilimumab-Related Toxicities .............................................44 
9.3.4.2. 
Procedures for Assessment of Subjects with Changes in Complement Levels ..........46 
9.3.4.3. 
Procedures for Assessment of Subjects with Symptomatic 
Thrombocytopenia ......................................................................................................46 
9.4. 
Labeling ......................................................................................................................47 
9.5. 
Drug Accountability ...................................................................................................47 

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9.6. 
Concomitant and Prohibited Medications ..................................................................47 
9.6.1. 
Concomitant Medications ...........................................................................................47 
9.6.2. 
Prohibited Medications ...............................................................................................47 
10. 
ADVERSE EVENT REPORTING ............................................................................48 
10.1. 
Adverse Events ...........................................................................................................48 
10.1.1. 
Definition of Adverse Events .....................................................................................48 
10.1.1.1. 
Adverse Event .............................................................................................................48 
10.1.1.2. 
Serious Adverse Event ................................................................................................48 
10.1.1.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .....................................49 
10.1.2. 
Recording Adverse Events .........................................................................................49 
10.1.3. 
Characterizing Adverse Events ...................................................................................49 
10.1.3.1. 
Description of Event ...................................................................................................49 
10.1.3.2. 
Date and Time of Onset ..............................................................................................50 
10.1.3.3. 
Relationship to Study Drug ........................................................................................50 
10.1.3.4. 
Immune-related AEs ...................................................................................................50 
10.1.3.5. 
Severity .......................................................................................................................51 
10.1.3.6. 
Grading of Laboratory Safety Tests for Reporting and Analysis ...............................52 
10.1.3.7. 
Management of Study Drug upon Occurrence of an Adverse Event .........................52 
10.1.3.8. 
Actions Taken for Management of Adverse Event ....................................................52 
10.1.3.9. 
Follow-up and Outcome of Adverse Events ...............................................................53 
10.1.3.10. Date and Time of Outcome .........................................................................................53 
10.1.4. 
Reporting Adverse Events ..........................................................................................54 
10.1.4.1. 
Where to Report Serious Adverse Events ..................................................................54 
10.1.4.2. 
Procedures for Reporting Serious Adverse Events to the Sponsor .............................54 
10.1.4.3. 
Other Reportable Events .............................................................................................54 
10.1.4.4. 
Requirements for Expedited and Periodic Reporting of Adverse Events ...................54 
11. 
ASSESSMENT OF EFFICACY ................................................................................55 
11.1. 
Tumor Response .........................................................................................................55 
11.2. 
Patient-Reported Outcomes (EORTC QLQ-C30) ......................................................55 
12. 
SAFETY ASSESSMENTS ........................................................................................57 
12.1. 
Vital Signs ..................................................................................................................57 
12.2. 
Laboratory Assessments .............................................................................................57 

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12.3. 
Other Safety Assessments ...........................................................................................58 
12.3.1. 
Physical Examination .................................................................................................58 
12.3.2. 
Electrocardiogram Monitoring ...................................................................................59 
12.3.3. 
ECOG Performance Status .........................................................................................59 
13. 
PHARMACOKINETICS ...........................................................................................60 
14. 
EXPLORATORY ASSESSMENTS ..........................................................................61 
14.1. 
Tumor Biomarkers ......................................................................................................61 
14.2. 
Anti-Drug Antibodies .................................................................................................61 
15. 
STATISTICAL ANALYSIS METHODS ..................................................................62 
15.1. 
Determination of Sample Size ....................................................................................62 
15.2. 
Analysis Populations ..................................................................................................62 
15.2.1. 
Screened Population ...................................................................................................62 
15.2.2. 
Intent-to-Treat Population ..........................................................................................62 
15.2.3. 
Safety Population ........................................................................................................62 
15.2.4. 
Pharmacokinetic Population .......................................................................................63 
15.3. 
Missing Data ...............................................................................................................63 
15.4. 
Analysis of Efficacy ...................................................................................................63 
15.4.1. 
Analysis of the Family of Primary Endpoints ............................................................64 
15.4.1.1. 
Analysis of Objective Response Rate .........................................................................64 
15.4.1.2. 
Primary Analysis of Overall Survival .........................................................................64 
15.4.2 
 Analysis of Secondary Efficacy Endpoints ...............................................................64 
15.5. 
Analysis of Safety .......................................................................................................65 
15.6. 
Analysis of Pharmacokinetics .....................................................................................66 
15.7. 
Analysis of Patient-Reported Outcomes .....................................................................66 
15.8. 
Exploratory Analyses ..................................................................................................66 
16. 
DATA COLLECTION ...............................................................................................67 
16.1. 
Required Data .............................................................................................................67 
16.2. 
Data Collection and Tracking .....................................................................................67 
17. 
ADDITIONAL STUDY RESPONSIBILITIES .........................................................68 
17.1. 
Investigator Responsibilities .......................................................................................68 
17.2. 
Study Data Reporting and Processing ........................................................................68 
17.3. 
Training .......................................................................................................................68 

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17.4. 
Monitoring the Investigational Site ............................................................................68 
17.5. 
Study Documentation .................................................................................................68 
17.6. 
Source Documentation ................................................................................................69 
17.7. 
Protocol Deviations ....................................................................................................69 
17.8. 
Study Supply Accountability ......................................................................................70 
17.9. 
Data Transmittal and Record Retention .....................................................................70 
17.10. 
Study Closeout ............................................................................................................70 
17.11. 
Audit/Inspections ........................................................................................................70 
18. 
ETHICAL CONSIDERATIONS................................................................................72 
18.1. 
Role of Sponsor ..........................................................................................................72 
18.2. 
Informed Consent .......................................................................................................72 
18.3. 
Confidentiality of Subjects .........................................................................................73 
18.4. 
Institutional and Ethics Review ..................................................................................73 
18.5. 
Financial Disclosure ...................................................................................................73 
19. 
LIST OF REFERENCES ............................................................................................74 
20. 
APPENDICES ............................................................................................................77 
20.1. 
ECOG .........................................................................................................................77 
20.2. 
RECIST v1.1 Criteria .................................................................................................78 
20.3. 
The use of irRECIST (Immune-Related Response Evaluation Criteria in 
Solid Tumors) in this study.........................................................................................83 
LIST OF TABLES 
Table 1: 
Schedule of Evaluations – Ipilimumab Alone (Arm A) .............................................21 
Table 2: 
Schedule of Evaluations – Ipilimumab with IMO-2125 (Arm B) ..............................23 
Table 3: 
Dose Modification Instructions for IMO-2125 ...........................................................44 
Table 4: 
Recommended ipilimumab dose modifications for selected toxicities ......................44 
Table 5:  
Estimating Severity Grade ..........................................................................................51 
Table 6: 
Date and Time of Outcome for Adverse Event by Outcome Class ............................53 
Table 7: 
Safety Laboratory Measurements ...............................................................................58 

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2. 
SYNOPSIS 
Name of Sponsor/Company: Idera Pharmaceuticals, Inc. 
Name of Investigational Product: IMO-2125  
Title of Study: A Randomized Phase 3 Comparison of IMO-2125 with Ipilimumab versus 
Ipilimumab Alone in Subjects with Anti-PD-1 Refractory Melanoma 
Study period: The planned end of study will be approximately 
56 months (the projected time for the required number of deaths 
to support the analysis of OS to occur) after the first subject is 
randomized. 
Phase of development: 
Phase 3 
Rationale: IMO-2125 is a synthetic phosphorothioate oligonucleotide that acts as a direct 
agonist of Toll-like receptor (TLR) 9 to stimulate the innate and adaptive immune systems.  
Activation of TLR9 by IMO-2125 induces high levels of interferon (IFN)-α from 
plasmacytoid dendritic cells (pDCs) along with an array of endogenous cytokines and 
chemokines.  Intratumoral IMO-2125 monotherapy has been shown to produce abscopal 
effects in mice, including anti-tumor activity associated with an increase in infiltrating CD8+ 
T cells, and durable and specific cytotoxic T cell responses against tumor antigens.  The 
combination of intratumoral IMO-2125 with an anti-cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) monoclonal antibody (mAb) results in improved tumor control compared 
to either agent alone. 
An ongoing Phase 1/2 clinical study of intratumoral IMO-2125 in combination with 
ipilimumab (NCT02644967) shows the combination to be well-tolerated over the entire range 
of IMO2125 doses tested, with biopsy evidence for dendritic cell activation followed by 
infiltration of tumor-specific immune cells.  Moreover, clinical responses (including durable 
complete response [CR]) have been seen in subjects previously refractory to programmed cell 
death-1 (PD-1) inhibitors.  Since no therapy has been shown to prolong survival following 
failure of first-line immunotherapy, this Phase 3 study is being performed to provide definitive 
evidence for superiority of the IMO2125/ipilimumab combination over currently available 
therapy.    
Objectives:  
Primary:  Compare the efficacy (measured by objective response rate [ORR] and overall 
survival [OS]) of intratumoral IMO-2125 in combination with ipilimumab versus ipilimumab 
alone. 
Secondary:  Assess other measures of clinical benefit, safety, pharmacokinetics (PK), and 
patient-reported outcomes (PROs).  
Exploratory:  Investigate potential biomarkers and the incidence of anti-IMO-2125 and anti-
ipilimumab antibodies. 
Study design:  
Randomized Phase 3 global, multi-center, open-label comparison of ipilimumab with and 
without intratumoral IMO-2125 in subjects with advanced melanoma who had confirmed 
disease progression while on a PD-1 inhibitor, e.g., nivolumab or pembrolizumab.  Subjects 
will be randomized 1:1 to treatment arms.  The primary endpoint family of the study includes 
ORR and OS. 

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Number of subjects (planned):  454 
Periodic data reviews will be performed by an Independent Data Monitoring Committee 
(IDMC) as described in the IDMC Charter. The first IDMC meeting will occur after 
approximately 20 subjects on each arm have been treated with two doses of ipilimumab.  This 
initial meeting will review safety only. 
Inclusion criteria 
1. Subjects must be willing and able to sign the informed consent and comply with the 
study protocol. 
2. Must be ≥18 years of age. 
3. Histologically confirmed metastatic melanoma with measurable (by Response 
Evaluation Criteria in Solid Tumors [RECIST] v1.1), Stage III (lymph node or in 
transit lesions) or Stage IVA, IVB, or IVC disease that is accessible for injection. Stage 
should be determined using the American Joint Committee on Cancer (AJCC) Cancer 
Staging Manual, Seventh Edition. 
4. Confirmed progression during or after treatment with a PD-1 inhibitor (cannot be part 
of a bi-specific antibody), e.g., nivolumab or pembrolizumab.  Confirmed progression 
is defined as: 
• Radiological progression (confirmed at least 4 weeks after the initial scan showing 
progressive disease); or  
• For progression based solely on worsening of non-target or new, non-measurable 
disease, confirmation by an additional scan at least 4 weeks after the initial scan 
unless progression is accompanied by correlative symptoms.   
In addition, all the following must hold:  
• No intervening anti-cancer therapy between the last course of PD-1 inhibitor 
treatment and the first dose of study treatment is allowed except for local 
measures (e.g., surgical excision or biopsy, focal radiation therapy). 
• The interval between last PD-1 inhibitor and start of study treatment should be 
at least 21 days with no residual anti-PD-1-related immune toxicities in excess 
of Grade 1 severity. 
• Subjects who had adjuvant anti-PD-1 treatment are eligible if they have either 
disease recurrence after the end of adjuvant treatment or on-treatment disease 
recurrence after ≥12 weeks of adjuvant treatment. 
• If BRAF mutation status is unknown, before randomization the subject must 
have BRAF testing performed using an approved assay method. 
• Patients with BRAF-positive tumor(s) are eligible for the study if they received 
prior treatment with a BRAF inhibitor (alone or in combination with a MEK 
inhibitor) or declined targeted therapy. 
5. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1. 
6. Adequate baseline organ function as defined by: 
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (1500/mm3) 

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• Platelet count ≥75 x 109/L (75,000/mm3) 
• Hemoglobin ≥8.0 g/dL (4.96 mmol/L) 
• Serum creatinine ≤1.5 x upper limit of normal (ULN) or calculated creatinine 
clearance ≥60 mL/minute (≤Grade 1) 
• Aspartate aminotransferase (AST) ≤2.5 x ULN; alanine aminotransferase 
(ALT) ≤2.5 x ULN; AST/ALT <5 x ULN if liver involvement (≤Grade 1) 
• Serum bilirubin ≤1.5 x ULN, except in subjects with Gilbert’s Syndrome who 
must have a total bilirubin <3 mg/dL (≤Grade 1) 
7. Women of childbearing potential (WOCBP) and men must agree to use effective 
contraceptive methods from screening until at least 90 days after the last dose of either 
ipilimumab or IMO-2125, whichever is later. 
Non-childbearing potential is defined as a woman who meets either of the following 
criteria: a) postmenopausal state defined as no menses for 12 months without an 
alternative medical cause, or b) documented hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy. 
Effective contraception methods are defined as one of the following: 
• True abstinence, defined as refraining from heterosexual intercourse, when this 
is in line with the preferred and usual lifestyle of the subject.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of a trial, and withdrawal are not 
acceptable methods of contraception. 
• Condoms and spermicide  
• Diaphragm and spermicide  
• Oral or implanted hormonal contraceptive (e.g., Implanon™)  
NOTE: For subjects in Sweden, low dose oral contraceptives are not permitted 
• An intra-uterine device  
8. WOCBP must have a negative pregnancy test (serum or urine) according to the 
Schedule of Evaluations (Table 1 and Table 2).  
Exclusion criteria 
1. Ocular melanoma. 
2. Prior therapy with a TLR agonist, excluding topical agents.  
3. Prior ipilimumab treatment with the exception of adjuvant treatment completed ≥6 
months prior to enrollment.  
4. Systemic treatment with IFN-α within the previous 6 months. 
5. Known hypersensitivity to any oligodeoxynucleotide. 
6. Active autoimmune disease requiring disease-modifying therapy at the time of 
screening. 

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7. Subjects with a requirement for receiving more than physiologic doses of systemic 
steroids (>10 mg/day of prednisone or equivalent) for the 2 weeks preceding start of 
study treatment. 
8. Subjects with another primary malignancy that has not been in remission for at least 
3 years with the exception of non-melanoma skin cancer, curatively treated localized 
prostate cancer with non-detectable prostate-specific antigen, cervical carcinoma in 
situ on biopsy or a squamous intraepithelial lesion on Papanicolaou (Pap) smear, and 
thyroid cancer (except anaplastic). 
9. Active systemic infections requiring antibiotics. 
10. Known active, hepatitis A, B, or C infection. 
11. Known diagnosis of human immunodeficiency virus (HIV) infection. 
12. Women who are pregnant or breast-feeding. 
13. Prior anaphylactic or other severe infusion reaction associated with human antibody 
administration that cannot be managed with standard supportive measures. 
14. Presence of known central nervous system, meningeal, or epidural metastatic 
disease.  However, subjects with known brain metastases are allowed if the brain 
metastases are stable for ≥4 weeks before the first dose of study treatment.  Stable is 
defined as neurological symptoms not present or resolved to baseline, no radiologic 
evidence of progression, and steroid requirement of prednisone ≤10 mg/day or 
equivalent. 
15. Impaired cardiac function or clinically significant cardiac disease. 

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Investigational product, dosage, and mode of administration:  
IMO-2125 will be supplied as an aqueous sterile solution. Each vial contains IMO-2125 
sodium salt equivalent to 8 mg/mL of IMO-2125 free acid compounded with 0.9% sodium 
chloride. Ipilimumab is a commercially available product. 
Subjects will be randomized (1:1) to receive either: 
1. Arm A – ipilimumab 3 mg/kg intravenous (i.v.) Weeks 1, 4, 7, and 10  
or 
2. Arm B – IMO-2125, 8 mg intratumorally Weeks 1, 2, 3, 5, 8, 11, 16, 20, and 24 in 
combination with ipilimumab 3 mg/kg i.v. Weeks 2, 5, 8, and 11 
IMO-2125 will be given prior to ipilimumab on days when both are to be administered.  
IMO-2125 will be administered intratumorally as a 1-4 mL injection to a single designated 
lesion throughout the study.  The injected tumor will be selected from (in order of priority) 
pathologic draining lymph nodes, superficial or subcutaneous (s.c.) metastases, or deep or 
visceral metastases, the latter requiring interventional radiology support.  The dose will be 
thoroughly distributed within the injected tumor using a single injection site and a fanning 
method to ensure even distribution.  Dosing volume will be adjusted on a sliding scale and 
based on the judgment of the investigator as the injected tumor shrinks to maintain a constant 
total dose.  Additional details are described in the Pharmacy Manual. In the event a full dose 
can no longer be practically administered into the injected tumor, another tumor may be 
selected.  In the event a complete tumor regression occurs prior to completion of therapy, any 
remaining IMO-2125 doses should be administered into the tumor bed, except in the case of 
visceral lesions for which injections should be stopped.  Treatment following disease 
progression is at the discretion of the Investigator.  Cross-over therapy will not be allowed for 
subjects assigned to Arm A.   
Dose Modification: 
The most common adverse events (AEs) following intratumoral administration of IMO-2125 
have been non-specific “flu-like” symptoms and mild to moderate injection site reactions.  In 
combination with ipilimumab, IMO-2125 has been associated with immune-related AEs 
(irAEs) (e.g., hypophysitis) and fever.  Subject management guidelines for AEs of key 
interest, including irAEs and potential class effects seen with other oligonucleotide drugs 
(e.g., symptomatic thrombocytopenia) are provided.  Refer to the current, locally approved 
ipilimumab package insert for specific guidance in managing irAEs associated with 
ipilimumab and additional guidance in Section 9.3.4.1 (Table 4).  IMO-2125 therapy should 
be continued if ipilimumab is discontinued early for toxicity.       
Dose modification instructions for IMO-2125 are provided in the table below: 
 
Event 
Action 
Dose Modification 
Local or mild systemic reaction 
(e.g., pyrexia) 
Supportive measures as required.  
Continue treatment with IMO-2125 per 
clinical discretion. 
None 
Severe systemic reaction for which 
more aggressive measures including 
hospitalization are required (e.g., 
severe hypotension) 
Supportive measures as required.  Hold 
further dosing until the event resolves to 
baseline or G1 and the re-treatment 
criteria below are met. 
None 

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Life-threatening AE 
(e.g., anaphylaxis) 
Supportive measures as required. 
Discontinue treatment 
Serious procedural complication 
related to deep or visceral injection 
(e.g. pneumothorax or hematoma 
formation) 
Supportive measures as required 
Discontinue visceral 
injections (treatment may 
be continued if a 
superficial lesion or 
tumor-involved lymph 
node is available for 
injection instead) 
     
Conventional supportive medications (including infliximab for immune-related colitis and 
growth factor support) are permitted. 
Criteria for re-initiation of treatment with each dose of study drug include:  
• ANC ≥1.5 x 109/L (1500/μL); 
• Platelets ≥75 x 109/L (75,000/μL); 
• Resolution of all clinically significant non-hematologic toxicities for which a 
causal association to study treatment cannot be ruled out to Grade ≤1 or baseline 
Duration of study:  
The Treatment Phase of the study is 10 weeks for subjects assigned to Arm A and 24 weeks 
for subjects assigned to Arm B.  Subjects who discontinue disease assessments due to disease 
progression or the start of new anticancer treatment (with or without disease progression), will 
enter the Survival Follow-up Period (in which they are contacted by telephone according to 
the Schedule of Evaluations).  Subjects who complete or discontinue study treatment for 
reasons other than disease progression or the start of new anticancer treatment but remain in 
the study will continue clinical and radiological disease evaluations in the Active Follow-up 
Period according to the Schedule of Evaluations.   
The planned end of study will be approximately 56 months (the projected time for the required 
number of deaths to support the analysis of OS to occur) after the first subject is randomized.  
Endpoints 
Primary Endpoint Family:   
The primary endpoint family (see Food and Drug Administration [FDA] Guidance for 
Industry, 2017) includes: 
• ORR by blinded independent review using RECIST v1.1 
• OS, defined as the time to death from any cause measured from the date of 
randomization 
Secondary: 
• ORR by investigator assessment using RECIST v1.1 
• Duration of response (DoR) by blinded independent review and by investigator 
assessment using RECIST v1.1, measured from the time that criteria are first met for 

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CR or partial response (PR) (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented 
• Durable response rate (DRR) by blinded independent review and investigator 
assessment using RECIST v1.1, defined as the rate of CR or PR lasting ≥6 months 
with onset during the first 12 months of treatment 
• Time to response (TTR), defined as time to first evidence of a complete or partial 
response (using RECIST v1.1) measured from the date of randomization, by blinded 
independent review and investigator assessment 
• Progression-free survival (PFS), defined as the time to disease progression or death 
from any cause measured from the date of randomization, by blinded independent 
review and investigator assessment (using RECIST v1.1) 
• Landmark PFS at 1 and 2 years by blinded independent review and investigator 
assessment (using RECIST v1.1) and landmark OS at 1 and 2 years  
• PRO using the European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire-Core 30 (EORTC QLQ-C30) 
• Safety, including AEs, laboratory and vital sign tests, electrocardiograms (ECGs), 
ECOG, and physical examination  
• Plasma PK of IMO-2125  
Exploratory: 
• Immunologic biomarkers (optional tumor biopsies) 
• Measurement of anti-IMO-2125 and anti-ipilimumab antibodies  
Study Assessments 
Efficacy: Tumor assessments will be performed at Screening and Week 12, then every 8 
weeks for the first year and every 12 weeks in subsequent years using consistent imaging 
modality, facilities, and reviewers.  Investigators should follow irRECIST guidelines for 
subject management and provide visit response assessments using RECIST v1.1 and 
irRECIST.  Blinded central reviewers will provide independent assessment of tumor response 
using RECIST v1.1 and modified irRECIST.     
PRO: Periodic assessments will be made using the EORTC-QLQ-C30. 
Safety: Assessments will include AEs, physical examination, vital signs, ECOG performance 
status, laboratory monitoring, periodic ECGs, thyroid function, complement levels, urinalysis, 
and pregnancy screening.  
Pharmacokinetics: Blood samples for IMO-2125 (Arm B only) PK analysis will be drawn 
according to the Schedule of Evaluations.   
Exploratory: Samples for optional tumor biopsies will be obtained in both treatment arms.  
Anti-IMO-2125 and anti-ipilimumab antibody formation will be assessed in subjects assigned 
to both arms.  Immunologic biomarker evaluations may include flow cytometry for immune 
cell subsets, immunohistochemistry, and gene expression profiling, among others.  

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Statistical methods 
In this study, ORR and OS comprise a primary endpoint family; both have a priori hypotheses 
and will be tested for statistical significance.  ORR will be tested first followed by OS.   The 
fallback method for the primary endpoint family will be applied to control the study-wise 
Type I error rate. 
Under the fallback method, α1 = 0.02 is assigned to the one-sided ORR test and an alpha of 0.005 
is saved for the one-sided OS test.  
• 
If the ORR test is significant at α1 = 0.02, this alpha is unused and will be passed to the OS 
test as an additional alpha of 0.02, giving a total alpha for the OS test of 0.025. The OS test 
will then be performed at the significance level of 0.025.   
• If the ORR test is not significant at 0.02 level, then this alpha of 0.02 will not be available 
to be passed on for the OS test. The OS test will be performed at the originally reserved 
alpha of 0.005.  
The analysis of ORR (assessed by blinded independent review using RECIST v1.1) will be 
performed using a Cochran-Mantel-Haenzsel (CMH) test comparing the ORR for the two 
treatment groups controlling for the randomization strata.  With 454 subjects randomized with 
a 1:1 ratio, this test will have 90% statistical power (calculated based on chi-square test) to 
demonstrate an increase in the ORR from the postulated response of 12% for ipilimumab 
alone in this setting to 24% for the IMO-2125 + ipilimumab combination, at a 0.02 level of 
significance.  The analysis of ORR will take place when all randomized subjects fall within 
one of the following categories: 
• completed scheduled study treatment and completed at least 28 weeks on the study;  
• prematurely discontinued study treatment and completed at least 28 weeks on the 
study;  
• withdrew, were lost to follow-up, or died before completing at least 28 weeks on the 
study.  
The analysis of OS will be performed using a stratified log-rank test controlling for the 
randomization strata.  A sample size of 454 subjects provides 90% power to test the 
alternative hypothesis of hazard ratio (HR) ≤ 0.677 at an α of 0.005 (one-sided).  The HR of 
0.677 corresponds to an improvement in the median survival from 11.4 months (the historical 
control for ipilimumab alone) to 16.9 months with the IMO-2125 + ipilimumab combination.   
The OS power calculations are based on log-rank test and assume that the trial will have ~20 
months of uniform accrual, an overall study duration up to 56 months, and a 10% drop-out 
rate. If, under the fallback method, a total alpha of 0.025 is available for the OS significance test, 
then this test will have 90% power to test the alternative hypothesis of HR ≤ 0.72 at an α of 0.025 
(one-sided) which corresponds to an improvement in the median survival from 11.4 months 
(the historical control for ipilimumab alone) to 15.8 months with the IMO-2125 + ipilimumab 
combination. 

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The analysis will be performed when the required number of deaths for the OS analysis (392) 
is reached, or approximately 36 months after the last subject is randomized, whichever occurs 
first.   
Progression-free survival will be assessed centrally and by investigator using RECIST v1.1 
and estimated by the Kaplan-Meier method.  Subjects who do not have a PFS event at the time 
of an analysis, including those who have started new anticancer therapy, withdrawn from the 
study, or been lost to follow-up without disease progression, will be censored at the date of the 
last valid disease assessment, defined as the latest assessment at which the subject had a 
RECIST v1.1 response of CR, PR, or stable disease (SD). 
Stratification factors will include duration of prior anti-programmed death receptor-1 (PD-1) 
therapy (≥12 weeks vs <12 weeks), metastasis stage (M1c vs other), and BRAF mutation 
status and prior targeted therapy (BRAF wild type, BRAF mutation positive with prior 
targeted therapy, or BRAF mutation positive with no prior targeted therapy) using block 
randomization.  Targeted therapy is the use of an approved BRAF or MEK inhibitor alone or 
in combination.   
Date of Synopsis: 4 June 2020 

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Table 1: 
Schedule of Evaluations – Ipilimumab Alone (Arm A) 
Evaluation 
Screening1 
Treatment Period2 
Active F/up3 
Survival 
F/up4 
 
Week 
1 
4 
7 
10 
12 
14 
 
 
Informed consent5 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion  
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
ECOG  
X 
X 
X 
X 
X 
 
X 
 
 
CBC with diff 
X 
X6 
X 
X 
X 
 
X 
X14 
 
Chemistry profile 
X 
X6 
X 
X 
X 
 
X 
X14 
 
CH50/C3/C4 
 
X 
 
 
 
 
X 
 
 
Coagulation7 
 
X 
 
 
 
 
X 
 
 
Urinalysis  
 
X 
 
 
 
 
X 
 
 
Thyroid function tests 
 
X 
X 
X 
X 
 
X 
X14 
 
Vital signs8 
 
X 
X 
X 
X 
X 
X 
 
 
ECG 
 
X 
 
 
 
 
X 
 
 
Directed physical 
X 
X  
X 
X 
X 
X 
 
 
 
Pregnancy test9 
X 
X 
 
 
 
 
X 
 
 
Ipilimumab dosing 
 
X 
X 
X 
X 
 
 
 
 
Disease assessment 
X 
 
 
 
 
X12 
 
X12 
 
PRO 
 
X13 
 
X13 
 
X13 
 
X13 
 
AE/conmeds 
Continuous10 
Serum samples for 
anti-drug antibodies16 
 
X 
 
 
 
 
X 
 
 
Tumor biopsies11 
X11 
 
 
X11 
 
 
 
 
 
Telephone contact 
 
 
 
 
 
 
 
 
X 
Anticancer treatment 
information 
 
 
 
 
 
 
 
 
X15 
AE=adverse event; aPTT=activated partial thromboplastin time; C3/C4=complement components C3 and C4; 
CBC=complete blood count; CH50=total hemolytic complement activity 50; diff=differential; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; eCRF=electronic case report form; 
F/up=Follow-up; ICF=informed consent form; INR=international normalized ratio; PK=pharmacokinetic(s); 
PRO=patient-reported outcome; PT=prothrombin time; TSH=thyroid stimulating hormone; USPI=US Prescribing 
Information; WOCBP=women of childbearing potential  
1. 
All Screening tests and assessments must be performed within 28 days before the date of randomization, except 
for ECOG and laboratory tests, which should be performed within 10 days before the first dose of study drug, 
and pregnancy test should be performed within 72 hours, if pregnancy test is not performed within 72 hours 
prior to randomization, it should be done on the first day of ipilimumab dosing. 
2. 
All assessments will occur within a ±3-day window.  Ipilimumab dosing should follow the product label 
(e.g., USPI).  
3. 
Subjects who discontinue study treatment due to completion of the planned treatment or for reasons other than 
disease progression or start of new anticancer treatment will enter the Active Follow-up Period. Assessments 
during the Active Follow-up Period will follow the schedule of the disease assessments and will occur at Week 
12 (±1 week), then every 8 weeks (±2 weeks) for the first year and every 12 weeks (±2 weeks) during 
subsequent years. 
4. 
Subjects who discontinue disease assessments due to either disease progression or the start of new anticancer 
treatment, with or without disease progression, will enter the Survival Follow-up Period (contacted by telephone 
every 3 months until death or the end of the study). Assessments will occur within a ±14-day window. 
5. 
Subjects must be randomized within 28 days after signing the ICF; the first dose of study drug should be 
administered within 2 days after randomization. 
6. 
CBC and chemistries do not have to be repeated if Screening tests are completed within 7 days of start of 
treatment. 
7. 
PT, aPTT, INR. 

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8. 
Vital signs will include systolic and diastolic blood pressure, body temperature, pulse rate, body weight, and 
height (Week 1 only).  Vital signs should be completed prior to treatment administration. 
9. 
WOCBP only.  Pregnancy test after randomization should be completed as deemed necessary by the 
Investigator or required by local law. 
10. During the Follow-up Periods, for 90 days after the last dose of study treatment, all SAEs, irAEs, AEs Grade 
≥3, and associated concomitant medications for their treatment must be reported. For the remainder of the 
Follow-up Periods, AE reporting should be limited to Treatment-related Grade ≥3 AEs and SAEs, and the 
associated concomitant medications. 
11. Optional (see Laboratory Manual). 
12. To inform treatment management decisions, disease assessments are to be completed at Week 12 (±1 week), 
then every 8 weeks (±2 weeks) for the first year and every 12 weeks (±2 weeks) during subsequent years. 
13. To minimize bias in the PRO data, disease and PRO assessments are to be completed prior to study drug 
administration and AE evaluations at Weeks 1, 7, and 12 (±1 week), then every 8 weeks (±2 weeks) for the first 
year and every 12 weeks (±2 weeks) during subsequent years. 
14. Per institutional practices following the frequency of active follow-up disease assessments. 
15. Follow-on anticancer treatment information will be collected during the telephone calls. 
16. Serum samples will be collected for analysis of anti- ipilimumab antibodies; details are provided in the 
Laboratory Manual. Baseline sample to be collected at Week 1 before the first dose of study treatment. 

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Table 2: 
Schedule of Evaluations – Ipilimumab with IMO-2125 (Arm B) 
Evaluation 
Screening1 
Combination Treatment2 
IMO Maintenance 
Active F/up3 
Survival 
F/up4 
 
Week 
1 
2 
3 
5 
8 
11 
12 
16 
20 
24 
 
 
Informed consent5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG  
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
CBC with diff 
X 
X6 
X 
X 
X 
X 
X 
 
X 
X 
X 
X18 
 
Chemistry profile 
X 
X6 
 
 
X 
X 
X 
 
X 
 
 
X18 
 
CH50/C3/C47 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Coagulation8 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Urinalysis  
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Thyroid function tests 
 
X 
 
 
X 
X 
X 
 
X 
 
 
X18 
 
Vital signs9 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
ECG 
 
X22 
 
 
 
 
X22 
 
X 
 
X 
 
 
Directed physical 
X 
X  
 
 
X 
X 
X 
 
 
 
 
 
 
Pregnancy test10 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
IMO-2125 dosing 
 
X 
X11 
X 
X11 
X11 
X11 
 
X20 
X20 
X20 
 
 
Ipilimumab dosing 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
Disease Assessment 
X 
 
 
 
 
 
 
X16 
 
  
 
X 
 
PRO 
 
X17 
 
 
 
X17 
 
X17 
 
 
 
X17 
 
AE/Conmeds 
Continuous12 
IMO-2125 PK samples13 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Serum samples for 
anti-drug antibodies14 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X19 
 
Tumor biopsies 
X15 
 
 
 
 
X15 
 
 
 
 
 
 
 
Telephone contact 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Anticancer treatment 
information 
 
 
 
 
 
 
 
 
 
 
 
 
X21 
AE=adverse event; aPTT=activated partial thromboplastin time; C3/C4=complement components C3 and C4; CBC=complete blood count; CH50=total 
hemolytic complement activity 50; diff=differential; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; eCRF=electronic case report 
form; F/up=Follow-up; ICF=informed consent form; IMO=IMO-2125; INR=international normalized ratio; PK=pharmacokinetic(s); PRO=patient-reported 
outcome; PT=prothrombin time; TSH=thyroid stimulating hormone; WOCBP=women of childbearing potential  

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1. 
All Screening tests and assessments must be performed within 28 days before the date of randomization, except for ECOG and laboratory tests, which 
should be performed within 10 days before the first dose of study drug, and pregnancy test should be performed within 72 hours, if not performed within 72 
hours of randomization, a pregnancy test should be repeated prior to the first dose of IMO-2125. 
2. 
All assessments and IMO-2125 dosing will occur within a ±3-day window.  IMO-2125 doses should be at least 5 days apart. 
3. 
Subjects who discontinue study treatment due to completion of the planned treatment or for reasons other than disease progression or start of new anticancer 
treatment will enter the Active Follow-up Period. Assessments during the Active Follow-up Period will follow the schedule of the disease assessments and 
will occur at Week 12 (±1 week), then every 8 weeks (±2 weeks) for the first year and every 12 weeks (±2 weeks) during subsequent years. 
4. 
Subjects who discontinue disease assessments due to either disease progression or the start of new anticancer treatment, with or without disease progression, 
will enter the Survival Follow-up Period (contacted by telephone every 3 months until death or the end of the study). Assessments will occur within a ±14-
day window. 
5. 
Subjects must be randomized within 28 days after signing the ICF; the first dose of study drug should be administered within 2 days after randomization. 
6. 
CBC and chemistries do not have to be repeated if Screening tests are completed within 7 days of start of treatment. 
7. 
Samples will be collected pre-dose, and at 1, 2 and 4 hours (±10 minutes) post-dose. 
8. 
PT, aPTT, INR. 
9. 
Vital signs will include systolic and diastolic blood pressure, body temperature, pulse rate, body weight, and height (Week 1 only).  Vital signs should be 
completed prior to treatment administration. 
10. WOCBP only.  Pregnancy test after randomization should be completed as deemed necessary by the Investigator or required by local law. 
11. IMO-2125 should be administered prior to ipilimumab.  
12. During the IMO Maintenance Period, all CTCAE Grade ≥2 irAEs and laboratory abnormalities (regardless of relationship to study drug) should be 
monitored until resolution, stabilization, or return to baseline. During the Follow-up Periods, for 90 days after the last dose of study treatment, all SAEs, 
irAEs, AEs Grade ≥3, and associated concomitant medications for their treatment must be reported. For the remainder of the Follow-up Periods, AE 
reporting should be limited to Treatment-related Grade ≥3 AEs and SAEs, and the associated concomitant medications. 
13. Blood samples for evaluation of plasma IMO-2125 concentrations will be collected pre-dose and at 1, 2, and 4 h post-dose (± 30 minutes) at Week 1 and 
Week 11 only.   
14. Serum samples will be collected for analysis of anti-IMO-2125 and anti-ipilimumab antibodies; details are provided in the Laboratory Manual. Baseline 
sample to be collected at Week 1 before the first dose of study treatment. 
15. Optional (see Laboratory Manual). 
16. To inform treatment management decisions, disease assessments are to be completed at Week 12 (±1 week), then every 8 weeks (±2 weeks) for the first year 
and every 12 weeks (±2 weeks) during subsequent years. 
17. To minimize bias in the PRO data, disease and PRO assessments are to be completed prior to study drug administration and AE evaluations at Weeks 1, 8, 
and 12 (±1 week), then every 8 weeks (±2 weeks) for the first year and every 12 weeks (±2 weeks) during subsequent years. 
18. Per institutional practices following the frequency of active follow-up disease assessments. 
19. Every 3 months during the Active Follow-up period and the samples should be collected at the closest Active follow-up visit. 
20. Maintenance doses of IMO-2125 should be administered as per dosing instructions (see Section 9.3.3.2). 
21. Follow-on anticancer treatment information will be collected during the telephone calls 
22. Week 1 performed pre-dose (within 1.5 hours of dosing IMO-2125) and 1 hour (± 30 minutes) post-dose.  Week 11 performed pre-dose (within 1.5 hours of 
dosing IMO-2125) and 1 hour (± 30 minutes) post-dose.  ECGs should be done in triplicate. 

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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
βhCG 
Beta human chorionic gonadotropin 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC0-t 
Area under the curve from 0 to last measurable plasma concentration 
AUC0–∞ 
Area under curve from 0 to infinity 
C3/C4 
Complement component 3/4 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CH50 
Total hemolytic complement activity 50 
CpG 
Unmethylated cytosine-guanine dinucleotides  
CL/F 
Clearance 
Cmax 
Maximum plasma concentration 
CR 
Complete response 
CRO 
Contract Research Organization 
CS 
Clinically significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte antigen 4 
DNA 
Deoxyribonucleic acid 
DRR 
Durable response rate 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 

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Abbreviation  
Definition 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IFN 
Interferon 
IMO 
Immune Modulatory Oligonucleotide 
IRA 
Independent Reviewing Authority 
IRB 
Institutional Review Board 
irAE(s) 
Immune-related adverse event(s) 
irCR 
Immune-related Complete Response 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
irPD 
Immune-related Progressive Disease 
irPR 
Immune-related Partial Response 
irSD 
Immune-related Stable Disease 
ITT 
Intent-to-Treat 
i.v. 
Intravenous(ly) 
IXRS 
Interactive voice/web response system 
mAb 
Monoclonal antibody 
MAPK 
Mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean residence time 
NCI 
National Cancer Institute 
ORR 
Objective response rate 
OS 
Overall survival 
Pap 
Papanicolaou 
PD 
Progressive disease 
PD-1 
Programmed cell death-1 
PD-L1 
Programmed death-ligand 1 
pDC 
Plasmacytoid dendritic cell 
PFS 
Progression-free survival 
PI 
Principal Investigator 

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Abbreviation  
Definition 
PK 
Pharmacokinetic  
PR 
Partial response 
PRO 
Patient-reported Outcome 
PT 
Prothrombin time 
QoL 
quality of life 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RNA 
Ribonucleic acid 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
s.c. 
Subcutaneous(ly) 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Terminal exponential half-life 
TEAE 
Treatment-emergent adverse event 
TIL 
Tumor-infiltrating lymphocyte 
TLR 
Toll-like receptor 
TNF-α 
Tumor necrosis factor-alpha 
tmax 
Time of Cmax 
ULN 
Upper limit of normal 
USPI 
United States Prescribing Information 
Vd/F 
Volume of distribution 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 

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4. 
BACKGROUND INFORMATION AND RATIONALE 
4.1. 
Refractory Melanoma: The Disease Under Study 
Melanoma is a malignant tumor of melanocytes which are found predominantly in skin, but also 
in the mucous membranes and eye.  Although melanoma is a rare form of skin cancer, it 
comprises over 75% of skin cancer deaths.  The incidence of melanoma has been increasing 
steadily over the last four decades.  Because melanoma is common in younger individuals, the 
years of life lost to melanoma are also disproportionately high when compared with other 
cancers.  The American Cancer Society estimates that there were approximately 76,000 new 
invasive melanoma cases and 10,000 deaths from the disease in the USA in 2016.  Fortunately, 
screening programs have had a major impact and most cases are now diagnosed at an earlier, and 
potentially curable, stage (Siegel, 2015).  However, patients with more advanced disease have a 
much poorer prognosis; median survival for patients with unresectable or metastatic disease is 
measured only in months.   
Several new drugs have been approved by the Food and Drug Administration (FDA) in recent 
years for the treatment of melanoma.  Ipilimumab was originally approved for the treatment of 
unresectable or metastatic melanoma in 2011 based on a demonstration of improved survival 
compared with control.  It has since been supplanted as first-line therapy based on superior 
outcomes (including survival) that have been shown with the programmed cell death-1 (PD-1) 
inhibitors, pembrolizumab and nivolumab.  Kinase inhibitors targeting BRAF or MEK have also 
had a major impact on outcome for patients whose tumors carry the BRAF V600E mutation.  
This represents only approximately half of the melanoma population, however, and re-treatment 
following the development of resistance has been largely ineffective (Simeone, 2017).   
For patients relapsing after immunotherapy (and a BRAF or MEK inhibitor if the targetable 
mutation is present), there are no effective therapeutic options.  Retrospective analyses of 
ipilimumab given as second-line immunotherapy show an objective response rate (ORR) of 10% 
to 13% (Long, 2016; Bowyer, 2016).  A small randomized study of ipilimumab vs the 
combination of nivolumab with ipilimumab is ongoing in subjects who have progressed or 
relapsed on PD-1 or programmed death-ligand 1 (PD-L1) inhibitors (NCT02731729).   
Chemotherapy and biochemotherapy carry significant toxicities and have not been shown to 
improve survival.  Clearly, additional therapeutic options are needed. 
4.2. 
Toll-like Receptor Agonists in the Treatment of Cancer 
Toll-like receptors (TLRs) are a family of pattern recognition receptors that can induce potent 
innate and adaptive immune responses.  Toll-like receptor 9 (TLR9) recognizes unmethylated 
cytosine-phosphate-guanine (CpG) dinucleotide motifs present in bacterial and viral 
deoxyribonucleic acid (DNA) and synthetic oligodeoxynucleotides and is expressed in 
endosomal compartments of human plasmacytoid dendritic cell (pDC) and B-cells.  Signaling 
through TLR9 induces cytokine production and secretion, including interferon (IFN)-α and 
T helper 1 (Th1)-type cytokines, B-cell proliferation, and upregulation of co-stimulatory 
molecules.  Accordingly, TLR9 agonists are being widely studied in the treatment of cancers, 
infectious diseases, allergy, asthma, and as vaccine adjuvants (Kandimalla and Agrawal, 2012; 
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The adaptive T-cell response is ultimately dictated by dendritic cells (DCs), whose function is to 
acquire novel antigens and then direct the activation and expansion of antigen-specific T cells.  
TLR signaling induces DC activation, a process that is characterized by enhanced expression of 
costimulatory molecules and increased secretion of cytokines necessary for activation and 
differentiation of naive T cells (Pulko, 2009).   A distinguishing characteristic of TLR9 agonists 
is their ability to induce strong CD4+ and CD8+ T-cell responses to many types of antigen when 
used as a vaccine adjuvant (Wang, 2005; Krieg, 2007). 
4.3. 
IMO-2125 
IMO-2125 is a synthetic phosphorothioate oligonucleotide that acts as a direct agonist of TLR9 
to stimulate the innate and adaptive immune systems.  IMO-2125 induces high levels of IFN-α 
from pDCs along with an array of endogenous cytokines and chemokines.  IMO-2125 also 
promotes B-cell proliferation and differentiation (Yu, 2008; Rodriguez-Torres, 2010).   
4.3.1. 
Nonclinical Experience with IMO-2125 
4.3.1.1. 
Nonclinical Pharmacology 
In vivo studies in mouse models of colon carcinoma, lymphoma, and melanoma indicate that 
intratumoral IMO-2125 monotherapy has been shown to produce abscopal effects in mice, 
including anti-tumor activity associated with an increase in infiltrating CD8+ T cells, and durable 
and specific cytotoxic T cell responses against tumor antigens (Jiang, 2015).  Intratumoral 
administration was more effective than s.c. administration.  When IMO-2125 was administered 
in combination with anti-PD-1 mAb or anti-CTLA-4 mAb a complementary effect on reduction 
in tumor growth was observed (Investigator’s Brochure). 
The only secondary pharmacologic effect of IMO-2125 identified was activation of the 
alternative complement pathway in non-human primates (Investigator’s Brochure). 
4.3.1.2. 
Nonclinical Toxicology 
General toxicology studies were conducted in rats and monkeys administered IMO-2125 by s.c. 
injection once weekly for 4 and 13 consecutive weeks. Findings in these studies were consistent 
with immune stimulation, the proposed mechanism of action (Investigator’s Brochure).  
In chronic twice-weekly administration toxicity studies (26 weeks in rats and 39 weeks in 
monkeys), findings in the liver (rats) and kidney (monkey) were similar to what has been noted 
with other oligonucleotides (Investigator’s Brochure). Monitoring for these potential effects is 
included in the ongoing and planned clinical studies using standard safety parameters for liver 
and kidney function.  In addition, lymphomas and leukemias that likely were secondary to 
chronic immune stimulation and sarcomas at the site of injection that were likely secondary to 
chronic irritation/inflammation at the injection sites were noted in rats (Investigator’s Brochure). 
Similar findings were not noted in monkeys (Investigator’s Brochure).  
Due to substantial differences in the pattern of TLR expression in rodents when compared with 
non-human primates and humans, the pharmacodynamic effects of chronic TLR9 stimulation in 
cynomolgus monkey may be more representative of the anticipated effects in humans than the 
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4.3.2. 
Clinical Experience with IMO-2125 
IMO-2125 has been studied previously as a potential treatment for subjects with chronic hepatitis 
C virus (HCV) infection with the FDA Division of Antiviral Products.  Two studies have been 
conducted with systemic administration of IMO-2125; both studies were conducted in subjects 
with HCV infection.  IMO-2125 was administered subcutaneously (s.c.) at dosages up to 
0.48 mg/kg/week in 96 subjects.  Study 2125-204 in subjects with melanoma refractory to PD-1 
inhibitors is currently ongoing.  Full details are provided in the IMO-2125 Investigator’s 
Brochure.  The most common adverse events (AEs) were mild to moderate flu-like symptoms 
and injection site reactions. 
4.3.2.1. 
IMO-2125 in Combination with Checkpoint Inhibitors (Study 2125-204) 
Study 2125-204 is an ongoing Phase 1/2 clinical study of intratumoral IMO-2125 in combination 
with ipilimumab or pembrolizumab in melanoma that is refractory to PD-1 inhibitors.  The study 
is being conducted in two phases.  Phase 1 of the study is open-label and is designed to explore 
escalating dose levels of IMO-2125 (from 4 mg to 32 mg) along with either ipilimumab or 
pembrolizumab with a primary endpoint of safety (and selection of the recommended phase 2 
dose[s] [RP2D(s)]).  Subjects in Phase 2 will be assigned to one of the combinations once the 
RP2D(s) have been determined in Phase 1.  The primary endpoint of Phase 2 is clinical activity, 
defined as objective response as assessed by the Investigator using immune-related Response 
Evaluation Criteria in Solid Tumors (irRECIST).  Other endpoints are ORR by Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1, safety, tumor response, pharmacodynamics, 
and pharmacokinetics (PK).  Serial biopsies of both the injected and a distant tumor are 
performed in all subjects for immunologic assessment.  Refer to the Investigator’s Brochure for 
more details.  
As of the 05 January 2017 data cut-off, 13 subjects have received IMO-2125 in planned 
escalating dose cohorts of 4, 8, 16, and 32 mg along with ipilimumab, and another 3 subjects 
have received 8 mg of IMO-2125 with pembrolizumab (dose escalation is ongoing).  Treatment 
has been generally well-tolerated, with no dose-limiting toxicity observed in any dose cohort to 
date.  One (8%) subject in the 4 mg IMO-2125 + ipilimumab group died due to progressive 
disease (PD) during the study follow-up period, approximately 5 months after completing all 
study treatment.  Seven (54%) subjects have reported serious adverse events (SAEs); however, 
none of the SAEs were considered treatment-related by the Investigator.  The most commonly 
reported treatment-emergent adverse events (TEAEs; reported in >5 subjects overall) for the 
IMO-2125 + ipilimumab combination are anemia, pyrexia, nausea, and vomiting.  Four instances 
of potential immune-related toxicity have been observed:  hypophysitis (2 events), adrenal 
insufficiency, and autoimmune hepatitis, the latter occurring in a subject who had previously 
experienced dose-limiting immune-related hepatitis while receiving ipilimumab monotherapy (in 
violation of the protocol eligibility criteria).  The outcome for these subjects has been good with 
routine supportive measures (Uemera 2017).  
Clinical activity is promising with 3 investigator-reported responses, including 1 complete 
response (CR).  Tumor biopsies obtained showed maturation of myeloid DC1 subset in the 
IMO-2125 injected lesion 24 hrs post-treatment compared with pre-treatment biopsy 
(Uemera 2017).   

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4.3.2.2. 
IMO-2125 in Refractory Solid Tumors (Study 2125-RST-101) 
This is an open-label, multi-center, Phase 1b study in subjects with refractory solid tumors with a 
planned enrollment of approximately 40 subjects in the Dose Evaluation Portion of the study.  
IMO-2125 will be administered intratumorally at dosages of 8, 16, 23, or 32 mg for up to 
one year.  The primary objectives are safety and determination of the RP2D for monotherapy 
dosing.  Additional objectives include evaluation of clinical activity, PK, pharmacodynamics, 
and immunologic correlates in tumor biopsies. 
4.4. 
Rationale for Study Design  
This study is a randomized, multi-center, international, open-label comparison of ipilimumab 
with and without intratumoral IMO-2125 in subjects with anti-PD-1 refractory melanoma.  The 
primary endpoint family comprises overall survival (OS) and ORR. 
4.4.1. 
Rationale for Population 
Immunotherapy has had a major impact on many cancers and PD-1 directed therapy is now 
recommended as the initial treatment for most patients with advanced melanoma (National 
Comprehensive Cancer Network [NCCN], 2016).  Mitogen-activated protein kinase (MAPK) 
inhibitors have also proven to be valuable, though their use is limited to settings where a BRAF 
V600 driver mutation is present.  Despite these advances, 67%, 66%, and 50% of patients, 
respectively, still fail to manifest a response (CR or partial response [PR]) to pembrolizumab, 
nivolumab, or the ipilimumab/nivolumab combination, respectively (Keytruda USPI, 2015; 
Opdivo USPI, 2016; Yervoy USPI, 2015).  No treatment has been specifically approved for use 
following failure of PD-L1 directed immunotherapy and treatment options are particularly 
limited for patients whose tumors lack a BRAF V600 driver mutation.  For these patients, 
clinical trials are recommended as an appropriate option (NCCN, 2016).   
4.4.2. 
Rationale for Ipilimumab Comparator 
Ipilimumab is recommended as a second-line immunotherapy option for patients who have not 
previously received it, and for previously-responding patients who have been off therapy for 
more than 3 months if they did not experience major toxicity with previous ipilimumab treatment 
(NCCN, 2016).  This recommendation is based on both controlled studies in 
immunotherapy-naïve patients and uncontrolled retrospective series of ipilimumab as second line 
immunotherapy (NCCN, 2016).  A recent post-hoc analysis of the pembrolizumab 
KEYNOTE-006 trial confirms that patients do respond to ipilimumab following failure of 
pembrolizumab treatment, and that clinical outcomes (including safety) are no different than the 
historical experience in untreated patients (Long, 2016).  
4.4.3. 
Rationale for Combining IMO-2125 with Ipilimumab 
Proof of concept for the effectiveness of intratumoral immune stimulation was established many 
years ago with Coley’s demonstration that localized injection of bacterial extracts could on 
occasion lead to cure (Coley, 1893).  Intratumoral BCG is also capable of inducing tumor 
regression in a substantial proportion of cases (Bast, 1974).  More recently, the genetically 
modified oncolytic virus, talimogene laherparepvec has shown durable clinical responses, 
including abscopal effects, when injected into cutaneous, s.c., or nodal melanoma lesions 
(Imlygic®, United States Prescribing Information [USPI]).   

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Since the immune cells targeted by TLR9 are present within the tumor microenvironment, 
agonists delivered directly into a single tumor deposit can generate a potent and specific systemic 
antitumor immune response while potentially inducing less autoimmune toxicity 
(Marabelle, 2014).  Preclinical studies have shown superiority of the intratumoral approach over 
systemic administration for both IMO-2125 (Jiang, 2015) and other TLR9 agonists (Lou, 2011).   
Although intratumoral delivery of pattern recognition receptor agonists like TLR9 is an effective 
means of creating an adaptive antitumor immune response, this can still be attenuated by 
dampening mechanisms such as immunosuppressive tumor-infiltrating regulator T cells and 
anergic/exhausted tumor infiltrating or peritumoral cytotoxic T cells (Conroy, 2008).  Therefore, 
combining a TLR9 agonist with checkpoint inhibitors or other modulators of the immune 
response to enhance systemic immunity is a logical strategy (Marabelle, 2014).   
This hypothesis has been validated in preclinical models.  The combination of intratumoral 
IMO-2125 with either an anti-cytotoxic-T lymphocyte antigen 4 (CTLA-4) or anti-PD-1 
antibody results in improved tumor control compared with either agent alone, along with 
regression of systemic lung metastases and infiltration of tumor infiltrating lymphocytes versus 
monotherapy with either agent (Wang, 2015a; Wang, 2015b).  Preliminary clinical experience is 
also promising as the combination of IMO-2125 with ipilimumab is well-tolerated and shows 
encouraging clinical activity in the setting of PD-1 refractory disease (Uemera, 2017).   
4.4.4. 
Rationale for Dose 
Previous clinical studies with systemic delivery (s.c.) of IMO-2125 in patients with chronic HCV 
infection at dose levels up to 0.48 mg/kg/week have shown good tolerability with clinically 
relevant, dose-dependent induction of IFN-α and other cytokines potentially important to the 
treatment of cancer (Rodriguez-Torres, 2010).  The most common AEs were mild to moderate 
flu-like symptoms and injection site reactions.     
Study 2125-204 is an ongoing Phase 1/2 clinical study designed to evaluate safety and 
preliminary efficacy of two checkpoint inhibitor combinations.  In this study, IMO-2125 is being 
administered intratumorally at 4, 8, 16, or 32 mg (corresponding to the dose range studied in 
HCV) in combination with either ipilimumab or pembrolizumab.  IMO-2125 injections are given 
at Weeks 1, 2, 3, 5, 8, and 11.  Ipilimumab is administered at the labeled dose of 3 mg/kg 
intravenously (i.v.) during Weeks 2, 5, 8, and 11.  The one week priming interval was chosen to 
allow migration of activated dendritic cells to the draining lymph nodes (Aarntzen, 2012).  As of 
28 March 2017, dose finding in the IMO-ipilimumab cohort is complete, while 
IMO- pembrolizumab dose-finding is ongoing.   A total of 18 subjects have been treated in the 
dose-escalation phase, half of whom received the 8 mg dose of IMO-2125.  Enrollment was not 
limited to superficial disease; thus, some study subjects have received IMO-2125 via deep or 
visceral injection. 
Preliminary data for this study have been reported (Section 4.3.2.1).  The RP2D of 8 mg for 
IMO-2125 was selected from the available options based upon acceptable safety, clinical activity 
(including one durable CR), and demonstration of early dendritic cell maturation followed by 
CD45+ tumor-infiltrating lymphocyte (TIL) infiltration in both injected and non-injected tumors.  
Evidence for systemic Th1 cytokine activation and presence of an IFNα signature in biopsied 
lesions were also documented (Haymaker, 2017).   

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The Phase 3 regimen adds maintenance doses of IMO-2125 at 16, 20, and 24 weeks following 
completion of combination therapy.  Prolonging the duration of IMO-2125 therapy provides 
continued innate immune stimulation in response to neoantigens that may emerge in response to 
treatment (Schumacher and Schreiber, 2015).  Safety follow-up to support this longer dosing 
period is now available for several 2125-204 study subjects and, along with pre-clinical 
toxicology assessment of 6 month continued dosing, does not suggest a risk for cumulative 
toxicity from these additional maintenance doses.  Study 2125-204 has recently been amended to 
assess dosing through 29 weeks; longer-term administration of IMO-2125 (approximately one 
year) is being evaluated in Study 2125-RST-101.  Refer to the Investigator’s Brochure for the 
most updated safety information.  

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5. 
STUDY OBJECTIVES  
5.1. 
Primary Objective 
The primary objective is to compare the efficacy (measured by ORR and OS) of intratumoral 
IMO-2125 in combination with ipilimumab versus ipilimumab alone. 
5.2. 
Secondary Objectives 
The secondary objectives are to assess other measures of clinical benefit, safety, PK, and 
patient-reported outcomes (PROs). 
5.3. 
Exploratory Objectives 
The exploratory objectives are to investigate potential biomarkers and the incidence of anti-IMO-
2125 and anti-ipilimumab antibodies. 

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6. 
STUDY ENDPOINTS 
6.1. 
Primary Endpoint Family 
The primary endpoint family (see FDA Guidance for Industry, 2017) includes: 
• ORR by blinded independent review using RECIST v1.1 
• OS, defined as the time to death from any cause measured from the date of 
randomization.  
6.2. 
Secondary Endpoints 
The secondary endpoints include:  
• ORR by investigator assessment using RECIST v1.1 
• Duration of response (DoR) by blinded independent review and by investigator 
assessment using RECIST v1.1, measured from the time that criteria are first met for 
CR or partial response (PR) (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented 
• Durable response rate (DRR) by blinded independent review and investigator 
assessment (using RECIST v1.1), defined as the rate of CR or PR lasting ≥6 months 
with onset during the first 12 months of treatment 
• Time to response, defined as time to a complete or partial response (using RECIST 
v1.1) measured from the date of randomization, by blinded independent review and 
investigator assessment 
• Progression-free survival (PFS), defined as the time to disease progression or death 
from any cause measured from the date of randomization, by blinded independent 
review and investigator assessment (using RECIST v1.1) 
• Landmark PFS at 1 and 2 years by blinded independent review and investigator 
assessment (using RECIST v1.1) and landmark OS at 1 and 2 years  
• PRO using the European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire-Core 30 (EORTC QLQ-C30) 
• Safety, including AEs, laboratory and vital sign tests, electrocardiograms (ECGs), 
ECOG, and physical examination  
• Plasma PK of IMO2125  
6.3. 
Exploratory Endpoints 
The exploratory endpoints include: 
• Immunologic biomarkers (optional tumor biopsies) 
• Measurement of anti-IMO-2125 and anti-ipilimumab antibodies 

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7. 
SUBJECTS TO BE RECRUITED 
7.1. 
Subject Recruitment  
Subject selection and recruitment will be organized and overseen by the Investigator at each site 
following approval of the study protocol by the respective Institutional Review Board (IRB) or 
Ethics Committee (EC).  All subjects who sign an informed consent, are screened, and either 
qualify or do not qualify for the study will be documented in the screening and enrollment log.  
Appropriate documentation will be made indicating the willingness of the subject to participate 
and consent to the conduct of the study before initiating any study-related procedures. 
An interactive voice/web response system (IXRS) will be used to register and randomize 
subjects into the study. 
7.2. 
Inclusion Criteria 
To be eligible for this study, subjects must meet all of the following inclusion criteria.  
1. Subjects must be willing and able to sign the informed consent and comply with the study 
protocol. 
2. Must be ≥18 years of age. 
3. Histologically confirmed metastatic melanoma with measurable (by RECIST v1.1), 
stage III (lymph node or in transit lesions) or stage IVA, IVB, or IVC disease that is 
accessible for injection. Stage should be determined using the American Joint Committee 
on Cancer (AJCC) Cancer Staging Manual, Seventh Edition (Edge, 2010). 
4. Confirmed progression during or after treatment with a PD-1 inhibitor (cannot be part of 
bi-specific antibody) e.g. nivolumab or pembrolizumab.  Confirmed progression is 
defined as: 
• Radiological progression (confirmed at least 4 weeks after the initial scan showing 
PD); or  
• For progression based solely on worsening of non-target or new, non-measurable 
disease, confirmation by an additional scan at least 4 weeks after the initial scan 
unless progression is accompanied by correlative symptoms.   
In addition, all the following must hold:  
a) No intervening anti-cancer therapy between the last course of PD-1 inhibitor 
treatment and the first dose of study treatment is allowed except for local measures 
(e.g., surgical excision or biopsy, focal radiation therapy). 
b) The interval between last PD-1 inhibitor and start of study treatment should be at least 
21 days with no residual anti-PD-1-related immune toxicities in excess of Grade 1 
severity. 
c) Subjects who had adjuvant anti-PD-1 treatment are eligible if they have either disease 
recurrence after the end of adjuvant treatment or on-treatment disease recurrence after 
≥12 weeks of adjuvant treatment. 
d) If subject BRAF mutation status is unknown, before randomization the subject must 
have BRAF testing performed using an approved assay method. 

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e) Patients with BRAF-positive tumor(s) are eligible for the study if they received prior 
treatment with a BRAF inhibitor (alone or in combination with a MEK inhibitor) or 
declined targeted therapy. 
5. ECOG Performance Status ≤1. 
6. Adequate baseline organ function as defined by: 
a) Absolute neutrophil count (ANC) ≥1.5 x 109/L (1500/mm3) 
b) Platelet count ≥75 x 109/L (75,000/mm3) 
c) Hemoglobin ≥8.0 g/dL (4.96 mmol/L) 
d) Serum creatinine ≤1.5 x upper limit of normal (ULN) or calculated creatinine 
clearance ≥60 mL/minute (≤Grade 1) 
e) Aspartate aminotransferase (AST) ≤2.5 x ULN; alanine aminotransferase (ALT) 
≤2.5 x ULN; AST/ALT <5 x ULN if liver involvement (≤Grade 1) 
f) Serum bilirubin ≤1.5 x ULN, except in subjects with Gilbert’s Syndrome who must 
have a total bilirubin <3 mg/dL (≤Grade 1) 
7. Women of childbearing potential (WOCBP) and men must agree to use effective 
contraceptive methods from screening until at least 90 days after the last dose of either 
ipilimumab or IMO-2125, whichever is later. 
Non-childbearing potential is defined as a woman who meets either of the following 
criteria: a) postmenopausal state defined as no menses for 12 months without an 
alternative medical cause, or b) documented hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy. 
Effective contraception methods are defined as one of the following: 
a) True abstinence, defined as refraining from heterosexual intercourse, when this is in 
line with the preferred and usual lifestyle of the subject.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a trial, and withdrawal are not acceptable methods of 
contraception. 
b) Condoms and spermicide  
c) Diaphragm and spermicide  
d) Oral or implanted hormonal contraceptive (e.g., Implanon™)  
NOTE: For subjects in Sweden, low dose oral contraceptives are not permitted 
e) An intra-uterine device  
8. WOCBP must have a negative pregnancy test (serum or urine) according to the Schedule 
of Evaluations (Table 1 and Table 2). 
7.3. 
Exclusion Criteria  
Subjects meeting any of the following criteria will be excluded from the study: 
1. Ocular melanoma. 
2. Prior therapy with a TLR agonist, excluding topical agents.  

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3. Prior ipilimumab with the exception of adjuvant treatment completed ≥6 months prior to 
enrollment.  
4. Systemic treatment with IFN-α within the previous 6 months. 
5. Known hypersensitivity to any oligodeoxynucleotide. 
6. Active autoimmune disease requiring disease-modifying therapy at the time of screening. 
7. Subjects with a requirement for receiving more than physiologic doses of systemic 
steroids (>10 mg/day of prednisone or equivalent) for the 2 weeks preceding start of 
study treatment. 
8. Subjects with another primary malignancy that has not been in remission for at least 
3 years with the exception of non-melanoma skin cancer, curatively treated localized 
prostate cancer with non-detectable prostate-specific antigen, cervical carcinoma in situ 
on biopsy or a squamous intraepithelial lesion on Papanicolaou (Pap) smear, and thyroid 
cancer (except anaplastic). 
9. Active systemic infections requiring antibiotics. 
10. Known active, hepatitis A, B, or C infection. 
11. Known diagnosis of human immunodeficiency virus (HIV) infection. 
12. Women who are pregnant or breast-feeding. 
13. Prior anaphylactic or other severe infusion reaction associated with human antibody 
administration that cannot be managed with standard supportive measures. 
14. Presence of known central nervous system, meningeal, or epidural metastatic 
disease.  However, subjects with known brain metastases are allowed if the brain 
metastases are stable for ≥4 weeks before the first dose of study treatment.  Stable is 
defined as neurological symptoms not present or resolved to baseline, no radiologic 
evidence of progression, and steroid requirement of prednisone ≤10 mg/day or 
equivalent.  
15. Impaired cardiac function or clinically significant cardiac disease. 

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8. 
STUDY DESIGN 
8.1. 
Overview 
This is a randomized Phase 3 global, multi-center, open-label comparison of ipilimumab with 
and without intratumoral IMO-2125 in subjects with advanced melanoma who had disease 
progression while on PD-1 directed therapy.  Confirmed progression is defined by irRECIST 
criteria (see Section 20.3).  Subjects will be randomized 1:1 to Arm A or B.  Randomization is 
stratified on the duration of prior anti-PD-1 therapy (≥12 weeks vs <12 weeks), metastasis stage 
(M1c vs other), and BRAF mutation status and prior targeted therapy (BRAF wild type, BRAF 
mutation positive with prior targeted therapy, or BRAF mutation positive with no prior targeted 
therapy) using block randomization.  Targeted therapy is the use of an approved BRAF or MEK 
inhibitor alone or in combination.  The primary endpoint family of the study comprises OS and 
ORR. 
8.1.1. 
Independent Review Facility 
Blinded independent review of all clinical and imaging results for response assessment will be 
performed centrally.  The composition and duties of the blinded, independent reviewers are 
described in a separate charter.   
8.1.2. 
Independent Data Monitoring Committee 
The Independent Data Monitoring Committee (IDMC) composition and duties are described in a 
separate charter.  Periodic data reviews will be performed by an IDMC as described in the IDMC 
Charter.  The first IDMC meeting will occur after approximately 20 subjects on each arm have 
been treated with two doses of ipilimumab, and subsequent meetings occurring at regular 
intervals after the initial meeting until the database lock for the final analysis of OS.  The initial 
meeting will review safety only.  The IDMC will assess benefit:risk on an ongoing basis and will 
recommend early stopping if the safety profile is not acceptable given the efficacy of the study 
treatment. 
8.2. 
Duration of Study 
8.2.1. 
Treatment Duration 
The Treatment Phase of the study is 10 weeks for subjects assigned to Arm A and 24 weeks for 
subjects assigned to Arm B. 
8.2.2. 
Study Duration 
The study is complete and final analysis will occur when approximately 392 randomized subjects 
have died, or approximately 36 months after the last subject is randomized, whichever occurs 
first; it is assumed this will take approximately 56 months after the first subject is randomized. 

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8.3. 
Study Drug Discontinuation and Study Withdrawal 
8.3.1. 
Subject Discontinuation of Study Drug 
Failure to complete Week 10 of study drug (Arm A) or Week 24 (Arm B) for any reason will be 
considered premature study drug discontinuation.  Reasons for premature study drug 
discontinuation include PD (by irRECIST or by clinical progression), death, intolerable AE, 
withdrawal of consent, lost to follow up, Investigator discretion, Sponsor decision, and 
premature termination of the study.   
Subjects who discontinue treatment prematurely prior to progression should continue to be 
followed according to the SOE (Active Follow-up).  The Investigator will document the date of 
and reason(s) for study treatment discontinuation on the electronic case report form (eCRF).  
Once a subject discontinues study treatment permanently, they will not be able to be retreated.  
Subjects who complete the planned study treatment and who have not progressed or started new 
anti-cancer therapy will enter the Active Follow-up Period and be followed according to the 
SOE.  Subjects will enter the Survival Follow-up Period at disease progression or the start of 
new anti-cancer therapy (with or without disease progression). 
8.3.2. 
Subject Withdrawal from the Study 
Subjects are free to withdraw consent from participation in the study at any time.  For any 
subject who withdraws consent due to an AE, the Investigator should arrange for the subject to 
be followed appropriately until the AE has resolved or stabilized (in the opinion of the 
Investigator). 
The Investigator will document the reason(s) for study withdrawal on the eCRF.  Idera and the 
Contract Research Organization (CRO) Medical Monitor should be informed when a subject is 
withdrawn from the study.  
8.3.3. 
Study and Subject Completion 
The study is complete when approximately 392 randomized subjects have died or approximately 
36 months after the last subject is randomized, whichever occurs first.   
A subject has completed the study at death.  Subjects who withdraw from the study (including 
withdrawal of consent for study participation, lost to follow-up, premature termination of the 
study, or withdrawal at the discretion of the Investigator) will not be considered to have 
completed the study.   
8.3.4. 
Lost to Follow-up 
Subjects are considered lost to follow-up if they cannot be contacted after at least 3 attempts over 
a 6-month period and it cannot be determined whether death has occurred.  
8.4. 
Number of Subjects  
The study will enroll approximately 454 subjects.  

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8.5. 
Benefits and Risk Assessment 
Patients with advanced melanoma who relapse after immunotherapy (and a BRAF or MEK 
inhibitor if indicated) have an estimated survival that is measured only in months with no 
approved therapeutic options.  Preliminary experience with the IMO-2125 + ipilimumab regimen 
is encouraging and the combination appears to be tolerable (Uemera, 2017).  Based on these 
data, the benefit:risk is likely to be favorable if the efficacy objectives of the study are achieved.     

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9. 
STUDY TREATMENTS 
9.1. 
IMO-2125 
IMO-2125, a novel phosphorothioate oligodeoxynucleotide, is composed of two strands of 
modified DNA joined at the 3´ ends.  IMO-2125 is a hygroscopic white to off-white amorphous 
solid obtained by lyophilization; it is highly soluble in aqueous media. 
IMO-2125 drug product is supplied as an aqueous sterile solution. Each vial contains IMO-2125 
sodium salt equivalent to 8 mg/mL of IMO-2125 free acid compounded with 0.9% sodium 
chloride. 
9.2. 
Ipilimumab 
Ipilimumab is a commercially available product. 
9.3. 
Drug Handling and Administration 
9.3.1. 
Drug Delivery to Site 
After the research site has submitted all approved regulatory and study start-up documents, an 
IXRS will be used to manage drug supply.  All IMO-2125 shipments are sent refrigerated.  Upon 
receipt, the pharmacist or appropriate technician/designee must inspect the contents, verify 
temperature conditions, and confirm receipt of goods.  
Drug inventory will be maintained by the site.  Resupply of IMO-2125 to the sites is detailed in 
the Pharmacy Manual.  
9.3.2. 
Drug Storage 
9.3.2.1. 
IMO-2125 Storage 
Vials of IMO-2125 drug product are to be stored at 2°C to 8°C and storage temperature must be 
continuously monitored.  IMO-2125 must be stored in a securely locked enclosure.  Access is 
strictly limited to the pharmacist or designated study personnel before preparation. 
9.3.2.2. 
Ipilimumab Storage 
Refer to locally issued ipilimumab package insert for subjects receiving this agent.  
9.3.3. 
Administration 
Subjects will be randomized (1:1) to receive either: 
1. Arm A – ipilimumab 3 mg/kg i.v. at Weeks 1, 4, 7, and 10  
or 
2. Arm B – IMO-2125, 8 mg intratumorally at Weeks 1, 2, 3, 5, 8, 11, 16, 20, and 24 in 
combination with ipilimumab 3 mg/kg i.v. at Weeks 2, 5, 8, and 11 

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9.3.3.1. 
Ipilimumab- Arm A 
Ipilimumab will be administered i.v. using a 90-minute infusion duration at 3 mg/kg on Weeks 1, 
4, 7, and 10 (Arm A) or Weeks 2, 5, 8, and 11 (Arm B).  Cross-over therapy will not be allowed 
for subjects assigned to Arm A.   
9.3.3.2. 
IMO-2125 + Ipilimumab- Arm B 
IMO-2125 will be given prior to ipilimumab on days when both are to be administered.  
IMO2125 will be administered intratumorally as a 1-4 mL injection to a single designated lesion 
throughout the study.  Subjects will remain at the study site for observation for a minimum of 30 
minutes following each administration of IMO2125.   
The injected tumor will be selected from (in order of priority) pathologic draining lymph nodes, 
superficial or s.c. metastases, or deep or visceral metastases, the latter requiring interventional 
radiology support for both IMO-2125 administration and selection of a lesion that can be safely 
injected multiple times.  The dose will be thoroughly distributed within the injected tumor using 
a single injection site and a fanning method to ensure even distribution.   
Dosing volume will be adjusted on a sliding scale and based on the judgment of the investigator 
as the injected tumor shrinks to maintain a constant total dose.  Additional details are described 
in the Pharmacy Manual. In the event a full dose can no longer be practically administered into 
the injected tumor, another tumor may be selected.  In the event a complete tumor regression 
occurs prior to completion of therapy, any remaining IMO-2125 doses should be administered 
into the tumor bed, except in the case of visceral lesions for which injections should be stopped.  
Treatment following disease progression is at the discretion of the Investigator.  More details on 
IMO-2125 dose preparation can be found in the Pharmacy Manual. 
9.3.4. 
Dose Modification 
The most common AEs following intratumoral administration of IMO-2125 have been non-
specific “flu-like” symptoms and mild to moderate injection site reactions.  In combination with 
ipilimumab, IMO-2125 has been associated with irAEs (Section 10.1.3.4) and fever.  Ipilimumab 
dosing will follow the local package insert.  IMO-2125 therapy should be continued if 
ipilimumab is discontinued early for toxicity.    
Dose modification instructions for IMO-2125 including its use in combination with ipilimumab 
are provided in Table 3.  

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Table 3: 
Dose Modification Instructions for IMO-2125 
Event 
Action 
Dose Modification 
Local or mild systemic 
reaction (e.g., pyrexia) 
Supportive measures as required.  
Continue treatment with IMO-
2125 per clinical discretion. 
None 
Severe systemic reaction for 
which more aggressive 
measures including 
hospitalization are required 
(e.g., severe hypotension) 
Supportive measures as required.  
Hold further dosing until the 
event resolves to baseline or 
Grade 1 and the re-treatment 
criteria below are met. 
None. 
Life-threatening AE 
(e.g., anaphylaxis) 
Supportive measures as required. 
Discontinue 
treatment 
Serious procedural 
complication related to deep or 
visceral injection (e.g. 
pneumothorax or hematoma 
formation) 
Supportive measures as required 
Discontinue visceral 
injections (treatment 
may be continued if 
a superficial lesion 
or tumor-involved 
lymph node is 
available for 
injection instead) 
Conventional supportive medications (including infliximab for immune-related colitis and 
growth factor support) are permitted. 
Criteria for re-initiation of treatment with each dose of study drug include:  
• ANC ≥1.5 x 109/L (1500/μL); 
• Platelets ≥75 x 109/L (75,000/μL); 
• Resolution of all clinically significant non-hematologic toxicities for which a causal 
association to study treatment cannot be ruled out to Grade ≤1 or baseline. 
If the subject does not meet these criteria, dosing will be delayed, and the subject should be 
re-evaluated within 48 to 72 hours.  If the next dose is delayed by more than 21 days for toxicity, 
the subject should be removed from study treatment unless approved by the medical monitor.  
9.3.4.1. 
Dose Modifications for Ipilimumab-Related Toxicities 
Please refer to the current, locally approved ipilimumab package insert for specific guidance in 
managing irAEs associated with ipilimumab.  Table 4 provides guidance on modifications to 
ipilimumab dosing for selected toxicities. 
Table 4: 
Recommended ipilimumab dose modifications for selected toxicities 
Organ system 
Adverse reaction 
Treatment modification 
Endocrine 
Symptomatic endocrinopathy 
Withhold ipilimumab 
Resume ipilimumab in 
patients with complete or 

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Organ system 
Adverse reaction 
Treatment modification 
partial resolution of adverse 
reactions (Grade 0 to 1), and 
who are receiving no more 
than physiologic doses of 
systemic steroids per local 
prescribing information. 
• Symptomatic reactions 
lasting 6 weeks or longer 
• Inability to reduce 
corticosteroid dose to 
physiologic doses per local 
prescribing information 
Permanently discontinue 
ipilimumab 
Ophthalmologic 
Grade 2 through 4 reactions  
• not improving to Grade 1 
within 2 weeks while 
receiving topical therapy 
or  
• requiring systemic 
treatment 
Permanently discontinue 
ipilimumab 
Enterocolitis 
Grade ≤2 
 
 
 
 
 
 
 
 
 
 
Grade 3 or 4 
 
Withhold ipilimumab; 
administer anti-diarrheal 
treatment and, if persistent for 
more than 1 week, initiate 
systemic corticosteroids at a 
dose of 0.5 mg/kg/day 
prednisone or equivalent.  
The use of infliximab is also 
permitted per institutional 
policies. 
 
Permanently discontinue 
ipilimumab   
Hepatitis 
Dermatitis 
Neuropathies 
Other immune-related 
toxicities 
Grade 2 
Withhold ipilimumab 
Resume ipilimumab in 
patients with complete or 
partial resolution of adverse 
reactions (Grade 0 to 1), and 
who are receiving no more 
than physiologic doses of 
systemic steroid per local 
prescribing information. 
• Grade 2 reactions lasting 6 
weeks or longer 
Permanently discontinue 
ipilimumab 

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Organ system 
Adverse reaction 
Treatment modification 
• Inability to reduce 
corticosteroid dose to 
physiologic doses per local 
prescribing information 
• Grade 3 or 4 
If the subject does not meet the criteria for resuming treatment, dosing will be delayed, and the 
subject should be re-evaluated within 48 to 72 hours.  If the next dose is delayed for toxicity by 
more than the period specified per the locally approved ipilimumab package insert, the subject 
should be discontinued from study treatment unless approved by the medical monitor. 
 
9.3.4.2. 
Procedures for Assessment of Subjects with Changes in Complement Levels 
Activation of complement in non-human primates is a well-described effect of phosphorothioate 
oligonucleotides, including IMO-2125.  Monkeys are thought to be particularly sensitive to 
oligonucleotide-induced complement activation and a similar direct oligonucleotide-induced 
complement activation has not been observed in humans or other species. 
Complement samples will be collected at Weeks 1 and 14 for Arm A and Weeks 1 and 11 for 
Arm B, according to the Schedule of Events table (see Table 1), and will be analyzed at a central 
laboratory (Medpace Reference Laboratories). If at any time during study participation, a subject 
experiences an acute drop in complement (total hemolytic complement assay, complement 
component 3, or complement component 4) levels ≥50% or a drop to an absolute value below the 
lower limit of normal with reference to baseline testing or most recent values on study, the 
Sponsor will notify the site and the following procedures should be performed by the 
investigator: 
1. Perform a safety evaluation and any necessary testing for the subject as clinically 
indicated. 
2. If the results of the safety evaluations suggest any safety concerns associated with the 
drop in complement levels, hold the study drug treatment. 
3. The patients should return to the clinic to have another serum sample drawn and sent to 
the central laboratory to confirm decreased complement levels. 
Based on the results of this work-up and the subject’s disease assessment/response to study drug, 
the Investigator, in discussion with the Sponsor’s Medical Monitor, will determine the subject’s 
risk/benefit profile and discuss appropriate next steps regarding the subject’s continued treatment 
with study drug. 
9.3.4.3. 
Procedures for Assessment of Subjects with Symptomatic Thrombocytopenia 
Severe thrombocytopenia has been reported in clinical studies with another oligonucleotide 
(FDA Briefing Document, 2015).  Most of these subjects had confirmed anti-platelet antibodies.  
These cases occurred 14 to 26 months after the onset of treatment, suggesting that risk increases 
with duration of exposure.  In the event of a precipitous drop in platelet counts (i.e., to 
<25 x 109/L), treatment with IMO-2125 should be held and an anti-platelet antibody count 

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obtained.  Treatment may be resumed once administration criteria (Section 9.3.4) are met.  
Anti-platelet, thrombolytic, or anticoagulant drugs should be used with caution. 
9.4. 
Labeling 
The product label contains the elements required by national and local authorities for 
investigational products.  IMO-2125 will be shipped directly to the Investigator site.  
9.5. 
Drug Accountability  
The Investigator is responsible for study drug accountability, reconciliation, and record 
maintenance.  In accordance with all applicable regulatory requirements, the Investigator or 
designated study personnel (e.g., Pharmacy) must maintain study drug accountability records 
throughout the study.  Further details are provided in the Pharmacy Manual. 
9.6. 
Concomitant and Prohibited Medications  
9.6.1. 
Concomitant Medications 
With the exception of the prohibited drugs listed in Section 9.6.2, concomitant prescription 
medications and over-the-counter drugs are permitted, including infliximab and growth factor 
support.  These should be recorded on the eCRF. 
9.6.2. 
Prohibited Medications 
The following medications are prohibited while the subject is in this study:  
• Anti-cancer therapies other than those specified in the protocol (see Section 7.2 for 
inclusion criteria related to anti-cancer therapies) 
• Oncolytic tumor viral therapies (e.g., Imlygic®) 
• Investigational/experimental medicines or vaccines  

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10. 
ADVERSE EVENT REPORTING 
10.1. 
Adverse Events 
Adverse events should be assessed continuously throughout the study and recorded on the eCRF.  
During the Follow-up Periods, for 90 days after the last dose of study treatment, all SAEs, irAEs 
(Section 10.1.3.4), AEs Grade ≥3, and associated concomitant medications for their treatment 
must be reported.  For the remainder of the Follow-up Periods, AE reporting may be limited to 
treatment-related Grade ≥3 AEs and SAEs, and the associated concomitant medications (see 
Table 1 and Table 2). 
10.1.1. 
Definition of Adverse Events 
10.1.1.1. Adverse Event 
An AE is any untoward medical occurrence temporally associated with the use of a medical 
product in a subject, whether or not the event is considered causally related to the medical 
product.1  An AE can be a new occurrence or an existing process that increases significantly in 
intensity or frequency.   
10.1.1.2. Serious Adverse Event  
An AE is serious when the subject outcome is one or more of the following: 
• Death.  
• Life-threatening, meaning that the subject was at immediate risk of death from the 
event at the time that the event occurred.  It does not include an event which 
hypothetically might have caused death if it occurred in a more severe form.  
• Hospitalization, initial or prolonged, meaning that a hospital admission and/or 
prolongation of a hospital stay was required for the treatment of the AE, or occurred 
as a consequence of the event.  It does not include a pre-planned elective hospital 
admission for treatment or diagnostic procedures, or, in general, a hospital admission 
of less than 24 hours duration.  
• Disability or incapacity that is persistent or significant.  
• Congenital anomaly or birth defect.  
• Important medical event that, although not immediately life-threatening, requires 
intervention in order to prevent one of the other serious outcomes listed above.  
Examples of such events are allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; blood dyscrasias or convulsions that do not result in 
hospitalization; or the development of drug dependency or drug abuse.  
 
1 A medical product may be a drug or a device being used either prior to or after regulatory approval.  The medical 
product in this protocol will hereafter be referred to as study drug (synonym: investigational agent).  

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10.1.1.3. Suspected Unexpected Serious Adverse Reaction (SUSAR)  
A SUSAR is defined as an SAE that meets both the following criteria with respect to study drug:  
• Suspected — is assessed as related or possibly related to study drug (see 
Section 10.1.3.3);  
• Unexpected — compared to the study drug-related AEs described in the 
Investigator’s Brochure, the event meets any of the following criteria: 
− The event was not previously described;  
− The event is now characterized as more severe (see Section 10.1.3.5);  
− The event is now characterized more specifically (e.g., an event of “interstitial 
nephritis” in a subject receiving an agent previously described as associated with 
“acute renal failure”). 
In clinical trials involving ill subjects, events considered related to the natural history of the 
disease under study or to lack of efficacy (that is, the event is considered more likely related to 
those factors than to other factors, including study drug) are not considered "unexpected."   
10.1.2. 
Recording Adverse Events 
Procedures for the collection and recording of AEs are as follows:  
• AEs are captured from the time of informed consent. Events will be recorded in the 
AE portion of the electronic data capture (EDC), with particular attention to whether 
the onset of the event was before or after the administration of the first dose of study 
drug.  All recorded events will be included in applicable line listings, but only events 
with onset after administration of the first dose will be included in summaries of 
TEAEs.   
• After the Active Follow-up Period, surveillance will be passive (only events brought 
to the Investigator’s attention will be considered) and only events assessed as 
SUSARs will be recorded (see Section 10.1.1.3). 
• In accordance with the FDA guidance document – Safety Reporting Requirements for 
Investigational New Drugs and Bioavailability/Bioequivalence Studies – disease 
progression does not require reporting as an AE or SAE.  However, signs and 
symptoms related to disease may be reported at the discretion of the Investigator.  
10.1.3. 
Characterizing Adverse Events 
For each AE recorded the following characteristics will be noted.   
10.1.3.1. Description of Event 
The diagnosis or description will be as specific and complete as possible (i.e., “lower extremity 
edema,” rather than just “edema”).  Whenever possible, signs and symptoms due to a common 
etiology will be reported as an integrated diagnosis; for example, cough, runny nose, sneezing, 
sore throat, and head congestion would be reported as “upper respiratory infection.”  

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10.1.3.2. Date and Time of Onset 
The date and time at which the event was first apparent will be recorded, if known.  The time of 
onset of symptoms may be appreciably earlier than the date and time the Investigator becomes 
aware of the event.  Some events may be apparent to the subject and Investigator independently, 
and information from each may contribute to the final report.  For example, a subject may report 
the onset of a rash 2 days prior to being seen by a physician who makes a diagnosis of herpes 
zoster based on appearance and laboratory confirmation.  In that case, there is a single AE, with 
the date of onset based on the date of the initial observation by the subject and a specific 
description (herpes zoster) based on the clinical exam and tests.      
10.1.3.3. Relationship to Study Drug 
This determination is based on the Investigator’s clinical judgment regarding the likelihood that 
the study drug caused the AE and may include consideration of some or all of the following 
factors:  
• Alternative possible causes of the AE, including the subject’s underlying disease or 
comorbid conditions, other drugs, other host and environmental factors. 
• Temporal sequence between the exposure to study drug and the AE.  
• Whether the clinical or laboratory manifestations of the AE are consistent with known 
actions or toxicity of the study drug.  
• Whether the AE resolved or improved with holding or stopping the study drug (i.e., 
dechallenge); or recurred or worsened with re-exposure to the drug (i.e., rechallenge).  
The relationship between the study drug and the AE will be described using one of the following 
categories:  
• Related — the study drug is more likely the cause of the AE than other factors.  
• Possibly related — there is a reasonable possibility that the study drug is the cause of 
the AE, including that the study drug and (an)other factor(s) are equally likely as 
causes of the AE. 
• Unlikely related — another factor is considered more likely the cause of the AE than 
the study drug. 
• Not related — another factor is considered to be the cause of the AE.  
Related and possibly related AEs may result from the use of the study drug as planned (per 
protocol), or from abuse, withdrawal, or over-dosage of the agent.  
10.1.3.4. Immune-related AEs 
Immune-related AEs (irAEs) are side effects associated with the increased activity of the 
immune system by immunotherapy agents such as checkpoint inhibitors, which can affect 
multiple organs of the body including the skin, gastrointestinal tract, endocrine system, liver, 
lungs, nervous system, and musculoskeletal system. The following list of AEs, which have been 
associated with the use of immunotherapy agents, will be considered to be immune-related and 
should be considered as such unless another etiology can be clearly established: 

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• Adrenal insufficiency 
• Hypophysitis 
• Hypopituitarism 
• Hypothyroidism 
• Hyperthyroidism 
• Other endocrinopathies  
• Colitis 
• Enterocolitis 
• Dermatitis 
• Autoimmune dermatitis  
• GuillainBarre syndrome 
• Hepatitis 
• Myasthenia gravis 
• Pneumonitis 
• StevensJohnson Syndrome 
• Toxic epidermal necrolysis 
• Uveitis 
• Iritis 
• Myocarditis 
• Any AEs that the Sponsor or investigator considers to be of autoimmune or immune-
related origin. 
Immune-related AEs will be identified as such in the eCRF, and the associated treatment for 
these AEs should be recorded including the drugs, doses, duration, and AE(s) being treated.  Any 
dose modifications to either study treatment should also be recorded including the start and end 
dates of the modification, the study drug doses, and any dose reductions.  See Section 9.3.4 for 
additional information about dose modifications. 
10.1.3.5. Severity 
The severity of clinical AEs (i.e., symptoms reported by the subject and/or signs observed by the 
Investigator) will be assessed using the guidelines summarized in Table 5 based on National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. 
Table 5:  
Estimating Severity Grade 
Grade 1/Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2/Moderate 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living a 
Grade 3/Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living b 
Grade 4/Life-threatening 
Life-threatening consequences; urgent intervention indicated 
Grade 5/Death 
Death related to adverse event 
a. Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 

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b. Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
10.1.3.6. Grading of Laboratory Safety Tests for Reporting and Analysis 
Treatment-emergent abnormal laboratory results will be handled as follows: 
• Graded using NCI-CTCAE Version 4.03 criteria 
• Reported as AEs when assessed as clinically significant (“CS”) using the procedures 
and criteria detailed in Section 10.1.2. 
All relevant and clinically significant laboratory results from hospitalizations occurring during 
the study must be entered into the EDC on an Unscheduled Visit eCRF. 
10.1.3.7. Management of Study Drug upon Occurrence of an Adverse Event 
For each AE the Investigator will indicate which one of the following actions regarding the 
administration of study drug was taken because of that AE:  
• Discontinued — study drug was stopped permanently due to the AE. 
• Dosing Interrupted — study drug regimen was modified by being temporarily halted 
or dosing was skipped; i.e., one or more doses were not administered, but drug was 
not stopped permanently. 
• Dose Reduced — study drug regimen was modified by subtraction; i.e., by 
decreasing the frequency. 
• Dose Not Changed — no change in the administration of study drug. 
For subjects whose treatment is paused due to events requiring dose modification (see 
Section 9.3.4) and then resumed at a decreased frequency, the management of study drug will be 
recorded as “Dose Reduced.” 
10.1.3.8. Actions Taken for Management of Adverse Event 
Adverse events will be followed and managed by the Investigator, including obtaining any 
supplemental studies needed to define the nature and/or cause of the event (e.g., laboratory tests, 
diagnostic procedures, consultation with other health care professionals).  
For each AE the Investigator will categorize as follows the actions taken to manage the AE:  
• Concomitant medication — one or more medications (prescription or over the 
counter) were started or increased in dose; non-medication actions may also have 
been ordered.  
• Other action — only non-medication action(s) were ordered as management of the 
AE (e.g., bed placed in Trendelenburg position, warm compresses applied to access 
site).  
• No action — no actions were ordered for management of the AE.  

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10.1.3.9. Follow-up and Outcome of Adverse Events 
If possible, AEs will be followed until resolved (synonyms: recovered, recuperated, ended) either 
with or without sequelae, including for subjects who prematurely discontinue study participation.  
For the purpose of SAE reporting, the end date of an SAE is the date that it no longer met the 
serious criteria, e.g. the discharge date is the end date for SAEs considered serious on the basis of 
hospitalization.  For AEs that are assessed as not drug-related and are not resolved at the end-of-
study visit, follow-up may be limited with the approval of the Medical Monitor.  
For subjects in Arm B (ipilimumab + IMO-2125), during the IMO Maintenance Period, all 
CTCAE Grade ≥2 irAEs and laboratory abnormalities (regardless of relationship to study drug) 
should be monitored until resolution, stabilization, or return to baseline (see Table 2). 
The outcome of each event will be described using the following categories:  
• Resolved without sequelae — the event resolved and subject returned to baseline.  
• Resolved with sequelae — the event resolved but the subject is left with residual 
problems (e.g., functional deficits, pain).  
• Resolving — at the last observation, the event was improving.  
• Not Resolved — at the last observation, the event was unchanged.  
• Death (Fatal) — to be used for the one AE which, in the judgment of the 
Investigator, was the primary cause of death.  
• Unknown — there were no observations after the onset (initial observation or report) 
of the event.  
Note: Resolving and Not Resolved may also be used for AEs that were unresolved at the time a 
subject died, but were not assessed as the primary cause of death.  For the purpose of SAE 
reporting, these categories are to be filled out as appropriate as of the date that the SAE form is 
filled out by the site. 
10.1.3.10. Date and Time of Outcome  
For each class of outcome as defined above, Table 6 indicates the date and time to be recorded.  
As discussed in detail for date/time of onset (see Section 10.1.3.2), determining the date/time an 
event resolved (ended) should reflect the type of event and the source of the information.  
Table 6: 
Date and Time of Outcome for Adverse Event by Outcome Class  
Outcome assigned to Adverse Event 
Date and Time to be Recorded 
Resolved (with or without sequelae) 
Date and time event observed or reported as resolved 
Death 
Date and time of death 
Resolving or Not Resolved 
Date and time of last observation 
Unknown 
None (see definition above) 
For the purpose of SAE reporting, these categories are to be filled out as appropriate as of the 
date that the SAE form is filled out by the site. 

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10.1.4. 
Reporting Adverse Events 
10.1.4.1. Where to Report Serious Adverse Events 
Serious AE reporting will be performed by the site via submission of a paper SAE form sent as a 
PDF by e-mail or fax to the pharmacovigilance vendor (see Emergency contact page for details); 
detailed training will be provided during site initiation.  Contact information for the Medical 
Monitor is provided in the Emergency Contact Information section of this protocol.  
10.1.4.2. Procedures for Reporting Serious Adverse Events to the Sponsor  
The SAE will be submitted by e-mail or fax to the pharmacovigilance vendor within 24 hours of 
the time the Investigator (or the Investigator's designee) becomes aware that the event has 
occurred.  The study specific SAE form should be used and each box/question should be filled 
out as pertinent to the date that the SAE form was filled out.   
Copies of relevant medical reports — including diagnostic procedures (e.g., laboratory, ECG, 
xray), surgical procedures, and consultations may be sent as accompanying documentation and 
may be requested if not available.  However, the relevant information from these documents 
needs to be included in the appropriate section of the study-specific SAE form, including the 
narrative as appropriate. 
10.1.4.3. Other Reportable Events 
Certain events that occur in the absence of an AE should be reported to the Sponsor.  These 
include the following: 
• Pregnancy exposure (subject becomes pregnant while taking study drug).  Should a 
female subject or partner of a male subject become pregnant during the study, the 
subject will inform the Investigator.  The subject will be asked to follow up with the 
study site to report the eventual outcome of the pregnancy.  The information will be 
tracked by the Sponsor.  
• Lactation exposure (subject was taking study drug while nursing an infant). 
• Accidental exposure (someone other than the subject was exposed to study drug).  
• Overdose (subject received more than the prescribed dose of study drug within a 
given timeframe).  
• Other medication errors that potentially place subjects at greater risk of harm than 
was previously known or recognized (e.g., study drug was administered via incorrect 
route). 
10.1.4.4. Requirements for Expedited and Periodic Reporting of Adverse Events 
Suspected unexpected serious adverse reactions are required to be reported rapidly to regulatory 
authorities and to IRBs (typically within 7 days of receipt by Idera or designated vendor for fatal 
or life-threatening SUSARs; within 15 days for all other SUSARs).  Therefore, as with all SAEs, 
the site must submit an SAE form with relevant information to the pharmacovigilance vendor 
within 24 hours of being made aware of the event. The Sponsor and the Investigator will work 
together to meet these reporting requirements.  

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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Tumor Response 
Tumor assessments will be performed at Screening and Week 12 (±1 week), then every 8 weeks 
(±2 weeks) for the first year and every 12 weeks (±2 weeks) in subsequent years using consistent 
imaging modality.  Investigators should follow modified irRECIST guidelines for patient 
management and provide visit response assessments using RECIST v1.1.  Blinded central 
reviewers will provide independent assessment of tumor response using RECIST v1.1 and 
modified irRECIST (see Section 20.2 and Section 20.3, respectively), as described in a charter.  
Efficacy evaluations should include clinical examination, assessment of cutaneous lesions with 
photography, and computed tomography (CT) or magnetic resonance imaging (MRI) scanning of 
known sites of disease.  Injected lesions will contribute to the assessment of overall tumor 
burden and may be selected as target lesions if appropriate.  Ultrasound studies performed for 
needle biopsy localization or IMO-2125 dosing should not be used as the sole means of assessing 
response.  Similarly, lesions that will be biopsied for exploratory analyses should generally not 
be considered target lesions for purposes of disease assessment when other measurable lesions 
are present.   
If present, skin lesions may be considered RECIST v1.1 (or irRECIST) target lesions when they 
are superficial and ≥10 mm diameter as assessed using calipers.  Documentation by color 
photography including a ruler to measure the size should be done and sent to the independent 
review facility for response assessment evaluation. 
The same method(s) of assessment should be used throughout the study for consistency.  For 
irRECIST, response assessments of immune-related CR (irCR), immune-related PR (irPR), and 
immune-related PD (irPD) must be confirmed by imaging ≥4 weeks after the initial 
documentation of response except progression based solely on substantial, unequivocal 
worsening of non-target or new, non-measurable disease accompanied by correlative symptoms 
(see Section 20.3).  For RECIST v1.1, response assessments of CR or PR must be confirmed by 
imaging ≥4 weeks after the initial documentation of response. 
Patients will be allowed to be treated until confirmed progression and per Investigator discretion. 
11.2. 
Patient-Reported Outcomes (EORTC QLQ-C30) 
The EORTC QLQ is an integrated system for assessing the health-related quality of life (QoL) of 
cancer patients participating in international clinical trials.  The EORTC has adopted a modular 
approach to QoL assessment, consisting of a core questionnaire to be administered, if necessary, 
with a module specific to tumor site, treatment modality, or a QoL dimension (Aaronson, 1993). 
The EORTC QLQ-C30 is the product of more than a decade of collaborative research.  It is a 
questionnaire for patient self-completion, composed of multi-item and single-item measures.  
These include five functional scales (physical, role, emotional, social, and cognitive), 
three symptom scales (fatigue, nausea and vomiting, and pain) and a global health status/ QoL 
scale, and six single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and 
financial difficulties) (Aaronson, 1993). 

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All of the scales and single-item measures range in score from 0 to 100.  A high scale score 
represents a higher response level.  Thus, a high score for a functional scale represents a 
high / healthy level of functioning, a high score for the global health status / QoL represents a 
high QoL, but a high score for a symptom scale / item represents a high level of 
symptomatology / problems. 
The EORTC QLQ-C30 will be administered to all subjects according to the Schedule of 
Evaluations (see Table 1 and Table 2).  To minimize bias in the PRO data, the PRO assessments 
are to be completed before study drug administration and AE assessments. 

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12. 
SAFETY ASSESSMENTS 
Adverse events will be continuously assessed during the study (see Section 10.1). 
12.1. 
Vital Signs 
Vital sign measurements will be taken at intervals as specified in the Schedule of Evaluations 
(Table 1 and Table 2).  Vital signs will include systolic and diastolic blood pressure, body 
temperature, pulse rate, body weight, height (Screening only).  Vital signs should be done prior 
to treatment administration.  
12.2. 
Laboratory Assessments 
Instructions for conducting laboratory assessments and processing samples will be provided in a 
study manual to the study staff before study initiation.  Laboratory tests will be performed at 
intervals as specified in the Schedule of Evaluations (Table 1 and Table 2).  Blood and urine 
samples will be analyzed for the analytes presented in Table 7.  

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Table 7: 
Safety Laboratory Measurements 
Hematology 
Chemistry 
Urinalysis by Dipstick 
Other 
Basophils 
Albumin 
Glucose 
Thyroid Profile 
Eosinophils 
Alkaline phosphatase 
pH 
TSH 
Lymphocytes 
ALT 
Leukocytes 
Free thyroxine (free T4) 
Atypical 
lymphocytes 
AST 
Nitrite 
Total or free triiodothyronine 
(total or free T3) 
Monocytes 
Total bilirubin 
Urobilinogen 
 
Neutrophils 
BUN 
Protein 
Coagulation 
Hematocrit 
Creatinine 
Blood 
PT 
Hemoglobin 
Calcium 
Specific gravity 
aPTT 
MCH 
CO2 
Ketones 
INR 
MCHC 
Sodium, chloride, and 
potassium 
Bilirubin 
 
MCV 
Cholesterol 
 
Complement 
Platelet count 
Glucose 
Microscopy 
CH50 
RBC count 
Lactate dehydrogenase 
Bacteria  
C3 
WBC count 
Phosphate 
Crystals 
C4 
 
Total protein 
Casts (cellular, granular, and 
hyaline) 
 
 
Triglycerides 
RBC 
 
 
Uric acid 
WBC 
 
 
βhCG for WOCBP 
Epithelial cells 
 
ALT=alanine aminotransferase; aPTT= activated partial thromboplastin time; AST=aspartate aminotransferase; 
βhCG=beta human chorionic gonadotropin; BUN=blood urea nitrogen; C3=complement component 3; 
C4=complement component 4; CH50=total complement activity 50; CO2=carbon dioxide; GGT=gamma 
glutamyltransferase; INR=international normalized ratio; MCH=mean corpuscular hemoglobin; MCHC=mean 
corpuscular hemoglobin concentration; MCV=mean corpuscular volume; PT=prothrombin time; RBC=red blood 
cell; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; WBC=white blood cell; 
WOCBP=women of childbearing potential. 
 
12.3. 
Other Safety Assessments 
12.3.1. 
Physical Examination  
A directed physical examination with clinical disease assessment will be performed as outlined 
in the Schedule of Evaluations (Table 1 and Table 2).  A medical history will be done at the 
Screening Visit and any clinically significant findings should be recorded as part of the medical 
history.  During the study, any new physical examination findings that the Investigator deems 
clinically significant should be recorded as AEs.   

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12.3.2. 
Electrocardiogram Monitoring  
A resting 12-lead ECG will be performed (in triplicate for Arm B only) at intervals as specified 
in the Schedule of Evaluations (Table 1 and Table 2).  Any clinically significant findings during 
the Screening Visit should be recorded as part of the medical history. 
12.3.3. 
ECOG Performance Status 
The subject’s ECOG performance status will be evaluated per guidance in Section 20.1 as 
outlined in the Schedule of Evaluations (Table 1 and Table 2). 

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13. 
PHARMACOKINETICS  
The timing of sample collection is provided in the Schedule of Evaluations (Table 1 and 
Table 2).  Plasma samples for analysis of IMO-2125 concentrations will be collected from 
subjects in Arm B only.  Samples for IMO-2125 analysis will be collected pre-dose and at 1, 2, 
and 4 hours post-dose at Week 1 and Week 11.  
Detailed instructions and materials for all blood sampling will be provided in a separate study 
manual and kits.  

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14. 
EXPLORATORY ASSESSMENTS  
14.1. 
Tumor Biomarkers  
The RNA from optional biopsies obtained from the subjects will have NanoString analyses 
performed using the NanoString nCounter® system for identification of putative prognostic and 
predictive biomarkers.  The nCounter® PanCancer Immune panel measures 770 genes 
representing 24 different immune cell types and 30 common cancer antigens.  The assessment of 
tumor genetic markers will be used to identify gene patterns that might be correlated to clinical 
response and gene pattern changes after IMO-2125 treatment compared to untreated samples 
(where available).  Putative biomarker(s) of response identified from these samples may be 
applicable for other tumor types. 
14.2. 
Anti-Drug Antibodies 
The development of antibodies to IMO-2125 and ipilimumab will be assessed in subjects at the 
timepoints indicated in the Schedule of Evaluations (Table 1 and Table 2).  

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15. 
STATISTICAL ANALYSIS METHODS 
15.1. 
Determination of Sample Size 
In this study, ORR and OS comprise a primary endpoint family; both have a priori hypotheses 
and will be tested for statistical significance.  ORR will be tested first followed by OS.   The 
fallback method for the primary endpoint family will be applied to control the study-wise Type I 
error rate.  Under the fallback method, α1 = 0.02 is assigned to the one-sided ORR test and an alpha 
of 0.005 is saved for the one-sided OS test. If the ORR test is significant at α1 = 0.02, this alpha is 
unused and will be passed to the OS test as an additional alpha of 0.02, giving a total alpha for the 
OS test of 0.025. 
With 454 subjects randomized with a 1:1 ratio, this test will have 90% statistical power 
(calculated based on chi-square test) to demonstrate an increase in the ORR from the postulated 
response of 12% for ipilimumab alone in this setting to 24% for the IMO-2125 + ipilimumab 
combination, at a 0.02 level of significance.  
A sample size of 454 subjects provides 90% power to test the alternative hypothesis of hazard 
ratio (HR) for OS ≤ 0.677 at an α of 0.005 (one-sided).  The HR of 0.677 corresponds to an 
improvement in the median survival from 11.4 months (the historical control for ipilimumab 
alone) to 16.9 months with the IMO-2125 + ipilimumab combination.  The OS analysis will be 
performed when 392 deaths are reached. 
The OS power calculations are based on log-rank test and assume that the trial will have ~20 
months of uniform accrual, an overall study duration up to 56 months, and a 10% drop-out rate.  
If under the fallback method a total alpha of 0.025 is available for the OS significance test, then this 
test will have 90% power to test the alternative hypothesis of HR ≤ 0.72 at an α of 0.025 (one-
sided) which corresponds to an improvement in the median survival from 11.4 months (the 
historical control for ipilimumab alone) to 15.8 months with the IMO-2125 + ipilimumab 
combination. 
15.2. 
Analysis Populations 
15.2.1. 
Screened Population 
The Screened Population consists of all subjects who provided written informed consent and 
who undergo study screening procedures.   
15.2.2. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) Population comprises all subjects in the Screened Population who were 
randomized.  This population will be analyzed using the treatment to which the subject was 
randomized regardless of the treatment actually received and will be the primary analysis set for 
efficacy analyses.  Any subject who receives a treatment randomization number will be 
considered to have been randomized. 
15.2.3. 
Safety Population 
The Safety Population comprises all subjects in the ITT Population who receive at least one dose 
of study treatment and will be based on the actual treatment received. 

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15.2.4. 
Pharmacokinetic Population 
The PK Population comprises all subjects who receive at least one dose of IMO-2125 with at 
least one measurable concentration of IMO-2125. 
15.3. 
Missing Data 
Missing data occurs when any requested data is not provided, leading to blank fields on the 
collection instrument.  These data will be indicated by the use of a “blank” in subject listing 
displays.  Answers such as “Not applicable” and “Not evaluable” are not missing. 
All available OS, PFS, and duration of response data will be analyzed using suitable statistical 
methods; subjects with shorter treatment and follow-up due to the natural history of their disease, 
or medical necessities of the treatment of their disease will not be considered to have missing 
time-to-event data.  For ORR and DRR, all subjects in the ITT population will be included in the 
denominator when calculating the percentages; that is, the imputed response will be negative.  
Missing QoL data from the EORTC QLQ-C30 will be imputed using the methods prescribed for 
EORTC QLQ instruments. 
Subjects with the designation of treatment relationship for AEs and SAEs missing will have the 
worst case assumed to impute the relationship: if relationship to study treatment is missing it will 
be assumed to be “Yes”. 
Partial dates will be imputed for AEs and concomitant medications.  Imputed dates are will not 
be used for deriving the last contact date for OS.  Imputed dates will be displayed in listings and 
identified as imputed.  Full details of imputing missing data and rules for analysis of measures 
with missing data will be included in the Statistical Analysis Plan (SAP). 
15.4. 
Analysis of Efficacy 
In this study, ORR and OS comprise a primary endpoint family; both have a priori hypotheses 
and will be tested for statistical significance.  ORR will be tested first followed by OS.   The 
fallback method for the primary endpoint family will be applied to control the study-wise Type I 
error rate. 
Under the fallback method, α1 = 0.02 is assigned to the one-sided ORR test and an alpha of 0.005 is 
saved for the one-sided OS test.  
• 
If the ORR test is significant at α1 = 0.02, this alpha is unused and will be passed to the OS 
test as an additional alpha of 0.02, giving a total alpha for the OS test of 0.025. The OS test 
will then be performed at the significance level of 0.025.   
• If the ORR test is not significant at 0.02 level, then this alpha of 0.02 will not be available to 
be passed on for the OS test. The OS test will be performed at the originally reserved alpha of 
0.005.  
Full details of all efficacy analyses will be in the SAP.  All efficacy analyses will use the ITT 
Population. 

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15.4.1. 
Analysis of the Family of Primary Endpoints 
15.4.1.1. Analysis of Objective Response Rate 
The analysis of ORR (assessed by blinded independent review using RECIST v1.1) will be 
performed using a CMH test comparing the ORR for the two treatment groups controlling for the 
randomization strata.  This is the only test of RECIST v1.1 ORR that will be done.  The analysis 
of ORR will take place when all randomized subjects fall within one of the following categories:    
• completed scheduled study treatment and completed at least 28 weeks on the study;  
• prematurely discontinued study treatment and completed at least 28 weeks on the study; 
• withdrew, were lost to follow-up, or died before completing at least 28 weeks on the 
study. 
 
15.4.1.2. Primary Analysis of Overall Survival  
Overall survival, defined as the time in months from randomization to death from any cause, will 
be analyzed using the Kaplan-Meier method after approximately 392 deaths have occurred, or 
approximately 36 months after the last subject is randomized, whichever occurs first.  Sensitivity 
analyses will be detailed in the SAP. 
The study hypotheses will be tested using a one-sided, stratified log-rank test.  If the null 
hypothesis is rejected at the appropriate alpha level in accordance with the fallback method, it 
will be concluded that OS in the IMO-2125 + ipilimumab combination arm is statistically 
significantly superior to the OS in the ipilimumab alone arm.     
Stratification factors will include duration of prior anti-programmed death receptor-1 (PD-1) 
therapy (≥12 weeks vs <12 weeks), metastasis stage (M1c vs other), and BRAF mutation status 
and prior targeted therapy (BRAF wild type, BRAF mutation positive with prior targeted 
therapy, or BRAF mutation positive with no prior targeted therapy) using block randomization.  
Targeted therapy is the use of an approved BRAF or MEK inhibitor alone or in combination.  
Stratification will use block randomization.  Depending on the distribution of the strata with the 
ITT, strata may be collapsed as appropriate.  The full details will be specified within the SAP.   
Subjects who have not died or who are lost to follow up at the data cut-off date will be censored 
at the last date they were known to be alive. 
15.4.2  
Analysis of Secondary Efficacy Endpoints 
The ORR assessed by investigator assessment using RECISTv1.1 will be summarized 
descriptively by treatment arm.  ORR will be estimated at each level of the stratification factors. 
Duration of response (DoR) by blinded independent review and investigator assessment using 
RECIST v1.1, measured from the time that criteria are first met for CR or PR (whichever is first 
recorded) until the first date that recurrent or progressive disease is objectively documented, will 
be summarized descriptively by the Kaplan-Meier method. If supported by the data, quartiles 
with corresponding 95% two-sided confidence intervals will be reported.  There will be no 
statistical tests of DoR. 

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Durable response rate, defined as CR or PR lasting ≥6 months with onset during the first 
12 months of treatment, will be estimated for the subjects with at least a PR using the same 
methods as for ORR.  The DRR will be reported for both blinded independent review and 
investigator assessment using RECIST v1.1.  There will be no statistical tests of DRR. 
Time to response (TTR), defined as time to a CR or PR (using RECIST v1.1) measured from the 
date of randomization, by blinded independent review and investigator assessment will be 
summarized descriptively.  There will be no statistical tests of TTR. 
Progression-free survival, defined as the time from randomization to disease progression or death 
from any cause, will be assessed using RECIST v1.1 by blinded independent review and 
investigator assessment and estimated by the Kaplan-Meier method.  Quartiles with 
corresponding 95% two-sided confidence intervals will be reported.  There will be no statistical 
tests of PFS.  Subjects who do not have a PFS event at the time of an analysis, including those 
who have started new anticancer therapy, withdrawn from the study, or been lost to follow-up 
without disease progression, will be censored at the date of the last valid disease assessment, 
defined as the latest assessment at which the subject had progressed RECIST v1.1 response of 
CR, PR, or stable disease.   
In addition, PFS by blinded independent review and investigator assessment using RECIST v1.1 
and OS will be estimated at 1 and 2 years.  Overall survival will be estimated at each level of the 
stratification factors.  
Amounts and patterns of missing PRO data from the EORTC QLQ-C30 instrument in the two 
arms will be described using counts and percentages and with appropriate figures.  Scores and 
changes from baseline in scores will be reported by visit.  A mixed model for repeated measures 
data will be used with treatment arm and stratification factors (as used in the primary analysis of 
OS) included as independent variables.  There will be no statistical tests of EORTC QLQ-C30 
data; all analyses will be descriptive. 
15.5. 
Analysis of Safety 
All safety analyses will use the Safety Population. 
All safety measures, including vital signs, laboratory values, ECOG performance status, and 
ECG values will be summarized descriptively; no formal statistical hypotheses will be tested.  
For laboratory values that are continuous, shift tables from baseline by scheduled visit and to 
worst case on study will be produced.  Worst case will be relative to the normal range for 
laboratory values that are not in the CTCAE; otherwise, the worst case will be the highest 
CTCAE grade.  For laboratory values that are bi-directional, separate shift summaries will be 
produced; for example, for shifts in CTCAE grade, both hypokalemia and hyperkalemia shifts 
will be shown.  Only scheduled visits will be included in the shift tables by visit; all visits will be 
included when determining the worst case on study. 
Adverse events will be tabulated by Medical Dictionary for Regulatory Activities (MedDRA) 
System Organ Class and Preferred Term for each treatment arm.  Adverse event summaries will 
include: overall, by severity, related AEs, SAEs, irAEs, and AEs leading to discontinuation of 
study treatment. 

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Concomitant medications will be coded by World Health Organization drug class and 
Anatomical Therapeutic Chemical text and summarized by treatment arm.  
15.6. 
Analysis of Pharmacokinetics 
Plasma concentration of IMO-2125 will be monitored for subjects in Arm B at Weeks 1 and 11. 
Plasma concentration data will be summarized using descriptive statistics. 
The relationship between PK parameters, safety, efficacy, and pharmacodynamics variables will 
be explored whenever possible in analyses independent from this protocol.  Complete details of 
the analyses of plasma IMO-2125 concentrations will be given in a separate PK SAP. 
15.7. 
Analysis of Patient-Reported Outcomes 
Patient-reported outcomes will be assessed using the EORTC QLQ-C30.  The number and 
percentage of subjects with each pattern of missing PRO data will be described for each 
treatment arm.  Changes from baseline in PRO scores will be summarized by visit and treatment 
arm.  If supported by the data, changes from baseline will be described using a mixed model for 
repeated measures.  Analyses will be prioritized by the most important patient-reported 
symptoms and functional impacts (i.e., physical function) that are responsive to treatment. 
All analyses of PRO data will be descriptive.  Full details of the analysis of PRO data will be in 
the SAP. 
15.8. 
Exploratory Analyses 
Ribonucleic acid from optional biopsies will be subjected to NanoString analysis.  NanoString 
nCounter system is used for identification of putative prognostic and predictive biomarker.  The 
nCounter PanCancer Immune panel is comprised of 770 genes representing 24 different immune 
cell types and 30 common cancer antigens.  Exploratory analysis will identify gene patterns 
associated with clinical response as well as gene pattern changes after IMO-2125 treatment 
compared with untreated samples (where available).   
Full details of the analyses of exploratory data will be described in a separate biomarker SAP. 

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16. 
DATA COLLECTION 
16.1. 
Required Data 
The full study dataset will be collected for all randomized subjects. 
All required data for this study will be collected in the eCRF and all data collected in this study 
will be listed in the clinical study report. 
16.2. 
Data Collection and Tracking 
Qualified study staff at each site will perform primary data collection from source-document 
reviews.  Idera or its designee will perform clinical monitoring, including review of eCRFs with 
verification to the source documentation. 
Laboratory and ECG data from the Screening Visit through the Active Follow-up Period will be 
collected at the participating site.  Central Laboratories may be used to track and analyze the 
complement, PK, and anti-drug antibody testing.   
Site staff will enter data into an eCRF.  The frequency and procedures for the handling of data 
within the clinical database will be documented in detail in the Data Management Plan.  

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17. 
ADDITIONAL STUDY RESPONSIBILITIES 
17.1. 
Investigator Responsibilities 
The Investigator should not deviate from the protocol.  In medical emergencies, the Investigator 
may use his/her medical judgment and may remove a study participant from immediate hazard 
before notifying Idera (or its designees) and the IRB in writing regarding the type of emergency 
and the course of action taken. 
17.2. 
Study Data Reporting and Processing 
The eCRF will be reviewed by the Principal Investigator (PI) at the site.  The PI will 
electronically sign the eCRF to verify that he or she has reviewed the recorded data.  This review 
and sign-off may be delegated to a qualified physician appointed as a sub-investigator by the PI.  
The transfer of duties to a sub-investigator will be recorded on the delegation list (kept on file at 
the site) and all sub-investigators are to be listed on appropriate regulatory forms (e.g., FDA 
Form 1572).  The Investigator must ensure that all site staff involved in the conduct of the study 
are trained on and familiar with the protocol and all study-specific procedures and that they have 
appropriate knowledge of the study agents. 
17.3. 
Training 
The training of appropriate clinical site personnel will be the responsibility of Idera or its 
designees.  The PI is responsible for ensuring that his or her staff conducts the study according to 
the protocol.  To ensure proper administration of study agents, uniform data collection, and 
protocol compliance, Idera or its designees will present a formal training session to study site 
personnel, to include instructions for study procedures, the investigational plan, instructions on 
in-hospital data collection, methods for soliciting data from alternative sources, schedules for 
follow up with the study site coordinators, and regulatory requirements.  Detailed feedback 
regarding completion of forms will be provided by Idera or its designees in the course of regular 
site monitoring. 
17.4. 
Monitoring the Investigational Site 
Monitoring of the study (which may be delegated by Idera to a CRO) will be performed 
according to the Study Monitoring Plan. 
17.5. 
Study Documentation 
Study documentation includes all eCRFs, source documents, monitoring logs, appointment 
schedules, Sponsor-Investigator correspondence, and regulatory documents (e.g., signed protocol 
and amendments, IRB/EC correspondence and approval, approved and signed subject consent 
forms, Statement of Investigator form, and clinical supplies receipts and distribution records). 
The Investigator will prepare and maintain complete and accurate study documentation in 
compliance with Good Clinical Practice (GCP) standards and applicable federal, state, and local 
laws, rules, and regulations; and, for each subject participating in the study, will promptly 
complete all eCRFs and such other reports as required by this protocol following completion or 
termination of the clinical study or as otherwise required pursuant to any agreement with Idera. 

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By signing the protocol, the Investigator acknowledges that, within legal and regulatory 
restrictions and institutional and ethical considerations, study documentation will be promptly 
and fully disclosed to Idera and its designees (if applicable) by the Investigator upon request and 
also will be made available at the Investigator’s site upon request for inspection, copying, 
review, and audit at reasonable times by representatives of Idera or responsible government 
agencies as required by law.  The Investigator agrees to promptly take any reasonable steps that 
are requested by Idera or its designees as a result of an audit to cure deficiencies in the study 
documentation and eCRFs. 
17.6. 
Source Documentation 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical study.  
Accordingly, source documents include, but are not limited to, laboratory reports, ECG tracings, 
x-rays, radiologist reports, subject diaries, biopsy reports, ultrasound photographs, subject 
progress notes, hospital charts, pharmacy records (including drug preparation worksheets), and 
any other similar reports or records of any procedure performed in accordance with the protocol. 
Whenever possible, the original recording of an observation should be retained as the source 
document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document. 
Regulations require that Investigators maintain information in the study subject’s medical 
records that corroborates data collected on the eCRF.  In order to comply with these regulatory 
requirements, the following information will be maintained and made available as required by 
the study monitors, auditors, and/or regulatory inspectors: 
1. Medical history/physical condition of the study subject before involvement in the study 
sufficient to verify protocol entry criteria 
2. Medical record documenting that informed consent was obtained for the subject’s 
participation in the study 
3. Dated and signed notes for each subject visit, including results of examinations 
4. Notations on abnormal lab results and their resolution 
5. Dated printouts or reports of special assessments (e.g., ECG reports) 
6. Description of AEs and follow up of the AEs (minimally, event description, severity, 
onset date, duration, relation to study device, outcome, and treatment for AE) 
7. Notes regarding concomitant medications taken during the study (including start and stop 
dates) 
8. Subject’s condition upon completion of or withdrawal from the study 
17.7. 
Protocol Deviations 
A protocol deviation is defined as an event where the Investigator or site personnel did not 
conduct the study according to the investigational study protocol or the Investigator Agreement. 

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17.8. 
Study Supply Accountability 
The Investigator will maintain complete and accurate records of the receipt and disposition of all 
investigational agents.  During the study, used, unused, or expired study drug vials may be 
destroyed according to local practice.  When the enrollment is complete, the Investigator will be 
notified by Idera and, in a timely manner, will destroy the remaining study drug in a documented 
fashion, as directed by Idera.  Please refer to the Pharmacy Manual for details about study drug 
accountability and destruction. 
17.9. 
Data Transmittal and Record Retention 
Required data will be entered in the appropriate eCRF at the time of or as soon as possible after 
the subject visit or the availability of test results.  All completed eCRFs will be reviewed at 
regular intervals according to the Study Monitoring Plan as the study proceeds. 
The Investigator will maintain the records of study drug disposition, final eCRFs, worksheets, 
and all other study-specific documentation; e.g., study file notebooks or source documentation, 
until notified by Idera that records may be destroyed.  
The Investigator(s) must maintain all Essential Documents (as listed in the International Council 
for Harmonisation [ICH] Guideline for GCP) until notified by Idera or its designees and in 
accordance with all local laws regarding retention of records. 
The Investigator must obtain written permission from Idera or its designees before disposing of 
any records.  In order to avoid any possible errors, the Investigator will contact Idera or its 
designees prior to the destruction of any study records.  The Investigator will promptly notify 
Idera or its designees in the event of accidental loss or destruction of any study records.  If the 
Investigator relocates, retires, or for any reason withdraws from the study, the study records may 
be transferred to an acceptable designee, such as another Investigator, another institution, or to 
Idera or its designees. 
17.10. 
Study Closeout 
Upon completion of the study (defined as all subjects have completed all follow-up visits, all 
eCRFs are complete, and all queries have been resolved), Idera or its designees will notify the 
site of closeout, and a study closeout visit will be performed.  All unused study materials will be 
collected and returned to Idera or its designees.  The study monitor will ensure that the 
Investigator’s regulatory files are up to date and complete, and that any outstanding issues from 
previous visits have been resolved.  Other issues to be reviewed at the closeout visit include: 
discussing retention of study files, possibility of site audits, publication policy, and notifying the 
IRB of study closure. 
17.11. 
Audit/Inspections 
The designated Idera or its designee’s quality assurance personnel may conduct audits at the 
study site.  Audits will include, but not be limited to: audit trail of data handling and processes, 
standard operating procedures, drug supply, presence of required documents, the informed 
consent process, and comparison of the eCRF with source documents.  The Investigator agrees to 
accommodate and participate in audits conducted at a reasonable time in a reasonable manner, as 
needed. 

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Regulatory authorities worldwide may also audit the Investigator during or after the study.  The 
Investigator should contact Idera immediately if this occurs and must fully cooperate with 
governmental audits conducted at a reasonable time in a reasonable manner. 

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18. 
ETHICAL CONSIDERATIONS 
By signing this protocol, the Investigator agrees to conduct the study in compliance with the 
protocol, the ICH GCP guidelines, the Declaration of Helsinki, and all applicable federal, state, 
and local laws, rules, and regulations relating to the conduct of the clinical study. 
18.1. 
Role of Sponsor 
As the study Sponsor, Idera has overall responsibility for the conduct of the study, including 
assurance that the study meets the regulatory requirements.  In this study, Idera will have certain 
direct responsibilities and will delegate other responsibilities to its designees (e.g., a CRO).  The 
designee will ensure adherence to the Sponsor’s general responsibilities and other 
responsibilities as agreed between the designee and Idera; e.g., selection of Investigators, 
monitoring, and protocol amendments.  
18.2. 
Informed Consent 
The Investigator has both ethical and legal responsibility to ensure that each subject being 
considered for inclusion in this study is given a full explanation of the study.  Written informed 
consent will be obtained from all subjects (or their guardians or legal representatives) before any 
study-related procedures (including any pre-treatment procedures, such as pre-procedure 
sedation) are performed or given.  
Written informed consent will be documented on an informed consent form (ICF) approved by 
the same Independent Reviewing Authority (IRA) responsible for approval of this protocol.  The 
ICF will conform to ICH GCP guidelines and to the institutional requirements for informed 
consent and applicable regulations.  The Investigator agrees to obtain approval from Idera of any 
ICF intended for use in the study, prior to submission for IRB approval. 
The ICF will be reviewed with the prospective study subject or his or her legal representative, 
and the Investigator or qualified designee will be available to answer questions regarding 
procedures, risks, and alternatives.  
Once the appropriate essential information has been provided to the subject and fully explained 
by the Investigator or qualified designee, and it is felt that the subject understands the 
implications of participating, the subject and the Investigator or designee will sign and date the 
IRB-approved written ICF.  The subject will receive a copy of the signed ICF.  The original 
signed and dated ICF will be kept in the site’s regulatory file.  Documentation of the subject’s 
informed consent for and participation in this study will be noted in the subject’s medical record.  
If the subject is illiterate, an impartial witness is required to be present during the entire informed 
consent reading and discussion.  Afterward, the subject should be asked to sign and date the ICF, 
if capable.  The impartial witness should also sign and date the ICF along with the individual 
who read and discussed the informed consent (i.e., study staff personnel). 
The subject or his or her legally acceptable representative will be informed in a timely manner if 
new information becomes available that may be relevant to the subject’s willingness to continue 
participation in the trial.  The communication of this information to the subject will be 
documented. 

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18.3. 
Confidentiality of Subjects 
The Investigator and his/her staff will be required to manage subject data collected for the study 
in accordance with applicable laws and regulations on personal data protection.  
Monitors, auditors, and other authorized representatives of Idera, the IRA approving the study, as 
well as any applicable regulatory authorities, will be granted access to the study subject’s 
original medical records for permitted study purposes, in accordance with applicable laws and 
regulations.  In any presentation of study results at meetings or in publications, subject identity 
will remain confidential.   
18.4. 
Institutional and Ethics Review  
This protocol and a subject ICF, participant information sheet, and any proposed advertising 
material, must be reviewed and approved by an IRB/EC, applicable regulatory authorities, and 
host institution(s) for written approval (where applicable) before enrollment of subjects and 
release of investigational product.  Documentation of IRB/EC approval and the approved consent 
form must be received by Idera or its designees prior to obtaining the subject’s informed consent.  
Amendments to the original approved documents, where applicable, will also be submitted to 
and approved by the above parties.  Investigators will comply with the appropriate IRB/EC 
reporting requirements. Any updates to the protocol by means of protocol amendment that 
impacts patient safety or changes the interpretation of scientific documents in support of conduct 
of the trial will be submitted as substantial amendment to competent authorities and health 
agencies in all countries where trial is open. 
18.5. 
Financial Disclosure 
In compliance with 21 CFR 54.4, any listed or identified Investigator or sub-investigator 
(including the spouse and any dependent children of said individuals) directly involved in the 
treatment or evaluation of research subjects will disclose the following information for the time 
period during which the Investigator is participating in the study and for 1 year following 
completion of the study: 
1. Any financial arrangement entered into between Idera and the Investigator whereby the 
value of the compensation to the Investigator for conducting the study could be 
influenced by the outcome of the study. 
2. Any other significant payments totaling > $10,000.00, exclusive of the costs of 
conducting this or other clinical studies, by Idera, such as a grant to fund ongoing 
research, compensation in the form of equipment, retainer for ongoing consultation, or 
honoraria. 
3. Any proprietary interest held by the Investigator in the product being evaluated. 
Any significant equity interest in Idera, including ownership interest, stock options, or other 
financial interest whose value cannot be determined through reference to public prices that 
exceeds $10,000.  

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19. 
LIST OF REFERENCES 
Aarmtzem EH, Srinivas M, Punt CJ, Figdor CG, Oyen WJ, de Vries IJ. Insight into the 
dynamics, localization and magnitude of antigen-specific immune responses by [(18)F]FLT PET 
imaging. Oncoimmunology. 2012;1:744-5. 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organisation for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst. 1993; 85:365-376. 
Bast RC, Zbar B, Borsos T, et al. BCG and cancer. N Engl J Med. 1974;290:1458-69. 
Bohnsack O, Ludajic K, Hoos A.  Adaptation of the immune-related response criteria: 
irRECIST. Ann Onc. 2014;25(Suppl-4):iv361-iv372. 
Bowyer S, Prithviraj P, Lorigan P, et al. Efficacy and toxicity of treatment with the anti-CTLA-4 
antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy. Br J 
Cancer. 2016;114:1084-9. 
Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas: with a 
report of ten original cases. Am J Med Sci. 1893;105:487-510. 
Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0, 28 May 2009. US 
Department of Health and Human Services, National Institutes of Health, National Cancer 
Institute. NIH Publication No. 03-5410. 
Conroy H, Marshall NA, Mills KHG.  TLR ligand suppression or enhancement of Treg cells? A 
double-edged sword in immunity to tumours. Oncogene. 2008;27:168-80. 
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC Cancer Staging 
Manual (7th ed). New York, NY: Springer; 2010. 
FDA Briefing Document: Peripheral and Central Nervous System Drugs Advisory Committee 
Meeting. NDA 206031. Drisapersen. Nov 2015. 
FDA Guidance for Industry: Multiple Endpoints in Clinical Trials. Jan 2017. 
Haymaker C, Uemura M, Murthy R, James M, Wang D, Brevard J, et al. Translational evidence 
of reactivated innate and adaptive immunity with intratumoral IMO-2125 in combination with 
systemic checkpoint inhibitors from a Phase I/II study in patients with anti-PD-1 refractory 
metastatic melanoma. American Association for Cancer Research Annual Meeting, Washington 
DC, April 1-5 2017. 
Hodi FS, Hwu WJ, Kefford R, et al.  Evaluation of immune-related Response Criteria and 
RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Onc. 
2016;34:1510-7. 
Imlygic package insert.  Thousand Oak, California: Amgen; 2015. 
Jiang W. Modulation of checkpoint expression in tumor microenvironment by intratumoral 
administration of a novel TLR9 agonist: rationale for combination therapy. 

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CRI-CIMT-EATI-AACR – The Inaugural International Cancer Immunotherapy Conference, 
New York, NY, September 16–19, 2015.  
Kandimalla ER, Agrawal S.  Modulation of endosomal Toll-like receptor-mediated immune 
responses by synthetic oligonucleotides. Adv Polym Sci. 2012;249:61-94. 
Keytruda package insert. County Cork, Ireland: Merck & Co., Inc. 2016. 
Krieg AM. Development of TLR9 agonists for cancer therapy. J Clin Invest. 2007;117:1184–94. 
Lan KKG and DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 1983: 
70(3):659-663. 
Long GV, et al. Outcomes in Patients Treated With Ipilimumab After Pembrolizumab in 
KEYNOTE-006.  Soc Mel Res, 2016. 
Lou Y, Liu C, Lizée G, Peng W, Xu C, Ye Y, et al. Antitumor activity mediated by CpG: the 
route of administration is critical. J Immunother. 2011;34:279-288. 
Marabelle A, Kohrt H, Caux C, et al.  Intratumoral immunization: A new paradigm for cancer 
therapy. Clin Cancer Res. 2014;20:1747-56.  
National Comprehensive Cancer Network, Clinical Practice Guidelines in Oncology, v3. 
Nishino M, Giobbie-Hurder A, Gargano M, et al. Developing a common language for tumor 
response to immunotherapy: immune-related response criteria using unidimensional 
measurements. Clin Cancer Res. 2013;19(14):3936-43. 
Opdivo package insert. Princeton, New Jersey: Bristol-Myers Squibb Company; 2017. 
Rodriguez-Torres M. IMO-2125, a TLR9 agonist, induces immune responses which correlate 
with reductions in viral load in null responder HCV patients. AASLD abstract, 2010. 
Schadendorf D, Hodi FS, Robert C, et al.  Pooled Analysis of Long-Term Survival Data From 
Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Onc. 
2015;33:1889-94. 
Schumacher TN and Schreiber RD. Neoantigens in cancer immunotherapy. Science. 
2015;348:69-74. 
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29. 
Simeone E, Grimaldi AM, Festino L, et al. Combination treatment of patients with BRAF- 
mutant melanoma: A new standard of care. BioDrugs. 2017;31:51-61. 
Struthers M, Bett AJ, Wisniewski T, et al. Synthesis and immunological activities of novel 
agonists of toll-like receptor 9. Cell Immunol. 2010;263:105–13.  
Uemera MA, Haymaker CL, Murthy R, et al. Intratumoral (i.t) IMO-2125 (IMO), a TLR9 
agonist, in combination with ipilimumab (ipi) in PD-L1 refractory melanoma (RM). 
ASCO-SITC, 2017 (abstract #178724). 
Wang D, Kandimalla ER, Yu D, et al. Oral administration of second-generation 
immunomodulatory oligonucleotides induces mucosal Th1 immune responses and adjuvant 
activity. Vaccine. 2005;23:2614-22. 

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Wang D, et al.  Intratumoral Administration of IMO-2125, a Novel TLR9 Agonist, Modulates 
the Tumor Microenvironment and Exerts Systemic Antitumor Activity Alone and in 
Combination with an Anti-CTLA-4  mAb. CRI-CIMT-EATI-AACR – The Inaugural 
International Cancer Immunotherapy Conference, New York, NY, September 16–19, 2015a.  
Wang D et al. Intratumoral Administration of IMO-2125, a Novel TLR9 Agonist, Modulates 
Tumor Microenvironment and Potentiates Antitumor Activity of Anti-PD-1 mAb in Murine 
Colon Carcinoma and Melanoma Models. AACR-NCI-EORTC International Conference on 
Molecular Targets and Cancer Therapeutics, Boston, MA, November 5-9, 2015b. 
Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin 
Cancer Res. 2009;15:7412-7420.  
Yervoy package insert. Princeton, New Jersey: Bristol-Myers Squibb Company; 2015. 
Yu D, Putta MR, Bhagat L, et al.  Impact of secondary structure of Toll-like receptor 9 agonists 
on interferon alpha induction. Antimicrob Agents Chemother. 2008;52:4320-5. 

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20. 
APPENDICES 
20.1. 
ECOG 
ECOG Performance Status: 
Grade  ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair 
5 
Dead 

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20.2. 
RECIST v1.1 Criteria 
 

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Appendix Table 1: 
Objective Response Status at Each Evaluation 
 
 

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Appendix Table 2: Objective Response Status at Each Evaluation for Subjects with 
Non-Target Disease Only 
 
 

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20.3. 
The use of irRECIST (Immune-Related Response Evaluation 
Criteria in Solid Tumors) in this study 
Throughout the study, subject management will be performed according to irRECIST (with the 
modification described below). irRECIST is based on the established RECIST (see Section 20.2) 
with changes that have been recommended as being better suited for assessing response to 
immunotherapeutic agents (Nishino, 2013; Bohnsack, 2014).  irRECIST differs from 
conventional RECIST in that the development of new lesions is not automatically scored as PD, 
since atypical response patterns can occur.  This reduces the risk of declaring a treatment to be 
ineffective based upon “pseudoprogression,” as has been well-documented for other 
immunotherapies (Hodi, 2016; Wolchok, 2009).   
Blinded central reviewers will assess tumor response rates using irRECIST with modifications 
according to Appendix Table 3.  In this study, irRECIST is modified as follows: 
For purposes of determining progression based solely on worsening of non-target or new, non-
measurable disease, “substantial, unequivocal worsening” requires confirmation by an additional 
scan (at least 4 weeks apart) unless it is accompanied by correlative symptoms.  
 

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Appendix Table 3: Objective Response using irRECIST 
Response assessment 
Description 
irCR 
• Complete disappearance of all lesions (and no new measurable 
or non-measurable lesions). 
• Pathological lymph nodes (target or non-target) must have 
diameter <10 mm in short axis. 
• Requires confirmation by consecutive assessment ≥4 weeks 
after first documentation. 
irPR 
• ≥30% decrease in tumor burden from baseline. 
• No unequivocal progression of baseline non-target lesions. 
• No unequivocal progression of new, non-measurable lesions. 
• Requires confirmation by consecutive assessment ≥4 weeks 
after first documentation. 
irSD 
• Not meeting criteria for irCR or irPR, in absence of irPD. 
irPD 
• ≥20% increase in tumor burden from nadir (the minimum 
recorded tumor burden). 
• The presence of new, measurable lesions does not define 
progression.  New measurable lesions are added to the 
assessment of tumor burden. 
• A substantial, unequivocal worsening of baseline non-target 
lesions is indicative of irPD. 
• A substantial, unequivocal worsening of new, non-measurable 
lesions is indicative of irPD. 
• Requires confirmation by consecutive assessment ≥4 weeks 
after the first documentation. 
irCR=immune-related complete response; irPD=immune-related progressive disease; irPR=immune-related 
partial response; irRECIST=Immune-related Response Evaluation Criteria in Solid Tumors; irSD=immune-
related stable disease