Clinical trial NCT03445533
Conditions: Metastatic Melanoma
Keywords: Melanoma PD1 PD-1 refractory metastatic IMO-2125 illuminate 301 TLR9 agonist advanced melanoma CTLA4 CTLA-4 immunotherapy skin cancer ILLUMINATE-301
Sponsor: Idera Pharmaceuticals, Inc.
Start date: 2018-05-30; Completion date: 2021-06-01
Enrollment: 481 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 3 comparison of ipilimumab with and without IMO-2125 in advanced melanoma

Detailed description:
A 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 anti-PD-1

Arms: arm 1: ipilimumab 3 mg/kg intravenous arm 2: IMO-2125 by intratumoral injection plus ipilimumab 3 mg/kg intravenous
Interventions: intervention 1: Ipilimumab intervention 2: Tilsotolimod with Ipilimumab
Intervention descriptions: intervention 1: Arm A: 4 doses administered intravenously at a dose of 3 mg/kg over 90 minutes on Weeks 1, 4, 7, and 10. intervention 2: IMO-2125 intratumoral injection administered as 9 doses on Weeks 1, 2, 3, 5, 8, 11, 16, 20, and 24. WITH (Arm B): Ipilimumab administered as 4 doses on Weeks 2, 5, 8, and 11. in combination with tilsotolimod

Protocol documents:
Prot_000.pdf: 
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 
 


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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 
effects seen in rodents. 


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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 
 

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STATISTICAL ANALYSIS PLAN 
Statistical Analysis Plan Version:  3.0 
Statistical Analysis Plan Version Date:  25 FEB 2021 
 
 
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 
Protocol Version Date:  4 JUN 2020 
 
 
Sponsor:  
Idera Pharmaceuticals, Inc. 
 
 
This document includes information and data that contain trade secrets and privileged or confidential 
information which is the property of Idera Pharmaceuticals, Inc.  This information must not be made public 
without written permission from Idera Pharmaceuticals, Inc. These restrictions on disclosure will apply equally 
to all future information supplied to you. 
 
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Signature page 
Authors: 
 
PROMETRIKA 
Lead Statistician 
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Signature 
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Author: 
Benny Chan, MS 
 
 
Title: 
Senior Biostatistican 
Company: 
PROMETRIKA, LLC 
 
 
 
 
 
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Approvers:   
By signing below, I approve of this version of the Statistical Analysis Plan. 
 
Name  
Signature 
Date 
(dd/mmm/yyyy) 
Approved by: 
Heidy Russell, PhD 
 
 
Title: 
Senior Director, Biostatistics 
Company: 
PROMETRIKA, LLC 
 
 
Name  
Signature 
Date 
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Company: 
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Table of Contents 
1 
MODIFICATION HISTORY ............................................................................................ 8 
2 
LIST OF ABBREVIATIONS .......................................................................................... 11 
3 
PURPOSE ........................................................................................................................ 13 
4 
STUDY DESIGN ............................................................................................................ 13 
4.1 
OBJECTIVES AND ENDPOINTS ................................................................... 14 
4.2 
PRIMARY STUDY HYPOTHESIS ................................................................. 15 
4.3 
STUDY TREATMENTS ................................................................................. 15 
4.4 
RANDOMIZATION PROCEDURES AND BLINDING .................................... 16 
4.5 
DETERMINATION OF THE SAMPLE SIZE ................................................... 16 
4.6 
PLANNED INTERIM ANALYSIS AND SAFETY REVIEWS .......................... 17 
4.6.1 
Interim Analysis of Overall Survival ......................................................... 17 
4.6.2 
Interim Sample Size Re-estimation ............................................................ 17 
4.6.3 
Independent Data Monitoring Committee Reviews ..................................... 17 
5 
CHANGES IN THE CONDUCT OF PLANNED ANALYSES ..................................... 17 
6 
STUDY ANALYSIS SETS ............................................................................................. 17 
6.1 
SCREENED SET ............................................................................................ 17 
6.2 
INTENT TO TREAT ANALYSIS SET ............................................................ 17 
6.3 
FULL ANALYSIS SET ................................................................................... 18 
6.4 
PER PROTOCOL ANALYSIS SET ................................................................. 18 
6.5 
SAFETY SET................................................................................................. 18 
6.6 
PHARMACOKINETIC ANALYSIS SET ......................................................... 18 
7 
GENERAL CONSIDERATIONS ................................................................................... 18 
7.1 
MULTICENTER STUDIES ............................................................................ 19 
7.2 
MULTIPLE COMPARISONS AND MULTIPLICITY ....................................... 19 
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8 
DATA HANDLING CONVENTIONS ........................................................................... 20 
8.1 
MISSING DATA ............................................................................................ 20 
8.1.1 
Imputation of Non-Date Missing Data ....................................................... 20 
8.1.2 
Imputation of Partial Dates ....................................................................... 21 
8.2 
DERIVED VARIABLES ................................................................................. 23 
8.2.1 
Reference Dates ...................................................................................... 23 
8.2.2 
Study Day for Safety ............................................................................... 23 
8.2.3 
Study Day for Efficacy ............................................................................ 23 
8.2.4 
Durations ................................................................................................ 23 
8.2.5 
Baseline Definition .................................................................................. 24 
8.2.6 
Change from Baseline .............................................................................. 24 
8.2.7 
Treatment Emergence Flag ....................................................................... 24 
8.2.8 
Multiple Assessments .............................................................................. 24 
8.2.8.1 Disease Assessment Scans ......................................................................................... 24 
8.2.8.2 Injected and Non-injected Lesions ............................................................................ 25 
8.2.9 
Other Assessments .................................................................................. 25 
8.2.10 Strata Used for Analysis ........................................................................... 26 
8.2.11 Other Derived Variables ........................................................................... 26 
8.3 
SAFETY PARAMETER RANGES .................................................................. 27 
8.3.1 
Laboratory Parameters ............................................................................. 27 
8.3.2 
ECG Parameters ...................................................................................... 27 
8.3.3 
Vital Signs .............................................................................................. 28 
9 
DEMOGRAPHICS, BASELINE DISEASE CHARACTERISTICS, AND SUBJECT 
DISPOSITION ......................................................................................................................... 28 
9.1 
DISPOSITION OF SUBJECTS ........................................................................ 28 
9.2 
PROTOCOL DEVIATIONS ............................................................................ 29 
9.3 
DEMOGRAPHIC AND BASELINE DISEASE CHARACTERISTICS ............... 29 
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9.4 
STRATIFICATION FACTORS ....................................................................... 30 
9.5 
CONCOMITANT MEDICATIONS ................................................................. 31 
10 EFFICACY ...................................................................................................................... 33 
10.1 ANALYSIS OF THE PRIMARY ENDPOINT FAMILY .................................... 34 
10.1.1 Independent Reviewer-Assessed ORR by RECIST v1.1 .............................. 34 
10.1.2 Sensitivity Analysis of ORR ..................................................................... 35 
10.1.3 Analysis of OS ........................................................................................ 36 
10.1.4 Sensitivity Analysis of Overall Survival .................................................... 36 
10.1.5 Sensitivity Analysis of Overall Survival using Imputed Death Dates ............. 37 
10.1.6 Subgroup Analyses of the Primary Endpoint Family ................................... 37 
10.2 ANALYSIS OF SECONDARY EFFICACY ENDPOINTS ................................. 38 
10.2.1 Investigator-Assessed ORR by RECIST v1.1 ............................................. 38 
10.2.2 Comparison of Best Overall Responses between Independent Review and 
Investigator ............................................................................................ 39 
10.2.3 Analysis of Injected and Non-injected Lesions ........................................... 39 
10.2.4 Durable Response Rate ............................................................................ 40 
10.2.5 Disease Control Rate ............................................................................... 40 
10.2.6 Duration of Response .............................................................................. 41 
10.2.7 Time to Response .................................................................................... 41 
10.2.8 Analysis of Progression-Free Survival ....................................................... 42 
11 SAFETY ANALYSES .................................................................................................... 43 
11.1 EXTENT OF EXPOSURE ............................................................................... 43 
11.2 ADVERSE EVENTS ...................................................................................... 44 
11.3 DEATHS AND SERIOUS ADVERSE EVENTS ............................................... 47 
11.4 ADVERSE EVENTS LEADING TO DISCONTINUATION OF STUDY 
TREATMENT (WITHDRAWAL),  DOSE INTERRUPTIONS, OR DOSE 
REDUCTIONS ............................................................................................... 47 
11.5 IMMUNE-RELATED ADVERSE EVENTS ..................................................... 48 
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11.6 ADVERSE EVENTS OF SPECIAL INTEREST ................................................ 50 
11.7 SUBGROUP ANALYSIS FOR ADVERSE EVENTS ........................................ 53 
11.8 CLINICAL LABORATORY EVALUATIONS ................................................. 53 
11.9 OTHER SAFETY MEASURES ....................................................................... 56 
11.9.1 Vital Signs and Weight ............................................................................ 56 
11.9.2 ECG....................................................................................................... 57 
12 PHARMACOKINETIC ANALYSES ............................................................................. 57 
13 PATIENT-REPORTED QUALITY OF LIFE ................................................................ 58 
13.1 SCORING THE EORTC QLQ-C30 RESULTS ................................................. 58 
13.2 SUMMARY OF EORTC QLQ-C30 RESULTS ................................................. 59 
13.3 ANALYSIS OF CHANGE FROM BASELINE IN EORTC QLQ-C30 SCORES .. 60 
13.4 ASSOCIATION BETWEEN CHANGE FROM BASELINE AND BEST 
OVERALL RESPONSE .................................................................................. 61 
14 PHARMACODYNAMIC AND BIOMARKERS ANALYSES ..................................... 61 
15 REFERENCES ................................................................................................................ 62 
16 APPENDICES ................................................................................................................. 63 
16.1 SCHEDULE OF EVENTS ............................................................................... 63 
16.2 LIST OF TABLES, LISTINGS, AND FIGURES ............................................... 67 
16.3 CONFIRMATION RESPONSE IN RECIST V1.1 ............................................. 80 
16.4 CENSORING RULE FOR PFS ........................................................................ 81 
16.5 CTCAE GRADES FOR LABORATORY TESTS .............................................. 82 
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1 
MODIFICATION HISTORY 
Version 
Effective Date  
Author(s) of 
Modification 
Notes on Modification 
1.0 
15-NOV-2018 
Alison Timm, 
Manager, Biostatistics, 
PROMETRIKA, LLC 
 
2.0 
21-JUL-2020 
Benny Chan, Senior 
Biostatistican, 
PROMETRIKA, LLC 
Revised description of the IDMC 
roles and responsibilities per updated 
Charter and Protocol v3.0. 
Added Full Analysis Set to include 
subjects who are treated and have at 
least one post-baseline record 
collected. This analysis set will be 
used in the sensitivity analyses for 
ORR and OS. 
“Modified irRECIST” was updated 
to “irRECIST” per Protocol v3.0. 
Modified the stratified analysis 
approach to combine subjects from 
small strata instead of dropping 
subjects from the analysis. 
Removed Modified ITT Population 
as no subjects will be dropped from 
the primary analysis. 
Added Per Protocol Analysis Set as a 
sensitivity analysis of the primary 
endpoint family. 
Added planned sensitivity analyses 
for OS. 
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Version 
Effective Date  
Author(s) of 
Modification 
Notes on Modification 
2.0  
 
 
Removed interim analysis of OS 
Updated the assumptions of the OS 
power calculations and changed the 
planned sample size per Protocol 
v4.0. 
Added duration of response and PFS 
by blinded independent review as a 
secondary endpoint.  
Modified analysis for injected and 
non-injected lesions to analyze at the 
subject level, create waterfall plots 
for responders only.  
Added AE tables for subjects with 
organ-injected lesions 
For QoL, it has been noted that some 
subjects has been using paper PRO 
instead of ePRO. Updated the 
corresponding analysis to run for 
paper PRO, and ePRO separately and 
combined as well.  Removed QoL 
missing assessment analysis. 
Remove summaries of irRECIST 
from all endpoints, and present 
irRECIST responses in a listing only. 
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Version 
Effective Date  
Author(s) of 
Modification 
Notes on Modification 
3.0 
22-JAN-2021 
Benny Chan, Senior 
Biostatistican, 
PROMETRIKA, LLC 
Change OS analysis: HR will be 
generated using a Cox proportional 
hazards model instead of Pike 
estimator.  
Clarify ORR definition and DOR 
censoring rule.  
Update to include selected laboratory 
tests for shift analysis. 
Add additional analyses for disease 
control rate, AE by injection status  
Update date imputation rules to be 
consistent with other studies in the 
2125 drug program 
Add clarifications for the exposure 
summary 
 
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2 
LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ADA 
Anti-drug Antibody 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
CYP 
Cytochrome P450 
DoR 
Duration of Response 
DRR 
Durable Response Rate 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30 
ePRO 
Electronic Patient-Reported Outcome 
FAS 
Full Analysis Set 
HR 
Hazard Ratio 
i.v. 
Intravenous 
IA 
Interim Analysis 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
irAE 
Immune-related Adverse Event 
irRECIST 
Immune-related Response Evaluation Criteria in Solid 
Tumors 
IRT 
Interactive Response Technology 
ITT 
Intent to Treat 
LDH 
Lactate Dehydrogenase 
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Abbreviation 
Definition 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit of Quantification 
LS 
Least Squares 
MedDRA 
Medical Dictionary for Medical Affairs 
MMRM 
Mixed Effect Model with Repeated Measures 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death-1 
PFS 
Progression-free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PRO 
Patient-reported Outcome 
PT 
Preferred Term 
QoL 
Quality of Life 
QTcF 
Fridericia’s Corrected QT Interval 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SI 
International System of Units 
SLD 
Sum of Longest Diameters 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
TLF 
Tables, Listings and Figures 
TTR 
Time to Response 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
 
 
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3 
PURPOSE 
This statistical analysis plan (SAP) is written to incorporate the revisions from the protocol 
amendment v4.0 and provides a description of the planned statistical analyses of the study 
2125-MEL-301 data to support the Clinical Study Report (CSR).  Mock displays for tables, 
listings, and figures (TLF) are in separate supporting documents. 
This SAP complies with the International Conference on Harmonisation (ICH) Harmonised 
Tripartite Guideline Topic E9, Statistical Principles for Clinical Trials.  It is based upon the 
following study documents: 
• Study Protocol v2.0 (dated 5 Feb 2018) 
• Study Protocol v3.0 (dated 10 Jul 2019) 
• Study Protocol v4.0 (dated 4 Jun 2020) 
All decisions regarding the final analysis of the study data, as defined in this SAP, will be 
made prior to locking of the study data. 
4 
STUDY DESIGN 
This Phase 3 study is being performed to provide definitive evidence for superiority of the 
IMO-2125/ipilimumab combination over ipilimumab alone.  
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 confirmed 
disease progression during or after treatment with a programmed cell death-1 (PD-1) 
inhibitor, e.g., nivolumab or pembrolizumab.  Confirmed progression is defined by irRECIST 
criteria. Subjects will be randomized 1:1 to ipilimumab alone or ipilimumab plus IMO-2125.  
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 Objective Response Rate (ORR) and Overall 
Survival (OS) as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 
Blinded independent review of all clinical and imaging results for response assessment will 
be performed centrally.  Periodic safety reviews will be performed by an Independent Data 
Monitoring Committee (IDMC) as described in the IDMC Charter.  
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Per protocol amendment v4.0, the planned interim analysis (IA) of OS will no longer be 
conducted, and the final analysis will occur when 392 randomized subjects have died or 
approximately 36 months after the last subject is randomized, whichever occurs first. 
4.1 
OBJECTIVES AND ENDPOINTS 
Table 1: 
Study objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
To compare the efficacy (measured by ORR 
and OS) of intratumoral IMO-2125 in 
combination with ipilimumab versus 
ipilimumab alone. 
The primary endpoint family (see FDA 
Guidance for Industry, 2017) includes: 
• ORR by blinded independent 
review using RECIST v1.1 
• OS 
Secondary 
 
• To assess other measures of clinical 
benefit.  
• To assess safety.  
• To assess IMO-2125 pharmacokinetics 
(PK). 
• To assess patient-reported outcomes 
(PROs) on quality of life (QoL). 
The secondary endpoints of this study are: 
• ORR by investigator assessment using 
RECIST v1.1  
• Duration of response (DoR) by 
blinded independent review and  
investigator assessment using RECIST 
v1.1 
• Durable response rate (DRR) by 
blinded independent review and  
investigator assessment using RECIST 
v1.1 
• Time to response (TTR) by blinded 
independent review and investigator 
assessment using RECIST v1.1 
• Progression-free survival (PFS), 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  
 
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Objectives 
Endpoints 
• Safety, including adverse events 
(AEs), laboratory and vital sign tests, 
electrocardiograms (ECGs), Eastern 
Cooperative Oncology Group (ECOG) 
Performance Status, and physical 
examination 
• Plasma PK of IMO-2125  
• PRO from the European Organisation 
for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30 
(EORTC QLQ-C30) 
Exploratory 
 
• To investigate potential biomarkers. 
• To investigate the incidence of 
anti-IMO-2125 and anti-ipilimumab 
antibodies. 
The exploratory endpoints include: 
• Immunologic biomarkers (optional 
tumor biopsies) 
• Measurement of anti-IMO-2125 and 
anti-ipilimumab antibodies 
 
4.2 
PRIMARY STUDY HYPOTHESIS 
ORR and OS comprise a primary endpoint family with a priori hypotheses to be tested.  For 
ORR, the hypotheses are to demonstrate an increase in the ORR from the expected response 
of 12% for ipilimumab alone to 24% for the IMO-2125 + ipilimumab combination. 
For OS, the hypotheses are to demonstrate improvement in the median survival from 11.40 
months (the historical control for ipilimumab alone) to 16.85 months with the IMO-2125 + 
ipilimumab combination (hazard ratio [HR] = 0.677). 
The corresponding hypotheses are: 
Ho: HR = 1 
versus 
Ha: HR ≤ 0.677 
 
4.3 
STUDY TREATMENTS  
Ipilimumab will be administered intravenous (i.v.) using a 90-minute infusion duration at 
3 mg/kg on Weeks 1, 4, 7, and 10 (ipilimumab alone or Weeks 2, 5, 8, and 11 (ipilimumab 
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with IMO-2125).  Cross-over therapy will not be allowed for subjects assigned to ipilimumab 
alone.  
IMO-2125 will be given prior to ipilimumab on days when both are to be administered.  
IMO-2125, 8 mg will be administered intratumorally as a 1 to 4 mL injection to a single 
designated lesion at Weeks 1, 2, 3, 5, 8, 11, 16, 20, and 24.  
4.4 
RANDOMIZATION PROCEDURES AND BLINDING 
This is an open-label trial.  Randomization will use a central Interactive Response 
Technology (IRT) system.  Subjects will be randomized in blocks of a 1:1 ratio to either 
ipilimumab with IMO-2125 or ipilimumab alone. Randomization is stratified by the duration 
of prior anti-PD-1 therapy (≥12 weeks vs <12 weeks), metastasis stage (M1c vs other) and 
BRAF mutation (BRAF wild type vs BRAF mutation positive with prior targeted therapy vs 
BRAF mutation positive without prior targeted therapy).  Despite this being an open label 
trial, the sponsor will make every effort to maintain the integrity of the trial by avoiding 
review of aggregated efficacy results by treatment arm during the course of the trial.   
4.5 
DETERMINATION OF THE 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 planned with a 1:1 randomization ratio, this test will have 90% statistical 
power (calculated based on chi-square test) to demonstrate an increase in the ORR from the 
expected response of 12% for ipilimumab alone to 24% for the IMO-2125 + ipilimumab 
combination, at a 0.02 one-sided level of significance.  
A sample size of 454 subjects also provides 90% power to test the alternative hypothesis of 
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 16.85 
months with the IMO-2125 + ipilimumab combination.  The number of required deaths to 
reach the 90% power is 392. 
 
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 a total alpha of 0.025 is available for the OS significance test under the fallback 
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method, then this test will have 90% power to test the alternative hypothesis of HR ≤ 0.72 at 
an α of 0.025 (one-sided). This 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. 
4.6 
PLANNED INTERIM ANALYSIS AND SAFETY REVIEWS 
4.6.1 Interim Analysis of Overall Survival 
An interim analysis on the primary endpoint family efficacy measure of OS was planned to 
be performed at 50% of the required number of deaths in the earlier versions of the protocol.  
Per protocol version 4.0, the sponsor decided that this interim analysis will no longer be 
performed.  
4.6.2 Interim Sample Size Re-estimation 
There is no sample size re-estimation planned for this study. 
4.6.3 Independent Data Monitoring Committee Reviews 
The IDMC composition and duties are described in a separate Charter.  The purpose of the 
IDMC is to provide independent evaluation of potential emerging risks to study participants, 
through ongoing evaluation of safety and clinical data contributing to an ongoing risk 
assessment of the study interventions, and make recommendations to the sponsor regarding 
the conduct of the study.  Please reference the IDMC charter for timing of IDMC meetings.   
5 
CHANGES IN THE CONDUCT OF PLANNED ANALYSES 
There are no planned analyses that differ from those specified in the protocol. 
6 
STUDY ANALYSIS SETS 
6.1 
SCREENED SET 
The Screened Set consists of all subjects who provided written informed consent and who 
undergo study screening procedures.  
6.2 
INTENT TO TREAT ANALYSIS SET 
The Intent to Treat (ITT) Analysis Set comprises all subjects in the Screened Set who were 
randomized.  The ITT Analysis Set will be analyzed using the treatment to which the subject 
was randomized regardless of the treatment actually received and will be the primary analysis 
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set for efficacy analyses.  Any subject who receives a treatment randomization number will 
be considered to have been randomized. 
6.3 
FULL ANALYSIS SET 
The Full Analysis Set (FAS) comprises all subjects in the ITT Analysis Set who were treated 
with at least one dose of study drug, and had at least one post-baseline evaluable tumor 
assessment.  The FAS will be analyzed using the treatment to which the subject was 
randomized regardless of the treatment actually received. Analysis of OS and ORR evaluated 
by RECIST v1.1 will be performed on the FAS as a sensitivity analysis.   
6.4 
PER PROTOCOL ANALYSIS SET 
The Per Protocol Analysis Set contains all subjects from the FAS without any exclusionary 
protocol deviations as defined in the Protocol Deviation Plan approved prior to database lock 
that could adversely affect the evaluation of the primary endpoint.  In addition, subjects need 
to have at least three doses of IMO-2125 and two doses of ipilimumab for the combination 
arm and two doses of ipilimumab for the ipilimumab alone arm.  Subjects will be analyzed 
according to their randomized treatment assignment.  Analysis of OS and ORR evaluated by 
RECIST v1.1 will be performed on the Per Protocol Analysis Set as a sensitivity analysis. 
6.5 
SAFETY SET 
The Safety Set comprises all subjects in the ITT Analysis Set who received at least one dose 
of any study treatment. The Safety Set will be analyzed based on the actual treatment 
received. 
6.6 
PHARMACOKINETIC ANALYSIS SET 
The PK Analysis Set comprises all subjects who received at least one dose of IMO-2125 with 
at least one measurable concentration of IMO-2125. 
7 
GENERAL CONSIDERATIONS 
Analysis datasets will be created according to Clinical Data Interchange Standards 
Consortium (CDISC) standards, and data will be displayed according to reporting standards 
in this SAP and TLF formats.  
SAS Version 9.4 or higher will be used to perform all data analyses and to generate tables, 
listings, and figures (TLFs).  
All data collected in the database will be presented in data listings. 
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For each subject, data up to the time of study completion, lost to follow-up, or withdrawal 
from study will be included in the appropriate analysis sets defined in Section 6.   
Continuous variables will be summarized in terms of the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Other descriptive statistics (e.g., 
quartiles, coefficient of variation) may be reported when appropriate.  Categorical variables 
will be summarized using frequency counts and percentages.  Analyses that use other 
descriptive statistics will be specified in the applicable SAP section. 
Summaries will order displays by ipilimumab with IMO-2125 first, followed by the 
ipilimumab alone arm.  Unless otherwise stated, summaries and figures will be reported by 
study arm.  Summary statistics of central tendency will use one more decimal place than the 
collected data.  Summary statistics of variability will use one more decimal place than the 
corresponding measure of central tendency.  For example, the mean and median for age in 
years will be presented to one decimal place and the standard deviation of age will be 
reported to 2 decimal places.  Percentages will be displayed to one decimal place, and 
proportions will be displayed to 4 decimal places.  Durations for treatment exposure (weeks), 
adverse events (weeks), and response (months) will be displayed to 1 decimal place. 
Planned visits will be used in all tables and figures that are by visit.  Generally, only planned 
visits will be used in the summaries, statistical analyses, and calculations of any derived 
parameters; unscheduled visits will be included in the listings.  However, both unscheduled 
and scheduled visits will be included in the determination of the worst-case (highest and/or 
lowest) post-baseline shifts for laboratory results, vital signs, and ECG. 
All listings will include subject number and randomized treatment arm.  The laboratory 
normal reference ranges will be provided and clinical laboratory test results outside the 
normal reference range will be flagged in the laboratory data listings. 
Unless otherwise stated, all listings will be sorted by treatment arm, and subject number if 
appropriate, and then by visit date and time. 
Deviations from the analyses pre-specified in this SAP will be identified in the CSR. 
7.1 
MULTICENTER STUDIES 
Data from all participating sites will be pooled for analysis.  
7.2 MULTIPLE COMPARISONS AND MULTIPLICITY 
The Type I error rate will be adjusted for tests of both endpoints (ORR and OS) in the 
primary endpoint family.  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. 
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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.  
No further adjustment of the Type I error rate will occur.  All analyses of secondary 
endpoints will be descriptive. 
8 
DATA HANDLING CONVENTIONS 
8.1 
MISSING DATA 
8.1.1 
Imputation of Non-Date Missing Data 
Unless otherwise explicitly specified, missing data will not be imputed, and analyses will be 
based on non-missing values.  
Missing data occur when any requested data is not provided, leading to blank fields on the 
collection instrument.  These data will be indicated by a “blank” in subject listing displays.   
All available time to progression or death data will be analyzed using appropriate statistical 
methods that allow for censoring when no progression or death is reported; therefore, 
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 progression or death data.  Subjects with premature study withdrawal (including loss 
to follow-up) will be included in all analyses for which they have relevant data and for which 
they are in the analysis set of interest.  Subjects who are randomized but are not treated will 
be censored on study day 1. 
For variables which determine the proportion of responses using RECIST v1.1, all subjects in 
the ITT Analysis Set will be included in the denominator when calculating the percentages; 
that is, missing response data will be imputed as “no response”.  
Subjects with the designation of treatment relationship for AEs and serious adverse events 
(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 “Related”.  
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AEs with a completely missing start date will be assumed to be treatment emergent unless the 
AE end date is before the date of the first dose of study treatment. 
Missing laboratory, vital, and other safety assessment values will not be imputed. 
Missing QoL PRO data will not be imputed. At the time of development of this SAP, it is 
noted that some subjects under protocol version 1 collected QoL data on paper and/or a 
mixture of paper and electronic media. The handling of mixed modality in the analysis is 
described in Section 13. 
There will be no other imputation for missing data other than as described in Section 8.1.2 for 
partial dates and times. 
In the event that the study is terminated, all available data will be listed and some selected 
analyses may be performed. 
8.1.2 
Imputation of Partial Dates 
Imputed dates will not be used to derive study day, durations (e.g., duration of adverse 
events), or elapsed time variables.  In addition, imputed dates are not used for deriving the 
last contact date for overall survival.  
Partial date imputation will follow Analysis Data Model (ADaM) conventions.  The ADaM 
approach is to populate the numeric date variables with the imputed date and add a flag 
variable to the dataset that indicates the level of imputation.  
The flag variable can contain the values: blank, 'D', 'M', 'Y'.  
blank: indicates that no imputation was done 
D = 'Day': indicates that the day portion of the date is imputed 
M = 'Month': indicates that the month and day portions of the date are imputed 
Algorithms for imputing partial dates for AE are as below: 
Adverse Event 
Imputations in the adverse events dataset are used for slotting events to the appropriate study 
time periods and for sorting in data listings.  The imputed dates will be used in the derivation 
of the treatment emergence flag.  They will not be used to calculate duration of AEs.  If an 
AE start or end date is partially or completely missing, then the duration of the AE will be set 
to missing. 
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Date 
Missing Element 
Rule 
Start Date 
day, month, and year 
• Do not impute completely missing AE start dates 
 
day, month only 
• If AE start year is same as the year of study start, set to the date of 
the first dose of study treatment; otherwise, 
• Set to January 1st of the year the AE started 
 
day only 
• If the AE start year and month are the same as the first dosing date, 
impute the missing day as the first dosing date; otherwise, 
• Set start date to the 1st of the month the AE started 
End Date 
any date element 
• No imputation for completely or partially missing AE end dates; as 
applicable, report the AE as ongoing and the AE duration as 
missing 
Concomitant Medication 
Partial concomitant medication start and end dates will be used to derive the reference 
variables for concomitant medication start and end relative to treatment; any imputed dates 
will be included in the analysis dataset with an identifier as imputed.  The reference variables 
will be used to differentiate before, during, and after treatment for the concomitant 
medication.  The imputed dates will not be used to calculate study day or duration.   
Date 
Missing Element 
Rule 
Start Date 
day, month, and year 
• If the medication start date is completely missing and the 
end date is either after the first dose date or completely 
missing, then set the missing start date as the first dose date. 
 
day, month only 
• If the medication start year is same as the year of study start, 
set to the first dose date; otherwise, 
• Set to January 1st of the year the concomitant medication 
started 
 
day only 
• If the medication start year and month are the same as the 
first dose date, impute the missing day as the first dose date; 
otherwise, 
• Set start date to the 1st of the month the concomitant 
medication started. 
End Date 
day, month, and year 
• If the end date is completely missing or Ongoing is checked, 
set the missing end date as the last contact date. 
 
day, month only 
• If the partial end date contains year only, set end date to the 
earliest of December 31st or the last contact date.  
 
day only 
• If the partial end date contains month and year, set the end 
date to the earliest of the last day of the end month reported 
or the last contact date. 
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8.2 
DERIVED VARIABLES 
The following sections provide a general description of the derived and transformed variables 
to be used in data analyses.  Separate analysis dataset specifications provide full details on all 
data derivations and transformations.   
8.2.1 
Reference Dates 
There are three reference dates: 
• Because age is an eligibility requirement, the reference date for age is the date initial 
informed consent for study participation was signed. 
• The safety reference date is the first treatment start date and will be used to calculate 
study day for safety measures. 
• The efficacy reference date is the date of randomization. 
8.2.2 
Study Day for Safety  
If the date of interest occurs on or after the safety reference date, then the safety study day 
will be calculated as (date of interest - safety reference date) + 1.  If the date of interest 
occurs before the safety reference date, then the safety study day will be calculated as (date 
of interest – safety reference date).  There is no safety study day 0. 
8.2.3 
Study Day for Efficacy 
If the date of interest occurs on or after the efficacy reference date, then the efficacy study 
day will be calculated as (date of interest - efficacy reference date) + 1.  If the date of interest 
occurs prior to the efficacy reference date, then efficacy study day will be calculated as (date 
of interest – efficacy reference date).  There is no efficacy study day 0.  Subjects randomized 
and not treated will be censored at study day 1. 
8.2.4 
Durations  
When durations which are initially calculated in days are to be reported in months, divide the 
number of days by 30.4375; to report in weeks divide the number of days by 7; to report in 
years divide the number of days by 365.25. 
Age will be calculated as the number of complete years between a subject's birth date and the 
date of informed consent.  If the birth date is incomplete, the subject's birth year will be used 
to calculate age. 
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8.2.5 
Baseline Definition 
Baseline is defined as the most recent, non-missing value prior to the first study treatment 
dose date and time.  For enrolled subjects who did not receive study treatment during the 
study, baseline is defined as the latest, non-missing collected value before the date of 
randomization. 
8.2.6 
Change from Baseline 
Change from baseline will only be calculated for measures that have post-baseline records.  
Change from baseline for safety measures is calculated as: 
•   visit value – baseline value. 
Percentage change from baseline is calculated as: 
• (change from baseline / baseline value) * 100 
If either the baseline or visit value is missing, the change from baseline and percentage 
change from baseline are set to missing. 
8.2.7 Treatment Emergence Flag 
A treatment emergence flag will be derived based on the AE start date (and time if available) 
to determine an AE occurred before or after first dose date of either study drug.  If an AE 
occurred prior to the first dose date, the AE will be designated as not treatment emergent.  If 
an AE occurred after the first dose date, the AE will be designated as treatment emergent.  If 
an AE occurred on the same date or the same date/time of first dose date(time), the AE will 
be designated as treatment emergent unless 'NOT APPLICABLE' was recorded for the action 
taken with both study drugs for the combination arm or the AE was considered related to the 
either study drug.  Similar rules will be applied to the ipilimumab alone arm. 
8.2.8 
Multiple Assessments 
8.2.8.1 Disease Assessment Scans 
When a subject has disease assessment imaging for a single visit on multiple dates, the date 
of the disease assessment will be assigned using the following rules:  For RECIST v1.1 
response, if the visit response is Progressive Disease (PD), the date of progression is the 
earliest of: 
• all dates of target lesion scans when the target lesion response is PD 
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• all dates of non-target lesion scans at which the non-target lesion status is unequivocal 
progression 
• all scan dates documenting new lesion(s) 
For both sets of response criteria, if more than one source of PD is reported, then the date 
assigned is the earliest across all sources of PD.  If none of the above dates is available, the 
date of the earliest scan (if available) or visit date for the assessment at which PD is reported 
is assigned.  If the visit response is PD by symptomatic deterioration, the date is the date of 
the disease assessment visit. 
If the visit response is Stable Disease (SD), the date of SD is the earliest date of any lesion 
assessment at the visit. 
If the visit response is Complete Response (CR) or Partial Response (PR), the date of CR or 
PR is the latest date of any lesion assessment at the visit.  If all assessment dates are missing 
or not reported, then a date of response cannot be assigned. 
8.2.8.2 Injected and Non-injected Lesions 
To explore the treatment effect of IMO-2125 between the measurable injected and non-
injected lesions, the sum of the longest diameters will be calculated separately among the 
injected lesions and the non-injected lesions for each subject at each nominal visit in the 
combination treatment arm (ipilimumab with IMO-2125).  Due to the potentially different 
numbers of injected and non-injected lesions involved in the calculation for each subject, the 
percent reduction from baseline in the sum of the longest diameters will be used for the 
analysis.  For each subject, the paired difference in the percent reduction between the injected 
and non-injected lesions will be calculated.  Any measurable new lesions noted post-baseline 
will be excluded from the calculation. 
8.2.9 Other Assessments 
All data will be reported according to the nominal visit for which it was reported (that is, no 
visit windows will be applied during dataset creation).  Unscheduled data will only be 
included in summaries of worst-case (highest and/or lowest) post-baseline assessments.  
If multiple safety assessments on different days are reported for the same scheduled 
assessment, then the latest assessment for that scheduled assessment will be analyzed.   
If multiple assessments are reported on the same date for the same scheduled planned time, 
then the worst-case result will be analyzed. 
Data from all assessments (scheduled and unscheduled), including multiple assessments, will 
be included in listings. 
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8.2.10 
Strata Used for Analysis 
As stated in the protocol, the strata may be collapsed as appropriate with the goal of avoiding 
strata with too few subjects (the threshold for number of subjects per stratum was pre-defined 
as 5%).  At the time of the finalization of the current version of the SAP, the distribution of 
subjects across randomization strata was known.  The distribution was provided to the 
Sponsor's medical monitor for review.  If a stratum had  <5% of subjects, the stratification 
factor level was combined with another based on clinical judgment. Based on this 
assessment, stratification factor levels were combined as follows: 
1. Metastasis stage M1c and BRAF mutation positive 
2. Metastasis stage M1c and BRAF mutation wild type 
3. Metastasis stage Other and BRAF mutation positive 
4. Metastasis stage Other and BRAF mutation wild type 
8.2.11 
Other Derived Variables 
ECG Corrected QT Interval  
Fridericia’s corrected QT (QTcF): QT interval / [(RR interval/1000)1/3], where RR interval is 
in msec.  If RR is missing, then the formula to use is:  QT interval / [(60/HR)1/3], where HR = 
heart rate in beats per minute. 
Body Mass Index (BMI) 
BMI will be calculated using the following formula: 
BMI (kg/m2) = Weight (kg) / [Height (cm)/100]2 
using the height measured at Screening and the weight measured at Day 1 (if available).  If 
weight at Day 1 is not available, the assessment at Screening will be used (if available).  If 
neither is available, then BMI is missing. 
Age 
Age at informed consent will be calculated using the following formula: 
Age (years) = floor((intck('month', BirthDate, InformedConsentDate) - 
(day(InformedConsentDate) < day(Birthdate))) / 12) 
In addition, age at informed consent will be categorized as 18-65, >65-75, or >75.  
Race 
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For subgroup analyses, race will be categorized as white and non-white. 
Region 
For subgroup analyses, region will be categorized as US and non-US. 
8.3 
SAFETY PARAMETER RANGES 
8.3.1 
Laboratory Parameters 
Reported laboratory values will be categorized using value ranges that reflect the severity 
grades in the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) v4.03 for the relevant laboratory parameters. See Appendix Section 16.5.  
Laboratory values will also be categorized relative to the normal range:  a value that is 
outside the reference range is either high abnormal (value above the upper limit of the normal 
[ULN] reference range) or low abnormal (value below the lower limit of the normal [LLN] 
reference range).   
Local laboratories were used in this study.  Some of the local laboratories did not provide 
reference ranges for the corresponding results.  For these cases, the reference ranges from the 
American College of Physicians will be used.  Below is the link to these reference ranges: 
https://annualmeeting.acponline.org/sites/default/files/shared/documents/for-meeting-
attendees/normal-lab-values.pdf 
8.3.2 
ECG Parameters 
To report QTcF values, categories referencing the grades in the NCI-CTCAE v4.03 will be 
used (see adverse event ‘Electrocardiogram QT corrected interval prolonged’).  Additionally, 
the post-baseline increase in corrected QT values will be summarized using the ranges below. 
ECG Parameter 
Reporting Range 
Unit 
Absolute QTcF interval 
≥450 to <481  
≥481 to <501 (Grade 2) 
≥501 
msec 
Increase from baseline QTcF 
Increase of ≥31 to ≤60 
Increase of >60 
msec 
The following criteria will be used to flag other clinically significant post-baseline ECG 
values:  
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ECG Parameter 
Out of Normal Ranges 
Unit 
PR interval 
<110 (L) and >220 (H) 
msec 
QRS interval 
<75 (L) and >110 (H) 
msec 
8.3.3 
Vital Signs 
The following criteria will be used to summarize heart rate shift tables: 
Vital Sign Parameter 
Reporting Range 
Unit 
 Heart Rate 
 < 50 
50 to 120 
> 120 
bpm 
To summarize blood pressure, the below categories will be used to produce shift tables. 
Vital Sign Parameter 
Reporting Range 
Unit 
Systolic Blood Pressure 
< 90 
≥90 to <120  
≥120 to <150  
≥150 to <180  
≥180  
mmHg 
Diastolic Blood Pressure 
< 50  
≥50 to <70 
≥70 to <90  
≥90 to <110  
≥110  
mmHg 
To summarize temperature, categories below will be used to produce shift tables. 
Vital Sign Parameter 
Reporting Range 
Unit 
 Temperature 
≤35 
> 35 to < 38 
 ≥38 
Degrees Celsius 
 
9 
DEMOGRAPHICS, BASELINE DISEASE CHARACTERISTICS, 
AND SUBJECT DISPOSITION 
Unless otherwise stated, all tables and listings in this section will be based on the ITT 
Analysis Set. 
9.1 
DISPOSITION OF SUBJECTS 
The number and percentage of subjects in each analysis set will be summarized, as will 
subject status at the end of the study, comprising completed (death), ongoing, or withdrawn 
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from the study, with reasons for study withdrawal; and study treatment status, comprising 
completed study treatment or prematurely discontinued study treatment, with reasons for 
premature discontinuation of study treatment.  Duration of active follow-up, defined as the 
duration between the date of randomization and the date of last disease assessment, in months 
as well as duration of survival follow-up defined as the duration between the date of 
randomization and the date of last contact or death, in months will be summarized 
descriptively. 
• Analysis Sets 
• Subject Status 
• Study Treatment Status 
• Duration of Active Follow-up  
• Duration of Survival Follow-up  
Reasons for study withdrawal and study treatment discontinuation will be presented in the 
order they are displayed in the electronic Case Report Form (eCRF). 
The following listings will be provided: 
• Subject disposition  
• Reasons for study withdrawal  
• Reasons for study treatment discontinuation  
This analysis will be repeated for FAS and Per Protocol Analysis Set for sensitivity analysis. 
9.2 
PROTOCOL DEVIATIONS 
Protocol deviations will be categorized as major or minor as defined in 2125-MEL-301 
Protocol Deviation Plan.  A subset of major protocol deviations will be further classified as 
exclusionary from the Per Protocol Analysis Set if they are considered having significant 
impact on the primary efficacy data. The following summary will be provided: 
• Major protocol deviations by category  
The following listings will be provided: 
• All inclusion and exclusion criteria violations  
• All protocol deviations including major designation and exclusionary classification 
from the Per Protocol Analysis Set 
9.3 
DEMOGRAPHIC AND BASELINE DISEASE CHARACTERISTICS 
The following summaries will be provided: 
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• Demographic and baseline characteristics (age at consent, age categories [18-65,  
>65-75, >75], race, ethnicity, sex, country, region, height, weight, BMI, baseline 
lactate dehydrogenase [LDH], LDH categories [≤ULN, >ULN], baseline 
neutrophil/lymphocyte ratio, and ratio categories [<2.5, ≥2.5])  
• Baseline disease characteristics (primary histology, stage, tumor PD-L1 
immunohistochemistry result, elevated LDH, BRAF mutation status, and ECOG 
performance status at baseline)  
• Prior systemic anticancer treatment history (all settings) 
• Prior systemic anticancer treatment history (unresectable/metastatic disease setting 
only) 
The following listings will be provided: 
• Demographic characteristics  
• Baseline disease characteristics (excluding ECOG performance status) 
• Medical history 
• Prior systemic anticancer treatment, including best response and reason for 
discontinuation if available  
• Prior cancer-related surgeries 
• Prior radiotherapy 
• ECOG performance status 
The demographic and baseline disease characteristics analyses will be repeated for FAS and 
Per Protocol Analysis Set for sensitivity analysis. 
9.4 
STRATIFICATION FACTORS 
The number of subjects at each stratification factor level at randomization and from the 
clinical data will be summarized using frequencies and percentages and listed.  The summary 
will be by marginal levels of 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 [i.e., negative], BRAF mutation positive with prior targeted therapy, or BRAF 
mutation positive with no prior targeted therapy) as well as the 12 stratification cells. The 
listing will show the randomized and clinical data stratification levels for each subject.  
The duration of anti-PD-1 therapy in weeks will be calculated using start and end dates 
reported on the Prior Systemic Anticancer Treatment page of the eCRF as (therapy end date – 
therapy start  date + 1)/7 when a therapy is referred to as “PD-1 inhibitor”. 
Metastasis stage will be identified from the Baseline Disease Characteristics page of the 
eCRF as M1c or Other (if not M1c). 
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BRAF mutation status is reported on the Baseline Disease Characteristics page of the eCRF 
as negative or positive.  Prior targeted therapy for BRAF mutation positive subjects will be 
identified as the treatment category of prior systemic anticancer therapy of BRAF inhibitor, 
MEK inhibitor, other targeted therapy, or any combination of these therapies for those 
subjects with “Positive” BRAF mutation. 
Section 8.2.10 describes how the stratification factors are combined.  The combined 
stratification levels will be summarized showing the levels with metastasis stage (M1c or 
Other) and BRAF mutation status (BRAF wild type or BRAF mutation positive). 
The following summaries will be provided: 
• Stratification factor levels as randomized 
• Stratification factor levels derived from the clinical data 
• Stratification factor levels as combined 
The following listing will be provided: 
• Stratification factor levels  
9.5 
CONCOMITANT MEDICATIONS 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary Version B3 Sep 2020.  A concomitant medication is defined as any drug or 
substance administered between the time of the first dose of study treatment and 30 days 
from the date of the last dose of study treatment, or taken to treat SAEs, irAEs, AEs of Grade 
3 or above that occurred within 90 days of the last dose of study treatment, or taken to treat 
Grade 3 or above treatment-related AEs and SAEs that occurred during either the Active or 
Survival follow-up periods.  This includes medications that were started prior to screening if 
their use continued during dosing.  If the start date or end date of concomitant medication is 
partial, use the imputation rules defined in Section 8.1.2 to impute the date and determine if 
the medication was concomitant.  
In the summary of concomitant medications, each subject is counted once within each unique 
term.  For example, if a subject takes Amoxicillin on two separate occasions, the subject is 
counted only once under the ingredient “Amoxicillin”.   
The summary of concomitant medications using the Safety Set will show the number and 
percentage of subjects taking concomitant medications by therapeutic class and preferred 
term (PT).  Anatomical Therapeutic Chemical (ATC) Level 4 will be used for the listing and 
summary. 
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A similar summary will also be generated for concomitant medications that were used to treat 
immune-related adverse event as recorded on the Concomitant Medication eCRF page.   
Another summary will be generated by category of concomitant immune-modulating 
medications that were used to treat irAEs.  These medication categories include thyroid 
hormone replacement therapies, systemic steroids, and immune-suppressants. Thyroid 
hormone replacement therapies will be identified by WHO drug ATC prefix H03, systemic 
steroids by WHO drug ATC prefix H02, and immuno-suppressants by WHO drug ATC 
prefix L04.  Any medications with one of these prefixes that were indicated on the 
Concomitant Medication eCRF page as being used to treat irAEs will be included in this 
summary by preferred term under the corresponding category. 
Cancer treatments including, but not limited to, radiotherapy, anticancer treatment, and 
surgery that occurred after the start of study treatment and were received during the study 
will be summarized separately. If a subject received more than one type of cancer treatment, 
he/she will be counted under each of them in the summary.  The best overall response from 
these cancer treatments and procedures will be included in the summary. Biopsies and other 
diagnostic procedures will not be considered as cancer treatment.  
IMO-2125 is a cytokine modulator that may indirectly affect cytochrome P450 (CYP) 
production or activity, and subsequently affect the exposure to CYP substrates. Therefore, 
increased AEs or decreased efficacy may occur in patients concurrently administered CYP-
sensitive substrates or substrates with a narrow therapeutic range. Any concomitant 
medications identified as CYP-sensitive substrates or substrates with a narrow therapeutic 
range will be summarized and listed including any AE(s) that started during the duration of 
the treatment.  The medications of interest are as follows: 
Drug Category 
Preferred Term 
Sensitive CYP3A4 
substrates 
budesonide, buspirone, eplerenone, eletriptan, 
felodipine, fluticasone, lovastatin, midazolam, 
saquinavir, sildenafil, simvastatin, triazolam, 
vardenafil 
CYP3A4 substrates with a 
narrow therapeutic range 
alfentanil, astemizole(a), cisapride(a), cyclosporine, 
diergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, terfenadine(a) 
Sensitive CYP1A2 
substrates 
duloxetine, alosetron 
 
CYP1A2 substrates with a 
narrow therapeutic range 
theophylline, tizanidine 
 
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Drug Category 
Preferred Term 
Sensitive CYP2C8 substrates 
 
repaglinide 
 
CYP2C8 substrates with a 
narrow therapeutic range 
paclitaxel 
 
CYP2C9 substrates with a 
narrow therapeutic range 
warfarin, phenytoin 
Sensitive CYP2C19 
substrates 
omeprazole 
CYP2C19 substrates with a 
narrow therapeutic range 
s-mephenytoin 
Sensitive CYP2D6 
substrates 
desipramine 
CYP2D6 substrates with a 
narrow therapeutic range 
thioridazine 
The following summaries will be provided: 
• Concomitant medications 
• Concomitant medications for irAEs by category (thyroid hormone replacement 
medications, systemic steroids, immune-suppressants)  
• Cancer treatments and surgeries after the start of study treatment  
• Concomitant sensitive and narrow therapeutic range CYP substrates 
The following listings will be provided: 
• Prior and concomitant medications 
• Cancer treatment after start of study treatment 
• Sensitive and narrow therapeutic range CYP substrate - concomitant medications for 
subjects who used CYP substrates during the study 
• Sensitive and narrow therapeutic range CYP substrate - treatment-emergent adverse 
events started during or after use of CYP substrates 
10 
EFFICACY 
The analysis of ORR will take place after all randomized subjects fall within one of the 
following categories: 
• completed scheduled study treatment and completed at least 28 weeks on the study; 
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• 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 OS study analysis will take place when 392 deaths have occurred or approximately 36 
months after the last subject is randomized, whichever occurs first.  All tables, figures, and 
listings will be produced for the final study analysis. All efficacy tables, listings, and figures 
will use the ITT Analysis Set.   
For determination of best overall response by RECIST v1.1, response assessments of CR and 
PR require confirmation by imaging ≥4 weeks after the initial documentation of CR or PR.  
10.1 
ANALYSIS OF THE PRIMARY ENDPOINT FAMILY  
10.1.1 Independent Reviewer-Assessed ORR by RECIST v1.1 
The final and sole analysis of ORR assessed by blinded independent review using RECIST 
v1.1 will test the response proportions of the two treatment arms using a stratified Cochran-
Mantel-Haenszel (CMH) test for two proportions by the randomized strata as defined in 
Section 9.4. To allow for adequate time for response and confirmation, the analysis of ORR 
will take place no sooner than when all randomized subjects 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; or withdrew, were lost to follow-up, 
or died before completing at least 28 weeks on the study. 
The generic SAS procedure call is: 
 
 
proc freq data=<dataset name>;  
 
 
   tables strata*response*treatment / cmh ;       
 
run; 
 
ORR is defined as the percentage of subjects achieving a CR or PR out of the total number of 
subjects included in the analysis population.  The CR or PR must occur prior to PD and the 
start of any subsequent anticancer therapy. Subjects with not evaluable, unknown, or missing 
best response will be handled as non-responders; i.e., they will be included in the 
denominator when calculating the ORR. The independent reviewer-assessed best overall 
response and ORR by RECIST v1.1 with 95%, two-sided, confidence intervals (CIs) using 
the Wald’s binomial method will be provided for each treatment arm.  The percentage 
difference of ORR between the two treatment arms with a 95%, two-sided CI, and the p-
value from the stratified CMH test will be provided. In support of ORR analysis, the 
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summary statistics for duration of active follow-up times for all subjects will be provided (see 
the summary under subject disposition). 
The following summary and figures will be provided: 
• Independent Reviewer-Assessed Response by RECIST v1.1 
• Swimmer’s Plot of Independent Reviewer-Assessed Response by RECIST v1.1 for 
ORR Responders 
• Waterfall Plot of Maximum Percent Reduction from Baseline in Individual Sum of 
the Longest Diameters of Target Lesions, Assessed by Independent Reviewer 
• Spider Plot of Individual Percent Change from Baseline in Sum of the Longest 
Diameters of Target Lesions Over Time, Assessed by Independent Reviewer 
The following efficacy listings will be provided: 
• Independent Reviewer-Assessed Target Lesions  
• Independent Reviewer-Assessed Non-Target Lesions  
• Independent Reviewer-Assessed New Lesions  
• Independent Reviewer-Assessed Response by RECIST v1.1 
• Independent Reviewer-Assessed Response by irRECIST  
• Independent Reviewer-Assessed RECIST v1.1 Tumor Response Endpoints (Best 
Overall Response, ORR, DCR, DRR, DoR) 
10.1.2 Sensitivity Analysis of ORR 
The main analysis of ORR will be repeated for FAS and Per Protocol Analysis Set as 
sensitivity analysis. In addition, a sensitivity analysis using an unstratified Chi-square test for 
two proportions will be performed. The “best case scenario” sensitivity analysis will also be 
performed with the subjects who do not have any tumor response prior to discontinuation 
imputed as responders, versus the main ORR analysis with these subjects imputed as non-
responders. 
The following summaries will be provided:  
• Objective Response Rate by RECIST v1.1 for FAS and Per Protocol Analysis Set 
• Un-stratified and Best Case Scenario Analysis of Objective Response Rate by 
RECIST v1.1 
Note: Un-stratified and “best case scenario” sensitivity analyses are included in the 
Independent Reviewer-Assessed Response by RECIST v1.1 table. 
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10.1.3 Analysis of OS 
The analysis of OS will be performed after 392 deaths or approximately 36 months after the 
last subject is randomized, whichever occurs first.  If the test for ORR is significant, based on 
the fallback method description in Section 4.5, overall survival will be tested using a one-
sided, stratified log-rank test with a significance level of 0.025.  The same strata used in the 
stratified analysis of ORR will be employed in the analysis of OS.  If the p-value is ≤0.025, 
the null hypothesis will be rejected with the conclusion that OS in the IMO-2125 + 
ipilimumab combination arm is statistically superior. Otherwise, if the test for ORR is not 
significant, the overall survival will be tested using a one-sided, stratified log-rank test with a 
significance level of 0.005.  If the p-value is ≤0.005, the null hypothesis will be rejected with 
the conclusion that OS in the IMO-2125 + ipilimumab combination arm is statistically 
superior.   
OS will be summarized with median, first, and third quartiles of Kaplan-Meier estimates with 
corresponding 95% CIs calculated by the Brookmeyer-Crowley method [Brookmeyer, 1982] 
with log-log transformation.  Kaplan-Meier estimates and 95% CIs will also be produced at 
OS landmark time points at 1 and 2 years.  The 95% CIs for Kaplan-Meier estimates at each 
of the OS landmark time points will be calculated using Greenwood’s formula with log-log 
transformation.  OS summaries will include the number of subjects at risk, the number of 
subjects who died, and the number of censored subjects. In addition, the survival follow-up, 
defined as the duration between the date of randomization and the date of last contact, in 
months will be analyzed by reverse Kaplan-Meier method, median and its corresponding 
95% CI will be summarized.  The figure will identify the number of subjects at risk at each 
scheduled visit and censored times on the curve.  The HR and a 95% CI will be estimated 
using a Cox proportional hazards model, stratified by the same strata used in the analysis of 
ORR. 
The following table and figure will be provided for OS: 
• Overall Survival  
• Kaplan-Meier Plot of Overall Survival  
The following efficacy listing will be provided: 
• Overall Survival 
10.1.4 Sensitivity Analysis of Overall Survival  
The analysis of OS will be repeated for FAS and Per Protocol Analysis Set. In addition, 
sensitivity analysis of stratification effects will be performed using an HR estimator with a 
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corresponding 95% CI that uses an un-stratified HR estimator and un-stratified log rank test 
for the ITT Analysis Set. 
The Kaplan-Meier plot of OS will be used to assess the proportionality of hazards and to 
determine if there is a delayed treatment effect.  If a delayed treatment effect is observed, 
results from a Fleming-Harrington weighted log-rank test with ρ = 0 and γ= 0.5 will be 
presented to test the equality of the survival curves between the treatement groups.  These 
weights were chosen a priori anticipating the survival curves could be similar for the first 3 
months. If appropriate based on the proportional hazards assessment, the restricted mean 
survival time will be compared between the treatment arms. These two sensitivity analyses 
will be conducted using the ITT Analysis Set. 
The following summaries will be provided for these sensitivity analyses of OS: 
• Overall Survival for FAS and Per Protocol Analysis Set 
• Un-stratified Overall Survival 
• Overall Survival Using Weighted Log-Rank Test 
• Overall Survival Using Restricted Mean Survival Times 
10.1.5 Sensitivity Analysis of Overall Survival using Imputed Death Dates 
As up to 10% of the enrolled subjects are anticipated to withdraw from the study early, a 
sensitivity analysis of OS will be performed where the missing death dates are imputed as the 
last known alive date +1 for the early withdrawn subjects.  Results will be summarized with 
median, first, and third quartiles of Kaplan-Meier estimates with corresponding 95% CIs 
calculated by the Brookmeyer-Crowley method with log-log transformation.  The HR and a 
95% CI will be estimated using a Cox proportional hazards model, stratified by the same 
strata used in the analysis of ORR. 
The following summary will be provided: 
• Overall Survival Using Imputed Death Dates 
10.1.6 Subgroup Analyses of the Primary Endpoint Family 
To investigate treatment effect in subgroups, independent reviewer-assessed ORR by 
RECIST v1.1 and OS will be analyzed for each of the following subgroups: 
• Metastasis stage (M1c and Other) 
• BRAF mutation status (BRAF wild type and BRAF mutation positive) 
• Duration of prior anti-PD-1 therapy (≥12 weeks and <12 weeks) 
• Region (US and non-US) 
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• Baseline ECOG (0 and ≥1) 
• Baseline LDH (Normal: ≤ ULN and Abnormal: > ULN) 
• Baseline LDH (≤ ULN, ULN to ≤ 2x ULN, > 2x ULN) 
• Baseline Neutrophil/Lymphocyte Ratio (<2.5 and ≥2.5) 
• Subjects who used CYP substrate concomitant medications and subjects who did not 
use CYP substrate concomitant medications 
The subgroup summaries for ORR by RECIST v1.1 with 95%, two-sided CIs using the 
Wald’s binomial method will be provided for each treatment arm within each subgroup.  The 
subgroup summaries of OS will be summarized by treatment arm within each subgroup with 
median, first, and third quartiles of Kaplan-Meier estimates with corresponding 95% CIs 
calculated by the Brookmeyer-Crowley method with log-log transformation. 
The following tables and figures will be provided for subgroup analyses: 
• Subgroup Analyses of Objective Response Rate  
• Subgroup Analyses of Overall Survival  
• Forest Plot of Proportion Differences for Objective Response Rate by Subgroup 
• Forest Plot of Hazard Ratios for Overall Survival by Subgroup 
10.2 
ANALYSIS OF SECONDARY EFFICACY ENDPOINTS  
10.2.1 Investigator-Assessed ORR by RECIST v1.1 
The best overall response and the point estimators of investigator-assessed ORR by RECIST 
v1.1 with corresponding 95%, two-sided CIs, will be provided.  The proportion difference for 
the ORR by RECIST v1.1 with corresponding 95%, two-sided CIs will be provided. 
The following table and figures will be provided: 
• Investigator-Assessed Response by RECIST v1.1 
• Swimmer’s Plot of Investigator-Assessed Response by RECIST v1.1 for ORR 
Responders 
• Waterfall Plot of Maximum Percent Reduction from Baseline in Individual Sum of 
the Longest Diameters of Target Lesions, Assessed by Investigator 
• Spider Plot of Individual Percent Change from Baseline in Sum of the Longest 
Diameters of Target Lesions, Assessed by Investigator 
The following efficacy listings will be provided: 
• Investigator-Assessed Target Lesions  
• Investigator-Assessed Non-Target Lesions  
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• Investigator-Assessed New Lesions  
• Investigator-Assessed Response by RECIST v1.1 
• Investigator-Assessed Response by irRECIST 
• Investigator-Assessed RECIST v1.1 Tumor Response Endpoints 
10.2.2 Comparison of Best Overall Responses between Independent Review and 
Investigator  
A summary of the differences in the best overall responses by RECIST v.1.1 between 
independent review and the investigator assessment will be presented by treatment arm and 
overall in a table format with the number and percentage of independent reviewer responses 
presented side-by-side with those for the investigator responses.  Comparison of the ORR 
responders and non-responders will be performed by treatment arm and overall to evaluate 
the number and percentage of concordant and discordant pairs of ORR responses (CR/PR 
versus non-CR/PR) between the independent reviewer and investigator. 
The following summary tables will be provided: 
• Concordance of Best Overall Response by Independent Reviewer and Investigator  
• Concordance of ORR by Independent Reviewer and Investigator  
10.2.3 
Analysis of Injected and Non-injected Lesions 
For each subject, the sum of longest diameters (SLD) will be calculated separately among the 
injected lesions and the non-injected lesions at each nominal visit only in the combination 
treatment arm (ipilimumab with IMO-2125).  Note that the sum of the shortest distance 
(SSD) will be calculated for lymph nodes instead and will be summarized together with SLD 
in the analysis. For each subject, the percent reduction from baseline in the SLD/SSD, and 
the paired difference in the percent reduction between the injected and non-injected lesions 
will be calculated and summarized by study visit.  Any new lesions noted post-baseline will 
be excluded from the calculation.  Any non-target lesions without measurement at baseline 
will be excluded from this analysis. The maximum percent reduction in SLD/SSD by 
injection status will be presented graphically in a waterfall plot for the ORR responders 
assessed by independent-reviewer using RECIST v.1.1 (i.e., those with best overall response 
of CR or PR). 
The following table and figure will be provided: 
• Paired Difference of Percent Reduction from Baseline in Individual Sum of the 
Longest Diameters Between Injected and Non-injected Lesions 
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• Waterfall Plot of Maximum Percent Reduction from Baseline in Individual Sum of 
the Longest Diameters of Measurable Lesions by Injection Status, ORR Responders 
Assessed by Independent Reviewer (injection status presented side-by-side) 
• Spider Plot of Individual Percent Change from Baseline in Sum of the Longest 
Diameters of Measurable Lesions by Injection Status, Assessed by Investigator 
(separate page by injection status) 
The following efficacy listing will be provided: 
• Sum of the Longest Diameters and Percent Change from Baseline in SLD by 
Injection Status 
10.2.4 Durable Response Rate 
The durable response rate will be derived separately for the assessments by blinded 
independent reviewer and the investigator.  DRR will be derived using RECIST v1.1, defined 
as the rate of CR or PR lasting ≥6 months from the date of first instance of confirmed CR or 
PR response which begin during the first 12 months of treatment.  The denominator will be 
the number of subjects included in the corresponding analysis set (e.g., ITT).  The calculation 
for the number of days in 6 months is 6*(365.25/12); the cutoff date for 6 months is therefore 
(scan date + 182.625). 
Summaries will include DRR by RECIST v1.1 with corresponding 95%, two-sided CIs using 
the Wald’s binomial method for each treatment arm. 
Summaries of DRR are included within the following summary outputs: 
• DRR based on Independent Reviewer-Assessed ORR by RECIST v1.1 
• DRR based on Investigator-Assessed ORR by RECIST v1.1 
Note: DRR analyses are included in the Independent Reviewer-Assessed Response and 
Investigator-Assessed Response by RECIST v1.1 tables. 
10.2.5 Disease Control Rate 
The disease control rate (DCR) is defined as the percentage of subjects achieving a confirmed 
CR, PR, or SD out of the total number of subjects included in the analysis population.  The 
CR, PR, or SD must occur prior to PD and the start of any subsequent anticancer therapy. 
Subjects with not evaluable, unknown, or missing best response will be handled as non-
responders; i.e., they will be included in the denominator when calculating the DCR. The 
independent reviewer-assessed DCR by RECIST v1.1 with 95%, two-sided CIs using the 
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Wald’s binomial method will be provided for each treatment arm.  A similar summary will be 
provided using the investigator-assessed DCR by RECIST v1.1. 
The following summaries will be for DCR: 
• Independent Reviewer-Assessed DCR by RECIST v1.1 
• Investigator-Assessed DCR by RECIST v1.1 
10.2.6 Duration of Response 
DoR will be derived separately for the assessments by blinded independent reviewer and the 
investigator.  DoR will be derived using RECIST v1.1, defined as the time in months 
between the date of the first instance of confirmed CR or PR as the best overall response to 
the day before the first date that recurrent or progressive disease is objectively documented or 
date of death. For subjects who have attained CR or PR as the best overall response but do 
not have progressive disease or died, they will be censored at the same time they will be 
censored for the primary definition of PFS (See Appendix Section 16.4). Subjects who do not 
respond will not be included in this analysis. 
DoR will be described using Kaplan-Meier estimates with 95% CIs.  If there are sufficient 
number of events, median, first and third quartiles, minimum and maximum for DoR with 
corresponding 95% CIs will be reported.  CIs will be estimated using the Brookmeyer-
Crowley method [Brookmeyer, 1982] with log-log transformation.  Summaries will also 
include the number of subjects at risk, the number of subjects with events, and the number of 
subjects censored.  
The following summaries and figures for DoR will be provided: 
• DoR based on Independent Reviewer-Assessed ORR by RECIST v1.1 for ORR 
Responder 
• DoR based on Investigator-Assessed ORR by RECIST v1.1 for ORR Responder 
• Kaplan-Meier Plot of DoR based on Independent Reviewer-Assessed ORR by 
RECIST v1.1 for ORR Responder  
• Kaplan-Meier Plot of DoR based on Investigator-Assessed ORR by RECIST v1.1 for 
ORR Responder  
10.2.7 Time to Response 
TTR will be derived as the time in months from the date of randomization to date of the scan 
for the first instance of confirmed CR or PR (using RECIST v1.1) by investigator and 
independent reviewer assessments.  Subjects who do not respond will not be included in this 
analysis. 
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TTR will be summarized descriptively with mean, standard deviation, median, minimum and 
maximum.  
The following summaries will be provided: 
• TTR based on Independent Reviewer-Assessed ORR by RECIST v1.1 for ORR 
Responder 
• TTR based on Investigator-Assessed ORR by RECIST v1.1 for ORR Responder 
10.2.8 Analysis of Progression-Free Survival 
PFS is defined as the time in months from the date of randomization to progression by 
RECIST v1.1 or death from any cause.  The date of disease progression will be the date of 
the scan for the first objectively documented PD per RECIST v1.1.  Subjects who do not 
progress including those who have started new anticancer therapy, withdrawn from the study, 
or been lost to follow-up without disease progression will have their PFS time censored at the 
last valid disease assessment, defined as a scheduled or unscheduled visit with a disease 
assessment of CR, PR, or SD (for RECIST v1.1). More detailed censoring rules are in 
Appendix Section 16.4. 
PFS assessed by investigator and independent reviewer will be analyzed using Kaplan-Meier 
method, the median, first and third quartiles with corresponding 95% CIs are calculated by 
the Brookmeyer-Crowley method with log-log transformation. If there are a sufficient 
number of events, Kaplan-Meier estimates and 95% CIs will also be produced at PFS 
landmark time points at 6 months, 1 and 2 years. The 95% CIs for Kaplan-Meier estimates at 
each of the PFS landmark time points will be calculated using Greenwood’s formula with 
log-log transformation.  Summaries will also include the number at risk, the number of 
subjects with events, and the number of subjects censored along with their corresponding 
reason for censoring.  Figures will use the Kaplan-Meier estimates and identify the number of 
subjects at risk at each scheduled visit and censored times on the curve. 
The following summaries and figures will be provided for PFS: 
• Summary of Independent Reviewer-Assessed PFS by RECIST v1.1 
• Summary of Investigator-Assessed PFS by RECIST v1.1 
• Kaplan-Meier Plot of Independent Reviewer-Assessed PFS by RECIST v1.1  
• Kaplan-Meier Plot of Investigator-Assessed PFS by RECIST v1.1  
The following efficacy listing will be provided: 
• Progression-free Survival by Independent Reviewer-Assessed and Investigator-
Assessed RECIST v1.1  
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11 
SAFETY ANALYSES 
All safety analyses will be based on the Safety Set as defined in Section 6.5.  Summaries of 
AEs will include only treatment-emergent AEs (TEAEs), defined as AEs with a start date on 
or after the date of first dose of study treatment or existing AEs which increase in CTCAE 
grade after the start of study treatment.  If it cannot be determined definitively whether the 
AE is treatment emergent due to missing or partial onset or end dates, then it will be counted 
as treatment emergent (see Section 8.2.7 for details).  
11.1 
EXTENT OF EXPOSURE 
Overall exposure will be summarized descriptively by treatment arm and separately by study 
drug.  For ipilimumab, summaries will include the number of infusions received, duration of 
treatment (weeks), cumulative dose received in milligrams per kilogram (mg/kg) and average 
dose (mg/kg), per infusion.  For IMO-2125, summaries will include the number of injections 
received, type of injected lesions per eCRF category (i.e., Superficial, Other deep soft tissue, 
Organ, and Other), duration of treatment (weeks), the cumulative dose received in milligrams 
(mg), and the average dose (mg) per injection. 
To summarize type of injected lesions per eCRF category, subjects will be counted under 
each type of injection if the subjects received more than one type of injection.  Furthermore, 
the type of injected lesions will also be reclassified into 3 categories: Superficial, Deep, or 
Visceral (Organ).  The Sponsor will perform a review of the ‘Other’ injection type and map 
them to the 3 specified categories. If a subject had more than one type of injected lesion 
during the study, the deepest type of injection will be counted in the summary. For example, 
a subject who had both deep and visceral injections will be counted under visceral.  
Treatment duration will be calculated in weeks for each subject and each treatment using the 
following formula: Treatment duration (weeks) = (last dose date - first dose date + 1) / 7. 
For IMO-2125, cumulative dose received is calculated as the sum of doses (mg) across all 
injections, and average dose is calculated as the cumulative dose divided by the sum of 
injections.  For ipilimumab, the dose (mg) divided by base weight (kg) will be derived for 
each subject at each dosing visit.  Cumulative dose received is calculated as the sum of dose 
per weight (mg/kg) across all infusions, and average dose is calculated as the cumulative 
dose divided by the sum of infusions. 
Dose reductions were permitted for patients dosed under Protocol Version 2.0 only.  Any 
dose modifications of study treatment due to irAE will be listed. 
The following summaries will be provided: 
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• IMO-2125 Exposure  
• Ipilimumab Exposure  
The following listings will be provided: 
• IMO-2125 Exposure  
• Ipilimumab Exposure  
• Dose Modifications Due to irAEs  
11.2 
ADVERSE EVENTS 
Grades of AEs will be assigned according to the CTCAE, Version 4.03.  AEs will be coded 
to the system organ class (SOC) and PT level using the Medical Dictionary for Regulatory 
Affairs (MedDRA) Dictionary Version 23.0.  Treatment-emergent AEs (TEAEs) will be 
summarized.  All AEs will be listed regardless of when they were reported. 
Summaries of TEAEs will count the number of subjects, not the number of events; that is, 
subjects with multiple occurrences of the same TEAE will be counted once.   
An overview summary of TEAEs, including counts and percentages of subjects with: any 
TEAEs; TEAEs of CTCAE Grade 3 or above;  TEAEs related to any study treatment; TEAEs 
related to IMO-2125; TEAEs related to ipilimumab; TEAEs related to any study treatment of 
CTCAE Grade 3 or above; TEAEs related to IMO-2125 of CTCAE Grade 3 or above; 
TEAEs related to ipilimumab of CTCAE Grade 3 or above; immune-related TEAEs (see 
Table 2 in Section 11.5 for the list of AEs); immune-related TEAEs of CTCAE Grade 3 or 
above, immune-related TEAEs related to any study treatment; immune-related TEAEs 
related to IMO-2125; immune-related TEAEs related to ipilimumab; TEAEs leading to IMO-
2125 discontinuation;  TEAEs leading to ipilimumab discontinuation; TEAEs leading to dose 
modifications (i.e., dose interruptions or dose reduction); SAEs; SAEs of CTCAE Grade 3 or 
above; SAEs related to any study treatment, SAEs related to IMO-2125; SAEs related to 
ipilimumab; fatal AEs; fatal AEs related to any study treatment, fatal AEs related to IMO-
2125; and fatal AEs related to ipilimumab will be produced.   
The frequency and percentage of TEAEs (all grades) will be summarized in descending order 
of total incidence by SOC and PT.  In the SOC row, the number of subjects with multiple 
events under the same SOC will be counted once. In addition, a separate table for the 
frequency and percentage of TEAEs (all grades) in descending order of total incidence by PT 
will be generated. Summaries of TEAEs of CTCAE Grade 3 or above will be produced 
similarly in descending order of total incidence by PT.    
A separate summary will be provided for study treatment-related TEAEs for each study 
treatment in descending order of total incidence by PT.  Treatment-related TEAEs are those 
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deemed as ‘possibly related’ or ‘related’ to the study drug by the investigator. In the IMO-
2125 + ipilimumab arm, TEAEs related to either study treatment will be reported.  Missing 
relationship to study treatment will be imputed as described in Section 8.1.1.  Similar 
analysis will be repeated for Grade 3 or above treatment-related TEAE by PT.   
In addition, a summary of number and percentage of subjects with any TEAE by maximum 
grade will be produced.  TEAEs will be sorted by PT in descending order of total incidence 
in the IMO-2125 + ipilimumab arm.  Each summary will report the number of subjects with 
at least one TEAE and the PT reported.  Subjects are counted once for each unique PT under 
the maximum grade.  A similar analysis will be repeated for treatment-related TEAE by PT 
and maximum grade.  In the IMO-2125 + ipilimumab arm, TEAEs related to either drug will 
be reported. This analysis will also be repeated for TEAE related to IMO-2125 and for TEAE 
related to ipilimumab in both the combination arm and ipilimumab alone arm. 
Cumulative TEAEs at 3, 6, 9, and 12 months from first dose will include all TEAEs with a 
start date on or before 3, 6, 9, or 12 months from the first dose date.  The calculation for the 
days in x months is x*(365.25/12); the cutoff date for x months is therefore (first dose date + 
x*(365.25/12)).  Incidence of subjects experiencing TEAEs up to the specified cut point from 
first dose will be summarized by PT and maximum grade.  A similar analysis will be 
repeated for treatment-related TEAEs up to the specified cut point from first dose. 
Incidence of TEAEs will be summarized by MedDRA PT and time of onset relative to the 
first exposure of the study drug by 3-week interval during the treatment period.  The first 
onset interval will start at the first dose date and end on the 21st day (Weeks 1-3); the second 
interval will start on the 22nd day and end on the 42nd day (Weeks 4-6); the third interval will 
start on the 43rd day and end on the 63rd day (Weeks 7-9); the fourth interval will start of the 
64th day and end on the 84th day (Weeks 10-12); the fifth interval will start from the 85th day 
and end on the 105th day (Weeks 13-15); the sixth interval will start from the 106th day and 
end on the 126th day (Weeks 16-18); the seventh interval will start from the 127th day and end 
on the 147th day (Weeks 19-21); and the last will start on the 148th day and end on the 168th 
day (Weeks 22-24).  Adverse events will be assigned to onset categories according to the 
relative study day when the AE started.  AEs with incomplete onset dates will be excluded 
from this analysis.  For subjects who experienced the same AE multiple times and within 
different onset categories, the event will be counted once in each of the categories in which it 
started.  For each onset category, AE incidences will be calculated by dividing the number of 
subjects who had each AE during that onset category by the number of subjects who have not 
dropped out or died at the start of the onset interval. For example, for onset category Weeks 
4-6, the denominator will be the number of subjects who have not dropped out or died by the 
start of Weeks 4-6 interval and were therefore in the risk set for that interval. 
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All AEs will be listed.  This listing will include treatment arm, age, sex, start date and study 
day, end date and study day, grade, serious (yes or no), irAE (yes or no), relationship to 
treatment (yes or no), action taken, outcome, and preferred and verbatim terms.   
The following summaries will be provided: 
• Overall Summary of Treatment-Emergent Adverse Events  
• Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
• Treatment-Emergent Adverse Events by Preferred Term 
• Treatment-Emergent Adverse Events by Preferred Term and Maximum Grade  
• Treatment-Related Treatment-Emergent Adverse Events by Preferred Term 
(including Treatment-Related, IMO-2125-Related, and Ipilimumab-Related) 
• Treatment-Related Treatment-Emergent Adverse Events by Preferred Term and 
Maximum Grade  
• Grade 3 or Above Treatment-Emergent Adverse Events by Preferred Term 
• Grade 3 or Above Treatment-Related Treatment-Emergent Adverse Events by 
Preferred Term  
• Cumulative TEAEs at Three Months by Preferred Term and Maximum Grade 
• Cumulative TEAEs at Six Months by Preferred Term and Maximum Grade 
• Cumulative TEAEs at Nine Months by Preferred Term and Maximum Grade 
• Cumulative TEAEs at Twelve Months by Preferred Term and Maximum Grade 
• Cumulative Treatment-Related TEAEs at Three Months by Preferred Term and 
Maximum Grade 
• Cumulative Treatment-Related TEAEs at Six Months by Preferred Term and 
Maximum Grade 
• Cumulative Treatment-Related TEAEs at Nine Months by Preferred Term and 
Maximum Grade 
• Cumulative Treatment-Related TEAEs at Twelve Months by Preferred Term and 
Maximum Grade 
• TEAE Incidence by Time to Onset in 3-Week Interval During the Treatment Period 
The following listings will be provided: 
• All Treatment-Emergent Adverse Events 
• Adverse Events Between Signing Consent and the Start of Study Treatment 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE as 
described in the protocol.  If any subject or subject’s partner becomes pregnant while on the 
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study, the information will be included in the CSR narratives and no separate table will be 
produced. 
11.3 
DEATHS AND SERIOUS ADVERSE EVENTS 
A summary of deaths will include the number of subjects who died, the primary reason for 
death, the number of deaths within 30 days of the last dose of study treatment, the number of 
subjects alive at last contact with follow-up ongoing, the number of subjects alive at last 
contact with follow-up ended. The frequency and percentage of serious TEAEs (all grades) 
will be summarized in descending order of total incidence by PT. A similar analysis will be 
repeated for treatment-related serious TEAE by PT, for serious TEAE related to IMO-2125 
by PT, and for serious TEAE related to Ipilimumab by PT.  Grade 3 or above serious TEAEs 
will also be summarized. Summaries of deaths and SAEs will be repeated for subjects who 
received visceral injection during the study drug administration.  Deaths will also be listed. 
The listing of SAEs will include a flag for those that are treatment-emergent and will display 
the SAE’s relationship to study treatment. 
The following summaries will be provided: 
• Serious Treatment-Emergent Adverse Events by Preferred Term 
• Grade 3 or Above Serious Treatment-Emergent Adverse Events by Preferred Term 
• Treatment-Related Serious Treatment-Emergent Adverse Events by Preferred Term 
(including Treatment-Related, IMO-2125-Related, and Ipilimumab-Related) 
• Treatment-Related Serious Treatment-Emergent Adverse Events by Preferred Term 
and Maximum Grade 
• Deaths 
The following listings will be provided: 
• All SAEs  
• TEAEs Leading to Death 
• All Deaths 
11.4 
ADVERSE EVENTS LEADING TO DISCONTINUATION OF STUDY 
TREATMENT (WITHDRAWAL),  DOSE INTERRUPTIONS, OR DOSE 
REDUCTIONS 
Dose reductions are only permitted for subjects enrolled under Protocol Version 2.0.  TEAEs 
leading to dose interruption and dose reduction will be listed. The following category of  
TEAEs will be summarized by PT: 
• TEAEs Leading to Permanent Discontinuation of IMO-2125 by Preferred Term  
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• IMO-2125-Related TEAEs Leading to Permanent Discontinuation of IMO-2125 by 
Preferred Term  
• TEAEs Leading to Permanent Discontinuation of Ipilimumab by Preferred Term  
• Ipilimumab-Related TEAEs Leading to Permanent Discontinuation of Ipilimumab by 
Preferred Term  
The following listings will be provided: 
• TEAEs Leading to Dose Interruption or Dose Reduction  
• TEAEs Leading to Treatment Discontinuation  
11.5 
IMMUNE-RELATED ADVERSE EVENTS 
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 were provided in the protocol as a guide to the investigators to 
identify the immune-related AEs.  Any AEs which have been associated with the use of 
immunotherapy agents were marked as immune-related in the CRF. 
• Adrenal insufficiency 
• Hypophysitis 
• Hypopituitarism 
• Hypothyroidism 
• Hyperthyroidism 
• Other endocrinopathies 
• Colitis 
• Enterocolitis 
• Dermatitis 
• Autoimmune dermatitis 
• Guillain Barre syndrome 
• Hepatitis 
• Myasthenia gravis 
• Pneumonitis 
• Stevens Johnson Syndrome 
• Toxic epidermal necrolysis 
• Uveitis 
• Iritis 
• Myocarditis 
• Any AEs that the Investigator considers to be of autoimmune or immune-related 
origin 
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In addition, the Sponsor medical team also reviews all the events coded under 17 selected 
MedDRA SOCs that have the potential to identify irAEs (see the list of SOCs below).  These 
AEs are reviewed relative to the dosing of either ipilimumab or tilsotolimod.  They are also 
assessed in the context of the usage of concomitant medications and other AEs that occurred 
around the same time.  This process allows for a holistic review of events in the context of 
other data elements, thereby providing an exhaustive process for potential irAE 
identification. 
Table 2 List of MedDRA SOCs Used by Sponsor in Identification of Additional 
Potential irAEs 
MedDRA SOCs  
Cardiac disorders 
Endocrine disorders 
Eye disorders 
Gastrointestinal disorders 
General disorders and administration site conditions 
Hepatobiliary disorders 
Immune system disorders 
Injury, poisoning and procedural complications 
Investigations 
Musculoskeletal and connective tissue disorders 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
Product issues 
Renal and urinary disorders 
Respiratory, thoracic and mediastinal disorders 
Skin and subcutaneous tissue disorders 
Surgical and medical procedures 
Vascular disorders 
 
The number and percentage of subjects who experienced at least one irAE will be tabulated.  
The preferred terms will be identified using the search strategy as described above. The 
frequency and percentage of immune-related TEAEs will be summarized by PT, as well as 
by PT and maximum grade. Similar analyses will be repeated for Grade 3 or above immune-
related TEAEs and for Grade 3 or above treatment-related immune-related TEAEs.  The 
frequency and percentage of treatment-related immune-related TEAEs will be summarized 
by PT and maximum grade. 
Similarly, the frequency and percentage of immune-related serious TEAEs will be 
summarized by PT and maximum grade. Similar analysis will be repeated for Grade 3 or 
above immune-related serious TEAEs by PT.  The number and percentage subjects who 
experienced immune-related TEAEs leading to permanent discontinuation of IMO-2125 and 
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subjects who experienced immune-related TEAEs leading to permanent discontinuation of 
ipilimumab will be presented by PT. 
A listing of immune-modulating medications which include thyroid hormone replacement 
therapies, systemic steroid and immuno-suppressants used after occurrence of irAE will be 
presented.  Thyroid hormone replacement therapies will be identified by WHO drug ATC 
prefix H03, systemic steroids by WHO drug ATC prefix H02, and immuno-suppressants by 
WHO drug ATC prefix L04. 
All irAEs will be listed.  This listing will include treatment arm, age, sex, verbatim term and 
the corresponding coded terms, start date and study day, end date and study day, grade, 
serious (yes or no), relationship to treatment (yes or no), action taken, and outcome.  It will 
also include an indicator for the source of the irAEs (CRF or sponsor-defined). 
The following summaries will be provided: 
• Immune-Related Treatment-Emergent Adverse Events by Preferred Term 
• Immune-Related Treatment-Emergent Adverse Events by Preferred Term and 
Maximum Grade  
• Grade 3 or Above Treatment-Related Immune-Related Treatment-Emergent Adverse 
Events by Preferred Term  
• Treatment-Related Immune-Related Treatment-Emergent Adverse Events by 
Preferred Term and Maximum Grade  
• Grade 3 or Above Treatment-Related Immune-Related Treatment-Emergent Adverse 
Events by Preferred Term  
• Immune-Related Serious Treatment-Emergent Adverse Events by Preferred Term and 
Maximum Grade  
• Grade 3 or Above Immune-Related Serious Treatment-Emergent Adverse Events by 
Preferred Term 
• Immune-Related TEAEs Leading to Permanent Discontinuation of IMO-2125 by 
Preferred Term  
• Immune-Related TEAEs Leading to Permanent Discontinuation of Ipilimumab by 
Preferred Term   
The following listing will be provided: 
• Immune-Related Treatment-Emergent Adverse Events  
11.6 
ADVERSE EVENTS OF SPECIAL INTEREST 
Systemic injection and infusion reaction such as cytokine release syndrome (CRS), 
anaphylactic and anaphylactoid reactions are deemed to be adverse events of special interest 
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(AESIs). From communication with U.S. Food and Drug Administration (FDA) on 11 
September 2020, the agency agreed with the Sponsor regarding the use of the American 
Society for Transplantation and Cellular Therapy (ASTCT) Consensus (Lee, 2019) for 
assessment of CRS events, and FDA’s guidance for the industry for immunogenicity 
assessment for evaluation of anaphylactic events.  FDA recommended to assess any fever 
(not attributable to any other cause), hypotension and hypoxia, and to include related organ 
toxicities associated with CRS with severity graded according to CTCAE 4.03.  FDA also 
recommended to include definitions of CRS, anaphylaxis, and hypersensitivity based on 
clinical diagnostic criteria and to provide an analysis based on the clinical criteria to 
distinguish CRS from anaphylaxis and hypersensitivity by presenting data on the nature, 
onset, frequency and severity, information about dose modifications and any evidence of 
recurrence with dose reduction or after drug withdrawal.  
The Sponsor has used the following nine MedDRA LLTs for the initial database search for 
AESIs reported within 14 days after any tilso injections:  anaphylaxis, cytokine release 
syndrome, infusion related reaction, injection site allergic reaction, injection related reaction, 
allergic reaction, anaphylactic reaction, anaphylactoid reaction, or systemic inflammatory 
response syndrome.  A listing of AEs corresponding to these LLTs was generated to be used 
for evaluation against the ASTCT definition for CRS as well as the FDA guidance document 
on anaphylactic reaction which are provided below as a reference: 
AE Term 
Definition 
CRS 
A supraphysiologic response following any immune therapy 
that results in the activation or engagement of endogenous or 
infused T cells and/or other immune effector cells. A qualified 
CRS event will include fever along with hypotension and/or 
hypoxia. 
Fever 
A disorder characterized by elevation of the body’s temperature 
above the upper limit of normal, and a temperature of 38.0 °C is 
considered grade 1 fever. 
Hypotension 
A disorder characterized by a blood pressure that is below the 
normal expected for an individual in a given environment. 
Hypoxia 
An Oxygen saturation (SaO2) <94% or an individual requiring 
supplemental oxygen to correct a deficit in oxygenation is 
considered to have hypoxia. Oxygen provided only as a comfort 
measure should not be used. 
Anaphylactic reaction 
Anaphylaxis is a serious, acute allergic reaction without a 
particular immunologic mechanism and based on the following 
clinical features:  
1. Acute onset of an illness (minutes to several hours) with 
involvement of the skin, mucosal tissue, or both, and at 
least one of the following: 
• Hypoxia 
• Hypotension 
2. Two or more of the following that occur rapidly after 
exposure to Tilsotolimod (minutes to several hours): 
• Involvement of the skin-mucosal tissue 
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AE Term 
Definition 
• Hypoxia 
• Hypotension 
• Persistent gastrointestinal symptoms 
3. Hypotension after exposure to Tilsotolimod when prior 
systemic reactions with Tilsotolimod has occurred 
(minutes to several hours) 
In order to perform a more comprehensive assessment of the AESIs, a search of all TEAEs 
which are coded under any of the following MedDRA SOC and started within 14 days after 
any tilsotolimod injections will also be conducted: 
• General disorders and administration site condition 
• Respiratory and mediastinal disorders vascular disorders 
• Immune system disorders (see Table 2 in Section 11.5) 
The AEs identified will be reviewed and classified by the Sponsor as CRS, anaphylactic 
reaction or hypersensitivity reaction.  The classification will be imported into the analysis 
dataset for summaries. 
Significant AESIs will be summarized, that include Grade 3 and above systemic injection and 
infusion reactions.  
Based on the strategy and definitions stated above, these AEs included under each event type 
will be determined based on a programmatic search of the AE datasets using the specified 
LLT in conjunction of a medical review of the AEs identified. The incidence of the AESIs 
under each event type will be summarized by MedDRA preferred term.   
Analyses of time to the first onset of the AESIs will be analyzed using the Kaplan-Meier 
product-limit method to estimate the quartiles and corresponding 95% confidence intervals 
for time to onset of each event. For this analysis, subjects who completed or prematurely 
terminated the study with the specified event will have the time to onset censored at the time 
of their completion or termination. 
A listing of subjects who were identified to have experienced AESIs will be presented with 
onset, frequency and severity, information about dose modifications and any evidence of 
recurrence with dose reduction or after drug withdrawal. 
Subject 
ID 
PT 
Sponsor 
assessed 
category  
Grade 
SAE 
Time 
to 
Onset 
Frequency 
Recurrence 
after dose 
modification 
Recurrence 
after drug 
withdrawal  
Related Organ 
Toxicities and 
grades  
Outcome 
Abbreviation: PT = Preferred Term. 
 
The following summaries will be provided: 
• Significant Treatment-Emergent Adverse Events of Interest by Preferred Term 
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•  Time to Onset of Significant Treatment-Emergent Adverse Events of Interest 
The following listing will be provided: 
• Significant Treatment-Emergent Adverse Events of Interest  
11.7 
SUBGROUP ANALYSIS FOR ADVERSE EVENTS 
Adverse events will be further examined by Injection Type as reclassified by the Sponsor in 
Section 11.1 [Visceral (Organ), Deep, and Superficial].  Any summaries by injection type 
will be performed for the combination treatment arm only. 
The following tables will be provided for the AE subgroup analysis: 
• Treatment-Emergent Adverse Events by Preferred Term and Injection Type  
• Grade 3 or Above Treatment-Emergent Adverse Events by Preferred Term and 
Injection Type  
• Serious Treatment-Emergent Adverse Events by Preferred Term and Injection Type 
• Deaths by Injection Type 
11.8 
CLINICAL LABORATORY EVALUATIONS 
The laboratory tests in Section 12.2 of the protocol, Laboratory Assessments, will be 
summarized as described in this section.   
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Category 
Analyte 
Hematology  
CBC: white blood cell (WBC), red blood cell (RBC), 
hemoglobin, hematocrit, platelet count, mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), mean corpuscular volume (MCV) 
Differential WBC count: neutrophils, monocytes, 
lymphocytes, eosinophils, basophils, atypical lymphocytes 
Coagulation 
prothrombin time (PT), activated partial thromoboplastin 
(aPTT), international normalized ratio (INR) 
Complement 
CH50, C3, C4 
Clinical Chemistry Panel  
Renal: Serum sodium, potassium, chloride, carbon dioxide 
(CO2), calcium, phosphate, creatinine, blood urea nitrogen, 
uric acid 
Endocrine: serum glucose, free thyroxine (free T4), total or 
free triiodothyronine (total or free T3), thyroid stimulating 
hormone (TSH) 
Liver: serum alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), lactate dehydrogenase (LDH), 
alkaline phosphatase, albumin, total protein, total bilirubin 
Lipids: Serum cholesterol, triglycerides 
Urinalysis 
Dipstick testing (urinalysis and microscopy will be conducted 
only if dipstick results are abnormal) 
 
Laboratory data will be presented in International System of Units (SI) and in the order 
presented in the protocol.  Laboratory grades will be reported using the CTCAE v4.03 (see 
Appendix Section 16.5); ungraded laboratory assessments will be reported using normal 
ranges. 
Laboratory tests that are graded for both low and high abnormal values will have both values 
summarized separately with directions (hyper- or hypo-) labeled accordingly.  
Separate summary tables of the observed and change from baseline values for hematology, 
chemistry, coagulation, and complement laboratory tests will be produced. 
Definition of the baseline assessment is in Section 8.2.5. 
The denominator in percentage calculations at each scheduled visit will be based on the 
number of subjects with a non-missing value at each visit. 
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Hematology and chemistry laboratory tests will be summarized using shift tables by 
treatment arm. Subjects must have a baseline and at least one non-missing post-baseline 
assessment to be included in the shift analysis.  
Summaries of shifts from baseline will be provided for hematology and chemistry laboratory 
tests that are graded by CTCAE v4.03 (Appendix Section 16.5).  This shift table will include 
a worst-case (defined as the highest CTCAE grade) post-baseline summary that includes data 
from both scheduled and unscheduled visits.  Categories based on value ranges for CTCAE 
grades will be shown for baseline and worst case post-baseline, with the number and 
percentage of subjects in each.  
Summaries of shifts from baseline with respect to the normal range will be provided for the 
following laboratory parameters: WBC, RBC, hematocrit, platelet count, neutrophils, 
lymphocytes, total bilirubin, creatinine, LDH, ALT, AST, and TSH.  This shift table will 
include both shift to lowest and shift to highest post-baseline with respect to the normal 
range. All data from both scheduled and unscheduled visits will be considered for the shifts.  
Categories of normal range, below the normal range, and above the normal range will be 
shown for baseline, the highest and the lowest post-baseline, with the number and percentage 
of subjects in each.  A figure showing the mean, median, quartiles, range, and outliers beyond 
the interquartile range (boxplot) for each treatment arm at each scheduled visit will be 
produced for hematology and chemistry parameters.  It will have the nominal visit 
assessment week on the horizontal axis and the parameter value on the vertical axis.  The 
number of subjects assessed in each treatment arm will be displayed below each visit. 
A paneled scatterplot of the ratio of maximum total liver function tests to ULN versus 
baseline liver function tests to ULN will be produced by treatment arm.  The liver function 
tests included in the plot are ALT, AST, total bilirubin, and alkaline phosphatase. 
Listing of all laboratory values will be provided with the CTCAE v4.03 grade (if applicable) 
and laboratory values LLN and ULN will be flagged. 
Summaries to be produced are: 
• Summary of Change from Baseline in Hematology 
• Summary of Change from Baseline in Chemistry 
• Summary of Change from Baseline in Coagulation 
• Summary of Change from Baseline in Complement 
• CTCAE Shifts from Baseline Grade in Hematology 
• CTCAE Shifts from Baseline Grade in Chemistry  
• Shifts from Baseline Relative to the Normal Range in Selected Laboratory Tests 
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Figures to be produced are:  
• Boxplot for Hematology 
• Boxplot for Chemistry 
• Liver Function Tests Maximum Values to ULN on Study vs Baseline to ULN 
Listings to be produced are: 
• Hematology 
• Chemistry 
• Coagulation 
• Complement 
• Dipstick Test and Urinalysis 
11.9 
OTHER SAFETY MEASURES 
The denominator in percentage calculations at each scheduled visit will be based on the 
number of subjects with non-missing values at each visit. 
11.9.1 
Vital Signs and Weight 
Blood pressure values will be categorized into the ranges as listed in Section 8.3.3. 
Summary of shifts in blood pressure from baseline will be provided.  This shift table will 
include a summary of the highest and the lowest post-baseline that includes data from both 
scheduled and unscheduled visits.  Categories will be shown for baseline, the highest and the 
lowest post-baseline, with the number and percentage of subjects in each. Subjects must have 
a baseline and at least one non-missing post-baseline assessment to be included in the shift 
analysis.  
Summary of shifts in heart rate and temperature from baseline to lowest and highest post-
baseline value will be provided. The actual values will be categorized into the ranges as listed 
in Section 8.3.3.  Number and percentage of subjects in each of the categories will be 
presented for the lowest and highest post-baseline. 
Summaries to be produced are:  
• Shifts in Blood Pressure from Baseline to Lowest and Highest Post-Baseline  
• Shifts in Heart Rate and Temperature from Baseline to Lowest and Highest Post-
Baseline  
The listing to be produced is: 
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• Vital Signs (including out of range indicator) 
11.9.2 
ECG 
QTcF values based on Fridericia’s formula will be calculated as described in Section 8.2.11 
and then rounded to integer values.  These integer values will be categorized into the 
following ranges: <450, 450-480, >480-500, and >500 msec.  Changes from baseline in 
QTcF values will be categorized into: 31-60 and >60 msec. 
The mean of the triplicate values at each time point will be used for the analyses of 
continuous ECG parameters.   A summary of the ECG data and their corresponding change 
from baseline will be provided.  A shift in QTcF table will include shifts to the highest post-
baseline that includes data from both scheduled and unscheduled visits.  Categories of each 
grade as defined above will be shown for baseline and post-baseline, with the number and 
percentage of subjects in each.  In addition, the changes in QTcF categories as defined above 
will be summarized at each scheduled visit and at the highest post-baseline. Subjects must 
have a baseline and at least one non-missing post-baseline assessment in order to be included 
in the shift analysis.   
The following summaries will be provided: 
• Summary of  Change from Baseline in ECG by Visit 
• Shifts in QTcF from Baseline to the Highest Post-Baseline  
• QTcF Increase from Baseline to the Highest Post-Baseline 
The following listing will be provided: 
• ECG   
12 
PHARMACOKINETIC ANALYSES 
For subjects in the ipilimumab + IMO-2125 arm, all subjects who received at least one dose 
of IMO-2125 with at least one measurable concentration of IMO-2125 will be included in the 
PK Analysis Set. Blood samples will be drawn for determination of IMO-2125 plasma 
concentrations at pre-dose, and at 1, 2, and 4 hours post-dose at Week 1 and Week 11.  
Descriptive summary statistics (number of non-missing observations (n), arithmetic mean, 
standard deviation, % coefficient of variation (CV) (which is 100* standard deviation/mean), 
median, minimum, maximum , geometric mean and geometric % CV will be reported for 
concentration values grouped by week and collection time point. For the calculation of mean 
concentrations, all concentrations below the Lower Limit of Quantification (LLOQ) will be 
treated as zero. 
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The following summary table will be provided: 
• Summary of Pharmacokinetic Concentrations 
Individual IMO-2125 values (by week, nominal and actual sampling time points) will be 
listed for all subjects. Other PK analyses are outside the scope of this SAP and will be 
described in a separate analysis plan. The following listing will be provided: 
• Pharmacokinetic Concentrations 
13 
PATIENT-REPORTED QUALITY OF LIFE 
All analyses of patient-reported quality of life data will be descriptive.  No p-values will be 
calculated; point and interval estimates will be reported.  All QoL tables, listings, and figures 
will use the ITT Analysis Set. 
The five functional scales (physical, role, cognitive, emotional, and social), three symptom 
scales (fatigue, pain, and nausea and vomiting), global health status / QoL scale, the single 
items assessing additional symptoms commonly reported by cancer patients (dyspnoea, loss 
of appetite, insomnia, constipation, and diarrhoea) and perceived financial impact of the 
disease, will be scored. At the time of this SAP, it is noted that some subjects under protocol 
version 2 collected QoL data on paper and/or a mixture of paper and electronic media. For 
that reason, all the analyses described below, unless stated otherwise, will be done for paper 
PROs and electronic-PROs (ePROs) separately. In addition, the analyses will be repeated 
with combined paper PRO and ePRO data.    
13.1 
SCORING THE EORTC QLQ-C30 RESULTS 
The five functional scales (physical, role, emotional, cognitive, and social), three symptom 
scales (fatigue, pain, and nausea and vomiting), global health status / QoL scale, and single 
items assessing additional symptoms commonly reported by cancer patients (dyspnoea, 
insomnia, appetite loss, constipation and diarrhoea) and perceived financial impact of the 
disease will be scored.  Scoring of all scales will use the EORTC QLQ-C30 Scoring Manual 
instructions for version 3.0 of the QLQ-C30 instrument.   
Let Ii be the score for the ith item on the QLQ-C30 instrument, i=1, 2, 3,…, 30, ranges be the 
difference between the possible maximum and the minimum response to individual items for 
scale s, and ns be the number of items on the scales. 
For all scales, the Raw Score, RS, is the mean of the component items:  
Raw Scores = RSs = (I1 + I2 +...+ Ins ) ÷ ns 
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Then for Functional scales:  
Scores = {1− (RSs− 1) ÷ ranges } ×100   
and for Symptom scales/items and the Global health status /QoL:   
Scores = {( RSs − 1) ÷ ranges }×100. 
Global health status / QoL Scale 
Number of 
Items 
Range 
V3.0 Item 
Numbers 
Global health status/QoL  
QL2  
2 
6 
29, 30  
Functional scales 
Physical functioning   
PF2  
5 
3 
1 to 5  
Role functioning   
RF2  
2 
3 
6, 7  
Emotional functioning  
EF  
4 
3 
21 to 24  
Cognitive functioning  
CF  
2 
3 
20, 25  
Social functioning  
SF  
2 
3 
26, 27  
Symptom scales / items * 
Fatigue  
FA  
3 
3 
10, 12, 18  
Nausea and vomiting  
NV  
2 
3 
14, 15  
Pain  
PA  
2 
3 
9, 19  
Dyspnoea  
DY  
1 
3 
8  
Insomnia  
SL  
1 
3 
11  
Appetite loss  
AP  
1 
3 
13  
Constipation  
CO  
1 
3 
16  
Diarrhoea  
DI  
1 
3 
17  
Financial difficulties  
FI 
1 
3 
28 
* Item range is the difference between the possible maximum and the minimum response to individual items;  
most items take values from 1 to 4, giving range = 3. 
13.2 
SUMMARY OF EORTC QLQ-C30 RESULTS 
EORTC QLQ-C30 scores for each scale and single-item measure will be summarized by 
baseline and all scheduled visits using the total number of subjects with a measurement on 
that scale at that visit, the mean, standard deviation, median, minimum, and maximum.  
These summaries will also report change from baseline using the same descriptive statistics.  
Box and whisker plots of change from baseline for each scale by visit will also be produced. 
The following summary and figure will be produced: 
• Summary of Change from Baseline in EORTC QLQ-C30 Assessment Scores by Visit 
Using ePRO, Paper PRO and Combined ePRO and Paper PRO Data 
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• Line Graph of Mean (+/-SE) Change from Baseline in EORTC QLQ-C30 Scores and 
Sub-Scale by Visit Using ePRO, Paper PRO and Combined ePRO and Paper PRO 
Data 
The listing to be produced is: 
• EORTC QLQ-C30 Assessments Scores Using ePRO, Paper PRO and Combined 
ePRO and Paper PRO Data 
13.3 
ANALYSIS OF CHANGE FROM BASELINE IN EORTC QLQ-C30 
SCORES 
The change from baseline in each EORTC QLQ-30 multi-item scale and single-item 
measures will be analyzed over all post treatment assessment time points using a mixed effect 
model for repeated measures (MMRM).  The combined data from both paper PRO and ePRO 
will be used for this analysis.  The main MMRM model will include treatment, visit, and 
treatment-by-visit timepoint interaction term as fixed effects, and stratification factors and 
baseline score as a covariate.     
Due to differences in the visit schedules for the treatment arms, Weeks 7 and 8 will be treated 
as the same visit.  The model-based point estimates including least squares (LS) means, 
treatment difference in the LS means, and 2-sided 95% CI for the difference for each visit 
will be reported.   
For each MMRM model, select the optimal model covariance structure according to the 
following steps. Note that if the SAS log contains “converge criteria not meet”, “G matrix (or 
D or Hessian) is not positive definite”, that model is considered not fitted.  
1. Use an unstructured covariance structure without a random subject effect. 
2. Use a spatial power covariance structure with a random subject effect 
If both these models can be fitted, choose the model with smaller AIC. If only one model is 
fitted, the fitted model will be the model selected.  
If neither of these models can be fitted, then try the next three options in order. Stop at the 
first model to be fitted. 
3. Use an autoregressive(1) covariance structure with a random subject effect. 
4. Use an autoregressive(1) covariance structure without a random subject effect. 
5. Use a compound symmetric covariance structure without a random subject effect. 
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If no model fits for a given analysis, do not produce any output. 
The generic SAS procedure call is  
 
proc mixed data=<SAS dataset name>; 
 
   class treatment visit subject; 
 
   model <change in scale name> = strata baseline visit treatment  
               visit*treatment; 
         random subject; 
 
   repeated visit / subject=usubjid type=UN; 
 
   lsmeans visit*treatment / diff=all cl alpha=0.05; 
 
run; 
 
The following summary will be produced: 
• MMRM Analysis of Change from Baseline in EORTC QLQ-C30 Assessment Scores 
by Visit Using Combined ePRO and Paper PRO Data 
13.4 
ASSOCIATION BETWEEN CHANGE FROM BASELINE AND BEST 
OVERALL RESPONSE 
To assess the association between QoL data and the best overall response for a subject, the 
change from baseline in EORTC QLQ-C30 scores will be summarized by best overall 
response categories. The best overall response for a subject will be dichotomized into 2 
levels:  response of CR or PR (i.e., ORR Responder), and response of SD, PD, or NE (i.e., 
ORR Non-Responder).   
The following summary will be produced: 
• Summary of Change from Baseline in EORTC QLQ-C30 Assessment Scores by Visit 
and RECIST v1.1 ORR Responder Using Combined ePRO and Paper PRO Data 
14 
PHARMACODYNAMIC AND BIOMARKERS ANALYSES 
Anti-drug Antibody (ADA) to IMO-2125 and ipilimumab will be listed. 
Analyses to investigate changes in expression levels of immunologic biomarkers over time in 
response categories will be conducted.  Those analyses are outside the scope of this analysis 
plan and will be described in a separate SAP. 
 
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15 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics, 
1982; 38:29-41. 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of 
the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). 
Published by: European Organisation for Research and Treatment of Cancer, Brussels 2001. 
Lan KKG and Demets DL.  Discrete sequential boundaries for clinical trials.  Biometrika.  
1983:70(3):659-663. 
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. 
 
 
 
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16 
APPENDICES 
16.1 
SCHEDULE OF EVENTS 
Table 2: 
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 
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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. 
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 3: 
Schedule of Evaluations – Ipilimumab with IMO-2125 (Arm B) 
Evaluation 
Screen 
-ing1 
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 
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 
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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 of 
the Protocol). 
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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16.2 
LIST OF TABLES, LISTINGS, AND FIGURES 
The IDMC TLFs will be generated based on the schedule as defined in the Charter.  The 
analysis of ORR will take place after all the randomized subjects either 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, or withdrew, were lost to 
follow-up, or died before completing at least 28 weeks on the study.  The final study analysis 
will take place when 392 deaths or approximately 36 months after the last subjects is 
randomized, whichever occurs first. All tables, figures, and listings will be produced for the 
final study analysis. 
Tables, figures, and listings that will be produced for the IDMC meetings are identified with 
IDMC, the additional TLFs requested by IDMC during the course of the study are 
confidential and will not be included in the list below; and the final analysis of objective 
response rate with ORR, and the final analysis of OS with Final.  The page header will 
indicate the timing of the analysis. 
Table Title 
Timing of Analysis 
14.1.1.1 Subject Disposition, All Subjects * 
IDMC, ORR, Final 
14.1.1.2 Subject Disposition, Full Analysis Set 
ORR, Final 
14.1.1.3 Subject Disposition, Per Protocol Analysis Set 
ORR, Final 
14.1.2 Duration of Active Follow-up Times, Intent to Treat Analysis Set 
ORR, Final 
14.1.3 Major Protocol Deviations by Category, Intent to Treat Analysis Set 
ORR, Final 
14.1.4.1 Demographic Characteristics, Intent to Treat Analysis Set * 
IDMC, ORR, Final 
14.1.4.2 Demographic Characteristics, Full Analysis Set 
ORR, Final 
14.1.4.3 Demographic Characteristics, Per Protocol Analysis Set 
ORR, Final 
14.1.5.1 Baseline Disease Characteristics, Intent to Treat Analysis Set 
IDMC, ORR, Final 
14.1.5.2 Baseline Disease Characteristics, Full Analysis Set 
ORR, Final 
14.1.5.3 Baseline Disease Characteristics, Per Protocol Analysis Set 
ORR, Final 
14.1.6.1 Prior Systemic Anticancer Treatment History in All Settings, Intent to 
Treat Analysis Set 
IDMC, ORR, Final 
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Table Title 
Timing of Analysis 
14.1.6.2 Prior Systemic Anticancer Treatment History in 
Unresectable/Metastatic Disease Setting Only, Intent to Treat Analysis Set 
ORR, Final 
14.1.7.1 Stratification Factor Levels as Randomized, Intent to Treat Analysis 
Set 
ORR, Final 
14.1.7.2 Stratification Factor Levels from the Clinical Data, Intent to Treat 
Analysis Set 
ORR, Final 
14.1.8.1 Concomitant Medications, Safety Set 
ORR, Final 
14.1.8.2 Concomitant Medications for irAEs by Category, Safety Set 
IDMC, ORR, Final 
14.1.8.3 Cancer Treatments and Surgeries after Start of Study Treatment, 
Safety Set 
ORR, Final 
14.2.1.1.1 Summary of Independent Reviewer-Assessed Response by RECIST 
v1.1, Intent to Treat Analysis Set * 
ORR, Final 
14.2.1.1.2 Sensitivity Analysis: Summary of Objective Response Rate by 
RECIST v1.1, Full Analysis Set 
ORR, Final 
14.2.1.1.3 Sensitivity Analysis: Summary of Objective Response Rate by 
RECIST v1.1, Per Protocol Analysis Set 
ORR, Final 
14.2.1.1.4 Sensitivity Analysis: Un-Stratified and Best Case Scenario Analysis 
of Objective Response Rate by RECIST v1.1, Full Analysis Set 
ORR, Final 
14.2.1.2 Summary of Investigator-Assessed Response by RECIST v1.1, Intent 
to Treat Analysis Set * 
ORR, Final 
14.2.1.3.1 Concordance of Best Overall Response by Independent Reviewer 
and Investigator, Intent to Treat Analysis Set * 
ORR, Final 
14.2.1.3.2 Concordance of Objective Response Rate by Independent Reviewer 
and Investigator, Intent to Treat Analysis Set 
ORR, Final 
14.2.1.4.1 Subgroup Analysis: Summary of Objective Response Rate by 
RECIST v1.1 by Metastasis Stage, Intent to Treat Analysis Set 
ORR, Final 
14.2.1.4.2 Subgroup Analysis: Summary of Objective Response Rate by 
RECIST v1.1 by BRAF Mutation and Prior Targeted Therapy, Intent to Treat 
Analysis Set 
ORR, Final 
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Table Title 
Timing of Analysis 
14.2.1.4.3 Subgroup Analysis: Summary of Objective Response Rate by 
RECIST v1.1 by Duration of Prior Anti-PD-1 Therapy, Intent to Treat 
Analysis Set 
ORR, Final 
14.2.1.4.4 Subgroup Analysis: Summary of Objective Response Rate by 
Country, Intent to Treat Analysis Set 
ORR, Final 
14.2.1.4.5 Subgroup Analysis: Summary of Objective Response Rate by 
Baseline ECOG, Intent to Treat Analysis Set 
ORR, Final 
14.2.1.4.6 Subgroup Analysis: Summary of Objective Response Rate by 
Baseline LDH, Intent to Treat Analysis Set 
ORR, Final 
14.2.1.4.7 Subgroup Analysis: Summary of Objective Response Rate by 
RECIST v1.1 by Baseline Neutrophil/Lymphocyte Ratio, Intent to Treat 
Analysis Set 
ORR, Final 
14.2.1.4.8 Subgroup Analysis: Summary of Objective Response Rate by 
RECIST v1.1 by CYP Substrate Concomitant Medications Use, Intent to Treat 
Analysis Set 
ORR, Final 
14.2.1.5.1 Summary of Duration of Response based on Independent Reviewer-
Assessed ORR by RECIST v1.1 for ORR Responders, Intent to Treat Analysis 
Set * 
ORR, Final 
14.2.1.5.2 Summary of Duration of Response based on Investigator-Assessed 
ORR by RECIST v1.1 for ORR Responders, Intent to Treat Analysis Set * 
ORR, Final 
14.2.1.6.1 Summary of Time to Response based on Independent Reviewer-
Assessed ORR by RECIST v1.1 for ORR Responders, Intent to Treat Analysis 
Set 
ORR, Final 
14.2.1.6.2 Summary of Time to Response based on Investigator-Assessed ORR 
by RECIST v1.1 for ORR Responders, Intent to Treat Analysis Set 
ORR, Final 
14.2.2 Paired Difference of Percent Reduction from Baseline in Individual 
Sum of the Longest Diameters Between Injected and Non-injected Lesions, 
Intent to Treat Analysis Set 
ORR, Final 
14.2.3.1.1 Summary of Overall Survival, Intent to Treat Analysis Set 
Final 
14.2.3.1.2 Sensitivity Analysis: Summary of Overall Survival, Full Analysis 
Set 
Final 
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Table Title 
Timing of Analysis 
14.2.3.1.3 Sensitivity Analysis: Summary of Overall Survival, Per Protocol 
Analysis Set 
Final 
14.2.3.2 Sensitivity Analysis: Summary of Overall Survival Using Imputed 
Death Dates, Intent to Treat Analysis Set 
Final 
14.2.3.3.1 Sensitivity Analysis: Summary of Un-Stratified Overall Survival, 
Intent to Treat Analysis Set 
Final 
14.2.3.3.2 Sensitivity Analysis: Summary of Overall Survival Using Weighted 
Log-Rank Test, Intent to Treat Analysis Set 
Final 
14.2.3.3.3 Sensitivity Analysis: Summary of Overall Survival Using Restricted 
Mean Survival Times, Intent to Treat Analysis Set 
Final 
14.2.3.4.1 Subgroup Analysis: Summary of Overall Survival by Metastasis 
Stage, Intent to Treat Analysis Set 
Final 
14.2.3.4.2 Subgroup Analysis: Summary of Overall Survival by BRAF 
Mutation Status and Prior Targeted Therapy, Intent to Treat Analysis Set 
Final  
14.2.3.4.3 Subgroup Analysis: Summary of Overall Survival by Duration of 
Prior Anti-PD-1 Therapy, Intent to Treat Analysis Set 
Final 
14.2.3.4.4 Subgroup Analysis: Summary of Overall Survival by Country, 
Intent to Treat Analysis Set 
Final 
14.2.3.4.5 Subgroup Analysis: Summary of Overall Survival by Baseline 
ECOG, Intent to Treat Analysis Set 
Final 
14.2.3.4.6 Subgroup Analysis: Summary of Overall Survival by Baseline LDH, 
Intent to Treat Analysis Set 
Final 
14.2.3.4.7 Subgroup Analysis: Summary of Overall Survival by Baseline 
Neutrophil/Lymphocyte Ratio, Intent to Treat Analysis Set 
Final 
14.2.3.4.8 Subgroup Analysis: Summary of Overall Survival by CYP Substrate 
Concomitant Medications Use, Intent to Treat Analysis Set 
Final 
14.2.4.1 Summary of Independent Reviewer-Assessed Progression Free 
Survival by RECIST v1.1, Intent to Treat Analysis Set 
Final 
14.2.4.2 Summary of Investigator-Assessed Progression Free Survival by 
RECIST v1.1, Intent to Treat Analysis Set 
Final 
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Table Title 
Timing of Analysis 
14.3.1.1 IMO-2125 Exposure, Safety Set * 
IDMC, ORR, Final 
14.3.1.2 Ipilimumab Exposure, Safety Set * 
IDMC, ORR, Final 
14.3.2.1 Overall Summary of Treatment-Emergent Adverse Events, Safety  
Set * 
IDMC, ORR, Final 
14.3.2.2.1 Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term, Safety Set  
IDMC, ORR, Final 
14.3.2.2.2 Treatment-Emergent Adverse Events by Preferred Term, Safety Set  
ORR, Final 
14.3.2.2.3 Treatment-Emergent Adverse Events by Preferred Term and 
Injection Type, Safety Set 
ORR, Final 
14.3.2.3 Treatment-Related Treatment-Emergent Adverse Events by Preferred 
Term, Safety Set 
IDMC, ORR, Final 
14.3.2.4.1 Treatment-Emergent Adverse Events by Preferred Term and 
Maximum Grade, Safety Set 
IDMC, ORR, Final 
14.3.2.4.2 Treatment-Related Treatment-Emergent Adverse Events by 
Preferred Term and Maximum Grade, Safety Set * 
ORR, Final 
14.3.2.5.1 Grade 3 or Above Treatment-Emergent Adverse Events by Preferred 
Term, Safety Set 
IDMC, ORR, Final 
14.3.2.5.2 Grade 3 or Above Treatment-Related Treatment-Emergent Adverse 
Events by Preferred Term, Safety Set 
ORR, Final 
14.3.2.5.3 Subgroup Analysis: Grade 3 or Above Treatment-Emergent Adverse 
Events by Preferred Term and Injection Type, Safety Set 
ORR, Final 
14.3.2.6.1 Immune-Related Treatment-Emergent Adverse Events by Preferred 
Term, Safety Set 
IDMC, ORR, Final 
14.3.2.6.2 Immune-Related Treatment-Emergent Adverse Events by Preferred 
Term and Maximum Grade, Safety Set * 
IDMC, ORR, Final 
14.3.2.6.3 Grade 3 or Above Immune-Related Treatment-Emergent Adverse 
Events by Preferred Term, Safety Set 
IDMC, ORR, Final 
14.3.2.7.1 Treatment-Related Immune-Related Treatment-Emergent Adverse 
Events by Preferred Term and Maximum Grade, Safety Set 
IDMC, ORR, Final 
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Table Title 
Timing of Analysis 
14.3.2.7.2 Grade 3 or Above Treatment-Related Immune-Related Treatment-
Emergent Adverse Events by Preferred Term, Safety Set 
IDMC, ORR, Final 
14.3.3.1 Cumulative Treatment-Emergent Adverse Events at Three Months by 
Preferred Term and Maximum Grade, Safety Set 
Final 
14.3.3.2 Cumulative Treatment-Emergent Adverse Events at Six Months by 
Preferred Term and Maximum Grade, Safety Set 
Final 
14.3.3.3 Cumulative Treatment-Emergent Adverse Events at Nine Months by 
Preferred Term and Maximum Grade, Safety Set 
Final 
14.3.3.4 Cumulative Treatment-Emergent Adverse Events at Twelve Months 
by Preferred Term and Maximum Grade, Safety Set 
Final 
14.3.3.5 Cumulative Treatment-Related Treatment-Emergent Adverse Events 
at Three Months by Preferred Term and Maximum Grade, Safety Set 
IDMC, Final 
14.3.3.6 Cumulative Treatment-Related Treatment-Emergent Adverse Events 
at Six Months by Preferred Term and Maximum Grade, Safety Set 
IDMC, Final 
14.3.3.7 Cumulative Treatment-Related Treatment-Emergent Adverse Events 
at Nine Months by Preferred Term and Maximum Grade, Safety Set 
IDMC, Final 
14.3.3.8 Cumulative Treatment-Related Treatment-Emergent Adverse Events 
at Twelve Months by Preferred Term and Maximum Grade, Safety Set 
IDMC, Final 
14.3.4 Treatment-Emergent Adverse Event by Preferred Term and Time to 
Onset, Safety Set 
ORR, Final 
14.3.5.1.1 Serious Treatment-Emergent Adverse Events by Preferred Term, 
Safety Set * 
IDMC, ORR, Final 
14.3.5.1.2 Subgroup Analysis: Serious Treatment-Emergent Adverse Events by 
Preferred Term and Injection Type, Safety Set 
ORR, Final 
14.3.5.2 Treatment-Related Serious Treatment-Emergent Adverse Events by 
Preferred Term, Safety Set 
ORR, Final 
14.3.5.3 Grade 3 or Above Serious Treatment-Emergent Adverse Events by 
Preferred Term, Safety Set 
ORR, Final 
14.3.5.4 Immune-Related Serious Treatment-Emergent Adverse Events by 
Preferred Term and Maximum Grade, Safety Set 
ORR, Final 
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Table Title 
Timing of Analysis 
14.3.5.5 Grade 3 or Above Immune-Related Serious Treatment-Emergent 
Adverse Events by Preferred Term, Safety Set 
ORR, Final 
14.3.5.6.1 Summary of Deaths, Safety Set * 
ORR, Final 
14.3.5.6.2 Subgroup Analysis: Summary of Deaths by Injection Type, Safety 
Set  
ORR, Final 
14.3.6.1 Treatment-Emergent Adverse Events Leading to Permanent 
Discontinuation of IMO-2125 by Preferred Term, Safety Set 
IDMC, ORR, Final 
14.3.6.2 IMO-2125-Related Treatment-Emergent Adverse Events Leading to 
Permanent Discontinuation of IMO-2125 by Preferred Term, Safety Set 
ORR, Final 
14.3.6.3 Treatment-Emergent Adverse Events Leading to Permanent 
Discontinuation of Ipilimumab by Preferred Term, Safety Set 
IDMC, ORR, Final 
14.3.6.4 Ipilimumab-Related Treatment-Emergent Adverse Events Leading to 
Permanent Discontinuation of Ipilimumab by Preferred Term, Safety Set 
ORR, Final 
14.3.6.5 Immune-Related Treatment-Emergent Adverse Events Leading to 
Permanent Discontinuation of IMO-2125 by Preferred Term, Safety Set 
ORR, Final 
14.3.6.6 Immune-Related Treatment-Emergent Adverse Events Leading to 
Permanent Discontinuation of Ipilimumab by Preferred Term, Safety Set 
ORR, Final 
14.3.7.1 Significant Treatment-Emergent Adverse Events by Preferred Term, 
Safety Set 
ORR, Final 
14.3.7.2 Time to Onset of Significant Treatment-Emergent Adverse Events, 
Safety Set 
ORR, Final 
14.3.8.1 Summary of Change from Baseline in Hematology, Safety Set 
ORR, Final 
14.3.8.2 Summary of Change from Baseline in Chemistry, Safety Set 
ORR, Final 
14.3.8.3 Summary of Change from Baseline in Coagulation, Safety Set 
ORR, Final 
14.3.8.4 Summary of Change from Baseline in Complement, Safety Set 
ORR, Final 
14.3.8.5 Summary of CTCAE Shifts from Baseline Grade in Hematology, 
Safety Set 
IDMC, ORR, Final 
14.3.8.6 Summary of CTCAE Shifts from Baseline Grade in Chemistry, Safety 
Set 
IDMC, ORR, Final 
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Table Title 
Timing of Analysis 
14.3.8.7 Summary of Shifts from Baseline Relative to the Normal Range in 
Selected Laboratory Tests, Safety Set 
ORR, Final 
14.3.9.1 Summary of Shifts in Blood Pressure from Baseline to Worst Case 
Post-Baseline, Safety Set 
IDMC, ORR, Final 
14.3.9.2 Summary of Shifts in Heart Rate and Temperature from Baseline to 
Lowest and Highest Post-Baseline, Safety Set 
IDMC, ORR, Final 
14.3.9.3 Summary of ECG Values by Visit, Safety Set 
ORR, Final 
14.3.9.4 Summary of Shifts in QTcF from Baseline from the Highest Post-
Baseline, Safety Set 
ORR, Final 
14.3.9.5 Summary of QTcF Increase from Baseline from the Highest Post-
Baseline, Safety Set 
IDMC, ORR, Final 
14.4.1 Summary of Pharmacokinetic Concentrations, PK Analysis Set 
ORR, Final 
14.5.1.1 Summary of Change from Baseline in EORTC QLQ-C30 Assessment 
Scores by Visit Using ePRO Data, Intent to Treat Analysis Set 
ORR, Final 
14.5.1.2 Summary of Change from Baseline in EORTC QLQ-C30 Assessment 
Scores by Visit Using Paper PRO Data, Intent to Treat Analysis Set 
ORR, Final 
14.5.1.3 Summary of Change from Baseline in EORTC QLQ-C30 Assessment 
Scores by Visit Using Combined ePRO and Paper PRO Data, Intent to Treat 
Analysis Set 
ORR, Final 
14.5.1.4 MMRM Analysis of Change from Baseline in EORTC QLQ-C30 
Assessment Scores by Visit Using Combined ePRO and Paper PRO Data, 
Intent to Treat Analysis Set 
ORR, Final 
14.5.1.5 Summary of Change from Baseline in EORTC QLQ-C30 Assessment 
Scores by Visit and RECIST v1.1 ORR Responder Using Combined ePRO and 
Paper PRO Data, Intent to Treat Analysis Set 
ORR, Final 
   * Topline outputs 
Listing Title 
Timing of Analysis 
16.2.1.1.1 Subject Disposition, All Subjects 
ORR, Final 
16.2.1.1.2 Reasons for Study Withdrawal, Intent to Treat Analysis Set 
ORR, Final 
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Listing Title 
Timing of Analysis 
16.2.1.1.3 Reasons for Treatment Discontinuation, Safety Set 
ORR, Final 
16.2.1.1.4 Inclusion and Exclusion Criteria Violations, All Subjects 
ORR, Final 
16.2.1.1.5 Protocol Deviations, Intent to Treat Analysis Set 
ORR, Final 
16.2.1.2.1 Demographic Characteristics, Intent to Treat Analysis Set 
ORR, Final 
16.2.1.2.2 Baseline Disease Characteristics, Intent to Treat Analysis Set 
ORR, Final 
16.2.1.2.3 Medical History, Intent to Treat Analysis Set 
ORR, Final 
16.2.1.2.4 Prior Systemic Anticancer Treatment, Intent to Treat Analysis Set 
IDMC, ORR, Final 
16.2.1.2.5 Prior Cancer-Related Surgeries, Intent to Treat Analysis Set 
ORR, Final 
16.2.1.2.6 Prior Radiotherapy, Intent to Treat Analysis Set 
ORR, Final 
16.2.1.2.7 ECOG Performance Status, Intent to Treat Analysis Set 
ORR, Final 
16.2.1.3.1 Stratification Factor Levels, Intent to Treat Analysis Set 
ORR, Final 
16.2.1.3.2 Prior and Concomitant Medications, Intent to Treat Analysis Set 
ORR, Final 
16.2.1.3.3 Cancer Treatments and Procedures after Start of Study Treatment, 
Intent to Treat Analysis Set 
ORR, Final 
16.2.1.3.4 Sensitive and Narrow Therapeutic Range CYP Substrate - 
Concomitant Medications, All Subjects Used CYP Substrates During the 
Study, Intent to Treat Analysis Set 
ORR, Final 
16.2.1.3.5 Sensitive and Narrow Therapeutic Range CYP Substrate - 
Treatment-Emergent Adverse Events Started During or After Use of CYP 
Substrates, Intent to Treat Analysis Set 
ORR, Final 
16.2.2.1.1 Independent Reviewer-Assessed Target Lesions, Intent to Treat 
Analysis Set 
ORR, Final 
16.2.2.1.2 Independent Reviewer-Assessed Non-Target Lesions, Intent to Treat 
Analysis Set 
ORR, Final 
16.2.2.1.3 Independent Reviewer-Assessed New Lesions, Intent to Treat 
Analysis Set 
ORR, Final 
16.2.2.1.4 Investigator-Assessed Target Lesions, Intent to Treat Analysis Set 
ORR, Final 
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Listing Title 
Timing of Analysis 
16.2.2.1.5 Investigator-Assessed Non-Target Lesions, Intent to Treat Analysis 
Set 
ORR, Final 
16.2.2.1.6 Investigator-Assessed New Lesions, Intent to Treat Analysis Set 
ORR, Final 
16.2.2.1.7 Sum of the Longest Diameters and Percent Change from Baseline in 
SLD by Injection Status, Intent to Treat Analysis Set 
ORR, Final 
16.2.2.2.1 Independent Reviewer-Assessed RECIST v1.1 Response, Intent to 
Treat Analysis Set 
ORR, Final 
16.2.2.2.2 Investigator-Assessed RECIST v1.1 Response, Intent to Treat 
Analysis Set 
ORR, Final 
16.2.2.2.3 Independent Reviewer-Assessed irRECIST Response, Intent to 
Treat Analysis Set 
ORR, Final 
16.2.2.2.4 Investigator-Assessed irRECIST Response, Intent to Treat Analysis 
Set 
ORR, Final 
16.2.2.2.5 Independent Reviewer-Assessed RECIST v1.1 Tumor Response 
Endpoints, Intent to Treat Analysis Set 
ORR, Final 
16.2.2.2.6 Investigator-Assessed RECIST v1.1 Tumor Response Endpoints, 
Intent to Treat Analysis Set 
ORR, Final 
16.2.2.2.7 Progression Free Survival by RECIST v1.1 Assessed by 
Independent Reviewer and Investigator and Overall Survival, Intent to Treat 
Analysis Set 
Final 
16.2.3.1.1 IMO-2125 Exposure, Safety Set 
IDMC, ORR, Final 
16.2.3.1.2 Ipilimumab Exposure, Safety Set 
IDMC, ORR, Final 
16.2.3.1.3 Dose Modifications Due to irAEs, Safety Set 
ORR, Final 
16.2.3.2.1 Treatment-Emergent Adverse Events, Safety Set 
IDMC, ORR, Final 
16.2.3.2.2 Adverse Events Between Signing Consent and the Start of Study 
Treatment, Safety Set 
ORR, Final 
16.2.3.2.3 Serious Adverse Events, Safety Set 
IDMC, ORR, Final 
16.2.3.2.4 Adverse Events Leading to Death, Safety Set 
IDMC, ORR, Final 
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Listing Title 
Timing of Analysis 
16.2.3.2.5 Treatment Emergent Adverse Events Leading to Dose Interruption 
or Dose Reduction of Study Treatment, Safety Set 
ORR, Final 
16.2.3.2.6 Treatment-Emergent Adverse Events Leading to Treatment 
Discontinuation, Safety Set 
IDMC, ORR, Final 
16.2.3.2.7 Treatment Related Treatment-Emergent Adverse Events, Safety Set 
IDMC, ORR, Final 
16.2.3.2.8 Deaths, Safety Set 
ORR, Final 
16.2.3.2.9 Immune-Related Treatment-Emergent Adverse Events, Safety Set 
ORR, Final 
16.2.3.2.9 Significant Treatment-Emergent Adverse Events of Interest, Safety 
Set 
ORR, Final 
16.2.3.3.1 Chemistry (Local), Safety Set 
ORR, Final 
16.2.3.3.2 Coagulation (Local), Safety Set 
ORR, Final 
16.2.3.3.3 Hematology (Local), Safety Set 
ORR, Final 
16.2.3.3.4 Complement (Central) - CH50/C3/C4, Safety Set 
ORR, Final 
16.2.3.3.5 Dipstick Test, Urinalysis (Local) and Microscopic Exam (Local), 
Safety Set 
ORR, Final 
16.2.3.4 Vital Signs, Safety Set 
ORR, Final 
16.2.3.5 ECG Assessments, Safety Set 
ORR, Final 
16.2.3.6 Pharmacokinetics Concentrations, PK Analysis Set 
ORR, Final 
16.2.3.7.1 EORTC QLQ-C30 Assessment Scores Using ePRO, Paper PRO 
and Combined ePRO and Paper PRO Data - Single-Item Measures, Intent 
to Treat Analysis Set 
ORR, Final 
16.2.3.7.2 EORTC QLQ-C30 Assessment Scores Using ePRO, Paper PRO 
and Combined ePRO and Paper PRO Data - Global Health Status/QoL and 
Functional Scale Scores, Intent to Treat Analysis Set 
ORR, Final 
16.2.3.7.3 EORTC QLQ-C30 Assessment Scores Using ePRO, Paper PRO 
and Combined ePRO and Paper PRO Data - Symptom Scales/Items Scores, 
Intent to Treat Analysis Set 
ORR, Final 
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Listing Title 
Timing of Analysis 
16.2.3.8 Anti-drug Antibodies, Safety Set 
IDMC, ORR, Final 
 
Figure Title 
Timing of Analysis 
14.1.1 Forest Plot of Proportion Differences for Objective Response Rate by 
Subgroup, Intent to Treat Analysis Set 
ORR, Final 
14.1.2.1 Swimmer's Plot of Independent Reviewer-Assessed Response by 
RECIST v1.1 for ORR Responders, Intent to Treat Analysis Set 
ORR, Final 
14.1.2.2 Waterfall Plot of Maximum Percent Reduction from Baseline in 
Individual Sum of the Longest Diameters Assessed by Independent Reviewer 
(Target Lesions Only), Intent to Treat Analysis Set 
ORR, Final 
14.1.2.3 Spider Plot of Individual Percent Change from Baseline in Sum of the 
Longest Diameters, Assessed by Independent Reviewer (Target Lesions Only), 
Intent to Treat Analysis Set 
ORR, Final 
14.1.2.4 Swimmer's Plot of Investigator-Assessed Response by RECIST v1.1 
for ORR Responders, Intent to Treat Analysis Set 
ORR, Final 
14.1.2.5 Waterfall Plot of Maximum Percent Reduction from Baseline in 
Individual Sum of the Longest Diameters Assessed by Investigator, Intent to 
Treat Analysis Set 
ORR, Final 
14.1.2.6 Spider Plot of Individual Percent Change from Baseline in Sum of the 
Longest Diameters, Assessed by Investigator, Intent to Treat Analysis Set 
ORR, Final 
14.1.3 Waterfall Plot of Maximum Percent Reduction from Baseline in 
Individual Sum of the Longest Diameters Among Measurable Lesions by 
Injection Status for ORR Responders, Intent to Treat Analysis Set 
ORR, Final 
14.1.4.1 Kaplan-Meier Plot of Independent Reviewer-Assessed DoR by 
RECIST v1.1 for ORR Responders, Intent to Treat Analysis Set 
ORR, Final 
14.1.4.2 Kaplan-Meier Plot of Investigator-Assessed DoR by RECIST v1.1 for 
ORR Responders, Intent to Treat Analysis Set  
ORR, Final 
14.1.5 Kaplan-Meier Plot of Overall Survival, Intent to Treat Analysis Set 
IDMC, Final 
14.1.6 Forest Plot of Hazard Ratios for Overall Survival by Subgroup, Intent to 
Treat Analysis Set 
Final 
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Figure Title 
Timing of Analysis 
14.1.7.1 Kaplan-Meier Plot of Independent Reviewer-Assessed PFS by 
RECIST v1.1, Intent to Treat Analysis Set 
Final 
14.1.7.2 Kaplan-Meier Plot of Investigator-Assessed PFS by RECIST v1.1, 
Intent to Treat Analysis Set 
Final 
14.2.1 Boxplot of Hematology by Visit, Safety Set 
IDMC, ORR, Final 
14.2.2 Boxplot of Chemistry by Visit, Safety Set 
IDMC, ORR, Fianl 
14.2.3 Liver Function Tests Maximum Values to ULN on Study vs Baseline to 
ULN, Safety Set 
ORR, Final 
14.2.4 Mean (+/-SE) Change from Baseline in EORTC QLQ-30 Assessment 
Scores and Sub-Scale by Visit, Intent to Treat Analysis Set 
ORR, Final 
 
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16.3 
CONFIRMATION RESPONSE IN RECIST V1.1 
The following table represents the general algorithm for confirming responses using RECIST 
v1.1. Confirmation of more complex cases, such as an NE from an unscheduled visit between 
two CRs, will be programmed appropriately.  
Overall Response First 
Timepoint 
Overall Response 
Subsequent Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR 
CR 
SD 
SD provided minimum 
criteria for SD duration are 
met at the first timepoint. 
Otherwise PD 
CR 
PD 
SD provided minimum 
criteria for SD duration are 
met at the first timepoint. 
Otherwise PD 
CR 
NE 
SD provided minimum 
criteria for SD duration are 
met at the first timepoint. 
Otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum 
criteria for SD duration are 
met at the first timepoint. 
Otherwise PD 
PR 
NE 
SD provided minimum 
criteria for SD duration are 
met at the first timepoint. 
Otherwise NE 
NE 
NE 
NE 
* In the case of SD, measurements must be assessed at least 12 weeks (or 84 days) from the 
date of randomization.  
[Source: https://recist.eortc.org/]  
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16.4 CENSORING RULE FOR PFS 
The following censoring rules will be used for PFS analysis to be consistent with FDA 
guidance on Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. 
[source: https://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf]  
Situation 
Date of Progression or Censoring 
Outcome 
No baseline tumor assessments Randomization 
Censored 
Progression documented 
between scheduled visits 
Earliest of:  
• Dates of target lesion scans when the 
target lesion response is PD; 
or  
• Dates of non-target scans at which the 
non-target lesion status is unequivocal 
progression; 
or 
• Dates of scans documenting new lesion 
(if progression is based on new lesion)  
Event 
No progression 
Date of the last valid disease assessment, 
defined as a scheduled or unscheduled visit 
with a disease assessment of CR, PR, or SD 
Censored 
Treatment discontinuation for 
undocumented progression 
Date of the last valid disease assessment, 
defined as a scheduled or unscheduled visit 
with a disease assessment of CR, PR, or SD 
Censored 
Treatment discontinuation for 
other reasons 
Date of the last valid disease assessment, 
defined as a scheduled or unscheduled visit 
with a disease assessment of CR, PR, or SD 
Censored 
New anticancer treatment 
started 
Date of the last valid disease assessment, 
defined as a scheduled or unscheduled visit 
with a disease assessment of CR, PR, or SD, 
prior to new anticancer treatment started 
Censored 
Death without documented 
progression and is not after 
two or more missed visits 
Date of death 
Event 
Death or progression after two 
or more missed visits 
Date of the last valid disease assessment, 
defined as a scheduled or unscheduled visit 
with a disease assessment of CR, PR, or SD 
Censored 
 
 
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16.5 
CTCAE GRADES FOR LABORATORY TESTS 
The following criteria will be used for laboratory shift in CTCAE tables.  
CTCAE v4.03 Term 
Lab 
Parameters 
Direction 
Grade 1    
Grade 2    
Grade 3    
Grade 4    
Hypoalbuminemia 
ALB 
hypo 
<LLN - 3 g/dL; <LLN - 30 g/L 
<3 - 2 g/dL; <30 - 20 g/L 
<2 g/dL; <20 g/L 
Life-threatening consequences; 
urgent intervention indicated 
Alkaline phosphatase increased 
ALP 
hyper 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Alanine aminotransferase increased 
ALT 
hyper 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Aspartate aminotransferase increased 
AST 
hyper 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Blood bilirubin increased 
BILI 
hyper 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
Cholesterol high 
CHOL 
hyper 
>ULN - 300 mg/dL; >ULN - 7.75 
mmol/L 
>300 - 400 mg/dL; >7.75 - 10.34 
mmol/L 
>400 - 500 mg/dL; >10.34 - 12.92 
mmol/L 
>500 mg/dL; >12.92 mmol/L 
Creatinine increased 
CREAT 
hyper 
>1 - 1.5 x baseline; >ULN - 1.5 x 
ULN 
>1.5 - 3.0 x baseline; >1.5 - 3.0 x 
ULN 
>3.0 baseline; >3.0 - 6.0 x ULN 
>6.0 x ULN 
Hyperglycemia 
GLUC 
hyper 
Fasting glucose value >ULN - 
160 mg/dL; Fasting glucose value 
>ULN - 8.9 mmol/L 
Fasting glucose value >160 - 250 
mg/dL; Fasting glucose value 
>8.9 - 13.9 mmol/L 
>250 - 500 mg/dL; >13.9 - 27.8 
mmol/L; hospitalization indicated 
>500 mg/dL; >27.8 mmol/L; 
life-threatening consequences 
Hypoglycemia 
GLUC 
hypo 
<LLN - 55 mg/dL; <LLN - 3.0 
mmol/L 
<55 - 40 mg/dL; <3.0 - 2.2 
mmol/L 
<40 - 30 mg/dL; <2.2 - 1.7 
mmol/L 
<30 mg/dL; <1.7 mmol/L; life-
threatening consequences; 
seizures 
Hemoglobin increased 
HGB 
hyper 
Increase in >0 - 2 gm/dL above 
ULN or above baseline if baseline 
is above ULN 
Increase in >2 - 4 gm/dL above 
ULN or above baseline if baseline 
is above ULN 
Increase in >4 gm/dL above ULN 
or above baseline if baseline is 
above ULN 
 - 
Anemia 
HGB 
hypo 
Hemoglobin (Hgb) <LLN - 10.0 
g/dL; <LLN - 6.2 mmol/L; <LLN 
- 100 g/L 
Hgb <10.0 - 8.0 g/dL; <6.2 - 4.9 
mmol/L;  <100 - 80g/L 
Hgb <8.0 g/dL; <4.9 mmol/L; <80 
g/L; transfusion indicated 
Life-threatening consequences; 
urgent intervention indicated 
Hyperkalemia 
K 
hyper 
>ULN - 5.5 mmol/L 
>5.5 - 6.0 mmol/L 
>6.0 - 7.0 mmol/L; hospitalization 
indicated 
>7.0 mmol/L; life-threatening 
consequences 
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CTCAE v4.03 Term 
Lab 
Parameters 
Direction 
Grade 1    
Grade 2    
Grade 3    
Grade 4    
Hypokalemia 
K 
hypo 
<LLN - 3.0 mmol/L 
<LLN - 3.0 mmol/L; 
symptomatic; intervention 
indicated 
<3.0 - 2.5 mmol/L; hospitalization 
indicated 
<2.5 mmol/L; life-threatening 
consequences 
Lymphocyte count increased 
LYM 
hyper 
 - 
>4000/mm3 - 20,000/mm3 
>20,000/mm3 
 - 
Lymphocyte count decreased 
LYM 
hypo 
<LLN - 800/mm3;  <LLN - 0.8 x 
10e9/L 
<800 - 500/mm3; <0.8 - 0.5 x 
10e9 /L 
<500 - 200/mm3; <0.5 - 0.2 x 
10e9 /L 
<200/mm3; <0.2 x 10e9 /L 
Neutrophil count decreased 
NEUT/ANC 
hypo 
<LLN - 1500/mm3; <LLN - 1.5 x 
10e9 /L 
<1500 - 1000/mm3; <1.5 - 1.0 x 
10e9 /L 
<1000 - 500/mm3; <1.0 - 0.5 x 
10e9 /L 
<500/mm3; <0.5 x 10e9 /L 
Hypophosphatemia 
PHOS 
hypo 
<LLN - 2.5 mg/dL; <LLN - 0.8 
mmol/L 
<2.5 - 2.0 mg/dL; <0.8 - 0.6 
mmol/L 
<2.0 - 1.0 mg/dL; <0.6 - 0.3 
mmol/L 
<1.0 mg/dL; <0.3 mmol/L; life-
threatening consequences 
Platelet count decreased 
PLAT 
hypo 
<LLN - 75,000/mm3; <LLN - 
75.0 x 10e9 /L 
<75,000 - 50,000/mm3; <75.0 - 
50.0 x 10e9 /L 
<50,000 - 25,000/mm3; <50.0 - 
25.0 x 10e9 /L 
<25,000/mm3; <25.0 x 10e9 /L 
Hypernatremia 
SODIUM 
hyper 
>ULN - 150 mmol/L 
>150 - 155 mmol/L 
>155 - 160 mmol/L; 
hospitalization indicated 
>160 mmol/L; life-threatening 
consequences 
Hyponatremia 
SODIUM 
hypo 
<LLN - 130 mmol/L 
 - 
<130 - 120 mmol/L 
<120 mmol/L; life-threatening 
consequences 
Hypertriglyceridemia 
TRIG 
hyper 
150 mg/dL - 300 mg/dL; 1.71 
mmol/L - 3.42 mmol/L 
>300 mg/dL - 500 mg/dL;  >3.42 
mmol/L - 5.7 mmol/L 
>500 mg/dL - 1000 mg/dL;  >5.7 
mmol/L - 11.4 mmol/L 
>1000 mg/dL; >11.4 mmol/L;  
life-threatening consequences 
White blood cell decreased 
WBC 
hypo 
<LLN - 3000/mm3; <LLN - 3.0 x 
10e9 /L 
<3000 - 2000/mm3; <3.0 - 2.0 x 
10e9 /L 
<2000 - 1000/mm3; <2.0 - 1.0 x 
10e9 /L 
<1000/mm3; <1.0 x 10e9 /L 
The table above is extracted from CTCAE v4.03, obtained from NIH website  
[Source: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm].   
 
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