Conditions: Metastatic Melanoma
Keywords: ILLUMINATE- 204 IMO-2125 tilsotolimod
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 53
Healthy volunteers: no

Brief summary:
The goal of the Phase 1 study was to find the recommended Phase 2 dose of the study drug IMO-2125 (tilsotolimod) that can be given in combination with ipilimumab (ipi) or pembrolizumab (pembro) to participants with metastatic melanoma and assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity when administered in combination with ipilimumab or pembrolizumab.

Detailed description:
The open-label single-arm Phase 2 study was designed to assess the recommended dose for safety, tolerability, pharmacokinetics (PK), immunogenicity, and efficacy of 8 mg IMO-2125 (tilsotolimod) when administered in combination with ipilimumab.

Arms:
arm 1: IMO-2125 intratumoral injection plus ipilimumab

Interventions: intervention 1: IMO-2125 intervention 2: Ipilimumab
Intervention descriptions: intervention 1: Drug: IMO-2125 Intratumoral injection administered as 9 doses on Weeks 1, 2, 3, 5, 8, 11, 17, 23, and 29. intervention 2: 4 doses administered intravenously at a dose of 3 mg/kg over 90 minutes on Weeks 2, 5, 8, and 11.

Protocol document:
Prot_000.pdf: 
IMO-2125 
Page 1 of 106 
Protocol 2125-204, Version 8.0 
Date: 27 March 2018 
Confidential 
PROTOCOL 2125-204 
Study Title 
A Phase 1/2 Study to Assess the Safety and Efficacy of 
Intratumoral IMO-2125 in Combination with Ipilimumab or 
Pembrolizumab in Patients with Metastatic Melanoma 
Investigational Drug: 
IMO-2125 
IND Number: 
125515 
EudraCT Number 
2017-003329-14 
Sponsor: 
Idera Pharmaceuticals, Inc. 
505 Eagleview Blvd., Suite 212 
Exton, PA 19341 
and 
167 Sidney Street 
Cambridge, MA 02139 
Protocol Number: 
2125-204 
Protocol Version: 
8.0 
Date: 
27 March 2018 
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 patients with informed consent forms, as required by government and 
International Council for Harmonisation regulations. I further agree to report to Idera 
Pharmaceuticals, Inc. any adverse experiences in accordance with the terms of this protocol and 
FDA (or applicable regulatory agency) regulations. 
 
 
Principal Investigator Name (print) 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 


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Version History 
Ver. No.  Approval Date 
Comment 
1.0 
23 June 2015 
Initial submission 
2.0 
08 September 2015 
Revisions based on Food and Drug Administration review and MD Anderson 
Cancer Center Clinical Research Committee review 
3.0 
11 January 2016 
Revisions made in order to align patient management with the labeled safety 
guidance for ipilimumab (Yervoy®, USPI) and current pivotal study designs for 
other agents in metastatic melanoma, as well as administrative updates and 
updates for clarity. 
4.0 
10 May 2016 
Revisions made to include IMO-2125 + pembrolizumab (Keytruda®, USPI) as a 
new treatment arm and to modify the secondary and exploratory 
objectives/endpoints Additional clarity around the rationale for study design and 
administrative changes have also been provided.  
5.0 
30 November 2016 
• Removed Phase 2 randomization and the concurrent start of the two Phase 2 
treatment arms to expedite the initiation of the Phase 2 ipilimumab + 
IMO-2125 treatment arm.  
• Allowed enrollment of additional Phase 1 cohorts at previously studied doses 
of IMO-2125 to facilitate selection of the RP2D(s).  
• In Phase 2, switched from irRC to irRECIST for objective response 
assessments. 
• Modification to enrollment criteria to provide a more homogeneous population 
for the primary efficacy analysis.  
• Added optional tumor biopsy at Week 1. 
6.0 
29 March  2017 
• Extended the IMO-2125 treatment period to 9 doses to further evaluate the 
safety and clinical effects of IMO-2125 in patients with metastatic melanoma. 
Delayed responses to treatment (>12 weeks after the start of treatment) have 
been noted in advanced melanoma patients treated with immunotherapy agents 
(Wolchok, 2009). To further evaluate safety and potential clinical responses to 
treatment with IMO-2125, Protocol Amendment 2125-204 Version 6.0 
extends the IMO-2125 treatment period. 
• Updated PK schedule. 
• 
Introduced the possible addition of cohorts for new immunotherapy 
combinations. Immunotherapy for the treatment of metastatic melanoma is a 
rapidly advancing field. There are new immunotherapy agents currently under 
investigation with some recently approved for marketed use. To expand the 
potential options for IMO-2125 development, the Sponsor may enroll patients 
in additional Phase 1 cohorts to investigate IMO-2125 in combination with 
other immunotherapies. 
• Corrections to irRC response assessments in Appendix 2 (Section 21.2). 


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7.0 
01 September 2017 
• Allows for enrollment of patients who have received prior ipilimumab, 
(including the ipilimumab/PD-1 inhibitor combination) now that preliminary 
safety and efficacy objectives have been achieved in the more restricted 
ipilimumab-naïve population 
• Increases the cohort size for the Phase 2 IMO-2125 + ipilimumab to improve 
the precision of the ORR estimate in the primary efficacy population. 
• Updates pembrolizumab dosing to use the 200 mg fixed dose to be consistent 
with the current labeling as of July 2017. 
• Updates the list for selection priority of the injected tumors. 
• Updates Section 9.2.1 to include an optional biopsy of the non-injected lesion 
at Week 2. 
• Clarifies that the concomitant medications reporting period starts at 30 days 
before the patient signs consent (Section 10.7.1). 
• Adds disease control rate (DCR) endpoint. 
• Clarifies that the assessment of exploratory endpoints will be based on 
assessments at Week 23 not Week 29. 
• Correction to the type of two-stage design for Phase 2 in the Synopsis and 
Section 16. 
• Additional updates in Section 16 (Statistical Analysis Methods) corresponding 
with the other updates. 
8.0 
27 March 2018 
• Update Idera Medical Monitor contact. 
• Change response criteria used in the primary efficacy endpoint in the Phase 2 
portion of the trial. 
• Add patient reported outcomes (PRO) assessments and corresponding 
statistical analysis text. 
• Inclusion of liquid-fill presentation of IMO-2125 as an option for use in the 
study. 
• Clarify post-treatment contraception use. 
• Clarify PK and cytokine sampling schedules. Please note the additional 
cytokine sample times on Day 1, 4 hours post-dose and pre-dose on Cycle 1 
Week 2, to better characterize the IMO-2125 activity. 
• Add descriptions of immune-related AEs to be evaluated by Sponsor. 
• Allow Idera to collect scans for potential central independent review. 
 
 


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EMERGENCY CONTACT INFORMATION 
 
Reporting of Serious Adverse Events (SAEs) 
 
Any SAE must be entered in the Medidata RAVE Electronic Data Capture (EDC) system within 
24 hours. 
If the EDC system is not accessible, SAEs must then be captured on the back-up paper SAE form 
and reported by fax within 24 hours to:  
CRO: SynteractHCR, Inc. 
Fax: 760-268-6500 
Phone:  760-268-8200 
Email: safetyfax@synteracthcr.com 
 
See Section 11.1 (Adverse Events) for definition and reporting procedure for SAEs. 
 
 
Sponsor Medical Monitor: 
Shah Rahimian, MD 
Sr. Medical Director, Medical Lead (Oncology) 
Phone: 484-348-1642 
Cell: 814-691-7377 
Email: srahimian@iderapharma.com 


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1. 
SYNOPSIS 
Name of Sponsor/Company: Idera Pharmaceuticals, Inc. 
Name of Investigational Product: IMO-2125  
Title of Study: A Phase 1/2 Study to Assess the Safety and Efficacy of Intratumoral IMO-2125 
in Combination with Ipilimumab or Pembrolizumab in Patients with Metastatic Melanoma 
Study period: End of study will be approximately 1 year after 
the last patient in Phase 2 has commenced study treatment. 
Phase of development: 
Phase 1/2 
Rationale: IMO-2125 is a synthetic phosphorothioate oligonucleotide that acts as a direct 
agonist of Toll-like receptor (TLR) 9, stimulates both the innate and adaptive immune systems, 
and induces the expression of an array of endogenous cytokines and chemokines, including 
interleukin (IL)-1β, IL-6, IL-12, interferon (IFN)-α, IFN-γ, interferon gamma-induced protein 
(IP)-10, tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein-1 (MCP-1). Of 
note, activation of TLR9 by IMO-2125 induces high levels of IFN-α from plasmacytoid dendritic 
cells (pDCs). This extensive profile of cytokines and chemokines results in the activation of both 
innate and adaptive immunity. Local innate immune activation through IMO-2125, administered 
by intratumoral injection may lead to enhanced induction and infiltration of tumor-specific CD8+ 
T cells and synergize with systemic therapies based on cytotoxic T lymphocyte antigen-4 
(CTLA-4)/programmed cell death-1 (PD-1) blockade, resulting in superior anti-melanoma 
activity. Ipilimumab is a monoclonal antibody that binds to CTLA-4 and is used in the treatment 
of metastatic melanoma that cannot be treated surgically. Pembrolizumab is a PD-1-blocking 
antibody indicated for the treatment of patients with unresectable or metastatic melanoma. In 
combination, IMO-2125 with either ipilimumab or pembrolizumab may offer a novel therapy to 
benefit patients with metastatic melanoma. 
Objectives:  
Primary: The primary objective of Phase 1 is to characterize the safety and determine a 
recommended Phase 2 dose (RP2D) of IMO-2125 when administered in combination with 
ipilimumab or when administered in combination with pembrolizumab in patients with 
metastatic melanoma. The maximum tolerated dose (MTD) and RP2D for IMO-2125 may differ 
between the combination of IMO-2125 and ipilimumab and the combination of IMO-2125 and 
pembrolizumab.  
The primary objective of Phase 2 is to assess preliminary clinical activity of IMO-2125 in 
combination with ipilimumab or in combination with pembrolizumab at the respective RP2D(s) 
in patients with metastatic melanoma that is not responsive to PD-1 inhibitor therapy, using 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 
Secondary: The secondary objectives of Phase 1 are to determine the plasma pharmacokinetics 
(PK) of single-dose IMO-2125 and repeat-dose IMO-2125 administered by intratumoral 
injection in combination with ipilimumab or pembrolizumab. An additional secondary objective 
of Phase 1 is to describe any preliminary antitumor activity.  
The secondary objectives of Phase 2 are to further assess the safety and tolerability of 
IMO-2125 in combination with ipilimumab or in combination with pembrolizumab in patients 
with metastatic melanoma and to assess treatment response using immune-related Response 


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Evaluation Criteria in Solid Tumors (irRECIST) and RECIST v1.1, overall survival (OS), OS at 
6 and 12 months, progression-free survival (PFS), PFS at 6 and 12 months, durable response rate 
(DRR), duration of response (DoR), and disease control rate (DCR). 
Exploratory: The exploratory objectives of Phase 1 and 2 are to assess patient reported 
outcomes (PRO), pre- and post-treatment blood biomarkers, pre- and post-treatment tumor 
biopsies for immunologic assessment, and explore any potential association between these 
biomarker measures and antitumor activity. In addition, anti-IMO-2125, anti-ipilimumab, and 
anti-pembrolizumab antibody formation will be assessed. 
Endpoints 
Primary: The primary endpoint of Phase 1 is to characterize the safety of IMO-2125 when 
administered in combination with ipilimumab or when administered in combination with 
pembrolizumab.  
The primary endpoint in Phase 2 is clinical activity, defined as objective response as assessed by 
the Investigator using RECIST v1.1.  
Secondary:  
The secondary endpoints in Phase 1 are: 
• PK assessments for IMO-2125; 
• ORR assessed using irRC and RECIST v1.1 
The secondary endpoints in Phase 2 include:  
• Safety and tolerability (type and frequency of AEs, clinical laboratory values, 
electrocardiograms [ECGs], and vital sign measurements) for each combination; 
• Duration of response using RECIST v1.1; 
• ORR and duration of response using irRECIST;  
• PFS, defined as time from the initiation of treatment to disease progression by 
irRECIST and RECIST v1.1, or death from any cause; 
• PFS at 6 and 12 months;  
• OS, defined as time from initiation of treatment to death from any cause;  
• OS at 6 and 12 months; 
• Durable response rate by irRECIST and RECIST v1.1, defined as the rate of complete 
response (CR) plus partial response (PR) lasting at least 180 days continuously and 
beginning within the first 12 months of study; 
• Disease control rate by irRECIST and RECIST v1.1, defined as the rate of CR, PR, or 
stable disease (SD).  
Exploratory: The pre- and post-treatment exploratory endpoints of Phase 1 and 2 include, but 
are not limited to, PRO using the European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire-CORE 30 (EORTC QLQ-C30), blood biomarkers (e.g., IFN-γ and 
other plasma cytokines) and tumor markers to assess any potential association between immune 
responses to IMO-2125 at the Week 8 tumor biopsy with tumor response in both injected and 


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uninjected tumor lesions at Week 13 or at Week 23 (depending on the protocol version under 
which the patients were enrolled). 
Study design: This is a two arm, open-label Phase 1/2 study to assess the safety, tolerability, PK, 
immunogenicity, and efficacy of IMO-2125 when administered in combination with ipilimumab 
or in combination with pembrolizumab. Patients with metastatic melanoma who have 
experienced symptomatic or confirmed radiographic progression during or after treatment with 
an anti-PD-(L)1 agent (alone or in combination) will be eligible. Prior BRAF or MEK inhibitor 
treatment is not required. The study will be conducted in two parts: a dose-escalation portion 
(Phase 1) to evaluate safety and tolerability of multiple dose levels and a Phase 2 portion to 
assess preliminary efficacy.  
Phase 1: The Phase 1 portion of the study will explore escalating dose levels of IMO-2125 (from 
4 to 32 mg with de-escalation to 2 mg allowed for each IMO-2125 combination). For each 
cohort, IMO-2125 will be administered as a once-weekly intratumoral injection for 3 consecutive 
weeks in Cycle 1, followed by intratumoral injections on Weeks 5, 8, 11, 17, 23, and 29 (Day 1 
of Cycles 2 through 7). Both ipilimumab and pembrolizumab will be administered as per the 
USPI every 3 weeks beginning Day 1 of Cycle 1 Week 2. Continued pembrolizumab dosing 
following the study period is permitted at the discretion of the Investigator for patients in the 
IMO-2125 + pembrolizumab treatment arm. The dosing schedule is summarized for Phase 1 and 
Phase 2 in the table below. 
Schedule of dosing for Phase 1 and Phase 2 
 
Cycle 
 
1 
2 
3 
4 
5 
6 
7 
Study week 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 
11 
12 
13 
17 
23 
29 
IMO-2125 + ipilimumab 
IMO-2125 
X X X 
- 
X 
- 
- 
X - 
- 
X 
- 
- 
X 
X 
X 
Ipilimumab 
- 
X 
- 
- 
X 
- 
- 
X - 
- 
X 
- 
- 
- 
- 
- 
IMO-2125 + pembrolizumab 
IMO-2125 
X X X 
- 
X 
- 
- 
X - 
- 
X 
- 
- 
X 
X 
X 
Pembrolizumab 
- 
X 
- 
- 
X 
- 
- 
X - 
- 
X  
X1 
Note: On weeks when the combinations are administered, administration of ipilimumab or pembrolizumab will be 
first, followed by IMO-2125. IMO-2125 administration must occur within a ±2 day window of the scheduled dosing 
day.  
1  For patients in the IMO-2125 + pembrolizumab treatment arm, continued pembrolizumab dosing per the approved 
product label is permitted at the discretion of the Investigator. 
 
Patients assigned to 11 weeks of IMO-2125 under previous versions of the protocol who have 
not yet reached the end of the Treatment Period may receive the Week 17, 23, and 29 injections 
at the discretion of the treating Investigator.  
Each cohort will be monitored for the occurrence of dose-limiting toxicities (DLTs). The 
DLT evaluation period will be Cycle 1 (Weeks 1 through 4). If a patient discontinues study 
participation before the DLT evaluation period is finished due to reasons other than experiencing 
a DLT, that patient must be replaced so that the cohort may be properly evaluated.  
There are 3 patients planned per cohort. During Phase 1, the Sponsor will assign patients to a 


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treatment arm (IMO-2125 + ipilimumab or IMO-2125 + pembrolizumab) by cohort. The 
Sponsor will maintain a prioritization schedule for cohort assignment in a separate document. A 
Cohort Review Committee (CRC) will be convened prior to each dose level escalation to review 
the available data and provide recommendations on study conduct. After completing the DLT 
evaluations for all planned IMO-2125 doses in either combination, supplemental cohorts of up to 
5 patients each may be enrolled with either combination at doses up to and including the MTD. 
CRC review is not required for initiation of these supplemental cohorts but safety review 
meetings will still take place monthly throughout Phase 1 of the study. After completion of either 
Phase 1 treatment arm and determination of the RP2D for that arm, the Phase 2 portion for the 
completed treatment arm may be initiated. It is not necessary for Phase 1 to be completed in both 
treatment arms before Phase 2 is started. After Phase 2 in either treatment arm is initiated, the 
Sponsor will assign the treatment arm, cohort, and phase for patients. 
Dose-limiting toxicity evaluations and CRC reviews for any additional immunotherapy 
combination cohorts will be done as described for the ipilimumab and pembrolizumab 
combinations. 
Phase 2: The Phase 2 portion of the study will assess preliminary efficacy, using 
investigator-assessed RECIST v1.1, of IMO-2125 + ipilimumab, IMO-2125 + pembrolizumab, 
and any additional combinations that are studied in Phase 1. The dose level of IMO-2125 to be 
administered for each treatment arm will be the RP2D for the combination, as determined in 
Phase 1.  
Phase 2 will enroll at least 60 patients treated at the IMO-2125 + ipilimumab RP2D. This will 
include at least 21 patients in the primary IMO-2125 + ipilimumab efficacy-evaluable population 
and up to 20 patients in the secondary IMO-2125 + ipilimumab efficacy-evaluable population. 
In the IMO-2125 + pembrolizumab Phase 2 cohort, enrollment will continue until 21 patients in 
the IMO-2125 + pembrolizumab efficacy-evaluable population have been treated at the 
IMO-2125 + pembrolizumab RP2D.  
Phase 1 patients treated at RP2D for either combination will contribute to these totals. A 
two-stage design will be used to test for clinically and statistically relevant clinical activity. A 
treatment arm will stop if an interim futility analysis shows there is insufficient evidence of a 
clinically relevant response rate after 10 patients (Stage 1). 
If a patient discontinues treatment before completing at least one efficacy evaluation for reasons 
other than toxicity, then that patient will be replaced, with the replacement assigned to the same 
treatment arm and dose level as the patient who dropped out early. 
Combination therapy in Phase 2 will continue using the same schedule as Phase 1, as presented 
in the schedule of dosing table. 
Assessments will be conducted as defined in the Schedule of Evaluations (Table 1 and Table 2). 
Number of patients (planned): The study will enroll approximately 90 to 100 patients. It is 
estimated that approximately 30 patients will be treated in the dose-finding portion of Phase 1 
and approximately 60 to 70 additional patients will be treated in the Phase 2 portion of the study. 


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Diagnosis and main criteria for inclusion and exclusion:   
These criteria apply to both the Phase 1 dose-escalation portion and the Phase 2 portion of this 
study. 
Inclusion criteria 
1) Patients must have histologically confirmed metastatic melanoma with measurable, 
stage III (lymph node or in transit lesions) or stage IVA, IVB, or IVC disease. 
2) Patients must have symptomatic or radiographic progression during or after treatment 
with a PD-(L)1 inhibitor administered either as monotherapy or in combination.  
a. The interval between last PD-(L)1 directed treatment and start of study treatment 
should be at least 21 days. 
b. Prior BRAF or MEK inhibitor treatment is not required. However, for patients 
with known BRAF status: 
i. Those with BRAF wild type may have had a maximum of two previous 
systemic regimens for the treatment of melanoma.  
ii. Those with a BRAF mutation may have had a maximum of three previous 
systemic regimens for the treatment of melanoma. 
c. Prior ipilimumab is permitted. 
d. Previous treatment with either a PD-1 inhibitor (for patients enrolling on the 
IMO-2125 + pembrolizumab combination) or CTLA-4 inhibitor (for patients 
enrolling on the IMO-2125 + ipilimumab combination) should not have been 
accompanied by DLT for which permanent discontinuation is recommended (per 
USPI).  
i. Patients with a history of Grade ≥2 gastrointestinal symptoms 
(e.g., diarrhea, colitis) during prior checkpoint inhibitor treatment should 
be discussed with the Idera Medical Monitor during the Screening Period 
before starting study treatment. 
3) Phase 1 patients must have at least two measurable tumor lesions ≥ 1.0 cm that are 
accessible to biopsy. Phase 2 patients must have at least one measurable lesion (per 
RECIST v1.1) which may be the same site that is used for the intratumoral injections. 
4) Patients must be ≥18 years of age. 
5) Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status 
≤2. 
6) Patients must meet the following laboratory criteria: 
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 
e. Aspartate aminotransferase (AST) ≤2.5 x ULN; alanine aminotransferase (ALT) 
≤2.5 x ULN; AST/ALT <5 x ULN if liver involvement 
f. Serum bilirubin ≤1.5 x ULN, except in patients with Gilbert’s Syndrome who 
must have a total bilirubin <3 mg/dL 


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7) Women of childbearing potential (WOCBP) and men must agree to use effective 
contraceptive methods from Screening throughout the study treatment period and until at 
least 90 days after the last dose of IMO-2125, 3 months after the last dose of ipilimumab, 
or at least 4 months after the last dose of pembrolizumab. 
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 patient. 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™)  
e. 
An intra-uterine device (IUD) 
8) WOCBP must have a negative pregnancy test (serum or urine) prior to the first dose of 
study treatment. 
9) Patients must be willing and able to sign the informed consent and comply with the study 
protocol. 
10) Patients must have an anticipated life expectancy >3 months. 
Exclusion criteria 
1) Patients who have received prior therapy with a TLR agonist, excluding topical agents. 
Patients who have received experimental vaccines or other investigational immune 
therapies should be discussed with the Medical Monitor to confirm eligibility. 
2) Patients who have received systemic treatment with IFN-α within the previous 6 months 
prior to enrolling into this study. 
3) Patients with known hypersensitivity to any oligodeoxynucleotide. 
4) Patients with active autoimmune disease requiring disease-modifying therapy. 
5) Patients requiring concurrent systemic steroid therapy higher than physiologic dose 
(7.5 mg/day of prednisone). 
6) Patients with any form of active primary or secondary immunodeficiency. 
7) Patients with another primary malignancy that has not been in remission for at least 
3 years. The following are exempt from the 3 year limit: 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). 
8) Patients with active systemic infections requiring antibiotics or active hepatitis A, B, 
or C. 


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9) Patients who are hepatitis B surface antigen positive. 
10) Patients with a known diagnosis of human immunodeficiency virus (HIV) infection. 
11) WOCBP who are pregnant or breast-feeding. 
12) Patients who have had prior anaphylactic or other severe infusion reaction associated 
with human antibody administration. 
13) Patients with known central nervous system, meningeal, or epidural disease. Patients with 
stable brain metastases following definitive local treatment are eligible if steroid 
requirement is less than 7.5 mg/day of prednisone (or equivalent). 
14) Patients with impaired cardiac function or clinically significant cardiac disease such as: 
a. New York Heart Association Class III or IV cardiac disease, including preexisting 
clinically significant ventricular arrhythmia, congestive heart failure, or 
cardiomyopathy 
b. Unstable angina pectoris ≤6 months prior to study participation 
c. Acute myocardial infarction ≤6 months prior to study participation 
d. Other clinically significant heart disease (i.e., Grade ≥3 hypertension, history of 
labile hypertension, or poor compliance with an anti-hypertensive regimen) 
15) Ocular melanoma. 
Investigational product, dosage, and mode of administration:  
In Phase 1, the starting dose of IMO-2125 will be 4 mg (Dose Level +1) for the ipilimumab 
combination, and 8 mg (Dose Level +2) for the pembrolizumab combination (with de-escalation 
to 2 mg allowed for each combination). IMO-2125 dose level escalation or de-escalation for each 
combination will be done independently of the other combinations, as appropriate, when the 
respective targets are functionally distinct.  
IMO-2125 will be administered by intratumoral injection for all doses and ipilimumab or 
pembrolizumab will be administered per the labeled guidance using commercial supplies. 
Administration of ipilimumab or pembrolizumab will precede IMO-2125 when administered in 
the same week; IMO-2125 dosing must occur on the scheduled dosing day (±2 day window). 
Note that tumor biopsies should be done prior to study treatment administration. If a full dose 
can no longer be practically administered into the designated tumor for injection, another tumor 
may be selected. In the event that complete tumor regression occurs in all accessible lesions prior 
to completion of therapy, any remaining IMO-2125 doses should be administered into the tumor 
bed, except in the case of visceral lesions where remaining doses should be given s.c. to 
minimize procedural risks.  
Dose escalation: Up to five dose levels for IMO-2125 are initially planned (as shown in the table 
below).  
Dose Level 
IMO-2125 
Ipilimumab 
Pembrolizumab 
-1 
2 mg 
3 mg/kg 
200 mg 
+1 
4 mg 
3 mg/kg 
200 mg 
+2 
8 mg 
3 mg/kg 
200 mg 
+3 
16 mg 
3 mg/kg 
200 mg 
+4 
32 mg 
3 mg/kg 
200 mg 
 


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In Phase 1, the study will enroll patients in planned cohorts of 3, beginning at Dose Level +1 for 
the ipilimumab treatment arm and beginning at Dose Level +2 for the pembrolizumab treatment 
arm once safety of the IMO-2125 + ipilimumab combination has been established for that level. 
A charter will be used to guide the CRC’s decision-making.  
Additionally, if, due to observed toxicity, it proves difficult to provide IMO-2125 for 
3 consecutive weeks in Cycle 1, the decision may be taken by the CRC to add cohorts where 
alternative schedules of IMO-2125 administration will be explored.  
The MTD will be determined from the assessment of DLTs during the first treatment cycle of 
each cohort. Using a prior beta(1,1) distribution of the DLT rate δ i for each dose level i, the 
MTD is defined as the highest dose level for which the mean of the posterior distribution of 
toxicity is closest to but less than 25% among all the evaluated doses i for which 
Pr (δ i > 0.25 | data) <0.80. 
The RP2D(s) will be selected from dose level(s) at or below the MTD. Additional dose levels 
may be studied if the MTD(s) have not been reached and pharmacodynamic activity is deemed to 
be inadequate. At the time of completion of the Phase 1 portion of the study, an analysis of the 
data will be performed.  
Assuming a prior beta(0.6, 1.4) distribution for the overall toxicity rate for a treatment, a Phase 2 
arm will terminate if the Pr (δt > 0.25 | data) >0.80, where δt is the DLT rate attributable to the 
treatment. 
Dose-limiting toxicities: Toxicity will be evaluated according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 toxicity criteria. 
Dose-limiting toxicities are defined in Section 8.1.5 and should be referenced throughout the 
Phase 1 and 2 portions of the study. The DLT evaluation period will be Cycle 1 (Weeks 1 
through 4).  
For the purposes of dose level escalation and determination of the MTD(s), only DLTs (as 
defined below) that occur during the first cycle of treatment will be considered in the decisions 
regarding dose level escalation; however, DLTs or other clinically significant toxicities that 
occur throughout the observation period will be considered when determining the RP2D(s) for 
use in this trial and in subsequent clinical trials. 
During Cycle 1 of the dose escalation portion, if two of the three patients in a cohort experience 
the same Grade 2, treatment-related AE, then subsequent increases in dose level will proceed in 
increments less than 100%. If more than one cohort is treated at the same dose level and greater 
than 67% of patients treated at that dose level experience the same Grade 2 treatment-related AE, 
dose level escalation will proceed in increments less than 100% (see table of planned dose level 
escalation above). In such a case, specific dose level increments will be decided by the CRC. 
Protocol-defined hematologic DLTs include: 
• CTCAE Grade 4 neutropenia ≥7 days; 
• CTCAE Grade 3 or 4 neutropenia with fever ≥38.5°C; 
• CTCAE Grade 3 thrombocytopenia with bleeding; 
• CTCAE Grade 4 thrombocytopenia ≥7 days. 


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Protocol-defined non-hematologic DLTs include: 
• Grade ≥3 vomiting or nausea ≥ 14 days despite the use of optimal anti-emetic 
treatments; 
• Grade ≥3 diarrhea ≥14 days despite the use of optimal anti-diarrheal treatments which 
should include infliximab as per institutional guidelines; 
• Serum creatinine >3.0 x ULN; 
• AST or ALT >5 x ULN; in patients with liver metastasis who entered the study with 
Grade 2 elevation of AST or ALT, an AST or ALT increase ≥ 50% relative to baseline 
and lasting ≥1 week; 
• Bilirubin ≥3.0 x ULN; 
• Bilirubin ≥2.0 x ULN with ALT >3 x ULN in patients without liver metastases; 
• Other non-hematologic toxicities of Grade ≥3, except for the following: 
o AEs related to underlying disease; 
o CTCAE Grade 3 fatigue <14 days; 
o Alopecia; 
o Isolated, asymptomatic elevations in biochemistry laboratory values lasting 
≤14 days. This includes electrolyte abnormalities that respond to medical 
intervention. 
Ipilimumab-related DLTs: 
• Grade ≥4 immune-mediated dermatitis (except skin reaction at site of injection); 
• Grade ≥3 immune-mediated endocrinopathy (with the exception of Grade 3 autoimmune 
thyroiditis that resolves to Grade 1 or baseline within 28 days of onset); 
• Grade ≥3 immune-mediated enterocolitis; 
• Grade ≥3 immune-mediated hepatitis with the exception of Grade 3 immune-mediated 
hepatitis that resolves to Grade 1 or baseline within 28 days of onset; 
• Grade ≥3 immune-mediated neuropathy, pancreatitis, meningitis, nephritis, and 
pneumonitis that are considered to be possibly, probably, or definitely related to study 
therapy as determined by the Investigator; 
• Any persistent IMO-2125-related toxicity that leads to a delay of scheduled (per 
standard of care) ipilimumab >14 days. 
Pembrolizumab-related DLTs: 
• Grade ≥3 pneumonitis or recurrent Grade 2 pneumonitis;  
• Grade ≥3 nephritis;  
• Grade ≥3 infusion-related reactions;  
• Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per 
day within 12 weeks; 
• Any Grade ≥3 treatment-related AE that recurs. 
If at any time during the study, a patient experiences a DLT as outlined above, the toxicity in 
question must be assessed for attribution based on the known toxicity profiles for ipilimumab, 
pembrolizumab, and IMO-2125. If assessment can be clearly attributed to one of the drugs in the 


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combination, then dosing should be interrupted and the toxicity should be followed until 
resolution, stabilization, or return to baseline. Treatment with the other agent may continue 
during this time period. If attribution cannot be clearly ascribed to one agent versus the other, 
then both IMO-2125 and ipilimumab (or pembrolizumab) should be stopped and the toxicity 
should be followed until resolution, stabilization, or return to baseline. If treatment is to be 
resumed, then re-initiation criteria must be met. If the DLT was clearly related to IMO-2125 or if 
attribution cannot be clearly determined, then IMO-2125 must be administered at a lower dose 
level (a minimum reduction of at least one dose level). If the DLT recurs after a dose level 
reduction, then treatment should be discontinued.  
Patients who experience a non-laboratory, IMO-2125-related DLT must be evaluated weekly, at 
a minimum, until resolution to Grade ≤1 or baseline and then at least monthly until return to 
baseline or stabilization of the event, whichever comes first. For abnormal laboratory values that 
qualify as DLTs, patients will be followed twice weekly until values return to Grade ≤1 or 
baseline, whichever comes first. 
Criteria for re-initiation of study treatment following occurrence of a DLT are as follows: 
• ANC must be ≥1.5 x 109/L (1500/μL); 
• Platelets must be ≥75 x 109/L (75,000/μL); 
• All clinically significant non-hematologic toxicities for which a causal association to 
study treatment cannot be ruled out must be Grade ≤1 (except alopecia) or returned to 
baseline. 
If the patient does not meet these criteria, dosing will be delayed and the patient should be 
re-evaluated within 48 to 72 hours. If the next cycle is delayed by more than 21 days for toxicity, 
the patient should be removed from study treatment. In these situations, if the patient is 
experiencing clinical benefit and has a favorable risk/benefit profile, study treatment with 
IMO-2125 may be continued if agreed upon by the Sponsor and the Investigator. 
Duration of study: The study treatment period is 29 weeks in the absence of intolerable toxicity 
or unequivocal disease progression. Continued treatment with pembrolizumab following the 
completion of IMO-2125 study treatment is at the discretion of the Investigator for patients in the 
IMO-2125 + pembrolizumab treatment arm.  
The study ends approximately 1 year after the last patient in Phase 2 has commenced study 
treatment. Patients who complete or discontinue study treatment prior to progression will be 
followed for clinical and radiological evidence of progression, PRO assessments, and 
immunogenicity assessments at least every 3 months until documentation of RECIST v1.1 
progressive disease (PD), start of a subsequent anti-cancer treatment regimen, withdrawal of 
consent, death, or Sponsor notification that follow-up is no longer required, whichever comes 
first. Best response to first subsequent therapy, AEs which are Grade ≥3, and concomitant 
medications used to treat these AEs, will also be captured during the follow-up phase of the 
study. 
After documentation of PD or use of a subsequent anti-cancer treatment regimen, all patients will 
be contacted by telephone every 3 months for survival follow-up until the site is notified by the 
Sponsor that survival follow-up is no longer required.  


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Assessments 
Safety: Safety assessments will include a comprehensive evaluation of AEs and/or toxicity based 
on: 
• Results of monitoring vital signs (blood pressure, heart rate, respiratory rate, and body 
temperature); 
• Results of clinical chemistry, hematology/coagulation, complement testing, thyroid 
function testing, and urinalysis tests; 
• ECG results; 
• Changes in physical examination; 
• Need for concomitant medications; 
• ECOG performance status. 
Hematology assessment will include a complete blood count (CBC) with a differential and a 
coagulation profile will include prothrombin time (PT) and activated partial thromboplastin 
time (aPTT). The clinical chemistry panel will include the liver function tests (AST, ALT, and 
serum bilirubin), blood urea nitrogen, complement (total hemolytic complement activity 50 
[CH50], and complement components C3 and C4), and serum creatinine. The urinalysis will 
include urinary protein. 
Pharmacokinetics: The plasma PK of single-dose IMO-2125 and the PK of repeat-dose 
IMO-2125 administered by intratumoral injection in combination with ipilimumab or 
pembrolizumab will be evaluated at each of the dose levels. The following parameters will be 
determined for IMO-2125 plasma PK, if appropriate: 
• Maximum plasma concentration (Cmax); 
• Time of Cmax (tmax); 
• Area under the curve from 0 to last measurable plasma concentration (AUC0-t). 
Serum concentrations of ipilimumab and pembrolizumab will be monitored on Weeks 2, 5, 8, 11, 
17, and 23. For patients who continue pembrolizumab treatment, pembrolizumab pre-dose PK 
samples should be collected before dosing at all visits. A post-dose pembrolizumab PK sample 
should be collected 30 minutes after the initiation of pembrolizumab infusion at Week 23 (if 
administered). 
Efficacy: Efficacy will be evaluated by clinical examination and imaging studies. Treatment 
decisions should be based on patient benefit as assessed by irRC in Phase 1 and by irRECIST in 
Phase 2 rather than RECIST v1.1.  
Exploratory: Exploratory variables will be assessed at pre-treatment and post-treatment and 
may include, but are not limited to: 
• PRO: Periodic assessments will be made using the EORTC-QTQ-C30 
• Biomarkers (CD8+ T cells, natural killer cells, pDC/myeloid DC, memory T cells in 
tumor tissue, T cells, and cytokine levels in blood) 
• Any potential association between these biomarkers and antitumor activity 


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• Gene profiling (with ribonucleic acid [RNA] and deoxyribonucleic [DNA] extraction) 
• Immunogenicity (antibodies to IMO-2125, ipilimumab, and pembrolizumab) 
For Phase 1, biopsies of the injected tumor will be performed at the Screening Visit (within 
21 days prior to first treatment); within 24 to 48 hours after IMO-2125 injection on Week 1 
(Cycle 1); Week 2 (Cycle 1; optional); during Week 8 (Cycle 3); and optionally at Week 13 
(Cycle 4) and at the time of disease progression or during Week 23, whichever is later. Tumor 
biopsies of the designated non-injected lesion will be performed at Screening, prior to the first 
dose of ipilimumab or pembrolizumab (optional), and during Week 8. For Phase 2, tumor 
biopsies are optional at all specified visits. Surgical methods (e.g., punch or core) are preferred 
over Fine Needle Aspiration where feasible. 
Biopsies should be done prior to study treatment administration. For those patients who have 
liver or other visceral metastases injected with IMO-2125, repeat biopsy of liver or other visceral 
tumor lesions may not always be possible. Therefore, repeat biopsies will be performed only 
when feasible in these patients. 
The Week 8 (Cycle 3) and Week 13 (Cycle 4) biopsies may be performed within a ±3 day 
window. If tumor response is observed early during initial treatment, the Week 8 biopsies may 
be performed at an earlier time point so as to ensure meaningful biomarker information is 
obtained prior to complete resolution of tumor. 
Statistical methods: Continuous variables will be summarized using descriptive statistics such 
as mean, standard deviation, median, and range. Categorical variables will be summarized by 
count and proportion, and if specified, with 95% confidence intervals for the proportion. Missing 
data will not be imputed except as described in the Statistical Analysis Plan. 
Data will be analyzed at the end of dose-finding for each treatment. Phase 2 data will be 
analyzed at the end of Phase 2 (approximately 1 year after the last patient in Phase 2 has 
commenced study treatment). 
Efficacy populations will include: 
• Primary Ipilimumab + IMO-2125 Efficacy Evaluable (PIIEE) Population: all patients 
who are ipilimumab-naïve on study entry (including those who received ipilimumab only 
in the adjuvant setting); and who are treated at the RP2D for the IMO-2125 + ipilimumab 
combination, regardless of which phase of the study they receive it; and who received at 
least one dose of each study drug. 
• Secondary Ipilimumab + IMO-2125 Efficacy Evaluable (SIIEE) Population: all patients 
who are not ipilimumab-naïve on study entry; and who are treated at the RP2D for the 
IMO-2125 + ipilimumab combination, regardless of which phase of the study they 
receive it; and who received at least one dose of each study drug. 
• Primary Pembrolizumab + IMO-2125 Efficacy Evaluable (PPIEE) Population: all 
patients who are treated at the RP2D for the IMO-2125 + pembrolizumab combination, 
regardless of which phase of the study they receive it; and who received at least one dose 
of each study drug. 
• Safety Population: all patients who received at least one dose of IMO-2125. 
• DLT Evaluable Population: all patients in the Safety Population who continue 


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participation in the study for the entire DLT evaluation period, or who discontinue 
prematurely due to a DLT. 
• PK Population: All subjects in the Safety Population who have ≥1 post-dose sample 
analyzed for study drug. 
Analysis of Efficacy 
The primary efficacy endpoint, ORR assessed by the Investigator using RECIST v1.1, will be 
analyzed for the first 21 efficacy-evaluable patients in the PIIEE Population using a one-sided, 
one sample exact binomial test with α = 0.025 in each test. The proportion of patients achieving 
an overall response will be tested against the null rates of 0.11 and 0.05 for ipilimumab and 
pembrolizumab, respectively. ORR by RECIST v1.1 will also be summarized descriptively for 
all subjects in the PIIEE. 
The ORR and DCR using irRECIST criteria will be summarized descriptively in the PIIEE, 
SIIEE, and PPIEE Populations by dose with the n, percentage, and exact 95% confidence 
intervals. DCR will also be summarized by RECIST v1.1. 
The OS and PFS proportions will be estimated at 6 and 12 months; OS and PFS will also be 
analyzed overall. For time-to-event endpoints (OS, PFS, and DoR), the Kaplan-Meier method 
will be used to estimate the probability of event-free survival. Patients who have not experienced 
the event at the data cut-off date for study closure will be censored. Patients who are lost to 
follow up will be censored at the last valid disease assessment for PFS and date of last contact 
for OS. Kaplan-Meier plots will be produced for OS and PFS by treatment arm. 
Analysis of Exploratory Endpoints 
Patterns of missing data will be described for PRO. Mean change from Baseline in the global 
health status score over time will be summarized and presented graphically. A mixed model for 
repeated measures may be used to assess the statistical significance of changes from Baseline. 
Exploratory endpoint analyses will be fully described in the statistical analysis plan. 
Determination of Sample Size 
The primary objective of Phase 2 is to assess the preliminary clinical activity, defined as the 
investigator-assessed ORR, of IMO-2125 in combination with ipilimumab or of IMO-2125 in 
combination with pembrolizumab in patients with progression on or following PD-(L)1 inhibitor 
therapy for metastatic melanoma. Given that two primary hypotheses are being tested (regarding 
the ORR of IMO-2125 and ipilimumab and the ORR of IMO-2125 and pembrolizumab), a 
Bonferroni correction has been applied to the alpha to control the Type I error rate for the trial. 
Assuming the ORR for patients who receive ipilimumab alone is at most 11% (the historical 
response rate in patients who are PD-1 inhibitor naïve), and a target ORR of 35% for patients 
who receive IMO-2125 + ipilimumab combination treatment, a sample size of 21 patients would 
achieve 77% power to detect a 24% difference in response rates using a one-sided significance 
level of 2.5%.  
The IMO-2125 + ipilimumab treatment arm will use a two-stage design with a targeted Type I 
error rate of 0.025 to test the null response rate of 0.11 against the alternative of at least 35%. 
With this method, 10 patients will be treated and monitored for a RECIST v1.1 response in the 
first stage. For this arm, if 2 or more patients have a RECIST v1.1 response in Stage 1, then the 


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treatment arm will continue to Stage 2, in which 11 more patients will be treated. If at least 6 of 
the 21 total patients have a RECIST v1.1 response, then the null hypothesis Ho will be rejected in 
favor of the alternative Ha. In this treatment arm, this design has statistical power of 77%, an 
expected sample size of 13.33 under the null hypothesis, and a probability of stopping at the end 
of the first stage of 69.7% if the response proportion is ≤0.11. 
Assuming a RECIST v1.1 ORR for patients who receive pembrolizumab alone following failure 
of a PD-1 inhibitor is at most 5%, and a target ORR of 35% for patients who receive IMO-2125 
+ pembrolizumab combination treatment, a sample size of 21 efficacy-evaluable patients would 
achieve 96% power to detect a 30% difference in response rates using a one-sided significance 
level of 2.5%. 
The IMO-2125 + pembrolizumab treatment arm will use a two-stage design with a targeted 
Type I error rate of 0.025 to test the null response rate against the alternative of at least 35%. If at 
least 1 patient has a RECIST v1.1 response in Stage 1, then the treatment arm will continue to 
Stage 2 and treat 11 additional patients. If at least 4 of the 21 total patients have a RECIST v1.1 
response, then the null hypothesis Ho will be rejected in favor of the alternative Ha. In this 
treatment arm, this design has statistical power of 96%, an expected sample size of 14.41, and a 
probability of stopping at the end of the first stage of 60% if the response proportion is ≤0.05. 
Analysis of PK 
For each cohort, the plasma IMO-2125 concentration data will be analyzed by 
non-compartmental PK analysis. Descriptive statistics will be provided for concentration data 
and all PK assessment values by study drug (IMO-2125, ipilimumab, and pembrolizumab), dose, 
and time, as appropriate. 
Dose proportionality using the power model will be evaluated in an exploratory manner, if the 
data permit. If insufficient data are available to assess dose proportionality using the power 
model, dose normalized data will be presented for a graphical assessment. 
The potential effects of IMO-2125 on the PK of ipilimumab and pembrolizumab will be 
evaluated. 
Date of Synopsis: 27 March 2018 
 


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Table 1: 
Phase 1: Schedule of Evaluations 
 
 
Treatment Period (Cycle 1) 
Follow-up 
 
 
1 
2 
3 
4 
5 
6 
7 
Safety 2 
Ongoing 3 
(every 3 months)  
Week 4 
Screen 5 
1 
2 
3 
5 
8 
11 
13 
14 
17 
20 
23 
26 
29/ 
EOT 
32 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demogr/med hx 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events  
Continuous 
X 7 
Concomitant Meds 
 
Continuous 
X 8 
ECOG  
X 
X 
 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
CBC with diff 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Coagulation 9 
X 
X 10 
 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Chemistry profile 
X 
X 10 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Thyroid functions 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
CH50/C3/C4 
X 
 
 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Urinalysis  
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Vital signs 11 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
ECG 
X 
 
X 12 
 
 
 
X12 
 
 
 
 
 
 
 
X 
 
Directed physical 13 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Tumor 
biopsies/biomarkers 14, 
19 
X 
X 15 
X 16 
 
 
X 
 
X 16 
 
 
 
X 16 
 
 
 
 
Blood biomarkers 19 
 
X 17 
X 17 
 
X18 
X18 
 
 
 
 
 
 
 
X 18 
 
 
Radiology 
X 
 
 
 
 
X 20 
 
 
 
X 20 
 
 
 
X 20 
X 21 
Response 22 
 
 
 
 
 
X 20 
 
 
 
X 20 
 
 
 
X 20 
X 21 
PRO 23 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 21 
IMO-2125 dosing 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
 
Ipilimumab dosing 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Pembrolizumab dosing 
 
 
X 
 
X 
X 
X 
 
X 24 
X 24 
X 24 
X 24 
X 24 
X 24 
X 24 
X 24 
PK testing 25 
 
X 
X 
X 
X 
X 
X 
 
X 26 
X 26 
X 26 
X 26 
X 26 
X 26 
X26 
 
Immunogenicity 27 
X 
 
X 
X 
 
 
X 
 
X 
 
X 
X 
X28 


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Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; C3=complement component 3; C4=complement component 4; CBC=complete 
blood count; CH50=total hemolytic complement activity 50; CR=complete response; Demogr=Demographic; diff=differential; ECG=electrocardiogram; 
ECOG=Eastern Cooperative Oncology Group; EOT= End of Treatment; hx=history; INR=international normalized ratio; irRC=immune-related response 
criteria; med=medical; PK=pharmacokinetic; PR=partial response; PRO=patient reported outcomes; PT=prothrombin time; RECIST=Response Evaluation 
Criteria in Solid Tumors 
1 Please note, the number of weeks per cycle varies. Cycle 1 is 4 weeks in length to account for an IMO-2125 priming dose. Cycles 2, 3, and 4 are 3 weeks in 
length, and Cycles 5, 6, and 7 are included as maintenance dosing and are 6 weeks in length. 
2 The Safety Follow-up Visit should be 21 days following the last dose of IMO-2125 (± 5 days). 
3 Includes ongoing follow-up every 3 months until documented disease progression, next melanoma treatment, withdrawal of consent, death, or Sponsor 
notification that follow-up is no longer required.  
4 All assessments and IMO-2125 dosing will occur within a ±2-day window. Ipilimumab and pembrolizumab will be dosed per their respective labels. 
5 All Screening tests and assessments must be performed within 21 days of the start of Week 1 of Cycle 1, unless otherwise noted. All patients who sign an 
informed consent and are screened and qualify for the study will be considered enrolled.  
6 Including melanoma history and prior melanoma treatment history. 
7 Grade ≤2 AEs do not need to be reported.  
8 Only concomitant medications for the treatment of Grade ≥3 AEs will be captured. 
9 PT, aPTT, INR. 
10 Chemistry profile and coagulation tests do not have to be conducted if Screening tests were conducted within 7 days of the Cycle 1 Week 1 Visit. 
11 Blood pressure, heart rate, respiratory rate, and temperature. 
12 Week 2 ECG pre-dose and at 2 hours post-IMO-2125 administration. Week 11 ECG at 2 hours post-IMO-2125 administration. 
13 Including assessment of melanoma lesions. 
14 Biopsy of the tumor to be injected with IMO-2125 and biopsy of a tumor that will not be injected. See Section 13.2 and the Laboratory Manual for details on 
the collection of biopsies and analyses of biomarkers. 
15 Biopsy of the injected tumor should occur within 24 to 48 hours after injection (no more than 48 hours). The blood biomarker samples will be collected on Day 
1 before IMO-2125 administration then 4 hours (serum for cytokines), and within 24 to 48 hours after the injection, and also pre-dose at the Cycle 1 Week 2 
Visit (serum for cytokines). 
16 Optional biopsy. 
17 The blood biomarker samples will be collected on Day 1 before IMO-2125 administration, then 4 hours (serum for cytokines), and within 24 to 48 hours after 
the injection, and also pre-dose at the Cycle 1 Week 2 Visit (serum for cytokines) 
18 To be collected pre-ipilimumab dosing and post-dosing. 
19 Biopsies and blood biomarker samples will not be performed ex-US. 
20 Radiologic assessment and Investigator assessment of response at Week 8, Week 17, and Week 29 may be conducted within a ±7-day window. 
21 At least every 3 months until progression, start of next melanoma treatment, withdrawal of consent, death, or Sponsor notification that follow up is no longer 
required. 
22 In Phase 1, response assessed using irRC and RECIST v1.1. Best response to first subsequent treatment should also be captured. Confirmatory scans for CR, 
PR, and progressive disease should be performed ≥4 weeks after the date the response was first documented. 
23 The PRO assessments should be completed before study drug administration and AE assessments. 
24 For patients assigned to the IMO-2125 + pembrolizumab treatment arm, continued pembrolizumab dosing per the approved product label is permitted at the 
discretion of the Investigator. 


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25 PK: blood sampling for analysis of plasma concentrations of IMO-2125 and serum concentrations of ipilimumab, and pembrolizumab (See Table 3 for specific 
collection times). 
26 For patients who continue pembrolizumab treatment, pembrolizumab pre-dose PK samples should be collected before dosing at all visits. A post-dose 
pembrolizumab PK sample should be collected 30 minutes after initiation of pembrolizumab infusion at Week 23 and Week 32. Pharmacokinetic samples at 
Week 32 are optional. 
27 Immunogenicity: blood sampling for analysis of antibodies to IMO-2125, ipilimumab, and pembrolizumab will be performed prior to any dosing at that visit. 
28 For patients in Ongoing Follow-up (i.e., those discontinued from study treatment before progression or new anticancer treatment), the immunogenicity samples 
are required at the scheduled visits. For patients in survival follow-up (i.e., after progressive disease or start of new anti-cancer treatment), immunogenicity 
assessments are optional (e.g., if a patient comes to the investigator site for a Survival Follow-up Visit rather than the usual telephone contact). 


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Table 2: 
Phase 2: Schedule of Evaluations 
 
 
Treatment Period (Cycle 1) 
Follow-up 
 
 
1 
2 
3 
4 
5 
6 
7 
Safety 2 
Ongoing 3 
(every 3 months)  
Week 4 
Screen 5 
1 
2 
3 
5 
8 
11 
13 
14 
17 
20 
23 
26 
29/ 
EOT 
32 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demogr/med hx 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events  
Continuous 
X 7 
Concomitant Meds 
 
Continuous 
X 8 
ECOG  
X 
X 
 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
CBC with diff 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Coagulation 9 
X 
X 10 
 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Chemistry profile 
X 
X 10 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Thyroid functions 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
CH50/C3/C4 
X 
 
 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Urinalysis  
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Vital signs 11 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
ECG 
X 
 
X 12 
 
 
 
X12 
 
 
 
 
 
 
 
X 
 
Directed physical 13 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Tumor 
biopsies/biomarkers 14, 17 
X 
X 15 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
Blood biomarkers 17 
 
X 16 
X 16 
 
 
X16 
 
 
 
 
 
 
 
 
 
 
Radiology 
X 
 
 
 
 
X 18 
 
 
 
X 18 
 
 
 
X 18 
X 19 
Response 20 
 
 
 
 
 
X 18 
 
 
 
X 18 
 
 
 
X 18 
X 19 
PRO 21 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 19 
IMO-2125 dosing 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
 
Ipilimumab dosing 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Pembrolizumab dosing 
 
 
X 
 
X 
X 
X 
 
X 22 
X 22 
X 22 
X 22 
X 22 
X 22 
X 22 
X 22 
PK testing 23 
 
X 
X 
X 
X 
X 
X 
 
X 24 
X 24 
X 24 
X 24 
X 24 
X 24 
X 24 
 
Immunogenicity 25 
X 
 
X 
X 
 
 
X 
 
X 
 
X 
X 
X26 


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Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; C3=complement component 3; C4=complement component 4; CBC=complete 
blood count; CH50=total hemolytic complement activity 50; CR=complete response; Demogr=Demographic; diff=differential; ECG=electrocardiogram; 
ECOG=Eastern Cooperative Oncology Group; EOT= End of Treatment; hx=history; INR=international normalized ratio; irRECIST=immune-related Response 
Criteria in Solid Tumors; med=medical; PK=pharmacokinetic; PR=partial response; PRO=patient reported outcomes; PT=prothrombin time; 
RECIST=Response Evaluation Criteria in Solid Tumors; RP2D=recommended Phase 2 dose 
1 Please note, the number of weeks per cycle varies. Cycle 1 is 4 weeks in length to account for an IMO-2125 priming dose. Cycles 2, 3, and 4 are 3 weeks in 
length, and Cycles 5, 6, and 7 are included as maintenance dosing and are 6 weeks in length. 
2 The Safety Follow-up Visit should be 21 days following the last dose of IMO-2125 (± 5 days). 
3 Includes ongoing follow-up every 3 months until documented disease progression, next melanoma treatment, withdrawal of consent, death, or Sponsor 
notification that follow-up is no longer required.  
4 All assessments and IMO-2125 dosing will occur within a ±2-day window. Ipilimumab and pembrolizumab will be dosed per their respective labels. 
5 All Screening tests and assessments must be performed within 21 days of the start of Week 1 of Cycle 1, unless otherwise noted. All patients who sign an 
informed consent and are screened and qualify for the study will be considered enrolled.  
6 Including melanoma history and prior melanoma treatment history. 
7 Grade ≤2 AEs do not need to be reported.  
8 Only concomitant medications for the treatment of Grade ≥3 AEs will be captured. 
9 PT, aPTT, INR.  
10 Chemistry profile and coagulation tests do not have to be conducted if Screening tests were conducted within 7 days of the Cycle 1 Week 1 Visit. 
11 Blood pressure, heart rate, respiratory rate, and temperature. 
12 Week 2 ECG pre-dose and at 2 hours post-IMO-2125 administration. Week 11 ECG at 2 hours post-IMO-2125 administration. 
13 Including assessment of melanoma lesions. 
14 In Phase 2, all tumor biopsies are optional. See Section 13.2 and the Laboratory Manual for details on the collection of biopsies and analyses of biomarkers. 
15 Biopsy of the injected tumor should occur within 24 to 48 hours after injection (no more than 48 hours). The blood biomarker samples will be collected on Day 
1 before IMO-2125 administration then 4 hours (serum for cytokines), and within 24 to 48 hours after the injection, and also pre-dose at the Cycle 1 Week 2 
Visit (serum for cytokines). 
16 In Phase 2, blood biomarker samples will be collected from at least 20 patients treated at the IMO-2125 RP2D after which the Sponsor will determine if 
additional samples are needed. The blood biomarker samples will be collected on Day 1 before IMO-2125 administration, then 4 hours (serum for cytokines), 
and within 24 to 48 hours after the injection, and also pre-dose at the Cycle 1 Week 2 Visit (serum for cytokines) and Cycle 3 Week 8 Visit. 
17 Biopsies and blood biomarker samples will not be performed ex-US. 
18 Radiologic assessment and Investigator assessment of response at Week 8, Week 17, and Week 29 may be conducted within a ±7-day window. 
19 At least every 3 months until progression, start of next melanoma treatment, withdrawal of consent, death, or Sponsor notification that follow up is no longer 
required. 
20 In Phase 2, response assessed using irRECIST and RECIST v1.1. Best response to first subsequent treatment should also be captured. Confirmatory scans for 
CR, PR, and progressive disease should be performed ≥4 weeks after the date the response was first documented. 
21 The PRO assessments should be completed before study drug administration and AE assessments. 
22 For patients assigned to the IMO-2125 + pembrolizumab treatment arm, continued pembrolizumab dosing per the approved product label is permitted at the 
discretion of the Investigator. 
23 PK: blood sampling for analysis of plasma concentrations of IMO-2125 and serum concentrations of ipilimumab, and pembrolizumab (See Table 3 for specific 
collection times). For each combination in Phase 2, the collection of plasma concentration samples will be done on at least 20 patients treated at the IMO-2125 
RP2D after which the Sponsor will determine if additional samples are needed. 


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24 For patients who continue pembrolizumab treatment, pembrolizumab pre-dose PK samples should be collected before dosing at all visits. A post-dose 
pembrolizumab PK sample should be collected 30 minutes after initiation of pembrolizumab infusion at Week 23 and Week 32. Pharmacokinetic samples at 
Week 32 are optional. 
25 Immunogenicity: blood sampling for analysis of antibodies to IMO-2125, ipilimumab, and pembrolizumab will be performed prior to any dosing at that visit. 
26 For patients in Ongoing Follow-up (i.e., those discontinued from study treatment before progression or new anticancer treatment), the immunogenicity samples 
are required at the scheduled visits. For patients in survival follow-up (i.e., after progressive disease or start of new anti-cancer treatment), immunogenicity 
assessments are optional (e.g., if a patient comes to the investigator site for a Survival Follow-up Visit rather than the usual telephone contact). 


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Table 3: 
Schedule of PK Blood Sampling for IMO-2125, Ipilimumab, and Pembrolizumab 
 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Safety 
Follow-up1 
 
Week 
1 
Week 
2 
Week 
3 
Week 
5 
Week 
8 
Week 
11 
Week 
14 
Week 
17 
Week 
20 
Week 
23 
Week 
26 
Week 29 
/EOT 
Week 32 
IMO-2125 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-dose 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
Post-dose 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
30 m (±5 m) 
X 
 
 
X 
 
 
 
 
 
X 
 
1 h (±10 m) 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
1.5 h (±10 m) 
X 
 
 
X 
 
 
 
 
 
X 
 
3 h (±15 m) 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Ipilimumab 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-dose 
 
X 
 
X 
X 
X 
 
X 3 
 
X 3 
 
 
 
Post-dose 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
90 m after start 
of infusion 
(±5 m)  
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Pembrolizumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-dose 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X2 
Post-dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
30 m after start 
of infusion 
(±5 m)  
 
X 
 
 
 
X 
 
 
 
X 
 
 
X2 
Abbreviations: EOT=End of Treatment; h=hour; m=minute; PK=pharmacokinetic  
1 Collection of PK samples at the Safety Follow-up Visit is optional. 
2 IMO-2125 (plasma samples) and ipilimumab (serum) PK samples may be collected at any time during the Safety Follow-up Visit. Optional pre- and post-dose 
pembrolizumab serum PK samples are collected for those patients continuing pembrolizumab treatment at this visit. If pembrolizumab treatment was stopped, a 
sample may be collected at any time during the visit. 
3 Pre-IMO-2125 dose. 
 
 
 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................7 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............28 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................34 
4. 
BACKGROUND INFORMATION AND RATIONALE..........................................38 
4.1. 
Metastatic Melanoma: The Disease Under Study ......................................................38 
4.2. 
Current Standard of Care Therapy ..............................................................................38 
4.3. 
Toll-like Receptors and Their Agonists ......................................................................39 
4.3.1. 
Toll-like Receptor Agonists in the Treatment of Solid Tumors .................................39 
4.4. 
IMO-2125 ...................................................................................................................40 
4.4.1. 
Mechanism of Action .................................................................................................40 
4.4.2. 
Nonclinical Pharmacodynamics .................................................................................40 
4.4.2.1. 
Studies in Models of Disease ......................................................................................41 
4.5. 
Previous Human Experience .......................................................................................41 
4.6. 
Rationale for Study Design and Selection of Dose ....................................................41 
4.6.1. 
Rationale for this Phase 1/2 Study ..............................................................................42 
4.6.1.1. 
Rationale for Intratumoral Injection of IMO-2125 .....................................................42 
4.6.2. 
Rationale for Population .............................................................................................42 
4.6.3. 
Rationale for Design ...................................................................................................43 
4.6.4. 
IMO-2125 Starting Dose Rationale ............................................................................43 
5. 
STUDY OBJECTIVES ..............................................................................................44 
5.1. 
Primary Objective .......................................................................................................44 
5.2. 
Secondary Objectives .................................................................................................44 
5.3. 
Exploratory Objectives ...............................................................................................44 
6. 
STUDY ENDPOINTS ................................................................................................45 
6.1. 
Primary Endpoints ......................................................................................................45 
6.2. 
Secondary Endpoints ..................................................................................................45 
6.3. 
Exploratory Endpoints ................................................................................................45 
7. 
PATIENTS TO BE RECRUITED..............................................................................46 
7.1. 
Patient Recruitment ....................................................................................................46 


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7.2. 
Inclusion Criteria ........................................................................................................46 
7.3. 
Exclusion Criteria .......................................................................................................48 
8. 
STUDY DESIGN .......................................................................................................49 
8.1. 
Overview .....................................................................................................................49 
8.1.1. 
Phase 1 ........................................................................................................................49 
8.1.2. 
Phase 2 ........................................................................................................................50 
8.1.3. 
Dose Escalation and Stopping Rules ..........................................................................51 
8.1.3.1. 
Phase 2 Stopping Rules ..............................................................................................51 
8.1.4. 
Cohort Review Committee .........................................................................................52 
8.1.5. 
Definition of Dose-limiting Toxicities .......................................................................52 
8.1.6. 
Safety Assessment for Immunologically Related Toxicity ........................................54 
8.2. 
Duration of Study .......................................................................................................55 
8.2.1. 
Treatment Duration .....................................................................................................55 
8.2.2. 
Study Duration ............................................................................................................55 
8.3. 
Number of Patients .....................................................................................................55 
8.4. 
Benefits and Risk Assessment ....................................................................................55 
9. 
STUDY PROCEDURES BY VISIT ..........................................................................56 
9.1. 
Screening (Up to 21 Days Before Day 1 of Week 1, Cycle 1) ...................................56 
9.2. 
Cycle 1 Dosing Days (Weeks 1, 2, and 3) ..................................................................57 
9.2.1. 
Pre-dose ......................................................................................................................57 
9.2.2. 
Study Drug Administration.........................................................................................57 
9.2.3. 
Post intratumoral IMO-2125 Injection .......................................................................57 
9.3. 
Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, and Cycle 7 Dosing Days 
(Weeks 5, 8, 11, 17, 23, and 29) .................................................................................58 
9.3.1. 
Pre-dose ......................................................................................................................58 
9.3.2. 
Study Drug Administration.........................................................................................58 
9.3.3. 
Post-dose .....................................................................................................................59 
9.4. 
Cycle 4 (Week 13) ......................................................................................................59 
9.5. 
Safety Follow-up Visit (21 Days after Last Dose of IMO-2125) ...............................59 
9.6. 
Early Withdrawal ........................................................................................................60 
9.7. 
Unscheduled Visits .....................................................................................................60 
10. 
STUDY TREATMENTS............................................................................................61 
10.1. 
IMO-2125 ...................................................................................................................61 


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10.2. 
Ipilimumab ..................................................................................................................61 
10.3. 
Pembrolizumab ...........................................................................................................61 
10.4. 
Drug Handling and Administration ............................................................................61 
10.4.1. 
Drug Delivery to Site ..................................................................................................61 
10.4.2. 
Drug Storage ...............................................................................................................61 
10.4.2.1. 
IMO-2125 Storage ......................................................................................................61 
10.4.2.2. 
Ipilimumab Storage ....................................................................................................62 
10.4.2.3. 
Pembrolizumab Storage ..............................................................................................62 
10.4.3. 
Administration ............................................................................................................62 
10.4.3.1. 
IMO-2125 ...................................................................................................................62 
10.4.3.2. 
Ipilimumab ..................................................................................................................62 
10.4.3.3. 
Dose Interruption for Ipilimumab-Related Toxicities ................................................63 
10.4.3.4. 
Pembrolizumab ...........................................................................................................64 
10.4.3.5. 
Dose Interruption for Pembrolizumab-Related Toxicities .........................................64 
10.4.3.6. 
Supportive Care Guidelines for Hypophysitis ............................................................65 
10.5. 
Labeling ......................................................................................................................65 
10.6. 
Drug Accountability ...................................................................................................65 
10.6.1. 
IMO-2125 Dose Reduction .........................................................................................65 
10.6.2. 
Discontinuation of Study Drug ...................................................................................66 
10.7. 
Concomitant and Prohibited Medications ..................................................................66 
10.7.1. 
Concomitant Medications ...........................................................................................66 
10.7.2. 
Prohibited Medications ...............................................................................................66 
11. 
ADVERSE EVENT REPORTING ............................................................................67 
11.1. 
Adverse Events ...........................................................................................................67 
11.1.1. 
Definition of Adverse Events .....................................................................................67 
11.1.1.1. 
Adverse Event .............................................................................................................67 
11.1.1.2. 
Serious Adverse Event ................................................................................................67 
11.1.1.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .....................................68 
11.1.2. 
Recording Adverse Events .........................................................................................68 
11.1.3. 
Characterizing Adverse Events ...................................................................................68 
11.1.3.1. 
Description of Event ...................................................................................................68 
11.1.3.2. 
Date and Time of Onset ..............................................................................................69 


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11.1.3.3. 
Relationship to Study Drug ........................................................................................69 
11.1.3.1. 
Immune-related Adverse Events .................................................................................70 
11.1.3.2. 
Severity .......................................................................................................................70 
11.1.3.3. 
Grading of Laboratory Safety Tests for Reporting and Analysis ...............................71 
11.1.3.4. 
Management of Study Drug upon Occurrence of an Adverse Event .........................71 
11.1.3.5. 
Actions Taken for Management of Adverse Event ....................................................71 
11.1.3.6. 
Follow-up and Outcome of Adverse Events ...............................................................71 
11.1.3.7. 
Date and Time of Outcome .........................................................................................72 
11.1.4. 
Reporting Adverse Events ..........................................................................................72 
11.1.4.1. 
Where to Report Serious Adverse Events ..................................................................72 
11.1.4.2. 
Procedures for Reporting Serious Adverse Events to the Sponsor .............................73 
11.1.4.3. 
Other Reportable Events .............................................................................................73 
11.1.4.4. 
Requirements for Expedited and Periodic Reporting of Adverse Events ...................74 
12. 
SAFETY ASSESSMENTS ........................................................................................75 
12.1. 
Vital Signs ..................................................................................................................75 
12.2. 
Laboratory Assessments .............................................................................................75 
12.3. 
Other Safety Assessments ...........................................................................................76 
12.3.1. 
Physical Examination .................................................................................................76 
12.3.2. 
Electrocardiogram Monitoring ...................................................................................77 
12.3.3. 
ECOG Performance Status .........................................................................................77 
13. 
PHARMACOKINETICS AND IMMUNE RESPONSE ...........................................78 
13.1. 
Pharmacokinetic Assessments ....................................................................................78 
13.2. 
Pharmacodynamic Markers of Immune Response .....................................................78 
13.2.1. 
Immunogenicity Analyses ..........................................................................................79 
13.2.2. 
Immunologic Evaluations ...........................................................................................79 
14. 
ASSESSMENT OF EFFICACY ................................................................................80 
14.1. 
Tumor Response .........................................................................................................80 
15. 
ASSESSMENT OF PATIENT REPORTED OUTCOMES ......................................81 
15.1. 
EORTC QLQ-C30 ......................................................................................................81 
16. 
STATISTICAL ANALYSIS METHODS ..................................................................82 
16.1. 
Determination of Sample Size ....................................................................................82 
16.2. 
Analysis Populations ..................................................................................................83 


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16.3. 
General Considerations ...............................................................................................83 
16.4. 
Analysis of Safety .......................................................................................................84 
16.5. 
Analysis of Pharmacokinetics .....................................................................................84 
16.6. 
Analysis of Efficacy ...................................................................................................84 
16.6.1. 
Analysis of Primary Treatment Effect Parameter .......................................................85 
16.6.2. 
Analysis of Secondary Treatment Effect Parameters .................................................85 
16.7. 
Exploratory Analyses ..................................................................................................85 
17. 
DATA COLLECTION ...............................................................................................86 
17.1. 
Required Data .............................................................................................................86 
17.2. 
Data Collection and Tracking .....................................................................................86 
18. 
STUDY RESPONSIBILITIES ...................................................................................87 
18.1. 
Investigator Responsibilities .......................................................................................87 
18.2. 
Study Data Reporting and Processing ........................................................................87 
18.3. 
Training .......................................................................................................................87 
18.4. 
Monitoring the Investigational Site ............................................................................87 
18.5. 
Study Documentation .................................................................................................87 
18.6. 
Source Documentation ................................................................................................88 
18.7. 
Protocol Deviations ....................................................................................................89 
18.8. 
Study Supply Accountability ......................................................................................89 
18.9. 
Data Transmittal and Record Retention .....................................................................89 
18.10. 
Study Closeout ............................................................................................................89 
18.11. 
Audit/Inspections ........................................................................................................90 
19. 
ETHICAL CONSIDERATIONS................................................................................91 
19.1. 
Role of Sponsor ..........................................................................................................91 
19.2. 
Informed Consent .......................................................................................................91 
19.3. 
Confidentiality of Patients ..........................................................................................92 
19.4. 
Authorization for Use and Disclosure of Protected Health Information ....................92 
19.5. 
Human Patient Protections .........................................................................................93 
19.5.1. 
Research Patient Selection and Justification of Exclusions .......................................93 
19.5.2. 
Risks/Discomforts of Study Participation ..................................................................93 
19.6. 
Institutional and Ethics Review ..................................................................................94 
19.7. 
Financial Disclosure ...................................................................................................94 


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20. 
LIST OF REFERENCES ............................................................................................95 
21. 
APPENDICES ............................................................................................................99 
21.1. 
Eastern Cooperative Oncology Group ........................................................................99 
21.2. 
Immune-Related Response Criteria (irRC) ..............................................................100 
21.3. 
irRECIST (Immune-Related Response Evaluation Criteria in Solid Tumors) .........101 
21.4. 
RECIST v1.1 Criteria ...............................................................................................102 
 
LIST OF TABLES 
Table 1: 
Phase 1: Schedule of Evaluations ...............................................................................21 
Table 2: 
Phase 2: Schedule of Evaluations ...............................................................................24 
Table 3: 
Schedule of PK Blood Sampling for IMO-2125, Ipilimumab, and 
Pembrolizumab ...........................................................................................................27 
Table 4: 
Schedule of Dosing for Phase 1 and Phase 2 ..............................................................49 
Table 5: 
Treatment Doses to be Investigated ............................................................................51 
Table 6: 
Phase 2 Stopping Boundaries .....................................................................................51 
Table 7:  
Estimating Severity Grade ..........................................................................................70 
Table 8: 
Date and Time of Outcome for Adverse Event by Outcome Class ............................72 
Table 9: 
Laboratory Measurements ..........................................................................................76 
Table 10: ORR and Confidence Intervals with an ORR of At Least 0.35 for Possible 
Sample Sizes ...............................................................................................................82 
 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
βhCG 
Beta human chorionic gonadotropin 
δ 
Dose-limiting toxicity rate 
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 CG dinucleotides (cytosine-phosphate-guanine) 
CL/F 
Clearance 
Cmax 
Maximum plasma concentration 
CPI 
Checkpoint inhibitor 
CR 
Complete response 
CRC 
Cohort Review Committee 
CRO 
Contract Research Organization 
CS 
Clinically significant 
CT  
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T lymphocyte antigen-4 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
DRR 
Durable response rate 
EC 
Ethics Committee 
ECG 
Electrocardiogram 


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Abbreviation  
Definition 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EE 
Efficacy Evaluable 
EORTC 
European Organisation for Research and Treatment of Cancer 
FDA 
Food and Drug Administration 
FNA 
Fine Needle Aspiration 
GCP 
Good Clinical Practice 
HCV 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IFN 
Interferon 
IL 
Interleukin 
IMO 
Immune Modulatory Oligonucleotide 
IP-10 
Interferon-inducible protein-10 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
irPD 
irRECIST progressive disease 
irRC 
Immune-related response criteria 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
ISR 
Injection site reaction 
IUD 
intra-uterine device 
i.v. 
Intravenous(ly) 
LFT 
Liver function test 
mAb 
Monoclonal antibody 
MCP 
Monocyte chemoattractant protein 
MRT 
Mean residence time 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NFκB 
Nuclear factor kappa-light-chain-enhancer of activated B cells 
NK 
Natural killer 


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Abbreviation  
Definition 
ORR 
Objective response rate 
OS 
Overall survival 
PAMP 
Pathogen-associated molecular pattern 
Pap 
Papanicolaou 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed cell death-1 
pDC 
Plasmacytoid dendritic cell 
PFS 
Progression-free survival 
PHI 
Protected health information 
PI 
Principal Investigator 
PIIEE 
Primary Ipilimumab + IMO-2125 Efficacy Evaluable 
PK 
Pharmacokinetic  
PPIEE 
Primary Pembrolizumab + IMO-2125 Efficacy Evaluable 
PR 
Partial response 
Pr 
Probability 
PRO 
Patient reported outcomes 
PT 
Prothrombin time 
QLQ-C30 
Quality of Life Questionnaire-CORE 30 
QoL 
Quality of life 
RANTES 
Regulated on activation, normal T cell expressed and secreted 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
s.c. 
Subcutaneous(ly) 
SD 
Stable disease 
SFU 
Safety Follow-up 
SIIEE 
Secondary Ipilimumab + IMO-2125 Efficacy Evaluable 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Terminal exponential half-life 
Th 
T helper 


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Abbreviation  
Definition 
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 product insert 
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. 
Metastatic 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. Melanoma causes the majority of skin cancer-related deaths. 
In 2014, 76,100 people in the US were newly diagnosed with either invasive or in situ melanoma 
and 9,710 cases were fatal. While the incidence of many types of cancer has remained stable or 
declined, the incidence rates are increasing for melanoma and the probability of developing 
melanoma increases with age (Siegel 2015). 
Although melanoma is a rare form of skin cancer, it comprises over 75% of skin cancer deaths. 
Patients with early (stage 1) lesions have 3-year survival rates (>90%); however, patients with 
late-stage melanoma often have poor prognoses and survival rates (≤10%) with a median 
survival of <8 months from time of diagnosis (Lachiewicz 2008). 
Melanoma treatment is dependent upon the stage of the cancer at the time of detection and the 
properties of the tumor. Tumors in early stages can be removed surgically. However, if a biopsy 
reveals that the cancer has metastasized and spread to lymph nodes, treatments are more likely to 
include radiation and chemotherapy regimens. While the goal of chemotherapy treatments is to 
induce apoptosis, or cell death, of the cancer cells, healthy noncancerous cells are often affected 
and are responsible for many of the adverse effects of systemic non-specific therapies. A new 
approach to cancer therapy is immunotherapy; stimulation of the patient’s own immune 
mechanisms that are responsible for naturally eliminating cancer cells. 
4.2. 
Current Standard of Care Therapy 
Melanoma that has metastasized is typically treated with systemic therapy; surgery and radiation 
can be used in a palliative manner to treat symptoms of local tumor growth. Cytotoxic 
chemotherapies (both alone and in combinations) have been used for more than 30 years and 
include alkylating agents (dacarbazine, temozolomide, and nitrosoureas), the platinum analogs, 
and the microtubular toxins (vinca alkaloids and toxanes) (Bhatia 2009). 
In 1998, the Food and Drug Administration (FDA) approved the use of recombinant interleukin 
(IL)-2 to treat advanced melanoma (Atkins, 1999; Atkins, 2000) and interferon (IFN)-α has also 
been used as treatment either after surgery or in combination with other melanoma therapies 
(Kirkwood, 2000). More recently, checkpoint inhibitors (CPIs) have emerged as a new 
immunology-based frontier to effect antitumor activity. Ipilimumab is a monoclonal antibody 
(mAb) targeted to cytotoxic T lymphocyte antigen-4 (CTLA-4). CTLA-4, present on CD4+ and 
CD8+ T lymphocytes is involved in maintaining a specific population of regulatory T cells and is 
a negative regulator of T cell activation (Brunet 1987; Levings 2001). By blocking the inhibitory 
action of CTLA-4, ipilimumab enhances immune function and has been found to augment T cell 
proliferation and activation (Walunas 1994). Pembrolizumab and nivolumab are mAbs targeted 
to programmed cell death-1 (PD-1) (Shin and Ribas 2015). The combination of ipilimumab with 
anti-PD-1 antibodies for the treatment of metastatic melanoma has demonstrated impressive 
antitumor activity, including 11.5 months median progression-free survival (PFS; Larkin 2015) 
and 61% objective response rate (ORR; Postow 2015), but with increased toxicity over 


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single-agent therapy. An unmet need remains in this patient population for novel CPI 
combination therapy approaches with improved safety profiles and an increased response rate 
(Zamarin and Postow 2015).  
Intratumoral administration of IMO-2125 is a logical complement to CPIs. Intratumoral 
IMO-2125 has been shown in nonclinical models to improve systemic antitumor immunity 
through stimulation of local antigen presentation, generation of cytotoxic T lymphocytes, and 
increasing the number and extent of tumor-infiltrating T cells, which is highly correlated with the 
effectiveness of CPI therapy (Tumeh 2014). 
4.3. 
Toll-like Receptors and Their Agonists 
The human innate immune system recognizes biochemical patterns that may be associated with 
pathogens (pathogen-associated molecular patterns, or PAMPs). Immune system cells contain 
toll-like receptors (TLRs) that recognize PAMPs. Ten functional TLRs have been identified in 
humans. Some TLRs are expressed on the cell surface and recognize PAMPs such as 
lipopeptides, lipopolysaccharides, and flagellin. Other TLRs are expressed intracellularly on 
endosomal membranes and recognize single- and double-stranded ribonucleic acid (RNA; 
TLRs 3, 7, and 8) or deoxyribonucleic acid (DNA) containing unmethylated cytosine-guanine 
(CpG) dinucleotides (TLR9), which are patterns associated with viruses or bacteria. The cellular 
distribution of TLRs also varies. TLR9 in humans is expressed only in plasmacytoid dendritic 
cells (pDCs) and B cells, both of which are components of the peripheral blood mononuclear 
cells (PBMCs) (Takeda and Akira 2005; Wickelgren 2006). Activation of some TLRs causes 
signaling cascades that can promote cytokine production through the nuclear factor 
kappa-light-chain-enhancer of activated B cells (NFκB) or an IFN regulator factor mechanism 
(Abreu 2010). 
TLR9 agonists induce pDCs to produce type I IFN and other cytokines and chemokines, which 
in turn activate other immune cells including T cells, monocytes, natural killer (NK) cells, and 
macrophages (Liu, 2005). Agonists of TLR9 also induce activation, differentiation, and 
proliferation of B cells (Bernasconi 2002). Together, the innate and adaptive immune responses 
generated through TLR9 produce a profile of potentially antitumor cytokines and chemokines, 
antigen-specific cytotoxic T lymphocytes, and enhanced antigen presentation capabilities (Liu 
2005).  
4.3.1. 
Toll-like Receptor Agonists in the Treatment of Solid Tumors 
Human TLR7 and TLR9 are expressed primarily on pDCs (Takeda and Akira 2005; Wickelgren 
2006), which play a fundamental role in the regulation of the immune response during tumor 
development. Plasmacytoid DCs are present in high numbers within cutaneous melanoma and 
tumor-draining lymph nodes; however, the infiltration of these cells is correlated with a poor 
clinical outcome. Within the melanoma tumor environment, pDCs were found to promote a T 
helper (Th) 2-type response with a regulatory immune profile, promoting tumor progression 
(Aspord 2013). In contrast, pDC activation via a TLR9 agonist facilitates Th1-type adaptive 
immune responses, including the generation of antigen-specific antibodies, cytotoxic T 
lymphocytes, and memory T cells, all of which can lead to T cell-mediated tumor destruction. 


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4.4. 
IMO-2125 
4.4.1. 
Mechanism of Action 
Immune Modulatory Oligonucleotide-2125 (IMO-2125), a novel phosphorothioate 
oligodeoxynucleotide, is composed of 2 strands of modified DNA joined at their 3’ ends. 
IMO-2125 was created by Idera Pharmaceuticals, Inc. through a structure activity approach to 
the design of TLR-targeted drug candidates based on modifications of classical CpG DNA (Yu, 
2002; Kandimalla, 2003; Kandimalla, 2005). IMO-2125 is designed to act as an agonist of 
TLR9.  
IMO-2125, acting as an agonist of TLR9, induces a broad spectrum of innate and adaptive 
immune responses, including antigen-specific cytotoxic T lymphocyte responses. IMO-2125 
stimulates pDCs and B cells through TLR9 to initiate a rapid innate immune response 
characterized by secretion of cytokines and chemokines including IL-1β, IL-6, IL-12, IFN-γ, 
interferon gamma-induced protein (IP)-10, tumor necrosis factor (TNF)-α, monocyte 
chemoattractant protein-1 (MCP-1), and, particular to pDC cells, high amounts of IFN-α. A 
secondary phase of the innate immune response is activation of NK cells, monocytes, and 
neutrophils and margination of lymphocytes out of systemic circulation. These hematological 
effects are evident consistently at 24 hours post-dose. T cells are induced by the 
cytokine/chemokine response into a Th1-type cellular response that includes production of 
cytotoxic T lymphocytes and antigen-specific memory T cells.  
4.4.2. 
Nonclinical Pharmacodynamics  
When IMO-2125 was subcutaneously (s.c.) administered into cynomolgus monkeys, plasma 
concentrations of IFN-α began to increase early, peaking at approximately 8 hours after 
treatment and remaining detectable for at least 96 hours at a dosage of 4 mg/kg (Trombino 
2007a). Other signs of immune stimulation following in vivo administration of IMO-2125 
included increased plasma concentrations of IL-12 and IP-10; changes in trafficking of white 
blood cells (WBCs), particularly a transient decrease peripheral blood lymphocytes at 24 hours 
post-dose; and increased expression of the activation marker CD69 on T cells, B cells, and NK 
cells (Trombino 2007b).  
Peripheral blood mononuclear cells, including pDCs and B cells, were isolated from healthy 
volunteers and stimulated in vitro with IMO-2125 for 6 to 48 hours (Bhagat 2007a, 
Bhagat 2007b, Bhagat 2007c, Bhagat 2007d, Bhagat 2007e). IFN-α and IP-10 were induced in a 
time- and concentration-dependent manner. IMO-2125 also induced multiple other cytokines and 
chemokines, including IL-1β, IL-12, MCP-1, and regulated on activation, normal T cell 
expressed and secreted (RANTES). Further indications of in vitro immune stimulation in these 
cultures were the induction of B cell proliferation and increased expression of CD86 and CD69 
activation markers on B cells and pDCs (Bhagat 2007f, Bhagat 2007g; Bhagat 2007h). 


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4.4.2.1. 
Studies in Models of Disease 
The nonclinical rationale for use of IMO-2125 in immune oncology comes from mechanism of 
action studies in vitro and in vivo and from antitumor activity in mouse xenograft models. 
Clinical proof of concept is derived from studies in patients with chronic hepatitis C virus (HCV) 
infection.  
• Cytokine induction profile in in vitro studies using human PBMCs and pDCs show 
IMO-2125 induces a wide range of cytokines and chemokines, including IFN-α, 
IP-10, MCP-1, MIP-1, MIP-1α, MIP-1β, and RANTES, which have been implicated 
in the intratumoral mechanism of action; 
• Induction of IFN-α and IP-10 in cynomolgus monkeys, with activation of T cells, 
B cells, and NK cells; 
• Tumor growth inhibition in murine xenograft models and induction of splenic 
CD8+ lymphocytes in combination with an anti-CTLA-4 mAb; 
• Induction of IFN-α and IP-10 in clinical studies. 
In summary, IMO-2125 has shown potent activity as a TLR9 agonist, particularly with regard to 
pDC production of IFN-α. Intratumoral administration in mouse xenograft models shows 
promising antitumor activity, especially in combination with an anti-CTLA-4 antibody 
representative of CPIs. IMO-2125 has been well tolerated in clinical studies with 4 weeks of 
once or twice weekly s.c. administration. The goal of the clinical development program for 
IMO-2125 in immune oncology is to demonstrate its safety and activity in combination with 
CPIs. This is the first study to evaluate IMO-2125 in combination with a marketed anti-CTLA-4 
mAb and anti-PD-1 mAb in recurrent or metastatic melanoma. 
4.5. 
Previous Human Experience 
IMO-2125 strongly induces production of endogenous IFN-α and has been studied previously as 
a potential treatment for patients with chronic 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 patients with HCV infection. IMO-2125 was administered s.c. at 
dosages up to 0.48 mg/kg/week in 96 patients. Full details are provided in the Investigator’s 
Brochure. The most common adverse events (AEs) were mild to moderate flu-like symptoms and 
injection site reactions (ISRs). 
4.6. 
Rationale for Study Design and Selection of Dose 
This study will be a 2-part study with two treatment arms. The primary objective of Phase 1 is to 
characterize the safety and determine a recommended Phase 2 dose (RP2D) of IMO-2125 when 
administered in combination with ipilimumab or when administered in combination with 
pembrolizumab in patients with metastatic melanoma. The maximum tolerated dose 
(MTD)/RP2D for IMO-2125 may differ between the combination of IMO-2125 and ipilimumab 
and the combination of IMO-2125 and pembrolizumab. The primary objective of Phase 2 is to 
assess preliminary clinical activity of each combination at the respective RP2D(s) in patients 
with metastatic melanoma that is not responsive to PD-1 inhibitor therapies, using Response 
Evaluation Criteria in Solid Tumors v1.1 (RECIST; Eisenhauer, 2009). 


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4.6.1. 
Rationale for this Phase 1/2 Study 
IMO-2125, a synthetic phosphorothioate oligonucleotide that acts as a direct agonist of TLR9, 
stimulates both the innate and adaptive immune systems, and induces the expression of an array 
of endogenous cytokines and chemokines, including IL-1β, IL-6, IL-12, IFN-α, IFN-γ, IP-10, 
TNF-α, and MCP-1. In preclinical studies IMO-2125 has shown dose-dependent antitumor 
activity associated with changes in the tumor microenvironment, increased T-cell infiltration, 
and induction of durable, tumor-specific memory. In combination with anti-CTLA-4 or 
anti-PD-1, IMO-2125 has shown greater antitumor activity than with either agent alone. 
Therefore, the combination of IMO-2125 with either ipilimumab or pembrolizumab may offer a 
novel therapy to benefit patients with metastatic melanoma.  
4.6.1.1. 
Rationale for Intratumoral Injection of IMO-2125 
Systemically administered TLR9 agonists have shown limited activity as cancer therapeutics 
alone or in combinations with other agents (Smith, 2014; Chan, 2015). Poor clinical responses 
after intravenous (i.v.) administration may be due, in part, to the fact that activated T cells failed 
to migrate to the tumor (Lou, 2011). Early studies by Nierkens (2009), showed that agonists of 
TLR9 were most effective when administered in close proximity to tumor antigens, and that i.v. 
and s.c. routes of TLR9 agonist administration were less effective than peri-tumoral injections 
(den Brok, 2004; Baines and Celis 2003; Heckelsmiller, 2002). 
In preclinical models, intratumoral IMO-2125 administration leads to a dose-dependent decrease 
in treated and distant tumor volume, increase in infiltrating CD8+ T cells, and specific cytotoxic 
T cell responses against tumor antigens which are associated with durable tumor specific 
immune memory. Intratumoral IMO-2125 administration modulates the tumor 
microenvironment by increasing infiltration of tumor-infiltrating lymphocytes (TILs) and by 
changing checkpoint gene expression. The combination of intratumoral IMO-2125 and an 
anti-CTLA-4 mAb resulted in improved inhibition of tumor growth, regression of systemic lung 
metastases and infiltration of TILs versus monotherapy with either agent. The combination of 
intratumoral IMO-2125 with an anti-PD-1 antibody also showed more potent antitumor activity 
than either agent alone (Wang CRI-CIMT-EATI-AACR Meeting, 2015; Wang, 
AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, 
2015).  
4.6.2. 
Rationale for Population 
Despite recent advances in the treatment of melanoma, only a small minority of patients 
experience dramatic clinical benefit from any of the available immunotherapies as single agents. 
The combination of ipilimumab with nivolumab is associated with higher response rates, but at 
the expense of significant additive toxicity, and median survival is still less than a year (Larkin, 
2015). Thus, new treatment approaches that build on the now-established proof of concept for 
immunotherapy are sorely needed. Patients who relapse after treatment with a PD-1 inhibitor 
have a particular unmet need since no therapy has been shown to be effective in this setting.  


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4.6.3. 
Rationale for Design 
The Phase 1/2 design allows for optimal dose selection for IMO-2125 in combination with 
ipilimumab or in combination with pembrolizumab, followed by expansion at the RP2D(s) to 
evaluate preliminary efficacy and to generate additional long-term safety follow up data.  
4.6.4. 
IMO-2125 Starting Dose Rationale 
In Phase 1, the starting dose level of IMO-2125 will be 4 mg, which was calculated based on the 
doses of IMO-2125 that have been administered s.c. to 96 patients with chronic HCV infection. 
These patients received dosages ranging from 0.04 to 0.48 mg/kg. Based on this prior human 
safety experience, a dosage of 0.08 mg/kg was selected as the starting dose and then set as a 
fixed dose by assuming a conservative patient weight of 60 kg for a calculated starting dose level 
of 4.8 mg. A lower dose level was selected as the fixed starting dose level (4 mg) as an added 
safety margin.  
IMO-2125 will be administered as a once-weekly intratumoral injection for the first 3 weeks of 
Cycle 1, followed by intratumoral injections on Weeks 5, 8, 11, 17, 23, and 29 (Day 1 of 
Cycles 2 through 7). Ipilimumab will be administered as a 90-minute i.v. infusion at 3 mg/kg 
once every 3 weeks for four cycles, consistent with the approved product label. Pembrolizumab 
will be administered as a 30-minute i.v. infusion at 200 mg once every 3 weeks for four cycles 
per the approved product label, after which continued administration is at the discretion of the 
Investigator for patients in the IMO-2125 + pembrolizumab treatment arm. Patients who initiated 
treatment at the 2 mg/kg dose may continue treatment using either the 200 mg dose or the 
2 mg/kg dose. If institutional practice requires certain patients to be treated using weight-based 
pembrolizumab dosing, those patients may be treated with the 2 mg/kg dose. 
Pembrolizumab safety compares favorably to ipilimumab (Robert, 2015), thus dosing of 
IMO-2125 in combination with pembrolizumab can be initiated at any dose level previously 
established as showing acceptable safety for the ipilimumab combination. IMO-2125 dose level 
escalation or de-escalation for each combination will be done independently of the other 
combinations, as appropriate, when the respective targets are functionally distinct (Parry, 2005).  
 


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5. 
STUDY OBJECTIVES  
5.1. 
Primary Objective 
The primary objective of Phase 1 is to characterize the safety and determine an RP2D of 
IMO-2125 when administered in combination with ipilimumab or when administered in 
combination with pembrolizumab in patients with metastatic melanoma. The MTD and RP2D 
for IMO-2125 may differ between the combination of IMO-2125 and ipilimumab and the 
combination of IMO-2125 and pembrolizumab. 
The primary objective of Phase 2 is to assess the preliminary clinical activity of IMO-2125 in 
combination with ipilimumab or in combination with pembrolizumab at the respective RP2D(s) 
in patients with metastatic melanoma that is not responsive to PD-1 inhibitor therapy, using 
RECIST v1.1 (Eisenhauer, 2009). 
5.2. 
Secondary Objectives 
The secondary objectives of Phase 1 are to determine the plasma pharmacokinetics (PK) of 
single-dose IMO-2125 and repeat-dose IMO-2125 administered by intratumoral injection in 
combination with ipilimumab or pembrolizumab. An additional secondary objective of Phase 1 
is to describe any preliminary antitumor activity. 
The secondary objectives of Phase 2 are to further assess the safety and tolerability of IMO-2125 
in combination with ipilimumab or in combination with pembrolizumab in patients with 
metastatic melanoma and to assess treatment response using immune-related Response 
Evaluation Criteria in Solid Tumors (irRECIST) and RECIST v1.1, overall survival (OS), OS at 
6 and 12 months, PFS, PFS at 6 and 12 months, durable response rate (DRR), duration of 
response (DoR), and disease control rate (DCR). 
5.3. 
Exploratory Objectives 
The exploratory objectives of Phase 1 and 2 are to assess patient reported outcomes (PRO), 
pre- and post-treatment blood biomarkers, pre- and post-treatment tumor biopsies for 
immunological assessment, and explore any potential association between these biomarker 
measures and antitumor activity. In addition, anti-IMO-2125, anti-ipilimumab, and 
anti-pembrolizumab antibody formation will be assessed. 


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6. 
STUDY ENDPOINTS 
6.1. 
Primary Endpoints 
The primary endpoint of Phase 1 is to characterize the safety of IMO-2125 when administered in 
combination with ipilimumab or when administered in combination with pembrolizumab.  
The primary endpoint in Phase 2 is clinical activity, defined as objective response as assessed by 
the Investigator using RECIST v1.1.  
6.2. 
Secondary Endpoints 
The secondary endpoints in Phase 1 are:  
• PK assessments for IMO-2125; 
• ORR assessed using irRC and RECIST v1.1 
The secondary endpoints in Phase 2 include: 
• Safety and tolerability (type and frequency of AEs, clinical laboratory values, 
electrocardiograms [ECGs], and vital sign measurements) for each combination; 
• Duration of response using RECIST v1.1; 
• ORR and duration of response using irRECIST;  
• PFS, defined as time from the initiation of treatment to disease progression by 
irRECIST and RECIST v1.1, or death from any cause;  
• PFS at 6 and 12 months; 
• OS, defined as time from initiation of treatment to death from any cause;  
• OS at 6 and 12 months;  
• Durable response rate by irRECIST and RECIST v1.1, defined as the rate of complete 
response (CR) plus partial response (PR) lasting at least 180 days continuously and 
beginning within the first 12 months of study; 
• Disease control rate by irRECIST and RECIST v1.1, defined as the rate of CR, PR, or 
stable disease (SD).  
6.3. 
Exploratory Endpoints 
The pre- and post-treatment exploratory endpoints of Phase 1 and 2 include, but are not limited 
to, PRO using the European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-CORE 30 (EORTC QLQ-C30), blood biomarkers (e.g., IFN-γ and other plasma 
cytokines) and tumor markers to assess any potential association between immune response to 
IMO-2125 at the Week 8 tumor biopsy with tumor response in both injected and uninjected 
tumor lesions at Week 13 or at Week 23 (depending on the protocol version under which the 
patients were enrolled). 


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7. 
PATIENTS TO BE RECRUITED 
7.1. 
Patient Recruitment  
Enrollment during the Phase 1 dose-escalation portion and the Phase 2 portion of the study is 
open to adult patients with advanced/metastatic melanoma.  
Patient selection and recruitment will be organized and overseen by the Investigator at the site 
following approval of the study protocol by the Institutional Review Board (IRB) or Ethics 
Committee (EC). All patients 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 patient to participate and consent to 
the conduct of the study before initiating any study-related procedures. 
7.2. 
Inclusion Criteria 
To be eligible for this study, all patients must meet all of the following inclusion criteria. These 
criteria apply to both the Phase 1 dose-escalation portion and the Phase 2 portion of this study. 
1. Patients must have histologically confirmed metastatic melanoma with measurable, 
stage III (lymph node or in transit lesions) or stage IVA, IVB, or IVC disease. 
2. Patients must have symptomatic or radiographic progression during or after treatment 
with a PD-(L)1 inhibitor administered either as monotherapy or in combination.  
a. The interval between last PD-(L)1 directed treatment and start of study treatment 
should be at least 21 days. 
b. Prior BRAF or MEK inhibitor treatment is not required. However, for patients with 
known BRAF status: 
i. Those with BRAF wild type may have had a maximum of two previous systemic 
regimens for the treatment of melanoma.  
ii. Those with a BRAF mutation may have had a maximum of three previous 
systemic regimens for the treatment of melanoma. 
c. Prior ipilimumab is permitted. 
d. Previous treatment with either a PD-1 inhibitor (for patients enrolling on the 
IMO-2125 + pembrolizumab combination) or CTLA-4 inhibitor (for patients 
enrolling on the IMO-2125 + ipilimumab combination) should not have been 
accompanied by dose-limiting toxicity (DLT) for which permanent discontinuation is 
recommended (per USPI).  
i. 
Patients with a history of Grade ≥2 gastrointestinal symptoms (e.g., diarrhea, 
colitis) during prior checkpoint inhibitor treatment should be discussed with the 
Idera Medical Monitor during the Screening Period before starting study 
treatment. 
3. Phase 1 patients must have at least two measurable tumor lesions ≥1.0 cm that are 
accessible to biopsy. Phase 2 patients must have at least one measurable lesion (per 
RECIST v1.1) which may be the same site that is used for the intratumoral injections. 
4. Patients must be ≥18 years of age. 


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5. Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2 
(Oken, 1982) (Section 21.1). 
6. Patients must meet the following laboratory criteria: 
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 
e. Aspartate aminotransferase (AST) ≤2.5 x ULN; alanine aminotransferase (ALT) 
≤2.5 x ULN; AST/ALT <5 x ULN if liver involvement 
f. Serum bilirubin ≤1.5 x ULN, except in patients with Gilbert’s Syndrome who must 
have a total bilirubin <3 mg/dL 
7. Women of childbearing potential (WOCBP) and men must agree to use effective 
contraceptive methods from Screening throughout the study treatment period and until at 
least 90 days after the last dose of IMO-2125, 3 months after the last dose of ipilimumab, 
or at least 4 months after the last dose of pembrolizumab. 
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 patient. 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™)  
e. 
An intra-uterine device (IUD) 
8. WOCBP must have a negative pregnancy test (serum or urine) prior to the first dose of 
study treatment. 
9. Patients must be willing and able to sign the informed consent and comply with the study 
protocol. 
10. Patients must have an anticipated life expectancy >3 months. 


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7.3. 
Exclusion Criteria  
Patients meeting any of the following criteria will be excluded from the study: 
1. Patients who have received prior therapy with a TLR agonist, excluding topical agents. 
Patients who have received experimental vaccines or other investigational immune 
therapies should be discussed with the Medical Monitor to confirm eligibility. 
2. Patients who have received systemic treatment with IFN-α within the previous 6 months 
prior to enrolling into this study. 
3. Patients with known hypersensitivity to any oligodeoxynucleotide. 
4. Patients with active autoimmune disease requiring disease-modifying therapy. 
5. Patients requiring concurrent systemic steroid therapy higher than physiologic dose 
(7.5 mg/day of prednisone). 
6. Patients with any form of active primary or secondary immunodeficiency. 
7. Patients with another primary malignancy that has not been in remission for at least 
3 years. The following are exempt from the 3 year limit: 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). 
8. Patients with active systemic infections requiring antibiotics or active hepatitis A, B, or 
C. 
9. Patients who are hepatitis B surface antigen positive. 
10. Patients with a known diagnosis of human immunodeficiency virus (HIV) infection. 
11. WOCBP who are pregnant or breast feeding. 
12. Patients who have had prior anaphylactic or other severe infusion reaction associated 
with human antibody administration. 
13. Patients with known central nervous system, meningeal, or epidural disease. Patients with 
stable brain metastases following definitive local treatment are eligible if steroid 
requirement is less than 7.5 mg/day of prednisone (or equivalent). 
14. Patients with impaired cardiac function or clinically significant cardiac disease such as: 
a. New York Heart Association Class III or IV cardiac disease, including preexisting 
clinically significant ventricular arrhythmia, congestive heart failure, or 
cardiomyopathy 
b. Unstable angina pectoris ≤6 months prior to study participation 
c. Acute myocardial infarction ≤6 months prior to study participation 
d. Other clinically significant heart disease (i.e., Grade ≥3 hypertension, history of labile 
hypertension, or poor compliance with an anti-hypertensive regimen) 
15. Ocular melanoma. 


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8. 
STUDY DESIGN 
8.1. 
Overview 
This is a two arm, open-label Phase 1/2 study to assess the safety, tolerability, PK, 
immunogenicity, and efficacy of IMO-2125 when administered in combination with ipilimumab 
or in combination with pembrolizumab. Patients with metastatic melanoma who have 
experienced symptomatic or confirmed radiographic progression during or after treatment with 
an anti-PD-(L)1 agent (alone or in combination) will be eligible. Prior BRAF or MEK inhibitor 
treatment is not required. The study will be conducted in two parts: a dose-escalation portion 
(Phase 1) to evaluate safety and tolerability of multiple dose levels and a Phase 2 portion to 
assess preliminary efficacy.  
8.1.1. 
Phase 1 
The Phase 1 portion of the study will explore escalating dose levels of IMO-2125 (from 4 to 
32 mg with de-escalation to 2 mg allowed for each IMO-2125 combination). For each cohort, 
IMO-2125 will be administered as a once-weekly intratumoral injection for 3 consecutive weeks 
in Cycle 1, followed by intratumoral injections on Weeks 5, 8, 11, 17, 23, and 29 (Day 1 of 
Cycles 2 through 7). Both ipilimumab and pembrolizumab will be administered as per the USPI 
every 3 weeks beginning Day 1 of Cycle 1 Week 2. Continued pembrolizumab dosing following 
the study period is permitted at the discretion of the Investigator for patients in the IMO-2125 + 
pembrolizumab treatment arm. The dosing schedule is summarized in Table 4. 
Table 4: 
Schedule of Dosing for Phase 1 and Phase 2 
 
Cycle 
 
1 
2 
3 
4 
5 
6 
7 
Study week 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 
11 
12 
13 
17 
23 
29 
IMO-2125 + ipilimumab 
IMO-2125 
X X X 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
X 
X 
X 
Ipilimumab 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
- 
- 
- 
IMO-2125 + pembrolizumab 
IMO-2125 
X X X 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
X 
X 
X 
Pembrolizumab 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
X  
X1 
Note: On weeks when the combinations are administered, administration of ipilimumab or pembrolizumab will be 
first, followed by IMO-2125. IMO-2125 administration must occur within a ±2 day window of the scheduled dosing 
day.  
1 For patients in the IMO-2125 + pembrolizumab treatment arm, continued pembrolizumab dosing per the approved 
product label is permitted at the discretion of the Investigator. 
 
Patients assigned to 11 weeks of IMO-2125 under previous versions of the protocol who have 
not yet reached the end of the Treatment Period may receive the Week 17, 23, and 29 injections 
at the discretion of the treating Investigator.  


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Each cohort will be monitored for the occurrence of DLTs. The DLT evaluation period will be 
Cycle 1 (Weeks 1 through 4). If a patient discontinues study participation before the DLT 
evaluation period is finished due to reasons other than experiencing a DLT, that patient must be 
replaced so that the cohort may be properly evaluated. More information about the review of 
DLTs and the escalation of dose levels between cohorts is provided in Section 8.1.3, 
Section 8.1.4, and Section 8.1.5. 
There are 3 patients planned per cohort. During Phase 1, the Sponsor will assign patients to a 
treatment arm (IMO-2125 + ipilimumab or IMO-2125 + pembrolizumab) by cohort. 
The Sponsor will maintain a prioritization schedule for cohort assignment in a separate 
document. A Cohort Review Committee (CRC) will be convened prior to each dose level 
escalation to review the available data and provide recommendations on study conduct. After 
completing the DLT evaluations for all planned IMO-2125 doses in either combination, 
supplemental cohorts of up to 5 patients each may be enrolled with either combination at doses 
up to and including the MTD. CRC review is not required for initiation of these supplemental 
cohorts but safety review meetings will still take place monthly throughout Phase 1 of the study. 
After completion of either Phase 1 treatment arm and determination of the RP2D for that arm, 
the Phase 2 portion for the completed treatment arm may be initiated. It is not necessary for 
Phase 1 to be completed in both treatment arms before Phase 2 is started. After Phase 2 in either 
treatment arm is initiated, the Sponsor will assign the treatment arm, cohort, and phase for 
patients.  
Dose-limiting toxicity evaluations and CRC reviews for any additional immunotherapy 
combination cohorts will be done as described for the ipilimumab and pembrolizumab 
combinations. 
8.1.2. 
Phase 2 
The Phase 2 portion of the study will assess preliminary efficacy, using investigator-assessed 
RECIST v1.1, of IMO-2125 + ipilimumab, IMO-2125 + pembrolizumab, and any additional 
combinations that are studied in Phase 1. The dose level of IMO-2125 to be administered for 
each treatment arm will be the RP2D for the combination, as determined in Phase 1.  
Phase 2 will enroll at least 60 patients treated at the IMO-2125 + ipilimumab RP2D. This will 
include at least 21 patients in the primary IMO-2125 + ipilimumab efficacy-evaluable population 
(as defined in Section 16.2) and up to 20 patients in the secondary IMO-2125 + ipilimumab 
efficacy-evaluable population. 
In the IMO-2125 + pembrolizumab Phase 2 cohort, enrollment will continue until 21 patients in 
the IMO-2125 + pembrolizumab efficacy-evaluable population have been treated at the 
IMO-2125 + pembrolizumab RP2D.  
Phase 1 patients treated at the RP2D for either combination will contribute to these totals.  
For each treatment arm, a two-stage design will be used and futility analyses performed as 
described in Section 16.1. 
If a patient discontinues treatment before completing at least one efficacy evaluation for reasons 
other than toxicity, then that patient will be replaced with the replacement assigned to the same 
treatment arm and dose level as the patient who dropped out early. 


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Combination therapy in Phase 2 will continue using the same schedule as Phase 1 (Table 4). 
8.1.3. 
Dose Escalation and Stopping Rules 
Up to five dose levels for IMO-2125 are initially planned (Table 5).  
Table 5: 
Treatment Doses to be Investigated 
Dose Level 
IMO-2125 
Ipilimumab 
Pembrolizumab 
-1 
2 mg 
3 mg/kg 
200 mg 
+1 
4 mg 
3 mg/kg 
200 mg 
+2 
8 mg 
3 mg/kg 
200 mg 
+3 
16 mg 
3 mg/kg 
200 mg 
+4 
32 mg 
3 mg/kg 
200 mg 
 
In Phase 1, the study will enroll patients in planned cohorts of 3, beginning at Dose Level +1 for 
the ipilimumab treatment arm and beginning at Dose Level +2 for the pembrolizumab treatment 
arm once safety of the IMO-2125 + ipilimumab combination has been established for that level. 
A charter will be used to guide the CRC’s decision-making.  
Additionally, if, due to observed toxicity, it proves difficult to provide IMO-2125 for 
3 consecutive weeks in Cycle 1, the decision may be taken by the CRC to add cohorts where 
alternative schedules of IMO-2125 administration will be explored.  
The MTD will be determined from the assessment of DLTs during the first treatment cycle of 
each cohort (Section 8.1.5). Using a prior beta(1,1) distribution of the DLT rate δ i for each dose 
level i, the MTD is defined as the highest dose level for which the mean of the posterior 
distribution of toxicity is closest to but less than 25% among all the evaluated doses i for which 
Pr (δ i > 0.25 | data) <0.80. 
The RP2D(s) will be selected from dose level(s) at or below the MTD. Additional dose levels 
may be studied if the MTD(s) have not been reached and pharmacodynamic activity is deemed to 
be inadequate. At the time of completion of the Phase 1 portion of the study, an analysis of the 
data will be performed.  
8.1.3.1. 
Phase 2 Stopping Rules 
Additional patients will be enrolled at the RP2D level(s) established in the Phase 1 portion of the 
study for a total of approximately 90 to 100 patients enrolled in the study. DLTs will be 
continuously monitored throughout the study. Assuming a prior beta (0.6, 1.4) distribution for 
the overall toxicity rate for a treatment, a Phase 2 arm will terminate if the Pr (δt > 0.25 | data) 
>0.80, where δt is the DLT rate attributable to the treatment. The decision rule for terminating 
due to toxicity is presented in Table 6. The method used to produce the decision rule and 
operating characteristics was designed by Thall (2006). 
Table 6: 
Phase 2 Stopping Boundaries 
If there are this many first-cycle DLTs or more 
3 
4 
5 
6 
7 
8 
9 
10 
Stop if this many patients (or fewer) have begun treatment  
7 
10 
13 
17 
20 
24 
27 
29 


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8.1.4. 
Cohort Review Committee 
The CRC composition and duties are described in a charter. Once the last patient in a given 
cohort has completed their first cycle of study treatment, a CRC meeting will be convened to 
review all safety data and decide whether DLTs were observed. Based on the CRC’s 
adjudication of DLTs observed in a cohort, they will guide decisions on the dose level that the 
subsequent cohort will be administered. 
A review of all relevant available data will occur between the Sponsor and participating 
Institution(s) at least monthly for the duration of the study.  
8.1.5. 
Definition of Dose-limiting Toxicities 
Toxicity will be evaluated according to the National Cancer Institute (NCI) Common 
Terminology Criteria for AEs (CTCAE) v4.03 toxicity criteria. Dose-limiting toxicities are 
defined as those events that will require dose modification; therefore, DLT criteria should be 
referenced throughout the Phase 1 and 2 portions of the study. The DLT evaluation period will 
be Cycle 1 (Weeks 1 through 4). 
For the purposes of dose level escalation and determination of the MTD(s), only DLTs (as 
defined below) that occur during the first cycle of treatment will be considered in decisions 
regarding dose level escalation; however, DLTs or other clinically significant toxicities that 
occur throughout the observation period will be considered when determining the RP2D(s) for 
use in this trial and in subsequent clinical trials. 
During Cycle 1 of the dose escalation portion, if two of the three patients in a cohort experience 
the same Grade 2, treatment-related AE, then subsequent increases in dose level will proceed in 
increments less than 100%. If more than one cohort is treated at the same dose level and greater 
than 67% of patients treated at that dose level experience the same Grade 2 treatment-related AE 
(Table 7), dose level escalation will proceed in increments less than 100%. In such a case, 
specific dose level increments will be decided by the CRC. 
Protocol-defined hematologic DLTs include: 
• CTCAE Grade 4 neutropenia ≥7 days; 
• CTCAE Grade 3 or 4 neutropenia with fever ≥38.5°C;  
• CTCAE Grade 3 thrombocytopenia with bleeding; 
• CTCAE Grade 4 thrombocytopenia ≥7 days. 
Protocol-defined non-hematologic DLTs include: 
• Grade ≥3 vomiting or nausea ≥14 days despite the use of optimal anti-emetic 
treatments; 
• Grade ≥3 diarrhea ≥14 days despite the use of optimal anti-diarrheal treatments which 
should include infliximab as per institutional guidelines; 
• Serum creatinine >3.0 x ULN; 


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• AST or ALT >5 x ULN; in patients with liver metastasis who entered the study with 
Grade 2 elevation of AST or ALT, an AST or ALT increase ≥50% relative to baseline 
and lasting ≥1 week; 
• Bilirubin ≥3.0 x ULN; 
• Bilirubin ≥2.0 x ULN with ALT >3 x ULN in patients without liver metastases; 
• Other non-hematologic toxicities of Grade ≥3, except for the following: 
− AEs related to underlying disease; 
− CTCAE Grade 3 fatigue <14 days; 
− Alopecia; 
− Isolated, asymptomatic elevations in biochemistry laboratory values lasting 
≤14 days. This includes electrolyte abnormalities that respond to medical 
intervention. 
Ipilimumab-related DLTs: 
• Grade ≥4 immune-mediated dermatitis (except skin reaction at site of injection); 
• Grade ≥3 immune-mediated endocrinopathy (with the exception of  Grade 3 
autoimmune thyroiditis that resolves to Grade 1 or baseline within 28 days of onset); 
• Grade ≥3 immune-mediated enterocolitis; 
• Grade ≥3 immune-mediated hepatitis with the exception of Grade 3 
immune-mediated hepatitis that resolves to Grade 1 or baseline within 28 days of 
onset; 
• Grade ≥3 immune-mediated neuropathy, pancreatitis, meningitis, nephritis, and 
pneumonitis that are considered to be possibly, probably, or definitely related to study 
therapy as determined by the Investigator; 
• Any persistent IMO-2125-related toxicity that leads to a delay of scheduled (per 
standard of care) ipilimumab >14 days. 
Pembrolizumab-related DLTs: 
• Grade ≥3 pneumonitis or recurrent Grade 2 pneumonitis;  
• Grade ≥3 nephritis;  
• Grade ≥3 infusion-related reactions;  
• Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent 
per day within 12 weeks; 
• Any Grade ≥3 treatment-related AE that recurs. 
If at any time during the study, a patient experiences a DLT as outlined above, the toxicity in 
question must be assessed for attribution based on the known toxicity profiles for ipilimumab, 
pembrolizumab, and IMO-2125. If assessment can be clearly attributed to one of the drugs in the 
combination, then dosing should be interrupted and the toxicity should be followed until 


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resolution, stabilization, or return to baseline. Treatment with the other agent may continue 
during this time period. If attribution cannot be clearly ascribed to one agent versus the other, 
then both IMO-2125 and ipilimumab (or pembrolizumab) should be stopped and the toxicity 
should be followed until resolution, stabilization, or return to baseline. If treatment is to be 
resumed, then re-initiation criteria must be met. If the DLT was clearly related to IMO-2125 or if 
attribution cannot be clearly determined, then IMO-2125 must be administered at a lower dose 
level (a minimum reduction of at least 1 dose level). If the DLT recurs after a dose level 
reduction, then treatment should be discontinued.  
Patients who experience a non-laboratory, IMO-2125-related DLT must be evaluated weekly, at 
a minimum, until resolution to Grade ≤1 or baseline and then at least monthly until return to 
baseline or stabilization of the event, whichever comes first. For abnormal laboratory values that 
qualify as DLTs, patients will be followed twice weekly until values return to Grade ≤1 or 
baseline, whichever comes first. 
Criteria for re-initiation of study treatment following occurrence of a DLT are as follows: 
• ANC must be ≥1.5 x 109/L (1500/μL); 
• Platelets must be ≥75 x 109/L (75,000/μL); 
• All clinically significant non-hematologic toxicities for which a causal association to 
study treatment cannot be ruled out must be Grade ≤1 (except alopecia) or returned to 
baseline. 
If the patient does not meet these criteria, dosing will be delayed and the patient should be 
re-evaluated within 48 to 72 hours. If the next cycle is delayed by more than 21 days for toxicity, 
the patient should be removed from study treatment. In these situations, if the patient is 
experiencing clinical benefit and has a favorable risk/benefit profile, study treatment with 
IMO-2125 may be continued if agreed upon by the Sponsor and the Investigator. 
8.1.6. 
Safety Assessment for Immunologically Related Toxicity 
Based on an incidence of Grade 3 or greater immune-mediated AEs associated with use of 
ipilimumab or pembrolizumab of approximately 12% to 15%, the following safety precautions 
will be followed. Examples of relevant toxicities include the following: enterocolitis, hepatitis, 
dermatitis, neuropathy, endocrinopathy, nephritis, pneumonitis, pancreatitis, non-infectious 
myocarditis, uveitis, and iritis. 
During dose level escalation, if any of the following is observed, the CRC will be convened to 
review all safety findings for all patients treated in that cohort and all previous cohorts, including 
those events that occurred beyond Cycle 1, to guide next steps. 
• If more than one patient experiences a Grade ≥3, immune-related adverse event 
(irAE) in a cohort of 3 patients;  
• If more than two patients experience a Grade ≥3 irAE in cohorts of 6 patients.  
During the Phase 2 portion of the trial, if the incidence of Grade ≥3 irAEs observed in Cycle 1 or 
in subsequent cycles of treatment exceeds 25%, the CRC will be convened to review all safety 
findings from all patients treated in the study to guide next steps. 


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8.2. 
Duration of Study 
8.2.1. 
Treatment Duration 
The study treatment period is 29 weeks (as per Table 4) in the absence of intolerable toxicity or 
unequivocal disease progression. Continued treatment with pembrolizumab following the 
completion of IMO-2125 study treatment is at the discretion of the Investigator for patients in the 
IMO-2125 + pembrolizumab treatment arm.  
8.2.2. 
Study Duration 
The study ends approximately 1 year after the last patient in Phase 2 has commenced study 
treatment. Patients who complete or discontinue study treatment prior to progression will be 
followed for clinical and radiological evidence of progression, PRO assessments, and 
immunogenicity assessments at least every 3 months until documentation of RECIST v1.1 
progressive disease (PD), start of a subsequent anti-cancer treatment regimen, withdrawal of 
consent, death, or Sponsor notification that follow-up is no longer required, whichever comes 
first. Best response to first subsequent therapy, AEs which are Grade ≥3, and concomitant 
medications used to treat these AEs, will also be captured during the follow-up phase of the 
study (Table 1 and Table 2).  
After documentation of PD or use of a subsequent anti-cancer treatment regimen, all patients will 
be contacted by telephone every 3 months for survival follow-up until the site is notified by the 
Sponsor that survival follow-up is no longer required.  
8.3. 
Number of Patients  
The study will enroll approximately 90 to 100 patients. It is estimated that approximately 
30 patients will be treated in the dose-finding portion of Phase 1 and approximately 60 to 
70 additional patients will be treated in the Phase 2 portion of the study. 
8.4. 
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 PROCEDURES BY VISIT 
Following is a listing of the procedures to be performed at each study visit. See the Schedules of 
Evaluations (Table 1 for Phase 1 and Table 2 for Phase 2) to view the study procedures in detail 
in a tabular format. 
9.1. 
Screening (Up to 21 Days Before Day 1 of Week 1, Cycle 1) 
The following information will be captured at the Screening Visit: 
• Informed consent 
• Inclusion/exclusion criteria 
• Demography and medical history, including melanoma history and melanoma 
treatment history 
• Physical examination (should include, but not be limited to, areas related to the 
inclusion/exclusion criteria in addition to height and body weight) and assessment of 
melanoma lesions 
• ECOG performance status (Oken, 1982) (Section 21.1) 
• Target tumor lesions will be identified and assessed per RECIST v1.1 criteria.  
• The injected and non-injected tumor lesions for biopsy (biopsies optional in Phase 2) 
will be identified and recorded on the electronic case report form (eCRF), if 
performed. 
• Tumor biopsies are to be performed by surgical method (e.g., core or punch) or Fine 
Needle Aspiration (FNA) within 21 days prior to first treatment 
• Radiological assessment  
• Vital signs 
• Electrocardiogram  
• Complete blood count (CBC) with differential and chemistry profile (including liver 
function tests [LFTs])  
• Complement (total complement activity 50 [CH50], complement component 3 [C3], 
and complement component 4 [C4]) 
• Coagulation tests 
• Thyroid function profile 
• Serum or urine pregnancy test for WOCBP 
• Urinalysis with microscopic exam 
• AEs 


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9.2. 
Cycle 1 Dosing Days (Weeks 1, 2, and 3) 
Adverse event and concomitant medication monitoring will be performed on an ongoing basis. 
9.2.1. 
Pre-dose 
Before dosing, the following will be performed: 
• Physical examination (any areas related to the inclusion/exclusion criteria and body 
weight) and assessment of melanoma lesions (Week 1 only) 
• Vital signs 
• ECOG Performance Status (Week 1 only) 
• CBC with differential and chemistry profile (including LFTs)  
• Coagulation tests (Week 1 only) 
• Thyroid function profile (Week 2 only) 
• ECG (Week 2 only) 
• AEs 
• Concomitant medication monitoring 
• PK assessments (see Table 3) 
• Immunogenicity assessments (Week 1 only) 
• In Phase 2, all tumor biopsies are optional. See Section 13.2 and the Laboratory 
Manual for details on the collection of biopsies and analyses of biomarkers.  
• Blood biomarker samples  
− Week 1: Blood for PBMC and serum for cytokines 
− Week 2: Serum for cytokines 
• PRO using the EORTC QLQ-C30 (Week 1 only) 
9.2.2. 
Study Drug Administration 
• IMO-2125 by intratumoral injection (Day 1 of Week 1, Week 2, and Week 3) 
• Ipilimumab or pembrolizumab i.v. infusion (Day 1 of Week 2 only) 
9.2.3. 
Post intratumoral IMO-2125 Injection 
• AEs (including DLTs) 
• Week 1 only: blood biomarker samples collected 4 hours (serum for cytokines) and 
24 to 48 hours post-dose (blood for PBMC and serum for cytokines).  
• In Phase 2, all tumor biopsies are optional. See Section 13.2 and the Laboratory 
Manual for details on the collection of biopsies and analyses of biomarkers.  


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• PK assessments (Weeks 1 and 2 only; see Table 3) 
• ECG (Week 2 only; 2 hours post-dose IMO-2125 administration) 
9.3. 
Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, and Cycle 7 Dosing Days 
(Weeks 5, 8, 11, 17, 23, and 29) 
9.3.1. 
Pre-dose 
Before dosing, the following will be performed: 
• Physical examination (any areas related to the inclusion/exclusion criteria and body 
weight) and assessment of melanoma lesions 
• Vital signs 
• ECOG Performance Status 
• CBC with differential and chemistry profile (including LFTs)  
• Complement (CH50, C3, C4) 
• Coagulation tests  
• Thyroid function profile  
• Urinalysis with microscopic exam (Weeks 8 and 17 only) 
• AEs 
• Concomitant medication monitoring 
• Radiological assessment (Weeks 8, 17, and 29/EOT only) 
• Investigator assessment of response (Weeks 8, 17, and 29/EOT only)  
• PK assessments (see Table 3) 
• Immunogenicity assessments (Weeks 5, 11, 17, 23, and 29/EOT only) 
• Blood biomarker assessments (Weeks 5, 8, and 29/EOT only during Phase 1 and 
Week 8 only during Phase 2) 
• The longest diameter of the injected tumor will also be assessed, when possible. 
• In Phase 2, all tumor biopsies are optional. See Section 13.2 and the Laboratory 
Manual for details on the collection of biopsies and analyses of biomarkers.  
• PRO using the EORTC QLQ-C30 (Weeks 8, 17, and 29/EOT only) 
9.3.2. 
Study Drug Administration 
• IMO-2125 by intratumoral injection  
• Ipilimumab or pembrolizumab i.v. infusion 


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9.3.3. 
Post-dose 
• AEs 
• PK assessments (Week 11 only; see Table 3) 
• Blood biomarker assessment (Weeks 5, 8, and 29/EOT only during Phase 1) 
• ECG (Week 11 only; 2 hours post-dose IMO-2125 administration) 
In addition, radiological assessment (computed tomography [CT]) and Investigator assessment of 
response will be conducted at Week 8 only (±7 days). 
9.4. 
Cycle 4 (Week 13)  
• Tumor biopsies by surgical method (e.g., core or punch) or FNA at Week 13 
(Cycle 4) are optional for both Phase 1 and Phase 2, and may occur within a ±3 day 
window 
9.5. 
Safety Follow-up Visit (21 Days after Last Dose of IMO-2125) 
The following information will be captured at the Safety Follow-up (SFU) Visit (21 
days ± 5 days following the last dose of IMO-2125): 
• Physical examination (any areas related to the inclusion/exclusion criteria and body 
weight) and assessment of melanoma lesions 
• Vital signs 
• ECOG Performance Status 
• CBC with differential and  chemistry profile (including LFTs)  
• Complement (CH50, C3, C4)  
• Coagulation tests  
• Thyroid function profile  
• Serum or urine pregnancy test for WOCBP 
• Urinalysis with microscopic exam  
• ECG 
• AEs 
• Concomitant medication monitoring 
• PK assessments (see Table 3) 
• Immunogenicity assessments  


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9.6. 
Early Withdrawal 
Any patient may withdraw from the study at any time for any reason, without prejudice for his or 
her continued care. Also, an Investigator may withdraw a patient from the study in cases of 
noncompliance or if, for any reason, he or she feels it is in the patient’s best interest.  
If a patient withdraws early, SFU Visit procedures should be performed if possible. Reasons for 
withdrawal must be recorded. 
9.7. 
Unscheduled Visits 
Unscheduled visits and assessments may be conducted at Investigator’s discretion in response to 
new clinical observations or AEs. If performed, unscheduled disease assessments will be 
recorded at an unscheduled visit. Appropriate data from unscheduled visits should be recorded in 
the eCRF. 


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10. 
STUDY TREATMENTS 
10.1. 
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 will be administered by intratumoral injection for all doses (between 2 and 32 mg; 
refer to Section 8.1).  
IMO-2125 drug product is supplied as lyophilized powder for reconstitution or as an aqueous 
sterile solution. For the lyophilized product, each 5-mL glass vial contains IMO-2125 sodium 
salt equivalent to 25 mg/vial of IMO-2125 free acid. IMO-2125 drug product contains no 
excipients or preservatives. For the 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. 
10.2. 
Ipilimumab 
Ipilimumab will be provided by the site as the commercially available product. 
10.3. 
Pembrolizumab 
Pembrolizumab will be provided by the site as the commercially available product. 
10.4. 
Drug Handling and Administration 
10.4.1. 
Drug Delivery to Site 
After the research site has submitted all approved regulatory and study start-up documents, Idera 
Pharmaceuticals, Inc. will initiate a requisition for IMO-2125 to be delivered to the site via its 
distribution facility. All IMO-2125 shipments are sent at 2°C to 8°C. Upon receipt, the 
pharmacist or appropriate technician/designee must inspect the contents, verify temperature 
conditions, and confirm receipt of goods. Ipilimumab and pembrolizumab will be provided by 
the site using commercial supplies.  
Drug inventory will be maintained by the site. The site must inform Idera Pharmaceuticals, Inc., 
in writing, by facsimile, or e-mail of additional study drug needs at least 2 weeks before the 
required receipt date.  
10.4.2. 
Drug Storage 
10.4.2.1. 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. Instructions for reconstitution will be included in the Pharmacy Manual. 
IMO-2125 must be stored in a securely locked enclosure. Access is strictly limited to the 
pharmacist before preparation. 


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10.4.2.2. Ipilimumab Storage 
Vials of ipilimumab are to be stored at 2°C to 8°C and protected from light (refer to the current 
Package Insert for more details).  
10.4.2.3. Pembrolizumab Storage 
Vials of pembrolizumab are to be stored at 2°C to 8°C and protected from light (refer to the 
current Package Insert for more details).  
10.4.3. 
Administration 
10.4.3.1. IMO-2125 
IMO-2125 will be administered to each patient at one of five dose levels: 2, 4, 8, 16, or 32 mg. 
IMO-2125 will be administered as a series of intratumoral injections administered as per Table 4. 
Patients will remain at the study site for observation for a minimum of 30 minutes following 
each administration of IMO-2125. A single tumor should be selected for injection throughout the 
study and designated as the “injected tumor” on the appropriate CRF. 
The injected tumor will be selected from (in order of priority) pathologic draining lymph nodes, 
superficial or s.c. metastases, or deep (visceral) metastases, the latter requiring interventional 
radiology support. A separate (i.e., “noninjected”) tumor lesion should be identified as the distant 
lesion to be biopsied (optional in Phase 2) and recorded on the CRF. Note that tumor biopsies 
should be done prior to study treatment administration. If a full dose can no longer be practically 
administered into the designated tumor for injection, another tumor may be selected. In the event 
that complete tumor regression occurs in all accessible lesions prior to completion of therapy, 
any remaining IMO-2125 doses should be administered into the tumor bed, except in the case of 
visceral lesions where remaining doses should be given s.c. to minimize procedural risks. 
The assigned dose of IMO-2125 will be administered into the “injected tumor” by qualified 
medical personnel using an appropriate method for needle localization. It is recommended that 
the tumors be injected with 25-gauge needle; however, the choice of needle will be at the 
Investigator’s discretion. IMO-2125 should be thoroughly distributed within the injected tumor 
while avoiding necrotic areas, with a fanning method (spread the injection across several angles 
throughout the lesions, to maximize the IMO-2125 in the injected lesion).  
The total injected dose should remain constant; however, injection volume may need to be 
adjusted if the “injected tumor” decreases in size (see the Pharmacy Manual for more details). In 
the event a full dose can no longer be practically administered into the “injected tumor,” another 
lesion may be selected. 
10.4.3.2. Ipilimumab 
Ipilimumab will be administered (per the current Package Insert) i.v. over 90 minutes at 3 mg/kg 
on Day 1 of every 3-week cycle, for a total of 4 doses, except in Cycle 1, where ipilimumab will 
be administered on Day 8. IMO-2125 administration should follow ipilimumab administration. 
Due to logistical reasons, it may not be feasible to always administer IMO-2125 and ipilimumab 
on the same day. In this situation, IMO-2125 must be administered within the ±2 day study visit 
window. 


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10.4.3.3. Dose Interruption for Ipilimumab-Related Toxicities 
A scheduled dose of ipilimumab will be withheld for any moderate immune-mediated adverse 
reactions or for symptomatic endocrinopathy. For patients with complete or partial resolution of 
AEs (Grade 0-1), and who are receiving less than 7.5 mg prednisone or equivalent per day, 
ipilimumab may be resumed at a dosage of 3 mg/kg every 3 weeks until administration of all 
4 planned doses or 16 weeks from first dose, whichever occurs earlier. 
Ipilimumab is to be permanently discontinued for any of the following: 
• Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 
7.5 mg prednisone or equivalent per day. 
• Failure to complete full treatment course within 16 weeks from administration of first 
dose. 
• Severe or life-threatening adverse reactions, including any of the following: 
− Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool 
frequency (7 or more over baseline), stool incontinence, need for i.v. hydration for 
more than 24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation 
− AST or ALT >5x the ULN or total bilirubin >3x the ULN 
− Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by 
full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic 
manifestations 
− Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia 
gravis 
− Severe immune-mediated reactions involving any organ system (e.g., nephritis, 
pneumonitis, pancreatitis, non-infectious myocarditis) 
− Immune-mediated ocular disease that is unresponsive to topical 
immunosuppressive therapy 
If a patient experiences moderate enterocolitis, the Investigator should administer anti-diarrheal 
treatment, and if persistent for more than 1 week should initiate systemic corticosteroids at a 
dose of 0.5 mg/kg/day prednisone or equivalent and infliximab according to institutional 
guidelines. Testing for latent tuberculosis (purified protein derivative skin test) is recommended. 
Mild to moderate dermatitis, such as localized rash and pruritis, should be treated 
symptomatically with administration of topical or systemic corticosteroids if there is no 
improvement of symptoms within 1 week. 
The Investigator should administer corticosteroid eye drops to patients who develop uveitis, 
iritis, or episcleritis. Ipilimumab should be permanently discontinued for immune-mediated 
ocular disease that is unresponsive to local immunosuppressive therapy. 
If patients need to discontinue ipilimumab due to any severe immune-related toxicities listed 
above, the Investigator may administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of 
prednisone or equivalent. Upon improvement to Grade 1 or less, the Investigator should initiate 


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corticosteroid taper and continue to taper over at least 1 month. Standard institutional practices 
may also be implemented to treat these patients. 
10.4.3.4. Pembrolizumab 
Pembrolizumab will be administered (per the current Package Insert) i.v. over 30 minutes at 
200 mg on Day 1 of every 3-week cycle, for a total of 4 doses, except in Cycle 1, where 
pembrolizumab will be administered on Day 8. For patients assigned to the 
IMO-2125 + pembrolizumab arm, at the discretion of the Investigator, after completing 
IMO-2125 study treatment, dosing of pembrolizumab may continue every 3 weeks per the 
approved label. IMO-2125 administration should follow pembrolizumab administration when 
co-administered during Cycles 1 to 7. Due to logistical reasons, it may not be feasible to always 
administer IMO-2125 and pembrolizumab on the same day. In this situation, IMO-2125 must be 
administered within the ±2 day study visit window. 
Patients who initiated treatment at the 2 mg/kg dose may continue treatment using either the 
200 mg dose or the 2 mg/kg dose. If institutional practice requires certain patients to be treated 
using weight-based pembrolizumab dosing, those patients may be treated with the 2 mg/kg dose. 
10.4.3.5. Dose Interruption for Pembrolizumab-Related Toxicities 
Withhold pembrolizumab for any of the following: 
• Grade 2 pneumonitis  
• Grade 2 or 3 colitis  
• Grade 3 or 4 endocrinopathies 
• Grade 2 nephritis  
• AST or ALT >3 and up to 5 x ULN or total bilirubin >1.5 and up to 3 x ULN 
• Any other severe or Grade 3 treatment-related adverse reaction 
Resume pembrolizumab in patients whose adverse reactions recover to Grade 0-1. 
Permanently discontinue pembrolizumab for any of the following: 
• Any life-threatening adverse reaction (excluding endocrinopathies controlled with 
hormone replacement therapy) 
• Grade 3 or 4 pneumonitis or recurrent pneumonitis of Grade 2 severity 
• Grade 3 or 4 nephritis  
• AST or ALT >5 x ULN or total bilirubin >3 x ULN; for patients with liver metastasis 
who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by ≥50% 
relative to baseline and lasts for at least 1 week 
• Grade 3 or 4 infusion-related reactions 
• Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per 
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• Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy) that do not recover to Grade 0-1 within 12 weeks after last 
dose of pembrolizumab 
• Any severe or Grade 3 treatment-related adverse reaction that recurs 
10.4.3.6. Supportive Care Guidelines for Hypophysitis 
Refer to the prescribing information for ipilimumab or pembrolizumab for additional 
information. 
Patients should be monitored for signs and symptoms of hypophysitis such as adrenal 
insufficiency, hyperthyroidism, or hypothyroidism. 
Patients being treated with ipilimumab should have treatment withheld if they develop 
symptomatic hypophysitis. Treatment with corticosteroids at a dose of 1 to 2 mg/kg/day of 
prednisone or equivalent should be initiated along with appropriate hormone replacement 
therapy. Consider a referral to an endocrinologist. Ipilimumab treatment may be resumed after 
resolution to Grade ≤1 and decrease of the corticosteroid dose to <7.5 mg/day prednisone or 
equivalent. Ipilimumab should be permanently discontinued for symptomatic reactions lasting 
≥6 weeks or inability to reduce the corticosteroid dose to <7.5 mg/day prednisone or equivalent. 
Patients being treated with pembrolizumab should have treatment withheld for hypophysitis 
Grade ≥2. Initiate treatment with corticosteroids and hormone replacement as clinically 
indicated. Consider a referral to an endocrinologist. Pembrolizumab treatment may be resumed 
after resolution to Grade ≤1. Pembrolizumab should be permanently discontinued for 
life-threatening hypophysitis not controlled with hormone replacement therapy, inability to 
decrease corticosteroid dose to <10 mg/day prednisone or equivalent within 12 weeks, persistent 
Grade 2 or 3 hypophysitis not controlled with hormone replacement therapy that does not resolve 
within 12 weeks, or recurrence of Grade 3 or higher hypophysitis. 
10.5. 
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.  
10.6. 
Drug Accountability  
Idera Pharmaceuticals, Inc. or designated Contract Research Organization (CRO) will provide 
drug accountability logs, a pharmacy binder, and other study drug preparation worksheets, as 
necessary. Each vial of IMO-2125 is labeled with a single-panel label. The accountability logs 
and worksheets are considered source documentation for each dose preparation. Instructions on 
how these forms should be used and filed will be reiterated at the site initiation visit. 
10.6.1. 
IMO-2125 Dose Reduction  
If at any time during the study, a patient experiences a DLT as outlined in Section 8.1.5, the 
toxicity must be assessed according to the guidelines described in that section to determine 
continued dosing (refer to Section 8.1.5). 


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The site must obtain the agreement of the clinical Medical Monitor for dosage reductions. If a 
patient is considered to have received an inadequate exposure to study drug relative to his or her 
planned dose level for non-study drug related reasons, he or she will be considered for 
replacement in the study, after discussion between Investigators, the site, and Idera 
Pharmaceuticals, Inc. If inadequate exposure to study drug is due to toxicity, this will be taken 
into account in the evaluation of DLT for that dose level (see Section 8.1.3). 
10.6.2. 
Discontinuation of Study Drug 
The study drug will be discontinued in any patient who is unable to tolerate it as evidenced by 
severe or persistent intolerable AEs despite dose modification. 
10.7. 
Concomitant and Prohibited Medications  
10.7.1. 
Concomitant Medications 
With the exception of the prohibited drugs listed in Section 10.7.2, concomitant prescription 
drugs and over-the-counter drugs are permitted. These should be recorded on the eCRF starting 
with medications taken 30 days before the patient signs the informed consent form (ICF). 
10.7.2. 
Prohibited Medications 
The following drugs are prohibited while the patient is in this study:  
• Anti-cancer therapies other than those specified in the protocol 
• Drugs that either stimulate or suppress the immune system: 
− Systemic steroid therapy higher than physiologic dose (>7.5 mg/day of 
prednisone or equivalent) 
Note: For patients with pre-existing endocrine insufficiency, stress doses of 
replacement steroid treatment may be given on the day of and the day after study 
treatment administration (i.e., dosing with IMO-2125, ipilimumab, or 
pembrolizumab). Additional need for steroid replacement should be discussed 
with the Medical Monitor. 
− Topical and inhaled steroids may be acceptable after consultation with the 
Medical Monitor 
− Live vaccines (attenuated vaccines are permitted) 
• Experimental vaccines 
• Investigational/experimental medicines  


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11. 
ADVERSE EVENT REPORTING 
11.1. 
Adverse Events 
Adverse events should be assessed continuously throughout the study and recorded on the eCRF. 
Reporting during the follow-up phase of the study should be limited to Grade ≥3 AEs, associated 
concomitant medications, and serious adverse events (SAEs; see Table 1 and Table 2). 
11.1.1. 
Definition of Adverse Events 
11.1.1.1. Adverse Event 
An AE is any untoward medical occurrence temporally associated with the use of a medical 
product in a patient, 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.  
11.1.1.2. Serious Adverse Event  
An AE is serious when the patient outcome is one or more of the following: 
• Death.  
• Life-threatening, meaning that the patient 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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11.1.1.3. 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 11.1.3.3);  
• 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 11.1.3.2);  
− The event is now characterized more specifically (e.g., an event of “interstitial 
nephritis” in a patient receiving an agent previously described as associated with 
“acute renal failure”). 
In clinical trials involving ill patients, 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."  Lack 
of efficacy is recorded as specified elsewhere in the Protocol.  
11.1.2. 
Recording Adverse Events 
Procedures for the collection and recording of AEs are as follows:  
• From obtaining informed consent through the SFU Visit, there will be active 
surveillance to identify all AEs. 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 
treatment-emergent AEs.  
• After the end of study, 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 11.1.1.3). 
• In accordance with the FDA guidance document – Safety Reporting Requirements for 
Investigational New Drugs (INDs) and Bioavailability/Bioequivalence (BA/BE) 
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.  
11.1.3. 
Characterizing Adverse Events 
For each AE recorded the following characteristics will be noted.  
11.1.3.1. 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 


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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.”  
11.1.3.2. 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 patient and Investigator independently, 
and information from each may contribute to the final report. For example, a patient may report 
the onset of a rash two 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 patient and a specific 
description (herpes zoster) based on the clinical exam and tests.     
11.1.3.3. 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 patient’s underlying disease or 
co-morbid 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 decreasing the dose level 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 another 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 during the use of the study drug as planned (per 
protocol), or from abuse, withdrawal or over-dosage of the agent.  


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11.1.3.1. Immune-related Adverse Events 
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:  
• Adrenal insufficiency 
• Hypophysitis 
• Hypopituitarism 
• Other endocrinopathies  
• Colitis 
• Enterocolitis 
• Dermatitis CTCAE Grade ≥3 
• Autoimmune dermatitis CTCAE Grade ≥3 
• Guillain Barre syndrome 
• Hepatitis 
• Myasthenia gravis 
• Pneumonitis 
• Stevens Johnson Syndrome 
• Toxic epidermal necrolysis 
• Uveitis 
• Iritis 
• Any AEs that the Investigator considers to be of autoimmune or immune-related 
origin (those AE terms designated as such in the eCRF). 
Immune-related AEs will be summarized in the clinical study report. 
11.1.3.2. Severity 
The severity of clinical AEs (i.e., symptoms reported by the patient and/or signs observed by the 
Investigator) will be assessed using the guidelines summarized in Table 7 based on CTCAE 
v4.03 criteria. 
Table 7:  
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 living1 
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 living2 
Grade 4/Life-threatening 
Life-threatening consequences; urgent intervention indicated 
Grade 5/Death 
Death related to adverse event 
1. Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
2. Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 


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11.1.3.3. 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 
• Assessed as potential DLT events based on pre-specified criteria (see Section 8.1.5)  
• Reported as AEs when assessed as clinically significant (“CS”) using the procedures 
and criteria detailed in Section 11.1.2. 
11.1.3.4. 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, 
i.e., 1 or more doses were not administered, but drug was not stopped permanently. 
• Dose Decreased — study drug regimen was modified by subtraction, i.e., by 
decreasing the frequency, strength or amount. 
• None — no change in the administration of study mediation.  
For patients whose treatment is paused and then resumed at a lower dose level due to events such 
as DLTs (see Section 8.1.5), the management of study drug will be recorded as “Dose 
Decreased.” 
11.1.3.5. 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.  
11.1.3.6. 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 patients who prematurely discontinue study participation. 
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.  


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The outcome of each event will be described using the following categories:  
• Resolved without sequelae — the event resolved and patient returned to baseline.  
• Resolved with sequelae — the event resolved but the patient 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 
patient died, but were not assessed as the primary cause of death. 
11.1.3.7. Date and Time of Outcome  
For each class of outcome as defined above, Table 8 indicates the date and time to be recorded. 
As discussed in detail for date/time of onset (see Section 11.1.3.2), determining the date/time an 
event resolved (ended) should reflect the type of event and the source of the information.  
Table 8: 
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) 
11.1.4. 
Reporting Adverse Events 
11.1.4.1. Where to Report Serious Adverse Events 
Serious AE reporting will be performed by the site using the EDC system; detailed training will 
be provided during site initiation. Reports and supporting materials relating to SAEs will be 
scanned and uploaded into the EDC system. Contact information for the Medical Monitor and 
the Pharmacovigilance services is provided in the Emergency Contact Information section of this 
protocol. 
In the event an SAE cannot be submitted via EDC, contact information is provided in the 
Emergency Contact Information section of this protocol for alternative submission methods.  


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11.1.4.2. Procedures for Reporting Serious Adverse Events to the Sponsor  
The initial notification of each SAE will be entered into the EDC system within 24 hours of the 
time the Investigator (or the Investigator's designee) becomes aware that the event has occurred. 
The following items will be entered into the appropriate EDC section (any items not available 
should be explicitly noted):  
• Protocol number, study site, patient number.  
• Investigator’s name and contact information (phone, email).  
• Description of the event (i.e., date and time of onset, initial assessment, treatments 
and course).  
• Current status of the patient and the event.  
• Criteria by which the event was assessed as serious.  
• Date of the first injection of study drug.  
• Date of the last injection of study drug prior to the event.  
• Assessment of relationship of study drug to the event.  
• Whether the study drug was discontinued or adjusted as a result of the event.  
The following additional information will be entered within 2 days for death and life-threatening 
events and within 4 days for all other SAEs: 
• Narrative summary of the event — to include specific information that will assist in 
understanding the event, e.g., relevant medical history, co-morbid conditions, 
physical exam, diagnostics, assessment, treatments (including concomitant 
medications), response to treatment, course, and outcome (if known); 
• Copies of relevant medical reports — including diagnostic procedures 
(e.g., laboratory, ECG, x-ray), surgical procedures, and consultations.  
Additional documentation may be submitted as part of a follow-up report. 
11.1.4.3. 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 (patient becomes pregnant while taking study drug). Should a 
female patient or partner of a male patient become pregnant during the study, the 
patient will inform the Investigator. The patient 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 (patient was taking study drug while nursing an infant). 
• Accidental exposure (someone other than the patient was exposed to study drug).  
• Overdose (patient received more than the prescribed dose of study drug within a 
given timeframe).  


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• Other medication errors that potentially place patients at greater risk of harm than was 
previously known or recognized (e.g., study drug was administered via incorrect 
route). 
11.1.4.4. 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/ECs (typically within 7 days for fatal or life-threatening SUSARs; within 
15 days for all other SUSARs). The Sponsor and the Investigator will work together to meet 
these reporting requirements.  
 


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12. 
SAFETY ASSESSMENTS 
12.1. 
Vital Signs 
Vital sign measurements will be taken at intervals as specified in the Schedules of Evaluations 
(Table 1 and Table 2) and Section 9. Where feasible, vital signs should be measured before 
having blood drawn for laboratory evaluations. Blood pressure measurements should be taken 
with the patient in a sitting position, preferably for approximately 5 minutes.  
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 Schedules of Evaluations (Table 1 and Table 2) and Section 9. Blood 
and urine samples will be analyzed for the analytes presented in Table 9.  


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Table 9: 
Laboratory Measurements 
Hematology 
Chemistry 
Urinalysis (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 
Occult blood 
PT 
Hemoglobin 
Calcium 
Specific gravity 
aPTT 
MCH 
CO2 
Ketones 
INR 
MCHC 
Sodium, chloride, and 
potassium 
Bilirubin 
 
MCV 
Cholesterol 
 
Complement 
Platelet count 
GGT 
Microscopy 
CH50 
RBC count 
Glucose 
Bacteria  
C3 
WBC count 
Lactate dehydrogenase 
Crystals 
C4 
 
Phosphate 
Casts (cellular, granular, and 
hyaline) 
 
 
Total protein 
RBC 
 
 
Triglycerides 
WBC 
 
 
Uric acid 
Epithelial cells 
 
 
βhCG for WOCBP 
 
 
βhCG=beta human chorionic gonadotropin; ALT=alanine aminotransferase; aPTT= activated partial thromboplastin 
time; AST=aspartate aminotransferase; BUN=blood urea nitrogen; C3=complement component 3; 
C4=complement component 4; CH50=total complement activity 50; 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; TSH=thyroid-
stimulating hormone; WBC=white blood cell; WOCBP=women of childbearing potential 
12.3. 
Other Safety Assessments 
12.3.1. 
Physical Examination  
A medical history will be taken at the Screening Visit. A physical examination (including special 
attention to each of the inclusion and exclusion criteria in the protocol) and assessments of 
melanoma lesions will be performed as outlined in the Schedules of Evaluations (Table 1 and 
Table 2).  
Patient height will be recorded at the Screening Visit only. 


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12.3.2. 
Electrocardiogram Monitoring  
A resting 12-lead ECG will be performed at intervals as specified in the Schedules of 
Evaluations (Table 1 and Table 2) and Section 9.  
12.3.3. 
ECOG Performance Status 
The patient’s ECOG performance status will be evaluated per guidance in Section 21.1 as 
outlined in the Schedules of Evaluations (Table 1 and Table 2). 


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13. 
PHARMACOKINETICS AND IMMUNE RESPONSE 
The timing of sample collection is provided in the Schedules of Evaluations (Table 1 and 
Table 2) and the Schedule of PK Blood Sampling (Table 3). Detailed instructions and materials 
for all blood sampling will be provided in a separate study manual and kits.  
13.1. 
Pharmacokinetic Assessments 
The plasma PK of single-dose IMO-2125 and the PK of repeat-dose IMO-2125 administered by 
intratumoral injection in combination with ipilimumab or pembrolizumab will be evaluated at 
each of the dose levels. The following parameters will be determined for IMO-2125 plasma PK, 
if appropriate: 
• Maximum plasma concentration (Cmax) 
• Time of Cmax (tmax) 
• Area under the curve from 0 to last measurable plasma concentration (AUC0-t) 
Serum concentrations of ipilimumab and pembrolizumab will be monitored on Weeks 2, 5, 8, 11, 
17, and 23. For patients who continue pembrolizumab treatment, pembrolizumab pre-dose PK 
samples should be collected before dosing at all visits. A post-dose pembrolizumab PK sample 
should be collected 30 minutes after initiation of pembrolizumab infusion at Week 23. 
For each combination in Phase 2, the collection of plasma concentration samples will be done on 
at least 20 patients treated at the IMO-2125 RP2D after which the Sponsor will determine if 
additional samples are needed. The Sponsor will then inform the Investigators whether or not to 
continue collecting plasma concentration samples. 
The relationship between PK assessments, safety, efficacy, and pharmacodynamics variables will 
be explored whenever possible. 
13.2. 
Pharmacodynamic Markers of Immune Response 
For Phase 1, biopsies of the injected tumor will be performed at the Screening Visit (within 
21 days prior to first treatment); within 24 to 48 hours after IMO-2125 injection on Week 1 
(Cycle 1); Week 2 (Cycle 1; optional); during Week 8 (Cycle 3); and optionally at Week 13 
(Cycle 4) and at the time of disease progression or during Week 23, whichever is later. Tumor 
biopsies of the designated non-injected lesion will be performed at Screening, prior to the first 
dose of ipilimumab or pembrolizumab (optional), and during Week 8. For Phase 2, tumor 
biopsies are optional at all specified visits. Surgical methods (e.g., punch or core) are preferred 
over FNA where feasible. 
For those patients who have liver or other visceral metastases injected with IMO-2125, repeat 
biopsy of liver or other visceral tumor lesions may not always be possible. Therefore, repeat 
biopsies will be performed only when feasible in these patients. Note that tumor biopsies should 
be done prior to study treatment administration. 
The Week 8 (Cycle 3) and Week 13 (Cycle 4) biopsies may be performed within a ±3 day 
window. If tumor response is observed early during initial treatment, the Week 8 biopsies may 


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be performed at an earlier time point so as to ensure meaningful biomarker information is 
obtained prior to complete resolution of tumor. 
Exploratory variables will be assessed at pre-treatment and post-treatment and may include, but 
are not limited to: 
• Biomarkers (CD8+ T cells, NK cells, pDC/myeloid DC, memory T cells in tumor tissue, 
T cells, and cytokine levels in blood) 
• Any potential association between these biomarkers and antitumor activity 
• Gene profiling (with RNA and DNA extraction) 
• Immunogenicity (antibodies to IMO-2125, ipilimumab, or pembrolizumab) 
13.2.1. 
Immunogenicity Analyses 
Exploratory analyses will include assessing the occurrence of antibodies to the administered 
oligonucleotide (anti-IMO-2125 antibodies), as well as antibodies to the administered 
ipilimumab or pembrolizumab (refer to Table 1 and Table 2). 
13.2.2. 
Immunologic Evaluations 
Immunologic evaluations will include, but not be limited to: 
• Immunophenotyping with flow cytometry (on biopsies from patients enrolled in the 
Phase 1 portion);  
• The assessment of TCR Vß CDR3 clonal diversity will be done using ImmunoSeq™ 
(Adaptive Biotechnologies, Seattle, WA);  
• NanoString gene expression analyses. 


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14. 
ASSESSMENT OF EFFICACY 
14.1. 
Tumor Response 
Tumor response will be assessed using immune-related response criteria (irRC) and 
RECIST v1.1 in Phase 1 and using irRECIST and RECIST v1.1 in Phase 2 (Section 21.2, 
Section 21.4, and Section 21.3, respectively). Efficacy evaluation should include clinical 
examination and CT or magnetic resonance imaging scanning of known sites of disease. 
Ultrasound studies performed for needle biopsy localization or IMO-2125 dosing should not be 
used to assess tumor status (in accordance with RECIST v1.1). The same method(s) of 
assessment should be used throughout the study for consistency wherever feasible. Response 
should be assessed at Weeks 8, 17, and 29 and at least every 3 months thereafter until 
progression or start of a new anti-cancer therapy (see Section 8.2.2). Response assessments of 
CR, PR, and progressive disease must be confirmed by imaging ≥4 weeks after the initial 
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15. 
ASSESSMENT OF PATIENT REPORTED OUTCOMES 
15.1. 
EORTC QLQ-C30 
The EORTC QLQ-C30 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 5 functional scales (physical, role, emotional, social, and cognitive), 3 symptom 
scales (fatigue, nausea and vomiting, and pain) and a global health status/QoL scale, and 6 single 
items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) 
(Aaronson, 1993). 
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 (Table 1 and Table 2). To minimize bias in the PRO data, the PRO assessments 
should be completed before study drug administration and AE assessments. 
 
 


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16. 
STATISTICAL ANALYSIS METHODS 
Please refer to Section 8.1.3 for the rules around dose level escalation and stopping. 
16.1. 
Determination of Sample Size 
The primary objective of Phase 2 is to assess the preliminary clinical activity, defined as the 
investigator-assessed ORR, of IMO-2125 in combination with ipilimumab or of IMO-2125 in 
combination with pembrolizumab in patients with progression on or following PD-(L)1 inhibitor 
therapy for metastatic melanoma. Given that two primary hypotheses are being tested (regarding 
the ORR of IMO-2125 and ipilimumab and the ORR of IMO-2125 and pembrolizumab), a 
Bonferroni correction has been applied to the alpha to control the Type I error rate for the trial. 
Assuming the ORR for patients who receive ipilimumab alone is at most 11% (the historical 
response rate in patients who are PD-1 inhibitor naïve), and a target ORR of 35% for patients 
who receive the IMO-2125 + ipilimumab combination treatment, a sample size of 21 patients 
would achieve 77% power to detect a 24% difference in response rates using a one-sided 
significance level of 2.5%.  
The IMO-2125 + ipilimumab treatment arm will use a two-stage design with a targeted Type I 
error rate of 0.025 to test the null response rate of 0.11 against the alternative of at least 35%. 
With this method, 10 patients will be treated and monitored for a RECIST v1.1 response in the 
first stage. For this arm, if 2 or more patients have a RECIST v1.1 response in Stage 1, then the 
treatment arm will continue to Stage 2, in which 11 more patients will be treated. If at least 6 of 
21 patients have a RECIST v1.1 response, then the null hypothesis Ho will be rejected in favor of 
the alternative Ha. In this treatment arm, this design has statistical power of 77%, an expected 
sample size of 13.33 under the null hypothesis, and a probability of stopping at the end of the 
first stage of 69.7% if the response proportion is ≤0.11.  
At least 60 patients may be enrolled in this arm, including the 21 ipilimumab-naïve patients who 
will be used to test the null hypothesis. These 60 patients will include those with primary 
exposure to ipilimumab. The purpose of treating ~40 patients in addition to those needed for the 
hypothesis test is to improve the precision of the ORR estimate in the primary efficacy 
population and to allow preliminary assessment of safety and preliminary efficacy in the 
population with prior exposure to ipilimumab. The 95% exact confidence intervals for a range of 
sample sizes for an ORR of at least 0.35 is in Table 10. 
Table 10: ORR and Confidence Intervals with an ORR of At Least 0.35 for Possible Sample 
Sizes 
n=21 
n=30 
n=35 
n=40 
n=45 
0.381 
( 0.1811, 0.6156) 
0.367 
(0.1993 , 0.5614) 
0.371 
(0.2147, 0.5508 
0.375 
(0.2273 , 0.5420) 
0.356 
(0.2187, 0.5122) 
Assuming a RECIST v1.1 ORR for patients who receive pembrolizumab alone following failure 
of a PD-1 inhibitor is at most 5%, and a target ORR for patients who receive the 
IMO-2125 + pembrolizumab combination treatment of 35%, a sample size of 


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21 efficacy-evaluable patients would achieve 96% power to detect a 30% difference in response 
rates using a one-sided significance level of 2.5%. 
The IMO-2125 + pembrolizumab treatment arm will use a two-stage design with a targeted 
Type I error rate of 0.025 to test the null response rate against the alternative of at least 35%. If at 
least 1 patient has a RECIST v1.1 response in Stage 1, then the treatment arm will continue to 
Stage 2 and treat 11 additional patients. If at least 4 of the 21 total patients have a RECIST v1.1 
response, then the null hypothesis Ho will be rejected in favor of the alternative Ha. In this 
treatment arm, this design has statistical power of 96%, an expected sample size of 14.41, and a 
probability of stopping at the end of the first stage of 60% if the response proportion is ≤0.05. 
16.2. 
Analysis Populations 
• Primary Ipilimumab + IMO-2125 Efficacy Evaluable (PIIEE) Population:  all patients 
who are ipilimumab-naïve on study entry (including those who received ipilimumab 
only in the adjuvant setting) and who are treated at the RP2D for the IMO-2125 + 
ipilimumab combination, regardless of which phase of the study they receive it; and 
who received at least one dose of each study drug. 
• Secondary Ipilimumab + IMO-2125 Efficacy Evaluable (SIIEE) Population:  all 
patients who are not ipilimumab-naïve on study entry and who are treated at the 
RP2D for the IMO-2125 + ipilimumab combination, regardless of which phase of the 
study they receive it; and who received at least one dose of each study drug. 
• Primary Pembrolizumab + IMO-2125 Efficacy Evaluable (PPIEE) Population:  all 
patients who are treated at the RP2D for the IMO-2125 + pembrolizumab 
combination, regardless of which phase of the study they receive it; and who received 
at least one dose of each study drug. 
• Safety Population: all patients who received at least one dose of IMO-2125.  
• DLT Evaluable Population: all patients in the Safety Population who continue 
participation in the study for the entire DLT evaluation period, or who discontinue 
prematurely due to a DLT. 
• PK Population: All subjects in the Safety Population who have ≥1 post-dose sample 
analyzed for study drug. 
16.3. 
General Considerations 
Continuous variables will be summarized using descriptive statistics such as mean, standard 
deviation, median, and range. Categorical variables will be summarized by count and proportion, 
and if specified, with 95% confidence intervals for the proportion. Missing data will not be 
imputed except as described in the Statistical Analysis Plan. 
Data will be analyzed at the end of dose-finding for each treatment. Phase 2 data will be 
analyzed at the end of Phase 2 (approximately 1 year after the last patient in Phase 2 has 
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16.4. 
Analysis of Safety 
Analysis of DLTs will be performed on the DLT Evaluable Population. All other safety analyses 
will be performed on the Safety Population. 
Dose-limiting toxicities will be summarized by dose level with the n and percentage.  
Vital signs, laboratory values, and ECG values will be summarized descriptively; no formal 
statistical hypotheses will be tested.  
For laboratory values that are continuous, shift tables from baseline to worst value on study will 
be produced. Laboratory values that are out of the normal range as graded by CTCAE criteria 
will be flagged in listings, and any values that are judged by the Investigator as clinically 
significant will also be flagged as such. 
Adverse events will be tabulated by MedDRA System Organ Class and Preferred Term. Adverse 
event tables will be produced by treatment group. Adverse event summaries will be as follows: 
overall, by severity, and related AEs. Listings of any deaths, SAEs, and AEs leading to 
discontinuation of treatment will be produced. 
Any abnormal findings from physical examinations will be reported as AEs. As such, physical 
examination results will not be summarized. 
Concomitant medications will be coded by World Health Organization drug class and 
Anatomical Therapeutic Chemical text and tabulated as such. The ECOG performance status will 
be tabulated by dose group and visit. 
16.5. 
Analysis of Pharmacokinetics 
For each cohort, the plasma IMO-2125 concentration data will be analyzed by 
non-compartmental PK analysis. Descriptive statistics will be provided for concentration data 
and all PK assessment values by study drug (IMO-2125, ipilimumab, and pembrolizumab), dose, 
and time, as appropriate. 
Dose proportionality using the power model will be evaluated in an exploratory manner, if the 
data permit. If insufficient data are available to assess dose proportionality using the power 
model, dose normalized data will be presented for a graphical assessment. 
The potential effects of IMO-2125 on the PK of ipilimumab and pembrolizumab will be 
evaluated. 
16.6. 
Analysis of Efficacy 
The primary analysis of efficacy in the Phase 2 IMO-2125 + ipilimumab arm, including the 
hypothesis test of the ORR, will be performed on the first 21 patients in the PIIEE Population as 
defined in Section 16.2. An analysis on those in the SIIEE Population will also be performed; 
efficacy analysis in the combined PIIEE and SIIEE Populations may also be summarized. The 
primary analysis of efficacy in the Phase 2 IMO-2125 + pembrolizumab arm will be performed 
on the PPIEE Population as defined in Section 16.2.  
Patients will be categorized into subgroups based on whether they had previously been treated 
with talimogene or another oncolytic viral vector prior to enrollment in this study. 


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16.6.1. 
Analysis of Primary Treatment Effect Parameter 
The primary efficacy endpoint, ORR assessed by the Investigator using RECIST v1.1, will be 
analyzed for the first 21 efficacy-evaluable patients in the PIIEE Population using a one-sided, 
one sample exact binomial test with α = 0.025 in each test. The proportion of patients achieving 
an overall response will be tested against the null rates of 0.11 and 0.05 for ipilimumab and 
pembrolizumab, respectively (Hodi, 2010). ORR by RECIST v1.1 will also be summarized 
descriptively for all subjects in the PIIEE. 
16.6.2. 
Analysis of Secondary Treatment Effect Parameters 
The ORR and DCR using irRECIST criteria will be summarized descriptively in the PIIEE, 
SIIEE, and PPIEE Populations by dose with the n, percentage, and exact 95% confidence 
intervals. DCR will also be summarized by RECIST v1.1. 
The OS and PFS proportions will be estimated at 6 and 12 months; OS and PFS will also be 
analyzed overall. For time-to-event endpoints (OS, PFS, and DoR), the Kaplan-Meier method 
will be used to estimate the probability of event-free survival. Patients who have not experienced 
the event at the data cut-off date for study closure will be censored. Patients who are lost to 
follow up will be censored at the last valid disease assessment for PFS and date of last contact 
for OS. Kaplan-Meier plots will be produced for OS and PFS by treatment arm. 
16.7. 
Exploratory Analyses 
Patterns of missing data will be described for PRO. Mean change from Baseline in the global 
health status score over time will be summarized and presented graphically. A mixed model for 
repeated measures may be used to assess the statistical significance of changes from Baseline. 
Exploratory endpoint analyses will be fully described in the statistical analysis plan.  


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17. 
DATA COLLECTION 
17.1. 
Required Data 
The full study dataset will be collected for patients who enter the treatment phase of the study, 
unless the patient withdraws consent. If a patient discontinues the study (for any reason, 
drug-related or other), every effort will be made to complete the SFU Visit within 21 days of the 
last dose (±5 days).  
All required data for this study will be collected by EDC and all data collected in this study will 
be listed in the clinical study report. 
17.2. 
Data Collection and Tracking 
Qualified study staff at each site will perform primary data collection from source-document 
reviews. The designated CRO will perform clinical monitoring, including review of eCRFs with 
verification to the source documentation. 
Safety laboratory and ECG data from the Screening Visit through the SFU Visit will be collected 
at the participating site. A Central Lab may be used to track and analyze the complement, PK 
and immunogenicity testing.  
Site staff will enter data into a 21 CFR Part 11 compliant 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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18. 
STUDY RESPONSIBILITIES 
18.1. 
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 Pharmaceuticals, Inc. (or its representative) and the IRB/EC in writing 
regarding the type of emergency and the course of action taken. 
18.2. 
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. 
18.3. 
Training 
The training of appropriate clinical site personnel will be the responsibility of the designated 
CRO. 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, the designated CRO 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 the designated CRO in the course of regular site monitoring. 
18.4. 
Monitoring the Investigational Site 
Monitoring of the study (which may be delegated by the Sponsor to a CRO) will be performed 
according to the Study Monitoring Plan. 
18.5. 
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 patient 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 regional, federal, state, 
and local laws, rules, and regulations; and, for each patient participating in the study, will 
promptly complete all eCRFs and such other reports as required by this protocol following 


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completion or termination of the clinical study or as otherwise required pursuant to any 
agreement with Idera Pharmaceuticals, Inc. 
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 the designated CRO and Idera Pharmaceuticals, Inc. 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 Pharmaceuticals, Inc. or responsible government agencies as required by law. The 
Investigator agrees to promptly take any reasonable steps that are requested by 
Idera Pharmaceuticals, Inc. or the designated CRO as a result of an audit to cure deficiencies in 
the study documentation and eCRFs. 
18.6. 
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, patient diaries, biopsy reports, ultrasound photographs, patient 
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 patient’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 patient before involvement in the study 
sufficient to verify protocol entry criteria 
2. Medical record documenting that informed consent was obtained for the patient’s 
participation in the study 
3. Dated and signed notes for each patient 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. Patient’s condition upon completion of or withdrawal from the study 


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18.7. 
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. 
18.8. 
Study Supply Accountability 
The Investigator will maintain complete and accurate records of the receipt and disposition of all 
investigational agents. When the enrollment is complete, the Investigator will be notified by 
Idera Pharmaceuticals, Inc. and, in a timely manner, will destroy the study drug in a documented 
fashion, as directed by Idera Pharmaceuticals, Inc. 
18.9. 
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 patient visit or the availability of test results. All completed eCRFs will be reviewed by a 
representative of the designated CRO 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 Pharmaceuticals, Inc. that records may be destroyed. Idera 
Pharmaceutical, Inc. retains the right to evaluate imaging studies used to make efficacy 
assessments, including central imaging facility review. 
The Investigator(s) must maintain all Essential Documents (as listed in the International Council 
for Harmonisation [ICH] Guideline for GCP) until notified by Idera Pharmaceuticals, Inc. or its 
designees, and in accordance with all local laws regarding retention of records. 
The Investigator must obtain written permission from Idera Pharmaceuticals, Inc. or its designees 
before disposing of any records. To avoid error, the Investigator will contact Idera 
Pharmaceuticals, Inc. before the destruction of any records pertaining to the study. The 
Investigator will promptly notify Idera Pharmaceuticals, Inc. or its designees in the event of 
accidental loss or destruction of any study records. In addition, Idera Pharmaceuticals, Inc. will 
be contacted if the Investigator plans to leave the institution so that arrangements can be made 
for the transfer of records. 
18.10. 
Study Closeout 
Upon completion of the study (defined as all patients have completed all follow-up visits, all 
eCRFs are complete, and all queries have been resolved), the designated CRO 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 Pharmaceuticals, Inc. or the designated CRO. 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/EC of study closure. 


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18.11. 
Audit/Inspections 
Quality assurance personnel from Idera Pharmaceuticals, Inc., or its partners, 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. 
Regulatory authorities worldwide may conduct inspections of the Investigator during or after the 
study. The Investigator should contact Idera Pharmaceuticals, Inc. immediately if this occurs and 
must fully cooperate with Regulatory Authorities inspections conducted at a reasonable time in a 
reasonable manner. 
Idera Pharmaceuticals, Inc. retains the right to conduct independent review of radiologic scans 
for up to 3 years following completion of the study. 
 


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19. 
ETHICAL CONSIDERATIONS 
By signing this protocol, the Investigator agrees to conduct the study in compliance with the 
protocol, the International Council for Harmonisation (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. 
19.1. 
Role of Sponsor 
As the study Sponsor, Idera Pharmaceuticals, Inc. has overall responsibility for the conduct of 
the study, including assurance that the study meets the regulatory requirements. In this study, 
Idera Pharmaceuticals, Inc. will have certain direct responsibilities and will delegate other 
responsibilities to the designated CRO. The CRO will ensure adherence to the Sponsor’s general 
responsibilities and other responsibilities as agreed between the designated CRO and Idera 
Pharmaceuticals, Inc., e.g., selection of Investigators, monitoring, and protocol amendments. 
19.2. 
Informed Consent 
The Investigator has both ethical and legal responsibility to ensure that each patient being 
considered for inclusion in this study is given a full explanation of the study. Written informed 
consent will be obtained from all patients (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 ICF approved by the same IRB/EC 
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 Pharmaceuticals, Inc. of any ICF intended for use in the 
study, prior to submission for IRB/EC approval. 
The consent form will be reviewed with the prospective study patient 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 patient and fully explained 
by the Investigator or qualified designee, and it is felt that the patient understands the 
implications of participating, the patient and the Investigator or designee will sign and date the 
IRB/EC-approved written ICF. The patient 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 patient’s 
informed consent for and participation in this study will be noted in the patient’s medical record.  
If the patient is illiterate, an impartial witness is required to be present during the entire informed 
consent reading and discussion. Afterward, the patient 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 patient 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 patient’s willingness to continue 


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participation in the trial. The communication of this information to the patient will be 
documented. 
19.3. 
Confidentiality of Patients 
Patient confidentiality will be maintained throughout the clinical study in a way that ensures the 
information can always be tracked back to the source data. For this purpose, a unique patient 
identification code (ID number and patient name code) will be used that allows identification of 
all data reported for each patient. 
Patient information collected in this study will comply with the standards for protection of 
privacy of individually identifiable health information as promulgated in the Health Insurance 
Portability and Accountability Act (HIPAA) and as mandated in 45 CFR 160 and 164. All 
records will be kept confidential and the patient’s name will not be released at any time. Patient 
records will not be released to anyone other than Idera Pharmaceuticals, Inc. or its designees, and 
responsible regulatory authorities, when requested. In all cases, caution will be exercised to 
assure the data are treated confidentially and that the patient’s privacy is guaranteed. 
19.4. 
Authorization for Use and Disclosure of Protected Health 
Information 
An authorization for use and disclosure of protected health information (PHI) under the HIPAA 
Privacy Rule (45 CFR 164.102 et seq) will be obtained from every study patient before, or at the 
time of, enrollment. It will be presented to, and signed by, the patient at the same time as the 
ICF. The Investigator is responsible for obtaining patients’ (or their legal representatives’) 
authorizations and signatures and for explaining the elements of the HIPAA authorization form if 
necessary. 
The HIPAA authorization may be either a separate form or included in the study ICF, dependent 
upon local requirements. If a separate HIPAA document is signed, the Investigator will append 
one signed original of each executed HIPAA authorization to the study patient’s signed ICF and 
file it in the site’s regulatory file. If a second copy of the signed ICF is filed in the patient’s 
medical records, an additional copy of the signed HIPAA authorization form will be appended. 
Patients will be given the other signed duplicate for their personal records. 
The HIPAA authorization form will contain all elements required under the HIPAA Privacy 
Rule. By law, site IRB/EC approval of the Sponsor-provided authorization form for use in this 
study is not required, and no such approval will be sought or requested. However, Idera 
Pharmaceuticals, Inc., upon request, will provide advance copies of its HIPAA authorization 
form to the Investigator or the site’s privacy board or privacy official and will work with the site 
to eliminate any concerns. 
The Investigator or the site will promptly inform Idera Pharmaceuticals, Inc. of any restrictions 
on the use or disclosure of PHI of any patient to which the site or the Investigator have agreed 
under the Privacy Rule. The Investigator or the site will also promptly inform Idera 
Pharmaceuticals, Inc. of any written revocation of any patient’s HIPAA authorization. 


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19.5. 
Human Patient Protections 
19.5.1. 
Research Patient Selection and Justification of Exclusions 
There will be no exclusion from participation in the study on the basis of ethnicity or race. 
Patients younger than 18 years of age will be excluded from the study, as the target population is 
adults. Women of childbearing potential will have serum- and urine-human chorionic 
gonadotropin testing before enrollment in order to avoid potential fetal exposure. Cognitively 
impaired individuals, prisoners, or other institutionalized persons will be allowed to participate 
only after documented consultation with the IRB/EC. 
Patients who are identified will be referred to the Investigator or authorized designee for 
screening. Patients will then undergo the screening process, during which they will have multiple 
opportunities to ask questions. The PI or authorized designee will provide a detailed discussion 
of the protocol and answer any remaining questions. The patient will be given time to consider 
study participation. No coercion or undue influence on this decision will be used. Only those 
patients who give written, informed consent, meet prescreening requirements, and successfully 
complete screening testing before the date of planned study drug administration will be 
considered for participation in the study. Specific consent is required for serum samples to be 
stored for future studies in coagulation and inflammation. Participation in the study is not 
contingent upon a patient’s agreement to provide additional serum samples. 
Blood specimens will be coded to ensure patient confidentiality.  
19.5.2. 
Risks/Discomforts of Study Participation 
IMO-2125 is designed to stimulate the immune system and some low-grade and transient signs 
and/or symptoms may occur: 
• Low-grade elevation in body temperature 
• Mild headache 
• Chills 
• Diaphoresis 
• Myalgia 
• Fatigue 
In addition, patients may experience some or none of the following manifestations of local site 
injection reactions: 
• Erythema (characteristically maximal by second day) 
• Induration (sometimes persisting for up to 1 week) 
• Pain (usually mild and requiring no treatment) 
• Tenderness to the touch 
Patients will undergo the study procedures detailed in Section 9, some of which can be expected 
to cause mild discomfort. 


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19.6. 
Institutional and Ethics Review  
This protocol and a patient 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 patients and 
release of investigational product. Documentation of IRB/EC approval and the approved consent 
form must be received by Idera Pharmaceuticals, Inc. or its designees prior to obtaining the 
patient’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. 
19.7. 
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 patients will disclose required information for the time period 
during which the Investigator is participating in the study and for 1 year following completion of 
the study. 
  


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20. 
LIST OF REFERENCES 
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. 
Abreu MT. Toll-like receptor signaling in the intestinal epithelium: how bacterial recognition 
shapes intestinal function. Nat Rev Immnol. 2010;10:131-144. 
Aspord C, Leccia MT, Charles J, Plumas J. Plasmacytoid dendritic cells support melanoma 
progression by promoting Th2 and regulatory immunity through OX40L and ICOSL. Cancer 
Immunol Res. 2013;1:402-415. 
Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in 
patients with metastatic melanoma: long-term survival update. Cancer J Sci. 
2000;Am 6 (Suppl 1): S11-4. 
Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, et al. High-dose 
recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 
270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17: 2105-2116. 
Baines J, Celis E. Immune-mediated tumor regression induced by CpG-containing 
oligodeoxynucleotides. Clin Cancer Res. 2003;9:2693-2700. 
Bernasconi N, Traggiai E, Lanzavecchia A. Maintenance of serological memory by polyclonal 
activation of human memory B cells. Science. 2002;298:2199-2202. 
Bhagat, L. Time dependent cytokine secretion by human PBMCs in vitro in response to 
IMO-2125 treatment. Idera Study. 2007a;Number PH2125-012. 
Bhagat, L. Time dependent cytokine secretion by human PBMCs in vitro in response to 
IMO-2125 treatment. Idera Study. 2007b;Number PH2125-012A. 
Bhagat L. Time dependent cytokine secretion by human pDCs in vitro in response to IMO-2125 
treatment. Idera Study. 2007c;Number PH2125-015A. 
Bhagat L. To test the concentration dependent effect of IMO-2125 on IFN-a secretion by human 
plasmacytoid dendritic cells in vitro. Idera Study. 2007d;Number PH2125-016. 
Bhagat L. To test the concentration dependent effect of IMO-2125 on IFN-a secretion by human 
PBMCs in vitro. Idera Study. 2007e;Number PH2125-019. 
Bhagat, L. To test the concentration dependent effect of IMO-2125 in human B-cell proliferation 
assays. Idera Study. 2007f;Number PH2125-026. 
Bhagat, L. Activation of human B-cells by IMO-2125: A flow cytometry study. Idera Study. 
2007g;Number PH2125-027. 
Bhagat, L. Activation of human pDCs by IMO-2125: A flow cytometry study. Idera Study. 
2007h;Number PH2125-028. 
Bhatia S, Tykodi SS, Thompson JA. Treatment of metastatic melanoma: an overview. Oncology. 
2009;23:488-496. 


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Bohnsack O, Ludajic K, Hoos A. Adaptation of the immune-related response criteria: irRECIST. 
Ann Onc. 2014;25(Suppl-4):iv361-iv372. 
Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, et al. A new member 
of the immunoglobulin superfamily--CTLA-4. Nature. 1987;328(6127):267-270. 
Chan E, Kwak EL, Hwang J, Heiskala M, de La Bourdonnaye G, Mita M. Open-label phase 1b 
study of FOLFIRI plus cetuximab plus IMO-2055 in patients with colorectal cancer who have 
progressed following chemotherapy for advanced or metastatic disease. Cancer Chemother 
Pharmacol. 2015 Jan 28. [Epub ahead of print]. 
Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03, 14 June 2010. U.S. 
Department of Health and Human Services, National Institutes of Health, National Cancer 
Institute. NIH Publication No. 09-5410. 
den Brok MH, Sutmuller RP, van der Voort R, Bennink EJ, Figdor CG, Ruers TJ, et al. In situ 
tumor ablation creates an antigen source for the generation of antitumor immunity. Cancer Res. 
2004;64:4024-4029. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45:228-247. 
Heckelsmiller K, Rall K, Beck S, Schlamp A, Seiderer J, Jahrsdörfer B, et al. Peritumoral CpG 
DNA elicits a coordinated response of CD8 T cells and innate effectors to cure established 
tumors in a murine colon carcinoma model. J Immunol. 2002;169:3892-3899. 
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved 
survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 
2010;363:711-723. 
Kandimalla ER, Bhagat L, Wang D, Yu D, Zhu FG, Tang J, et al. Divergent synthetic nucleotide 
motif recognition pattern: design and development of potent immunomodulatory 
oligodeoxyribonucleotide agents with distinct cytokine induction profiles. Nucleic Acids Res. 
2003;31(9):2393-2400. 
Kandimalla ER, Bhagat L, Li Y, Yu D, Wang D, Cong YP, et al. Immunomodulatory 
oligonucleotides containing a cytosine-phosphate-2'-deoxy-7-deazaguanosine motif as potent 
toll-like receptor 9 agonists. Proc Natl Acad Sci USA. 2005;102(19):6925-6930. 
Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, et al. High- and 
low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial 
E1690/S9111/C9190. J Clin Oncol. 2000;18:2444-2458. 
Lachiewicz AM, Berwick M, Wiggins CL, Thomas NE. Epidemiologic support for melanoma 
heterogeneity using the surveillance, epidemiology, and end results program. J Invest Dermatol. 
2008;128:1340-1342.  
Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in 
Untreated Melanoma. N Engl J Med. 2015;373(13):1270-1.  


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Levings MK, Sangregorio R, Roncarolo MG. Human cd25(+)cd4(+) t regulatory cells suppress 
naive and memory T cell proliferation and can be expanded in vitro without loss of function. 
J Exp Med. 2001;193:1295-1302. 
Liu YJ. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell 
precursors. Annu Rev Immunol. 2005;23:275-306. 
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. 
Nierkens S, den Brok MH, Roelofsen T, Wagenaars JA, Figdor CG, Ruers TJ, et al. Route of 
administration of the TLR9 agonist CpG critically determines the efficacy of cancer 
immunotherapy in mice. PLoS One. 2009;4:e8368. 
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. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. 
CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 
2005;25(21):9543-9553. 
Postow MA, Chesney J, Pavlick AC, Robert C, Grossman K, McDermott D, et al. Nicolumab 
and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 
2015;372(21):2006-17. 
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus 
Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521-2532. 
Shin DS, Ribas A. The evolution of checkpoint blockade as a cancer therapy: what’s here, what’s 
next? Curr Opin Immunol. 2015;33:23-35. 
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29. 
Smith DA, Conkling P, Richards DA, Nemunaitis JJ, Boyd TE, Mita AC, et al. Antitumor 
activity and safety of combination therapy with the Toll-like receptor 9 agonist IMO-2055, 
erlotinib, and bevacizumab in advanced or metastatic non-small cell lung cancer patients who 
have progressed following chemotherapy. Cancer Immunol Immunother. 2014;63(8):787-796.  
Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol. 2005;Jan;17(1):1-14. 
Thall PF, Cook JD, Estey E. Adaptive dose selection using efficacy-toxicity trade-offs: 
illustrations and practical considerations. J Biopharm Stat. 2006;16(5):623-638. 
Trombino AF. A report of cytometry and hematology analyses from samples collected in 
immunopharmacological screening of oligonucleotide test articles in cynomolgus monkeys. Idera 
Study. 2007a;Number PH2125-006. 
Trombino AF. Report of cytokine, flow cytometry and hematology analyses from samples 
collected in immunopharmacological screening of oligonucleotide test articles in cynomolgus 
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Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade 
induces responses by inhibiting adaptive immune resistance. Nature. 2014; 515(7528):568-571. 
Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, et al. CTLA-4 can 
function as a negative regulator of T cell activation. Immunity. 1994;1:405-413. 
Wickelgren I. Targeting the tolls. Science. 2006;312:184-187. 
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 
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strategies. Pharmacol Ther. 2015;S0163-7258. [Epub ahead of print]. 


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21. 
APPENDICES 
21.1. 
Eastern Cooperative Oncology Group 
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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21.2. 
Immune-Related Response Criteria (irRC) 
During Phase 1, subject management and response assessments will be performed according to 
irRC (Wolchok, 2009).  
Appendix Table 1: Overall Response using irRC: 
Response assessment 
Description 
irCR 
Complete disappearance of all lesions (whether measurable or 
not, and no new lesions) 
Confirmation by a repeat, consecutive assessment 
≥4 weeks after first documentation 
irPR 
Decrease in tumor burden ≥50% relative to baseline 
Confirmed by a consecutive assessment ≥4 weeks after 
first documentation 
irSD 
Not meeting criteria for irCR or irPR, in absence of irPD. 
A change in tumor burden of neither 50% decrease from 
baseline nor 25% increase from nadir can be determined. 
irPD 
Increase in tumor burden ≥25% relative to nadir (minimum 
recorded tumor burden) 
Confirmation by a repeat, consecutive assessment 
≥4 weeks after the first documentation 
Abbreviations: CR=complete response; irRC=Immune-related Response Criteria; PD=progressive disease; 
PR=partial response; SD=stable disease 
 
Appendix Table 2: Derivation of irRC overall responses 
Measurable response 
Non-measurable response 
 
Target and new, 
measurable lesions 
% change in tumor 
burden 
Non-target lesions 
New non-measurable 
lesions 
Overall irRC response 
↓ 1001 
Absent 
Absent 
irCR3 
↓ 1001 
Stable 
Any 
irPR3 
↓ 1001 
Unequivocal progression 
Any 
irPR3 
↓ ≥501 
Absent or Stable 
Any 
irPR3 
↓ ≥501 
Unequivocal progression 
Any 
irPR3 
↓ ≥50 to  ↑<251 
Absent or Stable 
Any 
irSD 
↓ ≥50 to   ↑<251 
Unequivocal progression 
Any 
irSD 
↑ ≥252 
Any 
Any 
irPD3 
1  Decrease relative to baseline 
2  Increase relative to nadir 
3  Confirmed by consecutive scan ≥4 weeks after first documentation 
 


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21.3. 
irRECIST (Immune-Related Response Evaluation Criteria in Solid 
Tumors) 
In Phase 2 of the study, patient management and response assessments will be performed 
according to irRECIST (Nishino, 2013; Bohnsack, 2014). For irRECIST, a unidimensional 
measurement is assessed for the longest diameter of each lesion. 
Target lesion: ≥10 mm in longest diameter (target nodal lesion ≥15 mm in shortest diameter), 
representative of the organs involved, and lend themselves to reproducible repeated 
measurements. Baseline target lesions are limited to a total of 5 with no more than 2 in any 
single organ. Previously irradiated lesions should not be selected as target lesions unless they 
have shown unequivocal progression after the radiation. 
Non-target lesion: all other lesions, including small lesions (<10 mm in longest diameter or 
nodal lesions ≥10 mm and <15 mm in shortest diameter) and all truly non-measurable lesions. 
Tumor burden: the sum of the longest diameters of all baseline target lesions (use shortest 
diameter for target nodal lesions) and all measurable new lesions. 
Appendix Table 1: Overall 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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21.4. 
RECIST v1.1 Criteria 
 


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Appendix Table 2: 
Objective Response Status at Each Evaluation 
 
 


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Appendix Table 3: 
Objective Response Status at Each Evaluation for Patients with 
Non-Target Disease Only 
 
 
 
 
 

SAP_001.pdf: 
as
 
 
Statistical Analysis Plan 
 
Sponsor Idera Pharmaceuticals, Inc. 
Protocol Number: 2125-204 
IND Number: 125515 
 
Protocol Title: A Phase 1/2 Study to Assess the Safety and Efficacy of Intratumoral 
IMO-2125 in Combination with Ipilimumab or Pembrolizumab in Subjects with 
Metastatic Melanoma 
Protocol Version 8: 27 March 2018 
 
 
Sponsor:  
 
Idera Pharmaceuticals, Inc. 
 
505 Eagleview Blvd, Suite 212 
 
Exton, PA 19341 
 
Prepared by:  
Lan Liu  
 
430 David Dr, Suite 500 
 
Morrisville, NC 27560 
 
 
Version 
Date 
Draft 1 
28 Jun 2016 
Draft 2 
26 July 2016 
Draft 3 
7 November 2016 
Draft 4 
6 February  2017 
Draft 5 
10 April 2017 
Draft 6 
01May 2017 
Draft 7 
28 July 2017 
Draft 8 
14 September 2017 
Draft 9 
03 January 2018 


Idera Pharmaceuticals, Inc  
                                                                            Statistical Analysis Plan 
Protocol Number: 2125-204 
 
Final 1.1, March 5th 2020 
 
 
Page 2/82 
CONFIDENTIAL 
Idera 2125-204-SAP_FINAL_05Mar2020_OG2.docx 
 
 
Draft 10 
30 January 2018 
Draft 11 
28 February 2018 
Final 
16 May 2018 
Final 1.1 
05 March 2020 
 


Idera Pharmaceuticals, Inc  
                                                                            Statistical Analysis Plan 
Protocol Number: 2125-204 
 
Final 1.1, March 5th 2020 
 
 
Page 3/82 
CONFIDENTIAL 
Idera 2125-204-SAP_FINAL_05Mar2020_OG2.docx 
 
 
 
Approval 
 
Upon review of this document, including table, listing, and figure shells, the undersigned 
approves the Statistical Analysis Plan. The analysis methods and data presentation are 
acceptable. 
 
 
 
 
 


Idera Pharmaceuticals, Inc  
                                                                            Statistical Analysis Plan 
Protocol Number: 2125-204 
 
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TABLE OF CONTENTS 
 
 
LIST OF ABBREVIATIONS ....................................................................................................... 7 
1. 
INTRODUCTION ................................................................................................................ 11 
2. 
STUDY OBJECTIVES ........................................................................................................ 11 
2.1 PRIMARY OBJECTIVE ..................................................................................................... 11 
2.2 SECONDARY OBJECTIVES ............................................................................................... 11 
2.3 EXPLORATORY OBJECTIVES .......................................................................................... 12 
3. 
STUDY DESIGN AND PLAN ............................................................................................ 12 
3.1 
OVERVIEW .................................................................................................................. 12 
3.1.1 
Phase 1 ............................................................................................................ 12 
3.1.2 
Phase 2 ............................................................................................................ 14 
3.1.3 
Dose Escalation and Stopping Rules .............................................................. 14 
3.1.3.1 Phase 2 Stopping Rules .................................................................................. 15 
3.1.4 
Cohort Review Committee ............................................................................. 16 
3.1.5 
Definition of Dose-limiting Toxicities ........................................................... 16 
3.1.6 
Safety Assessment for Immunologically Related Toxicity ............................ 19 
3.2 
DURATION OF STUDY ................................................................................................. 19 
3.2.1 
Treatment Duration ......................................................................................... 19 
3.2.2 
Study Duration and Study Completion ........................................................... 20 
3.3 
NUMBER OF SUBJECTS ............................................................................................... 20 
3.4 
SCHEDULES OF EVALUATIONS .................................................................................. 21 
4. 
DETERMINATION OF SAMPLE SIZE .......................................................................... 27 
5. 
GENERAL ANALYSIS CONSIDERATIONS ................................................................. 29 
6. 
ANALYSIS POPULATIONS .............................................................................................. 30 
7. 
STUDY POPULATION ...................................................................................................... 30 
7.1 
SUBJECT DISPOSITION ............................................................................................... 30 
7.2 
PROTOCOL DEVIATIONS ............................................................................................ 31 
7.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................ 31 
7.4 
CONCOMITANT MEDICATIONS .................................................................................. 31 
8. 
EFFICACY ANALYSES ..................................................................................................... 32 
8.1 
BEST OVERALL RESPONSE ........................................................................................ 33 
8.1.1 
Confirmed Response using RECIST v1.1 ...................................................... 33 
8.1.2 
Best Response at an Interim Analysis using RECIST v1.1 ............................ 35 
8.1.3 
Confirmed Response using irRC and irRECIST ............................................ 35 
8.1.4 
Derivation of irRECIST Confirmed Response for Phase 1 Subjects Treated at 
the RP2D...................................................................................................................... 36 


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8.1.5  Best Response at an Interim Analysis using irRECIST ..................................... 39 
8.2 
EXPLORATORY ENDPOINTS ....................................................................................... 39 
8.3 
BASELINE, WORST, AND BEST-CASE POST-BASELINE VALUES .............................. 39 
8.4 
MISSING DATA ............................................................................................................ 40 
8.5 
EFFICACY ENDPOINTS ............................................................................................... 41 
8.6 
INTERIM ANALYSIS .................................................................................................... 42 
8.7 
EXAMINATION OF SUBGROUPS .................................................................................. 42 
8.8 
MULTIPLE COMPARISON/MULTIPLICITY ................................................................. 43 
9 
METHODS OF EFFICACY ANALYSIS .......................................................................... 43 
9.1 
PHASE 1 ....................................................................................................................... 43 
9.2 
PRIMARY EFFICACY ANALYSES ................................................................................ 43 
9.3 
SECONDARY EFFICACY ANALYSES ........................................................................... 44 
9.3.1 
Evaluation of Response .................................................................................. 44 
9.3.2 
Evaluation of Time to Event Endpoints .......................................................... 45 
9.3.3 
Measurable Disease Assessment .................................................................... 45 
9.4 
EXPLORATORY ANALYSES......................................................................................... 45 
9.4.1 
Pharmacodynamic Markers ............................................................................ 45 
9.4.2 
Immunogenicity Analyses .............................................................................. 45 
10 SAFETY ANALYSES .......................................................................................................... 45 
10.1 EXTENT OF EXPOSURE ............................................................................................... 46 
10.2 ADVERSE EVENTS ....................................................................................................... 47 
10.3 CLINICAL LABORATORY EVALUATION .................................................................... 48 
10.4 VITAL SIGNS ............................................................................................................... 55 
10.5 PHYSICAL EXAMINATION .......................................................................................... 56 
10.6 ELECTROCARDIOGRAM ............................................................................................. 56 
10.7 ECOG ......................................................................................................................... 57 
10.8 SUBSEQUENT ANTI-CANCER THERAPY .................................................................... 57 
11 PRO FROM THE EORTC QLQ-C30 ANALYSES ......................................................... 57 
11.1 MISSING DATA ............................................................................................................ 57 
11.2 SCORING THE EORTC QLQ-C30 RESULTS ............................................................. 57 
11.3 SUMMARY OF EORTC QLQ-C30 RESULTS ............................................................. 58 
11.4 ANALYSIS OF CHANGE FROM BASELINE ................................................................... 59 
12 CHANGES TO PROTOCOL-SPECIFIED ANALYSES ................................................ 60 
13 REFERENCES ..................................................................................................................... 61 
14 APPENDICES ...................................................................................................................... 62 
APPENDIX A:  PRESENTATION OF DATA AND PROGRAMMING SPECIFICATIONS ............. 62 
APPENDIX B:  IMMUNE-RELATED RESPONSE CRITERIA ................................................... 64 
APPENDIX C: RECIST (RESPONSE EVALUATION CRITERIA IN SOLID TUMORS) VERSION 
1.1 GUIDELINES ..................................................................................................................... 66 
APPENDIX D: OVERALL RESPONSE USING IRRECIST ...................................................... 71 


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APPENDIX E:  LIST OF TABLES, FIGURES, AND LISTINGS .................................................. 72 
APPENDIX F:  TABLE, LISTING AND FIGURE LAYOUTS ...................................................... 82 
 
 
 


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LIST OF ABBREVIATIONS 
δ 
Dose-limiting toxicity rate 
ADaM 
Analysis data model  
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 
CH50 
Total hemolytic complement activity 50 
CL/F 
Clearance 
Cmax 
Maximum plasma concentration 
CR 
Complete response 
CRC 
Cohort Review Committee 
CS 
Clinically significant 
CT  
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T lymphocyte antigen-4 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DoR 
Duration of response 
DRR 
Durable response rate 
ECG 
Electrocardiogram 


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List of abbreviations continued  
 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EE 
Efficacy Evaluable 
FDA 
Food and Drug Administration 
ICH 
International Council for Harmonisation 
IMO 
Immune Modulatory Oligonucleotide 
irAE 
Immune-related adverse event 
irRC 
Immune-related response criteria 
irRECIST 
Immune-related reponse evaluation criteria solid tumors 
ISR 
Injection site reaction 
LFT 
Liver function test 
MLE 
Maximum Least-square Estimation 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PK 
Pharmacokinetic  
PR 
Partial response 
Pr 
Probability 
PRO 
Patient reported outcome 
PT 
Prothrombin time 
RBC 
Red blood cell 
RP2D 
Recommended Phase 2 dose 


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SAE 
Serious adverse event 
SD 
Stable disease 
ULN 
Upper limit of normal 
WBC 
White blood cell 


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DEFINITIONS 
Adverse Event  
An adverse event (AE) is any reaction, side effect, or 
other untoward event, regardless of relationship to study 
drug, which occurs anytime during the study. 
DLT Evaluable 
Population 
All subjects in the Safety Population who continue 
participation in the study for the entire DLT evaluation 
period, or who discontinue prematurely due to a DLT. 
DLT Evaluation Period 
The DLT evaluation period will be Cycle 1 (Weeks 1 
through 4). 
Safety Population 
All subjects who received at least one dose of IMO-
2125. 
Serious AE 
An AE occurring at any dose that: results in death; is a 
life-threatening experience; requires hospitalization or 
prolongation of an existing hospitalization; results in a 
persistent or significant disability/incapacity; or is a 
congenital anomaly/birth defect in the offspring of a 
subject who received study drug; or important medical 
event that, although not immediately life-threatening, 
requires intervention in order to prevent one of the listed 
serious outcomes listed.   
 
Study Drug 
IMO-2125 in combination with ipilimumab or 
pembrolizumab 
Treatment-emergent AE 
AEs with an onset date on or after the date of the initial 
dose of study drug, or an AE that worsens after the date 
of the initial dose of study drug. 
 


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1. INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of 
data collected within the scope of Idera Protocol Number: 2125-204 [A Phase 1/2 Study 
to Assess the Safety and Efficacy of Intratumoral IMO-2125 in Combination with 
Ipilimumab or Pembrolizumab in Subjects with Metastatic Melanoma]. The purpose of 
this plan is to provide specific guidelines from which the statistical analyses will proceed. 
Any deviations from this plan will be documented in the clinical study report (CSR). 
2. STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective of Phase 1 is to characterize the safety and determine a 
recommended Phase 2 dose (RP2D) of IMO-2125 when administered in combination 
with ipilimumab or when administered in combination with pembrolizumab in subjects 
with metastatic melanoma. The maximum tolerated dose (MTD) and RP2D for IMO-
2125 may differ between the combination of IMO-2125 and ipilimumab and the 
combination of IMO-2125 and pembrolizumab. 
 
The primary objective of Phase 2 is to assess preliminary clinical activity of IMO-2125 in 
combination with ipilimumab or in combination with pembrolizumab at the respective 
RP2D(s) in subjects with metastatic melanoma that is not responsive to PD-1 inhibitor 
therapy, using Response Evaluation Criteria in Solid Tumors v1.1. 
2.2 Secondary Objectives 
The secondary objectives of Phase 1 are to determine the plasma pharmacokinetics (PK) 
of single-dose IMO-2125 and repeat-dose IMO-2125 PK administered intratumorally in 
combination with ipilimumab and pembrolizumab. An additional secondary objective of 
Phase 1 is to describe any preliminary antitumor activity. 
 
The secondary objectives of Phase 2 are to further assess the safety and tolerability of 
IMO-2125 in combination with ipilimumab or in combination with pembrolizumab in 
subjects with metastatic melanoma and to assess treatment response using RECIST v1.1 
and irRECIST , overall survival (OS), OS at 6 months and 12 months, progression-free 
survival (PFS), PFS at 6 months and 12 months, durable response rate (DRR), duration of 
response (DoR), and disease control rate (DCR). 
 


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2.3 Exploratory Objectives 
The exploratory objectives of Phase 1 and 2 are to assess patient reported quality of life 
outcomes, pre- and post-treatment blood biomarkers, pre- and post-treatment tumor 
biopsies for immunological assessment, and explore any potential association between 
these biomarker measures and antitumor activity. In addition, anti-IMO-2125, anti-
ipilimumab, and anti-pembrolizumab antibody formation will be assessed. 
3. STUDY DESIGN AND PLAN 
3.1 Overview 
This is a two arm open-label Phase 1/2 study to assess the safety, tolerability, PK, 
immunogenicity, and efficacy of IMO-2125 when administered in combination with 
ipilimumab or in combination with pembrolizumab. Subjects with metastatic melanoma 
who have experienced symptomatic or confirmed radiographic progression to their most 
recent treatment regimen (anti-PD-[L]1 alone or in combination) will be eligible. Prior 
BRAF or MEK inhibitor treatment is not required. The study will be conducted in two 
parts: a dose-escalation portion (Phase 1) to evaluate safety and tolerability of multiple 
dose levels and a Phase 2 portion to assess preliminary efficacy.  
3.1.1 Phase 1 
The Phase 1 portion of the study is will explore escalating dose levels of IMO-2125 
(from 4 to 32 mg with de-escalation to 2 mg allowed for each IMO-2125 combination). 
For each cohort, IMO-2125 will be administered as a once-weekly intratumorally 
injection for 3 consecutive weeks in Cycle 1, followed by intratumorally injections on 
Weeks 5, 8, 11, 17, 23, and 29 (Day 1 of Cycles 2 through 7). Both ipilimumab and 
pembrolizumab will be administered as per the USPI every 3 weeks beginning Day 1 of 
Week 2. Continued dosing of pembrolizumab following the study treatment period is 
permitted at the discretion of the Investigator for subjects in the IMO-2125 + 
pembrolizumab treatment arm. The dosing schedule is summarized in Table 1. 


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Table 1: 
Schedule of Dosing for Phase 1 and Phase 2 
 
 
Cycle 
 
1 
2 
3 
4 
5 
6 
7 
Study week 
1 2 
3 4 
5 
6 
7 
8 
9 10 
11 
12 
13 
17 
23 
29 
IMO-2125 + ipilimumab 
IMO-2125 
X X X - 
X - 
- 
X - - 
X 
- 
- 
X 
X 
X 
Ipilimumab 
- 
X - 
- 
X - 
- 
X - - 
X 
- 
- 
- 
- 
- 
IMO-2125 + pembrolizumab 
IMO-2125 
X X X - 
X - 
- 
X - - 
X 
- 
- 
X 
X 
X 
Pembrolizumab 
- 
X - 
- 
X - 
- 
X - - 
X  
                  X 1 
 
Note: On weeks when the combinations are administered, administration of ipilimumab or 
pembrolizumab will be first, followed by IMO-2125. IMO-2125 administration must occur within a ±2 
day window of the scheduled dosing day. 
1 For subjects in the IMO-2125 + pembrolizumab treatment arm, continued pembrolizumab dosing per the 
approved product label is permitted at the discretion of the Investigator 
Subjects assigned to 11 weeks of IMO-2125 under previous versions of the protocol who 
have not yet reached the end of the Treatment Period may receive the Week 17, 23, and 
29 injections at the discretion of the treating Investigator.   
Each cohort will be monitored for the occurrence of DLTs. The DLT evaluation period 
will be Cycle 1 (Weeks 1 through 4). If a subject discontinues study participation before 
the DLT evaluation period is finished due to reasons other than experiencing a DLT, that 
subject must be replaced so that the cohort may be properly evaluated. More information 
about the review of DLTs and the escalation of dose levels between cohorts is provided 
in Section 3.1.3, Section 3.1.4, and Section 3.1.5. 
There are 3 subjects planned per cohort. During Phase 1, the sponsor will assign subjects 
to a treatment arm (IMO-2125 + ipilimumab or IMO-2125 + pembrolizumab) by cohort. 
After completing the DLT evaluations for all planned IMO-2125 doses in either 
combination, supplemental cohorts of up to 5 subjects each may be enrolled with either 
combination at doses up to and including the MTD. After completion of either Phase 1 
treatment arm and determination of the RP2D for that arm, the Phase 2 portion for the 


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completed treatment arm may be initiated. It is not necessary for Phase 1 to be completed 
in both treatment arms before Phase 2 is started.  
3.1.2 Phase 2 
The Phase 2 portion of the study will assess preliminary efficacy, using investigator-
assessed RECIST v1.1, of IMO-2125 + ipilimumab,  IMO-2125 + pembrolizumab, and 
any additional combinations that are studied in Phase 1. The dose level of IMO-2125 to 
be administered for each treatment arm will be the RP2D for the combination, as 
determined in Phase 1.  Phase 2 will enroll up to 60 subjects treated at the IMO-2125 + 
ipilimumab RP2D. This will include at least 21 subjects in the primary IMO-2125 + 
ipilimumab efficacy-evaluable population and up to 20 subjects in the secondary 
IMO-2125 + ipilimumab efficacy-evaluable population. In the IMO-2125 + 
pembrolizumab Phase 2 cohort, enrollment will continue until 21 subjects in the IMO-
2125 + pembrolizumab efficacy-evaluable population have been treated at the the IMO-
2125 + pembrolizumab RP2D. Phase 1 subjects treated at the RP2D for either 
combination may contribute to these totals.  A two-stage design will be used to test for 
clinically and statistically relevant clinical activity. A treatment arm will stop if an 
interim futility analysis shows there is insufficient evidence of a clinically relevant 
response rate after 10 subjects (Stage 1).     
If a subject discontinues treatment before completing at least one efficacy evaluation for 
reasons other than toxicity, then that subject will be replaced with the replacement 
assigned to the same treatment arm and dose level as the subject who dropped out early. 
Combination therapy in Phase 2 will continue using the same schedule as Phase 1 (see 
Table 1). 
3.1.3 Dose Escalation and Stopping Rules 
 Up to five dose levels for IMO-2125 are initially planned (Table 2).  
Table 2: 
Treatment Doses to be investigated 
 
Dose Level 
IMO-2125 
Ipilimumab 
Pembrolizumab 
-1 
2 mg 
3 mg/kg 
200 mg 
+1 
4 mg 
3 mg/kg 
200 mg 
+2 
8 mg 
3 mg/kg 
200 mg 
+3 
16 mg 
3 mg/kg 
200 mg 
+4 
32 mg 
3 mg/kg 
200 mg 


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In Phase 1, the study will enroll subjects in planned cohorts of 3, beginning at Dose Level 
+1 for the ipilimumab treatment arm and beginning at Dose Level +2 for the 
pembrolizumab treatment arm once safety of the IMO-2125 + ipilimumab combination 
has been established for that level.   
Additionally, if, due to observed toxicity, it proves difficult to provide IMO-2125 for 
3 consecutive weeks in Cycle 1, the decision may be taken by the CRC to add cohorts 
where alternative schedules of IMO-2125 administration will be explored.  
The MTD will be determined from the assessment of DLTs during the first treatment 
cycle of each cohort (Section 3.1.5). Using a prior beta(1,1) distribution of the DLT rate 
δi for each dose level i, the MTD is defined as the highest dose level for which the mean 
of the posterior distribution  of toxicity is closest to 25% among all the evaluated doses i 
for which Pr (δ i > 0.25 | data) < 0. 80. 
The RP2D(s) will be selected from dose level(s) at or below the MTD. Additional dose 
levels may be studied if the MTD(s) have not been reached and pharmacodynamic 
activity is deemed to be inadequate. At the time of completion of the Phase 1 portion of 
the study an analysis of the data will be performed.   
3.1.3.1 Phase 2 Stopping Rules 
Additional subjects will be enrolled at the RP2D level(s) established in the Phase 1 
portion of the study for a total of approximately 90 to 100 subjects enrolled in the study.  
DLTs will be continuously monitored throughout the study.  Assuming a prior beta (0.6, 
1.4) distribution for the overall toxicity rate for a treatment, a Phase 2 arm  will terminate 
if the Pr (δt > 0.25 | data) > 0.80, where δt is the DLT rate attributable to the treatment. 
The decision rule for terminating due to toxicity is presented in Table 3. The method 
used to produce the decision rule and operating characteristics was designed by Thall 
(2006). 
Table 3: 
Phase 2 Stopping Boundaries 
 
If there are this many first-cycle DLTs or more 
3 4 
5 
6 
7 
8 
9 
10 
Stop if this many subjects (or fewer) have 
begun treatment  
7 10 13 17 20 24 27 29 


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3.1.4 Cohort Review Committee 
The CRC composition and duties are described in a separate Charter.  A CRC meeting 
will be convened to review all safety data and decide whether DLTs were observed. 
Based on the CRC’s adjudication of DLTs observed in a cohort, they will guide decisions 
on the dose level that the subsequent cohort will be administered. 
 
A review of all relevant available data will occur between the Sponsor and participating 
institution(s) at least monthly for the duration of the study.   
3.1.5 Definition of Dose-limiting Toxicities 
Toxicity will be evaluated according to the National Cancer Institute (NCI) Common 
Terminology Criteria for AEs (CTCAE) v4.03 toxicity criteria. Dose-limiting toxicities 
are defined as those events that will require dose modification; therefore, DLT criteria 
should be referenced throughout the Phase 1 and 2 portions of the study. The 
DLT evaluation period will be Cycle 1 (Weeks 1 through 4). 
For the purposes of dose level escalation and determination of the MTD(s), only DLTs 
(as defined below) that occur during the first cycle of treatment will be considered in 
decisions regarding dose level escalation; however, DLTs or other clinically significant 
toxicities that occur throughout the observation period will be considered when 
determining the RP2D(s) for use in this trial and in subsequent clinical trials. 
During Cycle 1 of the dose escalation portion, if two of the three subjects in a cohort 
experience the same Grade 2, treatment-related AE, then subsequent increases in dose 
level will precede in increments less than 100%. If more than one cohort is treated at the 
same dose level and greater than 67% of subjects treated at that dose level experience the 
same Grade 2 treatment-related AE, dose level escalation will precede in increments less 
than 100% In such a case, specific dose level increments will be decided by the CRC. 


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Protocol-defined hematologic DLTs include: 
CTCAE Grade 4 neutropenia ≥ 7 days; 
CTCAE Grade 3 or 4 neutropenia with fever ≥ 38.5°C;  
CTCAE Grade 3 thrombocytopenia with bleeding; 
CTCAE Grade 4 thrombocytopenia ≥7 days. 
Protocol-defined non-hematologic DLTs include: 
Grade ≥3 vomiting or nausea ≥ 14 days despite the use of optimal anti-emetic 
treatments; 
Grade ≥3 diarrhea ≥ 14 days despite the use of optimal anti-diarrheal treatments 
which should include infliximab as per institutional guidelines; 
Serum creatinine > 3.0 x ULN; 
AST or ALT > 5 x ULN; in subjects with liver metastasis who entered the study 
with Grade 2 elevation of AST or ALT, an AST or ALT increase ≥50% 
relative to baseline and lasting ≥1 week; 
Bilirubin ≥ 3.0 x ULN; 
Bilirubin ≥ 2.0 x ULN with ALT > 3 x ULN in subjects without liver metastases; 
Other non-hematologic toxicities of Grade ≥3, except for the following: 
AEs related to underlying disease; 
CTCAE Grade 3 fatigue < 14 days; 
Alopecia; 
Isolated, asymptomatic elevations in biochemistry laboratory values lasting 
≤ 14 days. This includes electrolyte abnormalities that respond to medical 
intervention. 
Ipilimumab-related DLTs: 
Grade ≥4 immune-mediated dermatitis (except skin reaction at site of injection); 
Grade ≥3 immune-mediated endocrinopathy (with the exception of Grade 3 
autoimmune thyroiditis that resolves to Grade 1 or baseline within 28 days of 
onset); 
Grade ≥3 immune-mediated enterocolitis; 


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Grade ≥3 immune-mediated hepatitis with the exception of Grade 3 
immune-mediated hepatitis that resolves to Grade 1 or baseline within 28 days 
of onset; 
Grade ≥3 immune-mediated neuropathy, pancreatitis, meningitis, nephritis, and 
pneumonitis that are considered to be possibly, probably, or definitely related 
to study therapy as determined by the Investigator; 
Any persistent IMO-2125-related toxicity that leads to a delay of scheduled (per 
standard of care) ipilimumab > 14 days. 
Pembrolizumab-related DLTs: 
Grade ≥3 pneumonitis or recurrent Grade 2 pneumonitis;  
Grade ≥3 nephritis;  
Grade ≥3 infusion-related reactions;  
Inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks; 
Any Grade ≥3 treatment-related AE that recurs. 
If at any time during the study, a subject experiences a DLT as outlined above, the 
toxicity in question must be assessed for attribution based on the known toxicity profiles 
for ipilimumab, pembrolizumab, and IMO-2125.  If assessment can be clearly attributed 
to one of the drugs in the combination, then dosing should be interrupted and the toxicity 
should be followed until resolution, stabilization, or return to baseline. Treatment with 
the other agent may continue during this time period.  If attribution cannot be clearly 
ascribed to one agent versus the other, then both IMO-2125 and ipilimumab (or 
pembrolizumab) should be stopped and the toxicity should be followed until resolution, 
stabilization, or return to baseline. If treatment is to be resumed, then re-initiation criteria 
must be met.  If the DLT was clearly related to IMO-2125 or if attribution cannot be 
clearly determined, then IMO-2125 must be administered at a lower dose level (a 
minimum reduction of at least 1 dose level). If the DLT recurs after a dose level 
reduction, then treatment should be discontinued.  
Subjects who experience a non-laboratory, IMO-2125-related DLT must be evaluated 
weekly, at a minimum, until resolution to Grade ≤1 or baseline and then at least monthly 
until return to baseline or stabilization of the event, whichever comes first. For abnormal 
laboratory values that qualify as DLTs, subjects will be followed twice weekly until 
values return to Grade ≤1 or baseline, whichever comes first. 
Criteria for re-initiation of study treatment following occurrence of a DLT are as follows: 


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ANC must be ≥ 1.5 x 109/L (1500/μL); 
Platelets must be ≥ 75 x 109/L (75,000/μL); 
All clinically significant non-hematologic toxicities for which a causal association 
to study treatment cannot be ruled out must be Grade ≤1 (except alopecia) or 
returned to 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 cycle is delayed by more than 21 days 
for toxicity, the subject should be removed from study treatment. In these situations, if 
the subject is experiencing clinical benefit and has a favorable risk/benefit profile, study 
treatment with IMO-2125 may be continued if agreed upon by the Sponsor and the 
Investigator. 
3.1.6 Safety Assessment for Immunologically Related Toxicity 
Based on an incidence of Grade 3 or greater immune-mediated AEs associated with use 
of ipilimumab or pembrolizumab of approximately 12% to 15%, the following safety 
precautions will be followed. Examples of relevant toxicities include the following: 
enterocolitis, hepatitis, dermatitis, neuropathy, endocrinopathy, nephritis, pneumonitis, 
pancreatitis, non-infectious myocarditis, uveitis, and iritis. 
During dose level escalation, if any of the following is observed, the CRC will be 
convened to review all safety findings for all subjects treated in that cohort and all 
previous cohorts, including those events that occurred beyond Cycle 1, to guide next 
steps. 
If more than one subject experiences a Grade ≥3, immune-related adverse event 
(irAE) in a cohort of 3 subjects;  
If more than two subjects experience a Grade ≥3 irAE in cohorts of 6 subjects.  
During the Phase 2 portion of the trial, if the incidence of Grade ≥3 irAEs observed in 
Cycle 1 or in subsequent cycles of treatment exceeds 25%, the CRC will be convened to 
review all safety findings from all subjects treated in the study to guide next steps. 
3.2 Duration of Study 
3.2.1 Treatment Duration 
The study treatment period is 29 weeks (as per Table 1) in the absence of intolerable 
toxicity or unequivocal disease progression. Continued treatment with pembrolizumab 


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following the completion of study treatment is at the discretion of the Investigator for 
subjects in the IMO-2125 + pembrolizumab treatment arm.  
3.2.2 Study Duration and Study Completion 
The study ends approximately 1 year after the last subject in Phase 2 has commenced 
study treatment. Subjects who complete or discontinue study treatment prior to 
progression will be followed for clinical and radiological evidence of progression and 
immunogenicity assessment at least every 3 months until documentation of RECIST 
v1.1 progressive disease (PD), start of a subsequent anti-cancer treatment regimen, 
withdrawal of consent, death, or Sponsor notification that follow-up is no longer 
required, whichever comes first. Best response to first subsequent therapy, AEs which 
are Grade ≥3, and concomitant medications used to treat these AEs, will also be captured 
during the follow-up phase of the study (Table 4 and Table 5). 
After documentation of PD or use of a subsequent anti-cancer treatment regimen, all 
subjects will be contacted by telephone every 3 months for a survival follow-up until the 
site is notified by the Sponsor that survival follow-up is no longer required. A subject 
has completed the study at the earliest of death or study end.  
3.3 Number of Subjects  
The study will enroll up to approximately 90 to 100 subjects. It is estimated that 
approximately 30 subjects will be treated in Phase 1 and approximately 60 to 70 subjects 
will be treated in the Phase 2 portion of the study. 
  
 


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3.4 Schedules of Evaluations 
Table 4: 
Phase 1: Schedule of Evaluations 
 
 
Treatment Period (Cycle1) 
Follow-up 
 
 
1 
2 
3 
4 
 
5 
 
6 
 
7 
Safet
y2 
Ongoing 3 
(every 
3 months)  
Week 4 
Scree
n 5 
1 
2 
3 
5 
8 
1
1 
1
3 
1
4 
1
7 
2
0 
23 
2
6 
29/ 
EO
T 
32 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Excl
usion  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demog/med hx 
6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events  
 
Continuous 
X 7 
Concomitant 
Meds 
 
Continuous 
X 8 
ECOG  
X 
X 
 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
CBC with diff 
X 
X 
9 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
Coagulation 10 
X 
X 
9 
 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
Chemistry 
profile 
X 
X 
9 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
Thyroid 
functions 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
CH50/C3/C4 
X 
 
 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
Urinalysis  
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Vital signs 11 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
ECG 
X 
 
X 
12 
 
 
 
X
12 
 
 
 
 
 
 
 
X 
 
Directed 
physical 13 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Tumor 
biopsies/bioma
rkers 14 
X 
X 
15 
X 
16 
 
 
X 
 
X 
16 
 
 
 
 
X 
16 
 
 
 
Blood 
biomarkers 
 
X 
15 
X 
15 
 
X
17 
X1
7 
 
 
 
 
 
 
 
X 17 
 
 
Radiology 
X 
 
 
 
 
X 
18 
 
 
 
X 
18 
 
 
 
X 18 
 
X 19 
Response 20 
 
 
 
 
 
X 
18 
 
 
 
X 
18 
 
 
 
X 18 
 
X 19 
PRO21 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 19 
IMO-2125 
dosing 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
 


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Treatment Period (Cycle1) 
Follow-up 
 
 
1 
2 
3 
4 
 
5 
 
6 
 
7 
Safet
y2 
Ongoing 3 
(every 
3 months)  
Week 4 
Scree
n 5 
1 
2 
3 
5 
8 
1
1 
1
3 
1
4 
1
7 
2
0 
23 
2
6 
29/ 
EO
T 
32 
 
Ipilimumab 
dosing 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Pembrolizuma
b dosing 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 22 
X 22 
PK testing 23 
 
X 
X 
X 
X 
X 
X 
 
 
X 
24 
 
 
X 
24 
X 24 
X24 
 
Immunogenicit
y 25 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X26 
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; C3=complement component 3; 
C4=complement component 4; CBC=complete blood count; CH50=total hemolytic complement activity 50; 
CR=complete response; CT=computed tomography; Demogr=Demographic; diff=differential; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT= End of Treatment; hx=history; 
INR=international normalized ratio; irRC=immune-related response criteria; med=medical; PK=pharmacokinetic; 
PR=partial response; PRO = patient reported outcomes; PT=prothrombin time 
1 Please note, the number of weeks per cycle varies. Cycle 1 is 4 weeks in length to account for an IMO-2125 
priming dose. Cycles 2, 3, and 4 are 3 weeks in length, and Cycles 5, 6, and 7 are included as maintenance dosing 
and are 6 weeks in length. 
2 The Safety Follow-up Visit should be 21 days following the last dose of IMO-2125 (± 5 days). 
3 Includes ongoing follow-up every 3 months until documented disease progression, next melanoma treatment, 
withdrawal of consent, death, or Sponsor notification that follow-up is no longer required.  
4 All assessments and IMO-2125 dosing will occur within a ±2-day window. Ipilimumab and pembrolizumab will be 
dosed per their respective labels. 
5 All Screening tests and assessments must be performed within 21 days of the start of Week 1 of Cycle 1, unless 
otherwise noted. All patients who sign an informed consent and are screened and qualify for the study will be 
considered enrolled.  
6 Including melanoma history and prior melanoma treatment history. 
7 Grade ≤2 AEs do not need to be reported.  
8 Only concomitant medications for the treatment of Grade ≥3 AEs will be captured. 
9 CBC with differential should be done 24 to 48 hours after the IMO-2125 injection, to coincide with the post-
injection biopsy.  Chemistry profile and coagulation tests do not have to be conducted if Screening tests were 
conducted within 7 days of the Cycle 1 Week 1 Visit. 
10 PT, aPTT, INR. 
11 Blood pressure, heart rate, respiratory rate, and temperature. 
12 Week 2 ECG pre-dose and at 2 hours post-IMO-2125 administration. Week 11 ECG at 2 hours post-IMO-2125 
administration. 
13 Including assessment of melanoma lesions. 
14 Biopsy of the tumor to be injected with IMO-2125 and biopsy of a tumor that will not be injected. See 
Section 13.2 of the protocol and the Laboratory Manual for details on the collection of biopsies and analyses of 
biomarkers. 
15 Biopsy of the injected tumor should occur within 24 to 48 hours after injection (no more than 48 hours).  
Collection of blood for biomarkers should occur on Day 1 pre-IMO-2125 administration, 4 hours after IMO-2125 


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administration, and 24 to 48 hours after injection (coinciding with the 24-hour PK sample). At Week 2, collect 
before ipilimumab or pembrolizumab dosing. 
16 Optional biopsy. 
17 At Weeks 5 and 8, collect pre-ipilimumab or pre-pembrolizumab dosing and post-IMO-2125 dosing. At Week 
29/EOT collect pre-pembrolizumab dosing (for subjects in that arm who have pembrolizumab continued) and 
post-IMO-2125 dosing. If no ipilimumab or pembrolizumab is given at the specified visit(s) collect the samples 
pre- and post-IMO-2125 dosing. If no IMO-2125 if given, then collect pre- and post- ipilimumab or 
pembrolizumab. 
18 Radiologic assessment and Investigator assessment of response at Week 8, Week 17, and Week 29 may be 
conducted within a ±7-day window. 
19 At least every 3 months until progression, start of next melanoma treatment, withdrawal of consent, death, or 
Sponsor notification that follow up is no longer required. 
20 In Phase 1, response assessed using irRC and RECIST v 1.1. Best response to first subsequent treatment should 
also be captured. Confirmatory scans for CR, PR, and progressive disease should be performed ≥4 weeks after the 
date the response was first documented. 
21 To minimize bias in the PRO data, the PRO assessments should be completed before study drug administration 
and AE assessments. 
22 For patients assigned to the IMO-2125 + pembrolizumab treatment arm, continued pembrolizumab dosing per the 
approved product label is permitted at the discretion of the Investigator. 
23 PK: blood sampling for analysis of plasma concentrations of IMO-2125 and serum concentrations of ipilimumab, 
and pembrolizumab (See Table 3 of the protocol for specific collection times). 
24 For patients who continue pembrolizumab treatment, pembrolizumab pre-dose PK samples should be collected 
before dosing at all visits. A post-dose pembrolizumab PK sample should be collected 30 minutes after initiation 
of pembrolizumab infusion at Week 23. Pharmacokinetic samples at Week 33 are optional. 
25 Immunogenicity: blood sampling for analysis of antibodies to IMO-2125, ipilimumab, and pembrolizumab will be 
performed prior to any dosing at that visit. 
26 For patients in Ongoing Follow-up (i.e., those discontinued from study treatment before progression or new 
anticancer treatment), the immunogenicity samples are required at the scheduled visits. For patients in survival 
follow-up (i.e., after progressive disease or start of new anti-cancer treatment), immunogenicity assessments are 
optional (e.g., if a patient comes to the investigator site for a Survival Follow-up Visit rather than the usual 
telephone contact). 


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Table 5: 
Phase 2 Schedule of Evaluations 
 
 
Treatment Period (Cycle1) 
Follow-up 
 
 
1 
2 
3 
4 
 
5 
 
6 
 
7 
Safety2 
Ongoing 
3 
(every 
3 months)  
Week 4 
Screen 
5 
1 
2 
3 
5 
8 
11 
13 
14 
17 
20 
23 
26 
29/ 
EOT 
32 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demog/med hx 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events  
 
Continuous 
X 7 
Concomitant Meds 
 
Continuous 
X 8 
ECOG  
X 
X 
 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
CBC with diff 
X 
X 
9 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Coagulation 10 
X 
X 
9 
 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Chemistry profile 
X 
X 
9 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Thyroid functions 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
CH50/C3/C4 
X 
 
 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Urinalysis  
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Vital signs 11 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
ECG 
X 
 
X 
12 
 
 
 
X12 
 
 
 
 
 
 
 
X 
 
Directed physical 13 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Tumor 
biopsies/biomarkers 
14 
X 
X 
15 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
Blood biomarkers 
 
X 
16 
X 
16 
 
 
X16 
 
 
 
 
 
 
 
 
 
 
Radiology 
X 
 
 
 
 
X 
17 
 
 
 
X 
17 
 
 
 
X 17 
 
X 18 
Response 19 
 
 
 
 
 
X 
17 
 
 
 
X 
17 
 
 
 
X 17 
 
X 18 
PRO20 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 18 
IMO-2125 dosing 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
 
Ipilimumab dosing 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Pembrolizumab 
dosing 
 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 21 
X 21 
PK testing 22 
 
X 
X 
X 
X 
X 
X 
 
 
X 
23 
 
X 
23 
 
X 23 
X23 
 
Immunogenicity 24 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X25 


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Protocol Number: 2125-204 
 
Final 1.1, March 5th, 2020 
 
 
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Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; C3=complement component 3; 
C4=complement component 4; CBC=complete blood count; CH50=total hemolytic complement activity 50; 
CR=complete response; CT=computed tomography; Demogr=Demographic; diff=differential; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT= End of Treatment; hx=history; 
INR=international normalized ratio; irRC=immune-related response criteria; med=medical; PK=pharmacokinetic; 
PR=partial response; PRO = patient reported outcomes; PT=prothrombin time 
1 Please note, the number of weeks per cycle varies. Cycle 1 is 4 weeks in length to account for an IMO-2125 
priming dose. Cycles 2, 3, and 4 are 3 weeks in length, and Cycles 5, 6, and 7 are included as maintenance dosing 
and are 6 weeks in length. 
2 The Safety Follow-up Visit should be 21 days following the last dose of IMO-2125 (± 5 days). 
3 Includes ongoing follow-up every 3 months until documented disease progression, next melanoma treatment, 
withdrawal of consent, death, or Sponsor notification that follow-up is no longer required.  
4 All assessments and IMO-2125 dosing will occur within a ±2-day window. Ipilimumab and pembrolizumab will be 
dosed per their respective labels. 
5 All Screening tests and assessments must be performed within 21 days of the start of Week 1 of Cycle 1, unless 
otherwise noted. All patients who sign an informed consent and are screened and qualify for the study will be 
considered enrolled.  
6 Including melanoma history and prior melanoma treatment history. 
7 Grade ≤2 AEs do not need to be reported.  
8 Only concomitant medications for the treatment of Grade ≥3 AEs will be captured. 
9 CBC with differential should be done 24 to 48 hours after the IMO-2125 injection, to coincide with the post-
injection biopsy (if the biopsy is conducted).  Chemistry profile and coagulation tests do not have to be conducted 
if Screening tests were conducted within 7 days of the Cycle 1 Week 1 Visit. 
10 PT, aPTT, INR. 
11 Blood pressure, heart rate, respiratory rate, and temperature. 
12 Week 2 ECG pre-dose and at 2 hours post-IMO-2125 administration. Week 11 ECG at 2 hours post-IMO-2125 
administration. 
13 Including assessment of melanoma lesions. 
14 In Phase 2, all tumor biopsies are optional. See Section 13.2 of the protocol and the Laboratory Manual for details 
on the collection of biopsies and analyses of biomarkers. 
15 Biopsy of the injected tumor should occur within 24 to 48 hours after injection (no more than 48 hours).   
16 In Phase 2, blood biomarker samples will be collected from at least 20 patients treated at the IMO-2125 RP2D 
after which the Sponsor will determine if additional samples are needed. The blood biomarker samples will be 
collected on Day 1 before IMO-2125 administration, 4 hours after IMO-2125 administration, and 24 to 48 hours 
(coinciding with the 24-hour PK sample) after the injection. At Week 2 and Cycle 3 Week 8, collect before 
ipilimumab or pembrolizumab dosing. 
17 Radiologic assessment and Investigator assessment of response at Week 8, Week 17, and Week 29 may be 
conducted within a ±7-day window. 
18 At least every 3 months until progression, start of next melanoma treatment, withdrawal of consent, death, or 
Sponsor notification that follow up is no longer required. 
19 In Phase 2, response assessed using irRECIST and RECIST v 1.1. Best response to first subsequent treatment 
should also be captured. Confirmatory scans for CR, PR, and progressive disease should be performed ≥4 weeks 
after the date the response was first documented. 
20 To minimize bias in the PRO data, the PRO assessments should be completed before study drug administration 
and AE assessments. 
21 For patients assigned to the IMO-2125 + pembrolizumab treatment arm, continued pembrolizumab dosing per the 
approved product label is permitted at the discretion of the Investigator. 
22 PK: blood sampling for analysis of plasma concentrations of IMO-2125 and serum concentrations of ipilimumab, 
and pembrolizumab (See Error! Reference source not found.Table 3 of the protocol for specific collection 


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times). For each combination in Phase 2, the collection of plasma concentration samples will be done on at least 20 
patients treated at the IMO-2125 RP2D after which the Sponsor will determine if additional samples are needed. 
23 For patients who continue pembrolizumab treatment, pembrolizumab pre-dose PK samples should be collected 
before dosing at all visits. A post-dose pembrolizumab PK sample should be collected 30 minutes after initiation 
of pembrolizumab infusion at Week 23. Pharmacokinetic samples at Week 33 are optional. 
24 Immunogenicity: blood sampling for analysis of antibodies to IMO-2125, ipilimumab, and pembrolizumab will be 
performed prior to any dosing at that visit. 
25 For patients in Ongoing Follow-up (i.e., those discontinued from study treatment before progression or new 
anticancer treatment), the immunogenicity samples are required at the scheduled visits. For patients in survival 
follow-up (i.e., after progressive disease or start of new anti-cancer treatment), immunogenicity assessments are 
optional (e.g., if a patient comes to the investigator site for a Survival Follow-up Visit rather than the usual 
telephone contact). 


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                                                                            Statistical Analysis Plan 
Protocol Number: 2125-204 
 
Final 1.1, March 5th, 2020 
 
 
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Table 5.1: 
Schedule of PK Blood Sampling for IMO-2125, Ipilimumab, and 
Pembrolizumab 
 
Cycle 1 
Cycle 
2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 
7 
Safety 
Follow
-Up1 
 
Week 1 
Week 
2 
Week 
3 
Week 
5 
Week 8 
Week 
11 
Week 
14 
Week 
17 
Week 
20 
Week 23 
Week 26 
Week 
29/ 
EOT  
Week 
32 
IMO-2125 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-dose 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
Post-dose 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
30 m (±5 m) 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
1 h (±10 m) 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
1.5 h (±10 m) 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
3 h (±15 m) 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Ipilimumab 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-dose 
 
X 
 
X 
X 
X 
 
X3 
 
X3 
 
 
 
Post-dose 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
90 m after 
start of 
infusion (±5 
m)  
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Pembrolizumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-dose 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X2 
Post-dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
30 m after 
start of 
infusion (±5 
m)  
 
X 
 
 
 
X 
 
 
 
X 
 
 
X2 
Abbreviations: EOT=End of Treatment; h=hour; m=minute; PK=pharmacokinetic  
 
1 Collection of PK samples at the Safety Follow-up Visit is optional. 
2 IMO-2125 (plasma samples) and ipilimumab (serum) PK samples may be collected at any time during the Safety Follow-up Visit. Optional pre- 
and post-dose pembrolizumab serum PK samples are collected for those patients continuing pembrolizumab treatment at this visit. If 
pembrolizumab treatment was stopped, a sample may be collected at any time during the visit. 
3 Pre-IMO-2125 dose. 
 
 
 
4. DETERMINATION OF SAMPLE SIZE 
The primary objective of Phase 2 is to assess the preliminary clinical activity, defined as the 
investigator assessed RECIST v1.1 ORR, of IMO-2125 in combination with ipilimumab or of 
IMO-2125 in combination with pembrolizumab in subjects with progression on or following 
PD-(L)1 therapy for metastatic melanoma. Given that two primary hypotheses are being tested 
(regarding the ORR of IMO-2125 and ipilimumab and the ORR of IMO-2125 and 


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Protocol Number: 2125-204 
 
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pembrolizumab), a Bonferroni correction has been applied to the alpha to control for Type I 
error for the trial. 
Assuming the immune-related ORR for subjects who receive ipilimumab alone is at most 11% 
(the historical response rate in subjects who are PD-1 inhibitor naïve), and a target immune-
related ORR of 35% for subjects who receive the IMO-2125 ipilimumab combination treatment, 
a sample size of 21 subjects would achieve 77% power to detect a 24% difference in response 
rates using a one-sided significance level of 2.5%.  
The IMO-2125 + ipilimumab treatment arm will use a two-stage design with a targeted Type I 
error rate of 0.025 to test the null response rate of 0.11 against the alternative of at least 35%. 
With this method, 10 subjects will be treated and monitored for an RECIST v1.1 response in the 
first stage. For this arm, if 2 or more subjects have an RECIST v1.1 response in Stage 1, then the 
treatment arm will continue to Stage 2, in which 11 more subjects will be treated. If at least 6 of 
the 21 total subjects have an RECIST v1.1 response, then the null hypothesis Ho will be rejected 
in favor of the alternative Ha. In this treatment arm, this design has statistical power of 77%, an 
expected sample size of 13.33, and a probability of stopping at the end of the first stage of 69.7% 
if the response proportion is ≤ 0.11.  
 
The IMO-2125 + pembrolizumab treatment arm will use a two-stage design with a targeted Type 
I error rate of 0.025 to test the null response rate against the alternative of at least 35%. If at least 
1 subject has an RECIST v1.1 response in Stage 1, then the treatment arm will continue to Stage 
2 and treat 11 additional subjects. If at least 4 of the 21 total subjects have an RECIST v1.1 
response, then the null hypothesis Ho will be rejected in favor of the alternative Ha. In this 
treatment arm, this design has statistical power of 96%, an expected sample size of 14.41, and a 
probability of stopping at the end of the first stage of 60% if the response proportion is ≤0.05. 
 
 


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                                                                            Statistical Analysis Plan 
Protocol Number: 2125-204 
 
Final 1.1, March 5th, 2020 
 
 
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5. GENERAL ANALYSIS CONSIDERATIONS 
The statistical analyses will be reported using summary tables, listings, and figures (TLFs). The 
International Conference on Harmonisation (ICH) numbering convention will be used for all 
TLFs. Unless otherwise noted, all statistical testing will be one-sided and will be performed at 
the 0.025 significance level. Tests will be declared statistically significant if the calculated p-
value is less than or equal to the significance level of the test, usually 0.025. Continuous 
variables will be summarized with means, standard deviations, medians, minimums, and 
maximums. For continuous variables, descriptive statistics will include the number of non-
missing values, mean, standard deviation, median, 25th and 75th percentile, minimum, 
maximum, and 95% confidence intervals (CIs) as appropriate. All durations will be reported in 
months. 
 
For categorical variables, descriptive statistics will include counts and percentages per category. 
Statistics describing time-to-event variables will use the Kaplan-Meier method. Individual 
subject data obtained will be presented by subject in data listings. Dose group will be used to 
identify the dose and study treatment cohort in the Phase 1 portion of the trial; treatment arm 
will identify the treatment arm in the Phase 2 portion of the study.  All analysis will be done 
using these descriptors. 
 
The analyses described in this plan are considered a priori, in that they have been defined prior 
to database lock. All analyses and tabulations will be performed using SAS Version 9.2 or 
higher. Tables and listings will be presented in RTF format. All SAS programs will be 
validated by an independent programmer. In addition, all program output will undergo a senior 
level statistical review. The validation process will be used to confirm that statistically valid 
methods have been implemented and that all data manipulations and calculations are accurate. 
Checks will be made to ensure accuracy, consistency with this plan, consistency within tables, 
and consistency between tables and corresponding data listings. Upon completion of validation 
and quality review procedures, all documentation will be collected and filed by the project 
statistician or designee. 
 
 


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6. ANALYSIS POPULATIONS  
The following analysis population will be used for safety analyses:  
 
• Safety Population: all patients who received at least one dose of IMO-2125. 
 
The following analysis population will be used only for Cohort Review Committee meetings to 
determine if the dose may be escalated. 
• DLT Evaluable Population: all patients in the Safety Population who continue 
participation in the study for the entire DLT evaluation period, or who discontinue 
prematurely due to a DLT. 
  The following analysis populations will be used for efficacy analyses:  
 
• Primary Ipilimumab + IMO-2125 Efficacy Evaluable (PIIEE) Population: all patients 
who are ipilimumab-naïve on study entry (including those who received ipilimumab 
only in the adjuvant setting) and who are treated at the RP2D for the IMO-2125 + 
ipilimumab combination, regardless of which phase of the study they receive it; and 
who received at least one dose of each study drug. 
• Secondary Ipilimumab + IMO-2125 Efficacy Evaluable (SIIEE) Population:  all 
patients who are not ipilimumab-naïve on study entry and who are treated at the RP2D 
for the IMO-2125 + ipilimumab combination, regardless of which phase of the study 
they receive it; and who received at least one dose of each study drug.  
• Primary Pembrolizumab + IMO-2125 Efficacy Evaluable (PPIEE) Population:  all 
patients who are treated at the RP2D for the IMO-2125 + pembrolizumab 
combination, regardless of which phase of the study they receive it; and who received 
at least one dose of each study drug.  
 
7. STUDY POPULATION 
7.1 Subject Disposition 
Subject disposition will be summarized for all subjects. Summaries will include: the number of 
subjects screened, the number of enrolled subjects, the number of subjects in each analysis 
population, the number of subjects completing or withdrawing from the study, and the primary 
reason for discontinuation. 


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7.2 Protocol Deviations 
Major protocol deviations will be summarized by deviation category and treatment group.  All 
protocol deviations will be listed. 
7.3 Demographic and Baseline Characteristics 
Demographic variables include: age, sex, ethnicity, and race. Age will be calculated in years 
relative to the informed consent date. Other baseline characteristics include: medical history, 
baseline melanoma disease characteristics, selected previous melanoma treatment, height, 
weight, body mass index (BMI), etc. Descriptive statistics will be presented for demographic and 
baseline characteristics for the Safety Population.  
7.4 Concomitant Medications 
Concomitant medication verbatim terms on electric case report forms  (eCRFs) will be mapped 
to Anatomical/Therapeutic/Chemical (ATC) class and Preferred Names using the World Health 
Organization (WHO) Drug Dictionary Enhanced (version March 1, 2015). 
 
Concomitant medications will be summarized for each dose group as well as for all subjects in 
each treatment arm by WHO ATC class and preferred name. These summaries will present the 
number and percentage of subjects using each medication. Subjects may have more than one 
medication per ATC class and preferred name. At each level of subject summarization, a subject 
is counted once if he reported one or more medications at that level. Each summary will be 
ordered by descending order of incidence of ATC class and preferred name within each ATC 
class. 
 
Any concomitant medications identified as sensitive and narrow therapeutic range CYP substrates will be 
listed including any adverse event(s) that started during the duration of the IMO-2125 treatment.  The 
medications of interest are as follows: 
 
 


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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 
Alosetron, duloxetine 
 
CYP1A2 substrates with a 
narrow therapeutic range 
theophylline, tizanidine 
 
Sensitive CYP2C8 substrates 
 
repaglinide 
 
CYP2C8 substrates with a 
narrow therapeutic range 
paclitaxel 
 
CYP2C9 substrates with a 
narrow therapeutic range 
phenytoin , warfarin 
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 
 
8. EFFICACY ANALYSES 
The primary analysis of efficacy in the Phase 2 IMO-2125 + ipilimumab arm, including the 
hypothesis test of the ORR, will be performed on the first 21 patients in the PIIEE Population as 
defined in Section 6. An analysis of those in the SIIEE Population will also be performed; 
efficacy analysis in the combined PIIEE and SIIEE Population may also be summarized. The 
primary analysis of efficacy in the Phase 2 IMO-2125 + pembrolizumab arm will be performed 
on the PPIEE Population as defined in Section 6. 


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Patients will be categorized into subgroups based on whether they had previously been treated 
with talimogene or another oncolytic viral vector prior to enrollment in this study for some 
analyses. 
8.1 Best Overall Response 
The best overall response is the best response across all disease assessment visits after baseline 
taking into account requirements for conﬁrmation.  For any response criteria, the best overall 
response for each subject will be determined by examining investigator-assessed visit-level 
responses and determining the best confirmed response using the assignment rules in Section 
8.1.1 or Section 8.1.2, as appropriate (Paules et al, 2010).  Only visit-level disease assessments 
prior to the start of new anti-cancer therapy or response per the appropriate criteria will be 
considered. 
8.1.1 Confirmed Response using RECIST v1.1 
Table 6 shows how the investigator-assessed Best Overall Confirmed Response is assigned for 
each subject. The table is based on the Best Overall Response confirmation table in the RECIST 
v1.1 guidelines (Appendix C). 
 
 


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Table 6: 
Confirmed Response using RECIST V1.1 
Visit-Level  
Response 
Next Visit Level 
Response 
Confirmed Response 
CR 
CR 
CR (if visit-level disease assessments are > 28 days apart), 
otherwise SD 
CR 
PR 
PR (if visit-level disease assessments are > 28 days apart); 
otherwise SD 
CR 
SD 
SD  
CR, PR, SD 
PD 
SD  
CR, PR 
NE 
SD  
PR 
CR, PR 
PR (if visit-level disease assessments are > 28 days apart); 
otherwise, SD  
PR 
SD 
SD  
SD 
SD, CR, PR, PD, 
NE 
SD  
PD 
PD 
PD  
NE 
NE 
NE 
CR, PR, SD 
No 2nd visit 
SD  
PD 
No 2nd visit 
PD 
NE 
No 2nd visit 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease,  
NE = not evaluable. 
 
The minimum interval for confirmation of CR and PR is 28 days. Subjects must have at least one 
post-baseline disease assessment to be assigned SD as the best overall response; otherwise, there 
is no minimum interval for assignment of SD as the best overall response. Because scans of 
target and non-target lesions can be done on different dates, time between disease assessments is 
determined using the following algorithm:  (1) calculate the time in days between initial and 
confirmatory scans for all target and non-target lesions separately (conﬁrmatory assessment date 
- initial assessment date +1 ); (2) select the minimum time; and (3) compare to 28 days to 
determine if the confirmation criterion were met. Date of confirmed best overall response is 
determined using scan dates as follows: if BOR is CR or PR response date is the latest date of 
target or non-target lesion scan date or else use the assessment date. 
 


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8.1.2 Best Response at an Interim Analysis using RECIST v1.1 
Responses of CR and PR may not have had the opportunity to be confirmed at an interim 
analysis.  Therefore, if a subject has an unconfirmed response (i.e., one visit assessment of CR or 
PR) as the last disease assessment before an interim analysis, the best response in the interim 
analysis will be reported as an unconfirmed CR (uCR) or unconfirmed PR (uPR). 
8.1.3 Confirmed Response using irRC and irRECIST 
Table 7 incorporates the response confirmation rules indicated in the irRC and irRECIST 
guidelines (see Appendix B and Appendix D). 
Table 7 Confirmed Response using irRC or irRECIST 
Visit-Level  
Response 
Next Visit- 
Level 
Response 
Confirmed Response 
CR 
CR 
CR (if visit-level disease assessments are > 28 days apart), otherwise SD 
CR 
PR  
PR (if visit-level disease assessments are > 28 days apart), otherwise SD 
CR 
SD 
SD  
CR, PR, SD 
PD 
SD  
CR, PR 
NE 
SD  
PR 
CR, PR 
PR (if visit-level disease assessments are > 28 days apart); otherwise, SD  
PR 
SD 
SD  
SD 
SD, CR, PR, 
PD, NE 
SD  
PD 
PD 
PD (if visit-level disease assessments are > 28 days apart), otherwise, NE. 
CR, PR, SD 
No 2nd visit 
SD  
PD 
No 2nd visit 
NE  
NE 
No 2nd visit 
NE 
 
The minimum interval for confirmation of CR, PR and PD is 28 days. Subjects must have at least 
one post-baseline disease assessment to be assigned SD as the best overall response; otherwise, 
there is no minimum interval for assignment of SD as the best overall response. The same 
algorithm as for RECIST v1.1 criteria will be used to determine time between disease 
assessments for confirmation of CR, PR, and PD. 


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In some situations, it may be necessary to check across more than two sequential time points in 
order to determine whether or not a minimum duration criteria has been met.  The same logic as 
used for the pairs of time points should be applied.  For example, note the following examples. 
• For the triplet CR NE CR, if the minimum criteria for CR duration is met for the interval 
between the two CR assessments, then Confirmed Response = CR. Otherwise Confirmed 
Response = SD. 
• For the triplet CR CR CR, if the minimum criteria for CR duration is met for the interval 
between the first and third CR assessments, then Confirmed Response = CR. Otherwise 
Confirmed Response = SD. 
• For the triplet PR NE PR, if the minimum interval criteria for PR is met for the interval 
between the two PR assessments, then Confirmed Response = PR. Otherwise Confirmed 
Response = SD. 
• For the triplet PR PR PR, if the minimum interval criteria for PR is met for the interval 
between the first and third PR assessments, then Confirmed Response = PR. Otherwise 
Confirmed Response = SD. 
For confirmed progression using irRC and irRECIST. 
• For the triplet PD NE PD, if the minimum interval criteria for PD is met for the interval 
between the two PD assessments, then Confirmed Response = PD. Otherwise Confirmed 
Response = NE. 
• For the triplet PD PD PD, if the minimum interval criteria for PD is met for the interval 
between the first and third PD assessments but is not met between the first and second PD 
assessments or between the second and third PD assessments, then Confirmed Response = 
PD. Otherwise Confirmed Response = NE. 
8.1.4  Derivation of irRECIST Confirmed Response for Phase 1 Subjects Treated at the RP2D 
For both combinations, subjects enrolled in the Phase 1 portion of the trial will also be analyzed 
with the Phase 2 subjects. Therefore, the irRECIST response at each visit, as well as the overall 
confirmed best response, will be derived. These derived responses will be summarized as 
described in Section 8.1.3. 
 
Visit 1-Screening:- Derived baseline tumor burden will be the sum of the longest diameters of 
the lesions that have “Yes” for Baseline Target Lesion. Derived non-target lesions will be all 
lesions identified on the Non-Measurable Disease Assessment page. 
 
Subsequent disease assessments:-  Derived tumor burden will be the sum of the longest 
diameters of all Baseline Target Lesions and lesions identified as new lesions by “Yes” for “Is 
this a new lesion?” in the Measurable Disease Assessment page of the eCRF. Derived nadir 


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tumor burden will be the smallest tumor burden across all previous disease assessments, 
including baseline.  Derived non-target lesions will be all lesions identified on the Non-
Measurable Disease Assessment page. 
 
Derived Visit Measurable Response:- Using the derived baseline tumor burden, the percentage 
change from baseline will be calculated as: 
 
 
Derived percentage change from baseline: 
ቂ
(𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏−𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏𝑏𝑏𝑑𝑑𝑑𝑑𝑑𝑑)
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏
ቃ∗100% 
 
Using the derived nadir tumor burdens, the percentage change from nadir will be calculated for 
subjects with non-zero derived nadir: 
 
 
Derived percentage change from nadir:  
ቂ
(𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏−𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏)
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏
ቃ∗100% 
 
Subjects who have a value of 0 mm for their derived nadir  and a derived tumor burden of at least 
5 mm will have a missing derived percentage change from nadir and the derived visit measurable 
response will be PD.  Subjects who have a value of 0 mm for their derived nadir  and a derived 
tumor burden between 0 mm and 5 mm will have a missing derived percentage change from 
nadir and the derived visit measurable response will be SD.  Subjects with a derived nadir of 0 
and a derived tumor burden of 0 will have a derived visit measurable response of CR. 
 
Table 8: 
Measureable Lesion Evaluation 
Response 
Description of response  
irCR 
• Complete disappearance of all non-lymph 
node lesions and no new measurable or 
non-measurable lesions. 
• All measurable lymph nodes have diameter 
<10 mm in short axis. 
 
irPR 
• ≥30% decrease in tumor burden from 
baseline. 
 
irSD 
• Not meeting criteria for irCR, irPR, or 
irPD. 
irPD 
• ≥20% increase in tumor burden from nadir 
and tumor burden> 5 mm. 
 


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NE 
• Assigned if “Unable to evaluate longest 
diameter” is marked for at least one target 
lesion in the CRF page RECIST v1.1 
measurable disease. 
 
 
Derived Visit Non-Measurable Response: If there are no new non-measurable lesions, the 
derived visit non-measurable response is the Status of Non-Target Lesions from the Assessment 
of RECIST Response page of the eCRF. 
 
Lymph nodes will be identified from “Location” in the Measurable Disease Assessment page of 
the eCRF. 
 
Table 9: 
Non-measureable Lesion Evaluation 
Response 
Status of Non-measurable Lesion (eCRF)  
irCR 
• Absent 
 
Non-irCR/Non-irPD 
• Stable 
 irPD 
• Unequivocal Progression 
Not Done/Not 
Evauable 
• Assigned if the RECIST v1.1 non-target 
lesions response is Not Done or Not 
Evaluable. 
 
If there have been new non-measurable lesions identified, the derived visit non-measurable 
response will be irPD if any are assessed with “Unequivocal Progression”. 
 
The derived irRECIST response will be determined based on the following: 
 
Table 10: 
Overall irRECIST Response 
Target Lesion 
(Tumor burden) 
Non-Target Lesions 
New Lesions: Non-Target 
Overall  
(Time point) 
Response 
irCR 
irCR 
No 
irCR 
irCR 
Non-irCR/non-irPD 
No or Non-Unequivocal 
Progression 
irPR 
irCR 
NE 
No or Non-Unequivocal 
Progression 
irPR 


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Target Lesion 
(Tumor burden) 
Non-Target Lesions 
New Lesions: Non-Target 
Overall  
(Time point) 
Response 
irPR 
Non-irPD or not all 
evaluated 
No or Non-Unequivocal 
Progression 
irPR 
irSD 
Non-irPD or not all 
evaluated 
No or Non-Unequivocal 
Progression 
irSD 
Not evaluated 
Non-PD 
No or Non-Unequivocal 
Progression 
NE 
irPD 
Any 
Yes or No 
irPD 
Any 
irPD 
Yes or No 
irPD 
Any 
Any 
Unequivocal Progression 
irPD 
 
8.1.5  Best Response at an Interim Analysis using irRECIST 
Similar to assigning best response by RECIST v1.1 at an interim analysis, if a subject has an 
unconfirmed response (i.e., one visit assessment of CR or PR) by irRC or irRECIST as the last 
disease assessment before an interim analysis, the best response in the interim analysis will be 
reported as an unconfirmed CR (uCR or uirCR) or unconfirmed PR (uPR or uirPR). 
8.2 Exploratory Endpoints 
Exploratory endpoint analyses, except for analysis of patient reported outcome (PRO) quality of 
life using the EORTC QLQ-C30 results, are outside the scope of this Statistical Analysis Plan. 
8.3 Baseline, Worst, and Best-case Post-Baseline Values 
Unless otherwise noted, baseline is defined as the last non-missing value recorded before the first 
dose of study drug. Unscheduled visits will be used in the determination of baseline values, when 
applicable. 
 
Worst-case post-baseline values will be identified from all scheduled and unscheduled visits.  
For measures with degradation from both increases and decreases, Worst-cases will be identified 
and summarized for both.  
 
Best-case post-baseline values will be identified from all scheduled and unscheduled visits.  For 
measurable tumor assessment Best-case will be identified as the largest decrease, or, for subjects 
who have no decrease, the smallest increase in post-baseline assessment. 
 


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8.4 Missing Data 
Subjects who discontinue from the study before completing an on-study radiographic tumor 
evaluation will be counted as non-responders in the evaluation of ORR. 
 
Subjects who discontinue from the study or who are lost to follow-up without objective tumor 
progression while on treatment will be censored on the date of the last assessment documenting 
absence of disease progression in the evaluation of PFS and DoR.  Subjects who discontinue 
from the study or who are lost to follow-up before death will be censored at the date they were 
last known to be alive in the evaluation of OS. 
 
The following algorithms will be applied to missing and incomplete start and stop dates (i.e., 
AEs and concomitant medications): 
 
Start Dates 
• If the day portion of the start date is missing, then the start date will be estimated to be 
equal to the date of first dose of study drug, provided the start month and year are the 
same as the first dose of study drug and the stop date is either after the first dose of study 
drug or completely missing. Otherwise, the missing day portion will be estimated as ‘01’. 
• If both the day and month portions of the start date are missing, then the start date will be 
estimated to be equal to the date of first dose of study drug, provided the start year is the 
same as the first dose of study drug and the stop date is either after the first dose of study 
drug or completely missing. Otherwise, the event will be assumed to start on the first day 
of the given year (e.g., ??-???-2013 is estimated as 01-JAN-2013). 
• If the start date is completely missing and the stop date is either after the dose of study 
drug or completely missing, the start date will be estimated to be the date of first dosing 
of the study drug. Otherwise, the start date will be estimated to be the first day of the 
same year as the stop date. All other non-AE and non-concomitant medication day 
calculations where only partial dates are available will be handled as follows: the first day 
of the month will be used in the calculations if the day part of a start date is missing and 
January 1 will be employed if both the month and day parts of a start date are missing. 
 
Stop Dates 
• If only the end day is unknown, the day will be assumed to the last day of the month 
(e.g., ??-JAN-2013 will be treated as 31-JAN-2013).  
• If both the end day and month are unknown, the event will be assumed to have ceased on 
the last day of the year (e.g., ??-???-2013 will be treated as 31-DEC-2013).  
• If the stop date is completely missing or the event is continuing, the event will be 
assumed to be after first dose of study drug and will be imputed using the last known date 
on the study. 


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No imputations will be made for missing values other than those described in this section. 
Summaries will be based on observed data only. 
8.5 Efficacy Endpoints 
ORR is defined as the proportion subjects with a best confirmed overall response of complete 
response (CR) or partial response (PR), with assessment of response to be determined by the 
investigator using irRECIST and RECIST v1.1.   
OS is defined as the number of months from initiation of treatment to death from any cause.  
Subjects who have not died at their last contact will be censored on the date of last contact. The 
specifications for the time to death calculation are: 
• If death is reported either on AE or Death CRF pages, OS will be calculated as Date of 
Documentation of (Death – First Dose Date + 1)/ 30.4375. 
• Subjects will be censored at their last contact date if death is not reported at the data cut-
off date for study closure, and their survival time will be calculated as ([Last Contact 
Date - First Dose Date + 1] / 30.4375). Last contact date is defined as the last date 
reported among, Adverse Event (AE start date), the Study Exit Status, Hematology, 
Chemistry, Assessment of RECIST v1.1 Response, Assessment of irRECIST Response,  
Long Term Follow Up, Study Drug Administration (IMO-2125),  ipilimumab Infusion 
and pembrolizumab Infusion pages of the eCRF. 
• Subjects lacking data after the date of first dose who do not die will have their survival 
time censored on the date of first dose with duration of 1 day. 
 
PFS, defined as number of months from the initiation of treatment to disease progression using 
RECIST v1.1 or irRECIST or death from any cause, will be calculated as ([Date of 
Documentation of Death or Disease Progression – First Dose Date + 1]/30.43750. Subjects 
without reported progression at their last contact date will be censored on the date of their last 
valid disease assessment. A valid disease assessment is any disease assessment with overall visit-
level response of irCR irPR, irSD, or irPD (without subsequent confirmation) when using 
irRECIST and CR, PR, or SD when using RECIST v1.1.  Subjects who start new anti-cancer 
therapy before a PFS event will be censored on the date of initiation of new anti-cancer therapy 
(Subsequent Anti Cancer Therapy eCRF page). 
Duration of response, defined as the length of time from the first occurrence of confirmed 
response (CR or PR) until confirmed (if necessary) disease progression with assessment of 
response to be determined by the Investigator using the irRECIST, and RECIST v1.1. DoR will 
be calculated as [Date of Documentation of Death or Disease Progression – Date of First 
Objective Response]/30.4375. The censoring rules for PFS will be used for DoR.  Subjects who 


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fail to achieve a CR/irCR or PR/irPR during the study will be excluded from the analysis of 
DoR.   
8.6 
Interim Analysis  
There are 3 interim and 1 final analyses planned: 
 
• A planned analysis of phase 1 results at the completion of dose escalation for both 
combinations will be conducted.   
• An analysis of the safety and efficacy results in each phase 2 arm will be conducted 
separately after 21 subjects in the primary efficacy population (used in the two-stage 
design) have had at least 2 post-baseline disease assessments.   
• The final analysis by efficacy populations of all subjects in the IMO-2125 + ipilimumab 
arm will be done when all subjects have had at least 2 post-baseline disease assessments.   
8.7 
Examination of Subgroups 
Subjects will be categorized into subgroups based on whether they had previously been treated 
with talimogene or another oncolytic viral vector prior to enrollment in this study (yes or no).  
Another subgroup of interest is subjects with prior anti-PD-(L)1 as monotherapy or in 
combination therapy (e.g., prior treatment with nivolumab + ipilimumab) or subjects with prior 
CTLA-4; subjects will be categorized into subgroups based on such prior combination therapy 
(yes or no). ORR and DRR using RECIST v1.1 and irRECIST will be analyzed by these 
subgroups if the data support such analyses. 
Subjects will be categorized into subgroups based on whether or not they received CYP substrate 
concomitant medications. 
Subjects will be categorized into subgroups based on whether they had previously been treated 
with Oncolytic Virus, CTLA-4 Inhibitor monotherapy in metastatic setting, CTLA-4 Inhibitor 
monotherapy, PD-(L)1 Inhibitor monotherapy, CTLA-4 + PD-(L)1 Inhibitor combination or, 
Other PD-(L)1 combination in the  Previous Melanoma Treatment eCRF page; subjects can be in 
more than one subgroup. ORR, DRR, DCR, and BOR using RECIST and irRECIST will be 
analyzed by these subgroups if the data support such analyses. 
 
Other subgroups of interest are baseline LDH (elevated or not); disease stage (IV or earlier stage, 
Stage M1c); BRAF mutation positive with prior targeted therapy, BRAF mutation positive with 
no prior targeted therapy, BRAF wild type; 8 mg IMO-2125 and ipilimumab combination dose 
group; subjects without any major protocol deviations; subjects who received at least 1 dose of 
IMO-2125 and 2 doses of ipilimumab in combination in any phase; and duration of prior 
anti-PD-1 therapy (≥12 weeks and <12 weeks).  Subjects with unknown baseline LDH status will 
not be included in the subgroup analysis.  Targeted therapy is either a BRAF or MEK inhibitor, 


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or both.  Prior anti-PD-1 therapy is PD(L)-1 Inhibitor.  ORR, DRR,DCR, and BOR using 
RECIST and irRECIST will be analyzed by these subgroups if the data support such analyses. 
8.8 
Multiple Comparison/Multiplicity 
The study Type I error rate is split between the phase 2 hypothesis tests for each treatment arm, 
so that the ORR is tested at the 0.025 significance level for each. 
9 
METHODS OF EFFICACY ANALYSIS 
9.1 Phase 1  
Efficacy reporting will consist of listings of the best overall response by irRC and RECIST v1.1 
and change in tumor burden (sum of the longest diameters). 
9.2 
Primary Efficacy Analyses 
The primary efficacy endpoint, investigator-assessed ORR using RECIST v1.1, will be analyzed 
for all subjects in the PPIEE population and the first 21 patients in the PIIEE, as well as the 
PIIEE population and SIIEE population combined using a one-sided, one sample exact binomial 
test with α = 0.025 in each test. The proportion of subjects achieving a best confirmed response 
of CR or PR will be tested against the null rates of 0.11 and 0.05 for ipilimumab and 
pembrolizumab, respectively (Hodi et al, 2010).   
 
The primary efficacy analyses will test the following hypotheses: 
 
H0: The ORR assessed using the RECIST v1.1, for subjects in the IMO 2125 + ipilimumab 
treatment arm, is no larger than 0.11; 
H1: The ORR assessed using the RECIST v1.1, for subjects in the IMO 2125 +ipilimumab 
treatment arm, is at least 0.35.   
 
H0: The ORR assessed using the RECIST v1.1, for subjects in the IMO 2125 
+pembrolizumab treatment arm, is no larger than 0.05; 
H1: The ORR assessed using the RECIST v1.1, for subjects in the IMO 2125 
+pembrolizumab treatment arm, is at least 0.35.   
 


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9.3 
Secondary Efficacy Analyses 
9.3.1 Evaluation of Response  
Investigator assessments as reported on electric case report forms  (eCRFs) will be used to 
identify confirmed response as described in Section 8.1. The overall irRC/ irRECIST response 
categories are: Complete Response (irCR), Partial Response (irPR), Stable Disease (irSD), 
Progressive Disease (irPD), and Not Evaluable (irNE).  The overall RECIST v1.1 response 
categories are: Complete Response (CR), Partial Response (PR), Stable Disease (SD), 
Progressive Disease (PD), and Not Evaluable (NE). If any post-baseline scheduled tumor 
assessment is missed, that visit-level response for that visit will be ‘Not Done’.   
 
The ORR, DRR, and DCR will be estimated by the MLE for secondary response endpoints.  The 
MLE is  𝑝𝑝̂ = s1/n1 if the arm stops after Stage 1 and 𝑝𝑝̂ = (s1+s2)/(n1+n2) otherwise, where si=the 
number of subjects with a response in Stage i and ni=number of subjects in stage i, i=1,2.  All 
secondary response rate endpoints will be summarized descriptively by treatment arm for phase 
2 subjects with the number of subjects with a response, percentage, and exact two-sided 95% 
CIs. 
 
The number and percent of subjects in each of the best overall tumor response categories, using 
irRECIST and RECIST v1.1, will be summarized for phase 2 subjects. Exact two-sided 95% 
confidence intervals will be provided for each best overall tumor response category by treatment 
arm. 
Durable response rate (DRR) is defined as the proportion of subjects experiencing CR or PR by 
RECIST v1.1 (irCR or irPR by irRECIST) lasting approximately 6 months continuously and 
beginning within 12 months of the first dose of study treatment. The length of durable response 
is calculated as ((Date of Documentation of Death or Disease Progression – Date of First 
Objective Response + 1)/ 30.4375). 
 
The DRR using irRECIST and RECIST v1.1 will be summarized descriptively by treatment arm 
for phase 2 subjects with the number of subjects, percentage, and exact two-sided 95% CIs.  
 
Disease control rate (DCR) using irRECIST and RECIST v1.1 will be summarized descriptively 
by treatment arm for phase 2 subjects with the number of subjects, percentage, and exact two-
sided 95% CIs.  
 
Swimmers’ lane plots will also be produced showing time to response (RECIST v 1.1), duration 
of response, type of response, and duration of treatment for the phase 2 results. 


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9.3.2 Evaluation of Time to Event Endpoints  
The OS and PFS proportions will be estimated at 6 and 12 months; OS and PFS will also be 
analyzed overall with Kaplan-Meier estimate including median. For time-to-event endpoints 
(OS, PFS, and DoR), the Kaplan-Meier method will be used to estimate the probability of event-
free survival. The analyses of OS, PFS, and DoR will only be done for the subjects treated at the 
RP2D for each treatment arm. 
Kaplan-Meier plots will be produced for OS and PFS by treatment arm. 
Subgroup analysis of overall survival at 6 and 12 months, as well as progression-free survival, 
may be performed for the 8 mg IMO-2125 and ipilimumab combination dose group if data 
supports it.  
9.3.3 Measurable Disease Assessment 
The absolute and percent change from baseline for the sum of longest diameters of the baseline 
target lesions from measurable tumor assessment CRF page will be listed by dose group for 
phase 1 subjects and summarized and listed by treatment arm for phase 2 subjects at the Best-
case post baseline.  The summary may be repeated for injected and non-injected lesions 
separately.  
 
Waterfall plots of the maximum percentage change from baseline in measurable tumor burden 
(the sum of the longest diameter) will be produced for the phase 2 results.  The bars will not be 
coded for any factor but the treatment combinations will be distinct colors in the separate figures. 
 
Measurable disease assessment, non-measurable disease assessment, assessment of RECIST v1.1 
response, assessment of irRECIST response and assessment of irRC response data will be listed 
by subject.Exploratory Analyses 
9.4.1 Pharmacodynamic Markers 
Analysis of pharmacodynamic result is not in the scope of this analysis plan and will be 
addressed separately. 
9.4.2 Immunogenicity Analyses 
Immunogenicity results will be included in data listings only. 
10 SAFETY ANALYSES 
All safety analyses will be performed on the Safety Population.   


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10.1 Extent of Exposure 
Exposure will be calculated separately for IMO-2125, ipilimumab and pembrolizumab. Total 
number of doses (injections or infusions) per subject, total volume administered (mL) per 
subject, total dose administered (mg) for ipilimumab and pembrolizumab only, and the duration 
of treatment (months) will be summarized by each dose group. Duration of treatment is defined 
as the (last dose date minus the first dose date plus 1)/30.4375.  
 
Dose modifications will be reported separately for IMO-2125, ipilimumab and pembrolizumab. 
 
Dose modifications for IMO-2125 will be described by summarizing: 
• the number of subjects who had an injection delayed. The “injection delayed” 
determination will be based on the answer to the question of “Was Intratumoral Injection 
delayed?” on the “Study Drug Administration (IMO-2125)” CRF pages. The summary 
will be presented by dose group and overall as well as by cycle (phase 1) and by 
treatment arm (phase 2), with each injection given representing a new cycle. 
• the number of subjects who had dose decreased. The “dose decreased” determination will 
be based on the answer to the question of “Was planned dose decreased? on the “Study 
Drug Administration (IMO-2125)” CRF pages. The summary will be presented by dose 
group and overall as well as by cycle (phase 1) and by treatment arm (phase 2), with each 
injection given representing a new cycle. 
 
Dose modifications for ipilimumab and pembrolizumab will be described by summarizing: 
 
• the number of subjects who had infusion rate decreased. The “infusion  rate decreased” 
determination will be based on the answer to the question of “Was Infusion Rate 
decreased?” on the ipilimumab and pembrolizumab infusion CRF pages. The summary 
will be presented by dose group and overall as well as by cycle, with each infusion given 
representing a new cycle. 
• the number of subjects who had infusion discontinued. The “infusion discontinued” 
determination will be based on the answer to the question of “Was Infusion 
Discontinued? on the ipilimumab and pembrolizumab infusion  CRF pages. The 
summary will be presented by dose group and overall as well as by cycle, with each 
injection given representing a new cycle. 
• the number of subjects who had infusion interrupted. The “infusion interrupted?” 
determination will be based on the answer to the question of “Was infusioninterrupted? 
on the ipilimumab and pembrolizumab  infusion pages. The summary will be presented 
by dose group and overall as well as by cycle (phase 1) and by treatment arm (phase 2), 
with each infusion  given representing a new cycle. 
 


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Data listings for study drug administered will be provided. 
10.2 Adverse Events 
Adverse event summaries will be restricted to Treatment Emergent Adverse Events (TEAE), 
which are defined as those AEs that started on or after the date of first dose of study treatment 
and those existing AEs that worsened during the study. If it cannot be determined whether the 
AE is treatment emergent due to a partial onset date, then it will be counted as treatment 
emergent. Verbatim terms on electric case report forms  will be mapped to preferred terms and 
system organ classes using the Medical Dictionary for Regulatory Activities (MedDRA) (version 
16.1).  
 
Summaries displayed by system organ class and preferred terms will be ordered by descending 
order of incidence of system organ class and preferred term within each system organ class, with 
TEAEs of the same incidence displayed alphabetically.  Summaries displayed by preferred term 
will be ordered by descending order of incidence, with TEAEs of the same incidence displayed 
alphabetically.  
 
Summaries of the following types will be presented: 
 
• Overall summary of TEAEs which contain an overview of number of subjects with at 
least one TEAE, at least one IMO-2125-related TEAE, at least one ipilimumab-related 
TEAE, at least one pembrolizumab-related TEAE, at least one serious TEAE, at least one 
grade 3 or higher TEAE, at least one TEAE leading to discontinuation, at least one TEAE 
of action taken with IMO-2125 as drug withdrawn, at least one TEAE of action taken 
with ipilimumab as drug withdrawn, at least one TEAE of action taken with 
pembrolizumab as drug withdrawn, at least one immune-related TEAE, and at least one 
TEAE with fatal outcome.  The maximum severity by the CTCAE will also be included.  
• Subject incidence of TEAEs by MedDRA SOC and preferred term. 
• Subject incidence of TEAEs by preferred term. 
• Subject incidence of TEAEs by preferred term, and highest Common Terminology 
Criteria for Adverse Events (CTCAE) toxicity grade. At each level of subject 
summarization, a subject is classified according to the highest CTCAE toxicity grade if 
the subject reported more than one event. 
• Subject incidence of IMO-2125-related TEAEs by preferred term. Only those AEs 
reported as “Related”, “Possibly”, or “Probably”, or which have a missing relationship to 
IMO-2125 will be included in this summary. 
• Subject incidence of ipilimumab-related TEAEs by preferred term. Only those AEs 
reported as “Related”, “Possibly”, or “Probably”,  or which have a missing relationship to 
ipilimumab will be included in this summary. 


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• Subject incidence of pembrolizumab-related TEAEs by preferred term. Only those AEs 
reported as “Related”, “Possibly”, or “Probably”,  or which have a missing relationship to  
pembrolizumab will be included in this summary. 
• Subject incidence of serious TEAEs by preferred term. 
• Subject incidence of IMO-2125-related serious TEAEs by preferred term. Only those 
AEs marked as “Related”, “Possibly”, or “Probably”, or which have a missing 
relationship to IMO-2125 will be included in this summary. 
• Subject incidence of ipilimumab -related serious TEAEs by preferred term. Only those 
AEs reported as “Related”, “Possibly”, or “Probably”, or which  have a missing 
relationship to ipilimumab are considered for this summary. 
• Subject incidence of study pembrolizumab serious by preferred term. Only those AEs 
reported as “Related”, “Possibly”, or “Probably”, or which have a missing relationship to 
pembrolizumab are considered for this summary. 
• Subject incidence of TEAEs that have CTCAE grade 3 or higher by preferred term. 
• Subject incidence of TEAEs leading to study discontinuation by preferred term.  
• Subject incidence of TEAEs of action taken with IMO-2125 as drug withdrawn by 
preferred term.  
• Subject incidence of TEAEs of action taken with ipilimumab as drug withdrawn by 
preferred term.  
• Subject incidence of TEAEs of action taken with pembrolizumab as drug withdrawn by 
preferred term.  
• Subject incidence of immune-related TEAEs by preferred term. 
• Subject incidence of TEAEs with fatal outcome by preferred term.  
• Subjects with non-serious TEAEs by SOC and preferred term. 
 
irAEs will be determined from a list of pertinent MedDRA codes provided by the study sponsor.   
10.3 Clinical Laboratory Evaluation 
Laboratory parameters for serum chemistry, hematology, complement, and coagulation will be 
summarized by dose group in phase 1 and treatment arm in phase 2 using descriptive statistics at 
baseline and at worst-case post-baseline.  
 
Select laboratory parameters for serum chemistry, hematology, and coagulation will be assigned 
grades according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03. 
The complement parameters will be considered being worse if the post-baseline value is lower 
than baseline value. The worse case post-baseline value will be the lowest value after baseline. 
Complement parameter results with 50% decrease from baseline may be summarized separately. 
Shift tables assessing changes from baseline to assigned worst-case post-baseline in assigned 
CTCAE grade will be summarized.  Shift tables will use results from all visits (scheduled and 


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unscheduled).  For laboratory parameters that are not graded by the CTCAE v4.03, shift tables 
relative to the normal range will be produced and will also use results from all visits (scheduled 
and unscheduled).  The laboratory parameter will be summarized in applicable shift tables (by 
CTCAE v4.03 grade and/or relative to the normal range).  Laboratory parameters that have 
bidirectional Worst-cases (that is, laboratory parameters which have both  CTCAE or normal 
range shift for low values and for high values) will have the results for both directions reported.  
 
Shift tables will report the counts and percentages of subjects shifting for each dose group for 
phase 1 and by treatment arm for phase 2.  
 
Plots for each dose level showing the mean complement with standard error bars by visit will be 
produced for the phase 1 results.  For the phase 1 and 2 results combined, these plots will be by 
treatment arm.  
 
 


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Table 11: 
CTCAE Toxicity Grades: Hematology 
 
Analyte 
Standard 
Unit 
Directional 
Change 
Toxicity Grades 
(CTCAE v4.03) 
 
 
 
 
 
Hemoglobin[1] 
g/dL 
Decrease 
Grade 1:  < LLN – 10 g/dL 
 
 
 
Grade 2:  < 10 – 8 g/dL 
 
 
 
Grade 3:  < 8 g/dL 
 
 
 
Grade 4:  Not defined 
 
 
Increase 
Grade 1:  > ULN – (2+ULN) 
g/dL 
 
 
 
Grade 2:  > (2+ULN) – 
(4+ULN) g/dL 
 
 
 
Grade 3:  > 4+ULN g/dL 
 
 
 
Grade 4:  Not defined 
 
 
 
 
Lymphocytes 
x 10^3/uL 
Decrease 
Grade 1:  < LLN – 0.8 x 10^3/uL 
 
 
 
Grade 2:  < 0.8 – 0.5 x 10^3/uL 
 
 
 
Grade 3:  < 0.5 – 0.2 x 10^3/uL 
 
 
 
Grade 4:  < 0.2 x 10^3/uL 
Lymphocytes 
x10^9/L 
Increase 
Grade 1:  Not defined 
 
 
 
Grade 2:  >4.0 – 20.0 x 10^3/uL 
 
 
 
Grade 3:  >20.0 x 10^3/uL 
 
 
 
Grade 4:  Not defined 
 
 
 
 
Neutrophils 
x10^9/L 
Decrease 
Grade 1:  < LLN – 1.5 x 10^3/uL 
 
 
 
Grade 2:  < 1.5 – 1.0 x 10^3/uL 
 
 
 
Grade 3:  < 1.0 – 0.5 x 10^3/uL 
 
 
 
Grade 4:  < 0.5 x 10^3/uL 
 
 
 
 
Platelets 
x 10^3/uL 
Decrease 
Grade 1:  < LLN – 75.0 x 
10^3/uL 
 
 
 
Grade 2:  < 75.0 – 50.0 x 
10^3/uL 


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Grade 3:  < 50.0 – 25.0 x 
10^3/uL  
 
 
 
Grade 4:  < 25.0 x 10^3/uL 
 
 
 
 
 
WBC 
x 10^6/uL 
Decrease 
Grade 1:  < LLN – 3.0 x 10^3/uL 
 
 
 
Grade 2:  < 3.0 – 2.0 x 10^3/uL 
 
 
 
Grade 3:  < 2.0 – 1.0 x 10^3/uL 
 
 
 
Grade 4:  < 1.0 x 10^3/uL 
 
 
Increase 
Grade 1:  Not defined 
 
 
 
Grade 2:  Not defined 
 
 
 
Grade 3:  >100 x 10^3/uL 
 
 
 
Grade 4:  Not defined 
LLN=lower limit of normal.  ULN=upper limit of normal.  The LLN and ULN for 
each analyte will be determined from the normal range of each local laboratory. 
[1] For increased hemoglobin results, if the baseline value is above the ULN, the 
baseline value will be used instead of the ULN to assess grades 1, 2, and 3. 
Table 12: 
CTCAE Toxicity Grades: Coagulation 
 
Analyte 
Standard 
Unit 
Directional 
Change 
Toxicity Grades 
(CTCAE v4.03) 
 
aPTT 
sec 
Increase 
Grade 1:  >ULN – 1.5 x ULN 
 
 
 
Grade 2:  >1.5 – 2.5 x ULN 
 
 
 
Grade 3:  >2.5 x ULN 
 
 
 
Grade 4:  Not defined 
 
 
 
 
INR 
No units 
Increase 
Grade 1:  >ULN – 1.5 x ULN 
 
 
 
Grade 2:  >1.5 – 2.5 x ULN 
 
 
 
Grade 3:  >2.5 x ULN 
 
 
 
Grade 4:  Not defined 
 
 
 
 
LLN=lower limit of normal.  ULN=upper limit of normal.  The LLN and ULN for 
each analyte will be determined from the normal range of each local laboratory. 
 


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Table 13: 
CTCAE Toxicity Grades: Chemistry 
 
Analyte 
Standard  
Unit 
Directional  
Change 
Toxicity Grades 
(CTCAE v4.03) 
 
ALT (SGPT) 
U/L 
Increase 
Grade 1:  > ULN – 3.0 x ULN 
 
 
 
Grade 2:  > 3.0 – 5.0 x ULN 
 
 
 
Grade 3:  > 5.0 – 20.0 x ULN 
 
 
 
Grade 4:  > 20.0 x ULN 
 
 
 
 
AST (SGOT) 
U/L 
Increase 
Grade 1:  > ULN – 3.0 x ULN 
 
 
 
Grade 2:  > 3.0 – 5.0 x ULN 
 
 
 
Grade 3:  > 5.0 – 20.0 x ULN 
 
 
 
Grade 4:  > 20.0 x ULN 
 
 
 
 
 
Alkaline 
Phosphatase 
U/L 
Increase 
Grade 1:  > ULN – 2.5 x ULN 
 
 
 
Grade 2:  > 2.5 – 5.0 x ULN 
 
 
 
Grade 3:  > 5.0 – 20.0 x ULN 
 
 
 
Grade 4:  > 20.0 x ULN 
 
 
 
 
 
Albumin 
g/dL 
Decrease 
Grade 1:  < LLN – 3 g/dL 
 
 
 
Grade 2:  < 3 – 2 g/dL 
 
 
 
Grade 3:  < 2 g/dL 
 
 
 
Grade 4:  Not defined 
 
 
 
 
Calcium 
mg/dL 
Decrease 
Grade 1:  < LLN – 8.0 mg/dL 
 
 
 
Grade 2:  < 8 – 7.0 mg/dL 
 
 
 
Grade 3:  <7 – 6 mg/dL 
 
 
 
Grade 4:  < 6 mg/dL 
Calcium 
mg/dL 
Increase 
Grade 1:  ULN - 11.5 mg/dL 
 
 
 
Grade 2:  > - 11.5 – 12.5 mg/dL 


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Grade 3:  > 12.5  - 13.5 mg/dL 
 
 
 
Grade 4:  > 13.5 mg/dL 
 
 
 
 
 
Cholesterol 
mg/dL 
Increase 
Grade 1:  >ULN - 300 mg/dL 
 
 
 
Grade 2:  >300 – 400 mg/dL 
 
 
 
Grade 3:  >400 - 500 mg/dL 
 
 
 
Grade 4:  >500 mg/dL 
 
 
 
 
Creatinine 
mg/dL 
Increase 
Grade 1:  > ULN – 1.5 x ULN 
 
 
 
Grade 2:  > 1.5 – 3.0 x ULN 
 
 
 
Grade 3:  > 3.0 – 6.0 x ULN 
 
 
 
Grade 4:  > 6.0 x ULN 
 
 
 
 
GGT 
 
Increase 
Grade 1 >ULN - 2.5 x ULN 
 
 
 
Grade 2:  >2.5 - 5.0 x ULN 
 
 
 
Grade 3:  >5.0 - 20.0 x ULN 
 
 
 
Grade 4:  >20.0 x ULN 
 
 
 
 
Glucose 
mg/dL 
Decrease 
Grade 1 <LLN - 55 mg/dL 
 
 
 
Grade 2:  <55 – 40 mg/dL 
 
 
 
Grade 3:  <40 - 30 mg/dL 
 
 
 
Grade 4:  <30 mg/dL 
Glucose 
mg/dL 
Increase 
Grade 1: <ULN – 160 mg/dL 
 
 
 
Grade 2:  160- 250 mg/dL 
 
 
 
Grade 3:  <250 - 500 mg/dL 
 
 
 
Grade 4:  <500  mg/dL 
 
 
 
 
Phosphate 
mg/dL 
Decrease 
Grade 1: <LLN – 2.5 mg/dL 
 
 
 
Grade 2:  <2.5 - 2 mg/dL 
 
 
 
Grade 3:  <2 - 1 mg/dL 


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Grade 4:  <1 mg/dL 
 
 
 
 
Potassium* 
mEq/L 
Decrease 
Grade 1: <LLN - 3.0 mEq/L 
 
 
 
Grade 2: <LLN - 3.0 mEq/L 
 
 
 
Grade 3:  <3 – 2.5. mEq/L 
 
 
 
Grade 4:  <2.5  mEq/L 
 
 
Increase 
Grade 1 >ULN – 5.5 mEq/L 
 
 
 
Grade 2:  5.5>- 6 mEq/L 
 
 
 
Grade 3:  >6 - 7 mEq/L 
 
 
 
Grade 4:  >7 mEq/L 
 
 
 
 
 
Sodium 
mEq/L 
Decrease 
Grade 1:  < LLN – 130 mEq/L 
 
 
 
Grade 2:  Not defined 
 
 
 
Grade 3:  < 130 – 120 mEq/L 
 
 
 
Grade 4:  < 120 mEq/L 
 
mEq/L 
Increase 
Grade 1:  > ULN – 150 mEq/L 
 
 
 
Grade 2:  > 150 – 155 mEq/L  
 
 
 
Grade 3:  > 155 – 160 mEq/L 
 
 
 
Grade 4:  > 160 mEq/L 
 
 
 
 
Total Bilirubin 
mg/dL 
Increase 
Grade 1:  > ULN – 1.5 x ULN 
 
 
 
Grade 2:  >1.5 – 3.0 x ULN 
 
 
 
Grade 3:  >3.0 – 10.0 x ULN 
 
 
 
Grade 4:  >10.0 x ULN 
 
 
 
 
Uric Acid* 
mg/dL 
Increase 
Grade 1 < ULN - 10 mg/dL 
 
 
 
Not Defined 
 
 
 
Grade 3 < ULN - 10 mg/dL  
 
 
 
Grade 4:  <10 mg/dL 
 
 
 
 


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LLN=lower limit of normal.  ULN=upper limit of normal.  The LLN and ULN for 
each analyte will be determined from the normal range of each local laboratory. 
 
* Indicates laboratory values for which CTCAE grade is not based on the laboratory 
value; clinical symptoms are also involved. 
 
Urinalysis results will not be summarized but will be listed.  
 
Data listings of laboratory results will be provided for each subject. Laboratory values that are 
out of the normal range will be flagged in listings, and those that are graded by the CTCAE 
v4.03 will have the assigned grade included in the listing.   
10.4 Vital Signs 
Vital signs (weight, blood pressure, heart rate, respiratory rate, and body temperature) will be 
summarized by dose group and treatment arm using descriptive statistics at baseline and at 
worst-case post-baseline. Changes from baseline at worst-case post-baseline relative to the 
normal range will also be summarized. The wost case post-baseline for weight, blood pressure, 
hear rate, and respiratory rate will be derived in two direcdtions by their highest increase and 
decrease respectively.  
 
Diastolic BP and Systolic BP will be assigned grades according to NCI Common Terminology 
Criteria for Adverse Events (CTCAE) v4.03. Shift tables assessing changes from baseline to 
Worst-case assigned post- baseline in CTCAE grade will be presented.  
Table 14: 
CTCAE Toxicity Grades: Vital Signs 
 
Vital 
Standard 
Unit 
Directional 
Change 
Toxicity Grades 
(CTCAE v4.03) 
 
 
 
 
 
Diastolic BP 
mm Hg 
Increase 
Grade 1:  80 - 89 
 
 
 
Grade 2:  90 - 99 
 
 
 
Grade 3:  >=100 
 
 
 
 
 
Systolic BP 
mm Hg 
Increase 
Grade 1: 120 - 139 
 
 
 
Grade 2:  140 - 159 
 
 
 
Grade 3:  >=160 


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In addition, shift table assessing changes from baseline to worst decrease post-baseline, in 
normal range will be summarized for temperature.  
 
Table 15: 
Normal Range Vital Signs 
Vital 
Standard Unit 
Range  
Temperature  F 
Low : < 60 
 
 
Normal:  60 -100 
 
 
High: > 100 
 
Data listings of vital signs will be provided for each subject. 
10.5 Physical Examination 
Physical examination results will be included in data listings only.  
10.6 Electrocardiogram 
QTcF in msec will be calculated using the following formula for all subjects: 
 
 
 
 
 
QTcF = QT/(RR)0.33. 
 
Overall interpretation results for ECG will be summarized using shift tables (Normal, Abnormal 
NCS, Abnormal CS) comparing baseline to follow-up. Descriptive statistics at baseline and at 
Worst-case post-baseline as well as changes from baseline will be summarized QTcF.   
 
In addition, a categorical summary of abnormal QTcF values will be presented. 
• At each visit, the number of subjects with QTcF values of > 450 ms, > 480 ms, and > 
500 ms will be presented. 
•  At each post-baseline visit, the number of subjects with change from baseline values in 
QTcF of > 30 ms and > 60 ms will be presented.   
 
Frequency counts and percentages of subjects shifting from baseline status at worst decrease 
post-baseline subjects will be summarized; subjects with missing baseline or missing post-
baseline result will also be summarized. The shift will be based on QTcF range (≤450, > 450 to ≤ 
480, > 480 to ≤ 500, > 500 msec). 
 


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A scatterplot of the baseline and worst-case on-treatment QTcF measures will be produced.  
Reference lines at equivalence (i.e., 45o), an increase of 30 ms, and an increase of 60 ms, as well 
as absolute references lines at 450 and 500 ms for both axes, will be included. 
10.7 ECOG 
The frequency counts and percentages of subjects for each ECOG performance status scale will 
be presented for baseline and worst-case post-baseline. A shift table from baseline to the worst-
case post-baseline will be generated as well.  
 
ECOG performance status data will be listed for each subject. 
10.8 Subsequent Anti-Cancer Therapy 
Subsequent Anti-Cancer Therapy data status data will be listed for each subject 
 
11 PRO FROM THE EORTC QLQ-C30 ANALYSES 
Analyses of EORTC QLQ-C30 data will use the Safety Population and be by treatment arm.  No 
missing items or forms will be imputed. 
11.1 Missing Data 
Patterns of missing EORTC QLQ-C30 data will be summarized descriptively using the following 
categories:  no missing measurements, no baseline measurement, no post-baseline measurement, 
1 missing post-baseline measurement, 2 missing post-baseline measurements, 3 missing post-
baseline measurements, and 4+ missing post-baseline measurements.  These categories are 
mutually exclusive and collectively exhaustive; that is, every subjects will be in one and only one 
category for this summary.  Subjects will be assigned to a category using the order given; that is, 
a subject with 1 possible QoL measurement that is missing will be in the no post-baseline 
category, not the 1 missing post-baseline measurement category.  For each category, the number 
and percentage of subjects in each category will be calculated.  The denominator to use for 
percentages is the number of subjects in the safety population for each treatment arm.   
11.2 Scoring the EORTC QLQ-C30 Results 
Scoring of all scales will use the EORTC QLQ-C30 Scoring Manual instructions for version 3.0 
of the QLQ-C30 instrument.   


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Let Ii be the score for the ith item on the QLQ-C3 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 scale s. 
For all scales, the RawScore, RS, is the mean of the component items:  
 
RawScores = RSs = (I1 + I2 +...+ Ins ) ÷ ns  
 
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 
Version 
3.0 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. 
11.3 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 


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scale at that visit, the mean, standard error, 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. 
11.4 Analysis of Change from Baseline 
For each of the EORTC QLQ-C30 multi-item scales and single-item measures, a mixed model 
for repeated measures will be run.   
For one analysis, the best overall response for a subject will be dichotomized into 2 levels:  
response of CR or PR, and response of SD, PD, or NE.  Another analysis will use a different 
dichotomization:  response of CR, PR, or SD, and response of PD or NE.   
 
The SAS procedure call is  
 
 
 
Proc mixed data=<SAS dataset name>; 
 
 
 
   class visit response subject; 
 
 
 
   model <scale name> = visit response visit*response /  htype= 1,3; 
 
 
 
   repeated subject; 
 
 
 
   lsmeans visit*response / diff; 
 
 
 
run; 
 
Only differences in least square means between each post-baseline visit and the baseline visit 
will be reported.  The dataset structure will have a separate record for each subject, visit, scale or 
single-item measure, and score. 
 
 


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12 CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
The efficacy analysis in the combined PIIEE and SIIEE Population are added.    
 
 
 
 


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13 REFERENCES 
Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0, 28 May 2009. U.S. 
Department of Health and Human Services, National Institutes of Health, National Cancer 
Institute. NIH Publication No. 03-5410. 
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved 
survival with ipilimumab in subjects with metastatic melanoma. N Engl J Med. 
2010;363:711-723. 
Paules M, Casey M, Williams G, Swann SR, Murphy PS, Salazar VM, et al. Recommendations 
for capture, validation and summarisation of data from studies using RECIST.  Eur J Cancer. 
2011; 47:697-701  
Thall PF, Cook JD, Estey E. Adaptive dose selection using efficacy-toxicity trade-offs: 
illustrations and practical considerations. J Biopharm Stat. 2006;16(5):623-638. 
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.  


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14 APPENDICES 
Appendix A:  Presentation of Data and Programming Specifications 
 
General  
• Specialized text styles, such as bold, italics, borders, shading, superscripted and 
subscripted text will not be used in tables, figures, and data listings unless they add 
significant value to the table, figure, or data listing. 
• Only standard keyboard characters are to be used in tables and data listings. 
• Special characters, such as non-printable control characters, printer-specific, or font-
specific characters, will not be used on a table, figure, or data listing. 
• Hexadecimal character representations are allowed (e.g., µ, a, ß). 
• All footnotes will be left justified and at the bottom of a page. Footnotes should be used 
sparingly and must add value to the table, figure, or data listing. 
 
Tables 
• Formal organization of tabulations may be changed during programming if appropriate, 
e.g., tables for the different variables may be combined into a single table, or tables with 
more than one variable may be split into several tables. 
• Means and medians will be presented to one more decimal place than the raw data. 
Standard deviations will be presented to two more decimal places than the raw data. 
Minimums and maximums will be reported with the same number of decimal places as 
the raw data.  
• Percentages will be presented to the tenths place. 
• For frequency counts of categorical variables, categories whose counts are zero will be 
displayed for the sake of completeness. For example, if none of the subjects discontinue 
due to “lost to follow-up,” this reason will be included in the table with a count of 0. 
Categories with zero counts will not have zero percentages displayed. 
• Lower and upper confidence interval values should be presented to one decimal place 
more than the raw/derived data (i.e., to the same number of decimal places as the mean). 
• Percentiles (e.g., 25%, 75%) should be presented to one decimal place more than the 
raw/derived data. 
• For all inferential analyses, p-values will be rounded to four decimal places (or at the 
highest level of precision) with a leading zero (0.0001). P-values less than 0.0001 will be 
presented as “<0.0001”. 
• The first footnote will be “Source: xxx”, where xxx indicates the source listing number(s) 
and/or source datatset(s) (e.g., ADaM).   
 


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Figures 
• Legends will be used for all figures with more than one variable or item displayed. 
• Figures will be in black and white (no color) unless colors add value to the clarity and 
readability of a figure. Lines should be wide enough to see the line after being copied. 
• The first footnote will be “Source: xxx”, where xxx indicates the source table(s) or listing 
number(s), and/or source dataset(s) (e.g., ADaM).   
 
Listings 
• Formal organization of the listing may be changed during programming if appropriate, 
e.g., additional variables may be included, change in the column order, or the listing may 
be split into multiple parts due to space constraints, etc. 
• If not otherwise specified, all data listings will be sorted by sequence/treatment, center, 
subject number, visit, and date/time as appropriate.   
• All date values will be presented in a SAS date (e.g., 29AUG2001) format.  
• All observed time values will be presented using a 24-hour clock HH:MM:SS format 
(e.g., 01:35:45 or 11:26). Seconds will only be reported if they were measured as part of 
the study. 
 
 
 
 


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Appendix B:  Immune-Related Response Criteria 
Definition of Best Response According to irRC Criteria: 
Best response 
irRC 
New, measureable lesions 
(i.e., ≥ 5x5 mm) 
Incorporated into tumor burden 
New, non-measureable 
lesions (i.e., < 5x5 mm) 
Do not define progression (but preclude irRC) 
Non-index lesions 
Contribute to defining irRC (complete disappearance required) 
CR 
Disappearance of all lesions in 2 consecutive observations not 
less than 4 weeks apart 
PR 
≥ 50% decrease in tumor burden compared with baseline in 
2 observations at least 4 weeks apart  
SD 
50% decrease in tumor burden compared with baseline cannot 
be established no 25% increase compared with nadir 
PD 
At least 25% increase in tumor burden compared with nadir 
(at any single time point) in 2 consecutive observations at least 
4 weeks apart 
Abbreviations: CR=complete response; irRC=Immune-related Response Criteria; 
PD=progressive disease; PR=partial response; SD=stable disease 
 
 


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Appendix Table 1: Derivation of irRC overall responses 
 
Data source: Wolchok JD, et al. Clin Cancer Res. 2009;15(23):7412-20. 


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Appendix C: RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 
Guidelines 


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Appendix Table 2: 
Objective Response Status at Each Evaluation 
 
 
Appendix Table 3: Objective Response Status at Each Evaluation for Subjects with 
Non-Target Disease Only 
 
Appendix Table 4 – Best overall response when conﬁrmation of CR and PR required. 
 
 
 
 


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Appendix D: Overall Response Using irRECIST 
 
 
 


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Appendix E:  List of Tables, Figures, and Listings 
The following TLF numbering is completed according to ICH guidelines.  The ICH heading 
number and description are in bold. Minor changes from this planned index do not need to be 
amended in the SAP.    
 
Formal organization of tabulations may be changed during programming if appropriate, e.g., 
tables for the different variables may be combined into a single table, or tables with more than 
one variable may be split into several tables. 
 
The same safety analyses will be done for both phases. Separate efficacy analysis TLFs will be 
done for phase 1 and phase 2.   
 
 
 


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List of Tables 
Phase 1 and Phase 2 Demographic and Safety Tables   
 
ICH 
Heading 
Table 
Number 
 
Table Description 
14.1 
 
Demographics and Baseline Characteristics 
 
14.1.1 
Subject Disposition 
 
14.1.2 
Protocol Deviations 
 
14.1.3 
Demographic Characteristics (Safety Population) 
 
14.1.4 
Baseline Characteristics (Safety Population) 
 
14.1.5 
Body Systems with Relevant Diseases or Disorders at 
Baseline (Safety Population) 
 
14.1.6 
Baseline Melanoma Characteristics (Safety Population) 
 
14.1.7 
Concomitant Medications (Safety Population) 
 
14.1.8 
Selected Previous Melanoma Treatment (Safety Population) 
 
14.3 
 
Safety Analyses 
14.3.1 
 
Adverse Events 
 
14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Event 
(Safety Population) 
 
14.3.1.2.1 
Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term (Safety Population) 
 
14.3.1.2.2 
Non-SeriousTreatment-Emergent Adverse Events by System 
Organ Class and Preferred Term (Safety Population) 
 
14.3.1.2.3 
Treatment-Emergent Adverse Events by Preferred Term 
(Safety Population) 
 
14.3.1.2.4 
Treatment-Emergent Adverse Events by Preferred Term and 
Maximum CTCAE Toxicity Grade  (Safety Population) 
 
14.3.1.3.1 
IMO-2125-Related Treatment-Emergent Adverse Events by 
Preferred Term (Safety Population) 
 
14.3.1.3.2 
Ipilimumab-Related Treatment-Emergent Adverse Events by 
Preferred Term (Safety Population) 
 
14.3.1.3.3 
Pembrolizumab-Related Treatment-Emergent Adverse Events 
by Preferred Term (Safety Population) 
14.3.2 
 
Deaths, Other Serious and Significant Adverse Events 
 
14.3.2.1. 
Serious Treatment-Emergent Adverse Events by Preferred 
Term  (Safety Population) 
 
14.3.2.2.1 
IMO-2125-Related Serious Treatment-Emergent Adverse 
Events by Preferred Term (Safety Population) 


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ICH 
Heading 
Table 
Number 
 
Table Description 
 
14.3.2.2.2 
Ipilimumab-Related Serious Treatment-Emergent Adverse 
Events by Preferred Term (Safety Population) 
 
14.3.2.2.3 
Pembrolizumab-Related Serious Treatment-Emergent Adverse 
Events by Preferred Term (Safety Population) 
 
14.3.2.4 
Treatment-Emergent Adverse Events with CTCAE Grade 3 or 
Higher by Preferred Term (Safety Population) 
 
14.3.3.5 
Treatment-Emergent Adverse Events Leading To 
Discontinuation  by Preferred Term (Safety Population) 
 
14.3.2.6.1 
Treatment-Emergent Adverse Events of Action Taken with 
IMO-2125 as Drug Withdrawn  by Preferred Term (Safety 
Population) 
 
14.3.2.6.2 
Treatment-Emergent Adverse Events of Action Taken with 
Ipilimumab as Drug Withdrawn  by Preferred Term (Safety 
Population) 
 
14.3.2.6.3 
Treatment-Emergent Adverse Events of Action Taken with 
Pembrolizumab as Drug Withdrawn  by Preferred Term 
(Safety Population) 
 
14.3.3.7 
Immune-Related Treatment-Emergent Adverse Events by 
Preferred Term (Safety Population) 
 
14.3.3.8 
Treatment-Emergent Adverse Events with Fatal Outcome by 
Preferred Term (Safety Population) 
14.3.4 
 
Laboratory  
 
14.3.4.1.1 
Hematology (Safety Population) 
 
14.3.4.1.2.1 
Hematology – Shift from Baseline Relative to the Normal 
Range  (Safety Population) 
 
14.3.4.1.2.2 
Hematology – CTCAE Shift from Baseline (Safety 
Population) 
 
14.3.4.2.1 
Coagulation (Safety Population) 
 
14.3.4.2.2.1 
Coagulation – Shift from Baseline Relative to the Normal 
Range (Safety Population) 
 
14.3.4.2.2.2 
Coagulation – CTCAE Shift from Baseline (Safety 
Population) 
 
14.3.4.3.1 
Serum Chemistry (Safety Population) 
 
14.3.4.3.2.1 
Serum Chemistry – Shift from Baseline Relative to the 
Normal Range (Safety Population) 
 
14.3.4.3.2.2 
Serum Chemistry – CTCAE Shift from Baseline (Safety 
Population) 
 
14.3.4.4.1 
Complement Testing (Safety Population) 


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ICH 
Heading 
Table 
Number 
 
Table Description 
 
14.3.4.4.2 
Complement Testing – Shift from Baseline Relative to the 
Normal Range (Safety Population) 
 
14.3.4.4.3 
Complement Testing – >=50% Decrease from Baseline 
(Safety Population) 
14.3.5 
 
Extent of Exposure 
 
14.3.5.1.1 
Study Drug (IMO-2125) Exposure (Safety Population) 
 
14.3.5.1.2 
Ipilimumab Exposure (Safety Population) 
 
14.3.5.1.3 
Pembrolizumab Exposure (Safety Population) 
 
14.3.5.2.1 
Dose Modifications for Study Drug (IMO-2125) (Safety 
Population) 
 
14.3.5.2.2 
Dose Modifications for Ipilimumab (Safety Population) 
 
14.3.5.2.3 
Dose Modifications for Pembrolizumab (Safety Population) 
14.3.6 
 
Vital Signs 
 
14.3.6.1 
Vital Signs (Safety Population) 
 
14.3.6.2 
Vital Signs – Shift from Baseline Relative to the Normal 
Range (Safety Population) 
 
14.3.6.3 
Vital Signs – CTCAE Shift from Baseline (Safety Population) 
14.3.7 
 
Electrocardiogram 
 
14.3.7.1.1 
Electrocardiogram – Overall Interpretation (Safety Population) 
 
14.3.7.1.2 
 
Electrocardiogram – Overall Interpretation Shift from 
Baseline (Safety Population) 
 
14.3.7.2.1 
Electrocardiogram – Abnormal QTcF Results (Safety 
Population) 
 
14.3.7.2.2 
Electrocardiogram – QTcF Shift from Baseline (Safety 
Population) 
14.3.8 
 
ECOG Performance Status 
 
14.3.8.1 
ECOG –Shift from Baseline (Safety Population) 
 
 
 


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Efficacy Phase 2  
 
ICH 
Heading 
Table 
Number 
 
Table Description 
14.2 
 
EFFICACY Analyses 
 
14.2.1.1.1a 
Best Overall Response, ORR, Durable Response Rate, and 
Disease Control Rate – RECIST v1.1 (PIIEE and/or PPIEE 
Populations) 
 
14.2.1.1.1b 
Best Overall Response, ORR, Durable Response Rate, and 
Disease Control Rate – RECIST v1.1 (PIIEE and SIIEE 
Populations) 
 
14.2.1.1.2 
Best Overall Response, ORR, Durable Response Rate, and 
Disease Control Rate – RECIST v1.1 (SIIEE Population) 
 
14.2.1.2.1a 
Best Overall Response, ORR, Durable Response Rate, and 
Disease Control Rate – irRECIST (PIIEE and/or PPIEE 
Populations) 
 
14.2.1.2.1b 
Best Overall Response, ORR, Durable Response Rate, and 
Disease Control Rate – irRECIST (PIIEE and SIIEE 
Populations) 
 
14.2.1.2.2 
Best Overall Response, ORR, Durable Response Rate, and 
Disease Control Rate – irRECIST (SIIEE Population) 
14.2.2 
 
Tumor Response – Subgroup Analysis  
 
14.2.2.1.1.1a 
Best Overall Response, ORR, Durable Response Rate, and 
Disease Control Rate by Subgroups of Interest – RECIST v1.1 
(PIIEE and/or PPIEE Populations) 
 
14.2.2.1.1.1b 
Best Overall Response, ORR, Durable Response Rate, and 
Disease Control Rate by Subgroups of Interest – RECIST v1.1 
(PIIEE and SIIEE Populations) 
 
14.2.2.1.1.2 
Best Overall Response, ORR, Durable Response Rate, and 
Disease Control Rate by Subgroups of Interest – RECIST v1.1 
(SIIEE Population) 
 
14.2.2.1.2.1a 
Best Overall Response, ORR, Durable Response Rate, and 
Disease Control Rate by Subgroups of Interest – irRECIST  
(PIIEE and/or PPIEE Populations) 
 
14.2.2.1.2.1b 
Best Overall Response, ORR, Durable Response Rate, and 
Disease Control Rate by Subgroups of Interest – irRECIST  
(PIIEE and SIIEE Populations) 


Idera Pharmaceuticals, Inc  
                                                                            Statistical Analysis Plan 
Protocol Number: 2125-204 
 
Final 1.1, March 5th, 2020 
 
 
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Heading 
Table 
Number 
 
Table Description 
 
14.2.2.1.2.2 
Best Overall Response, ORR, Durable Response Rate, and 
Disease Control Rate by Subgroups of Interest – irRECIST  
(SIIEE Population) 
14.2.3 
 
Survival, PFS, and Duration of Response 
 
14.2.3.1a 
Overall Survival (OS) (PIIEE and/or PPIEE Populations ) 
 
14.2.3.1b 
Overall Survival (OS) (PIIEE and SIIEE Populations ) 
 
14.2.3.2.1a 
Progression-Free Survival (PFS) – RECIST v1.1 (PIIEE 
and/or PPIEE Populations ) 
 
14.2.3.2.1b 
Progression-Free Survival (PFS) – RECIST v1.1 (PIIEE and 
SIIEE Populations ) 
 
14.2.3.2.2a 
Progression-Free Survival (PFS) –  irRECIST (PIIEE and/or 
PPIEE Populations ) 
 
14.2.3.2.2b 
Progression-Free Survival (PFS) –  irRECIST (PIIEE and 
SIIEE Populations ) 
 
14.2.3.3.1a 
Duration of Response (DOR) – RECIST v1.1 (PIIEE and/or 
PPIEE Populations ) 
 
14.2.3.3.1b 
Duration of Response (DOR) – RECIST v1.1 (PIIEE and 
SIIEE Population) 
 
14.2.3.3.2a 
Duration of Response (DOR) –  irRECIST (PIIEE and/or 
PPIEE Populations ) 
 
14.2.3.3.2b 
Duration of Response (DOR) –  irRECIST (PIIEE and SIIEE 
Population) 
14.2.4 
 
Measurable Disease Assessment 
 
14.2.4.1.2 
Change from Baseline in the Sum of the Longest Diameters 
(PIIEE and/or PPIEE Populations ) 
14.2.5 
 
Patient Reported Outcomes – Quality of Life 
 
14.2.5.1 
Missing EORTC QLQ-C30 Responses 
 
14.2.5.2 
EORTC QLQ-C30 Scores by Scale 
 
14.2.5.3 
EORTC QLQ-C30 Change from Basline –Response vs. Non-
Response 
 
14.2.5.4 
EORTC QLQ-C30 Change from Basline –Disease Control vs. 
Disease Progression or Not Evaluable 


Idera Pharmaceuticals, Inc  
                                                                            Statistical Analysis Plan 
Protocol Number: 2125-204 
 
Final 1.1, March 5th, 2020 
 
 
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List of Figures 
 
Phase 1 
ICH 
Heading 
Table 
Number 
Table Description 
 
14.3.1 
Box plot of Complement testing  by visit (Safety  Population )  
 
14.3.2 
A scatterplot of the baseline and worst-case on-treatment QTcF (Safety  
Population ) 
 
Phase 2 
ICH 
Heading 
Table 
Number 
Table Description 
 
14.2.1 
Waterfall Plot of Maximum Changes from Baseline in the 
Measurable Tumor Burden (PIIEE and PPIEE Populations ) 
 
14.2.2 
Overall  Survival  (PIIEE and PPIEE Populations ) 
 
14.2.3.1 
PFS  - RECIST v1.1  (PIIEE and PPIEE Populations ) 
 
14.2.3.2 
PFS  - irRECIST  (PIIEE and PPIEE Populations ) 
 
14.3.1.1 
Box plot of Complement testing by Treatment arm  (Safety  
Population)  
 
14.3.2.1 
A scatterplot of the baseline and worst-case on-treatment QTcF 
(Safety  Population ) 
 
 
 


Idera Pharmaceuticals, Inc  
                                                                            Statistical Analysis Plan 
Protocol Number: 2125-204 
 
Final 1.1, March 5th, 2020 
 
 
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List of Data Listings (Phase 1 and Phase 2) 
 
ICH 
Heading 
Listing 
Number 
 
Listing Description 
CRF page(s) 
16.2 
 
SUBJECT DATA LISTINGS 
 
16.2.1 
 
Discontinued Subjects 
 
 
16.2.1.1 
Subject Disposition 
Study Exit Status, 
Derived 
16.2.2 
 
Protocol Deviations 
 
 
16.2.2.1 
Protocol Deviations  
Derived 
 
16.2.2.2 
Inclusion/Exclusion Criteria 
Inclusion/Exclusion 
Findings 
16.2.4 
 
Demographic Data 
 
 
16.2.4.1 
Demographics 
Demographics 
 
16.2.4.2.1 
Medical History 
Medical History 
 
16.2.4.2.2 
Melanoma Characteristics 
Melanoma 
Characteristics 
 
16.2.4.3 
Prior and Concomitant Medications 
Concomitant 
Medications 
 
16.2.4.3.1 
Sensitive and Narrow Therapeutic Range 
CYP Substrate Concomitant Medications 
(All Subjects with CYP Substrates) 
Concomitant Meds 
 
16.2.4.4 
Previous Melanoma Treatment ** 
Previous Melanoma 
Treatment 
16.2.5 
 
Compliance and/or Drug Concentration 
data  
 
 
16.2.5.1.1 
Study Drug Administration (IMO-2125) 
Study Drug 
Administration 
(IMO-2125) 
 
16.2.5.1.2 
Ipilimumab Infusion 
Ipilimumab Infusion 
 
16.2.5.1.3 
Pembrolizumab Infusion 
Pembrolizumab 
Infusion 
16.2.6 
 
Individual Efficacy Response Data 
 
 
16.2.6.1 
Measurable Disease Assessment 
Measurable Disease 
Assessment 
 
16.2.6.2 
Non-Measurable Disease Assessment 
Non-Measurable 
Disease Assessment 
 
16.2.6.3 
Assessment of RECIST Response 
Assessment of 
RECIST Response 


Idera Pharmaceuticals, Inc  
                                                                            Statistical Analysis Plan 
Protocol Number: 2125-204 
 
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Heading 
Listing 
Number 
 
Listing Description 
CRF page(s) 
 
16.2.6.4 
Assessment of irRC Response* 
Assessment of irRC 
Response 
 
16.2.6.4 
Assessment of irRECIST Response ** 
Assessment of irRC 
Response 
 
16.2.6.5 
Derived Efficacy Data  
Derived 
 
16.2.6.5.1 
Derived irRECIST response for Phase 1 
Subjects taking RP2D  ** 
Derived 
 
16.2.6.7 
Tumor Biopsies 
Tumor Biopsies 
16.2.7 
 
Adverse Events  
 
 
16.2.7.1 
Adverse Events 
Adverse Events 
 
16.2.7.2 
Serious Adverse Events 
Adverse Events 
 
16.2.7.3 
Deaths 
Death 
 
16.2.7.4 
Treatment-Emergent Adverse Events in 
All Subjects with CYP Substrates 
Comed and AE 
16.2.8 
 
Individual Laboratory Measurements by 
Subject 
 
 
16.2.8.1 
Hematology 
Hematology 
 
16.2.8.2 
Chemistry 
Chemistry 
 
16.2.8.3 
Coagulation 
Coagulation 
 
16.2.8.4 
Urinalysis 
Urinalysis 
 
16.2.8.5 
Thyroid Function Tests 
Thyroid Function 
Tests 
 
16.2.8.6 
Complement Testing (CH50/C3/C4) 
Complement 
Testing 
(CH50/C3/C4) 
 
16.2.8.7 
Immunogenicity Blood Sample with 
Ipilimumab/ Pembrolizumab Concentration 
Immunogenicity 
Blood Sample 
 
16.2.8.8 
Biomarker Blood Sample 
Biomarker Blood 
Sample 
 
16.2.8.9 
Vital Signs 
Vital Signs 
 
16.2.8.10 
Physical Examination 
Physical 
Examination 
 
16.2.8.11 
Electrocardiogram 
ECG /ECG - Post-
Dose 
 
16.2.8.12 
ECOG 
ECOG Performance 
Status 
 
16.2.8.13 
Long Term Follow Up 
Long Term Follow 
Up 


Idera Pharmaceuticals, Inc  
                                                                            Statistical Analysis Plan 
Protocol Number: 2125-204 
 
Final 1.1, March 5th, 2020 
 
 
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Idera 2125-204-SAP_FINAL_05Mar2020_OG2.docx 
 
 
ICH 
Heading 
Listing 
Number 
 
Listing Description 
CRF page(s) 
 
16.2.8.14 
Subsequent Anti Cancer Therapy 
Subsequent Anti 
Cancer Therapy 
 
 
* Only for Phase 1 
** Only for Phase 2 
 
 


 
 
Appendix F:  Table, Listing and Figure Layouts 
See separate document for table, listing and figure mock shells