Clinical trial NCT02252146
Conditions: Diffuse Large B Cell Lymphoma
Keywords: DLBCL MYD88 L265P Lymphoma Diffuse Large B Cell Lymphoma Idera IMO 8400
Sponsor: Idera Pharmaceuticals, Inc.
Start date: 2014-06-01; Completion date: 2016-12-01
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Recent reports have identified a specific oncogenic mutation L265P of the MYD88 gene in approximately 30% of the patients with the activated B-cell (ABC) type of Diffuse Large B Cell Lymphoma (DLBCL). MYD88 is an initial adapter linker protein in the signaling pathway of the Toll Like Receptors (TLRs), including the endosomal TLRs 7, 8, and 9, for which the ligands are nucleic acids. IMO-8400 is an oligonucleotide specifically designed to inhibit ligand activation of TLRs 7,8, and 9. Recent studies indicate that in the presence of L265P mutation ligand activation of those TLRs results in markedly increased signaling with subsequent increased cell activation, cell survival, and cell proliferation. The scientific rationale for assessing the use of IMO-8400 to treat patients with DLBCL and the L265P mutation is based on laboratory observations that IMO-8400 inhibits ligand-based activation of cells with the mutation and decreases the survival and proliferation of the cell populations responsible for the propagation of the disease.

Detailed description:
Eligible subjects will be enrolled and assigned to one of five dose cohorts. Treatment will be administered by subcutaneous injection until progression or intolerable toxicity.

Arms: arm 1: IMO-8400 0.3 mg/kg twice weekly, 0.6 mg/kg twice weekly, or 1.2 mg/kg twice weekly
Interventions: intervention 1: IMO-8400
Intervention descriptions: intervention 1: MO-8400 given subcutaneously twice weekly

Protocol documents:
Prot_000.pdf: 
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PROTOCOL 8400-402 
Study Title 
Phase 1/2 Open-label, Multiple-dose, Dose-escalation Study to 
Evaluate the Safety and Tolerability of IMO-8400 in Patients with 
Relapsed or Refractory Diffuse Large B-cell Lymphoma and 
Presence of the MYD88 L265P Mutation 
Investigational Drug: IMO-8400 
FDA IND: 
119651 
Sponsor: 
Idera Pharmaceuticals, Inc. 
167 Sidney Street  
Cambridge, MA 02139 
Protocol Number: 
8400-402 
Protocol Version: 
4.0 
Date: 
29 Jan 2016 
 
 
 
 


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Protocol Approval Page 
 
 
Study Title 
Phase 1/2 Open-label, Multiple-dose, Dose-escalation Study to 
Evaluate the Safety and Tolerability of IMO-8400 in Patients with 
Relapsed or Refractory Diffuse Large B-cell Lymphoma and 
Presence of the MYD88 L265P Mutation 
Protocol Number: 
8400-402 
Protocol Version: 
4.0 
Date: 
29 Jan 2016 
 
 
 
Approved for the Sponsor by:  
 
Mark Cornfeld, MD, MPH 
Medical Lead, Oncology  
Idera Pharmaceuticals, Inc. 
 
 
 
Signature 
Date 
 
 
 
 
 


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Revision History 
 
Ver. No. 
Date 
Comment 
1.0 
07 Mar 2014 
Initial release 
2.0 
07 Nov 2014 
Added: Pre-screening for L265P mutation, 
Revised: Assay for MYD88 L265P mutation advanced from commercial Clinical 
Laboratory Improvement Amendments (CLIA)-assays to Investigational Use Only 
(IUO) level assay; exclusion laboratory results: defined specific analytes and 
exclusionary values related to hematology, renal, hepatic and coagulation function. 
Deleted: Provision for self-administration of study drug; use of 50 mg vials of drug 
product; details of dose preparation (now in Study Pharmacy Manual) 
Administrative and technical clarifications 
Version 2.0 was not released. 
2.1 
12 Nov 2014 
Technical revisions to specifications of MYD88 L265P assay 
This version tracks all changes from version 1.0. 
3.0 
09 Jun 2015 
Addition of complement component 3 (C3) complement testing for safety assessments; 
establishes Cohort Review Committee in place of Dose Review Committee; changes 
dose-limiting toxicity (DLT) language; revises inclusion criteria to include a positive 
MYD88 L265P result from any CLIA-compliant assay; revises exclusion criteria to include 
diffuse large B-cell lymphoma (DLBCL) variants; revises dosing for expansion cohorts; 
removes extended treatment under a separate protocol and allows for responding or stable 
patients to remain on study until disease progression or intolerable toxicity; follows 
patients for survival. 
4.0 
29 Jan 2016 
Updates patient population; clarifies and separates study by Phase 1 (dose escalation) and 
Phase 2 (dose expansion cohort); adds additional dose escalation cohorts; adds an interim 
analysis for futility in Phase 2; clarifies both study phases including dose escalation rules, 
number of patients expected to be enrolled, and rationale for enrollment; clarifies inclusion 
criteria; updates statistical analysis procedures and rationale, including determination of 
sample size; clarifies cohort review committee procedures and responsibilities; clarifies 
that bone marrow biopsy is optional and lymph node biopsy is required; adds safety 
procedures for patients with symptomatic thrombocytopenia; adds pre-treatment criteria; 
adds definition for other reportable events in safety analyses; other administrative and 
technical clarifications and procedural clarifications. 
 
 


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Contact Information  
Any serious adverse event (SAE) must be reported within 24 hours using the study Electronic 
Data Capture (EDC) system. 
See Section 10.5 for detailed reporting procedures. 
 
Table 1: 
Emergency and Pharmacovigilance Contacts  
Role in Study 
Name, Title, Address 
Telephone and Email 
24-Hour Emergency 
Contact 
Mark Cornfeld MD, MPH 
Medical Lead, Oncology 
Idera Pharmaceuticals, Inc. 
505 Eagleview Blvd., Suite 212 
Exton, PA 19341 
 
Office: +1 484 348 1629 
Cell: +1 609 240 7312 
email: mcornfeld@iderapharma.com 
Pharmacovigilance 
Contact 
Theresa Wehrle, RN 
Sr. Safety Specialist, Safety and 
Pharmacovigilance 
INC Research, LLC 
4800 Falls of the Neuse Road 
Raleigh, NC 27609 
Office: +1 919 926 5732 
email: twehrle@incresearch.com  
 
Table 2: 
Study Contact Information 
Role in Study 
Name, Title, Address 
Telephone and Email 
Responsible Physician 
Mark Cornfeld MD, MPH 
Medical Lead, Oncology 
Idera Pharmaceuticals, Inc. 
505 Eagleview Blvd., Suite 212 
Exton, PA 19341 
 
Office: +1 484 348 1629 
Cell: +1 609 240 7312 
email: mcornfeld@iderapharma.com 
 
Clinical Trial Manager 
Lindsey Simov 
Idera Pharmaceuticals, Inc. 
167 Sidney Street 
Cambridge, MA 02139 
 
Office: +1 617 679 5533 
email: lsimov@iderapharma.com 
Medical Monitors 
Mark Cornfeld MD, MPH 
Medical Lead, Oncology 
Idera Pharmaceuticals, Inc. 
505 Eagleview Blvd., Suite 212 
Exton, PA 19341 
 
Office: +1 484 348 1629 
Cell: +1 609 240 7312 
email: mcornfeld@iderapharma.com 
 
 
Joanna Horobin, MB, ChB 
Sr. Vice President, Chief Medical Officer 
Idera Pharmaceuticals, Inc. 
167 Sidney Street 
Cambridge, MA 02139 
 
Office: +1 617 679 5510 
Cell: +1 781 249 2166 
email: jhorobin@iderapharma.com  
Project Manager 
Nickie Ann Ryan, CCRA 
Project Manager, Early Phase Oncology 
INC Research, LLC 
3201 Beechleaf Ct., Suite 600 
Raleigh, NC 27609 
 
Office: +1 919 257 6503 
Email: Nickie.Ryan@incresearch.com  
 


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1. 
SYNOPSIS 
1.1. 
Protocol Information 
Protocol Number 
8400-402 
Protocol Title 
Phase 1/2 Open-label, Multiple-dose, Dose-escalation Study to Evaluate the Safety and 
Tolerability of IMO-8400 in Patients with Relapsed or Refractory Diffuse Large B-cell 
Lymphoma and Presence of the MYD88 L265P Mutation 
Sponsor 
Idera Pharmaceuticals, Inc. 
Name of Finished Product 
IMO-8400 for Injection, 150 mg 
Name of Active ingredient 
IMO-8400 
Phase of Development 
1/2 
Indication (Target) 
Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL) 
Number of Patients 
Up to 30 patients in planned dose escalation cohorts and up to 29 patients in an expansion 
phase 
Number of Sites 
Multiple Centers in the US 
Est. Date First Patient Enrolled  
Q2 2014 
Est. Date Last Patient Enrolled  
Q2 2017  
Est. Date Last Patient Last Visit 
Q4 2017 
1.2. 
Objectives 
1.2.1. 
Primary Objective 
 To evaluate the safety and tolerability of escalating dose levels of IMO-8400 
administered by subcutaneous (SC) injection in patients with relapsed or refractory 
non-GCB subtype diffuse large B-cell lymphoma (DLBCL). 
1.2.2. 
Secondary Objectives 
 To assess the treatment effect (clinical activity) in patients with non-GCB subtype 
DLBCL with myeloid differentiation primary response gene (88) (MYD88) L265P 
mutations using disease-specific international guidelines for classifying clinical 
response [1].  
 To identify an optimal dose of IMO-8400 for further clinical evaluation in B-cell 
malignancies. 
 To characterize the pharmacokinetics of escalating dose levels of IMO-8400 
administered by SC injection.  
1.2.3. 
Exploratory Objectives 
 To investigate associations between the treatment effect of IMO-8400 and selected 
biomarkers (e.g., serum cytokines). 
 To assess the potential immunogenicity of IMO-8400 administered by SC injection. 


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1.3. 
Study Design and Methodology 
1.3.1. 
Brief Background  
IMO-8400 is a second-generation oligonucleotide antagonist of Toll-like receptors (TLRs) 7, 8 
and 9, which blocks immune activation mediated through those receptors.  
MYD88 is the initial linker protein in the TLR signaling pathway. Recent studies indicate a high 
frequency of mutation in MYD88 in patients with B-cell malignancies, particularly 
DLBCL  subtypes with poor prognosis [2]. Specifically, the gain-of-function L265P mutation is 
found in almost a third of DLBCL with the activated B-cell (ABC) phenotype. In vitro studies of 
B-cell tumor lines indicate that (a) this mutation is associated with an increase in cell activation, 
proliferation, and survival [3], and (b) loss of endosomal TLRs results in markedly decreased cell 
proliferation and survival [4]. Data from Idera indicate that treatment of such cell lines with 
IMO-8400 has a similar effect [5].  
Recently reported clinical experience with IMO-8400 in patients with Waldenström’s 
Macroglobulinemia (WM), a B-cell malignancy almost always driven by the MYD88 L265P 
mutation [6], indicate that the treatment is active and well-tolerated at dose levels up to 
1.2 mg/kg/twice weekly [7]. Dose escalation is continuing in that setting as the maximum 
tolerated dose (MTD) has not been reached. 
The current study represents the first clinical trial of IMO-8400 in patients with DLBCL.  
1.3.2. 
Study Overview 
This is an open-label, multiple-dose, dose escalation study of IMO-8400 in patients with relapsed 
or refractory DLBCL of non-GCB subtype. The study is a Phase 1/2 study in which Phase 1 will 
consist of a dose escalation to determine the recommended Phase 2 dose (RP2D). Phase 2 is a 
Simon two-stage design [8], consisting of an open-label treatment of patients at the RP2D. 
Initially 10 patients will be treated at the RP2D. If at least two of the 10 patients respond, the 
study will enroll 19 more patients, for a total of 29 patients in the Phase 2 portion. 
A study schematic is represented in Figure 1. 
Figure 1: 
Study Schematic 
 


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1.3.3. 
Phase 1: Dose Escalation 
The dose escalation cohorts will permit systematic evaluation of the safety and tolerability of 
IMO-8400 at increasing dose levels in order to identify the maximum tolerated dose (MTD).  
 The planned dose escalation cohort levels for IMO-8400 are 0.3, 0.6, and 1.2 mg/kg 
administered twice weekly and 2.4 and 3.6 mg/kg administered once weekly 
(Table 3). Additional dose levels, schedules, and routes of administration may be 
evaluated based upon the emerging data. Dosing is based on body weight 
(Section 8.1). Doses will be administered by SC injection.  
 The Investigators and Sponsor will review available toxicity information (including 
adverse events [AEs] that are not dose-limiting toxicities [DLTs]), pharmacokinetic 
(PK) and activity data to determine the MTD (Section 1.3.5). 
Table 3: 
Planned Dose Escalation Cohorts 
Dose Level 
IMO-8400 Dose (mg/kg)  
Frequency 
Initial Cohort Size 
1 (starting dose) 
0.3 
Twice Weekly 
3-6 
2 
0.6  
Twice Weekly 
3-6 
3 
1.2 
Twice Weekly 
3-6 
4 
2.4 
Weekly 
3-6 
5 
3.6 
Weekly 
3-6 
Procedures for patient safety are summarized below and presented in detail in the sections 
indicated:  
 Explicit definitions for identifying suspected adverse reactions as DLT events 
(Section 6.3.1). 
 All injections of study medication will be administered by trained personnel. Patients 
will be observed for 2 hours following the first treatment and for at least 30 minutes 
following all other treatments (Section 8.4).  
 Detailed provisions for management of study drug in individual patients based on 
safety, tolerability, and disease response (Section 6.5).  
 Constitution of a Cohort Review Committee (CRC) comprised of the Idera Medical 
Monitor and Investigators from participating sites to decide whether to continue or 
halt dose escalation, or explore intermediate dose levels (Section 6.3.2).  
1.3.4. 
Phase 2: Dose Expansion Cohort 
Once the RP2D has been established, additional patients will be treated in a dose expansion 
phase that is designed to better characterize the safety, tolerability and preliminary anti-tumor 
activity of the study drug when provided at the RP2D to patients with non-GCB subtype DLBCL 
with MYD88 L265P mutations. Phase 2 utilizes a Simon two-stage design [8], consisting of an 
open-label treatment of patients at the RP2D. Initially 10 patients will be treated at the RP2D. If 
at least two of the 10 patients respond, the study will enroll 19 more patients, for a total of 


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29 patients in the Phase 2 portion. Additional dose-expansion cohorts may be added if clinical 
activity is seen during the dose escalation phase in tumors that lack this mutation. 
1.3.5. 
Dose Escalation Enrollment and Review 
Each dose escalation cohort is expected to enroll at least three patients, with a maximum of 
six patients. The number of patients enrolled in any of the planned dose escalation cohorts can be 
reduced if safety at that dose level has already been demonstrated in a related population 
(e.g., WM). 
 If the initial three patients complete all 4 weeks of treatment without a DLT event, the 
CRC will conduct a dose escalation review.  
 If one of the initial three patients experiences a DLT event prior to completing 
Cycle 1, then enrollment at that dose level will continue to a total of six patients and 
the dose escalation review will be done when all six patients have completed Cycle 1. 
 If two patients at a dose-level experience DLT events during the Cycle 1, then no 
further patients will be enrolled until the CRC completes a review, which should be 
done as soon as feasible.  
 Furthermore, cohorts may be expanded to include additional patients if such patients 
can be enrolled ≤7 days after the third (or sixth) patient was first dosed with 
IMO-8400. 
The CRC review will include all available safety data. To facilitate standardizing the dose 
escalation reviews across different cohorts, the focus will be on observations from Cycle 1 at that 
dose level. 
The following represent anticipated outcomes for the review process: 
 Approval of enrollment in the expansion cohort at that dose level, if applicable.  
 Dose escalation – progression to the next planned dose level.  
 Continue cohort enrollment (applicable only to review after three patients) – enroll up 
to six patients at the current dose level to obtain additional safety data for subsequent 
review. 
 Increase the number of patients treated at a given pre-specified or intermediary dose 
level to better define the safety profile of IMO-8400 and enhance the clinical 
experience at each participating site. Dose escalation decisions will be made once the 
last patient in a cohort completes Cycle 1. 
 Dose de-escalation – enrollment of an intermediate level contingency cohort to 
facilitate identifying the MTD.  
 No further dose escalation enrollment – at this time the CRC will indicate the dose 
level they consider represents the MTD.  
The CRC comprises experienced clinicians, who will make recommendations based on their 
judgment. In consideration of the dynamic nature of early phase studies, those recommendations 
may include alternative courses of action not anticipated here. 


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1.3.6. 
Management of Study Treatment in Individual Patients 
Each enrolled patient will receive IMO-8400 at the assigned dose level until disease progression, 
intolerable toxicity (despite dose modification), withdrawal of consent, start of another 
anti-cancer therapy, or study completion, whichever occurs first.   
For DLT events, provision is made for pausing treatment for up to 3 weeks and, if the acute 
toxicity improves sufficiently, resuming treatment at a lower dose level (Section 6.5.2). Patients 
who are tolerating treatment at dose levels below those deemed acceptable by the CRC may be 
eligible for dose escalation upon discussion and approval with the Idera Medical Monitor. 
1.4. 
Study Structure  
 Pre-screening of patients who are deemed to be at high risk of recurrence can be 
performed by testing for the MYD88 L265P mutation at any point during the course 
of their disease. This would allow patients rapid access to study participation if they 
relapse or are refractory to standard therapy, without the delay associated with 
mutation testing. 
 Screening will be done within 21 days prior to Cycle 1, Day 1 (the first treatment 
with study drug). See Section 9.2 for details of Screening and Section 9.4 for details 
of the enrollment process.  
 Treatment is scheduled to be administered until disease progression, intolerable 
toxicity (despite dose modification), withdrawal of consent, start of another 
anti-cancer therapy, or study completion, whichever occurs first. 
 Assessment for treatment response will continue throughout the patient’s 
participation or until disease progression. 
 End-of-Treatment (EOT) visit will be performed within 7 days of the decision to 
terminate treatment.  
 End-of-Study (EOS) visit will be performed 30 to 35 days after the last dose of study 
drug.  
Detailed schedules of events are presented in Section 1.9. 
1.5. 
Diagnosis and Patient Selection Criteria  
1.5.1. 
Pre-screening for MYD88 L265P Mutation 
Patients with relapsed and refractory DLBCL have severe and progressive illness. Both 
Investigators and patients want to avoid delaying treatment for even the 7 to 10 days required for 
testing for the presence of the MYD88 L265P mutation, which is associated with poor prognosis, 
and increased risk for disease progression and death [9]. Available data indicate that the mutation 
is present at diagnosis and its impact on outcome can persist through current standard of care 
treatment [10]. 
Therefore, if a result for the MYD88 L256P mutation has already been identified using a Clinical 
Laboratory Improvement Amendments (CLIA)-compliant assay, then this result can be used for 
eligibility purposes so that the patient can continue additional screening procedures. Every 


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attempt will be made to gain access to additional lymphatic tissue in order to confirm the 
presence of the MYD88 L265P mutation using the Abbott Molecular tissue-based assay under 
development as a potential companion diagnostic. A blood sample will also be taken to explore 
the potential development of a plasma-based assay for detection of the MYD88 L265P mutation.  
1.5.2. 
Inclusion Criteria 
To be eligible for this study, a patient must meet all of the following criteria:  
1. Have a primary diagnosis of DLBCL of non-GCB subtype, established according to the 
World Health Organization (WHO) criteria [11]. 
2. Be at least 18 years of age. 
3. Have signed the current approved Informed Consent Form. 
4. Have Eastern Cooperative Oncology Group (ECOG) performance status ≤2. 
5. Has, prior to enrollment, safety laboratory tests meeting the following criteria: 
 Hemoglobin ≥7.5 g/dL 
 Absolute neutrophil count (ANC) ≥1,000/μL 
 Platelets ≥50,000/μL  
 Serum creatinine ≤2.5x Upper limit of normal (ULN) 
 Serum aspartate transaminase (AST) ≤2.5x ULN  
 Serum alanine transaminase (ALT) ≤2.5x ULN  
 Total bilirubin ≤1.5x ULN  
 Prothrombin time (PT) ≤1.5x ULN 
6. Have no history or current clinical evidence of lymphoma involvement in the central 
nervous system (CNS). 
7. Have received at least one course of therapy consistent with the recommendations of the 
National Comprehensive Cancer Network [10]. 
8. Have either (a) received an autologous stem cell transplant, or (b) been assessed as 
ineligible for the procedure, or (c) declined the procedure. 
9. Have relapsed or progressed (“refractory”) based on the criteria for assessing response 
from the International Harmonization Project [1] (Section 9.6).  
10. Have tumor tissue that tests positive for a MYD88 mutation using a 
CLIA-compliant assay. (Note: patients whose tumors do not harbor MYD88 L265P 
mutations are eligible for the dose escalation phase of the study.) 
11.  For women of childbearing potential and men, agree to use effective contraceptive 
methods from Screening, through the study, and for at least 4 weeks after the last dose of 
study drug. Effective birth control (contraception) methods are defined as one of the 
following: 


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 Abstinence.  
 Condoms and spermicide.  
 Diaphragm and spermicide.  
 Oral or implanted hormonal contraceptive (e.g., Implanon™).  
 An intra-uterine device. 
Non-childbearing potential is defined as a female who meets either of the following 
criteria:  
 Age ≥50 years and no menses for at least 3 years. 
 Documented hysterectomy, bilateral tubal ligation or bilateral oophorectomy. 
12. For women of childbearing potential, have a negative serum or urine pregnancy test prior 
to enrollment.  
13. Have at least one site of measurable disease during dose expansion phase (patients with 
evaluable disease permitted during dose escalation). 
14. Be willing and able to comply with this protocol. 
1.5.3. 
Exclusion Criteria 
Patients with any of the following will be excluded from enrollment in the study: 
1. DLBCL of GCB subtype.  
2. Due to their aggressive nature and/or occurrence in the setting of immunodeficiency 
(secondary to human immunodeficiency virus [HIV] or advanced age), the following 
B-cell neoplasms will be excluded: 
 Intravascular large B-cell lymphoma 
 Primary mediastinal (thymic) large B-cell lymphoma 
 Epstein-Barr virus (EBV) DLBCL of the elderly 
 Large B-cell lymphoma arising in human herpesvirus 8 (HHV-8)-associated 
Castleman disease 
 Plasmablastic lymphoma 
 Anaplastic lymphoma kinase (ALK)+ large B-cell lymphoma 
 Primary effusion lymphoma 
 Burkitt lymphoma 
3. Has known hypersensitivity to any oligodeoxynucleotide. 
4. Is nursing.  
5. Has a body mass index (BMI) of >34.9 kg/m2. 
6. Has an indeterminate or positive result on screening test for antibody to  


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 Human immuno-deficiency virus (HIV-1 or -2) 
 Hepatitis C virus (HCV), unless documented to have had a potentially curative course 
of anti-viral treatment and to have no detectable viremia at current screening.  
7. Has a positive test for hepatitis B surface antigen (HBsAg). 
8. Has known complement deficiency such as properdin deficiency or hereditary 
angioedema. 
9. Is, at the initiation of study drug, receiving chronic systemic corticosteroid therapy 
>20 mg of prednisone daily (or equivalent); steroids administered topically or by 
inhalation are permitted. 
10. Has, at the initiation of study drug, received cytotoxic chemotherapy within the past 
3 weeks or rituximab within the past 2 months; for other anti-cancer therapies (approved 
or investigational) the interval will be determined in consultation with the Medical 
Monitor. 
11. Has, at the initiation of study drug, an active infection requiring systemic antibiotics. 
12. Has had within the 4 weeks prior to initiation of study drug, or is expected to have during 
the study period, surgery requiring general anesthesia.  
13. Has life expectancy of less than 3 months. 
14. Has heart failure of Class III or IV (New York Heart Association criteria). 
15. Has other significant medical conditions (chronic or active within the past 6 months), 
including, but not limited to: cardiac disease (e.g., unstable angina, myocardial infarction, 
ventricular arrhythmia); uncontrolled seizure disorder; liver disease; uncontrolled 
diabetes. 
16. Has 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 (PSA), 
and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on a Pap 
smear. 
17. Has any other condition that would, in the opinion of the Investigator, potentially 
compromise the patient’s safety, compliance, or successful completion of the clinical 
trial. 
1.6. 
Treatments 
1.6.1. 
Investigational Product, Dosage and Mode of Administration 
IMO-8400 administered as follows:  
 Dose levels of 0.6 to 3.6 mg/kg/week by body weight at Screening to be given as 
SC injections (Section 8.4).  
 Injection volume not to exceed 1.2 mL/site, with multiple sites used per dose as 
necessary. 


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 Dose to be recalculated if change in body weight from Screening exceeds 10% (±). 
 Injections will be administered in the four quadrants of the abdomen or in the upper 
thighs, rotating injection site(s) each time IMO-8400 is administered (Section 8.4).  
1.6.2. 
Reference Therapy, Dosage and Mode of Administration 
Not applicable.  
1.7. 
Criteria for Evaluation 
1.7.1. 
Pharmacokinetics 
Pharmacokinetic samples will be obtained as scheduled in relation to the first dose administered 
at each of Cycles 1, 2, 4, and 6 (Day 1 of each cycle). The following PK samples will be 
collected: pre-dose, at 1 (±5 minutes), 2 (±10 minutes), and 4 (±15 minutes) hours post-dose. 
Pharmacokinetic samples will also be taken at the EOT and EOS visits. Plasma samples will be 
analyzed for IMO-8400 concentration using a validated bioanalytical method.  
For each cohort, the plasma IMO-8400 concentration data will be analyzed by 
non-compartmental PK analysis. The following parameters will be determined as appropriate: 
observed maximum plasma concentration (Cmax), time of Cmax (Tmax), and area under the curve 
from 0 to last measurable plasma concentration (AUC0-t).  Pharmacokinetic parameters will be 
compared across IMO-8400 dose levels. 
1.7.2. 
Safety 
Assessments for safety include: 
 Ongoing monitoring for clinical AEs and concomitant medications.  
 Symptom review and vital signs at each scheduled visit.  
 Physical exam and electrocardiogram (ECG) (Section 9.7). 
 Laboratory safety tests (hematology, serum complement, clinical chemistry, 
coagulation, urinalysis) (Section 9.8). 
 Injection site reactions (ISRs) (Section 9.7.5). 
 Additional unscheduled assessments at Investigator’s discretion. 
1.7.3. 
Treatment Effect 
A limited physical examination will be performed at every cycle focusing on known sites of 
disease. Assessments of disease status by radiological assessment for patients receiving 
IMO-8400 will be conducted every 8 weeks or as indicated based on new signs, symptoms or 
laboratory findings. During follow up (Section 6.5.6), patients discontinued from treatment for 
reasons other than progressive disease will be assessed per Revised Response Criteria for 
Lymphoma (Section 16.2) at a minimum of every 12 weeks for overall survival (OS) until 
documentation of progressive disease, initiation of new anti-cancer therapy, or the end of the 
study, whichever comes first. Following disease progression during survival follow up, patients 


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will be contacted every 12 weeks for the subsequent use of anti-cancer therapy as well as for 
survival until study completion. Disease status will be classified based on the criteria of the 
International Harmonization Project [1] (Section 9.6). Time to progression and duration of 
response will be measured as defined (Section 12.4).  
1.8. 
Statistical Methods 
Analysis Populations: 
 DLT Evaluable Population: patients enrolled in the Phase 1 dose escalation portion of 
the study who receive all planned doses of study drug during the DLT observation 
period or who discontinue treatment due to AEs. 
 Safety/Intent-to-Treat (ITT) Population: all patients who received at least 
one injection of study drug. 
 Efficacy Evaluable (EE) Population: all patients who are MYD88 L265P mutation 
positive and have been treated at the RP2D. 
 Per Protocol (PP) Population: all patients in the EE who had no major protocol 
violations that would potentially influence treatment effect. 
 Pharmacokinetic (PK) Population: all patients who had both a pre-dose and at least 
one analyzable post-dose PK sample. 
CRC review will be performed on the DLT Evaluable Population for the dose being considered. 
Safety analyses will be performed using the Safety/ITT Population. Efficacy endpoints (analysis 
of treatment effect [Section 12.4]) will be analyzed for the EE and PP Populations. Response will 
also be tabulated for the Safety/ITT Population.  Pharmacodynamic and immunogenicity 
assessments will be analyzed for the Safety/ITT Population. Pharmacokinetic results will be 
analyzed by non-compartmental PK analysis. Descriptive statistics will be provided for all PK 
parameter values by dose and time, as appropriate. 
Primary Safety and Tolerability Endpoints: 
 Number of DLTs 
 Frequency and intensity of AEs 
 Physical examination findings, including vital signs 
 Laboratory safety tests including hematology, chemistry, coagulation, urinalysis and 
complement levels 
 Assessment of ISRs 
 ECG findings 
Primary Efficacy Endpoint: 
 Proportion of responders at the RP2D with the MYD88 L265 mutation 
Secondary Efficacy Endpoints: 
 Duration of response 


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 Time to response 
 Proportion of responders at all dose levels 
 OS 
 Progression-free survival 
Safety Analyses 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 16.0 and tabulated by event, grade, and relationship to study treatment. Safety analyses 
will be descriptive in nature; no statistical hypothesis testing will be performed. Laboratory 
assessments for hematology, chemistry, coagulation, and special safety tests (C3, C4, and CH50) 
will be tabulated via shift tables, tabulating each patient’s category at baseline via National 
Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), 
version 4.03 grading (normal and Grade 1 will be combined) versus their highest NCI-CTCAE 
grade on study. Injection site reactions will be summarized by incidence for each dose group and 
overall and by worst grade on study. Time-to-event analyses will be performed for ISRs. 
Efficacy Analyses 
The definition of a responder is a patient who achieves a complete response (CR) or partial 
response (PR) based on the Revised Response Criteria for Malignant Lymphoma proposed by 
the International Working Group [1] (Section 9.6 and Section 16.2).  
As per the Simon two-stage design, after 10 subjects are treated at the RP2D until disease 
progression or clinical response, if one or fewer of those subjects respond, the study will end. If 
two or more of those initial 10 subjects respond, 19 more subjects will be enrolled. If six or more 
subjects out of 29 treated at the RP2D respond, then the null hypothesis will be rejected. 
Secondary efficacy endpoints include the duration of response, time to response, proportion of 
responders at all dose levels, OS, and progression-free survival; these will be analyzed both 
globally across all cohorts and by dose level, reporting Kaplan-Meier estimated median, as well 
as the number of events and number of patients censored. 


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1.9. 
Schedule of Study Events  
Table 4: 
Schedule of Study Evaluations 


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Visit1 
Pre-screen
2 
Screen
3 
Treatment Period 
EOT
4 
EOS5 
F/U 
Survival F/U 
Cycle 
 
 
Cycle 1 
Even Numbered 
Cycles 
Odd Numbered Cycles 
 
 
Every 12 
wks. 
(±4 wks.) 
Every 12 
wks. 
(±4 wks.) 
Day   
≤21  
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
 
 
 
 
Evaluation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent
6 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor genotyping7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood draw for genotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography and medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam
8 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Vital signs
9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test
10 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Radiologic imaging11,12 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Bone marrow biopsy
13 
 
 
X 
X 
 
Lymph node biopsy 
 
X14 
X15 
 
 
Assessment of response12 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
ECOG 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Hematology16 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Chemistry panel16 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Coagulation panel 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Complement 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Urinalysis 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
12-lead ECG17 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK18 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
PD and investigational studies
19 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Study drug administration20 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Assessment of injection site(s)20,21 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/concomitant medications20 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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AE = adverse event; CLIA = Clinical Laboratory Improvement Amendments; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS = End-of-Study; 
EOT = End-of-Treatment; OS = overall survival; F/U = Follow up; PD = pharmacodynamic; PK = pharmacokinetic 
1. 
All Days for a given Cycle are relative to the day of the first injection of study drug, designated Day 1 for that cycle; all times are relative to treatment, designated 0 hour; 
“pre-dose” vital signs are to occur within 1 hour prior to treatment; all other pre-dose procedures are to occur prior to treatment on the same calendar day. 
2. 
Pre-screening procedures involve only tumor genotyping and require a separate consent (Section 9.2). 
3. 
Screening procedures may be performed up to 21 days prior to Day 1. 
4. 
If treatment is terminated prematurely for any reason, the EOT visit will be performed within 7 days of the decision to terminate. 
5. 
EOS Visit will be performed 30 to 35 days after the last dose of study drug if treatment is terminated prematurely for any reason. 
6. 
Informed consent must be signed prior to all study-specific pre-screening and/or screening procedures. 
7. 
A tumor sample will be submitted to a central laboratory (Section 9.2) or alternatively previously confirmed by any outside CLIA-compliant assay and confirmed and 
approved by the Sponsor. 
8. 
Physical exam includes body weight and, only at Screening, height; a directed physical examination at the discretion of the Investigator is acceptable while on study 
treatment. Complete physical examination is required prior to enrollment and EOT and EOS. 
9. 
Vital signs comprise heart rate, blood pressure, respiratory rate and temperature. Vital signs will be obtained pre-dose (within 1 hour prior to treatment) and post-dose within 
30 min (±5 min) of treatment. On Day 1 of Cycle 1, Week 1, post-dose vital signs will also be obtained at 2 hours (±20 min). 
10. Serum or urine pregnancy testing for women of child-bearing potential. 
11. Radiologic imaging of chest, abdomen, and pelvis, performed during the last week of even cycles (every 8 weeks [± 1 week]) while the patient is receiving IMO-8400; 
patients discontinued from treatment for reasons other than progressive disease will be assessed per Revised Response Criteria for Lymphoma [1] (Section 16.2) at a 
minimum of every 12 weeks (± 4 days) for OS until documentation of progressive disease, initiation of new anti-cancer therapy, or the end of the study, whichever comes 
first. 
12. Assessment of response should be performed using the same imaging modalities throughout the study; assessment should be performed during the last week of all even 
numbered cycles (every 8 weeks [± 1 week]) while the patient is receiving active treatment with IMO-8400. 
13. If available, bone marrow biopsy will be processed locally (see the Laboratory Manual for more details). 
14. Archival or fresh tissue should be submitted for confirmation of diagnosis and exploratory analyses (see the Laboratory Manual for more details). 
15. Should be collected at least once between 4 and 24 hours post-treatment (Section 9.5). 
16. Hematology and chemistry full panels will be performed on Day 1 of each cycle; focused panels will also be performed on Day 15 of each cycle through Cycle 6. For Cycle 7 
and on all testing will not be repeated on Day 15 unless more frequent monitoring is clinically indicated (refer to Section 9.8.1 for details). 
17. If Screening and Day 1 Cycle 1 are performed within 24 hours then the 12-lead ECG will be performed only at Screening. 
18. On Cycles 1, 2, 4, and 6 (Day 1 of each cycle): a pre-dose sample is required. Additionally, post-dose PK samples are obtained at 1 (±5 min), 2 (±10 min) and 4 hours 
(±15 min). Pharmacokinetic samples will also be taken at EOT and EOS (Sections 9.9). 
19. Pharmacodynamic set involves one sample for serum cytokines and one sample for antibodies to IMO-8400 taken at Screening, pre-dose at Cycles 1, 2, 4, and 6 (Day 1 of 
each cycle), EOT, and EOS.  
20. Except for Cycle 1 and study days that require a physical examination or laboratory safety tests to be performed, study drug administration, assessment of injection site(s), and 
assessment of AEs and con-meds may optionally be performed at a non-study site by a trained healthcare professional approved by the Sponsor, including at home by a 
visiting nurse (Section 8.6). 
21. Assessment of all prior injection site(s) with grading and measurement of any reaction (Section 9.7.5). In addition, on dosing days, the planned injection site will be assessed 
to confirm it is appropriate for use. 


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Table 5: 
Estimation of Blood Volumes Required From Screening through 
End-of-Study1 
Tests 
Vol 
(mL) 
Pre-screen 
Screen 
Maximum 
Volume Per 
Cycle  
(mL) 
EOT 
(mL) 
EOS 
(mL) 
Safety Lab Tests 
19 
 
19 
38 
19 
19 
PK2 
5 
 
 
20 
5 
5 
Serum Cytokines 
4 
 
4 
4 
4 
4 
Antibodies to IMO-8400 
4 
 
4 
4 
4 
4 
TLR Plasma 
6 
6 
 
 
 
 
Serology 
10 
 
10 
 
 
 
Total mL blood drawn 
48 
6 
37 
66 
32 
32 
EOS = End-of-Study; EOT = End-of-Treatment; PD = pharmacodynamic; PK = pharmacokinetic; TLR = toll-like receptor; 
Vol = volume 
1. 
The volumes shown are estimates; final volumes may vary, but will not be more than 15% greater than shown. 
2. 
PK set involves a total of four samples: pre-dose, 1, 2, and 4 hours post-dose. 


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2. 
TABLE OF CONTENTS  
PROTOCOL 8400-402 ....................................................................................................................1 
1. 
SYNOPSIS ...................................................................................................................5 
1.1. 
Protocol Information .....................................................................................................5 
1.2. 
Objectives .....................................................................................................................5 
1.2.1. 
Primary Objective .........................................................................................................5 
1.2.2. 
Secondary Objectives ...................................................................................................5 
1.2.3. 
Exploratory Objectives .................................................................................................5 
1.3. 
Study Design and Methodology ...................................................................................6 
1.3.1. 
Brief Background ..........................................................................................................6 
1.3.2. 
Study Overview ............................................................................................................6 
1.3.3. 
Phase 1: Dose Escalation ..............................................................................................7 
1.3.4. 
Phase 2: Dose Expansion Cohort ..................................................................................7 
1.3.5. 
Dose Escalation Enrollment and Review .....................................................................8 
1.3.6. 
Management of Study Treatment in Individual Patients ..............................................9 
1.4. 
Study Structure .............................................................................................................9 
1.5. 
Diagnosis and Patient Selection Criteria ......................................................................9 
1.5.1. 
Pre-screening for MYD88 L265P Mutation .................................................................9 
1.5.2. 
Inclusion Criteria ........................................................................................................10 
1.5.3. 
Exclusion Criteria .......................................................................................................11 
1.6. 
Treatments ..................................................................................................................12 
1.6.1. 
Investigational Product, Dosage and Mode of Administration ..................................12 
1.6.2. 
Reference Therapy, Dosage and Mode of Administration .........................................13 
1.7. 
Criteria for Evaluation ................................................................................................13 
1.7.1. 
Pharmacokinetics ........................................................................................................13 
1.7.2. 
Safety ..........................................................................................................................13 
1.7.3. 
Treatment Effect .........................................................................................................13 
1.8. 
Statistical Methods ......................................................................................................14 
1.9. 
Schedule of Study Events ...........................................................................................16 
2. 
TABLE OF CONTENTS ...........................................................................................20 
3. 
LIST OF ABBREVIATIONS.....................................................................................27 
4. 
INTRODUCTION ......................................................................................................31 


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4.1. 
Diffuse Large B-cell Lymphoma: the Disease under Study .......................................31 
4.1.1. 
Current Standard of Care Therapy for NHL ...............................................................32 
4.2. 
Toll-like Receptors – Overview ..................................................................................33 
4.3. 
Toll-like Receptors in B-cell Malignancy ..................................................................34 
4.4. 
Rationale for the Current Study ..................................................................................35 
4.4.1. 
Overview of IMO-8400 ..............................................................................................36 
5. 
STUDY OBJECTIVES ..............................................................................................38 
5.1. 
Primary Objective .......................................................................................................38 
5.2. 
Secondary Objectives .................................................................................................38 
5.3. 
Exploratory Objectives ...............................................................................................38 
6. 
INVESTIGATIONAL PLAN .....................................................................................39 
6.1. 
Overall Study Design ..................................................................................................39 
6.2. 
Phase 1: Dose Escalation ............................................................................................39 
6.3. 
Dose Escalation Procedures ........................................................................................40 
6.3.1. 
Definition of a Dose-Limiting Toxicity ......................................................................40 
6.3.2. 
Cohort Review Committee .........................................................................................41 
6.3.3. 
Dose Escalation Enrollment and Review ...................................................................41 
6.4. 
Phase 2: Dose Expansion Cohort ................................................................................42 
6.5. 
Management of Individual Patients ............................................................................43 
6.5.1. 
Duration of Treatment ................................................................................................43 
6.5.2. 
Dose Modification in Patients with DLT Events ........................................................43 
6.5.3. 
Procedures for Assessment of Patients with Decreases in Complement 
Levels ..........................................................................................................................43 
6.5.4. 
Procedures for Assessment of Patients with Symptomatic Thrombocytopenia .........44 
6.5.5. 
Classification of Patients at Termination of Treatment ..............................................45 
6.5.6. 
Study Duration ............................................................................................................45 
6.6. 
Criteria for Replacement of Patients ...........................................................................46 
6.6.1. 
Definition of a Evaluable Patient ................................................................................46 
6.6.2. 
Replacement of Patients .............................................................................................46 
6.7. 
Maximum Number of Patients....................................................................................46 
6.8. 
Treatment Assignment ................................................................................................46 
6.9. 
Criteria for Study Termination ...................................................................................46 
6.10. 
Discussion of Study Design and Treatment Regimens ...............................................46 


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6.10.1. 
Rationale for Study Design .........................................................................................47 
6.10.2. 
Rationale for Treatment Regimens in Current Protocol .............................................47 
6.10.2.1. 
Dosing Regimen .........................................................................................................47 
7. 
SELECTION OF PATIENTS.....................................................................................49 
7.1. 
Source of Patients and Recruitment Methods .............................................................49 
7.2. 
Presence of MYD88 L265P Mutation ........................................................................49 
7.3. 
Patient Restrictions during the Conduct of the Study .................................................49 
8. 
STUDY TREATMENT ..............................................................................................50 
8.1. 
Study Treatments to be Administered ........................................................................50 
8.2. 
Description and Manufacture of Study Drug ..............................................................50 
8.3. 
Reconstitution of IMO-8400 for Injection ..................................................................51 
8.4. 
Administration of Study Treatments ..........................................................................51 
8.4.1. 
Pre-Treatment Criteria ................................................................................................51 
8.4.2. 
Variances in Dose Administration Schedule ..............................................................51 
8.5. 
Prior and Concomitant Medications ...........................................................................51 
8.5.1. 
Prohibited Treatments .................................................................................................52 
8.6. 
Treatment Compliance ................................................................................................52 
8.7. 
Accountability of Investigational Drug Supplies .......................................................52 
8.7.1. 
Disposition of Study Drug ..........................................................................................53 
9. 
STUDY EVENTS AND EVALUATIONS ................................................................54 
9.1. 
Schedule of Events .....................................................................................................54 
9.2. 
Screening, including Sequence of Procedures ............................................................54 
9.3. 
Determination of Presence or Absence of MYD88 L265P Mutation in 
DLBCL .......................................................................................................................54 
9.4. 
Enrollment Procedure .................................................................................................55 
9.5. 
Disease Evaluations ....................................................................................................55 
9.6. 
Assessment of Response to Treatment .......................................................................55 
9.7. 
General Clinical Assessments .....................................................................................56 
9.7.1. 
Medical History, including DLBCL ...........................................................................56 
9.7.2. 
Physical Examination and Body Weight ....................................................................57 
9.7.3. 
Vital Signs ..................................................................................................................57 
9.7.4. 
Electrocardiogram .......................................................................................................57 
9.7.5. 
Injection Site Reaction Assessments ..........................................................................58 


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9.8. 
Safety Laboratory Studies ...........................................................................................59 
9.8.1. 
Safety Laboratory Tests ..............................................................................................59 
9.8.2. 
Reporting of Safety Laboratory Tests .........................................................................60 
9.8.3. 
Repeating Abnormal Laboratory Tests .......................................................................60 
9.9. 
Pharmacokinetic Assessments ....................................................................................60 
9.10. 
Pharmacodynamic and Investigational Studies ..........................................................60 
10. 
SAFETY ASSESSMENTS ........................................................................................62 
10.1. 
Definition of AEs ........................................................................................................62 
10.1.1. 
Adverse Event .............................................................................................................62 
10.1.2. 
Serious Adverse Event ................................................................................................62 
10.1.3. 
Suspected, Unexpected Serious Adverse Reaction ....................................................63 
10.2. 
Investigator Assessment of Safety Laboratory Tests ..................................................63 
10.3. 
Recording Adverse Events .........................................................................................64 
10.4. 
Characterizing Adverse Events ...................................................................................64 
10.4.1. 
Description of Event ...................................................................................................64 
10.4.2. 
Date and Time of Onset ..............................................................................................64 
10.4.3. 
Relationship to Study Drug ........................................................................................65 
10.4.4. 
Intensity (Severity) .....................................................................................................65 
10.4.5. 
Grading of Laboratory Safety Tests for Reporting and Analysis ...............................66 
10.4.6. 
Management of Study Drug upon Occurrence of an AE ............................................66 
10.4.7. 
Actions Taken for Management of AE .......................................................................66 
10.4.8. 
Follow up and Outcome of AEs .................................................................................67 
10.4.9. 
Date and Time of Outcome .........................................................................................67 
10.5. 
Reporting Adverse Events ..........................................................................................68 
10.5.1. 
Where to Report SAEs ................................................................................................68 
10.5.2. 
Procedures for Reporting SAEs to the Sponsor ..........................................................68 
10.5.3. 
Other Reportable Events .............................................................................................69 
10.5.4. 
Requirements for Expedited and Periodic Reporting of AEs .....................................69 
10.5.5. 
Notification of SUSARs to the Investigator by the Sponsor ......................................69 
11. 
DATA QUALITY ASSURANCE ..............................................................................70 
11.1. 
Compliance .................................................................................................................70 
11.2. 
Training and Qualifications of Site Personnel ............................................................70 


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11.3. 
Source Documents ......................................................................................................70 
11.3.1. 
Medical Records .........................................................................................................70 
11.3.2. 
Study-Specific Source Documents .............................................................................71 
11.4. 
Electronic Case Report Forms ....................................................................................71 
11.5. 
Protocol Deviations ....................................................................................................72 
11.6. 
External Review of the Study Conduct at Participating Sites ....................................72 
11.7. 
Study Monitoring Visits .............................................................................................73 
11.7.1. 
Site Qualification and Initiation Visits .......................................................................73 
11.7.2. 
Interim Monitoring Visits ...........................................................................................73 
11.7.3. 
Study Closeout Visit ...................................................................................................74 
11.8. 
Resolution of Deficiencies ..........................................................................................74 
11.9. 
Retention of Records ..................................................................................................74 
11.10. 
Data Management .......................................................................................................75 
12. 
STATISTICAL METHODS .......................................................................................76 
12.1. 
Sample Size Determination and Study Power ............................................................76 
12.2. 
Analysis Populations ..................................................................................................76 
12.3. 
Analysis of Safety .......................................................................................................76 
12.4. 
Analysis of Treatment Effect ......................................................................................77 
12.4.1. 
Assessments ................................................................................................................77 
12.4.1.1. 
Primary Treatment Effect Parameter ..........................................................................77 
12.4.1.2. 
Secondary Treatment Effect Parameters ....................................................................78 
12.5. 
Exploratory Analyses ..................................................................................................78 
12.6. 
Identification of Study Event Days and Times ...........................................................78 
12.7. 
Interim Analysis ..........................................................................................................78 
12.8. 
Handling Missing Data ...............................................................................................79 
12.9. 
Changes in the Planned Analyses ...............................................................................79 
13. 
ETHICAL CONSIDERATIONS................................................................................80 
13.1. 
Independent Ethics Committee ...................................................................................80 
13.1.1. 
Initial Review Prior to Study Initiation ......................................................................80 
13.1.2. 
Subsequent Submissions to the IEC ...........................................................................81 
13.2. 
Written Informed Consent ..........................................................................................81 
13.2.1. 
Obtaining Informed Consent from Patients Who Are Not Literate ............................82 


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13.2.2. 
Special Informed Consent Situations Not Applicable to This Protocol .....................82 
13.2.3. 
Protection of Patient Information ...............................................................................82 
14. 
STUDY ADMINISTRATION ...................................................................................83 
14.1. 
Registration of Study ..................................................................................................83 
14.2. 
Changes in the Conduct of the Study .........................................................................83 
14.3. 
Confidentiality ............................................................................................................83 
14.4. 
Financial Disclosure ...................................................................................................83 
14.5. 
Publication Policy .......................................................................................................84 
14.6. 
Authorship and Acknowledgement ............................................................................84 
15. 
LIST OF REFERENCES ............................................................................................85 
16. 
DIAGNOSTIC AND RESPONSE CLASSIFICATIONS CITED .............................88 
16.1. 
WHO Classification of Mature B-cell neoplasms [11] ...............................................88 
16.2. 
Classification of Disease Response for DLBCL ........................................................89 
16.3. 
Efficacy End Point Definitions ...................................................................................90 
17. 
INVESTIGATOR’S AGREEMENT ..........................................................................91 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic ...........................................................................................................6 
Figure 2: 
TLR and BCR Signaling Pathways in B-cells. ...........................................................34 
Figure 3: 
Study Schematic .........................................................................................................39 
 
LIST OF TABLES 
Table 1: 
Emergency and Pharmacovigilance Contacts ...............................................................4 
Table 2: 
Study Contact Information ...........................................................................................4 
Table 3: 
Planned Dose Escalation Cohorts .................................................................................7 
Table 4: 
Schedule of Study Evaluations ...................................................................................16 
Table 5: 
Estimation of Blood Volumes Required From Screening through 
End-of-Study1 .............................................................................................................19 
Table 6: 
Broad Classification of Hematologic Malignancies ...................................................31 
Table 7: 
Incidence of MYD88 L265P Mutation in Selected B-cell Malignancies ...................35 
Table 8: 
Clinical Studies with IMO-8400 .................................................................................37 
Table 9: 
Physical and Chemical Properties of Active Ingredient (Drug Substance) ................50 


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Table 10: Formulation of IMO-8400 for Injection (Drug Product) ............................................50 
Table 11: Summary of Evaluation of Response to Treatment and Disease Status .....................56 
Table 12: IMO-8400 Subcutaneous Injection Site Grading (Local Reactions) ..........................58 
Table 13: Intensity of AE of Injection Site Reactiona ................................................................59 
Table 14: Reporting the Date and Time of Onset of AE for Different Types of Events ............64 
Table 15: Estimating Severity Grade ..........................................................................................66 
Table 16: Date and Time of Outcome for AE by Outcome Class ..............................................67 
 
 


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3. 
LIST OF ABBREVIATIONS 
Abbreviation Explanation 
ABC 
Activated B-cell 
ADL 
Activity of daily living 
AE 
Adverse event 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AP 
Alkaline phosphatase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC0-t  
Area under the curve from 0 to last measurable plasma concentration 
BA 
Bioavailability 
BCR 
B-cell receptor 
BE 
Bioequivalence 
BMI 
Body mass index 
BP 
Blood pressure 
BTK 
Bruton's tyrosine kinase 
C3 
Complement component 3 
C4 
Complement component 4 
CBC 
Complete blood count 
CH50 
50% hemolytic complement assay 
CK 
Creatine phosphokinase 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Observed maximum plasma concentration 
CNS 
Central nervous system 
CPG 
Cytosine guanine dinucleotide motifs 
CR  
Complete response 
CRC 
Cohort Review Committee 
CRO 
Clinical research organization 
CRP 
C-reactive protein 
CS 
Clinically significant 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DC 
Dendritic cell 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 


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EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EE 
Efficacy Evaluable 
EHR 
Electronic health record 
EOS 
End-of-Study 
EOT 
End-of-Treatment 
FDA 
Food and Drug Administration (US) 
FDG 
[18F]fluorodeoxygluse 
FFPE 
Formalin-fixed, paraffin-embedded 
GCB 
Germinal center B-cell 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HHV-8 
Human herpesvirus 8 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
Ig 
Immunoglobulin 
ITT 
Intent-to-Treat 
IL 
Interleukin 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IP-10 
Interferon-inducible protein 10 
IRAK 
Interleukin receptor activated kinase 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 
ITT 
Intent-to-Treat 
IUO 
Investigational Use Only 
LDH 
Lactate dehydrogenase 


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Jak 
Janus kinase 
LPS 
Lipopolysaccharide 
MALT 
Mucosa-associated lymphoid tissue  
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MTD 
Maximum tolerated dose 
MYD88  
Myeloid differentiation primary response gene (88) 
MZL 
Marginal zone B-cell lymphoma 
NA 
Not applicable 
NCI-CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events 
NCS 
Not clinically significant 
NF-κB 
Nuclear factor kappa-light-chain-enhancer of activated B-cells 
NHL 
Non-Hodgkin’s lymphoma 
OS 
Overall survival 
PD 
Pharmacodynamic(s) 
PET 
Positron emission tomography 
PHI 
Protected health information 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PR 
Partial response 
PSA 
Prostate-specific antigen 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RBC 
Red blood cell 
R-CHOP 
Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SCID 
Severe combined immunodeficient 
SD 
Stable disease 
STAT 
Signal transducer and activator of transcription 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
Th1 
T helper cell, type 1 
TLR 
Toll-like receptor 


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Tmax 
Time of observed maximum plasma concentration 
TMF 
Trial Master File  
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia 
WBC 
White blood cell 
WHO 
World Health Organization 
WMA 
World Medical Association 
WM 
Waldenström’s Macroglobulinemia 
β-hCG 
Beta-human chorionic gonadotropin 
 


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4. 
INTRODUCTION 
4.1. 
Diffuse Large B-cell Lymphoma: the Disease under Study  
Hematological malignancies are cancers affecting blood, bone marrow, and lymph nodes; they 
may derive from either myeloid or lymphoid cell lines. Those arising from the lymphoid line 
may originate from lymphatic tissue within the bone marrow or outside it, including lymph 
nodes or lymphatic structures in the skin, gastrointestinal tract or other body sites (Table 6). 
Lymphoid tumors arising outside the bone marrow may spread to the marrow and impair the 
production of hematopoietic cells, resulting in pancytopenia.  
Table 6: 
Broad Classification of Hematologic Malignancies 
Cell Line of Origin 
Site of Origin 
General Classes 
Examples 
Myeloid 
Bone Marrow 
Leukemia 
Acute Myelogenous Leukemia 
Chronic Myelogenous Leukemia 
 
 
Myelodysplasia 
Myelodysplastic Syndrome 
Myeloproliferative Disease 
Lymphoid 
Bone Marrow1 
Leukemia 
Lymphocytic Leukemia 
Lymphoblastic Leukemia 
 
Extra-marrow1,2 
Hodgkin Lymphoma  
Nodular Sclerosing Hodgkin Lymphoma 
 
 
Non-Hodgkin Lymphoma  
 
Lymphoplasmacytic Lymphoma  
(Waldenström’s Macroglobulinemia) 
Diffuse Large B-cell Lymphoma 
1. 
Lymphoid malignancies arising in the marrow are also referred to as “precursor cell neoplasms” and those arising outside 
the marrow as “mature cell neoplasms.”  
2. 
Sites of origin outside the bone marrow include lymph nodes or lymphatic structures in the skin, gastrointestinal tract, and 
other body sites. 
Non-Hodgkin lymphomas (NHL) represent a heterogenous group of lymphoid malignancies. The 
primary differentiation is based on lymphocyte cell type: B-cell, T-cell, NK-cell. The complete 
World Health Organization (WHO) classification currently includes over 30 specific mature 
B-cell neoplasms [11] (Section 16.1) distinguished by multiple different factors, including: 
 Histologic appearance, e.g., follicular, mantle cell, diffuse large B-cell 
 Tissue or structure of origin or primary involvement: spleen, mucosa-associated 
lymphoid tissue (MALT), marginal zone, mediastinum (thymus), skin (cutaneous), 
intravascular 
 Immunoglobulin production: Waldenström’s Macroglobulinemia (WM) 
(immunoglobulin [Ig]M), multiple myeloma (IgG, IgA), heavy chain diseases 
 Associated virus, e.g., Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), 
Human immunodeficiency virus (HIV) 
Current estimates for the United States are approximately 70,000 new cases of NHL annually 
and 19,000 deaths [12]. The incidence of NHL rises steadily with advancing age from rates of 
2.4 cases per 100,000 in the 20- to 24-year age-group, to 8 cases per 100,000 for 35- to 


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39-year-olds, to 119.4 cases per 100,000 among those age 80- to 84-years. The median age at 
diagnosis is ~70 years old.  
Among the cases of NHL, ~85% arise from B-cells and the most common of the mature B-cell 
malignancies is diffuse large B-cell lymphoma (DLBCL), representing ~31% of all NHL. Some 
rare forms of diffuse large B-cell tumors are recognized as specific diagnoses, including: 
 DLBCL associated with chronic inflammation  
 Primary cutaneous DLBCL, leg type  
 Intravascular large B-cell lymphoma 
 Primary DLBCL of the central nervous system (CNS) 
 T-cell/histiocyte rich large B-cell lymphoma 
 Primary mediastinal (thymic) large B-cell lymphoma 
 EBV-positive DLBCL of the elderly 
 Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease 
Recent molecular analyses have proposed subtyping DLBCL based on gene expression profiles 
into two classes designated activated B-cell subtype ([ABC]; representing ~28% of DLBCLs) 
and germinal center B-cell (GCB) subtype (representing most of the remaining DBLCLs)[13]. 
Germinal center B-cell subtype-DLBCL has been associated with a higher response rate to 
standard treatments and an overall improved prognosis, with 60% five-year survival, compared 
to 39% for patients with non-GCB tumor profiles [13]. The ABC phenotype, which is driven by 
myeloid differentiation primary response gene (88) (MYD88) mutation in a significant 
proportion of patients (Table 7), has a particularly poor prognosis when compared with GCB 
subtype-DLBCL, and thus represents an important unmet medical need [14]. 
4.1.1. 
Current Standard of Care Therapy for NHL 
Treatment strategies in NHL vary depending on the specific disease and stage. Diffuse large 
B-cell lymphoma is considered an aggressive lymphoma with the potential for rapid disease 
progression. Intensive chemotherapy is typically the initial treatment of choice; rituximab (an 
anti-CD20 monoclonal antibody) plus combination cytotoxic chemotherapy (cyclophosphamide, 
doxorubicin, vincristine, and prednisone [R-CHOP]) represents the most commonly used 
regimen. 
Options for treating relapsed or refractory disease include: 
 Bone marrow or stem cell transplantation 
 Repeat of initial therapy 
 Other combinations of rituximab and chemotherapy  
 Radiolabeled monoclonal antibodies 
 Immunomodulatory drugs (e.g., lenalidomide)  


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In some reports, these strategies have improved progression-free survival for patients with 
relapsed/refractory NHL, but definitive survival advantage is less clear and most patients die 
from the disease. New treatments are needed for advanced, recurrent B-cell malignancies and 
current practice guidelines recommend inclusion of these patients in investigational trials [10]. 
4.2. 
Toll-like Receptors – Overview  
Toll-like receptors (TLRs) are a family of host sensors for “foreign” constituents (e.g., nucleic 
acids, lipopolysaccharides, peptidoglycans from viruses, bacteria, fungi) that “sound the alarm” 
and activate host immune defenses. The natural ligands for TLR7 and 8 are single-stranded 
ribonucleic acid (RNA) from viruses, and for TLR9, unmethylated cytosine-guanine dinucleotide 
motifs (CpG), which are characteristic of bacterial deoxyribonucleic acid (DNA). Binding of 
these ligands to the cognate receptor results in intracellular signaling, generation of nuclear 
factor kappa-light-chain-enhancer of activated B-cells (NF-κB), and production of 
pro-inflammatory (Th1) chemokines and cytokines, including interferon (IFN)-α, tumor necrosis 
factor (TNF-α) and interleukin (IL)-12. Of note, TLRs 7, 8, and 9 are located in the endosome, 
whereas most other TLRs are located on the host cell surface. In man, the endosomal TLRs are 
constitutively expressed primarily on dendritic cells (DCs) and B-cells. 
Although foreign constituents are the intended ligands for the nucleic acid TLRs, multiple 
studies indicate that activation by endogenous nucleic acids is central to the development and 
persistence of autoimmunity and inflammatory diseases [15, 16, 17, 18, 19]. As detailed below, 
recent evidence suggests this process can also contribute to the malignant phenotype of B-cell 
tumors.  
The TLR signaling pathway (Figure 2, left panel) comprises a series of cytoplasmic proteins that 
result in generation of NF-κB, which translocates to the nucleus and mediates increased 
expression of genes involved in cell survival, proliferation, and cytokine production. In B-cells, 
the other major mechanism for activation is binding of specific antigen to the B-cell receptor 
(BCR). There are several signaling pathways associated with the BCR (Figure 2, right panel), 
including one that generates increased NF-κB. The constituents of that BCR signaling pathway 
are, in general, distinct from those of the TLR pathway.  


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Figure 2: 
TLR and BCR Signaling Pathways in B-cells.  
TLR signaling 
BCR signaling [3] 
 
 
4.3. 
Toll-like Receptors in B-cell Malignancy  
A central feature of malignant cell transformation is the development of dysregulated or 
autonomous cell activation resulting in increased cell proliferation and survival. This can be the 
result of specific ‘oncogene’ mutations or defects in the control of the expression of critical 
genes. Chromosomal abnormalities, both point mutations and translocations, are common among 
hematological malignancies, have an established role in diagnosis, and are increasingly used in 
guiding specific approaches to treatment. 
Studies of B-cell malignancies have identified changes in the BCR signaling pathway, and more 
recently in the TLR signaling pathway, that drive NF-κB expression and the malignant 
phenotype. These changes include:  
 Mutations in MYD88, the adapter (linker) protein that binds to TLRs [20]. 
 Mutations in BCR signaling pathway genes, including CD79A/B and CARD11 [3]. 
 Increased expression of MYD88 [21]. 
The most common alteration identified to date in MYD88 is the L265P mutation. This mutation 
is present in over 90% of WM, in ~30% of ABC-DLBCL, and at lower frequencies in other, 
more common lymphomas (Table 7). Among patients with DLBCL, both increased expression of 
MYD88 [21] and the L265P mutation [9] have been associated with markedly poorer outcomes.  


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Table 7: 
Incidence of MYD88 L265P Mutation in Selected B-cell Malignancies 
Disease 
Incidence of 
Disease 
(20141) 
MYD88 L265P Mutation 
Reference for 
Frequency of 
L265P  
% Patients  
Incidence  
(Est. 20132) 
DLBCL 
17,387 
10% 
1,739 
[9] 
ABC-DLBCL3 
4,868 
29% 
1,412 
[2] 
Waldenström’s Macroglublinemia 
876 
91% 
797 
[22] 
Chronic Lymphocytic Leukemia 
14,586 
5% 
729 
[23,24] 
Primary CNS Lymphoma 
1,200 
37% 
444 
[25,26] 
Marginal Zone Lymphoma4  
4,868 
6.5% 
316 
[2,27] 
ABC-DLBCL = Activated B-cell (type) Diffuse Large B-cell Lymphoma; CNS = central nervous system; DLBCL = Diffuse 
Large B-cell Lymphoma; MALT = Mucosa-Associated Lymphoid Tissue Lymphoma; NHL = Non-Hodgkin’s lymphoma; 
SEER = Surveillance Epidemiology and End Results dataset 
1. 
Diagnosis-specific 2014 incidence is based on the age-adjusted annual US incidence of 70,800 NHL cases estimated using 
the SEER[28], and the relative counts of specific diagnoses within the dataset.  
2. 
Estimated incidence of L265P mutation is based on 2011 disease incidence and the reported frequency of the mutation in the 
disease.  
3. 
ABC-type represents ~28% of all DLBCL. In studies subtyping DLBCL, most instances of L265P mutations have been in 
those with ABC-subtype.  
4. 
Marginal Zone Lymphoma is also referred to as MALT. 
Recent in vitro studies of B-cell tumor lines with L265P mutation suggest that TLR signaling 
directly contributes to the malignant phenotype of these cells [4]. Specifically, cell proliferation 
and survival decreased markedly under the following conditions: 
 Impaired expression of endosomal TLRs, using an inhibitory RNA. 
 Enzymatic elimination of endogenous nucleic acids in the culture supernatant. 
Idera Pharmaceuticals, Inc. has conducted independent studies using B-cell tumor lines, 
including LY10, a cell line with the L265P mutation and increased MYD88 expression. 
LY10 cells cultured in vitro with IMO-8400 demonstrate decreased growth and survival. Severe 
combined immunodeficient (SCID) mice inoculated with LY10 developed progressive disease 
and died. Treatment with IMO-8400 prolonged median survival from 33 to 48 days [5].  
4.4. 
Rationale for the Current Study 
Taken together, the above data directly support the hypothesis that an antagonist of TLR7, 8, and 
9 would have a therapeutic effect in patients with B-cell malignancies, specifically, those 
characterized by MYD88 L265P mutation or increased MYD88 expression.  
IMO-8400 is a synthetic oligonucleotide that functions as an antagonist for TLRs 7, 8, and 9 and 
blocks cell activation mediated through ligand binding. In human studies, IMO-8400 has been 
administered once weekly by subcutaneous (SC) injection in two completed clinical trials, 
including a 4-week Phase 1 study of healthy adults administered 0.3 or 0.6 mg/kg 
(Study 8400-001) and a 12-week Phase 2a study of patients with moderate to severe plaque 
psoriasis administered 0.075, 0.15, 0.3, or 0.6 mg/kg (Study 8400-201). All treatments were 
well-tolerated. There were no deaths, serious adverse events (SAEs), discontinuations due to 


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treatment-related adverse events (TEAEs), and no clinically meaningful changes in laboratory 
measurements, 12-lead electrocardiograms (ECGs), or physical examination findings in either 
study.  
IMO-8400 is also currently being evaluated in an ongoing, open-label study at weekly dose 
levels of 0.6 mg/kg/week, 1.2 mg/kg/week, or 2.4 mg/kg/week (1.2 mg/kg twice weekly) in 
patients with WM (Study 8400-401) as well as in an extension study for patients completing 
Study 8400-401 (Study 8400-404) (see Section 4.4.1 and Investigator Brochure [IB] for study 
details). Recently reported interim results from Study 8400-401 show that IMO-8400 is 
well-tolerated and demonstrate evidence of clinical activity [7]. Dose escalation is ongoing in 
this study as a maximum tolerated dose (MTD) has not been reached. 
The current study represents the first use of IMO-8400 in patients with DLBCL.  
4.4.1. 
Overview of IMO-8400 
IMO-8400 was created by Idera Pharmaceuticals, Inc. using a structure-activity approach to 
design synthetic oligonucleotide drug candidates that target TLRs. IMO-8400 is designed as an 
antagonist for endosomal TLR7, TLR8, and TLR9. Non-clinical studies (reviewed in detail in 
the IB) demonstrated that IMO-8400 has the following characteristics:  
 Acts as an antagonist for activation of TLR7, 8 and 9, specifically blocking the 
activity of agonists for those receptors, including inhibiting generation of NF-κB and 
induction of cytokines and chemokines (e.g., TNF-α, IL-12, IL-1β, 
interferon inducible protein 10 [IP-10], IL-6, IFN-α). 
 Has no agonist activity; that is, does not induce Th1 cytokines/chemokines.  
 Is specific for endosomal TLRs 7, 8, and 9; that is, has no effect on activation of other 
unrelated TLRs, such as TLR4, whose natural ligand is bacterial 
lipopolysaccharide (LPS).  
 Has potent therapeutic activity in animal models of autoimmune diseases to inhibit 
the progression or reverse the clinical and immunologic manifestations of disease. 
Further, Idera has recently completed studies both in vitro and in mice examining the effect of 
IMO-8400 on human lymphoma B-cell lines, including cell lines with and without mutations in 
the TLR signaling pathway. These studies demonstrate that IMO-8400 has the following effects: 
 Inhibits constitutive activation of cell signaling pathways, including NF-κB, 
interleukin receptor activated kinase (IRAK), signal transducer and activator of 
transcription (STAT)-3, Janus kinase (Jak)/STAT, and Bruton's tyrosine kinase 
(BTK), in human lymphoma cell lines with the MYD88 L265P mutation.  
 Decreases in vitro cell survival and proliferation in a time- and 
concentration-dependent manner in human lymphoma cell lines with the 
MYD88 L265P mutation.  
 Decreases tumor cell growth in vivo, as indicated by decreased serum levels of 
tumor-secreted human cytokine and increased mouse survival time in a disseminated 


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xenograft model using OCI-Ly10, a human lymphoma cell line with the 
MYD88 L265P mutation. 
 Decreases tumor growth and serum levels of tumor-secreted human IL-10 in an 
SC xenograft mouse model using OCI-Ly10, a human lymphoma cell line with the 
MYD88 L265P mutation.  
 Does not impact tumor growth and tumor-secreted human cytokines in an 
SC xenograft mouse model using SU-DHL-6, a human lymphoma cell line with 
wild-type MYD88. 
 Clinical studies with IMO-8400 are summarized in Table 8, and the IB. Clinical 
experience with IMO-8400 related to the rationale for the dosing regimen in the 
current study is provided in Section 6.10.2.1. 
Table 8: 
Clinical Studies with IMO-8400  
Protocol No.  
Protocol Title 
Status 
8400-001 
A Phase 1, Single-Dose Escalation and 4-week Multiple-Dose Escalation Study of the 
Safety and Pharmacokinetics of IMO-8400 in Healthy Volunteers 
Completed 
8400-201 
A Randomized, Double-Blind, Placebo-Controlled, 12-week Dose-Ranging Trial of 
IMO-8400 in Patients with Moderate to Severe Plaque Psoriasis 
Completed 
8400-401 
Phase 1/2 Open-label, Multiple-dose, Dose escalation Study to Evaluate the Safety 
and Tolerability of IMO-8400 in Patients with Relapsed or Refractory Waldenström’s 
Macroglobulinemia 
Ongoing 
8400-404 
An Extension Study to Evaluate the Long-Term Safety, Tolerability, and Clinical 
Activity of IMO-8400 in Patients with Relapsed or Refractory Waldenström’s 
Macroglobulinemia who Completed Study 8400-401 
Ongoing 
8400-211 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial of IMO-8400 in 
Patients with Dermatomyositis 
Ongoing 


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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objective 
 To evaluate the safety and tolerability of escalating dose levels of IMO-8400 
administered by SC injection in patients with relapsed or refractory non-GCB subtype 
DLBCL.  
5.2. 
Secondary Objectives 
 To assess the treatment effect (clinical activity) in patients with non-GCB subtype 
DLBCL with MYD88 L265P mutations using disease-specific international 
guidelines for classifying clinical response [1].  
 To identify an optimal dose of IMO-8400 for further clinical evaluation in B-cell 
malignancies. 
 To characterize the pharmacokinetics of escalating dose levels of IMO-8400 
administered by SC injection.  
5.3. 
Exploratory Objectives 
 To investigate associations between the treatment effect of IMO-8400 and selected 
biomarkers (e.g., serum cytokines). 
 To assess the potential immunogenicity of IMO-8400 administered by SC injection.  


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is an open-label, multiple-dose, dose escalation study of IMO-8400 in patients with relapsed 
or refractory DLBCL of non-GCB subtype. The study is a Phase 1/2 study in which Phase 1 will 
consist of a dose escalation to determine the recommended Phase 2 dose (RP2D). Phase 2 is a 
Simon two-stage design [8], consisting of an open-label treatment of patients at the RP2D. 
Initially 10 patients will be treated at the RP2D. If at least two of the 10 patients respond, the 
study will enroll 19 more patients, for a total of 29 patients in the Phase 2 portion. 
A study schematic is represented in Figure 3. 
Figure 3: 
Study Schematic 
 
6.2. 
Phase 1: Dose Escalation  
The dose escalation cohorts will systematically evaluate the safety and tolerability of IMO-8400 
at increasing dose levels in order to identify the MTD.  
 The planned dose escalation cohort levels for IMO-8400 are 0.3, 0.6, and 1.2 mg/kg 
administered twice weekly and 2.4 and 3.6 mg/kg administered once weekly 
(Table 3). Additional dose levels, schedules, and routes of administration may be 
evaluated based upon the emerging data. Dosing is based on body weight 
(Section 8.1). Doses will be administered by SC injection. 
 The Investigators and Sponsor will review available toxicity information (including 
AEs that are not dose-limiting toxicities [DLTs]), pharmacokinetic (PK) and activity 
data to determine the MTD (Section 6.3.3). 


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6.3. 
Dose Escalation Procedures 
6.3.1. 
Definition of a Dose-Limiting Toxicity 
The safety and tolerability of IMO-8400 will be assessed using reported and observed AEs as 
well as scheduled safety observations including vital signs, physical examination, laboratory 
safety tests (hematology, serum complement, chemistry, and coagulation), urinalysis, and ECGs.  
A DLT can be either a clinical or laboratory AE. 
A potential DLT event is defined as a TEAE (Section 10.1) that meets protocol-defined criteria 
for events of hematological and non-hematological origin. It must be related to study treatment 
(assessed as not related to disease, intercurrent illness, or concomitant medication). For the 
purposes of dose escalation and determination of the MTD, only DLTs that occur during the first 
cycle of treatment will be necessarily considered for discussions regarding dose escalation. 
Clinically significant toxicities or TEAEs that meet the definition of dose limiting but occur after 
Cycle 1 (dose modifying events) may be considered when determining the RP2D. 
Protocol-defined hematologic DLT criteria: 
 Grade 4 neutropenia lasting ≥ 7 days 
 Grade 3 or 4 neutropenia with fever ≥38.5°C 
 Grade 3 thrombocytopenia with bleeding that requires transfusion therapy 
 Grade 4 thrombocytopenia 
Protocol-defined non-hematologic DLT criteria: 
 Grade 3 vomiting or nausea despite the use of optimal anti-emetic treatments 
 Grade 3 diarrhea despite the use of optimal anti-diarrheal treatments 
 Serum creatinine ≥ 3.0x upper limit of normal (ULN) 
 Bilirubin ≥ 3.0x ULN 
 Bilirubin 2.0-3.0x ULN with ≥ Grade 2 ALT in patients without liver metastases 
 Bilirubin 2.0-3.0x ULN with ≥ Grade 3 ALT or ALT > 5x ULN in patients with liver 
metastases 
 Other non-hematologic toxicities of ≥ Grade 3 except for the following: 
 AEs related to underlying disease 
 Fatigue 
 Alopecia 
 Isolated, asymptomatic elevations in biochemistry laboratory values lasting ≤7 
days. This includes electrolyte abnormalities that respond to medical intervention. 


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The Cohort Review Committee (CRC) will review all DLTs to assess causality, i.e., relationship 
to study drug (Section 10.4.3).The definition of DLT event will be applicable in the following 
contexts:  
 CRC review determining dose escalation (Section 6.3.2).  
 CRC review in defining the MTD. 
 Investigator (and Medical Monitor) review for determining discontinuation of study 
treatment in individual patients. 
6.3.2. 
Cohort Review Committee  
The CRC is comprised of the Idera Medical Monitor and Investigators from participating sites. 
Once the last patient in a given cohort has completed a cycle of study treatment, a CRC meeting 
will be convened to review all safety data and decide whether to continue or halt dose escalation, 
further expand individual dose levels to gain additional safety data, or explore lower or 
intermediate dose levels.  
The CRC will conduct a review of safety data upon completion of each dose escalation cohort 
and periodically during Dose Expansion (Phase 2).  
In addition to end-of cohort meetings, the CRC will convene periodically to review safety data 
for ongoing patients and patients in follow up. 
The roles of the CRC are to:  
 Review and provide definitive adjudication on individual DLTs, if needed 
(Section 6.3.1). 
 Perform dose escalation review and make specific recommendations for the progress 
of the study (Section 6.3.3). 
 Determine the MTD. 
6.3.3. 
Dose Escalation Enrollment and Review 
Each dose escalation cohort is expected to enroll at least three patients, with a maximum of six 
patients. The number of patients enrolled in any of the planned dose escalation cohorts can be 
reduced if safety at that dose has already been demonstrated in a related population (e.g., WM). 
 If the initial three patients complete all 4 weeks of treatment without a DLT event, the 
CRC will conduct a dose escalation review.  
 If one of the initial three patients experiences a DLT event prior to completing 
Cycle 1, then enrollment at that dose level will continue to a total of six patients and 
the dose escalation review will be done when all six patients have completed Cycle 1. 
 If two patients at a dose-level experience DLT events during the Cycle 1, then no 
further patients will be enrolled until the CRC completes a review, which should be 
done as soon as feasible.  


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 Furthermore, cohorts may be expanded to include additional patients if such patients 
can be enrolled ≤7 days after the third (or sixth) patient was first dosed with 
IMO-8400. 
The CRC review will include all available safety data. To facilitate standardizing the dose 
escalation reviews across different cohorts, the focus will be on observations from Cycle 1 at that 
dose level.  
The following represent anticipated outcomes for the review process:  
 Approval of enrollment in the expansion cohort at that dose level, if applicable.  
 Dose escalation – progression to the next planned dose level.  
 Continue cohort enrollment (applicable only to review after three patients) – enroll up 
to six patients at the current dose level to obtain additional safety data for subsequent 
review. 
 Increase the number of patients treated at a given pre-specified or intermediary dose 
level to better define the safety profile of IMO-8400 and enhance the clinical 
experience at each participating site. Dose escalation decisions will be made once the 
last patient in a cohort completes Cycle 1.  
 Dose de-escalation – enrollment of an intermediate level contingency cohort to 
facilitate identifying the MTD. 
 No further dose escalation enrollment – at this time the CRC will indicate the dose 
level they consider represents the MTD.  
The CRC comprises experienced clinicians, who will make recommendations based on their 
judgment. In consideration of the dynamic nature of early phase studies, those recommendations 
may include alternative courses of action not anticipated here.  
6.4. 
Phase 2: Dose Expansion Cohort 
Once the RP2D has been established, additional patients will be treated in a dose expansion 
phase that is designed to better characterize the safety, tolerability and preliminary anti-tumor 
activity of the study drug when provided at the RP2D to patients with non-GCB subtype DLBCL 
with MYD88 L265P mutations. Phase 2 utilizes a Simon two-stage design [8], consisting of an 
open-label treatment of patients at the RP2D. Initially 10 patients will be treated at the RP2D. If 
at least two of the 10 patients respond, the study will enroll 19 more patients, for a total of 
29 patients in the Phase 2 portion. Additional dose-expansion cohorts may be added if clinical 
activity is seen during the dose escalation phase in tumors that lack this mutation. 
Treatment will continue until disease progression, intolerable toxicity (despite dose 
modification), withdrawal of consent, start of another anti-cancer therapy, or study completion, 
whichever occurs first. 


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6.5. 
Management of Individual Patients 
6.5.1. 
Duration of Treatment  
Each enrolled patient will receive IMO-8400 at the assigned dose level until disease progression, 
intolerable toxicity (despite dose modification), withdrawal of consent, start of another 
anti-cancer therapy, or study completion, whichever occurs first. 
Patients discontinued from treatment for reasons other than progressive disease will be assessed 
at a minimum of every 12 weeks for overall survival (OS) until documentation of progressive 
disease, initiation of new anti-cancer therapy, or the end of the study, whichever comes first. 
Patients who are tolerating treatment may be escalated to any dose level that has been deemed 
safe by the CRC upon discussion and approval with the Idera Medical Monitor. In certain 
instances, patients may be deriving clinical benefit despite objectives signs of progressive 
disease such as radiologic progression. It can be anticipated that based on the study drug’s 
mechanism of action, through an immunologic mediated effect, signs of radiologic response may 
be delayed. Based on these considerations, continuing to treat some patients past progressive 
disease may be considered after discussion between the Sponsor and Investigator.  
6.5.2. 
Dose Modification in Patients with DLT Events  
Patients determined to have a DLT event may resume treatment at the next lowest dose level 
(Table 3) after dose interruption and with dose modification if all of the following criteria are 
met:  
 The patient is receiving >0.6 mg/kg/week; patients receiving 0.6 mg/kg/week will be 
discontinued.  
 The patient has not previously had dose interruption and/or adjustment for a 
DLT event. 
 Both the Investigator and the Medical Monitor consider that continued treatment with 
study drug is in the patient’s interest.  
 The DLT event improves at least two grades or returns to baseline within 14 days of 
the last dose administered.  
Patients who do not resume treatment within 21 days of their last dose will have treatment 
discontinued permanently and will proceed to End-of-Treatment (EOT) and End-of-Study (EOS) 
visits.  
6.5.3. 
Procedures for Assessment of Patients with Decreases in Complement Levels 
Activation of complement in non-human primates is a well-described effect of phosphorothioate 
oligonucleotides, including IMO-8400. Monkeys are thought to be particularly sensitive to 
oligonucleotide-induced complement activation and a similar direct oligonucleotide-induced 
complement activation has not been observed in humans or other species. Specifically, in a 
39 week chronic toxicity study conducted in cynomolgus monkeys, 3 of 28 animals administered 
IMO-8400 at dose levels ≥ 6 mg/kg/week were found dead or sacrificed moribund during the 
study with necropsy findings of myocardial degeneration/necrosis, glomerulonephritis, and/or 
hepatocellular necrosis. Adverse microscopic findings were also noted in two 6 mg/kg/week-


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treated animals that survived to the terminal sacrifice. Findings consisted of minimal 
degeneration/necrosis of the myocardium in one animal and slight subacute vasculitis in the heart 
of the other. Of the five animals on study with adverse, treatment-related, anatomic pathology 
findings, all had perturbations in serum complement and serum chemistry parameters consistent 
with an acute phase response (most notably globulin and C-reactive protein [CRP]) in the weeks 
and months prior to either their unscheduled deaths or the scheduled terminal necropsy. Effects 
on clinical pathology parameters associated with the target organ toxicity in these animals 
(increased troponin I concentrations, liver enzyme activities, and/or urine protein:urine creatinine 
ratio) occurred later in the study when compared to effects on serum complement and serum 
chemistry parameters that were consistent with an acute phase response. 
If at any time during study participation, a patient experiences an acute drop in complement 
component (CH50, C3 or C4) levels, defined as ≥ 50% with reference to baseline testing or most 
recent values on study or a drop to an absolute value of < 10 mg/dL, the following procedures 
and testing should be performed: 
1. Hold study drug treatment 
2. Repeat the serum complement test to confirm decreased complement levels 
3. Query patient for recent change in signs or symptoms suggestive of a rheumatologic or 
vasculitic event, i.e., recent appearance of a rash or bruising, new onset symptoms such 
as fever, arthralgias, or fatigue 
4. Perform physical examination with careful attention to findings suggestive of vasculitis; 
i.e., rash, palpable purpura, petechiae 
5. Perform repeat complete blood count (CBC) with platelets, or review most recent 
CBC/platelets 
6. Perform repeat urinalysis, or review most recent urinalysis with special attention to 
findings suggestive of glomerulonephritis; i.e., presence of protein, blood, red blood cell 
(RBC) casts or white blood cell (WBC) casts  
7. Perform an ECG 
Based on the results of this work-up and the patient’s disease assessment/response to study drug, 
the Investigator in discussion with the Sponsor’s medical monitor, will determine the patient’s 
risk/benefit profile and discuss appropriate next steps regarding the patient’s continued 
participation in the study. 
6.5.4. 
Procedures for Assessment of Patients with Symptomatic Thrombocytopenia 
Severe thrombocytopenia has been reported in clinical studies with another oligonucleotide [29]. 
Most of these patients had confirmed anti-platelet antibodies. These cases occurred 14 to 
26 months after the onset of treatment, suggesting that risk increases with duration of exposure. 
In the event of a precipitous drop in platelet counts (i.e., to <25 x 109/L), treatment with 
IMO-8400 should be held and an anti-platelet antibody count obtained. Treatment can be 
resumed once pre-treatment criteria (Section 8.4.1) are met. Antiplatelet, thrombolytic, or 
anticoagulant drugs should be used with caution. 


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6.5.5. 
Classification of Patients at Termination of Treatment 
To provide for consistent accounting of patient disposition when study treatment is discontinued 
in an individual patient for any reason, the Investigator will complete the appropriate electronic 
case report form (eCRF) and select the primary reason for discontinuation of treatment from the 
following standard categories:  
 DLT event – defined above.  
 Disease progression – as defined above.  
 AE, other than DLT – this includes any AE (clinical or laboratory; serious or 
non-serious; regardless of relation to study drug), that represents the reason study 
drug was discontinued, including:  
– The medical judgment of the Investigator based on the best interests of the 
patient.  
– The patient’s request based on any AE.  
 Withdrawal of consent – the patient desired to withdraw from further participation in 
the study in the absence of a clinical issue. If the patient gave a reason for 
withdrawing (e.g., leaving area), it should be recorded in the eCRF. 
 Lost to follow up – the patient stopped coming for visits.  
 Study termination – by the Sponsor, for any reason.  
When study treatment is discontinued prematurely for any reason, the EOT and EOS visits will 
be performed as specified (Section 1.4). If a patient cannot be seen, attempts will be made to 
contact the patient by telephone to inquire about reasons for stopping participation and get 
updated information on any unresolved AEs.  
6.5.6. 
Study Duration 
The study will end following completion of the response assessment in the expansion phase or 
approximately 6 months after the last patient has begun treatment. Study treatment may be 
discontinued in an individual patient before this planned duration as described in Section 6.5.5. 
Follow up: 
All treated patients will have an EOT visit within 7 days of the decision to discontinue treatment 
to collect data for safety, PK, progressive disease, immunogenicity and tumor response. An EOS 
visit will occur 30-35 days after the patient’s last administration of study drug. Additionally, 
patients discontinued from treatment for reasons other than progressive disease will be assessed 
per Revised Response Criteria for Lymphoma (Section 16.2) at a minimum of every 12 weeks 
for OS until documentation of progressive disease, initiation of new anti-cancer therapy, or the 
end of the study, whichever comes first. 
Survival follow up: 
Following disease progression, patients will be contacted every 12 weeks for the subsequent use 
of anti-cancer therapy as well as for survival until study completion. 


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6.6. 
Criteria for Replacement of Patients  
6.6.1. 
Definition of a Evaluable Patient 
A patient will be considered evaluable for purposes of CRC review if they meet either of the 
following criteria:  
 Received at least one dose of study drug and had treatment discontinued because of a 
DLT event as defined in Section 6.3.1; or 
 Completed Cycle 1 successfully as scheduled and completed Cycle 2, Day 1 
assessment procedures. 
See Section 12 for additional discussion of analysis for safety and efficacy.  
6.6.2. 
Replacement of Patients  
A patient who does not meet criteria for “evaluable” may be replaced to assure the requirements 
for completing the cohort are met. Replacement patients will be identified by distinctive patient 
numbers and will receive the same dose level as the patient being replaced.  
6.7. 
Maximum Number of Patients  
The maximum exposures to IMO-8400, the investigational agent in this study, will be as follows:  
 Maximum number of patients: Up to 59 patients in planned escalation and expansion 
cohorts; potential for additional patients in contingency cohorts or as replacements. 
 Treatment is until progression or intolerable toxicity, therefore the maximum number 
of dose levels is not pre-specified. 
6.8. 
Treatment Assignment 
Enrollment procedures are presented in Section 9.4. 
6.9. 
Criteria for Study Termination 
The Sponsor reserves the right to discontinue or suspend the study at any time, at an individual 
site or overall, for safety or for administrative reasons. In the event of such action, the Sponsor 
will:  
 Promptly inform the impacted Investigators and institutions, the regulatory 
authorities, and the Institutional Review Board (IRB) of the action and the reason(s) 
for the action. 
 Arrange for all study documentation to be archived at the site (Section 11.9) or 
returned to the Sponsor, as appropriate; and for any remaining study medication to be 
properly disposed of (Section 8.7.1).  
6.10. 
Discussion of Study Design and Treatment Regimens 
This protocol represents the first clinical trial of IMO-8400 in patients with DLBCL. 


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6.10.1. 
Rationale for Study Design 
The open-label study design is consistent with both the study objectives and current principles 
for the evaluation of investigational drugs in patients with advanced malignancy.  
The dose escalation design with enrollment guided by safety experience and reviewed by a 
CRC are standard for a Phase 1 study and serve to minimize the number of patients required and 
to assure patient safety is protected. 
The Phase 2 portion of the study is designed to test whether the clinical activity of IMO-8400 is 
greater than a null response rate of 10% (see Section 12.1 for sample size analysis). It is designed 
with an interim analysis for futility. Results from this study will guide further development of 
IMO-8400 in oncology/hematology. 
6.10.2. 
Rationale for Treatment Regimens in Current Protocol 
6.10.2.1. Dosing Regimen 
Starting dose/Safety. Following the completion of Study 8400-001 performed in healthy 
volunteers, Study 8400-201 was conducted in patients with moderate to severe plaque psoriasis. 
A total of 46 patients were enrolled in the study and treatment with IMO-8400 was administered 
SC weekly for 12 weeks. Thirty five patients were treated with IMO-8400 at dose levels 0.075, 
0.15, 0.3, or 0.6 mg/kg/week, and eleven patients were randomized to placebo (saline). 
IMO-8400 was safe and well-tolerated in doses up to 0.6 mg/kg/week in patients with psoriasis. 
A concurrent Phase 1/2 study of IMO-8400 is ongoing in patients with relapsed/refractory 
WM (Study 8400-401). This is an open-label, multiple-dose, dose escalation study and is 
evaluating the safety, tolerability, and preliminary clinical activity of IMO-8400. As of the most 
recent interim analysis from September 2015, 19 patients have been enrolled at dose levels up to 
1.2 mg/kg given twice weekly. The most frequently noted AEs (>10%) were fatigue, injection 
site erythema, headache, injection site pain, nausea, and pain in extremity, all of which were 
low-grade. Grade 3 AEs were limited to neutropenia (two patients), anemia (2), and arthritis (1). 
No Grade 4 AEs were reported. A single episode of DLT (arthritis flare) was reported in one of 
eight patients enrolled in the 1.2 mg/kg/twice weekly cohort. Dose escalation is ongoing as the 
MTD has not been reached [7].  
Dose regimen. The initial clinical indications for development of IMO-8400 were autoimmune 
diseases, where TLR antagonism serves to modulate the immune system and decrease 
inappropriate immune activation. In this context, once weekly dosing was assessed as 
appropriate and sufficient.  
In B-cell malignancies, cell responses, proliferation, and survival are abnormal. In vitro studies 
with cell lines bearing the MYD88 L265P indicate pathologic activation of TLR signaling 
pathways, with apparent overreaction to TLR ligands. The application of TLR antagonism in this 
context is expected to require more sustained receptor blockade than physiologic 
immunomodulation. Therefore, in this initial trial of DLBCL, a life-threatening, aggressive 
malignancy, more intensive dosing is considered appropriate.  
As noted the starting regimen (0.3 mg/kg twice weekly) represents simple dose fractionation of 
the total weekly exposure that has been observed to be well-tolerated in healthy volunteers and in 


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patients with psoriasis (0.6 mg/kg once weekly). Dose escalation will proceed based on review of 
safety experience with dose fractionation at this level. 
Dose Escalation. Sequential dose escalation is consistent with current practices and is supported 
by dose response in the dose escalation Study 8400-401 that is ongoing in patients with WM.  
Study Population. Patients with non-GCB subtype DLBCL have a poor prognosis following 
relapse with presence of the MYD88 L265 mutation being an independent predictor of poor 
outcome [9]. IMO-8400 has been shown to be effective in pre-clinical lymphoma models that 
carry this mutation [5]. Preliminary evidence for clinical activity has also been established in a 
related B-cell malignancy (WM) in patients both with and without MYD88 L265 mutations [7]. 


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7. 
SELECTION OF PATIENTS 
7.1. 
Source of Patients and Recruitment Methods 
Following receipt of IRB approval, the Investigator may initiate patient recruitment (Section 13). 
To reach an economically and socially diverse population, the study may be announced in 
newspapers and on relevant Internet websites; prior to use, the form and content of such 
announcements will be submitted to the IRB for approval (Section 13). 
7.2. 
Presence of MYD88 L265P Mutation 
Detection of the MYD88 L265P mutation in the patient’s tumor is based on analysis either by an 
assay performed at a central laboratory approved by the Sponsor or from a prior result using a 
Clinical Laboratory Improvement Amendments (CLIA)-compliant assay (Section 9.3). 
Additional immunophenotype, genotype, and gene expression data that has been determined by 
the site will be collected and may be used to justify inclusion (Section 1.5.2).  
7.3. 
Patient Restrictions during the Conduct of the Study  
In the interest of their safety and to facilitate assessment of both safety and treatment effect, the 
patients participating in this study will be requested to agree to the following restrictions during 
the study:  
 Not start any new prescription medications, except as prescribed or approved by their 
Investigator or if required in an emergency. 
 Not take any over-the-counter medications, herbal medications, or experimental 
medicines except as instructed or approved by their Investigator.  


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8. 
STUDY TREATMENT  
8.1. 
Study Treatments to be Administered 
All patients will receive the investigational study drug, IMO-8400, at the weekly exposure level 
designated for the cohort in which they are enrolled. Instructions for dose preparation are 
provided in the Pharmacy Manual. Weekly exposure levels are calculated as mg/kg based on 
body weight at Screening. The dose is to be recalculated if change in body weight from 
Screening exceeds 10% (±). Dose volume per injection site should not exceed 1.2 mL/site, with 
multiple sites used per dose as necessary.  
8.2. 
Description and Manufacture of Study Drug 
All manufacture, packaging and labeling operations will be performed according to Good 
Manufacturing Practice (GMP) and Good Clinical Practice (GCP) guidelines, as well as 
US regulations.  
Table 9: 
Physical and Chemical Properties of Active Ingredient (Drug Substance) 
Name 
IMO-8400  
Drug Class 
Oligonucleotide antagonist of Toll-like receptors (TLRs) 7, 8 and 9 
INN 
NA 
Molecular Formula 
C179H216N52Na17O101P17S17 (sodium salt) 
Molecular Weight 
6174 (sodium salt) 
Appearance 
Hygroscopic white to off-white amorphous solid obtained by lyophilization 
Solubility 
Freely soluble in aqueous media 
Melting Point 
Amorphous powder, decomposes without a defined melting point. 
Table 10: 
Formulation of IMO-8400 for Injection (Drug Product) 
Name 
IMO-8400 for Injection, 150 mg 
Active Ingredient 
IMO-8400 
Excipients 
Each vial contains nitrogen (National Formulary). 
How Supplied 
Sterile, lyophilized powder for reconstitution packaged in a clear, round 5-mL glass vial with a 
rubber stopper and aluminum overseal. Each vial contains 150 mg (as labeled) IMO-8400 free acid, 
corrected for moisture and impurities. 
Storage 
The sealed vials of formulated drug product should be stored at 2-8°C. 
Preparation and 
Handling 
For dose levels of 0.6 mg/kg per injection or lower, vials are reconstituted using Sterile Saline for 
Injection, United States Pharmacopeia (USP); for higher dose levels, using Sterile Water for 
Injection, USP (to be provided by study site). Formulations used for dose levels of 2.4 mg/kg or 
higher will be prepared with 200 mg/mL active drug concentration. Detailed dose preparation 
instructions and flow sheets will be provided in the Pharmacy Manual.  
Administration 
The dose is administered as SC injection(s), not to exceed 1.2 mL/site, with multiple sites used per 
dose as necessary, using a fresh sterile needle (approximately 26 g); see Section 8.4 regarding the site 
of injection. 


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8.3. 
Reconstitution of IMO-8400 for Injection 
IMO-8400 is provided as 150 mg of lyophilized powder in a 5-mL vial, to be reconstituted into 
solution for injection prior to use. The active drug concentration for all dose levels of 
2.4 mg/kg/dose and higher will be 200 mg/mL. Detailed dose preparation instructions and flow 
sheets are provided in the Pharmacy Manual. 
8.4. 
Administration of Study Treatments 
Each dose of IMO-8400 will be administered as SC injection(s), not to exceed 1.2 mL/site, with 
multiple sites used per dose as necessary. For example, a 300 mg dose would be administered as 
two separate injections of 0.75 mL. The injection sites should be selected based on the following:  
 There are six potential areas for injection: the four quadrants of the abdomen (upper 
and lower on the left and right) and the thigh of each leg. 
 Injection site(s) should be rotated; that is, assuming all injection areas are suitable, 
each area would be used once every six dose injections.  
If, because of injury or other issue, an injection site area will be used more frequently than once 
every 2 weeks, the Investigator should discuss the situation with the Medical Monitor. 
8.4.1. 
Pre-Treatment Criteria 
IMO-8400 should not be administered until the following conditions are met: 
 Hemoglobin ≥7.5 g/dL 
 ANC ≥1,000/µL 
 Platelets ≥50,000/µL 
 All other laboratory abnormalities to baseline or grade ≤1 
8.4.2. 
Variances in Dose Administration Schedule 
Dosing should ideally be performed on the same day each week; however, allowances of up to 
48 hours (±) will be made for unavoidable scheduling conflicts.  
If, for any reason (e.g., scheduling or toxicity), dosing is interrupted more than five calendar days 
beyond expected, then the next dose should be administered as soon as feasible and the schedule 
reset. 
If, for any reason, dosing is interrupted more than 21 calendar days, the patient should be 
discontinued from study treatment and should complete EOT and EOS visits.  
8.5. 
Prior and Concomitant Medications 
Prior treatments for DLBCL will be recorded in the eCRF as well as treatments for any 
significant illness in the past year.  
Any concomitant medication used from time of Screening through last study visit will be 
recorded in the eCRF, including dose, dosage regimen, and indication (reason for its 
prescription).  


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8.5.1. 
Prohibited Treatments 
The exclusion criteria specify treatments prohibited at the time of study entry (Section 1.5.3). 
While patients are receiving study treatment, other treatments for DLBCL are prohibited. 
Patients who discontinue treatment prematurely and have completed the EOT visit, may receive 
available or investigational treatment for their disease at any time based on the judgment of their 
physician. If such treatment is initiated prior to the EOS visit (scheduled for 30 to 35 days after 
last dose of study drug), this will be recorded in concomitant medications and considered in 
assessment of any new AEs.  
8.6. 
Treatment Compliance  
All doses of study drug will be administered by trained personnel. Injections of study drug may 
be administered in one of two contexts:  
 Study site – defined as the site designated by the participating Investigator. On study 
days when a physical examination or laboratory safety test is scheduled it is expected 
that study drug will be administered at the study site.  
 Non-study site administration by a visiting nurse – With the agreement of the patient 
and the Investigator, doses not administered at the study site may be administered by 
a visiting nurse who has been trained in the protocol and approved by the Sponsor.  
The Sponsor will arrange for a Central Pharmacy to prepare and dispense the patient’s study 
treatment, which will be packaged as required and shipped to the patient by overnight delivery 
service. To protect the integrity of the treatment, patients will be instructed to hold the shipping 
container unopened in a cool, dry, protected place.  
 The visiting nurse will open the container, inspect the materials, confirm they are 
correct, and proceed with pre-dose procedures, study drug administration, and 
post-dose procedures.  
The used syringe and packaging materials will be disposed of per policy of the Central 
Pharmacy.  
The visiting nurse will maintain appropriate source documents; the events will be entered into 
the Electronic Data Capture (EDC) system and copies of the source documents provided to the 
site.  
8.7. 
Accountability of Investigational Drug Supplies 
Study drug will be provided by the Sponsor. The Investigator at each study site and a designated 
pharmacist at the Central Pharmacy are responsible for the control of the study drug, and will 
identify trained and experienced personnel to handle it in accordance with the protocol and 
appropriate GCP and GMP principles. (Central Pharmacy will be responsible for study drug 
stored at Central Pharmacy and dispensed to patients for non-study site administration). This 
includes:  
 Storing the drug in a secure, controlled-access location. 


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 Storing the drug under the specified conditions, including daily monitoring and 
recording of storage temperature. 
 Maintaining records of the receipt of study drug and providing acknowledgement of 
receipt. 
 Dispensing and administering study drug only in accordance with the protocol, 
including proper labeling of individual doses prepared in syringes ready for use.  
 Maintaining drug accountability records indicating the disposition of study drug, 
including a Drug Dispensing Log containing the following information: 
 Identification of the patient to whom the study drug was dispensed. 
 Date(s) and quantity of the study drug dispensed to the patient.  
 Having all records and drug supplies available for inspection by the study monitor.  
Treatment administered to patients at non-study sites by a visiting nurse will be prepared by a 
Central Pharmacy from supply provided by the Sponsor. The Central Pharmacy is also required 
to comply with the specifications above. 
8.7.1. 
Disposition of Study Drug 
At any time during or after completion of the study, the site must obtain written authorization 
from the Sponsor regarding the final disposition of any remaining study drug; that disposition 
must be appropriately documented. Typical procedures for handling any remaining study drug 
include the following: 
 Returning study drug to the Sponsor.  
 Destroying study drug at the study site according to the site’s institutional standard 
operating procedure. 


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9. 
STUDY EVENTS AND EVALUATIONS 
9.1. 
Schedule of Events 
The schedules for all study evaluations are detailed in Table 4. An estimate of blood volumes 
required is shown in Table 5.  
The schedule is presented relative to the day and time of dosing. All days are relative to the 
calendar day of the first treatment of study drug, designated Cycle 1, Day 1. All times are 
relative to treatment, designated 0 hour. “Pre-dose” vital signs are to occur within 1 hour prior to 
treatment; all other pre-dose procedures are to occur prior to treatment on the same calendar day. 
9.2. 
Screening, including Sequence of Procedures 
Pre-screening for the MYD88 L265P mutation may be performed as detailed in Section 1.5.1. 
Protocol screening may be initiated up to 21 days prior to dosing. Written informed consent will 
be obtained before any study-specific procedures are performed and will be recorded in source 
documentation. The site will maintain a Patient Identification Log indicating all consented 
patients. Patients being considered for Phase 2 (Dose Expansion) should not undergo any 
additional screening work-up unless the MYD88 L265P mutation has already been documented 
(local or central lab; Section 1.5.1).  
9.3. 
Determination of Presence or Absence of MYD88 L265P Mutation in 
DLBCL 
Prior to enrolling a patient into the study, the patient’s tumor is to be tested for the 
MYD88 L265P mutation using a CLIA-compliant assay performed at any point during the 
course of the patient’s disease. If this has not been done, tumor may be sent to the Sponsor’s 
designated central laboratory to perform testing for the presence of the mutation. If this analysis 
had been previously performed using a CLIA-compliant assay, all attempts should be made to 
procure either the original tumor tissue (previously collected at the time of diagnosis or at any 
point during the course of the patient’s disease) or a fresh biopsy, if tissue is readily available 
(e.g., a superficial lymph node), to repeat/confirm the mutation testing at the Sponsor’s 
designated central laboratory and to perform other investigational studies (Section 9.10). The 
sample will comprise formalin-fixed, paraffin-embedded (FFPE) tissue that is known to have a 
meaningful proportion of representative tumor cells and is submitted either as a cell block or as 
unstained sections. The latter should include the following:  
 At least two unstained, mounted sections, 3 to 4 µm thick (to be processed for routine 
histology). 
 Unmounted sections (“curls” or “slices”) totaling 20 µm thick (e.g., five curls each 
4 µm thick or two curls each 10 µm thick). The curls will be placed in a labeled 
microfuge tube for transport. 
The sample will be analyzed using an assay from Abbott Molecular in development as a 
potential companion diagnostic, and the results reported as either “MYD88 L265P mutation 
detected” or “L265P mutation not detected”. Samples may be retained for up to 1 year after the 


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end of the study (i.e., last patient, last visit) to support possible future development of a 
companion diagnostic assay. 
9.4. 
Enrollment Procedure 
The following procedure is to assure that patients enrolled across multiple sites are assigned to 
the appropriate cohort and receive the appropriate dose level. Patients who have completed all 
screening procedures will have eligibility data entered into the study EDC (electronic data 
capture) system, including the Investigators assessment of the patient’s eligibility. The Sponsor 
or Sponsor’s designated representative will review the data; the patient’s assigned dose level will 
then be provided in writing (by email and/or fax) to both the Investigator and the site pharmacy.  
9.5. 
Disease Evaluations 
Radiologic Imaging – Radiographic tumor evaluation by PET/computed tomography (CT) scan 
or CT scan of chest, abdomen, and pelvis will be performed within 21 days prior to first dose of 
study treatment. 
Repeat, radiologic assessments will be performed every 8 weeks while the patient is receiving 
active treatment with IMO-8400. Patients discontinued from treatment for reasons other than 
progressive disease will have radiologic tumor assessments performed every 12 weeks as a part 
of follow up (Section 6.5.6) until documentation of progressive disease, initiation of new 
anti-cancer therapy, or the end of the study, whichever comes first. The same radiographic 
assessments used at Screening should be used at all subsequent radiographic evaluations. Interim 
scans may be done at the request of the Investigator based on new clinical indications, signs or 
symptoms. Copies of the radiologic reports and images may be requested by the Sponsor for 
central review.  
Lymph node biopsy – Archival or fresh tumor tissue should be submitted to the central lab for 
confirmation of diagnosis and exploratory analyses (as described in Section 9.10). At least 
one post-treatment biopsy should also be performed in order to evaluate target engagement. 
These should be collected between 4 and 24 hours post-treatment and may be obtained at any 
time during study participation. Instructions for submitting biopsy sections are provided (see the 
Laboratory Manual for more details). 
9.6. 
Assessment of Response to Treatment  
Following enrollment, the patient’s disease status will be assessed every 8 weeks during study 
treatment, and at the EOT visit to permit evaluation of the response to treatment. In addition to 
routine clinical examination, these assessments will include PET\CT scanning or CT alone, and 
lymph node biopsy, as detailed in Section 9.5.  
Table 11 summarizes the criteria for response to treatment. The full text of the International 
Working Group classification [1] is provided in Section 16.2.  


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Table 11: 
Summary of Evaluation of Response to Treatment and Disease Status 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
Complete 
Response 
(CR) 
Disappearance 
of all evidence 
of disease 
No residual FDG-avid or 
PET-positive nodes;  
PET-negative mass of any size 
permitted  
Not palpable, nodules 
disappeared 
Infiltrate cleared on 
repeat biopsy;  
if indeterminate by 
morphology, IHC 
should be negative 
Partial 
Response 
(PR) 
Regression of 
measurable 
disease and 
no new sites 
>50% decrease in SPD of up to 6 
largest dominant masses;  
no increase in size of other nodes 
>50% decrease in SPD 
of nodules (for single 
nodule in greatest 
transverse diameter);  
no increase in size of 
liver or spleen 
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified 
Stable 
Disease 
(SD) 
Failure to attain 
CR/PR or 
progressive 
disease 
PET-positive at prior sites of disease 
and no new sites 
 
 
 
 
a) FDG-avid or PET positive prior to 
therapy; PET positive at prior sites of 
disease and no new sites on CT or 
PET 
 
 
 
 
b) Variably FDG-avid or PET 
negative; no change in size of 
previous lesions on CT 
 
 
Progressive 
Disease 
Any new lesion 
or increase by 
>50% of 
previously 
involved sites 
from nadir 
Appearance of a new lesion(s) 
>1.5 cm in any axis, or 
>50% increase in SPD of more than 
one node, or  
>50% increase in longest diameter of 
a previously identified node >1 cm in 
short axis 
> 50% increase from 
nadir in the SPD of any 
previous lesions 
New or recurrent 
involvement 
 
 
Lesions PET positive if FDG-avid 
lymphoma or PET positive prior to 
therapy 
 
 
FDG = [18F]fluorodeoxyglucose; PET = positron emission tomography; CT = computed tomography; 
IHC = immunohistochemistry; SPD = sum of the products of the diameters. 
See Section 16.2 for the complete, original table.  
9.7. 
General Clinical Assessments 
9.7.1. 
Medical History, including DLBCL 
Prior to enrollment, the Investigator will obtain a comprehensive medical history to ensure 
eligibility of the patients, including the following items:  
 A detailed review of the course of the patient’s malignancy, including clinically 
significant complications such as systemic infections, bleeding events, etc. 
 Prior treatments, including supportive therapy (agent, best clinical response, AEs 
related to treatment, and reason for discontinuation). 


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 Relevant current or past abnormalities or diseases (including surgical procedures) of 
the following systems: allergic (including drug sensitivity), cardiovascular, 
dermatologic, endocrine/metabolic, gastrointestinal, gynecologic, 
hematologic/lymphatic, hepatic/biliary, immunologic, infectious, musculoskeletal, 
neurologic/psychiatric, renal, and respiratory. 
Past history should include all significant illnesses that the patient has experienced during the 
12 months prior to obtaining informed consent, including illnesses that have resolved as well as 
those that are active. Illnesses active at the time of informed consent will be regarded as 
concomitant illnesses. After obtaining informed consent, concomitant illnesses that worsen or 
new illnesses that emerge will be documented as AEs (Section 10). 
9.7.2. 
Physical Examination and Body Weight 
Complete physical examinations will include examination of general appearance, skin, neck 
(including thyroid), eyes, nose, throat, heart, lungs, abdomen, lymph nodes, extremities, 
reproductive (in event of recent history, symptoms, or AEs related to reproductive system) and 
nervous system and measurement of body weight. Complete physical examination is required 
prior to enrollment and EOT and EOS. Directed physical examinations may be performed while 
on study treatment at the discretion of the Investigator. Exam of reproductive system, when 
needed, may be performed by the Investigator or delegated to a specialist. 
Height and weight will be evaluated prior to enrollment and the BMI will be calculated. 
Any clinically significant changes in physical exam identified after obtaining informed consent 
will be reported as AEs (Section 10). 
9.7.3. 
Vital Signs 
Vital signs include heart rate (HR), blood pressure (BP), respiratory rate (RR), and temperature. 
Vital signs will be performed once weekly for patients receiving once weekly dosing and twice 
weekly for patients receiving twice weekly dosing, immediately before each administration 
(within 1 hour of treatment) and post-dose (within 30 min [±5 min] of treatment). Vital signs 
should be after the patient has been sitting comfortably for 5 minutes with the BP cuff in place 
on the non-dominant arm. Blood pressure and HR measurements will be taken first and may be 
done manually or by automated recorder; RR will be determined by observation for at least 
30 seconds; temperature will be obtained using an electronic (rapid reading) device.  
Vital sign measurements will be assessed by the Investigator as either ‘normal’, ‘abnormal, not 
clinically significant’, or ‘abnormal, clinically significant’. Clinically significant abnormal vital 
sign measurements will be reported as an AE, and, if possible, should be repeated at clinically 
relevant intervals until resolved or stabilized.  
9.7.4. 
Electrocardiogram 
Standard 12-lead ECG will be obtained after the patient has been semi-recumbent for 
~10 minutes. The following ECG parameters will be recorded: ventricular rate, RR interval, 
PR interval, QRS interval, and QT interval; also QTc, if available, including method of 
calculation.  


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9.7.5. 
Injection Site Reaction Assessments 
Injection site reactions will be documented in detail for each individual injection as described in 
Table 12 and recorded in the injection site assessment form in the eCRF. 
The Investigator will assess the injection site as scheduled and perform the following:  
 Pain, tenderness, pruritus and induration: grade using the scale provided;  
 For induration, also record the actual maximal linear diameter as a continuous 
variable;  
 Erythema, record the actual maximal linear diameter as a continuous variable;  
 Blisters, ulceration, necrosis: indicate presence or absence and record the maximal 
linear diameter, if applicable.  
Table 12: 
IMO-8400 Subcutaneous Injection Site Grading (Local Reactions) 
Finding 
Mild 
Moderate 
Severe 
Pain 
Present; no limitations in 
ADL 
Limitations in age-appropriate 
instrumental ADL  
or requires repeated non-narcotic 
pain reliever 
Limitations in self-care ADL 
or interferes with sleep,  
or requires repeated narcotic 
pain reliever 
Tenderness 
Mild discomfort with 
pressure 
Discomfort with touch 
Discomfort elicited by clothing 
or bedsheets 
Pruritus 
(itch) 
Present, but minimally 
distracting 
Present, distracting during routine 
activities 
Interferes with sleep 
Induration  
(swelling, edema) 
Present; no limitations in 
ADL 
Limitations in age-appropriate 
instrumental ADL  
or requires repeated treatment 
(excluding systemic steroids). 
Limitations in self-care ADL 
or requires treatment with 
systemic steroids 
Pain: discomfort or unpleasant feeling (e.g., headache) experienced while at rest or with activity; in addition to location, the 
patient’s description may include intensity as well a distinctive quality (e.g., burning, stabbing).  
Tenderness: discomfort elicited when the area is touched either intentionally or accidently.  
Pruritus (itch): an unpleasant sensation that evokes the desire or reflex to scratch. (In contrast, pain and tenderness evoke a reflex 
to withdraw.) 
Activities of daily living (ADL) are classified into two subsets:  
– instrumental ADL, e.g., preparing meals, shopping for groceries or clothes, using the telephone, managing money;  
– self-care ADL, e.g., bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not being 
bedridden. 
Injection site reactions may also be captured on the AE form. When reporting injection site 
reactions as an AE, the Investigator should report in the verbatim term the words “injection site 
reaction,” along with the specific reaction symptom (such as erythema), and select the severity 
grade based on the National Cancer Institute-Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) guidelines which are presented in Table 13. 


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Table 13: 
Intensity of AE of Injection Site Reactiona 
Mild 
Moderate 
Severe 
Life-threatening 
Tenderness with or without 
associated symptoms  
(e.g., warmth, erythema, itching) 
Pain;  
lipodystrophy;  
edema;  
phlebitis 
Ulceration or necrosis; 
severe tissue damage; 
operative intervention indicated 
Life-threatening 
consequences;  
urgent intervention 
indicated 
a. Based on NCI-CTCAE v.4.03. Definition of Injection Site Reaction: A disorder characterized by an intense adverse reaction 
(usually immunologic) developing at the site of an injection. 
9.8. 
Safety Laboratory Studies 
Safety laboratory tests (with the exception of serum complement testing) indicated below will be 
performed by a local laboratory. Serum complement procedures for collecting, processing, and 
transporting the required blood sample will be detailed in the laboratory manual.  
The Investigator may order additional local laboratory tests consistent with their routine standard 
of care.  
9.8.1. 
Safety Laboratory Tests  
Hematology Panel  
*Hemoglobin  
*Hematocrit  
*Red blood cell count (RBC) 
*White blood cell (WBC) count  
*Platelet count  
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin 
concentration (MCHC) 
Mean corpuscular volume (MCV) 
*WBC differential (absolute cell counts): 
- Neutrophils  
- Lymphocytes  
- Monocytes  
- Eosinophils  
- Basophils  
Clinical Chemistry Panel 
*Glucose  
*Urea  
*Creatinine 
*Sodium 
*Potassium 
*Chloride 
*Bicarbonate  
Calcium  
Magnesium 
Phosphate  
Uric Acid 
Cholesterol  
Triglycerides 
LDL  
HDL 
CRP 
*Alanine aminotransferase (ALT) 
*Aspartate aminotransferase (AST) 
*Alkaline phosphatase (AP) 
*Total bilirubin  
Total protein  
Albumin  
Lactate dehydrogenase (LDH) 
Creatine phosphokinase (CK) 
β-2-microglobulin 
* Laboratory tests comprising the focused panel to be performed during Cycles 1-6 on Day 15 of each Cycle. Hematology and 
Chemistry full panels will be performed on Day 1 of each Cycle. For Cycle 7 and subsequent cycles, testing will not repeated 
on Day 15 unless more frequent monitoring is clinically indicated. 
Serum Complement Testing 
Complement component 3 (C3) 
Complement component 4 (C4) 
50% hemolytic complement (CH50) 


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Coagulation Panel 
Prothrombin Time (PT) 
Activated partial thromboplastin time (aPTT) 
International normalized ratio (INR) 
Fibrinogen 
Urinalysis 
Specific gravity, pH, ketones, glucose, protein, blood (commercial dipstick may be used);  
microscopic examination, including quantitation of WBCs and RBCs. 
Serologic tests (Screening only) 
Hepatitis B surface antigen (HBsAg) 
Antibody to HIV-1 and HIV-2 
Antibody to hepatitis C virus (HCV) 
Pregnancy tests (females only) 
beta-human chorionic gonadotropin (β-hCG) 
Females of child-bearing potential (defined in Section 1.5.2) must have a negative pregnancy test within 21 days of the first 
dose of study drug (Cycle 1, Day 1).  
9.8.2. 
Reporting of Safety Laboratory Tests 
Procedures for the Investigator assessment of the results are detailed in Section 10.2. Procedures 
for the analysis of laboratory data are described in Section 10.4.5.  
9.8.3. 
Repeating Abnormal Laboratory Tests 
Laboratory tests showing abnormal or exclusionary values prior to enrollment may be repeated 
no more than once, except non-negative screening serology results will be exclusionary and will 
not be repeated. After dosing, abnormal laboratory tests assessed as “clinically significant” 
values may be repeated as often as deemed clinically necessary by the Investigator until the test 
values are clinically acceptable or until an explanation other than drug effect is given.  
9.9. 
Pharmacokinetic Assessments 
Blood samples for plasma levels of IMO-8400 will be collected as scheduled (Table 4). Samples 
will be analyzed for IMO-8400 concentration using a validated bioanalytical method. For each 
cohort, the plasma IMO-8400 concentration data will be analyzed by non-compartmental PK 
analysis. The following parameters will be determined as appropriate: observed maximum 
plasma concentration (Cmax), time of Cmax (Tmax), and AUC from 0 to last measurable plasma 
concentration (AUC0-t).  Pharmacokinetic parameters will be compared across IMO-8400 dose 
levels. Descriptive statistics will be provided for all PK parameter values by dose and time, as 
appropriate. 
9.10. 
Pharmacodynamic and Investigational Studies 
The central laboratory will distribute samples to the specialty laboratories that will perform the 
following studies on the tumor sample and on serum and plasma samples collected as scheduled 
to assess the pharmacologic effects of the investigational agent; to maximize consistency, tests 
may be batched. The clinical significance of these tests is unknown at this time and therefore the 
results will not be assessed by the Investigator.  


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Tumor cells (from archival or fresh sample of tumor or from the bone marrow biopsy) may be 
assayed for:  
 Presence of somatic mutations in other genes encoding proteins in the TLR and 
BCR signaling pathways (e.g., CARD11, IRAK4, Btk).  
Pre-dose serum samples will be assayed for:  
 Levels of cytokines such as IL-6, IL-12, IL-17, IP-10; additional or alternative 
cytokines may be assessed using the samples collected. 
 Antibodies to IMO-8400.  
Plasma samples will be assayed for MYD88 L265P mutation and may be assayed for additional 
mutations.  
Bone marrow biopsy – Bone marrow aspirate and/or biopsy is not required for disease 
assessment and is an optional procedure; however, any available specimens may be submitted for 
exploratory analyses whenever marrow is obtained. Instructions for submitting to the central 
laboratory are provided (see the Laboratory Manual for more details). 


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10. 
SAFETY ASSESSMENTS 
10.1. 
Definition of AEs 
10.1.1. 
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.  
An AE in a clinical trial may be any of the following:  
 Unfavorable and unintended symptom reported by the patient — patients will be 
encouraged to report treatment-emergent AEs spontaneously; general, non-directed 
questioning may also be used to elicit reports of AEs.  
 Clinical sign detected by the Investigator — observations by other study personnel 
will be reported to the Investigator for evaluation.  
 Abnormal result from a laboratory study or other diagnostic procedure that meets at 
least one of the following criteria:  
– Results in termination of study drug. 
– Leads to treatment.  
– Leads to further diagnostic tests (other than a single repeat for confirmation). 
– Is assessed as “clinically significant” by the Investigator (Section 10.2).  
10.1.2. 
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.  
                                                 
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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 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.  
10.1.3. 
Suspected, Unexpected Serious Adverse Reaction  
A suspected, unexpected serious adverse reaction (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 (Section 10.4.3). 
 Unexpected — compared to the study drug-related AEs described in the IB, the event 
meets any of the following criteria: 
– The event was not previously described. 
– The event is now characterized as more severe (Section 10.4.4). 
– 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.  
10.2. 
Investigator Assessment of Safety Laboratory Tests 
The Investigator will review the results of all Safety Laboratory tests (Section 9.8.2) and 
designate any results outside of the reference range as either of the following:  
 Abnormal, not clinically significant (NCS). 
 Abnormal, clinically significant (CS). 
In making this judgment, the Investigator will consider all available information, including the 
patient’s clinical condition, all available laboratory results (central and local), and the potential 
for false positive test results. In addition, laboratory studies that result in the actions specified in 
Section 10.1.1 will be classified as CS.  
Any result assessed as CS will be recorded as an AE unless it is consistent with one or more of 
the following:  
 Process noted in the medical history. 
 Ongoing AE already recorded. 
 Expected course of the primary disease under study.  


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10.3. 
Recording Adverse Events 
Procedures for the collection and recording of AEs are as follows:  
 From obtaining informed consent through EOS, there will be active surveillance to 
identify all AEs. Events will be recorded in the AE portion of the EDC, with 
particular attention to whether the onset of the event was before or after the 
administration of the first dose of study drug. All recorded events will be included in 
applicable line listings, but only events with onset after administration of the first 
dose will be included in summaries of TEAEs (Section 12.3). 
 After the EOS, surveillance will be passive (only events brought to the Investigator’s 
attention will be considered) and only events assessed as SUSARs will be recorded 
(Section 10.1.3). 
 In accordance with 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.  
10.4. 
Characterizing Adverse Events 
For each AE recorded the following characteristics will be noted.  
10.4.1. 
Description of Event  
The diagnosis or description will be as specific and complete as possible (i.e., “lower extremity 
edema”, rather than just “edema”). Whenever possible, signs and symptoms due to a common 
etiology will be reported as an integrated diagnosis; for example, cough, runny nose, sneezing, 
sore throat and head congestion would be reported as “upper respiratory infection”.  
10.4.2. 
Date and Time of Onset  
The date and time at which the event was first apparent. Table 14 summarizes the basis for 
reporting the date and time of onset for the different types of AEs.  
Table 14: 
Reporting the Date and Time of Onset of AE for Different Types of Events  
Type of Event 
Examples 
Source of Date and Time of Onset 
Symptom 
Headache, feverish, paresthesiae  
When first experienced by the patient 
Sign (Finding) 
Elevated BP, enlarged liver on physical 
exam 
When first observed by the Investigator or other study 
staff 
Laboratory / 
diagnostic result 
Neutropenia, hyperglycemia,  
lesions on brain scan 
When lab sample was obtained or diagnostic study 
performed 
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 2 days before being seen by a physician who makes a 
diagnosis of herpes zoster based on appearance and laboratory confirmation. In that case, there is 


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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.  
10.4.3. 
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 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.  
10.4.4. 
Intensity (Severity) 
The intensity (synonym: 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 15 
[30]. 


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Table 15: 
Estimating Severity Grade 
Mild 
Transient or mild discomfort (< 48 hours); no medical intervention/therapy required. 
Moderate 
Mild to moderate limitation in activity; some assistance may be needed; no or minimal 
medical intervention/therapy required. 
Severe 
Marked limitation in activity; some assistance usually required; medical 
intervention/therapy required; hospitalizations possible. 
Life-threatening 
Extreme limitation in activity; significant assistance required; significant medical 
intervention/therapy required; hospitalization or hospice. 
10.4.5. 
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 (Section 6.3.1). 
 Reported as AEs when assessed as “clinically significant” using the procedures and 
criteria detailed in Section 10.2.  
10.4.6. 
Management of Study Drug upon Occurrence of an AE 
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 (withdrawn) — study drug was stopped permanently due to the AE. 
 Dosing Interrupted — study drug regimen was modified by being temporarily halted, 
i.e., one 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 medication.  
For patients whose treatment is paused and then resumed at a lower dose level as detailed in 
Section 6.5.2, the management of study drug will be recorded as “Dose Decreased”.  
10.4.7. 
Actions Taken for Management of AE 
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 
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 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 
SC access site).  
 No action — no actions were ordered for management of the AE.  
10.4.8. 
Follow up and Outcome of AEs 
If possible, AEs will be followed until resolved (synonyms: recovered, recuperated, ended) either 
with or without sequelae, including for patients who prematurely discontinue treatment. For AEs 
that are assessed as not drug-related and are not resolved at the EOS visit, follow up may be 
limited with the approval of the Medical Monitor.  
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. 
10.4.9. 
Date and Time of Outcome  
For each class of outcome as defined above, Table 16 indicates the date and time to be recorded. 
As discussed in detail for date / time of onset (Section 10.4.2), determining the date/ time an 
event resolved (ended) should reflect the type of event and the source of the information.  
Table 16: 
Date and Time of Outcome for AE by Outcome Class  
Outcome assigned to AE 
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) 


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10.5. 
Reporting Adverse Events 
10.5.1. 
Where to Report SAEs  
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 service is provided in Table 1 and Table 2.  
In the event an SAE cannot be submitted via EDC, contact information is provided in Table 1 for 
alternative submission methods. 
10.5.2. 
Procedures for Reporting SAEs 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).  
 Date of the first treatment with study drug.  
 Date of the last treatment with study drug prior the event.  
 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.  
 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.  
Thereafter, supplemental (follow up) reports will be submitted via the EDC system as any 
additional information (e.g., more definitive outcome regarding events previously reported as 
ongoing or unknown outcome) becomes available to the Investigator (either directly or as a result 
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10.5.3. 
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).  
 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). 
10.5.4. 
Requirements for Expedited and Periodic Reporting of AEs  
Suspected unexpected serious adverse reactions are required to be reported rapidly to regulatory 
authorities and to IRBs (typically within 7 days for fatal or life-threatening SUSARs; within 
14 days for all other SUSARs). The Sponsor and the Investigator will work together to meet 
these reporting requirements.  
10.5.5. 
Notification of SUSARs to the Investigator by the Sponsor  
In accordance with regulatory requirements, the Sponsor will notify the Investigator of the 
occurrence of SUSARs reported by other Investigators in this or in other studies involving the 
study drug. The Investigator will promptly inform his/her IRB of such communications from the 
Sponsor and will document that notification in the Investigator’s Regulatory Binder.  


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11. 
DATA QUALITY ASSURANCE 
11.1. 
Compliance 
The Sponsor and the Investigator will conduct the study in accordance with:  
 The protocol — as approved by applicable regulatory authorities. 
 Ethical standards and procedures — as detailed in Section 13. 
 “Good Clinical Practices” and “Good Manufacturing Practices” — as detailed in 
documents issued by the International Council for Harmonisation (ICH). 
 Applicable national regulations — e.g., in the US, 21 CFR.  
11.2. 
Training and Qualifications of Site Personnel  
All site personnel involved in the study will be trained regarding the protocol and the study drug. 
This includes, but is not limited to, pharmacy, nursing and medical personnel involved in 
handling and administering the study drug, monitoring the patients and collecting clinical data.  
The Sponsor (or designee) will provide formal training sessions either off-site (e.g., Investigators 
Meeting) or on-site (e.g., site initiation visit). Topics covered will include, but not be limited to, 
background of the investigational drug, the protocol, study events, study procedures, data 
collection and recording, expedited and routine reporting of AEs, and regulatory requirements. It 
is the responsibility of the Investigator to document that all participating study personnel have 
received adequate training.  
11.3. 
Source Documents  
Source documents are the originals of any documents used by the Investigator, hospital, or 
institution that verify the existence of the patient and substantiate the integrity of the data 
collected during the trial.  
11.3.1. 
Medical Records 
Medical records related to the patient’s routine clinical care, including prior to or during the 
study:  
 Information obtained from the patient’s personal physicians or other third parties 
regarding the patient’s medical history or prior physical condition. 
 Reports of imaging studies, hospitalizations, surgical procedures.  
 Laboratory reports, including clinical pathology and diagnostic histologic pathology.  
 Medication prescription and administration records.  
 Data and reports from automated instruments (e.g., ECGs, cardiac monitors, vital 
signs).  
 Medical records relating to scheduled and unscheduled clinical visits. 


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It is expected that Investigator’s clinical practice will include medical records that meet current 
best practices for readability and documentation. Electronic health record (EHR) systems should 
meet current regulatory requirements for “protected health information” (PHI), including, at a 
minimum, security requirements for electronic signature and audit trails for changes.  
11.3.2. 
 Study-Specific Source Documents 
Study-specific source documents include, but are not limited to, the following: 
 The Informed Consent Form (ICF), signed and dated by the patient. 
 The site patient identification log.  
 Any reports noted above that are scheduled as part of the protocol and have been 
annotated to indicate the significance of any abnormal findings (Section 10.4.5). 
 Concomitant medication prescription and administration records;  
 Records relating to scheduled and unscheduled study visits, including, but not limited 
to, results of examinations, observations relating to AEs, and concomitant 
medications.  
Study-specific source documents must meet the following requirements:  
 Be prepared at the time of the events or activities described (i.e., contemporaneously). 
 Indicate both the date and time recorded. 
 Identify the source of all recorded information (e.g., the patient, direct observations of 
the recorder, lab reports, external / historical sources).  
 Have text that is readable, unambiguous, and applies best medical record practices 
(e.g., minimal use of abbreviations; proper numerical, dose, and posology formats).  
 Have all entries signed and dated by the recorder.  
Study-specific paper documents must meet the following additional requirements: 
 Be written legibly in dark ink (preferably black), including signature and date.  
 In the event that any entry needs to be changed, a single line will be made through the 
original entry, the correct information added next to it, and the action initialed, dated, 
and explained (if appropriate). The original entry must not be obscured or obliterated 
by multiple cross-out, correction fluid or overlay of other material.  
Study-specific source document forms created by the site must be reviewed by the Sponsor prior 
to use. 
11.4. 
Electronic Case Report Forms 
The Sponsor will provide a regulatory-compliant EDC system for reporting study data to a 
central facility holding the trial database. All study personnel will be trained on the system and 
each will have a unique login password and electronic signature.  


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The Investigator (or qualified sub-Investigator approved by the Sponsor) will review all eCRFs 
and indicate their concurrence by (electronic) signature.  
11.5. 
Protocol Deviations 
A protocol deviation is defined as an event in which the Investigator or site personnel did not 
conduct the study according to the Protocol, including compliance requirements and agreements. 
Guidelines for minor procedural variations (e.g., collection time of blood samples) will be agreed 
to and documented by the Investigator and the Sponsor prior to starting the study. Events 
conforming to those guidelines will not be considered deviations.  
For protocol deviations relating to individual patients, the event and relevant circumstances will 
be recorded on source documents and on the appropriate eCRF; reported to the Sponsor in a 
timely manner; and presented in the Clinical Study Report (CSR).  
Deviations that are not patient-specific (e.g., unauthorized use of an investigational agent outside 
the protocol, either human administration or laboratory use) will be reported to the Sponsor in 
writing and copies placed in the Trial Master File (TMF).  
Deviations that can be anticipated should, if possible, be discussed with the Sponsor before being 
implemented. 
11.6. 
External Review of the Study Conduct at Participating Sites 
All study-related materials at the site are subject to external review to ensure the safety of the 
patients, the integrity of the study data, and compliance with all applicable regulatory and 
oversight requirements. 
There are several different classes of review: 
 Monitoring — review by the Sponsor or authorized representatives, typically from the 
clinical research organization (CRO) coordinating the clinical conduct of the trial. As 
detailed below, visits may be conducted before, during, and after the conduct of the 
study. 
 Audits — systematic, independent review by the quality assurance department of the 
Sponsor or authorized representatives, potentially from an organization not involved 
in the clinical conduct of the study. 
 Regulatory review — performed by representatives of regulatory authorities with 
responsibility for oversight of the trial or approval of the investigational agent. These 
authorities may be from the country where the site is located or from another country.  
Monitoring and auditing visits on behalf of the Sponsor will be scheduled with the Investigator 
in advance and will be conducted at a reasonable time. To facilitate these visits, the Investigator 
will assure that the following are available: 
 Appropriate space, facilities and access to all source documents (including access to 
computerized records either electronically or as complete print outs).  
 Consent forms, eCRFs, SAE forms, and medical records for all screened and enrolled 
patients.  


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 Timely access to site personnel, including the Investigator, sub-Investigator(s), and 
other study personnel on the day of the visit to resolve any questions that arise. 
Regulatory authorities may visit and review the site and/or Investigator during or after the study 
and may or may not notify the Investigator or the Sponsor in advance. The Investigator will fully 
cooperate with regulatory audits conducted at a reasonable time in a reasonable manner. The 
Investigator will notify the Sponsor immediately of any contact by or communication from 
regulatory authorities regarding the study.  
11.7. 
Study Monitoring Visits 
11.7.1. 
Site Qualification and Initiation Visits 
Before an investigational site can enter a patient into the study, a representative of Idera 
Pharmaceuticals, Inc. will visit the site to perform the following: 
 Inspect the facilities (e.g., clinical and administrative areas, pharmacy, laboratory).  
 Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, as well as the responsibilities of Idera and its representatives.  
 Review the site TMF, including documentation related to the protocol, the 
Investigator, and other study site personnel; correspondence to and from the IRB, the 
Sponsor, and their representatives.  
 Review the standard operating procedures and current practices relating to clinical 
and pharmacy activities, data handling, the IRB oversight and the informed consent 
process. 
11.7.2. 
Interim Monitoring Visits 
During the study, a monitor from or representing Idera will visit the investigational site, for the 
following:  
 Provide information and support to the Investigator(s). 
 Confirm that facilities remain acceptable. 
 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product is being 
appropriately handled and accounted for. 
 Perform source data verification, including verifying the data in the eCRFs against 
the relevant source documents (Section 11.3) and resolving any discrepancies noted.  
 Record and report any protocol deviations.  
 Confirm that AEs and SAEs have been properly documented on eCRFs; that any 
SAEs have been forwarded to Idera Pharmaceuticals, Inc.; and that SAEs meeting 
criteria for reporting have been forwarded to the IRB.  
Between visits the monitor will be available as needed to provide information or support to the 
Investigator(s) or other staff. 


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11.7.3. 
Study Closeout Visit 
The study will be considered complete when all of the following have occurred:  
 All treated patients have completed all scheduled visits plus any unscheduled follow 
up required by AEs.  
 All eCRFs have been completed, submitted and all queries resolved.  
 The trial database has been locked.  
The Sponsor or designee will then conduct a study closeout visit, which may include, but is not 
limited to, the following:  
 Review the site TMF to assure all required regulatory documents are current and 
complete.  
 Resolve any open issues from prior monitoring, audit or inspection visits.  
 Review the site’s provisions for meeting the requirements for retention study records.  
 Discuss possible future site audits.  
 Review the Sponsor’s publication policy.  
 Confirm compliance with requirements for notifying the IRB of study events, 
including closure.  
 Collect any unused study materials for either return to the Sponsor or disposal in a 
manner approved by the Sponsor.  
11.8. 
Resolution of Deficiencies  
The Investigator agrees to take promptly any reasonable steps requested by the Sponsor to 
resolve any deficiencies identified as a result of monitoring, audits, inspections, protocol 
deviations, or review of any other study documentation. Failure to take adequate remedial action 
can result in suspension or termination of the study at the site. 
11.9. 
Retention of Records 
All study-related materials at the site (e.g., source documents, eCRFs, TMF) will be retained 
according to ICH guidelines and applicable regulations.  
The study drug is being developed under a US IND application; regulations require all 
study-related materials be retained for at least 2 years after one of the following events: 
 Approval of a New Drug Application based on this study.  
 Notification by the Sponsor that no further application will be filed.  
The Investigator will use the following procedures regarding retained records:  
 Contact the Sponsor before destructing any records pertaining to the study. 
 Provide the Sponsor an opportunity to collect the records.  
 Obtain written permission from the Sponsor to destroy the records.  


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 Notify the Sponsor if the Investigator plans to leave the institution so that 
arrangements can be made for the transfer of records.  
Clinical and laboratory samples that are unstable may be disposed with the written approval of 
the Sponsor.  
11.10. 
Data Management  
A detailed Data Management Plan will be prepared separately and approved by the Sponsor.  


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12. 
STATISTICAL METHODS 
The sections below indicate the overall structure and approach to the analysis of this study. A 
detailed Statistical Analysis Plan (SAP) incorporating these sections below will be prepared 
separately and approved by the Sponsor. The SAP will define populations for analysis, outline all 
data handling conventions, including software, and specify additional statistical methods to be 
used for analysis of safety, efficacy and PK.  
12.1. 
Sample Size Determination and Study Power 
Following identification of the RP2D, up to an additional 29 patients will be enrolled at the 
RP2D.  
Simon’s two‐stage design [8] will be used to test the response rate at the RP2D. The null 
hypothesis that the true response rate is 10% will be tested against a one‐sided alternative. In the 
first stage, 10 patients will be accrued. If there are one or fewer responses in these 10 patients, 
the study will be stopped. Otherwise, 19 additional patients will be accrued for a total of 29. The 
null hypothesis will be rejected if six or more responses are observed in 29 patients. This design 
yields a type I error rate of 4.7% and power of 80.5% when the true response rate is 30%.  
12.2. 
Analysis Populations 
Analysis Populations: 
 DLT Evaluable Population: patients enrolled in the Phase 1 dose escalation portion of 
the study who receive all planned doses of study drug during the DLT observation 
period or who discontinue treatment due to AEs. 
 Safety/Intent-to-Treat (ITT) Population: all patients who received at least 1 injection 
of study drug. 
 Efficacy Evaluable (EE) Population: all patients who are MYD88 L265p mutation 
positive and are treated at the RP2D. 
 Per Protocol (PP) Population: all patients in the EE who had no major protocol 
violations that would potentially influence treatment effect. 
 Pharmacokinetic (PK) Population: all patients who had both a pre-dose and at least 
one analyzable post-dose PK sample. 
CRC review will be performed on the DLT Evaluable Population for the dose being considered. 
Safety analyses will be performed using the Safety/ITT Population. Efficacy endpoints will be 
analyzed for the EE and PP Populations. Response will also be tabulated for the 
Safety/ITT Population. Pharmacodynamic and immunogenicity assessments will be analyzed for 
the Safety/ITT Population.  
12.3. 
Analysis of Safety  
Safety analyses will be performed on the Safety/ITT Population. Safety observations will be 
analyzed using descriptive statistics and tabulation. No formal statistical comparisons are 


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planned. All safety data will be presented in listings. Only TEAEs (onset after the administration 
of the first dose of study drug) will be summarized in the Tables. 
Primary Safety and Tolerability Endpoints: 
 Number of DLTs 
 Frequency and intensity of AEs 
 Physical examination findings, including vital signs 
 Laboratory safety tests including hematology, chemistry, coagulation, urinalysis and 
complement levels 
 Assessment of injection site reactions (ISRs) 
 ECG findings 
Safety Analyses 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 16.0 and tabulated by event, grade, and relationship to study treatment. Safety analyses 
will be descriptive in nature; no statistical hypothesis testing will be performed. Laboratory 
assessments for hematology, chemistry, coagulation, and special safety tests (C3, C4, and CH50) 
will be tabulated via shift tables, tabulating each patient’s category at baseline via National 
Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), 
version 4.03 grading (normal and Grade 1 will be combined) versus their highest NCI-CTCAE 
grade on study. Injection site reactions will be summarized by incidence for each dose group and 
overall and by worst grade on study. Time-to-event analyses will be performed for ISRs. 
12.4. 
Analysis of Treatment Effect 
Analyses of treatment effect will be performed on both the EE and the PP Populations.  
12.4.1. 
Assessments 
Patients will be assessed as per the schedule of events. Response status will be classified using 
disease-specific criteria as proposed by the International Working Group [1] (Section 9.6 and 
Section 16.2).  
12.4.1.1. Primary Treatment Effect Parameter 
The primary treatment effect parameter is the proportion of responders at the RP2D with the 
MYD88 L265 mutation. The definition of a responder is a patient who achieves a complete 
response (CR) or partial response (PR) based on the Revised Response Criteria for Malignant 
Lymphoma proposed by the International Working Group [1] (Section 9.6 and Section 16.2). 
As per the Simon two-stage design, after 10 subjects are treated at the RP2D until disease 
progression or clinical response, if one or fewer of those subjects respond, the study will end. If 
two or more of those initial 10 subjects respond, 19 more subjects will be enrolled. If six or more 
subjects of 29 treated at the RP2D respond, the null hypothesis that Presponse ≤ 10% may be 
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12.4.1.2. Secondary Treatment Effect Parameters 
The International Working Group specifies a number of outcome metrics related to time [1] 
(Section 16.3). The parameters considered most relevant to this study are: duration of response, 
time to response, proportion of responders at all dose levels, OS, and progression-free survival; 
these will be analyzed both globally across all cohorts and by dose level, reporting Kaplan-Meier 
estimated median, as well as the number of events and number of patients censored.  
12.5. 
Exploratory Analyses 
The following investigational factors will be analyzed with regard to response status:  
 Presence or absence of MYD88 L265P mutation in tumor cells. 
 Serum cytokine levels.  
 Serum levels of antibody to IMO-8400. 
12.6. 
Identification of Study Event Days and Times 
Study events will be recorded using the calendar date and (where applicable) the time to the 
nearest minute.  
For purposes of post-study analysis (e.g., tables and listings), study days will be designated as 
follows:  
 Day 1 is defined as the calendar day of the first treatment with study drug.  
 The days prior to Day 1 are designated Day –1, Day –2, etc.; there is no Day 0.  
 The days following the day of the first treatment with study drug are designated 
Day 2, Day 3, etc. 
 The day of the last treatment with study drug is indicated by adding the suffix "L", 
e.g., if the last treatment is administered on Day 43, it will be displayed as "Day 
43L". 
 The days following the last treatment with study drug are designated Day 1P, Day 2P, 
etc.  
The times of events related to dosing of study drug will be designated as minutes or hours before 
or after the time of dosing (i.e., the SC injection of study drug), which is designated as 
t = 0 (zero). Thus, 15 minutes prior to dosing is t = –15 min; 2 hour after dosing is designated 
t = 2 h.  
12.7. 
Interim Analysis 
An interim analysis is planned after 10 patients are treated at the RP2D. If fewer than two 
patients respond, the study will stop. If two or more patients respond, the study will continue 
until 29 patients are enrolled and treated at the RP2D. 


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12.8. 
Handling Missing Data 
Missing data will not be imputed. In time-to-event analyses using Kaplan-Meier methodology, 
patients who do not experience the event of interest will be censored. Rules for censoring of data 
will be described in the SAP. 
Further details for handling of missing, duplicated or unscheduled data will be given in the SAP.  
12.9. 
Changes in the Planned Analyses 
If changes to the analyses planned in the protocol are made, then these will be listed in the CSR, 
along with an explanation as to why they occurred. 


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13. 
ETHICAL CONSIDERATIONS 
The study will be conducted in accordance with: 
 The current version of “Ethical Principles For Medical Research Involving Human 
Subjects” as adopted by the World Medical Association (WMA)[31].2  
 Local laws and regulations for the use of investigational therapeutic agents.  
13.1. 
Independent Ethics Committee 
13.1.1. 
Initial Review Prior to Study Initiation  
Prior to initiating the study, the Investigator will submit the following to an Independent Ethics 
Committee (IEC)3 for approval: 
 Study protocol. 
 Investigator’s Brochure. 
 Informed Consent Form and any other written documents to be given to the patient; 
 Details of any compensation to participants.  
 Copies of any proposed public announcements of the trial (e.g., advertisements, web 
postings). 
 Any other requested document(s). 
The study will not commence until the IEC has issued a letter of approval signed and dated by 
the IEC chair or authorized person which includes the following items:  
 Protocol number, full title, version number and date.  
 Version date of the ICF.  
 Version date of the applicable IB.  
 Date the protocol and consent form were reviewed and approved by the IEC.  
The Sponsor or designee will be provided copies of all correspondence between the Investigator 
and the IEC. In addition, prior to study initiation, the Sponsor will be provided one of the 
following to verify that the IEC was appropriately qualified to approve the protocol: 
                                                 
2 This document, commonly referred to as the “Declaration of Helsinki”, was issued in 1964 and has been amended 
or clarified at subsequent WMA Assemblies. Only the current document is considered official by WMA. The 
most recent version was approved in October 2013 (Fortaleza, Brazil).  
3 ICH E6, which specifies GCP, requires “an independent body (a review board or a committee, institutional, 
regional, national or supernational) …. whose responsibility it is to ensure the protection of the rights, safety, and 
well-being of human subjects involved in a trial…” In this protocol, the body performing this function will be 
referred to as the IEC (Independent Ethics Committee); in practice, many alternative designations are used, e.g., 
Institutional Review Board (IRB).  


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 Documentation that on the date of the approval, the IEC met all currently applicable 
regulatory requirements for policies and procedures (e.g., membership, quorum, and 
approval procedures).  
 A memo listing the voting members of the IEC who were present at the meeting the 
protocol was approved, including their titles, occupations, and institutional 
affiliations.  
13.1.2. 
Subsequent Submissions to the IEC  
After the initial approval, the Sponsor and Investigator will submit the following to the IEC: 
 Any new information that may be relevant to a patient’s willingness to initiate or 
continue participation in the trial. 
 Any proposed amendments to the protocol.  
 Proposed revisions to the ICF that incorporate new information or procedures.  
 Copies of any proposed public announcements of the trial.  
 At least annually, a report of the study’s progress.  
 Notification of any decision by the Investigator or Sponsor to suspend or terminate 
the study and the reason(s) for such action.  
13.2. 
Written Informed Consent 
Informed Consent Forms submitted to the IEC must be (a) based on a master document provided 
by the Sponsor and (b) reviewed and approved by the Sponsor prior to submission to the IRB. 
The Sponsor must also review and approve any changes requested by the IRB prior to the ICF 
being used. 
Informed consent will be obtained prior to conducting any study procedures that are not part of 
the patient’s routine medical care. During the consent process, each patient will:  
 Be advised of the nature and risk of the study by the Investigator or designated study 
personnel.  
 Be given full opportunity to read the ICF, ask any questions, and consider whether to 
participate.  
 Provide informed consent voluntarily.  
The ICF will be signed and dated by the patient and by the person who provided the information. 
A copy of the signed ICF will be provided to the patient; the original will be retained by the 
Investigator as a source document. The informed consent process will be noted in the source 
documents.  
The patient will be informed in a timely manner if new information becomes available that may 
be relevant to the patient’s willingness to continue participation in the trial. Communication of 
this information to the patient will be noted in the source documents. 


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13.2.1. 
Obtaining Informed Consent from Patients Who Are Not Literate 
If the site proposes to enroll patients who are not literate, or who are literate in a language other 
than English, then the operating guidelines of the approving IRB should specify appropriate 
regulatory-compliant procedures.  
Typically, if a patient is not literate, then ICF must be signed (or marked) by the patient and 
signed by an impartial witness who was present during the entire informed consent process. For 
patients who are literate in a language other than English, the consent process typically includes 
either:  
 An approved translation of the ICF in the appropriate language. 
 Presentation by an approved translator who presents the required consent information 
in the patient’s native language plus the patient signing a generic (“short form”) 
consent in their native language indicating that the study-specific information has 
been presented to them verbally in their native language and they have had the usual 
opportunity to have any questions answered.  
13.2.2. 
Special Informed Consent Situations Not Applicable to This Protocol  
Patients may not be enrolled if they meet any of the following conditions which require specific 
provisions and approvals not provided for in this protocol:  
 Are not able to provide informed consent (e.g., are acutely or permanently impaired).  
 Are at increased risk of coercion (e.g., prisoners, institutionalized persons). 
13.2.3. 
Protection of Patient Information 
The identity and collected data of each patient (“protected health information”) will be kept 
confidential and will be protected in accordance with applicable local regulations, including:  
 Each patient will be assigned a unique patient number, which will be used on the 
eCRF in place of the patient’s name.  
 Computer systems for collecting and analyzing the data will have restricted access.  
 In publications, aggregate data will be used wherever possible; any individual data 
will be redacted of unique identifying characteristics.  
The informed consent process will comply with local requirements relating to (a) disclosure of 
the data to be collected and (b) authorization for its use. When permitted, these issues will be 
included in the ICF. In the event a separate form is required, the following will apply: 
 The Sponsor must review and approve the separate form. 
 The form will be signed and dated by, and copies provided to, the required parties.  
 A completed copy of the form will be placed in the trial files with the completed ICF.  


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14. 
STUDY ADMINISTRATION 
14.1. 
Registration of Study 
The Sponsor will register the trial on clinicaltrials.gov in accordance with applicable US 
regulatory requirements and the guidelines of the International Committee of Medical Journal 
Editors (ICMJE) regarding registration of controlled clinical trials (“clinically directive trials”).  
14.2. 
Changes in the Conduct of the Study  
After the protocol has been approved by the governing IEC and regulatory authority, substantial 
changes in the conduct of the study will only be made as formal protocol revisions, which must 
be reviewed and approved by the Sponsor and the Investigator prior to submission to the 
applicable IEC and regulatory body. Changes will only be implemented after the revised protocol 
is approved as required. 
Changes to contract information or designated study personnel (page 4) may be handled 
administratively.  
14.3. 
Confidentiality 
This protocol, the applicable IB, the results of the study and other related information provided 
by the Sponsor represent confidential and proprietary material of the Sponsor. They will be 
available only to the Investigator, personnel directly involved in the study, and authorized 
members and staff of the applicable IEC. These parties agree not to disclose these materials to 
others.  
14.4. 
Financial Disclosure 
In compliance with US 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 the following information for the time 
period during which the Investigator is participating in the study and for 1 year following 
completion of the study: 
 Any financial arrangement between Idera Pharmaceuticals, Inc. and the Investigator 
in which the value of the compensation to the Investigator for conducting the study 
could be impacted by the outcome of the study. 
 Payments (exclusive of the costs of conducting this or other clinical studies) by Idera 
Pharmaceuticals, Inc. totaling >$10,000, including, but not limited to, grants to fund 
ongoing research, compensation in the form of equipment, retainer for ongoing 
consultation, or honoraria. 
 Any proprietary interest held by the Investigator in the product being evaluated. 
 Equity interest in Idera Pharmaceuticals, Inc. that exceeds $10,000, including 
ownership interest, stock options, or other financial interest whose value cannot be 
determined through reference to public prices.  


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14.5. 
Publication Policy 
Idera Pharmaceuticals, Inc. recognizes the importance of communicating the results of scientific 
studies, including clinical trials, and, therefore, encourages their publication in reputable 
scientific journals and presentation at seminars or conferences. Idera also has legitimate 
corporate and shareholder responsibilities, including, but not limited to, protecting confidential 
information about its proprietary products and obtaining patent protection for its intellectual 
property.  
Therefore, the following procedures apply to any communication (including written, oral, or 
electronic; manuscript, abstract, other publication, or presentation) of results or information 
arising from this study (including any ancillary studies involving trial patients) to any third 
parties:  
 The proposed communication will be prepared in collaboration with the Sponsor.  
 The final proposed version must be submitted to Idera for review and comment at 
least 30 days prior to presentation, submission for publication or other dissemination. 
 In the event Idera reasonably determines that a proposed communication contains 
confidential or patentable material, they may require either of the following:  
– The material be removed from the communication;  
– The communication be delayed for up to 60 additional days to permit filing the 
appropriate intellectual property protection. 
These procedures apply regardless of whether the study is completed as planned or is terminated 
prematurely for any reason.  
The first publication from this study is expected to be a summary of all protocol results, jointly 
produced by the Sponsor and the participating Investigators.  
14.6. 
Authorship and Acknowledgement 
All publications will give Idera Pharmaceuticals, Inc. and/or their personnel appropriate credit 
(i.e., authorship or acknowledgement) for any direct contribution made by them. 
Authorship will be decided jointly by the Investigators and the Sponsor. Manuscripts will 
conform to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, 
including, but not limited to, the standards for authorship contained therein. 


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15. 
LIST OF REFERENCES 


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1 Cheson B, Pfistner B, Juweid ME et al. Revised response criteria for malignant lymphoma. J 
Clin Oncol. 2007; 25(5):579-586.  
2 Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MyD88 mutations in human 
lymphoma. Nature. 2011; 470(7332): 115–119. 
3 Young RM, Staudt LM. Targeting pathologic B cell receptor signaling in lymphoid 
malignancies. Nature Rev Drug Discovery. 2013; 12:229-243. 
4 Lim K-H, Barton GM, Staudt LM. Oncogenic MyD88 mutants require Toll-like receptors. 
Amer Assoc Cancer Res, 2013 Annual Meeting, Abstract 2332. 
5 Bhagat L, Wang D, Jiang W, et al. IMO‐8400, a selective antagonist of TLRs 7, 8 and 9, 
inhibits MYD88 L265P mutation‐driven signaling and cell survival: A potential novel 
approach for treatment of B‐cell lymphomas harboring MYD88 L265P mutation. Abstract, 
AACR Annual Meeting 2014, San Diego, California, April 5-9, 2014. 
6 Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenstrom’s 
macroglobulinemia. N Engl J Med 2012; 367:826-33. 
7 Thomas, S, Harb W, Beck T, et al. Interim Results From a Phase 1/2, Open-Label, 
Dose-Escalation Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenström’s 
Macroglobulinemia Abstract, ASH Annual Meeting 2015 
8 Simon R. Optimal two-stage design for phase II clinical trials. Control Clin Trials. 1989; 
10(1):1-10. 
9 Fernandez-Rodriguez C, Bellosillo B, Garcia-Garcia M, et al. MyD88 (L265P) mutation is an 
independent prognostic factor for outcome in patients with diffuse large B-cell lymphoma. 
Leukemia 2014; 28, 2104–2106. 
10 NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphoma. Version 
2.2013. National Comprehensive Cancer Network. 
http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf.  Accessed on-line 5 Nov 2013 
11 Campo E, Swerdlow SH, Harris NL, et al. The 2008 WHO classification of lymphoid 
neoplasms and beyond: evolving concepts and practical applications. Blood. 2008; 
17(19):5019-5032. 
12 SEER Cancer Statistics Factsheets: Non-Hodgkin Lymphoma. National Cancer Institute. 
Bethesda, MD, http://seer.cancer.gov/statfacts/html/nhl.html. Accessed 5 November 2013.  
13 Hill BT, Sweetenham J. Clinical implications of the molecular subtypes of diffuse large 
B-cell lymphoma. Leuk Lymphoma. 2012;53:763-769. 
14 Lenz, G, Wright G, Dave SS, et al. Stromal Gene Signatures in Large-B-Cell Lymphomas N 
Engl J Med. 2008; 359:2313-23. 
15 Green N, Marshak-Rothstein A. Toll-like receptor driven B cell activation in the induction of 
systemic autoimmunity. A Sem Immunol. 2011; 23:106-112.  
16 Marshak-Rothstein A, Rifkin I. Immunologically Active Autoantigens: The Role of Toll-Like 
Receptors in Development of Chronic Inflammatory Disease. Ann Rev Immunol. 2007; 
25:419-441. 
17 Sun S, Rao N, Venable J, et al. TLR7/9 Antagonists as Therapeutics for Immune-Mediated 
Inflammatory Disorders. Inflamm Alerrgy Drug Targets. 2007; 6:223-235. 
18 Cros J, Cagnard N, Woollard K, et al. Human CD14dim Monocytes Patrol and Sense Nucleic 
Acids and Viruses via TLR7 and TLR8 Receptors. Immunity. 2010; 33:1-12. 
19 Demaria O, Pagni P, Traub S, et al. TLR8 deficiency leads to autoimmunity in mice. J Clin 
Invest. 2010; 120:3651-3662. 
 
                                                 


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20 Wang JQ, Jeelall YS, Horikawa K. Emerging targets in human lymphoma: targeting the 
MyD88 mutation. Blood Lymph Cancer 2013;3:53–61. 
21 Choi JW, Kim Y, Lee J-H, Kim Y-S. MyD88 expression and L265P mutation in diffuse large 
B-cell lymphoma. Hum Pathol. 2013; 44:1375-1381. 
22 Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s 
macroglobulinemia. N Engl J Med. 2012;367(9):826–833 
23 Puente XS, Pinyol M, Quesada V, et al. Whole-genome sequencing identifies recurrent 
mutations in chronic lymphocytic leukaemia. Nature. 2011;475(7354):101–105. 
24 Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic 
lymphocytic leukemia. N Engl J Med. 2011;365(26):2497–2506. 
25 Montesinos-Rongen M, Godlewska E, Brunn A, Wiestler OD, Siebert R, Deckert M. 
Activating L265P mutations of the MyD88 gene are common in primary central nervous 
system lymphoma. Acta Neuropathol. Dec 2011;122(6):791–792. 
26 Gonzalez-Aguilar A, Idbaih A, Boisselier B, et al. Recurrent mutations of MyD88 and 
TBL1XR1 in primary central nervous system lymphomas. Clin Cancer Res. Oct 1, 
2012;18(19):5203–5211. 
27 Li ZM, Rinaldi A, Cavalli A, et al. MyD88 somatic mutations in MALT lymphomas. Br J 
Haematol. 2012;158(5):662–664. 
28 Ries LAG, Eisner MP, Kosary CL, eds. SEER Cancer Statistics Review, 1975-2011. 
Bethesda, MD: National Cancer Institute. Available at: http://seer.cancer.gov/csr/1975_2011/. 
Accessed 6 July 2014. 
29 FDA Briefing Document: Peripheral and Central Nervous System Drugs Advisory Committee 
Meeting. NDA 206031. Drisapersen. 2015 Nov. 
30 Common Terminology Criteria for AEs (CTCAE). Version 4.0, 28 May 2009. US 
Department of Health and Human Services, National Institutes of Health, National Cancer 
Institute. NIH Publication No. 03-5410.  
31 Ethical Principles For Medical Research Involving Human Subjects. World Medical 
Association. Available at (accessed 8 October 2013) 
http://www.wma.net/en/30publications/10policies/b3/. 


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16. 
DIAGNOSTIC AND RESPONSE CLASSIFICATIONS CITED 
16.1. 
WHO Classification of Mature B-cell neoplasms [11] 
 Chronic lymphocytic leukemia/small lymphocytic lymphoma 
 B-cell prolymphocytic leukemia  
 Splenic marginal zone lymphoma  
 Hairy cell leukemia 
 Splenic lymphoma/leukemia, unclassifiable 
– Splenic diffuse red pulp small B-cell lymphoma  
– Hairy cell leukemia-variant 
 Lymphoplasmacytic lymphoma 
 Waldenström’s Macroglobulinemia 
 Heavy chain diseases 
– Alpha heavy chain disease  
– Gamma heavy chain disease  
– Mu heavy chain disease 
 Plasma cell myeloma 
 Solitary plasmacytoma of bone  
 Extraosseous plasmacytoma 
 Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue 
(MALT lymphoma) 
 Nodal marginal zone B-cell lymphoma (MZL) 
– Pediatric type nodal MZL 
 Follicular lymphoma 
– Pediatric type follicular lymphoma  
 Primary cutaneous follicle center lymphoma  
 Mantle cell lymphoma 
 Diffuse large B-cell lymphoma (DLBCL), not otherwise specified  
– T cell/histiocyte rich large B-cell lymphoma 
– Primary DLBCL of the CNS 
– Primary cutaneous DLBCL, leg type 


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– Epstein-Barr virus (EBV)-positive DLBCL of the elderly 
 DLBCL associated with chronic inflammation  
 Lymphomatoid granulomatosis 
 Primary mediastinal (thymic) large B-cell lymphoma  
 Intravascular large B-cell lymphoma 
 Anaplastic lymphoma kinase (ALK)+ large B-cell lymphoma  
 Plasmablastic lymphoma 
 Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease 
 Primary effusion lymphoma 
 Burkitt lymphoma 
 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and 
Burkitt lymphoma 
 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and 
classical Hodgkin lymphoma 
See Section 1.5 for specific diagnoses eligible for and excluded from this study.  
16.2. 
Classification of Disease Response for DLBCL  
Reproduced from Reference [1]. 
 


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16.3. 
Efficacy End Point Definitions 
Reproduced from Reference [1]. 
 
 


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17. 
INVESTIGATOR’S AGREEMENT 
I have read the foregoing protocol (Protocol 8400-402, Version 4.0) and agree to the following: 
 The protocol contains all necessary details for carrying out this study.  
 I will conduct the study as detailed in the protocol and will abide by all its 
provisions. 
 I will conduct the study in compliance with ICH Guidelines for Good Clinical 
Practice, the requirements of the IRB and all applicable government regulations. 
 I will train and supervise all individuals delegated to assist me in conducting this 
study, including providing copies of the protocol and all pertinent information and 
discussing the material with them to ensure they are fully informed regarding the 
investigational drug, the protocol and their responsibilities and obligations.  
 I will use only the current informed consent form approved by the Sponsor (or 
their designee) and by the IRB responsible for this study.  
 I will fulfill all requirements for submitting pertinent information to the IRB and 
to the Sponsor, including reportable serious AEs.  
 I will complete all case report forms, including resolution of queries, in a timely 
manner.  
 I will provide the Sponsor (or their designee) with access to any source 
documents from which case report form information may have been derived. 
 I will provide the Sponsor with complete, signed statements of financial 
disclosure as required. 
 I understand that the information in this protocol and the referenced Investigator’s 
Brochure is confidential and that its disclosure to any third parties (other than 
those approving or conducting the study) is prohibited. I will take the necessary 
precautions to protect this information from loss, inadvertent disclosure or access 
by third parties.  
 
 
Signature of Investigator 
 
Date 
 
Investigator (printed name): 
 
Title: 
 
Address: 
 
 
 
Facility / Site of Investigation:  
 
Facility address: 
 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Page 1 of 32 
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STATISTICAL ANALYSIS PLAN 
 
Phase 1/2 Open-label, Multiple-dose, Dose-escalation Study to Evaluate the 
Safety and Tolerability of IMO-8400 in Patients with Relapsed or Refractory 
Diffuse Large B-cell Lymphoma and Presence of the MyD88 L265P Mutation 
 
Protocol Number: 
Protocol Version and Date: 
8400-402 
Version 4.0, 29 January 2016 
Version 3.0, 09 June 2015 
Version 2.1, 12 November 2014 
Version 2.0, 07 November 2014 
Version 1.0, 07 March 2014 
Name of Test Drug: 
IMO-8400 
Phase: 
Phase 1/2 
Methodology: 
Open-label, Multiple-dose, Dose-escalation, Multicenter 
Sponsor: 
Idera Pharmaceuticals, Inc. 
167 Sidney Street 
Cambridge, MA  02139 
Sponsor Representatives: 
Suzanne Swann, PhD 
Principal Statistician 
Idera Pharmaceuticals, Inc. 
Statistical Analysis Plan Date: 
11 November 2016 
Statistical Analysis Plan 
Version:  
Final Version 1.0 
 
 
 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of 
Idera Pharmaceuticals, Inc. and any unauthorized use or disclosure of such information  
without the prior written authorization of Idera Pharmaceuticals, Inc. is expressly prohibited. 
 
 
 


Statistical Analysis Plan 
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APPROVAL SIGNATURE PAGE 
Protocol Title: 
Phase 1/2 Open-label, Multiple-dose, Dose-escalation Study to 
Evaluate the Safety and Tolerability of IMO-8400 in Patients 
with Relapsed or Refractory Diffuse Large B-cell Lymphoma 
and Presence of the MyD88 L265P Mutation 
Sponsor: 
Idera Pharmaceuticals, Inc. 
167 Sidney Street 
Cambridge, MA 02139 
Protocol Number: 
8400-402 
Document Date / Version: 
11 November 2016 / Final Version 1.0 
Veristat, LLC. Author: 
Debora Manning, MPH 
Biostatistician 
Veristat, LLC 
118 Turnpike Road 
Southborough, MA 01772 
 
Signature:______________________________________ 
 
Date:__________________________________________ 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidances and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments.  All changes to the 
planned analyses will be described in the clinical study report. 
Sponsor Signatory: 
Suzanne Swann, PhD 
Principal Statistician 
Idera Pharmaceuticals, Inc. 
 
 
Signature:______________________________________ 
 
Date:__________________________________________ 


Statistical Analysis Plan 
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TABLE OF CONTENTS 
Section 
Page 
2. 
Statistial Analysis Plan Objectives ................................................................................. 8 
3. 
Information From the Study Protocol ........................................................................... 9 
3.1. 
Introduction and Objectives ............................................................................... 9 
3.1.1. 
Introduction ............................................................................................. 9 
3.1.2. 
Study Objectives ..................................................................................... 9 
3.2. 
Study Design ....................................................................................................... 10 
3.2.1. 
Synopsis of Study Design ..................................................................... 10 
3.2.2. 
Stopping Rules ...................................................................................... 11 
3.2.3. 
Cohort Review Committee (CRC) ........................................................ 12 
3.2.4. 
Study Procedures .................................................................................. 12 
3.2.5. 
Safety, Efficacy, and Pharmacokinetic Parameters .............................. 16 
4. 
Patient Population .......................................................................................................... 18 
4.1. 
Population Definitions ....................................................................................... 18 
4.2. 
Protocol Deviations ............................................................................................ 18 
5. 
General Statistical Methods .......................................................................................... 19 
5.1. 
Sample Size Justification ................................................................................... 19 
5.2. 
General Methods ................................................................................................ 19 
5.3. 
Computing Environment................................................................................... 20 
5.4. 
Baseline Definitions ............................................................................................ 20 
5.5. 
Methods of Pooling Data ................................................................................... 20 
5.6. 
Adjustments for Covariates .............................................................................. 20 
5.7. 
Multiple Comparisons ....................................................................................... 20 
5.8. 
Subpopulations ................................................................................................... 20 
5.9. 
Withdrawals, Dropouts, Loss to Follow-up ..................................................... 20 
5.10. Missing Data ....................................................................................................... 20 
5.11. Visit Windows..................................................................................................... 20 
5.12. Interim Analyses ................................................................................................ 21 
6. 
Study Analyses ............................................................................................................... 22 
6.1. 
Patient Disposition ............................................................................................. 22 
6.2. 
Demographics, Baseline Characteristics, and Medical History ..................... 22 
6.3. 
Safety Analyses ................................................................................................... 22 


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Section 
Page 
6.3.1. 
Study Drug Exposure ............................................................................ 22 
6.3.2. 
Adverse Events ..................................................................................... 23 
6.3.3. 
Laboratory Data .................................................................................... 24 
6.3.4. 
Vital Signs............................................................................................. 25 
6.3.5. 
Physical Examination ........................................................................... 26 
6.3.6. 
Electrocardiogram ................................................................................. 26 
6.3.7. 
Concomitant Medications ..................................................................... 26 
6.4. 
Efficacy Analyses ............................................................................................... 26 
6.5. 
Pharmacokinetic Analyses ................................................................................ 27 
6.6. 
Pharmacodynamic Analyses ............................................................................. 27 
7. 
Changes to Planned Analyses ....................................................................................... 28 
8. 
References ....................................................................................................................... 29 
9. 
Clinical Study Report Appendices ............................................................................... 30 
9.1. 
Statistical Tables and Figures to be Generated ............................................... 30 
9.2. 
Data Listings to be Generated .......................................................................... 30 
10. 
Revision History ............................................................................................................. 31 
 


Statistical Analysis Plan 
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TABLES AND FIGURES INCLUDED IN THE TEXT 
Table/Figure 
Page 
Table 2-1 
Planned Dose Escalation Cohorts ........................................................................ 11 
Table 2-2 
Schedule of Study Evaluations ............................................................................ 13 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ABC 
Activated B-cell 
AE 
Adverse event 
ATC 
Anatomic Therapeutic Class 
BCR 
B-cell receptor 
CI 
Confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CRC 
Cohort review committee 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOS 
End of study 
EOT 
End of treatment 
GCB 
 
Germinal center B-cell  
ICH 
International Conference on Harmonisation 
IRB 
Institutional review board 
ISR 
Injection site reaction 
ITT 
Intent-to-treat 
IWG 
International Working Group 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
MyD88 
Myeloid differentiation primary response gene (88) 
NCI 
National Cancer Institute 
NF-kB 
Nuclear factor kappa-light-chain-enhancer of activated B-cells  
NHL 
Non-Hodgkin’s lymphoma 
PD 
Pharmacodynamic 


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Abbreviation 
Definition 
PK 
Pharmacokinetic(s) 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
Rel Day 
Relative study day 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TLR 
Toll-like receptors 
WHO 
World Health Organization 
WM 
Waldenström’s macroglobulinemia 
 
 


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2. 
STATISTIAL ANALYSIS PLAN OBJECTIVES 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objectives. Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided. The statistical analyses 
and summary tabulations described in this SAP will provide the basis for the results sections of 
the clinical study report (CSR) for this trial. 
This SAP will also outline any differences in the currently planned analytical objectives and 
analyses than those planned in the study protocol. 


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3. 
INFORMATION FROM THE STUDY PROTOCOL 
3.1. 
Introduction and Objectives 
3.1.1. 
Introduction 
Non-Hodgkin lymphomas (NHL) represent a heterogenous group of lymphoid malignancies. 
Current estimates for the United States are approximately 70,000 new cases of NHL annually 
and 19,000 deaths (NCI, 2013). The primary differentiation is based on lymphocyte cell type: B-
cell, T-cell, or NK-cell. Approximately 85% of NHL arises from B-cells and the most common 
of the mature B-cell malignancies is diffuse large B-cell lymphoma (DLBCL), representing 
~31% of all cases. DLBCL is considered an aggressive lymphoma with the potential for rapid 
disease progression. 
IMO-8400 is a second-generation oligonucleotide antagonist of Toll-like receptors (TLR) 7, 8 
and 9, which blocks immune activation mediated through those receptors. In a Phase 1 study, 
IMO-8400 was administered to healthy adults by subcutaneous (SC) injection at single doses 
and multiple doses (once weekly for 4 weeks) up to 0.6 mg/kg (see Protocol Section 4.4.1 for 
details). All treatments were well tolerated, with mild injection site reactions and no pattern of 
systemic reactions or laboratory changes. 
Myeloid differentiation primary response gene (88) (MyD88) is the initial linker protein in the 
TLR signaling pathway. Recent studies indicate a high frequency of mutations in MyD88 in 
patients with B-cell malignancies, particularly DLBCL subtypes with poor prognosis (Ngo, 
2011). Specifically, the gain-of-function L265P mutation is found in almost a third of DLBCL 
with the activated B-cell (ABC) phenotype. In vitro studies of B-cell tumor lines indicate that 
(a) this mutation is associated with an increase in cell activation, proliferation, and survival, and 
(b) loss of endosomal TLRs results in markedly decreased cell proliferation and survival (Young 
and Staudt, 2013; Lim, 2013). Data from Idera indicate that treatment of such cell lines with 
IMO-8400 has a similar effect (Bhagat, 2014).  
Recently reported clinical experience with IMO-8400 in patients with Waldenström’s 
macroglobulinemia (WM), a B-cell malignancy almost always driven by the MYD88 L265P 
mutation, indicate that the treatment is active and well tolerated at dose levels up to 1.2 mg/kg 
twice weekly (Treon, 2012; Thomas, 2015). Dose escalation is continuing in that setting as the 
maximum tolerated dose (MTD) has not been reached. 
The current study represents the first clinical trial of IMO-8400 in patients with DLBCL. 
On September 26, 2016, accrual to this trial was suspended by the Sponsor after 5 patients had 
been enrolled and treated. No further patients will be enrolled. As a result, limited efficacy 
results will be presented. 
3.1.2. 
Study Objectives 
3.1.2.1. 
Primary Objective 
The primary objective is to evaluate the safety and tolerability of escalating dose levels of 
IMO-8400 administered by SC injection in patients with relapsed or refractory non-germinal 
center B-cell (GCB) subtype DLBCL. 
3.1.2.2. 
Secondary Objectives 
The secondary objectives are as follows:  


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 To assess the treatment effect (clinical activity) in patients with non-GCB subtype 
DLBCL with MYD88 L265P mutations using disease-specific international guidelines 
for classifying clinical response (Cheson, 2007) 
 To identify an optimal dose of IMO-8400 for further clinical evaluation in B-cell 
malignancies 
 To characterize the pharmacokinetics (PK) of escalating dose levels of IMO-8400 
administered by SC injection 
3.1.2.3. 
Exploratory Objectives 
The exploratory objectives are as follows:  
 To investigate associations between the treatment effect of IMO-8400 and selected 
biomarkers (e.g., serum cytokines) 
 To assess the potential immunogenicity of IMO-8400 administered by SC injection 
3.2. 
Study Design 
3.2.1. 
Synopsis of Study Design 
This is an open-label, multiple-dose, dose escalation study of IMO-8400 in patients with 
relapsed or refractory DLBCL of non-GCB subtype. The study is a Phase 1/2 study. Phase 1 
consists of a dose escalation to determine the recommended Phase 2 dose (RP2D). Phase 2 uses 
a Simon 2-stage optimal design to evaluate open-label treatment of patients at the RP2D 
(Simon, 1989). Initially, 10 patients will be treated at the RP2D. If at least 2 of the 10 patients 
respond, the study will enroll 19 more patients, for a total of 29 patients in the Phase 2 portion. 
A study schematic is represented in Figure 1 of the protocol. 
Patients are eligible to enroll on the basis of a positive MYD88 L265P mutation assay 
performed using any Clinical Laboratory Improvement Amendments (CLIA) compliant assay at 
any point during the course of their disease. Patients whose tumors do not harbor MYD88 
L265P mutations are eligible for the dose escalation phase of the study only (Phase 1), but the 
L265P mutation is required to be eligible for the expansion phase of the study (Phase 2). 
3.2.1.1. 
Phase 1: Dose Escalation 
The dose escalation cohorts will systematically evaluate the safety and tolerability of IMO-8400 
at increasing dose levels in order to identify the MTD. 
 The planned dose escalation cohort levels for IMO-8400 are 0.3, 0.6, and 1.2 mg/kg 
administered twice weekly and 2.4 and 3.6 mg/kg administered once weekly (Table 3-1). 
One or more dosing levels may be skipped based on demonstration of safety from other 
studies concurrently conducted on IMO-8400. Additional dose levels, schedules, and 
routes of administration may be evaluated based upon the emerging data. Dosing is 
based on body weight (see Protocol Section 8.1). Doses will be administered by SC 
injection. 
 The Investigators and Sponsor will review available toxicity information (including 
adverse events [AEs] that are not dose-limiting toxicities [DLTs]), PK and activity data 
to determine the MTD (see Section 3.2.5.1). 


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Table 3-1 
Planned Dose Escalation Cohorts 
Dose Level 
IMO-8400 Dose (mg/kg) 
Frequency 
Initial Cohort Size 
1 (starting dose) 
0.3 
Twice Weekly 
3-6 
2 
0.6 
Twice Weekly 
3-6 
3 
1.2 
Twice Weekly 
3-6 
4 
2.4 
Weekly 
3-6 
5 
3.6 
Weekly 
3-6 
Each dose escalation cohort is expected to enroll at least 3 patients, with a maximum of 6 
patients. The number of patients enrolled in any of the planned dose escalation cohorts can be 
reduced if safety at that dose level has already been demonstrated in a related population (e.g., 
WM). A cohort review committee (CRC) comprised of the Idera Medical Monitor and 
Investigators from participating sites will decide whether to continue or halt dose escalation, or 
explore intermediate dose levels (see Section 3.2.3).  
The following dose escalation procedures will be used:  
 If the initial 3 patients complete all 4 weeks of treatment without a DLT event, the CRC 
will conduct a dose escalation review. 
 If 1 of the initial 3 patients experiences a DLT event prior to completing Cycle 1, then 
enrollment at that dose level will continue to a total of 6 patients and the dose escalation 
review will be done when all 6 patients have completed Cycle 1. 
 If ≥2 patients at a dose-level experience DLT events during the Cycle 1, then no further 
patients will be enrolled until the CRC completes a review, which should be done as 
soon as feasible. 
 Furthermore, cohorts may be expanded to include additional patients if such patients can 
be enrolled ≤7 days after the third (or sixth) patient was first dosed with IMO-8400. 
To facilitate standardizing the dose escalation reviews across different cohorts, the focus will be 
on observations from Cycle 1 at that dose level. 
3.2.1.2. 
Phase 2: Dose Expansion Cohort 
Once the RP2D has been established, additional patients will be treated in a dose expansion 
phase that is designed to better characterize the safety, tolerability, and preliminary anti-tumor 
activity of the study drug when provided at the RP2D to patients with non-GCB subtype 
DLBCL with MYD88 L265P mutations. Phase 2 will use a Simon 2-stage design. Patients from 
Phase 1 treated at the RP2D, who are non-GCB subtype and MYD88 L265P mutation positive, 
will be included in the Phase 2 dose-expansion phase. Additional patients will be enrolled in the 
cohort until a total of 10 patients are treated at the RP2D.  If at least 2 of the 10 patients respond, 
the study will enroll 19 more patients, for a total of 29 patients in the Phase 2 portion. 
Additional dose-expansion cohorts may be added if clinical activity is seen during the dose 
escalation phase in tumors that lack this mutation. 
3.2.2. 
Stopping Rules 
The Sponsor reserves the right to discontinue or suspend the study at any time, at an individual 
site or overall, for safety or for administrative reasons. In the event of such action, the Sponsor 


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will promptly inform the impacted Investigators and institutions, the regulatory authorities, and 
the Institutional Review Board (IRB) of the action and the reason(s) for the action. 
3.2.2.1. 
Stopping Rules for Individual Patients 
Each enrolled patient will receive IMO-8400 at the assigned dose level until disease 
progression, intolerable toxicity (despite dose modification), withdrawal of consent, start of 
another anti-cancer therapy, or discontinuation of the study, whichever occurs first. 
For DLT events, provision is made for pausing treatment for up to 3 weeks and, if the acute 
toxicity improves sufficiently, resuming treatment at a lower dose level (Protocol Section 6.5.2). 
Patients who are tolerating treatment at dose levels below those deemed acceptable by the CRC 
may be eligible for dose escalation upon discussion and approval with the Idera Medical 
Monitor. 
3.2.3. 
Cohort Review Committee (CRC) 
The CRC is comprised of the Idera Medical Monitor and Investigators from participating sites. 
Once the last patient in a given cohort has completed a cycle of study treatment, a CRC meeting 
will be convened to review all safety data and decide whether to continue or halt dose 
escalation, further expand individual dose levels to gain additional safety data, or explore lower 
or intermediate dose levels. In addition to end-of-cohort meetings, the CRC will convene 
periodically, including during Dose Expansion (Phase 2), to review safety data for ongoing 
patients and patients in follow up. 
The roles of the CRC are to:  
 Review and provide definitive adjudication on individual DLTs, if needed (see Section 
3.2.5.1.1) 
 Perform dose-escalation review and make specific recommendations for the progress of the 
study (see Section 3.2.1.1) 
 Determine the MTD (see Section 0) 
A patient will be considered evaluable for purposes of CRC review if they meet the criteria to be 
included in the DLT Evaluation Population defined in Section 4.1.   
3.2.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 3-2.  The 
schedule is presented relative to the day and time of dosing.  
 
 
 


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Table 3-2 
Schedule of Study Evaluations 
 
Visit1 
Pre-
Screen
2 
Screen
3 
Treatment Period 
EOT
4 
EOS5 
F/U 
Survival F/U 
Cycle 
 
 
Cycle 1 
Even Numbered 
Cycles 
Odd Numbered 
Cycles 
 
 
Every 12 
wks.  
( +/- 4 wks.) 
Every 12 
wks.  
( +/- 4 wks.) 
Day    
≤ 21  
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
 
 
 
 
Evaluation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent
6 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor genotyping7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood draw for genotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography and medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam
8 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Vital Signs
9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test
10 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Radiologic Imaging11,12 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Bone Marrow Biopsy
13 
 
 
X 
X 
 
Lymph Node Biopsy 
 
X14 
X15 
 
 
Assessment of Response12 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
ECOG 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Hematology16 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Chemistry panel16 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Coagulation panel 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Complement 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Urinalysis 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
12-lead ECG17 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 


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Visit1 
Pre-
Screen
2 
Screen
3 
Treatment Period 
EOT
4 
EOS5 
F/U 
Survival F/U 
Cycle 
 
 
Cycle 1 
Even Numbered 
Cycles 
Odd Numbered 
Cycles 
 
 
Every 12 
wks.  
( +/- 4 wks.) 
Every 12 
wks.  
( +/- 4 wks.) 
Day    
≤ 21  
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
 
 
 
 
Evaluation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK18 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
PD and Investigational Studies
19 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Study Drug Administration20 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Assessment of Injection Site(s)20,21 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/concomitant medications20 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE = adverse event; CLIA = Clinical Laboratory Improvement Amendments; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS = End-of-Study; 
EOT = End-of-Treatment; OS = overall survival; F/U = Follow up; PD = pharmacodynamic; PK = pharmacokinetic. 
1. 
All days for a given Cycle are relative to the day of the first injection of study drug, designated Day 1 for that cycle; all times are relative to treatment, designated 0 hour; 
“pre-dose” vital signs are to occur within 1 hour prior to treatment; all other pre-dose procedures are to occur prior to treatment on the same calendar day. 
2. 
Pre-screening procedures involve only tumor genotyping and require a separate consent (protocol Section 9.2). 
3. 
Screening procedures may be performed up to 21 days prior to Day 1. 
4. 
If treatment is terminated prematurely for any reason, the EOT visit will be performed within 7 days of the decision to terminate. 
5. 
EOS Visit will be performed 30 to 35 days after the last dose of study drug if treatment is terminated prematurely for any reason. 
6. 
Informed consent must be signed prior to all study-specific pre-screening and/or screening procedures. 
7. 
A tumor sample will be submitted to a central laboratory (protocol Section 9.2) or alternatively previously confirmed by any outside CLIA-compliant assay and confirmed 
and approved by the Sponsor. 
8. 
Physical exam includes body weight and, only at Screening, height; a directed physical examination at the discretion of the Investigator is acceptable while on study 
treatment. Complete physical examination is required prior to enrollment and EOT and EOS. 
9. 
Vital signs comprise heart rate, blood pressure, respiratory rate and temperature. Vital signs will be obtained pre-dose (within 1 hour prior to treatment) and post-dose within 
30 min (±5 min) of treatment. On Day 1 of Cycle 1, Week 1, post-dose vital signs will also be obtained at 2 hours (±20 min). 
10. 
Serum or urine pregnancy testing for women of child-bearing potential. 
11. 
Radiologic imaging of chest, abdomen, and pelvis, performed during the last week of even cycles (every 8 weeks [± 1 week]) while the patient is receiving IMO-8400; 
patients discontinued from treatment for reasons other than progressive disease will be assessed per Revised Response Criteria for Lymphoma (protocol Section 16.2) at a 
minimum of every 12 weeks (± 4 days) for OS until documentation of progressive disease, initiation of new anti-cancer therapy, or the end of the study, whichever comes 
first. 
12. 
Assessment of response should be performed using the same imaging modalities throughout the study; assessment should be performed during the last week of all even 
numbered cycles (every 8 weeks [± 1 week]) while the patient is receiving active treatment with IMO-8400. 
13. 
If available, bone marrow biopsy will be processed locally (see the Laboratory Manual for more details). 
14. 
Archival or fresh tissue should be submitted for confirmation of diagnosis and exploratory analyses (see the Laboratory Manual for more details). 


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15. 
Should be collected at least once between 4 and 24 hours post-treatment (protocol Section 9.5). 
16. 
Hematology and chemistry full panels will be performed on Day 1 of each cycle; focused panels will also be performed on Day 15 of each cycle through Cycle 6. For 
Cycle 7 and on all testing will not be repeated on Day 15 unless more frequent monitoring is clinically indicated (refer to protocol Section 9.8.1 for details). 
17. 
If Screening and Day 1 Cycle 1 are performed within 24 hours then the 12-lead ECG will be performed only at Screening. 
18. 
On Cycles 1, 2, 4, and 6 (Day 1 of each cycle): a pre-dose sample is required. Additionally, post-dose PK samples are obtained at 1 (±5 min), 2 (±10 min) and 4 hours 
(±15 min). Pharmacokinetic samples will also be taken at EOT and EOS (protocol Sections 9.9). 
19. 
Pharmacodynamic set involves one sample for serum cytokines and one sample for antibodies to IMO-8400 taken at Screening, pre-dose at Cycles 1, 2, 4, and 6 (Day 1 of 
each cycle), EOT, and EOS. 
20. 
Except for Cycle 1 and study days that require a physical examination or laboratory safety tests to be performed, study drug administration, assessment of injection site(s), 
and assessment of AEs and con-meds may optionally be performed at a non-study site by a trained healthcare professional approved by the Sponsor, including at home by a 
visiting nurse (protocol Section 8.6). 
21. 
Assessment of all prior injection site(s) with grading and measurement of any reaction (protocol Section 9.7.5). In addition, on dosing days, the planned injection site will be 
assessed to confirm it is appropriate for use. 
 


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3.2.5. 
Safety, Efficacy, and Pharmacokinetic Parameters 
3.2.5.1. 
Safety Parameters 
The safety and tolerability of IMO-8400 will be assessed using reported and observed AEs and 
injection site reactions (ISRs) as well as scheduled safety observations including vital signs, 
physical examination, laboratory tests (hematology, serum complement, chemistry, coagulation, 
urinalysis, and pregnancy tests [for females only]), and electrocardiograms (ECGs).  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 16.0. Laboratory values will be graded according to the National Cancer 
Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.  
3.2.5.1.1. Definition of Dose Limiting Toxicity and Maximum Tolerated Dose  
A DLT can be either a clinical or laboratory AE. A potential DLT event is defined as a 
treatment emergent adverse event (TEAE) that meets protocol-defined criteria for events of 
hematological and non-hematological origin. It must be related to study treatment (assessed as 
not related to disease, intercurrent illness, or concomitant medication).  For the purposes of dose 
escalation and determination of the MTD, only DLTs that occur during the first cycle of 
treatment will be considered for discussions regarding dose escalation. Clinically significant 
toxicities or TEAEs that meet the definition of dose limiting but occur after Cycle 1 (dose 
modifying events) may be considered when determining the RP2D. 
Protocol-defined hematologic DLT criteria: 
 Grade 4 neutropenia lasting ≥ 7 days 
 Grade 3 or 4 neutropenia with fever ≥38.5°C 
 Grade 3 thrombocytopenia with bleeding that requires transfusion therapy 
 Grade 4 thrombocytopenia 
Protocol-defined non-hematologic DLT criteria: 
 Grade 3 vomiting or nausea despite the use of optimal anti-emetic treatments 
 Grade 3 diarrhea despite the use of optimal anti-diarrheal treatments 
 Serum creatinine ≥ 3.0 x ULN 
 Bilirubin ≥ 3.0 x ULN 
 Bilirubin 2.0-3.0 x ULN with ≥ Grade 2 ALT in patients without liver metastases 
 Bilirubin 2.0-3.0 x ULN with ≥ Grade 3 ALT or ALT > 5 x ULN in patients with liver 
metastases 
 Other non-hematologic toxicities of ≥ Grade 3 except for the following: 
o AEs related to underlying disease 
o Fatigue 
o Alopecia 


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o Isolated, asymptomatic elevations in biochemistry laboratory values lasting ≤ 7 days. 
This includes electrolyte abnormalities that respond to medical intervention. 
The CRC will review all DLTs to assess causality, i.e., relationship to study drug.  The 
definition of a DLT event will be applicable in the following contexts:  
 Cohort Review Committee review determining dose escalation.  
 Cohort Review Committee review in defining the MTD. 
 Investigator (and Medical Monitor) review for determining discontinuation of study 
treatment in individual patients. 
The MTD is the dose level meeting both of the following criteria:  
 It is below the level at which 2 or more patients experienced DLTs during the first 4 weeks 
of treatment. 
 It is a dose level at which no more than 1 patient experienced DLTs during the first 4 weeks 
of treatment. 
3.2.5.2. 
Efficacy Parameters 
As no further enrollment into Protocol 8400-402 is planned after 5 patients (see Section  for 
further detail), only one efficacy parameter will be assessed: distribution of best overall 
response per the International Working Group (IWG) response criteria (Cheson, 2007). Due to 
limited data, no other efficacy endpoints will be analyzed.  
3.2.5.3. 
Pharmacokinetic Parameters 
Blood samples for plasma levels of IMO-8400 will be collected as scheduled (Table 3-2).  
Samples will be analyzed for IMO-8400 concentration using a ligand binding (hybridization) 
bioanalytical method (estimated sensitivity, 20 ng/ml). Pharmacokinetic (PK) parameters and 
details for analysis will be described in a separate analysis plan.  
3.2.5.4. 
Pharmacodynamic Parameters 
Pharmacodynamic assessments as described in the protocol were not all performed due to the 
early termination of the trial. All PD data that was collected, which includes nuclear factor 
kappa-light-chain-enhancer of activated B-cells (NF-kB) and cytokine data, will be listed.    
 


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4. 
PATIENT POPULATION 
4.1. 
Population Definitions 
The following patient populations will be evaluated and used for presentation and analysis of 
the data: 
 DLT Evaluable Population: All patients enrolled in the Phase 1 dose escalation portion 
of the study who receive all planned doses of study drug during the DLT observation 
period or who discontinue treatment due to AEs. 
 Safety Population:  All patients who received at least 1 injection of study treatment. 
The CRC review will be performed on the DLT Evaluable Population for the dose being 
considered. Safety analyses will be performed using all available information for the Safety 
Population. The limited efficacy data will also be presented using the Safety Population.  
4.2. 
Protocol Deviations 
All protocol deviations will be presented in a data listing. 
Relevant Output 
Listing 16.2.2.3   
Protocol Deviations 


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5. 
GENERAL STATISTICAL METHODS 
5.1. 
Sample Size Justification 
To identify the MTD/RP2D of IMO-8400 in this population, the sample size in the Phase 1 
portion of the study will start with 3 patients, and expand as described in Section 3.2.1.1. The 
maximum number of patients expected in the dose escalation cohort is approximately 30 
patients, and will be dependent upon tolerability results observed at each dose level.  
Following identification of the MTD, up to 29 additional patients will be enrolled at the 
RP2D.  Simon’s two‐stage optimal design will be used to test the response rate at the RP2D 
(Simon, 1989). The null hypothesis that the true response rate is 10% will be tested against a 
one‐sided alternative. In the first stage, 10 patients will be accrued. If there is at most 1 response 
in these 10 patients, the study will be stopped. Otherwise, 19 additional patients will be accrued 
for a total of 29. The null hypothesis will be rejected if 6 or more responses are observed in 29 
patients. This design yields a type I error rate of 4.7% and power of 80.5% when the true 
response rate is 30%. 
5.2. 
General Methods 
All data listings that contain an evaluation date will contain a relative study day (Rel Day). For 
the purpose of analysis, relative study day is defined as follows:  
 Rel Day 1 is defined as the calendar day of the first injection of study drug. 
 The days prior to Rel Day 1 are designated Rel Day –1, Rel Day –2, etc; there is no Rel Day 
0. 
 The days following the day of the first injection of study drug are designated Rel Day 2, Rel 
Day 3, etc. 
The times of events related to dosing of study drug will be designated as minutes or hours 
before or after the time of dosing (i.e., the subcutaneous injection of study drug), which is 
designated as t = 0 (zero). Thus, 15 minutes prior to dosing is t = –15 min; 2 hours after dosing 
is designated t = 2 h. 
All output will be produced as Microsoft Word files, sorted and labeled according to the 
International Conference on Harmonisation (ICH) recommendations, and formatted to the 
appropriate page size(s). 
Tabulations will be produced for safety parameters. For categorical variables, summary 
tabulations of the number and percentage of patients within each category (with a category for 
missing data) of the parameter will be presented. For continuous variables, the number of 
patients, mean, median, standard deviation, minimum, and maximum values will be presented.  
Data will be presented by patient and summarized by dose level and overall, including a pooled 
cohort of all IMO-8400 dosed groups. Only dose groups that enrolled at least 1 patient will be 
presented.  
Relevant Output 
Table 14.0.1   
Treatment Codes Applicable to Tables and Listings 


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5.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software Version 9.3 
or above, unless otherwise noted.   
5.4. 
Baseline Definitions 
For all analyses, baseline will be defined as the most recent measurement prior to the first 
administration of study drug. 
5.5. 
Methods of Pooling Data 
Data will be pooled across all study sites.  
5.6. 
Adjustments for Covariates 
No formal statistical analyses that adjust for possible covariate effects are planned. 
5.7. 
Multiple Comparisons 
No adjustments for multiple comparisons will be made. As the primary purpose of this study is 
to assess the safety and tolerability of IMO-8400, efficacy assessments are secondary and the 
type I error rate will not be adjusted. 
5.8. 
Subpopulations 
No analyses of subpopulations are planned.  
5.9. 
Withdrawals, Dropouts, Loss to Follow-up 
During Phase 1, a patient who does not meet the criteria to be included in the DLT Evaluable 
Population defined in Section 4.1 may be replaced to assure the requirements for completing the 
cohort are met.  Replacement patients will be identified by distinctive patient numbers and will 
receive the same dose level as the patient being replaced.  
5.10. 
Missing Data 
Missing data will not be imputed, except as described in this section. All the data recorded on 
the eCRF will be included in data listings that will accompany the CSR.   
When tabulating AE data, partial dates will be handled as follows. If the day of the month is 
missing, the onset day will be set to the first day of the month unless it is the same month and 
year as study treatment.  In this case, in order to conservatively report the event as treatment-
emergent, the onset date will be assumed to be the first date of treatment. If the onset day and 
month are both missing, the day and month will be assumed to be January 1, unless the event 
occurred in the same year as the study treatment. In this case, the event onset will be coded to 
the day of treatment in order to conservatively report the event as treatment-emergent. A 
missing onset date will be coded as the first day of treatment.  Listings will present all data as 
reported (i.e., without imputations). 
5.11. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule; visits outside of this 
schedule will be listed as a protocol deviation. Data will be tabulated by nominal visit and a 
windowing strategy will not be employed.  


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Unscheduled assessments will not be summarized in tabulations that present data by visit.  
However, in shift tables or summaries of best response, data from unscheduled assessments will 
be included. All data from unscheduled assessments will be listed. 
In data listings, the relative day of all dates will be presented.  
5.12. 
Interim Analyses 
Interim safety data will be examined on an ongoing basis to ensure patient safety and to comply 
with the clinical trial dose escalation rules.  
The protocol-specified interim analysis of efficacy in Phase 2 will not be conducted due to the 
early termination of the study. 


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6. 
STUDY ANALYSES 
6.1. 
Patient Disposition 
By-patient listings of patient disposition, inclusion and exclusion criteria, reasons for screen 
failure, and study populations will be produced.  
Relevant Output 
Listing 16.2.1.1   
Patient Disposition 
Listing 16.2.1.2   
End of Treatment (EOT) Visit Status 
Listing 16.2.1.3   
End of Study (EOS) Visit Status 
Listing 16.2.2.1   
Listing of Inclusion/Exclusion Criteria Not Met 
Listing 16.2.2.2   
Listing of Reasons for Screen Failure 
Listing 16.2.3.1   
Study Populations 
 
6.2. 
Demographics, Baseline Characteristics, and Medical History 
Demographics, baseline characteristics, medical history, disease history, MyD88L265P 
mutation status, and prior treatments will be listed. Medical history will be coded using 
MedDRA version 16.0 (or later).   
Relevant Output: 
Listing 16.2.4.1   
Demographic Characteristics 
Listing 16.2.4.2   
Medical History 
Listing 16.2.4.3A   
Disease History: Part 1 
Listing 16.2.4.3B   
Disease History: Part 2 
Listing 16.2.4.4   
Prior Therapy 
Listing 16.2.4.5    
MyD88 L265P Mutation Status 
 
6.3. 
Safety Analyses 
Safety analyses will be conducted using the Safety Population, and presented by dose level and 
overall. Safety data will be analyzed using descriptive statistics and tabulation. No formal 
statistical comparisons are planned. All safety data will be presented in listings. 
6.3.1. 
Study Drug Exposure 
Study drug exposure will be tabulated by the number of weeks of study drug received, where a 
week of study drug received is defined as any week during which the patient received at least 1 
dose. Cumulative dose (mg) will be summarized using descriptive statistics, where cumulative 
dose is the actual dose injected summed across all visits. The actual dose for each injection will 
be presented in mg/kg and calculated as follows, using body weight measured at screening: dose 
(mg/kg) = dose volume (mL) × dose concentration (mg/mL) / body weight (kg) 
 
The number of missed doses will be tabulated, as well as the reason the dose was missed per 
patient (i.e. if a patient missed multiple doses for the same reason, they will only be counted 
once for that reason). Dosing information for each patient will be presented in a data listing.  
Relevant Output: 


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Table 14.3.5.1   
Study Drug Exposure (Safety Population) 
Listing 16.2.5.1   
Study Drug Exposure 
6.3.2. 
Adverse Events 
Adverse events will be coded using the MedDRA coding system and displayed in tables and 
data listings using SOC and preferred term. 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined as:  
 any AE with onset after the first administration of study medication (Day 1) through the 
end of study (EOS) visit,  
 any AE that was present at baseline but worsened in intensity, or 
 any AE with missing onset date.  
TEAEs will be summarized by patient incidence rates; therefore, in any tabulation, a patient 
contributes only once to the count for a given TEAE (SOC or preferred term), regardless of the 
number of episodes of a particular AE term reported.  No formal hypothesis-testing analysis of 
TEAE incidence rates will be performed. 
In an overview of TEAEs, a summary of the number and percentage of patients with any TEAE, 
TEAE related to study drug, TEAE ≥ Grade 3, serious adverse event (SAE), DLT, TEAE 
leading to discontinuation of study treatment, TEAE leading to dose modification, and TEAE 
leading to death will be produced.   
Summary tables by preferred term will be produced for the following:  
 All TEAEs (this summary will also be produced by SOC and preferred term) 
 All TEAEs by relationship to study drug (drug-related, not drug-related) where drug-related 
AEs include events with probable, possible, and missing relationships 
 All TEAEs by maximum severity grade (i.e. Grade 1, Grade  2, Grade 3, Grade 4, or Grade 
5) 
 All SAEs 
 All non-serious TEAEs 
 TEAEs leading to discontinuation of study treatment 
 TEAEs leading to dose modification 
Observed ISRs ≥ Grade 2 will be summarized by dose level and overall, by worst grade on 
study.  Pain, tenderness, pruritus, and induration will be summarized using number and 
percentage of patients by toxicity grade. Induration and erythema measurements (mm) will be 
summarized descriptively, including quartiles and 90th percentiles. Blisters, ulceration and 
necrosis measurements (mm) will be summarized descriptively, including quartiles and 90th 
percentiles, as well as categorically by grade.  For each summary, the worst grade is counted per 
patient and symptom.  
All AEs occurring from the time of signing informed consent will be listed. Additionally, a 
glossary of AE verbatim terms by preferred term and SOC will be provided.  
By-patient listings will also be provided for the following: AEs leading to death, SAEs, TEAEs 
leading to discontinuation of study treatment, TEAEs leading to dose-modification, and DLTs. 


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Relevant Output: 
Table 14.3.1.1   
Overview of Adverse Events (Safety Population) 
Table 14.3.1.2A   
Incidence of Adverse Events by MedDRA Preferred Term (Safety 
Population) 
Table 14.3.1.2B   
Incidence of Adverse Events by MedDRA System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.3   
Incidence of Adverse Events by Relationship to Study Drug and by 
MedDRA Preferred Term (Safety Population) 
Table 14.3.1.4   
Incidence of Adverse Events by Maximum Severity Grade and by 
MedDRA Preferred Term (Safety Population) 
Table 14.3.1.5  
Incidence of Serious Adverse Events by MedDRA Preferred Term 
(Safety Population) 
Table 14.3.1.6  
Incidence of Non-Serious Adverse Events by MedDRA Preferred Term 
(Safety Population) 
Table 14.3.1.7   
Incidence of Adverse Events Leading to Discontinuation of Treatment by 
MedDRA Preferred Term (Safety Population) 
Table 14.3.1.8   
Incidence of Adverse Events Leading to Dose Modification by MedDRA 
Preferred Term (Safety Population) 
Table 14.3.1.9  
Incidence of Observed Injection Site Reactions ≥ Grade 2 by Worst 
Grade Post Baseline (Safety Population) 
Table 14.3.2.1   
Listing of Adverse Events Leading to Death  
Table 14.3.2.2   
Listing of Serious Adverse Events 
Table 14.3.2.3   
Listing of Adverse Events Leading to Discontinuation of Treatment 
Table 14.3.2.4   
Listing of Adverse Events Leading to Dose Modification 
Listing 16.2.7.1   
Adverse Events by Patient and MedDRA System Organ Class / Preferred 
Term 
Listing 16.2.7.2   
Adverse Events by MedDRA Preferred Term and Patient  
Listing 16.2.7.3   
Glossary of Adverse Event Verbatim Terms by MedDRA System Organ 
Class, Preferred Term, and Patient 
Listing 16.2.7.4A   
Injection Site Reactions: Part 1 – Assessments 
Listing 16.2.7.4B   
Injection Site Reactions: Part 2 – Patient Reported Reactions 
Listing 16.2.7.4C   
Injection Site Reactions: Part 3 – Observed Reactions 
6.3.3. 
Laboratory Data 
Clinical laboratory values will be reported in conventional International System of Units (SI) 
units.  
Shift tables relative to the CTCAE grade and, for laboratory results not graded by the CTCAE, 
relative to the normal range, will be produced for hematology, chemistry, coagulation, and 
serum complement parameters.  
Laboratory CTCAE grades shift from baseline to the worst grade post baseline over all visits 
(scheduled and unscheduled) will be tabulated using number and percentage of patients.  
Laboratory parameters that do not have CTCAE grades will be summarized by shift from 
baseline to the worst-case post baseline relative to the normal range (i.e. to highest increase and 
lowest decrease from baseline) for all visits (scheduled and unscheduled), again tabulated using 
number and percentage of patients.  


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All laboratory data will be listed, including serum complement data, urinalysis, serologic tests 
(for screening only), and pregnancy tests (females only). Abnormal laboratory values will be 
flagged and the CTCAE grade included. 
Relevant Output: 
Table 14.3.5.2A   
Shifts from Baseline to Worst CTCAE Grade Post-Baseline in 
Hematology Parameters by Dose Group (Safety Population) 
Table 14.3.5.2B   
Shifts from Baseline to Worst CTCAE Grade Post-Baseline in Chemistry 
Parameters by Dose Group (Safety Population) 
Table 14.3.5.2C   
Shifts from Baseline to Worst CTCAE Grade Post-Baseline in 
Coagulation Parameters by Dose Group (Safety Population) 
Table 14.3.5.3A 
Shifts from Baseline to Lowest Decrease or Highest Increase Post-
Baseline Relative to the Normal Range in Hematology Parameters by 
Dose Group (Safety Population) 
Table 14.3.5.3B 
Shifts from Baseline to Lowest Decrease or Highest Increase Post-
Baseline Relative to the Normal Range in Chemistry Parameters by Dose 
Group (Safety Population) 
Table 14.3.5.3C 
Shifts from Baseline to Lowest Decrease or Highest Increase Post-
Baseline Relative to the Normal Range in Coagulation Parameters by 
Dose Group (Safety Population) 
Table 14.3.5.3D 
Shifts from Baseline to Lowest Decrease or Highest Increase Post-
Baseline Relative to the Normal Range in Serum Complement Parameters 
by Dose Group (Safety Population) 
Listing 16.2.8.1A 
Central Laboratory Results: Hematology  
Listing 16.2.8.1B 
Local Laboratory Results: Hematology   
Listing 16.2.8.2A 
Central Laboratory Results: Chemistry  
Listing 16.2.8.2B 
Local Laboratory Results: Chemistry 
Listing 16.2.8.3A 
Central Laboratory Results: Urinalysis 
Listing 16.2.8.3B 
Local Laboratory Results: Urinalysis 
Listing 16.2.8.4A 
Central Laboratory Results: Coagulation 
Listing 16.2.8.4B 
Local Laboratory Results: Coagulation 
Listing 16.2.8.5 
Central Laboratory Results: Serum Complement  
Listing 16.2.8.6A 
Central Laboratory Results: Serology 
Listing 16.2.8.6B 
Local Laboratory Results: Serology 
Listing 16.2.8.7 
Urine Pregnancy Test Results 
6.3.4. 
Vital Signs  
Bi-directional shift tables from baseline to worse value post-baseline relative to the normal 
range will be tabulated using number and percentage of patients, separately by increases or 
decreases in value for each parameter (i.e. to highest increase and lowest decrease from 
baseline).  This summary will include values from unscheduled visits. 
Vital sign measurements will be listed. 
Relevant Output: 
Table 14.3.5.4   
Shifts from Baseline to Lowest Decrease or Highest Increase Post-
Baseline Relative to the Normal Range for Vital Signs (Safety 
Population) 


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Listing 16.2.9.1   
Vital Signs 
6.3.5. 
Physical Examination 
All physical examination findings and ECOG Performance Status will be listed. 
Relevant Output: 
Listing 16.2.9.2   
Physical Examination Findings 
Listing 16.2.9.3 
ECOG Performance Status 
6.3.6. 
Electrocardiogram 
Electrocardiogram results will be summarized descriptively, including the number and 
percentage of patients with a QT interval corrected for heart rate using Fridericia’s formula 
(QTcF) > 400 msec, > 450 msec, > 480 msec, and > 500 msec and increase from baseline QTcF 
of ≥ 30 msec and ≥ 60 msec. QTcF will be derived for all patients using the formula: 
QT/(RR^(1/3)), where RR = 60/heart rate if not collected separately.  
All ECG data will be listed. 
Relevant Output: 
Table 14.3.5.5   
Summary of Maximum QTc Interval Prolongation and Change from 
Baseline in QTc Interval (Safety Population) 
Listing 16.2.9.4   
12-Lead Electrocardiogram Interval and Overall Assessment 
6.3.7. 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary Version Q12013 (or later).  
Any medications that did not end prior to first dose will be classified as a concomitant 
medication, as well as medications that are ongoing or those missing an end date.  
Concomitant medications will be listed. 
Relevant Output: 
Listing 16.2.9.5   
Concomitant Medication 
6.4. 
Efficacy Analyses 
Best overall response, summarized by the number and percentage of patients in each best overall 
response category, will be presented using the Safety Population. No other efficacy analyses 
will be presented.  
All efficacy data will be listed.  
Relevant Output: 
Table 14.2.1   
Summary of Best Overall Response (Safety Population) 
Listing 16.2.6.1   
Disease Response  
Listing 16.2.6.2  
Tumor Assessment 
Listing 16.2.6.3A   
Radiological Imaging: Part 1 – General Assessment 
Listing 16.2.6.3B   
Radiological Imaging: Part 2 – Lesion Assessment 
Listing 16.2.6.3C   
Radiological Imaging: Part 3 – Spleen and Liver Assessment 
Listing 16.2.6.4   
Bone Marrow Biopsy Results  


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6.5. 
Pharmacokinetic Analyses 
All PK analyses will be conducted outside the scope of this analysis plan. Date and time of PK 
data collection will be listed. 
Relevant Output 
Listing 16.2.5.2   
Pharmacokinetic Collection Dates 
6.6. 
Pharmacodynamic Analyses 
Pharmacodynamic collection dates and any corresponding results, including serum cytokine 
results, will be listed.   
Relevant Output 
Listing 16.2.5.3   
Pharmacodynamic Collection Dates and Results 
Listing 16.2.5.4   
Serum Cytokines  
 


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7. 
CHANGES TO PLANNED ANALYSES 
The protocol describes efficacy parameters for this study in Sections 1.8, 12.4, and 12.5. Due to 
the premature closure of the study, this document states that the only efficacy summary will be 
best overall response. No additional summaries of efficacy will be presented. Sections 1.8 and 
12.3 of the protocol also describe time-to-event analyses for ISRs; this safety analysis is not 
included in this document.  
 
Sections 1.8 and 12.2 of the protocol defines an Intent-to-treat/Safety Population. This 
population is renamed to “Safety Population” for this document, as described in Section 4.1. 
Section 12.2 of the protocol also describes a Per-Protocol and Efficacy Evaluable Population to 
be evaluated. Due to the limited enrollment in this study, and the lack of efficacy summaries, the 
Safety Population will be used for presentation of efficacy data.  
 
If additional changes to the analyses planned in the protocol are made, then these will be listed 
in the CSR, along with an explanation as to why they occurred. 
 


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8. 
REFERENCES 
 
Cheson B, Pfistner B, Juweid ME et al. Revised response criteria for malignant lymphoma. J 
Clin Oncol. 2007; 25(5):579-586. 
 
Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MyD88 mutations in human 
lymphoma. Nature. 2011;470(7332): 115–119. 
 
Young RM, Staudt LM. Targeting pathologic B cell receptor signaling in lymphoid 
malignancies. Nature Rev Drug Discovery. 2013; 12:229-243. 
 
Lim K-H, Barton GM, Staudt LM. Oncogenic MyD88 mutants require Toll-like receptors. 
Amer Assoc Cancer Res, 2013 Annual Meeting, Abstract 2332. 
 
Bhagat L, Wang D, Jiang W, et al. IMO-8400, a selective antagonist of TLRs 7, 8 and 9, inhibits 
MYD88 L265P mutation-driven signaling and cell survival: A potential novel approach for 
treatment of B-cell lymphomas harboring MYD88 L265P mutation. Abstract, AACR 
Annual Meeting 2014, San Diego, California, April 5-9, 2014. 
 
Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s 
macroglobulinemia. N Engl J Med 2012; 367:826-33. 
 
Thomas S, Harb W, Beck T, et al. Interim Results From a Phase 1/2, Open-Label. Dose-
Escalation Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenströms’s 
Macroglobulinemia Abstract, ASH Annual Meeting 2015. 
 
Simon R. Optimal two-stage design for phase II clinical trials. Control Clin Trials. 1989; 10(1):1 
10. 
 
SEER Cancer Statistics Factsheets: Non-Hodgkin Lymphoma. National Cancer Institute. 
Bethesda, MD, http://seer.cancer.gov/statfacts/html/nhl.html. Accessed 5 November 2013.


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9. 
CLINICAL STUDY REPORT APPENDICES 
 
9.1. 
Statistical Tables and Figures to be Generated 
 
9.2. 
Data Listings to be Generated 


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10. 
REVISION HISTORY 
Not applicable; this is the first draft of this document.  


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