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 Waldenstrom's Macroglobulinemia
Phase: PHASE1
Conditions: Waldenstrom's Macroglobulinemia
Sponsor: Idera Pharmaceuticals, Inc.

IMO-8400 
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 PROTOCOL 8400-401 
 
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 Waldenström’s Macroglobulinemia 
Investigational Drug: 
IMO-8400 
FDA IND: 
119651 
Sponsor: 
Idera Pharmaceuticals, Inc. 
167 Sidney Street  
Cambridge, MA 02139 
Protocol Number: 
8400-401  
Protocol Version: 
7.0 
Date: 
14 March 2016 
 
 
 
 
 
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Statement of Confidentiality 
This document contains Idera Pharmaceuticals’ privileged or confidential information and is 
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you, your staff and applicable institutional review board(s). The information is not to be 
disclosed to others without written authorization from Idera Pharmaceuticals, Inc. 

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Contact Information  
Any serious adverse event (SAE) must be reported within 24 hours. 
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 
Vice President & 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 
Vice President & 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 
Vice President & 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 
Nicole Pusey 
Project Manager, Early Phase Oncology 
INC Research, LLC 
3201 Beechleaf Ct., Suite 600 
Raleigh, NC 27609 
Office: +1 919 341 3302 
email: nicole.pusey@incresearch.com  
 
 
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1. 
SYNOPSIS 
1.1. 
Protocol Information 
Protocol Number 
8400-401 
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 
Waldenström’s Macroglobulinemia 
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 Waldenström’s Macroglobulinemia  
Number of Patients 
Approximately 60 patients in planned escalation and expansion cohorts; potential 
for additional patients in contingency cohorts or as replacements 
Number of Sites 
Multiple Centers in the US 
Date first patient enrolled  
Q2 2014 
Est. date last patient enrolled  
Q4 2016  
Est. date last patient last visit 
Q2 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 
Waldenström’s Macroglobulinemia (WM).  
1.2.2. 
Secondary Objectives 
• To assess the treatment effect (clinical activity) of escalating dose levels of 
IMO-8400 using disease-specific international guidelines for classifying clinical 
response [1].  
• To identify an optimal dose of IMO-8400 for further clinical evaluation. 
• To characterize the pharmacokinetics (PK) 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 correlate the presence of myeloid differentiation primary response gene (88) 
L265P mutation with clinical outcome. 
• 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 and Rationale 
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 SC injection at single-doses and multiple-doses 
(once weekly for 4 weeks) up to 0.6 mg/kg (see Section 4.4 for details).  All treatments were 
well-tolerated, with mild injection site reactions (ISRs) and no pattern of systemic reactions or 
laboratory changes.  
In recent studies, a high frequency of mutation in the signaling pathway downstream of TLR7, 8, 
and 9 has been identified in patients with B-cell malignancies, including more than 90% of 
patients with WM [2].  In vitro studies of B-cell tumor lines indicate that such mutations are 
associated with an increase in cell activation, proliferation, and survival [3], and that 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 (see 
Investigator’s Brochure for details).  
The current study represents the first clinical trial of IMO-8400 in patients with B-cell 
malignancy.  
1.3.2. 
Study Overview 
This is an open-label, multiple-dose, dose escalation study of IMO-8400 in patients with relapsed 
or refractory WM.  
1.3.3. 
Dose-escalation Cohorts 
The dose-escalation cohorts (3 to 6 patients each) will systematically evaluate the safety and 
tolerability of IMO-8400 at increasing dose levels in order to identify the maximum tolerated 
dose (MTD)/recommended Phase 2 dose (RP2D).  
• The planned dose escalation cohort levels for IMO-8400 are 0.6, 1.2, 2.4, and 
3.6 mg/kg administered once weekly and 1.2 mg/kg administered twice weekly 
(Table-3). Additional dose levels, schedules, and routes of administration may be 
evaluated based upon the emerging data. Weekly exposure is based on body weight 
(see Section 8.1 for details). Doses will be administered by SC injection.  
• For Dose Level 3 (refer to Table-3), the total dose will be divided into 2 equal 
portions (1.2 mg/kg twice weekly), administered as separate SC injections over the 
course of the week, preferably 72 to 96 hours apart (minimum 48 hours) (see 
Section 8.4 for details).  
• Once safety has been established for the 2.4 mg/kg/week as a divided weekly dose 
(1.2 mg/kg twice weekly), the same dose level of 2.4 mg/kg/week and subsequent 
dose levels will be given as a once weekly administration. 
• Once the RP2D/MTD has been established, patients being treated at lower dose levels 
may have their doses escalated to the RP2D/MTD upon discussion and agreement 
between the Sponsor and the Investigator.  
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Table-3. 
Planned Dose Escalation Cohorts 
Dose Level 
IMO-8400 Dose (mg/kg)  
Frequency 
Initial Cohort Size 
1 (starting dose) 
0.6 
Once Weekly 
3-6 
2 
1.2  
Once Weekly 
3-6 
3 
1.2 
Twice Weekly 
3-6 
4 
2.4 
Once Weekly 
3-6 
5 
3.6 
Once Weekly 
3-6 
1.3.4. 
Dose-escalation Procedures 
Procedures for patient safety are summarized below and presented in detail in the protocol 
sections indicated:  
• Explicit definitions for identifying suspected adverse reactions as dose-limiting 
toxicity (DLT) events (see Section 6.3.1 for details). 
• Explicit definition for MTD (see Section 6.3.2). 
• All injections of study medication will be administered by study personnel and all 
patients observed for 2 hours following the first injection (including the first injection 
of a new dose level in the case of intra-patient dose escalation) and for at least 30 min 
following all other injections.  
• Detailed provisions for management of study drug in individual patients based on 
safety, tolerability, and disease response (see Section 6.5).  
• Constitution of a Data Review Committee (DRC) 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 6.3.3). 
1.3.5. 
Dose-escalation Enrollment and Review 
Each dose-escalation cohort is expected to enroll at least 3 patients, with a maximum of 6.  
• If the initial 3 patients all complete 4 weeks of treatment without a DLT event, the 
DRC will conduct a dose-escalation review.  
• If 1 of the initial 3 patients experiences a DLT event prior to completing 4 weeks of 
treatment, 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 4 weeks 
treatment. 
• If 2 patients at a dose-level experience DLT events during the first 4 weeks of 
treatment, then no further patients will be enrolled until the DRC completes a review, 
which should be done as soon as feasible.  
The DRC review will include all safety data available for the cohort.  The following represent 
anticipated outcomes for the review process.  
• Dose escalation – progression to the next planned dose level.  
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• Continue cohort enrollment (applicable only to review after 3 patients) – enroll up to 
6 patients at the current dose level to obtain additional safety data for subsequent 
review. 
• Dose de-escalation – enrollment of intermediate dose levels for exploration of other 
schedules of administration (see Section 6.5.2).  
• Approve enrollment in an expansion cohort at a selected dose level, if applicable (see 
Section 1.3.6). 
• No further dose escalation enrollment – at this time the DRC will indicate the dose 
level that they consider represents the MTD.  
1.3.6. 
Expansion Cohorts 
The expansion cohorts provide for additional enrollment at agreed upon dose levels to assess the 
dose dependence of clinical response.   
Once the MTD or a potential RP2D and/or schedule have been established during dose 
escalation, up to 22 patients will be treated at the RP2D level according to this schedule.  The 
Sponsor may decide at any point during the expansion phase to modify the RP2D based on 
emerging data including, but not limited to, safety, DLTs, PK, and clinical activity.  If such a 
change is made, enrollment may continue at the selected dose level in up to 22 patients.  
1.3.7. 
Management of Study Treatment in Individual Patients 
Each enrolled patient will receive IMO-8400 at the assigned dose level until the earliest of: 
• Clinical DLT event – see Section 6.3.1.  
− Study treatment will be discontinued in patients determined to have a clinical 
DLT event until resolution and may only be resumed after discussion with an 
Idera Medical Monitor and agreement that it is in the patient’s best interest to 
continue. 
− For a dose modifying event (DME), provision is made for interrupting dosing for 
up to 3 weeks and, if the acute toxicity improves sufficiently, resuming treatment 
at a lower dose level based on discussion between the sponsor’s designated 
medical monitor and the treating physician. 
− For DLT laboratory 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 (see Section 6.5.2 for details).  
− The Investigator will review with the Medical Monitor decisions to discontinue, 
pause, and/or restart study treatment. 
• Disease progression – based on scheduled assessments at Week 1 of each cycle.  
Unscheduled assessments may be conducted in response to new clinical observations.  
Disease status will be classified according to international guidelines [1] (see 
Section 9.5 for details).  
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• Termination of participation in the study – due to adverse event (AE), withdrawal of 
consent, intolerable toxicity, or loss to follow up.  
In certain instances, patients may be deriving clinical benefit despite objective 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, 
provided the conditions in Section 6.5.1 are met. 
1.4. 
Study Structure  
• Screening will be done within 21 days prior to Day 1 (the first injection of study 
drug). See Section 9.2 for details of screening and Section 9.3 for details of the 
enrollment process.  
• Treatment is scheduled to be administered in 8-week cycles until progressive disease, 
unacceptable toxicity, withdrawal of consent, or end of study.  
• Assessments for treatment response (or disease progression) are scheduled every 
8 weeks ± 1 week (at the start of a new cycle) for clinical assessments (see 
Section 9.4.1), and every 4 weeks ± 1 week for laboratory assessments (see 
Section 9.4.2). 
• End-of-Treatment (EOT) visit will be performed within 5 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.  
A detailed schedule of events is presented in Table-4.  
1.5. 
Diagnosis and Patient Selection Criteria  
1.5.1. 
Qualifying Disease 
To be eligible for this study, a patient must have WM meeting all of the following criteria:  
1. Primary diagnosis established according to criteria of the Second International Workshop 
on WM [5] (see Section 16.1).  
2. Has relapsed or progressed (“refractory”) based on the criteria for assessing response 
from the VIth International Workshop on WM [1] (see Section 9.5).  
3. Has, at Screening, serum monoclonal Immunoglobulin M protein ≥ 0.5 g/dL.  
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1.5.2. 
Inclusion Criteria 
To be eligible for this study, a patient must meet all of the following inclusion criteria: 
1. Be at least 18 years of age 
2. Have signed the current approved informed consent form 
3. Have an Eastern Cooperative Oncology Group Performance Status ≤ 2 
4. Patients must meet the following laboratory criteria 
- Hemoglobin ≥ 7.5 g/dL 
- Absolute neutrophil count ≥ 1.0 x 109/L (1000/mm3)  
- Platelets ≥ 50,000/μL  
- Serum creatinine ≤ 2.5 x the upper limit of normal (ULN)  
- Serum aspartate aminotransferase ≤ 2.5 x ULN  
- Serum alanine aminotransferase ≤ 2.5 x ULN  
- Total bilirubin ≤ 1.5 x ULN  
- Prothrombin time ≤ 1.5 x ULN 
5. Life expectancy > 3 months 
6. 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: 
– 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 
7. For women of childbearing potential, have a negative serum pregnancy test at Screening  
8. Be willing and able to comply with this protocol 
1.5.3. 
Exclusion Criteria 
Patients with any of the following will be excluded from participation in the study: 
1. Has known hypersensitivity to any oligodeoxynucleotide 
2. Is nursing 
3. Has body mass index > 34.9 kg/m2 
4. Has an indeterminate or positive test for antibody to human immunodeficiency virus 
(HIV-1 or -2) or hepatitis C virus 
5. Has a positive test for hepatitis B surface antigen  
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6. Has known complement deficiency such as properdin deficiency or hereditary 
angioedema 
7. 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 
8. Has, at the initiation of study drug, received cytotoxic chemotherapy or a Bruton’s 
tyrosine kinase (BTK)-inhibitor (e.g. ibrutinib) 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 
9. Has, at the initiation of study drug, an active infection requiring systemic antibiotics 
10. 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  
11. Has active autoimmune cytopenia (anemia, thrombocytopenia, leukopenia) requiring 
concomitant therapy 
12. Has heart failure of Class III or IV (New York Heart Association criteria) 
13. Has sensory or motor neuropathy of Grade 4 (National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE v4.03 criteria]) 
14. 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; or uncontrolled 
diabetes 
15. Has any other condition that would, in the opinion of the Investigator, potentially 
compromise the safety or compliance of the patient or may preclude the patient’s 
successful completion of the clinical trial 
16. History of another primary malignancy that has not been in remission for at least 3 years.  
The following are exempt from the 3 year limit: nonmelanoma skin cancer, curatively 
treated localized prostate cancer with nondetectable prostate specific antigen, and 
cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on PAP smear 
17. Lactating or pregnant women 
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.  
• Injection volume will not exceed 1.2 mL/site, with multiple sites used per dose as 
necessary. 
• Dose to be recalculated if change in body weight from Screening exceeds 10% (±).  
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• Injections will be administered in the 4 quadrants of the abdomen or in the upper 
thighs, rotating injection site each time IMO-8400 is administered (see Section 8.4).  
• Scheduled duration of study treatment is until withdrawn consent, progressive 
disease, end of study, or intolerable toxicity with provision for dose adjustment in the 
event of a laboratory DLT or occurrence of a DME (see Section 6.5).  
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 first weekly dose 
administered on Day 1 of every cycle, at pre-dose and at 1 (± 5 minutes), 2 (± 10 minutes), and 
4 (± 15 minutes) hours post-dose.  A PK sample will also be taken at the EOT and EOS visits.  
Plasma samples will be analyzed for IMO-8400 concentration using a validated bioanalytical 
method.  Pharmacokinetic analysis will be conducted on an individual basis.  
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.  
• Symptom review and vital signs at each scheduled visit.  
• Physical exam and electrocardiogram (ECG) (see Section 9.6). 
• Laboratory safety tests (hematology, serum complement, clinical chemistry, 
urinalysis) every 4 weeks (Section 9.7). 
• Injection site reactions (see Section 9.6.5) 
• Additional unscheduled assessments at Investigator’s discretion. 
Adverse events will be graded according to NCI CTCAE version 4.03.  Adverse events will be 
coded using Medical Dictionary for Regulatory Activities version 16.0 and tabulated by event, 
grade, and relationship to study therapy.  Laboratory results, vital signs, and ECG parameters 
will be summarized using descriptive statistics.  Laboratory values will also be graded according 
to NCI CTCAE, version 4.03, and summarized using shift tables.  
1.7.3. 
Treatment Effect 
Assessments of disease status will be conducted at Screening, every 4 weeks ± 1 week (Week 1 
and Week 5 of each cycle; for laboratory assessments, see Section 9.4.2), every 8 weeks 
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± 1 week (Week 1 of each cycle; for clinical assessments, see Section 9.4.1), every 12 weeks 
± 4 weeks during the Follow-up Phase, at the EOT visit, and at the EOS visit.  Disease 
assessments will be classified based on the guidelines of the VIth International Workshop [1].  
Time to progression and duration of response will be measured as defined. See Section 9.5 for 
details.  Patients discontinued from the study for reasons other than progressive disease will be 
assessed at a minimum of every 12 weeks ± 4 weeks until documentation of progressive disease, 
initiation of a subsequent anti-cancer therapy, or until the study ends, for up to 6 months from the 
first treatment (Cycle 1, Day 1) for the last patient enrolled, whichever comes first.  
1.8. 
Statistical Methods 
Safety observations will be analyzed using descriptive statistics and tabulation.  
Following identification of the MTD/RP2D, up to an additional 22 patients will be enrolled at the 
MTD or proposed RP2D level.  With a total sample size of 22 patients, there is a 90% probability 
to detect an AE with a true incidence rate of 10%.  A secondary objective of this study is to 
determine the treatment effect of IMO-8400 in patients enrolled at the MTD/RP2D.  Using the 
exact binomial distribution with a 1-sided test and an alpha of 0.05, there is 79% power to detect 
a response rate of 33% as compared to a null response rate of 10%. 
 
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1.9. 
Schedule of Assessments  
Table-4.  
Schedule of Study Events 
Visit1 
Scrn2 
Day 1 
Treatment Period 
EOT3 
EOS3 
F/U 
Cycle 
 
 
Cycle 1 
Even Numbered 
Cycles 
Odd Numbered 
Cycles 
 
 
Every 12 weeks 
(± 4 weeks) 
Week 
 
 
2-4 
5 
6-8 
1 
2-4 
5 
6-8 
1 
2-4 
5 
6-8 
 
 
 
Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients who discontinue 
for reasons other than 
progressive disease should 
be assessed per Response 
Assessment in WM24 until 
documentation of 
progressive disease, start of 
new anti-cancer therapy, 
until the study ends, or for 
up to 6 months from the 
last patient’s first treatment 
cycle, whichever one 
comes first. 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cryoglobulin & Cold Agglutinin Lab 
Tests6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination8  
X 
X 
X8 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Body weight7 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Height measurement 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs9,10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical assessment for Tumor 
Status11 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Total IgM & Monoclonal Protein Lab 
Tests12 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
ECOG7 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
CT or MRI imaging13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Safety Laboratory Tests14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis7 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
12-lead ECG15 
X 
X15 
 
X15 
 
X15 
 
X15 
 
X15 
 
X15 
 
X 
 
Pregnancy test (females only)16 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK17 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Serum Cytokines18 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Antibodies to IMO-840018 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Serum NF-κB19 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Initial Dx Bone Marrow Slides20 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Biopsy & Aspirate21 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Assessment of Injection Site22 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Administration10, 23 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
AE & Concomitant Med Monitoring 
From Screening to EOS Visit 
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Abbreviations:  AE=adverse event; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOS=end-of-study; 
EOT=end-of-treatment; F/U=Follow-up; IgM=immunoglobulin M; NF-κB=nuclear factor kappa-light-chain-enhancer of activated B cells; 
PK=pharmacokinetic; MRI=magnetic resonance imaging; Scrn=Screening; WM=Waldenström’s macroglobulinemia 
1 Day 1 is the day of the first injection of study drug.  All weeks for a given cycle are relative to the day of the first injection of study drug for that Cycle and are 
defined as Day 1 through Day 7, inclusive; all times are relative to injection, designated 0 hour; “pre-dose” vital signs are to occur within 1 hour prior to 
injection; all other pre-dose procedures are to occur prior to injection on the same calendar day. 
2 Screening procedures may be performed up to 21 days prior to Day 1. 
3 If treatment is terminated prematurely for any reason, the EOT visit will be performed within 5 days of the decision to terminate; the EOS visit will be 
performed 30 to 35 days after the last dose of study drug. 
4 Informed consent must be signed prior to all study-specific screening procedures. 
5 Medical history includes, but is not limited to, a detailed review of the patient’s malignancy, prior treatments, relevant current or past abnormalities or diseases, 
and signs and symptoms of WM at baseline. 
6 Cryoglobulin and cold agglutinin laboratory testing to be performed at Screening (local laboratory). 
7 To occur pre-dose. 
8 During Cycle 1 only, physical examination will be done on Week 2.  In subsequent cycles, physical examinations will be done every 4 weeks. 
9 Vital signs comprise heart rate, blood pressure, respiratory rate and temperature. Vital signs will be obtained pre-dose (within 1 hour prior to injection) and 
post-dose at 30 (± 5) min after dosing. On Day 1 of Cycle 1, Week 1, post-dose vital signs will also be obtained at 2 hours (± 20 min). 
10 For patients who receive a second weekly dose, vital signs will be obtained pre-dose (within 1 hour prior to injection) and post-dose at 30 (± 5) min after 
dosing, and assessment of the injection site, as previously noted, will be conducted. 
11 Clinical assessment for tumor status will be conducted pre-dose on dosing visits and will include assessment for lymphadenopathy, hepatomegaly, and 
splenomegaly (see Section 9.4.1 for details).  
12 Assessments will be conducted pre-dose on dosing visits, and includes total serum IgM, monoclonal serum IgM, serum free light chains, urine free light 
chains, serum viscosity, and serum β2-microglobulin; see Section 9.4.2 for details. 
13 CT or MRI imaging of chest, abdomen, and pelvis with the same modality used for every assessment; see Section 9.4 for details. 
14 The full panel of safety laboratory tests (hematology, serum complement, chemistry and coagulation) will be done pre-dose on Day 1, and Weeks 1 and 5 of 
each cycle (including pre-treatment criteria presented in Section 8.4.1); a focused panel (hematology, selected chemistry) will be done pre-dose on Weeks 3 and 
7 of each cycle; see Section 9.7.1 for details. Unscheduled tests to confirm decreases in serum complement levels will be performed (see Section 6.5.4).  
15 ECGs are to be performed pre-dose and 2 hours post-dose on Day 1 of Cycle 1 and pre-dose at the first dosing visit of Weeks 1 and 5 of each cycle thereafter. 
In addition, an ECG is to be performed at 2 hours post-dose on Day 1 of each odd-numbered cycle. 
16 Serum pregnancy testing will be done pre-dose and evaluated at the central laboratory. 
17 PK samples will be collected as scheduled in relation to the first dose administered on Day 1 of every cycle.  Samples will be obtained pre-dose (within 1 hour 
prior to injection) and post-dose at 1 hour (± 5 min), 2 hours (± 10 min) and 4 hours (± 15 min) after dosing. PK samples will also be taken at EOT and EOS. 
18 Serum for cytokines and antibodies to IMO-8400 will be collected as scheduled in relation to the first dose administered on Day 1 of every cycle and will be 
obtained pre-dose (within 1 hour prior to injection).   
19 Serum samples for NF-κB analysis will be obtained pre-dose (within 1 hour prior to injection) and post-dose at 4 hours (± 15 min)  (see Section 9.9 for details) 
and will be submitted to central laboratory. 
20 Bone marrow slides will be obtained from initial WM diagnosis. 
21 Bone marrow biopsy and aspirate will be collected at Screening, EOT, and to document complete response as appropriate (see Section 16.2) and submitted to 
central laboratory (see Section 9.4.4 and Section 12.4.1).  If patients have a bone marrow biopsy within 4 weeks of EOT, the biopsy will not be repeated at 
EOT. The Screening Visit sample will also be assayed for the MyD88 L265P mutation. 
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22 Assessment of all prior injection site(s) with grading and measurement of any reaction (see Section 9.6.5).  In addition, on dosing days, the planned injection 
site will be assessed to confirm it is appropriate for use. 
23 Schedule applies to all patients receiving once weekly dosing and to the first weekly dose for all patients receiving twice weekly dosing (see Section 1.3.2 and 
Section 8.4 for details). 
24 Response assessment is summarized in Section 16.2 and includes total serum IgM, serum monoclonal IgM, bone marrow histology, adenopathy/organomegaly, 
cytopenias, and symptoms (see Section 9.5 for details). Total IgM and monoclonal protein lab tests (see Section 9.4.2 for details) will be submitted to central 
laboratory. 
 
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Table-5.  
Estimation of Blood Volumes Required From Screening through End-of-Study 
Tests 
Volume 
(mL) 
Screening 
(mL) 
Maximum Volume Per 
8-week Cycle (mL) 
EOT  
(mL) 
EOS 
(mL) 
Safety Lab Tests (full) 
19 
19 
38 
19 
19 
Safety Labs (focused) 
10 
 
20 
 
 
PK 
2 
 
8 
2 
2 
Serum Cytokines 
4 
4 
4 
4 
4 
Antibodies to IMO-8400 
4 
4 
4 
4 
4 
Serum NF-κB 
10 
 
20 
10 
10 
Tumor Assessments 
15 
15 
30 
15 
15 
Pregnancy test (F only) 
(extra blood volume is not 
required) 
X 
X 
X 
X 
X 
Serology 
10 
10 
 
 
 
Total mL blood drawn 
 
52 
124 
54 
54 
Abbreviations:  EOS=end-of-study; EOT=end-of-treatment; F=female; NF-κB=nuclear factor kappa-light-chain-
enhancer of activated B cells; PK=pharmacokinetic 
Note: The volumes shown are estimates; final volumes may vary, but will not be more than 15% greater than shown.  
 
 
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2. 
TABLE OF CONTENTS  
PROTOCOL 8400-401 ....................................................................................................................1 
1. 
SYNOPSIS ...................................................................................................................4 
1.1. 
Protocol Information .....................................................................................................4 
1.2. 
Objectives .....................................................................................................................4 
1.2.1. 
Primary Objective .........................................................................................................4 
1.2.2. 
Secondary Objectives ....................................................................................................4 
1.2.3. 
Exploratory Objectives .................................................................................................4 
1.3. 
Study Design and Methodology ...................................................................................5 
1.3.1. 
Brief Background and Rationale ..................................................................................5 
1.3.2. 
Study Overview .............................................................................................................5 
1.3.3. 
Dose-escalation Cohorts ..............................................................................................5 
1.3.4. 
Dose-escalation Procedures .........................................................................................6 
1.3.5. 
Dose-escalation Enrollment and Review ......................................................................6 
1.3.6. 
Expansion Cohorts........................................................................................................7 
1.3.7. 
Management of Study Treatment in Individual Patients ..............................................7 
1.4. 
Study Structure .............................................................................................................8 
1.5. 
Diagnosis and Patient Selection Criteria ......................................................................8 
1.5.1. 
Qualifying Disease ........................................................................................................8 
1.5.2. 
Inclusion Criteria ..........................................................................................................9 
1.5.3. 
Exclusion Criteria .........................................................................................................9 
1.6. 
Treatments ..................................................................................................................10 
1.6.1. 
Investigational Product, Dosage and Mode of Administration ..................................10 
1.6.2. 
Reference Therapy, Dosage and Mode of Administration ..........................................11 
1.7. 
Criteria for Evaluation ................................................................................................11 
1.7.1. 
Pharmacokinetics .......................................................................................................11 
1.7.2. 
Safety ...........................................................................................................................11 
1.7.3. 
Treatment Effect ..........................................................................................................11 
1.8. 
Statistical Methods ......................................................................................................12 
1.9. 
Schedule of Assessments ............................................................................................13 
2. 
TABLE OF CONTENTS ...........................................................................................17 
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3. 
LIST OF ABBREVIATIONS.....................................................................................25 
4. 
INTRODUCTION ......................................................................................................27 
4.1. 
Waldenström’s Macroglobulinemia (WM): the Disease under Study .......................27 
4.1.1. 
Current Standard of Care Therapy for WM ...............................................................27 
4.2. 
Role of Toll-like Receptors (TLRs) in B-cell Malignancy .........................................28 
4.3. 
Rationale for the Current Study ..................................................................................30 
4.4. 
Overview of IMO-8400 ..............................................................................................31 
4.4.1. 
Clinical Experience with WM .....................................................................................32 
4.4.2. 
Benefit/Risk Aspects ....................................................................................................32 
5. 
STUDY OBJECTIVES ..............................................................................................33 
5.1. 
Primary Objective .......................................................................................................33 
5.2. 
Secondary Objectives .................................................................................................33 
5.3. 
Exploratory Objectives ...............................................................................................33 
6. 
INVESTIGATIONAL PLAN .....................................................................................34 
6.1. 
Overall Study Design ..................................................................................................34 
6.2. 
Dose-escalation Cohorts .............................................................................................34 
6.3. 
Dose-escalation Procedures ........................................................................................35 
6.3.1. 
Definition of a Dose-Limiting Toxicity and Dose Modifying Event ...........................35 
6.3.2. 
Definition of Maximum Tolerated Dose and Recommended Phase 2 Dose ...............36 
6.3.3. 
Dose-escalation Enrollment and Review ....................................................................36 
6.4. 
Expansion Cohorts ......................................................................................................37 
6.5. 
Management of Individual Patients ............................................................................37 
6.5.1. 
Duration of Treatment ................................................................................................37 
6.5.2. 
Dose Modification in Patients with Laboratory DLT Events or DMEs .....................38 
6.5.3. 
Management of Systemic Injection Reactions ............................................................38 
6.5.4. 
Procedures for Assessment of Patients with Changes in Complement Levels ...........39 
6.5.5. 
Procedures for Assessment of Patients with Symptomatic Thrombocytopenia ..........39 
6.5.6. 
Classification of Patients at Termination of Treatment .............................................40 
6.6. 
Criteria for Replacement Patients ...............................................................................40 
6.6.1. 
Definition of a Evaluable Patient ...............................................................................40 
6.6.2. 
Replacement Patients ..................................................................................................40 
6.7. 
Maximum Number of Patients and Maximum Exposures .........................................41 
6.8. 
Treatment Assignment ................................................................................................41 
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6.9. 
Criteria for Study Termination ...................................................................................41 
6.10. 
Discussion of Study Design and Treatment Regimens ...............................................41 
6.10.1. 
Rationale for Study Structure .....................................................................................41 
6.10.2. 
Rationale for Treatment Regimens in Current Protocol ............................................42 
6.10.2.1. 
Dosing Regimen .........................................................................................................42 
6.10.2.2. 
Duration of Treatment ................................................................................................42 
7. 
SELECTION OF PATIENTS.....................................................................................43 
7.1. 
Source of Patients and Recruitment Methods .............................................................43 
7.2. 
Patient Restrictions during the Conduct of the Study .................................................43 
8. 
STUDY TREATMENT ..............................................................................................44 
8.1. 
Study Treatments to be Administered ........................................................................44 
8.2. 
Description and Manufacture of Study Drug ..............................................................44 
8.3. 
Reconstitution of IMO-8400 for Injection ..................................................................44 
8.4. 
Administration of Study Treatments ..........................................................................45 
8.4.1. 
Pre-Treatment Criteria ...............................................................................................45 
8.4.2. 
Variances in Dose Administration Schedule ..............................................................45 
8.5. 
Assigning Patients to Treatment Groups ....................................................................46 
8.6. 
Prior and Concomitant Medications ...........................................................................46 
8.6.1. 
Prohibited Treatments ................................................................................................46 
8.6.2. 
Other restrictions ........................................................................................................46 
8.7. 
Treatment Compliance ................................................................................................46 
8.8. 
Accountability of Investigational Drug Supplies .......................................................47 
8.8.1. 
Disposition of Study Drug ..........................................................................................47 
9. 
STUDY EVENTS AND EVALUATIONS ................................................................48 
9.1. 
Schedule of Events .....................................................................................................48 
9.2. 
Screening Procedure ...................................................................................................48 
9.3. 
Enrollment Procedure .................................................................................................49 
9.4. 
Assessments of Waldenström’s Macroglobulinemia ..................................................49 
9.4.1. 
Clinical Assessments ...................................................................................................49 
9.4.2. 
Laboratory Assessments Relating to Total IgM and Monoclonal Protein .................49 
9.4.3. 
Radiologic Imaging ....................................................................................................50 
9.4.4. 
Bone marrow biopsy and aspirate ..............................................................................50 
9.5. 
Evaluation of Response to Treatment and Disease Status ..........................................50 
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9.6. 
General Clinical Assessments .....................................................................................50 
9.6.1. 
Medical History, including WM .................................................................................50 
9.6.2. 
Physical Examination and Body Weight .....................................................................51 
9.6.3. 
Vital Signs ...................................................................................................................51 
9.6.4. 
Electrocardiogram ......................................................................................................51 
9.6.5. 
Injection Site Reaction (ISR) Assessments ..................................................................52 
9.7. 
Safety Laboratory Studies ...........................................................................................53 
9.7.1. 
Safety Laboratory Tests ..............................................................................................53 
9.7.2. 
Reporting of Safety Laboratory Tests .........................................................................54 
9.7.3. 
Repeating Abnormal Laboratory Tests .......................................................................54 
9.8. 
Pharmacokinetic Assessments ....................................................................................54 
9.9. 
Investigational Laboratory Studies .............................................................................54 
10. 
SAFETY ASSESSMENTS (ADVERSE EVENTS) ..................................................56 
10.1. 
Definition of Adverse Events .....................................................................................56 
10.1.1. 
Adverse Event .............................................................................................................56 
10.1.2. 
Serious Adverse Event ................................................................................................56 
10.1.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .......................................57 
10.2. 
Investigator Assessment of Safety Laboratory Tests ..................................................57 
10.3. 
Recording Adverse Events .........................................................................................58 
10.4. 
Characterizing Adverse Events ...................................................................................58 
10.4.1. 
Description of Event ...................................................................................................58 
10.4.2. 
Date and Time of Onset ..............................................................................................58 
10.4.3. 
Relationship to Study Drug .........................................................................................59 
10.4.4. 
Severity .......................................................................................................................59 
10.4.5. 
Grading of Laboratory Safety Tests for Reporting and Analysis ...............................60 
10.4.6. 
Management of Study Drug upon Occurrence of an Adverse Event ..........................60 
10.4.7. 
Actions Taken for Management of AE ........................................................................60 
10.4.8. 
Follow-up and Outcome of AEs ..................................................................................61 
10.4.9. 
Date and Time of Outcome .........................................................................................61 
10.5. 
Reporting Adverse Events ..........................................................................................62 
10.5.1. 
Where to Report SAEs ................................................................................................62 
10.5.2. 
Procedures for Reporting SAEs to the Sponsor ..........................................................62 
10.5.3. 
Other Reportable Events .............................................................................................63 
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10.5.4. 
Requirements for Expedited and Periodic Reporting of Adverse Events ...................63 
10.5.5. 
Notification of SAEs to the Investigator by the Sponsor .............................................63 
11. 
DATA QUALITY ASSURANCE ..............................................................................64 
11.1. 
Compliance .................................................................................................................64 
11.2. 
Training and Qualifications of Site Personnel ............................................................64 
11.3. 
Source Documents ......................................................................................................64 
11.3.1. 
Study-Specific Source Documents ..............................................................................65 
11.4. 
Electronic Case Report Forms ....................................................................................65 
11.5. 
Protocol Deviations ....................................................................................................66 
11.6. 
External Review of the Study Conduct at Participating Sites ....................................66 
11.7. 
Study Monitoring Visits .............................................................................................67 
11.7.1. 
Site Qualification and Initiation Visits .......................................................................67 
11.7.2. 
Interim Monitoring Visits ...........................................................................................67 
11.7.3. 
Study Closeout Visit ....................................................................................................68 
11.8. 
Resolution of Deficiencies ..........................................................................................68 
11.9. 
Retention of Records ..................................................................................................68 
11.10. 
Data Management .......................................................................................................69 
12. 
STATISTICS ..............................................................................................................70 
12.1. 
Sample Size Determination and Study Power ............................................................70 
12.2. 
Analysis Populations ..................................................................................................70 
12.3. 
Analysis of Safety .......................................................................................................70 
12.4. 
Analysis of Treatment Effect ......................................................................................71 
12.4.1. 
Assessments .................................................................................................................71 
12.4.1.1. 
Primary Treatment Effect Parameter ..........................................................................71 
12.4.1.2. 
Secondary Treatment Effect Parameters ....................................................................71 
12.5. 
Exploratory Analyses ..................................................................................................72 
12.6. 
Identification of Study Event Days and Times ...........................................................72 
12.7. 
Handling Missing Data ...............................................................................................72 
12.8. 
Changes in the Planned Analyses ...............................................................................72 
13. 
ETHICAL CONSIDERATIONS................................................................................73 
13.1. 
Independent Ethics Committee (IEC) .........................................................................73 
13.1.1. 
Initial Review Prior to Study Initiation ......................................................................73 
13.1.2. 
Subsequent Submissions to the IEC ............................................................................74 
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13.2. 
Written Informed Consent ..........................................................................................74 
13.2.1. 
Obtaining Informed Consent from Patients Who Are Not Literate ............................75 
13.2.2. 
Special Informed Consent Situations Not Applicable to This Protocol ......................75 
13.2.3. 
Protection of Patient Information ...............................................................................75 
14. 
STUDY ADMINISTRATION ...................................................................................76 
14.1. 
Registration of Study ..................................................................................................76 
14.2. 
Changes in the Conduct of the Study .........................................................................76 
14.3. 
Confidentiality ............................................................................................................76 
14.4. 
Financial Disclosure ...................................................................................................76 
14.5. 
Publication Policy .......................................................................................................77 
14.6. 
Authorship and Acknowledgement ............................................................................77 
15. 
LIST OF REFERENCES ............................................................................................78 
16. 
CRITERIA FROM THE INTERNATIONAL WORKSHOPS ..................................80 
16.1. 
Diagnostic Criteria for Waldenström’s Macroglobulinemia ......................................80 
16.2. 
Classification of Disease Response for Waldenström’s Macroglobulinemia .............81 
16.3. 
Efficacy Measure Definitions .....................................................................................82 
17. 
INVESTIGATOR’S AGREEMENT ..........................................................................83 
 
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List of Tables 
Table-1.  
Emergency and Pharmacovigilance Contacts ...............................................................3 
Table-2.  
Study Contact Information ...........................................................................................3 
Table-3. 
Planned Dose Escalation Cohorts .................................................................................6 
Table-4.  
Schedule of Study Events ...........................................................................................13 
Table-5.  
Estimation of Blood Volumes Required From Screening through End-of-
Study ...........................................................................................................................16 
Table-6.  
Incidence of MyD88 L265P mutation in selected B-cell malignancies .....................30 
Table-7.  
Clinical Studies with IMO-8400 in Addition to This Study .......................................32 
Table-8. 
Planned Dose Escalation Cohorts ...............................................................................34 
Table-9.  
Physical and Chemical Properties of Active Ingredient (Drug Substance) ................44 
Table-10.  Formulation of IMO-8400 for Injection (Drug Product) ............................................44 
Table-11. IMO-8400 Subcutaneous Injection Site Grading (Local Reactions) ..........................52 
Table-12. Intensity of AE of Injection Site Reactiona ................................................................53 
Table-13.  Reporting the Date and Time of Onset of adverse events for Different Types 
of Events .....................................................................................................................58 
Table-14.  Estimating Severity Grade ..........................................................................................60 
Table-15.  Date and Time of Outcome for Adverse Event by Outcome Class ............................61 
 
 
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List of Figures 
Figure-1.  TLR and BCR Signaling Pathways in B-cells ............................................................29 
 
 
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3. 
LIST OF ABBREVIATIONS 
Abbreviation  Explanation 
ABC-DLBCL 
Activated B-cell (type) Diffuse Large B-cell Lymphoma 
AE 
Adverse event 
ALT 
Alanine amino-transferase 
AP 
Alkaline phosphatase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate amino-transferase 
β-hCG 
Beta-human chorionic gonadotropin 
BA 
Bioavailability 
BCR 
B-cell receptor 
BE 
Bioequivalence 
BP 
Blood pressure 
BTK 
Bruton’s tyrosine kinase 
C3 
Complement component 3 
C4 
Complement component 4 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CH50 
50% hemolytic complement assay 
CK 
Creatine phosphokinase 
CNS 
Central nervous system 
CR 
Complete response 
CRP 
C-reactive protein 
CS 
Clinically significant 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose-limiting toxicity 
DME 
Dose modifying event 
DNA 
Deoxyribonucleic acid 
DRC 
Data Review Committee 
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) 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL 
High density lipoprotein 
HIV 
Human immunodeficiency virus 
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HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent ethics committee 
IFN 
Interferon 
IgM 
Immunoglobulin M 
IL 
Interleukin 
IND 
Investigational new drug 
INN 
International nonproprietary name 
INR 
International normalized ratio 
IP-10 
Interferon-inducible protein-10 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 
ITT 
Intent-to-treat 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MTD 
Maximum tolerated dose 
MyD88  
Myeloid differentiation primary response gene (88) 
MR 
Minor response 
MRI 
Magnetic resonance imaging 
NA 
Not applicable 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NF-κB 
Nuclear factor kappa-light-chain-enhancer of activated B cells 
NCS 
Not clinically significant 
PP 
Per-protocol 
PR 
Partial response 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin Time 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TLR 
Toll-like receptor 
TMF 
Trial master file  
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia 
VGPR 
Very good partial response 
WBC 
White blood cell 
WM 
Waldenström’s macroglobulinemia 
WMA 
World Medical Association 
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4. 
INTRODUCTION 
4.1. 
Waldenström’s Macroglobulinemia (WM): 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.  Malignancies arising from the myeloid 
line include acute and chronic myelogenous leukemia, myelodysplastic syndromes, and 
myeloproliferative diseases.  Those arising from the lymphoid line include lymphoma, 
lymphocytic leukemia, multiple myeloma, and WM.  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. 
Waldenström’s macroglobulinemia is a distinct B-cell lymphoproliferative disorder characterized 
by a lymphoplasmacytic infiltrate in the bone marrow and high levels of a monoclonal 
immunoglobulin M (IgM) in the serum [6,7].  The disease can have a chronic, indolent course, 
with patients remaining asymptomatic for years.  The principal complications include:  
− Manifestations of the monoclonal gammopathy, including symptomatic 
hyperviscosity, cryoglobulinemia, and cold agglutinin disease. 
− Disease-related cytopenia. 
− Bulky adenopathy or organomegaly. 
− Severe neuropathy. 
− Amyloidosis. 
− Disease transformation. 
4.1.1. 
Current Standard of Care Therapy for WM 
Current recommendations are that asymptomatic patients with WM are observed and that 
treatment should not be based on IgM levels alone.  Treatment should be initiated in response to 
the clinical complications noted above [6,8].  Selection of therapeutic agents may be tailored to 
the disease manifestations.  The most common first-line regimens are combinations including the 
following agents: 
− Rituximab (anti-CD20 monoclonal antibody). 
− Cyclophosphamide or chlorambucil (alkylating agents). 
− Doxorubicin (anthracycline antibiotic). 
− Vincristine (alkaloid). 
− Prednisone (corticosteroid). 
− Fludarabine or cladribine (nucleoside analogs). 
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Ibrutinib has recently received Food and Drug Administration approval for the treatment of WM 
on the basis of a response rate of 61.9% (including complete response [CR], very good partial 
response [VGPR], and partial response [PR]) in a Phase 2 study of 63 patients.  
Plasmapheresis is used for symptomatic hyperviscosity and other complications of high serum 
levels of monoclonal IgM protein.  
Salvage therapy for patients with refractory or relapsing disease is diverse and use of 
investigational agents is often considered appropriate.  Approaches in current practice include 
(a) alternative combinations of the agents noted above, with the possible addition of bortezomib 
or thalidomide, and (b) transplantation with autologous stem cells or allogenic bone marrow 
[6,7].  
Many of the agents used in refractory or relapsing WM are cytotoxic or sharply 
immunosuppressive and have substantial safety risks in elderly patients characteristic of this 
disease.  A novel targeted agent that provided a beneficial treatment effect with a better 
tolerability profile would address an unmet need in WM.  
4.2. 
Role of Toll-like Receptors (TLRs) in B-cell Malignancy 
Toll-like receptors 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, which are located on the host cell surface. In man, the endosomal 
TLRs are expressed primarily on dendritic cells 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. [9,10,11,12,13].  
The TLR signaling pathway (Figure-1, 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-1, 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-1.  TLR and BCR Signaling Pathways in B-cells 
 TLR signaling 
BCR signaling [3] 
 
Abbreviations:  BCR=B-cell receptor; TLR=Toll-like receptor 
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.  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 BCR pathway genes, including CD79A/B and CARD11 [3]. 
• Increased expression of myeloid differentiation primary response gene (88) (MyD88), 
the adapter (linker) protein that binds to TLRs [14]. 
• Mutations in MyD88 [15]. 
The most common alternation identified to date in MyD88 is the L265P mutation.  Table-6 
displays the frequency of MyD88 L265P among B-cell malignancies and proliferative diseases.  
The mutation is present in over 90% of WM, in ~30% of Activated B-cell-like Diffuse Large 
B-cell Lymphoma, and at lower frequencies in other, more common lymphomas.  
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Table-6.  
Incidence of MyD88 L265P mutation in selected B-cell malignancies 
Disease 
Incidence of 
Disease 
(SEER 2001) 
% Patients with 
MYD88 L265P 
mutation 
Estimated  
Incidence 2013a  
(New cases/year) 
Reference for 
MyD88 
frequency 
ABC-DLBCL 
6,789b 
29% 
2,150 
[16] 
Waldenström’s 
macroglobulinemia 
1,144 
91% 
1,200 
[2] 
Chronic Lymphocytic Leukemia 
16,984 
3%, 7% 
925 
[17,18] 
Primary CNS Lymphoma 
1,200 
36%, 38% 
480 
[19,20] 
Marginal Zone Lymphomac  
3,247 
9%, 4% 
225 
[16,21] 
Abbreviations:  ABC-DLBCL=Activated B-cell (type) Diffuse Large B-cell Lymphoma; CNS=central nervous 
system; DLBCL=Diffuse Large B-cell Lymphoma; MyD88=Myeloid differentiation primary response gene (88); 
SEER=Surveillance Epidemiology and End Results 
a. New cases/year are adjusted + 10% due to population growth since data collection [22,23] 
b. Incidence of DLBCL, 24,246; ABC-type represents 28% of all DLBCL.  
c. Marginal Zone Lymphoma is also referred to as MALT, Mucosa-Associated Lymphoid Tissue Lymphoma 
Recent in vitro studies of B-cell tumor lines with L265P mutation suggest that increased TLR 
signaling 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 demonstrated decreased growth and survival (see 
Investigator Brochure for details).  Severe combined immunodeficient mice inoculated with 
LY10 developed progressive disease and died.  Treatment with IMO-8400 prolonged median 
survival from 33 to 48 days (see Investigator’s Brochure for details).  
Taken together, these data directly support the hypothesis that an antagonist of TLR7, 8, and 9 
would have a therapeutic effect in patients with B-cell malignancies, particularly those 
characterized by MyD88 L265P mutation or increased MyD88 expression.  
4.3. 
Rationale for the Current Study 
IMO-8400 is a synthetic oligonucleotide that blocks activation mediated through TLR7, 8 and 9; 
that is, it functions as an antagonist for those receptors.  
To date, IMO-8400 in doses up to 0.6 mg/kg once weekly has been administered for 4 weeks in 
healthy volunteers and for 12 weeks in a completed Phase 2 psoriasis study (see Section 4.4 for 
details).  All treatments were well-tolerated, with mild injection site reactions and no pattern of 
systemic reactions or laboratory changes. 
As detailed above, recent studies indicate a role for TLR activation and subsequent signal 
amplification by MyD88 L265P mutation in the activation, proliferation, and increased survival 
of malignant B-cells.  
The current protocol represents the first use of IMO-8400 in patients with a B-cell malignancy.  
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4.4. 
Overview of IMO-8400 
IMO-8400 has been created by Idera Pharmaceuticals, Inc. using a structure-activity approach to 
design TLR-targeted drug candidates.  IMO-8400 is a synthetic oligonucleotide designed to 
inhibit immune responses mediated through endosomal TLR7, TLR8, and TLR9.  
Non-clinical studies (reviewed in detail in the Investigator’s Brochure) have demonstrated that 
IMO-8400 is an immunomodulatory agent with 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, IFN-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.  
• 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 laboratory 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 constitutively active cell signaling pathways, including NF-κB, IRAK, 
STAT-3, Jak/Stat, and 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 cytokine, and increased mouse survival time in a disseminated 
xenograft model using OCI-Ly10, a human lymphoma cell line with the MYD88 
L265P mutation. 
• Decreases tumor growth and serum levels of tumor-secreted IL-10 in a subcutaneous 
(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 cytokines in a 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-7 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. 
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Table-7.  
Clinical Studies with IMO-8400 in Addition to This Study 
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 
8400-402 
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 
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 
Abbreviations: MyD88=Myeloid differentiation primary response gene (88) 
4.4.1. 
Clinical Experience with WM 
As of August 2015, 19 patients have been treated in this Phase 1 study with IMO-8400 at doses 
of 0.6, 1.2, and 2.4 mg/kg/week.  IMO-8400 was generally well tolerated at all dose levels.  Most 
reported adverse events (AEs) deemed related or possibly related to study drug were mild or 
moderate (National Cancer Institute Common Terminology Criteria for Adverse Events 
[NCI CTCAE] grade 1 or 2).  The most common AEs observed were fatigue, injection site 
erythema, headache, injection site pain, nausea, and pain in extremity.  Reported injection site 
reactions included grade 1 erythema, grade 1 pain, and grade 1 induration.  No injection site 
blistering, necrosis, pruritus, ulceration, or tenderness were reported.  Grade 3 AEs reported as 
possibly or probably related to study drug included neutropenia, anemia, and arthritis.  One of 
88 patients treated at the 2.4 mg/kg dose level experienced a dose-limiting toxicity (DLT) that 
was deemed possibly related to study drug; this patient experienced a grade 3 probable flare of 
pre-existing arthritis.  No deaths or grade 4 events were reported.  
Early signals of efficacy include 3 responses among 11 patients treated at the 0.6 and 1.2 mg/kg 
dose levels.  Among 6 evaluable patients treated at the highest dose level (2.4 m/kg), 3 had 
responses and 2 had stable disease [24].   
4.4.2. 
Benefit/Risk Aspects 
The starting dose level for the present study (0.6 mg/kg once weekly by SC injection) has been 
well tolerated for up to 4 weeks in healthy volunteers and up to 12 weeks in patients with 
moderate to severe psoriasis.  The majority of treatment-emergent adverse events (TEAEs) are 
mild injection site reactions; there were no treatment-related serious adverse events (SAEs) or 
discontinuations due to AEs.  This starting dose is, therefore, considered to represent minimal 
risk.  
In the context that patients enrolled in this study have no therapeutic options likely to extend 
their survival, the clinical and safety profile demonstrated thus far with IMO-8400 justifies their 
inclusion and their treatment until progression. 
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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 WM.  
5.2. 
Secondary Objectives 
• To assess the treatment effect (clinical activity) of escalating dose levels of 
IMO-8400 using disease-specific international guidelines for classifying clinical 
response [1].  
• To identify an optimal dose of IMO-8400 for further clinical evaluation. 
• To characterize the pharmacokinetics (PK) 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 correlate the presence of MyD88 L265P mutation with clinical outcome. 
• 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 WM. 
6.2. 
Dose-escalation Cohorts 
The dose escalation cohorts (3 to 6 patients each) will systematically evaluate the safety and 
tolerability of IMO-8400 at increasing dose levels in order to identify the MTD/recommended 
Phase 2 dose (RP2D).  
• The planned dose escalation cohort levels for IMO-8400 are 0.6, 1.2, 2.4, and 
3.6 mg/kg administered once weekly and 1.2 mg/kg administered twice weekly 
(Table-8). Additional dose levels, schedules, and routes of administration may be 
evaluated based upon the emerging data. Weekly exposure is based on body weight 
(see Section 8.1 for details). Doses will be administered by SC injection.  
• For Dose Level 3 (refer to Table-8), the total dose will be divided into 2 equal 
portions (1.2 mg/kg twice weekly), administered as separate SC injections over the 
course of the week, preferably 72 to 96 hours apart (minimum 48 hours) (see 
Section 8.4 for details).  
• Once safety has been established for the 2.4 mg/kg/week as a divided weekly dose 
(1.2 mg/kg twice weekly), the same dose level of 2.4 mg/kg/week and subsequent 
dose levels will be given as a once weekly administration. 
• Once the RP2D/MTD has been established, patients being treated at lower dose levels 
may have their doses escalated to the RP2D/MTD upon discussion and agreement 
between the Sponsor and the Investigator.  
Table-8. 
Planned Dose Escalation Cohorts 
Dose Level 
IMO-8400 Dose (mg/kg)  
Frequency 
Initial Cohort Size 
1 (starting dose) 
0.6 
Once Weekly 
3-6 
2 
1.2  
Once Weekly 
3-6 
3 
1.2 
Twice Weekly 
3-6 
4 
2.4 
Once Weekly 
3-6 
5 
3.6 
Once Weekly 
3-6 
 
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6.3. 
Dose-escalation Procedures 
6.3.1. 
Definition of a Dose-Limiting Toxicity and Dose Modifying Event 
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 
tests (hematology, chemistry, and coagulation), urinalysis, and electrocardiograms (ECGs).  
A DLT can be either a clinical or laboratory AE. 
A potential DLT event is defined as a treatment-emergent AE (see Section 10.1) which occurs 
within the first 5 weeks of treatment and meets any of the following criteria using NCI CTCAE 
grading (see Section 10.4.4):  
• Is a clinical event of Grade 3 or higher severity, except for the following: 
− Alopecia 
− Grade 3 fatigue 
− Grade 3 nausea/vomiting that has not been treated with optimal anti-emetic 
treatments 
− Grade 3 diarrhea that has not been treated with optimal anti-diarrheal treatments 
− AE related to the underlying disease 
• Is a confirmed laboratory finding of Grade 3 or higher severity (see Section 10.4.5) 
and has been assessed as related to IMO-8400 (any relationship other than “not 
related”) with the exceptions of neutropenia and thrombocytopenia.  DLTs with 
respect to neutropenia/thrombocytopenia are outlined below: 
− Grade 4 neutropenia lasting > 7 days  
− Grade 3 or 4 neutropenia with a sustained temperature > 101.3o F 
− Grade 3 thrombocytopenia associated with clinically significant bleeding that 
requires transfusion therapy 
− Grade 4 thrombocytopenia  
Clinically significant toxicities or TEAEs that meet the definition of dose-limiting but occurring 
after Week 5 of Cycle 1 are defined as dose modifying events (DMEs) and may be considered 
when determining the RP2D.   
The Data Review Committee (DRC) is comprised of the Idera Medical Monitor and 
Investigators from participating sites. The DRC will review all potential DLT events to assess 
causality, i.e., relationship to study drug (see Section 10.4.3).  Events will be considered DLT 
events unless they are unanimously assessed as “Not related,” that is, a factor other than study 
drug is the cause of the event (see Section 10.4.3).   
The definition of a DLT event will be applicable in the following contexts: 
• DRC review determining dose escalation (see below). 
• DRC review in defining the MTD (see below) or RP2D. 
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• Investigator (and Medical Monitor) review for determining pausing or 
discontinuation of study treatment in individual patients (see Section 6.5). 
6.3.2. 
Definition of Maximum Tolerated Dose and Recommended Phase 2 Dose 
The MTD is the highest 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. 
The RP2D will be a dose at or below the MTD based on clinical data. 
6.3.3. 
Dose-escalation Enrollment and Review 
Each dose-escalation cohort is expected to enroll at least 3 patients, with a maximum of 6.  
• If the initial 3 patients all complete 4 weeks of treatment without a DLT event, the 
DRC will conduct a dose-escalation review.  
• If 1 of the initial 3 patients experiences a DLT event prior to completing 4 weeks of 
treatment, 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 4 weeks 
treatment. 
• If 2 patients at a dose level experience DLT events during the first 4 weeks of 
treatment, then no further patients will be enrolled until the DRC completes a review, 
which should be done as soon as feasible.  
Once the last patient in a given cohort has a completed 4 weeks of study treatment, a 
DRC meeting will be convened to review all safety data and to decide whether to continue or 
halt dose escalation, or explore intermediate dose levels.  To facilitate standardizing the 
dose-escalation reviews across different cohorts, the focus will be on observations from the first 
4 weeks of treatment at that dose level.  
The following represent anticipated outcomes for the review process (refer to DRC Charter for 
full details):  
• Dose escalation – progression to the next planned dose level.  
• Continue cohort enrollment (applicable only to review after 3 patients) – enroll up to 
6 patients at the current dose level to obtain additional safety data for subsequent 
review. 
• Dose de-escalation – enrollment of intermediate dose levels for exploration of other 
schedules of administration (see Section 6.5.2).  
• Approve enrollment in an expansion cohort at a selected dose level, if applicable (see 
Section 6.4). 
• No further dose escalation enrollment – at this time the DRC will indicate the dose 
level that they consider represents the MTD.  
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6.4. 
Expansion Cohorts 
The expansion cohorts provide for additional enrollment at agreed upon dose levels to assess the 
dose dependence of clinical response.   
Once the MTD or a potential RP2D and/or schedule have been established during dose 
escalation, up to 22 patients will be treated at the RP2D level according to this schedule.  The 
Sponsor may decide at any point during the expansion phase to modify the RP2D based on 
emerging data including, but not limited to, safety, DLTs, PK, and clinical activity.  If such a 
change is made, enrollment may continue at the selected dose level in up to 22 patients.  
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 the earliest of: 
• Clinical DLT event – see Section 6.3.  
− Study treatment will be discontinued in patients determined to have a clinical 
DLT event until resolution and may only be resumed after discussion with an 
Idera Medical Monitor and agreement that it is in the patient’s best interest to 
continue. 
− For a DME, provision is made for interrupting dosing for up to 3 weeks and, if the 
acute toxicity improves sufficiently, resuming treatment at a lower dose level 
based on discussion between the sponsor’s designated medical monitor and the 
treating physician. 
− For DLT laboratory 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 (see Section 6.5.2 for details).  
− The Investigator will review with the Medical Monitor decisions to discontinue, 
pause, and/or restart study treatment. 
• Disease progression – based on scheduled assessments at Week 1 of each cycle.  
Unscheduled assessments may be conducted in response to new clinical observations.  
Disease status will be classified according to international guidelines [1] (see 
Section 9.5 for details).  
• Termination of participation in the study – due to AE, withdrawal of consent, 
intolerable toxicity, or loss to follow up.  
In certain instances, patients may be deriving clinical benefit despite objective 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, 
provided the following conditions are met: 
• Patient has not achieved an objective response on study and then developed 
progressive disease; 
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• Patient has not experienced a period of clinically significant stable disease on study 
and then developed progressive disease; 
• Patient must be re-evaluated 4 to 6 weeks after initial progression in order to confirm 
progressive WM disease; 
• If the follow-up assessment does not confirm progressive disease, patient may resume 
regularly scheduled follow-up per protocol; 
• Patient must not have symptoms/signs indicative of clinically significant disease 
progression; 
• Patient must not have a decline in Eastern Cooperative Oncology Group (ECOG) 
performance status; 
• Patient must not have rapidly progressive disease or tumor progression at critical 
anatomic sites (e.g., cord compression) requiring urgent medical intervention. 
6.5.2. 
Dose Modification in Patients with Laboratory DLT Events or DMEs  
Patients determined to have a laboratory DLT event or DME (Section 6.3.1) may resume 
treatment 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 
laboratory DLT event or DME. 
• Both the Investigator and the Medical Monitor consider that continued treatment with 
study drug is in the patient’s interest.  
• The abnormal laboratory parameter(s) representing the DLT event or DME improve 
at least 2 grades or back to baseline within 14 days of the last dose administered.  
If, for any reason, dosing is interrupted more than 21 calendar days due to toxicity, the patient 
should be discontinued from study treatment unless the Investigator and the Idera Medical 
Monitor agree that it is in the patient’s best interest to continue. 
If dose modification is required, patients should resume dosing at the next lowest dosing level 
(see Table-8).    
6.5.3. 
Management of Systemic Injection Reactions 
Fever, chills, and rigors have been reported in the first 24 hours following IMO-8400 injection. 
These symptoms have responded well to symptomatic measures without long-term 
consequences.  Prophylaxis with acetaminophen and diphenhydramine may be considered for 
patients who experience these symptoms with prior injections.  Treatment should be 
discontinued for patients who experience more significant reactions (e.g., anaphylaxis or 
cardiovascular collapse) and full supportive care provided, as per institutional practice.    
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6.5.4. 
Procedures for Assessment of Patients with Changes 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.  These findings correlated with changes in serum complement levels. 
Alterations in serum complement in these animals were noted in the weeks to months preceding 
their unscheduled deaths. 
If at any time during study participation, a patient experiences an acute drop in complement 
(50% hemolytic complement assay [CH50], complement component 3 [C3], or complement 
component 4 [C4]) levels ≥ 50% or a drop to an absolute value below the lower limit of normal 
with reference to baseline testing or most recent values on study, the 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 
casts or white blood cell 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. 
6.5.5. 
Procedures for Assessment of Patients with Symptomatic Thrombocytopenia 
Severe thrombocytopenia has been reported in clinical studies with another oligonucleotide [25]. 
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 
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resumed once pre-treatment criteria (Section 8.4.1) are met. Antiplatelet, thrombolytic, or 
anticoagulant drugs should be used with caution. 
6.5.6. 
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 from the following standard categories:  
• DLT event – defined above.  
• Disease progression – as defined above.  
• Adverse Event, 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 for any reason, the End-of-Treatment (EOT) and 
End-of-Study (EOS) visits will be performed as specified (see 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.  
6.6. 
Criteria for Replacement Patients  
6.6.1. 
Definition of a Evaluable Patient 
A patient will be considered evaluable for purposes of DRC review if they meet either of the 
following criteria:  
• Received at least 1 dose of study drug and had treatment discontinued because of a 
DLT event as defined in Section 6.3.1; or 
• Received all doses of study drug in the first 4 weeks of treatment and completed 
Week 5 assessment procedures. 
See Section 12 for additional discussion of analysis for safety and efficacy.  
6.6.2. 
Replacement 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.  
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6.7. 
Maximum Number of Patients and Maximum Exposures 
The maximum exposures to IMO-8400, the investigational agent in this study, will be as follows:  
• Maximum number of patients: Approximately 60 patients in planned escalation and 
expansion cohorts; potential for additional patients in contingency cohorts or as 
replacements. 
• Maximum dose level: Undefined (pending dose escalation results). The planned dose 
escalation cohort levels for IMO-8400 are 0.6, 1.2, 2.4, and 3.6 mg/kg administered 
once weekly and 1.2 mg/kg administered twice weekly 
• Maximum duration of exposure: undefined (treatment is until study completion or 
until the patient experiences intolerable toxicity, disease progression, or withdraws 
consent, whichever comes first as defined in Section 6.10.2.2). 
6.8. 
Treatment Assignment 
See Section 9.3. 
6.9. 
Criteria for Study Termination 
The study ends approximately 6 months following enrollment of the last patient.  The Sponsor 
reserves the right to discontinue or suspend the study earlier for safety or administrative reasons 
at any time, at an individual site or overall.  Should the study be terminated and/or the site closed 
for whatever reason, all study documentation must be archived and study medication must be 
destroyed according to local policy or returned to the Sponsor or its representative per Sponsor’s 
instructions. 
If the trial is terminated prematurely or suspended, the Sponsor will promptly inform the 
participating Investigators and institutions, the regulatory authorities, and the Institutional 
Review Board (IRB) of the termination or suspension and the reason(s) for the action. 
6.10. 
Discussion of Study Design and Treatment Regimens 
This protocol represents the first clinical trial of IMO-8400 in patients with B-cell malignancies 
and the third clinical trial of IMO-8400 overall. 
6.10.1. 
Rationale for Study Structure 
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 DRC 
are standard for a Phase 1 study and serve to minimize the number of patients required and to 
assure patient safety is protected. 
The expansion cohorts will permit preliminary signal-seeking and guide further development of 
IMO-8400 in oncology/hematology. 
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6.10.2. 
Rationale for Treatment Regimens in Current Protocol 
6.10.2.1. Dosing Regimen 
Starting dose/Safety.  The proposed starting dose (0.6 mg/kg/week) is consistent with the safety 
experience in protocol 8400-001, the Phase 1 study, in which that dose was administered for 
4 weeks without incident to healthy volunteers; and in protocol 8400-201, the Phase 2a study, in 
which that dose was administered for 12 weeks to patients with moderate to severe plaque 
psoriasis.  The primary TEAEs observed were mild injection sites reactions; there were no 
treatment-related changes in laboratory studies, including tests of liver and renal function.  
Dosing interval. Once and twice weekly dosing are supported by animal studies of autoimmune 
diseases and in vivo tumor growth. 
Dose escalation. Numerically larger increases in hemoglobin and a faster time to response were 
seen in patients dosed at the highest dose level studied in the current trial [24].  In the absence of 
dose-limiting toxicity, further dose escalation to determine the extent of disease control that can 
be attained is appropriate and consistent with standard oncology Phase 1 trial design. 
6.10.2.2. Duration of Treatment 
Treatment with IMO-8400 will continue until study completion or until the patient experiences 
intolerable toxicity, disease progression, or withdraws consent, whichever comes first.   
Follow-Up.  Additionally, patients who have discontinued study treatment for reasons other than 
progressive disease will be assessed per Response Assessment in WM from the VIth International 
Workshop, at a minimum of every 12 weeks (± 4 weeks) until documentation of progressive 
disease, start of new anti-cancer therapy, or until study completion, for up to 6 months from the 
last patient’s first treatment (Cycle 1, Day 1), whichever comes first. 
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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 (see 
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 (see Section 13). 
7.2. 
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, 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 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. 
Abbreviations:  INN=international nonproprietary name; NA=not applicable; TLR=Toll-like receptor 
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 IMO-8400 free acid, as 
labeled, corrected for moisture and impurities. 
Storage 
The sealed vials of formulated drug product should be stored at 2-8°C. 
Preparation and 
handling 
Vials are reconstituted using Sterile Saline or Sterile Water for Injection, USP (to be provided 
by study site). The choice of diluent and the reconstitution volume are determined by the vial 
strength and the dose level assigned; see Pharmacy Manual for details.  
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. 
Abbreviations:  SC=subcutaneous; USP=United States Pharmacopeia 
8.3. 
Reconstitution of IMO-8400 for Injection  
Detailed dose-preparation instruction and flow-sheets are provided in the Pharmacy Manual.  
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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 1.5 mL dose volume would be 
administered as two separate injections of 0.75 mL.  The injection sites should be selected based 
on the following:  
• Areas for injection are the 4 quadrants of the abdomen (upper and lower on the left 
and right) and the upper thigh of each leg. 
• Injection sites should be rotated, that is, no injection area used more than once every 
6 injections.  
In the event these guidelines cannot be accommodated due to injury or other issue, the 
Investigator should discuss the situation with the Idera 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 
These parameters will be measured at local laboratories at Week 1 and Week 5 of each cycle. 
8.4.2. 
Variances in Dose Administration Schedule 
Once weekly dosing: for patients assigned to dose levels of 0.6, 1.2, 2.4, or 3.6 mg/kg/week.  
The expectation is that patients will be dosed each week on the same day of the week.  To allow 
for holidays and other scheduling issues, individual doses may be administered up to 2 calendar 
days earlier or later than expected, while remaining on the same schedule.  Doses should not be 
administered fewer than 5 calendar days after the preceding dose.  
If, for any reason (e.g., scheduling or toxicity), dosing is interrupted more than 2 calendar days 
beyond expected, then the next dose should be administered as soon as feasible and the schedule 
reset to once weekly on the next convenient weekday. 
Twice weekly dosing: for patients assigned to the dose level of 1.2 mg/kg twice weekly 
(2.4 mg/kg/week). The total weekly exposure will be administered as a 2 separate SC injections 
of 1.2 mg/kg per injection, respectively, over the course of the week.  The expectation is that 
patients will be dosed twice each week on the same day of the week, with (approximately) 72 or 
96 hours (3 or 4 calendar days, respectively) between injections.  The minimum interval between 
successive doses may not be less than 48 hours (2 calendar days).  If, for any reason 
(e.g., scheduling or toxicity), the interval between successive doses is 6 or more calendar days, 
then the next dose should be administered as soon as feasible and the twice weekly dosing 
schedule resumed. 
Extended dosing interruptions.  If, for any reason, dosing is interrupted for more than 
21 calendar days due to toxicity, the patient should be discontinued from study treatment unless 
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the Investigator and the Idera Medical Monitor agree that it is in the patient’s best interest to 
continue.  
8.5. 
Assigning Patients to Treatment Groups  
See Section 9.3.  
8.6. 
Prior and Concomitant Medications 
Prior treatments for WM 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).  
8.6.1. 
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 WM 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 days after last 
dose of study drug), this will be recorded in concomitant medications and considered in 
assessment of any new AEs.  
8.6.2. 
Other restrictions 
None. 
8.7. 
Treatment Compliance  
All doses of study drug will be administered by study 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 is scheduled (that is, at Day 1 and at the first 
weekly doses of Weeks 2 and 5 of Cycle 1 and at Weeks 1 and 5 of additional 
cycles), 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 by 
overnight delivery service.  To protect the integrity of the treatment, the shipping 
container must be held 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. 
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− 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. 
8.8. 
Accountability of Investigational Drug Supplies 
Study drug will be provided by the Sponsor.  The Investigator at each study site is 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 the patient).  This 
includes:  
• Storing the drug in a secure, controlled-access location. 
• 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. 
• 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.  
8.8.1. 
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 schedule for all study events is detailed in Table-4.  Table-5 gives an estimate of blood 
volumes required.  
The schedule is presented relative to the day and time of dosing.  All Days are relative to the 
calendar day of the first injection of study drug, designated Day 1.  All weeks are relative to 
Week 1 of each cycle, defined as Day 1 through Day 7, inclusive.  All times are relative to 
injection, designated 0 hour; “pre-dose” vital signs are to occur within 1 hour prior to injection; 
all other pre-dose procedures are to occur prior to injection on the same calendar day.  
9.2. 
Screening Procedure 
The screening evaluation may be performed up to 21 days prior to dosing.  Written informed 
consent will be obtained before any study-specific procedures are performed.  The consent 
procedure must be recorded in source documentation.  All patients who sign an informed consent 
form (ICF) will be entered into the EDC system within 48 hours of consent.  To minimize patient 
risk and discomfort, the radiologic imaging and bone marrow biopsy scheduled at Screening will 
be performed only after the patient meets all other inclusion and exclusion criteria.  
Waldenström’s macroglobulinemia is a rare disease and patients often travel considerable time 
and distance to be managed at tertiary referral centers.  To facilitate rapid completion of 
screening and enrollment and thereby avoid the need for multiple trips, Investigators may, with 
the approval of the Sponsor, perform screening laboratory studies at their local laboratory, 
including safety labs (see Section 9.7), cryoglobulins and cold agglutinins, and qualifying total 
serum IgM and monoclonal serum IgM protein levels (see Section 9.4.2).  In such cases, central 
laboratory tests scheduled at Screening will be handled as follows:  
• Concurrent safety labs (see Section 9.7) will not be submitted to the central lab.  
• Blood and urine samples will be submitted to the central lab for the tests relating to 
monoclonal protein (see Section 9.4.2) and to Investigational studies (see Section 9.9) 
to support longitudinal data analysis.  
Pre-dose on Day 1, safety labs will be sent to the central laboratory for all patients as scheduled 
and used as the baseline (pre-treatment) safety laboratory values to support longitudinal analysis.  
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9.3. 
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 and are assessed as eligible by the Investigator will be reviewed with the 
Sponsor or the Sponsor’s designated representative.  After acceptance, the Investigator and site 
pharmacy will be provided the following information in writing (by email and/or fax):  
• The patient’s assigned unique study number, to be marked on all study-specific 
documents.  
• The patient’s assigned dose level.  
9.4. 
Assessments of Waldenström’s Macroglobulinemia  
Laboratory assessments for disease status (see Section 9.4.2) will be conducted at Screening, 
every 4 weeks ± 1 week (Week 1 and Week 5 of each cycle), every 12 weeks ± 4 weeks during 
the Follow-up Phase, at the EOT visit, and at the EOS visit.   
Clinical assessments for disease status (see Section 9.4.1) will be conducted at Screening, every 
8 weeks ± 1 week (Week 1 of every cycle), every 12 weeks ± 4 weeks during the Follow-up 
Phase, at the EOT visit, and at the EOS visit.   
Radiologic imaging will be performed at Screening and at EOT visit or as clinically indicated.  
Bone marrow biopsy and aspirate will be performed at Screening, EOT, and to document 
complete response as appropriate (see Section 16.2).    
A medical history specific to WM will be collected at Screening and will include, but is not 
limited to: a detailed review of the patient’s malignancy, prior treatments, relevant current or past 
abnormalities or diseases, and signs and symptoms of WM at baseline (Section 9.6.1). 
9.4.1. 
Clinical Assessments  
• ECOG performance status.  
• Clinical assessment for tumor status including assessment of lymphadenopathy, 
hepatomegaly and splenomegaly.  
9.4.2. 
Laboratory Assessments Relating to Total IgM and Monoclonal Protein  
The following laboratory assessments will be performed by a central laboratory approved by the 
Sponsor.  As noted above, patients being enrolled on the basis of local lab data may be qualified 
based on local results for serum IgM monoclonal protein levels, but at the time of Screening they 
will still have blood and urine samples submitted so that the panel below may be performed at 
the central lab.  
• Total serum IgM by nephelometry (i.e., total IgM or IgM). 
• Quantification of serum IgM monoclonal and total protein by densitometry, 
i.e., Serum Protein Electrophoresis with immunofixation (i.e., monoclonal IgM or 
M-spike). 
• Serum Free Light Chains (sFLC) and ratio. 
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• Serum β2-microglobulin. 
• Serum viscosity. 
• Urine Free Light Chains (uFLC) and ratio. 
9.4.3. 
Radiologic Imaging 
Computed tomography or magnetic resonance imaging scan of chest, abdomen and pelvis to 
assess for lymphadenopathy and organomegaly.  Modality of the scan must be consistent 
throughout the study.  Interim scans may be performed at the request of the Investigator and with 
the approval of the Idera Medical Monitor based on new signs or symptoms.  
9.4.4. 
Bone marrow biopsy and aspirate 
The procedures for collecting, processing, and transporting bone marrow biopsy and aspirate 
specimens will be detailed in the Bone Marrow Biopsy manual.  Bone marrow biopsy and 
aspirate specimens will be sent to the central pathologist for confirmation of disease status, flow 
cytometry, and to the central laboratory for investigational studies of tumor cells (see 
Section 9.9).  The percent lymphoplasmacytic cell involvement will be noted for each biopsy 
performed.  Bone marrow biopsy and aspirate will be performed at Screening, EOT, and to 
document complete response as appropriate (see Section 16.2). 
9.5. 
Evaluation of Response to Treatment and Disease Status 
The criteria for response to treatment are provided in Section 16.2 (based on the full text of the 
VIth International Workshop classification [1]). Central laboratory serum total IgM and serum 
monoclonal IgM values are to be used to evaluate response to treatment (refer to Section 9.4.2). 
The Third International Workshop for WM also defined the following categories [26]:  
Not evaluable response: Reserved for situations in which there is insufficient data for a 
determination of response to treatment.  
Delayed response: A delayed response is described particularly after treatment with purine 
analogue or monoclonal antibody.  The recommendation was that patients should be followed for 
at least 12 weeks after treatment initiation to be considered unresponsive to therapy.  
9.6. 
General Clinical Assessments 
9.6.1. 
Medical History, including WM 
At the Screening visit, 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, duration, best clinical response, 
AEs related to treatment, and reason for discontinuation). 
• Relevant current or past abnormalities or diseases (including surgical procedures) of 
the following systems: allergic (including drug sensitivity), cardiovascular, 
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dermatologic, endocrine/metabolic, gastrointestinal, gynecologic, 
hematologic/lymphatic, hepatic/biliary, immunologic, infectious, musculoskeletal, 
neurologic/psychiatric, renal, and respiratory. 
• A separate eCRF will be provided to record signs and symptoms of WM at Baseline, 
including but not limited to: bleeding events, fatigue, anemia, thrombocytopenia, 
leukemia/neutropenia, fever, hyperviscosity, neuropathy, lymphadenopathy, weight 
loss, headache, night sweats, and vision changes. 
Past history should include all significant illnesses that the patient has experienced and have 
resolved within the 12 months prior to signing informed consent.  Illnesses active at the time of 
informed consent will be regarded as concomitant illnesses.  Concomitant illnesses that worsen 
or illnesses with onset after obtaining informed consent will be recorded on the AE form in the 
EDC (see Section 10), with particular attention to whether the onset was before or after 
administration of the first dose of study drug.  If a WM sign or symptom recorded at Screening 
worsens, it will be captured as an AE. 
9.6.2. 
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.  Exam of reproductive system when needed 
may be performed by the Investigator or delegated to a specialist. 
Height and weight will be evaluated at Screening and the body mass index will be calculated. 
Any clinically significant changes in physical exam identified after obtaining informed consent 
will be recorded using the AE form in the EDC (see Section 10). 
9.6.3. 
Vital Signs 
Vital signs include heart rate (HR), blood pressure (BP), respiratory rate, and temperature.  
Where feasible, vital signs should be measured before blood is drawn and 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. Respiratory rate 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.  
9.6.4. 
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, QT interval, QTc interval, and QTc method. Electrocardiograms are to be 
performed at Screening, at pre-dose and 2 hours post-dose on Day 1 of Cycle 1, and pre-dose at 
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the first dosing visit of Weeks 1 and 5 of each cycle thereafter. In addition, an ECG is to be 
performed at 2 hours post-dose on Day 1 of each odd-numbered cycle. 
9.6.5. 
Injection Site Reaction (ISR) Assessments 
Injection site reactions will be documented in detail for each individual injection as described in 
Table-11.   Each ISR shall also be captured on the AE 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-11. 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. 
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-12. 
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Table-12. 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. 
9.7. 
Safety Laboratory Studies 
The laboratory tests indicated below will be performed by a central laboratory designated by the 
Sponsor (except for sites approved to use local laboratory results for screening as detailed in 
Section 9.2).  The procedures for collecting, processing, and transporting the required blood 
samples will be detailed in the laboratory manual.  
The Investigator may order additional local laboratory tests consistent with their routine standard 
of care.  
9.7.1. 
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  
C-reactive protein (CRP) 
Magnesium 
Calcium  
Phosphate  
Uric Acid 
Cholesterol  
Triglycerides 
Low density lipoprotein (LDL)  
High density lipoprotein (HDL) 
*Alanine aminotransferase (ALT) 
*Aspartate aminotransferase (AST) 
*Alkaline phosphatase (AP) 
*Total bilirubin  
Total protein  
Albumin  
Lactate dehydrogenase (LDH) 
Creatine phosphokinase (CK) 
* Laboratory tests comprising focused panel to be performed on Weeks 3 and 7 of each cycle.  
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Serum Complement Testing 
Complement component 3 (C3) 
Complement component 4 (C4) 
50% hemolytic complement (CH50) 
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 white blood cells and red blood cells. 
Serologic tests (Screening only) 
Hepatitis B surface antigen (HBsAg) 
Antibody to human immunodeficiency 
virus (HIV)-1 and HIV-2 
Antibody to hepatitis C virus (HCV) 
Pregnancy tests (Females only) 
beta-human chorionic gonadotropin (β-hCG) 
9.7.2. 
Reporting of Safety Laboratory Tests 
Results of safety laboratory tests are expected to be available to the Investigator within 48 hours. 
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.  
9.7.3. 
Repeating Abnormal Laboratory Tests 
Laboratory tests showing abnormal or exclusionary values at Screening may be repeated no more 
than once.  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.  
9.8. 
Pharmacokinetic Assessments 
Blood samples for plasma levels of IMO-8400 will be collected as scheduled.  Samples will be 
analyzed for IMO-8400 concentration using a validated bioanalytical method (estimated 
sensitivity, 20 ng/mL).  Pharmacokinetic data will be analyzed on an individual basis.  
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. 
9.9. 
Investigational Laboratory Studies 
The following laboratory studies relate to assessing the pharmacologic effects of the 
investigational agent.  Samples will be collected as scheduled and sent to the Central Lab, where 
they will then be sent to Sponsor-designated qualified labs for testing.  The clinical significance 
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of these tests is unknown at this time and therefore the results will not be assessed by the 
Investigator.  
Tumor cells from the bone marrow biopsy samples will be assayed for:  
• Presence of MyD88 L265P mutation, and, if indicated, other somatic mutations in 
genes encoding proteins in the TLR and BCR signaling pathways (e.g., CARD11, 
IRAK4, BTK).  Samples will be retained for up to 1 year after completion of the 
study to support possible future development of a companion diagnostic assay. 
Serum samples will be assayed for:  
• Levels of cytokines IL-6, IL-12, IL-17, IP-10; additional or alternative cytokines may 
be assessed using the samples collected.  
• Antibodies to IMO-8400.  
• NF-κB pathway inhibition.  
 
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10. 
SAFETY ASSESSMENTS (ADVERSE EVENTS) 
10.1. 
Definition of Adverse Events 
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 TEAEs 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 (see 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.  
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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• Congenital anomaly or birth defect.  
• Important medical event that, although not immediately life-threatening, requires 
intervention in order to prevent one of the other serious outcomes listed above.  
Examples of such events are allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; blood dyscrasias or convulsions that do not result in 
hospitalization; or the development of drug dependency or drug abuse.  
10.1.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
A SUSAR is defined as an SAE that meets both the following criteria with respect to study drug:  
• Suspected — is assessed as related or possibly related to study drug (see 
Section 10.4.3);  
• Unexpected — compared to the study drug-related AEs described in Investigator’s 
Brochure, the event meets any of the following criteria: 
− The event was not previously described;  
− The event is now characterized as more severe (see Section 10.4.4);  
− 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 (see Section 9.7.2) 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 (see Section 12.2).   
• 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 
(see Section 10.1.3). 
• In accordance with the FDA guidance document – Safety Reporting Requirements for 
Investigational New Drugs (INDs) and Bioavailability/Bioequivalence (BA/BE) 
Studies – disease progression does not require reporting as an AE or SAE. However, 
signs and symptoms related to disease may be reported at the discretion of the 
Investigator.  
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-13 summarizes the basis for 
reporting the date and time of onset for the different types of AEs.  
Table-13.  Reporting the Date and Time of Onset of adverse events 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 blood pressure, 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 
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is a single AE, with the date of onset based on the date of the initial observation by the patient 
and a specific description (herpes zoster) based on the clinical exam and tests.  
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. 
Severity 
The severity of clinical AEs (i.e., symptoms reported by the patient and/or signs observed by the 
Investigator) will be assessed using the guidelines summarized in Table-14 [27]. 
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Table-14.  Estimating Severity Grade 
Grade 1/Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated 
Grade 2/Moderate 
Minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily livinga 
Grade 3/Severe 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
livingb 
Grade 4/Life-threatening 
Life-threatening consequences; urgent intervention indicated 
Grade 5/Death 
Death related to adverse event 
a. Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, ect. 
b. Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
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 (see 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 Adverse Event 
For each AE the Investigator will indicate which one of the following actions regarding the 
administration of study drug was taken because of that AE:  
• Discontinued (withdrawn) — study drug was stopped permanently due to the AE. 
• Dosing Interrupted — study drug regimen was modified by being temporarily halted, 
i.e., 1 or more doses were not administered, but drug was not stopped permanently. 
• Dose Decreased — study drug regimen was modified by subtraction, i.e., by 
decreasing the frequency, strength or amount. 
• None — no change in the administration of study mediation.  
For patients whose treatment is paused and then resumed at a lower dose level 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).  
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For each AE the Investigator will categorize as follows the actions taken to manage the AE:  
• Concomitant medication — 1 or more medications (prescription or over-the-counter) 
were started or increased in dose; non-medication actions may also have been 
ordered.  
• Other action — only non-medication action(s) were ordered as management of the 
AE (e.g., bed placed in Trendelenburg position, warm compresses applied to 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 study participation.  
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-15 indicates the date and time to be recorded. 
As discussed in detail for date/time of onset (see 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-15.  Date and Time of Outcome for Adverse Event by Outcome Class  
Outcome assigned to Adverse Event 
Date and Time to be Recorded 
Resolved (with or without sequelae) 
Date and time event observed or reported as resolved 
Death 
Date and time of death 
Resolving or Not Resolved 
Date and time of last observation 
Unknown 
None (see definition above) 
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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 services is provided in Table-1 and Table-2. 
In the event a 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).  
• Description of the event (i.e., date and time of onset, initial assessment, treatments 
and course).  
• Current status of the patient and the event.  
• Criteria by which the event was assessed as serious.  
• Date of the first injection of study drug.  
• Date of the last injection of study drug prior to the event.  
• Assessment of relationship of study drug to the event.  
• Whether the study drug was discontinued or adjusted as a result of the event.  
The following additional information will be entered within 2 days for death and life-threatening 
events and within 4 days for all other SAEs;  
• Narrative summary of the event — to include specific information that will assist in 
understanding the event, e.g., relevant medical history, co-morbid conditions, 
physical exam, diagnostics, assessment, treatments (including concomitant 
medications), response to treatment, course, and outcome (if known); 
• Copies of relevant medical reports — including diagnostic procedures 
(e.g., laboratory, ECG, x-ray), surgical procedures, and consultations.  
Additional documentation may be submitted as part of a follow-up report. 
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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 Adverse Events  
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 SAEs to the Investigator by the Sponsor  
In accordance with regulatory requirements, the Sponsor or designee 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 Code of Federal Regulations 
(CFR).  
• FDA guidance document: Safety Reporting Requirements for INDs and BA/BE 
Studies 
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.  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. 
• Medication prescription and administration records.  
• Laboratory reports, including clinical pathology and diagnostic histologic pathology.  
• Reports of imaging studies. 
• 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,” including, at a 
minimum, security requirements for electronic signature and audit trails for changes.  
11.3.1. 
Study-Specific Source Documents 
Study-specific source documents include, but are not limited to, the following: 
• The ICF, signed and dated by the patient. 
• The site screening log.  
• Any clinical reports noted above that are scheduled as part of the protocol and have 
been annotated to indicate the significance of any abnormal findings (see 
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); 
• Text should be readable and unambiguous, including application of best medical 
record practices (e.g., minimal use of abbreviations; proper numerical, dose and 
posology formats);  
• Entries will be signed and dated by the recorder.  
Study-specific paper documents must meet the following additional requirements: 
• Be written legibly in dark (preferably black) ink, 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 
contract 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 Pharmaceuticals, Inc. 
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 Pharmaceuticals, Inc. 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 (see 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.  
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Between visits the monitor will be available as needed to provide information or support to the 
Investigator(s) or other staff. 
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 Investigational New Drug 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.  
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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.  
• 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. 
STATISTICS 
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 MTD/RP2D, up to an additional 22 patients will be enrolled at the 
MTD or proposed RP2D level.  With a total sample size of 22 patients, there is a 90% probability 
to detect an AE with a true incidence rate of 10%.  A secondary objective of this study is to 
determine the treatment effect of IMO-8400 in patients enrolled at the MTD/RP2D.  Using the 
exact binomial distribution with a 1-sided test and an alpha of 0.05, there is 79% power to detect 
a response rate of 33% as compared to a null response rate of 10%. 
12.2. 
Analysis Populations 
Safety/Intent-to-treat (ITT) Population — all patients who received at least 1 dose of study 
treatment. 
Efficacy Evaluable (EE) Population – all patients who completed ≥1 cycle of therapy or those 
who discontinued due to progressive disease or DLT. 
Per-Protocol (PP) Population — all patients who have adequate data at baseline and at 1 or 
more scheduled post-treatment tumor assessment and have no major protocol deviations.  For 
patients who discontinue study treatment for any reason and start another treatment of their 
malignancy, no subsequent response assessments will be used for efficacy evaluation.  
12.3. 
Analysis of Safety  
Safety analyses will be conducted on the Safety/ITT Population.  Safety observations will be 
analyzed using descriptive statistics and tabulation.  No formal statistical comparisons are 
planned. All safety data will be presented in listings.  
• Safety Endpoints 
− AEs. 
− Concomitant medications. 
− Clinical observations (e.g., vital signs, physical examination). 
− Laboratory tests, (e.g., clinical chemistry, hematology, coagulation, urinalysis). 
− ECGs. 
− Injection site reactions. 
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• Analyses  
− TEAEs: by dose level, intensity, and relationship to investigational product.  
− Treatment-emergent changes in severity grade of laboratory tests (see 
Section 10.4.5) will be summarized as “shift tables.” 
− Descriptive statistics will be summarized for vital signs and ECG parameters by 
dose level and visit. 
− Concomitant medications will be summarized by WHO Drug Class and ATC text. 
− Injection site reactions will be summarized by incidence for each dose group and 
overall by worst grade on study.  Time-to-event analyses will be performed for 
injection site reactions. 
12.4. 
Analysis of Treatment Effect 
Analyses of treatment effect will be performed on both the EE and PP populations. 
12.4.1. 
Assessments 
Laboratory assessments for disease status (see Section 9.4.2) will be conducted at Screening, 
every 4 weeks ± 1 week (Week 1 and Week 5 of each cycle), every 12 weeks ± 4 weeks during 
the Follow-up Phase, at the EOT visit, and at the EOS visit.  Clinical assessments for disease 
status (see Section 9.4.1) will be conducted at Screening, every 8 weeks ± 1 week (Week 1 of 
every cycle), every 12 weeks ± 4 weeks during the Follow-up Phase, at the EOT visit, and at the 
EOS visit.  Radiologic imaging will be performed at Screening and at EOT visit or as clinically 
indicated.  Bone marrow biopsy and aspirate will be performed at Screening, EOT, and to 
document complete response as appropriate (see Section 16.2).  
12.4.1.1. Primary Treatment Effect Parameter 
The primary treatment effect parameter is objective response rate, defined as the occurrence of 
CR, VGPR, PR, or MR.  
12.4.1.2. Secondary Treatment Effect Parameters 
The VIth International Workshop specifies a number of outcome metrics related to time [1] (see 
Section 16.3).  The following parameters are considered most relevant to this time-limited study 
and will be analyzed both globally across all cohorts and by dose level.  
• Distribution of response categories by treatment group and overall. 
• Time to progression – Time from the initiation of treatment to disease progression 
with deaths due to unrelated causes censored.  
• Progression-free survival – Time from the initiation of treatment to disease 
progression or death from any cause. 
• Time to best observed response – Time from the initiation of treatment to best 
observed category of response. 
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• Percent and absolute change in quantitative serum levels of monoclonal and total 
IgM.  
Kaplan-Meier analyses will be used to analyze time to event data.  Analysis of IgM data will be 
performed using a repeated measures mixed model.  MyD88 L265P mutation status will be used 
as a covariate in statistical analyses. 
12.5. 
Exploratory Analyses 
The following investigational factors will be analyzed with regard to disease status:  
• Presence or absence of MyD88 L265P mutation in tumor cells. 
• Serum cytokine levels.  
• Serum levels of antibody to IMO-8400. 
• NF-κB inhibition. 
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 injection of 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 injection of study drug are designated Day 2, 
Day 3, etc. 
• The day of the last injection of study drug is indicated by adding the suffix "L," 
e.g., if the last injection is administered on Day 43, it will be displayed as "Day 43L." 
• The days following the last injection of 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. 
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.  
12.8. 
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)[28];2  
• local laws and regulations for the use of investigational therapeutic agents.  
13.1. 
Independent Ethics Committee (IEC) 
13.1.1. 
Initial Review Prior to Study Initiation  
Prior to initiating the study, the Investigator will submit the following to an IEC3 for approval: 
• Study protocol; 
• Investigator’s Brochure; 
• ICF 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 Investigator’s Brochure;  
• Date the protocol and consent form were reviewed and approved by the IEC.  
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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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: 
• 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 IEC.  
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 sufficient opportunity to read the ICF, to ask any questions, and to 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.  
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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. 
13.2.1. 
Obtaining Informed Consent from Patients Who Are Not Literate 
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.  
Note that this process is not applicable to patients who are literate in a language other than 
English; they must be provided an approved, certified translation of the ICF in that language. 
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);  
• Are less than 18 years of age.  
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.  
Methods to be used to protect the data will include the following:  
• 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 3) may be handled 
administratively.  
14.3. 
Confidentiality 
This protocol, the applicable Investigator’s Brochure, 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 
The information developed during the conduct of this clinical study is considered confidential by 
Idera. This information may be disclosed as deemed necessary by Idera. 
To allow for the use of the information derived from this clinical study and to ensure compliance 
with current regulations, the Investigator is obliged to provide Idera with complete test results 
and all data developed in this study. The information obtained during this study may be made 
available to other physicians who are conducting similar studies and to the FDA or other 
regulatory authorities. Such information may be disclosed as deemed necessary by Idera. 
Idera intends that the data from this study will be presented and published. The Idera staff in 
collaboration with the Investigator will be responsible for writing presentations and manuscripts 
for publication. Investigators will not be allowed to publish or present the data from this study 
without prior agreement with Idera. 
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 
1 Owen RG, Kyle RA, Stone MJ, et al. Response Assessment in Waldenström’s 
Macroglobulinemia: update from the VIth International Workshop. Br J Haematology 2012; 
160:171-176.  
2 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. 
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 Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological Definition of Waldenström’s 
Macroglobulinemia: Consensus Panel Recommendations from the Second International 
Workshop on Waldenström’s Macroglobulinemia. Sem. Oncol. 2003; 30: 110-115.  
6 Dimopoulos MA, Gertz, MA, Kastritis E, et al. Update on Treatment Recommendations from 
the Fourth International Workshop on Waldenström’s Macroglobulinemia. J Clin Oncol. 
2008; 27: 1-8. 
7 Treon SP. How I treat Waldenström macroglobulinemia. Blood. 2009;114(12):2375-85. 
8 Johnson SA, Birchall J, Luckie C. Guidelines on the management of Waldenström’s 
Macroglobulinemia. Br J Haematol. 2006;132:683-97. 
9 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.  
10 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. 
11 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. 
12 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. 
13 Demaria O, Pagni P, Traub S, et al. TLR8 deficiency leads to autoimmunity in mice. J Clin 
Invest. 2010; 120:3651-3662. 
14 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. 
15 Wang JQ, Jeelall YS, Horikawa K. Emerging targets in human lymphoma: targeting the 
MYD88 mutation. Blood Lymph Cancer 2013;3:53–61. 
16 Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human 
lymphoma. Nature. 2011;470(7332): 115–119. 
17 Puente XS, Pinyol M, Quesada V, et al. Whole-genome sequencing identifies recurrent 
mutations in chronic lymphocytic leukaemia. Nature. 2011;475(7354):101–105. 
18 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. 
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19 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. 
20 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. 
21 Li ZM, Rinaldi A, Cavalli A, et al. MYD88 somatic mutations in MALT lymphomas. Br J 
Haematol. 2012;158(5):662–664. 
22 Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma 
incidence patterns by WHO subtype in the United States, 1992–2001. Blood. 2006;107:265-
276. 
23 Ries LAG, Eisner MP, Kosary CL, eds. SEER Cancer Statistics Review, 1975-2001. 
Bethesda, MD: National Cancer Institute. Available at: http://seer.cancer.gov/csr/1975_2001/. 
Accessed 25 Sept 2013. 
24 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. 
25 FDA Briefing Document: Peripheral and Central Nervous System Drugs Advisory Committee 
Meeting. NDA 206031. Drisapersen. 2015 Nov. 
26 Kimby E, Treon SP, Anagnostopoulos A, et al. Update on Recommendations for Assessing 
Response from the Third International Workshop on Waldenström’s Macroglobulinemia. Clin 
Lymphoma & Myeloma. 2006; 6: 380-383. 
27 Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0, 28 May 2009. 
U.S. Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute. NIH Publication No. 03-5410. 
28 WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human 
Subjects, Available at (accessed 8 October 2013) 
http://www.wma.net/en/30publications/10policies/b3/ 
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16. 
CRITERIA FROM THE INTERNATIONAL WORKSHOPS 
16.1. 
Diagnostic Criteria for Waldenström’s Macroglobulinemia  
The following is reproduced from the “Recommendations from the Second International 
Workshop on Waldenström’s Macroglobulinemia” [5]. 
 
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16.2. 
Classification of Disease Response for Waldenström’s Macroglobulinemia  
Reproduced from Reference [1]. 
 
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16.3. 
Efficacy Measure Definitions 
Reproduced from Reference [1]. 
 
 
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17. 
INVESTIGATOR’S AGREEMENT 
I have read the foregoing protocol (Protocol 8400-401, Version 7.0) 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 GCP, 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 ICF 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 SAEs.  
• 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 (dd-mmm-yyyy) 
 
Investigator (printed name): 
 
Title: 
 
Address: 
 
 
Facility / Site of Investigation:   
Facility address: 
 
 
 
Idera Pharmaceuticals, Inc. 
Confidential and Proprietary