Clinical trial NCT02927964
Conditions: Grade 1 Follicular Lymphoma Grade 2 Follicular Lymphoma Grade 3a Follicular Lymphoma Recurrent Follicular Lymphoma Refractory Follicular Lymphoma Mantle Cell Lymphoma Marginal Zone Lymphoma
Sponsor: Robert Lowsky
Start date: 2016-11-07; Completion date: 2023-05-18
Enrollment: 21 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This phase Ib/II trial studies the side effects and best dose of toll-like receptor 9 (TLR9) agonist SD-101 when given together with ibrutinib and radiation therapy and to see how well they work in treating patients with Low Grade Follicular Lymphoma, Marginal Zone Lymphoma, or Mantle Cell Lymphoma that has come back after a period of improvement or no longer responds to treatment. Immunostimulants such as TLR9 agonist SD-101 may increase the ability of the immune system to fight infection and disease. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving TLR9 agonist SD-101 with ibrutinib and radiation therapy may induce an immune response and prolong anti-tumor response.

Detailed description:
Primary Objective:

Phase 1b: - To determine the recommended phase 2 dose (RP2D) of intratumoral SD 101 in combination with ibrutinib and radiation in subjects with relapsed or refractory B cell lymphoma . - To determine the safety and tolerability of SD 101 in combination with ibrutinib and radiation in subjects with relapsed or refractory B cell lymphoma

Phase 2: -To evaluate the efficacy of intratumoral SD 101 in combination with ibrutinib and radiation in subjects with relapsed or refractory B cell lymphoma by assessing overall response rate

Secondary Objective:

Phase 2: - To evaluate progression free survival after treatment with intratumoral SD 101 in combination with ibrutinib and radiation in subjects with relapsed or refractory B cell lymphoma

\- To evaluate the induction of tumor-specific immune responses by treatment with intratumoral SD-101 in combination with ibrutinib and radiation in patients with relapsed or refractory B cell lymphoma

Arms: arm 1: Patients undergo radiation therapy on days 1 and 2. Within 12 hours of the completion of radiation therapy, patients receive TLR9 agonist SD-101 IT on day 2 and on days 9, 16, 23, 30 and 37. Patients also receive ibrutinib PO daily beginning on day 9 for 96 weeks or in the absence of disease progression or unexpected toxicity.
Interventions: intervention 1: Ibrutinib intervention 2: Radiation Therapy intervention 3: TLR9 Agonist SD-101
Intervention descriptions: intervention 1: Given PO intervention 2: Undergo radiation therapy intervention 3: Given IT

Protocol documents:
Prot_SAP_001.pdf: 
Protocol Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
IRB-36750 
Page 1 of 70 
 24 January 2020 
Intratumoral Injection of SD-101, an Immunostimulatory CpG,  
in combination with Ibrutinib and Local Radiation in  
Relapsed or Refractory Low-Grade Follicular Lymphoma  
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Dr 
Stanford, CA  94305 
Protocol Director  
Ronald Levy, MD 
Stanford University Medical Center 
269 Campus Drive, CCSR, Room 1105 
Stanford, CA  94305 
Phone:  650-725-6452 
Fax:  650-736-1454 
levy@stanford.edu 
Sub-Investigators 
Michael Khodadoust, MD, PhD 
Stanford University Cancer Center 
875 Blake Wilbur Dr 
Stanford, CA  94305 
Ranjana Advani, MD 
Stanford University Cancer Center 
875 Blake Wilbur Dr 
Stanford, CA  94305 
Richard Hoppe,  MD 
Stanford University Cancer Center 
875 Blake Wilbur Dr 
Stanford, CA  94305 
Robert Lowsky MD 
Blood and Marrow Transplant 
875 Blake Wilbur Dr;  Clinic E 
Stanford, CA  94305 
Matthew Frank 
Stanford University Cancer Center 
875 Blake Wilbur Dr 
Tanaya Shree 
Stanford University Cancer Center 
875 Blake Wilbur Dr 
Stanford, CA  94305 
Biostatistician 
Balasubramanian Narasimhan 
Study Coordinator  
 
IRB number: 
IRB-36750 
IND number: 
IND 111985 (Robert Lowsky, MD) 
Date: ? 
 24 January 2020 
 


Protocol for Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
IRB-36750 
Page 2 of 70 
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Document History 
Notes 
27 April 2016 
Initial Approval 
25 July 2016 
Revision 1, change statistician 
4 October 2016 
Harmonize versioning and version date 
Add IRB-number and IND number 
Re-format title page 
Duplicate figure deleted 
9 January 2017 
Language supplied in memo from manufacturer 
was used to modify drug dilution instructions 
to align with current available drug 
formulation from manufacturer. 
Other corrections and administrative changes: 
Corrects schedule of events table (adds 
missing “x”s) 
Harmonization of fonts and spacing within 
document 
Correct misplaced phrase in 
Synopsis / Sample Size  
15 March 2017 
Addition of measurement of tumor-specific 
immune responses as an additional secondary 
endpoint 
Multiple revisions of the exclusion criteria 
Adjustment of the research samples collected: 
Number of sample tubes adjusted 
Timepoints of sample collection adjusted 
Addition of an optional FNA procedure on day 
4 
Corrects timing of post-treatment FNA to week 
6 from week 8 
Addition of defined acceptable visit windows 
for all visits 
17 October 2017 
Expanded inclusion criteria to include mantle 
cell lymphoma and marginal zone lymphoma 
in addition to previous population of 
low-grade follicular lymphoma 
Added language supporting efficacy of ibrutinib 
in mantle cell lymphoma and marginal zone 
lymphoma 
Decreased period of monitoring after SD-101 
injection from 60 minutes to 30 minutes 
24 October 2017 
IND version of 17 October 2017 changes 


Protocol for Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
IRB-36750 
Page 3 of 70 
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Document History 
Notes 
7 November 2017 
Removed requirement for prior biopsy from 
inclusion criteria 
Clarified that SAEs will be tracked until 
30 days after last dose of study treatment 
Consolidated Week 6 and 8 procedures into 
single Week 6 visit  
Adjusts distribution of ibrutinib to delete 
distribution event at Week 4 
Study coordinator updated 
17 November 2017 
IND version of 7 November 2017 changes 
(version reconciliation) 
21 February 2018 
Removed Tempus tube blood draw from all 
visits and deleted visits where that was the 
only event 
Distribution of Ibrutinib on Week 2 Day 10 was 
moved to Week 2 Day 9 
18 April 2018 
Made explicit that in the case of suspected 
pseudoprogression, patients may continue on 
trial until the next response assessment 
7 December 2018 
Updated study personnel 
Removed eligibility criteria regarding history of 
fever 
Changed phase 2 dose from maximum tolerated 
dose to recommended phase 2 dose 
Added that vital signs should be checked 30 
minutes after each injection 
Removed all non-treatment events from 
Treatment Day 1  
24 January 2019 
Updated study personnel 
Updated Treatment “Weeks” to “Days 
Clarified dose and schedule modifications with 
SD-101  
Clarified re-treatment after hypersensitivity 
reaction with  SD-101 
Added APPENDIX E: Contraception 
Guidelines 
 
 


Protocol for Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
IRB-36750 
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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ............................................................................................................. 7 
SCHEMA ..................................................................................................................................... 10 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 11 
1. 
OBJECTIVES ............................................................................................................. 12 
1.1. 
PRIMARY OBJECTIVES .................................................................................................... 12 
1.2. 
SECONDARY OBJECTIVES ............................................................................................... 12 
2. 
BACKGROUND ......................................................................................................... 12 
2.1 
NON-HODGKIN’S LYMPHOMA ........................................................................................ 12 
2.2 
INVESTIGATIONAL AGENTS ............................................................................................ 13 
2.2.1 
SD-101 ..................................................................................................................................................................... 13 
2.2.2  Ibrutinib ................................................................................................................................................................. 15 
2.2.3 
Radiotherapy ....................................................................................................................................................... 17 
2.3 
RATIONALE .................................................................................................................... 17 
2.4 
STUDY DESIGN .............................................................................................................. 20 
2.5 
CORRELATIVE STUDIES BACKGROUND .......................................................................... 20 
2.5.1  CTL activity against autologous tumor (performed if adequate tumor sample): ................. 20 
2.5.2 
Immunophenotyping of treated and untreated tumor sites: .......................................................... 21 
2.5.3. Anti-tumor antibody response (performed if adequate tumor sample): ................................... 21 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES .............. 21 
3.1 
INCLUSION CRITERIA ..................................................................................................... 21 
3.2 
EXCLUSION CRITERIA .................................................................................................... 22 
3.3 
INFORMED CONSENT PROCESS ....................................................................................... 23 
3.4 
RANDOMIZATION PROCEDURES ..................................................................................... 23 
3.5 
STUDY TIMELINE ........................................................................................................... 23 
4. 
TREATMENT PLAN ................................................................................................ 23 
4.1 
DOSE DE-ESCALATION STUDY DESIGN ........................................................................... 23 
4.2 
INFORMED CONSENT AND SCREENING PERIOD .............................................................. 25 
4.3 
TREATMENT PERIOD: ..................................................................................................... 26 
4.3.1 
Day 1: ....................................................................................................................................................................... 26 
4.3.2 
Day 2: ....................................................................................................................................................................... 26 
4.3.3 
Day 4 (+/- 1 day): ............................................................................................................................................... 26 
4.3.4 
Day 9 (+/- 2 days) .............................................................................................................................................. 27 
4.3.5 
Day 16 (+/- 2 days) ............................................................................................................................................ 27 
4.3.6 
Day 23 (+/- 2 days); Day 30 (+/- 2 days) ................................................................................................. 27 
4.3.7 
Day 37  .................................................................................................................................................................... 27 
4.3.8 
Weeks 12, 24, 36, 48, 60, 72, 84: .................................................................................................................. 28 
4.3.9 
Final Study Visit .................................................................................................................................................. 28 
4.4 
FOLLOW-UP PERIOD ...................................................................................................... 29 
4.5 
DURATION OF THERAPY ................................................................................................. 29 
4.6  
DURATION OF FOLLOW UP ............................................................................................. 29 
4.7 
RADIOTHERAPY ADMINISTRATION ................................................................................ 29 
4.8 
INVESTIGATIONAL AGENT ADMINISTRATION:  SD-101 ................................................. 29 


Protocol for Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
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4.9 
INVESTIGATIONAL AGENT ADMINISTRATION:  IBRUTINIB .............................................. 31 
4.10 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............... 31 
4.10.1 Prohibited Therapies ........................................................................................................................................ 31 
4.10.2 Restricted Therapies ......................................................................................................................................... 31 
4.11 
CRITERIA FOR REMOVAL FROM STUDY .......................................................................... 32 
4.12 
ALTERNATIVES .............................................................................................................. 32 
5. 
INVESTIGATIONAL AGENT INFORMATION .................................................. 32 
5.1 
 SD-101 ......................................................................................................................... 32 
5.2 
IBRUTINIB ...................................................................................................................... 35 
5.3 
RADIOTHERAPY ............................................................................................................. 40 
5.4 
AVAILABILITY ............................................................................................................... 40 
5.5 
AGENT ORDERING ......................................................................................................... 40 
5.4 
AGENT ACCOUNTABILITY .............................................................................................. 41 
6. 
DOSE MODIFICATIONS ......................................................................................... 41 
6.1 
DOSE MODIFICATIONS OF SD-101 ................................................................................. 41 
6.2 
RE-TREATMENT AFTER HYPERSENSITIVITY REACTION (HSR) FOR SD-101 .................. 41 
6.3 
DOSE MODIFICATIONS FOR IBRUTINIB ........................................................................... 41 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES .................................. 42 
7.1  
OVERVIEW: .................................................................................................................... 42 
7.2 
MANAGEMENT OF SAFETY DATA: .................................................................................. 42 
7.3 
ASSESSING ADVERSE EVENTS: ...................................................................................... 44 
7.4 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................... 44 
7.4.1 
Adverse Events ..................................................................................................................................................... 44 
7.4.2 
Serious Adverse Events .................................................................................................................................... 45 
7.4.3 
Requirements related to reporting to Janssen Scientific Affairs, LLC ......................................... 45 
8. 
CORRELATIVE/SPECIAL STUDIES .................................................................... 47 
8.1 
BLOOD AND TISSUE ACQUISITION ................................................................................... 47 
8.2 
STORAGE OF BLOOD AND TISSUE SAMPLES ..................................................................... 47 
8.3 
LYMPHOCYTE ACTIVITY AGAINST AUTOLOGOUS TUMOR (PERFORMED IF ADEQUATE 
TUMOR SAMPLE): ........................................................................................................... 48 
8.4 
IMMUNOPHENOTYPING OF TREATED AND UNTREATED TUMOR SITES .............................. 48 
8.5 
ANTI-TUMOR ANTIBODY RESPONSE (PERFORMED IF ADEQUATE TUMOR SAMPLE): ......... 48 
9. 
STUDY CALENDAR ................................................................................................. 49 
10. 
MEASUREMENTS .................................................................................................... 51 
10.1 
PHASE 1B - PRIMARY OUTCOME MEASURE ................................................................... 51 
10.1.1 Dose-Limiting Toxicity Definition ............................................................................................................... 51 
10.1.2 Measurement Methods ..................................................................................................................................... 51 
10.1.3 Measurement Time Points .............................................................................................................................. 51 
10.2 
PHASE 2 - PRIMARY OUTCOME MEASURE ..................................................................... 52 
10.2.1 Relevant Subset ................................................................................................................................................... 52 
10.2.2 Response Definition ........................................................................................................................................... 52 
10.2.3 Measurement Methods ..................................................................................................................................... 54 
10.2.4 Measurement Time Points .............................................................................................................................. 54 
10.3 
PHASE 2 - SECONDARY OUTCOME MEASURE – PROGRESSION FREE SURVIVAL .............. 54 
10.3.1 Relevant Subset ................................................................................................................................................... 55 


Protocol for Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
IRB-36750 
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10.3.2 Progression-free Survival Definition ......................................................................................................... 55 
10.3.3 Measurement Methods ..................................................................................................................................... 55 
10.3.4 Measurement Time Points .............................................................................................................................. 55 
10.4 
PHASE 2 - SECONDARY OUTCOME MEASURE – INDUCTION OF TUMOR-SPECIFIC IMMUNE 
RESPONSES .................................................................................................................... 55 
10.4.1 Relevant Subset ................................................................................................................................................... 55 
10.4.2 Tumor-specific Immune Response Definition ........................................................................................ 55 
10.4.3 Measurement Methods ..................................................................................................................................... 55 
10.4.4 Measurement Time Points .............................................................................................................................. 55 
11. 
REGULATORY CONSIDERATIONS .................................................................... 56 
11.1 
INSTITUTIONAL REVIEW OF PROTOCOL .......................................................................... 56 
11.2 
DATA AND SAFETY MONITORING PLAN ......................................................................... 56 
11.3 
DATA MANAGEMENT PLAN ........................................................................................... 56 
11.4 
CONFIDENTIALITY ......................................................................................................... 56 
12. 
STATISTICAL CONSIDERATIONS ...................................................................... 57 
12.1 
STATISTICAL DESIGN ..................................................................................................... 57 
12.2 
PRIMARY ANALYSIS ....................................................................................................... 57 
12.2.1 Analysis Population ........................................................................................................................................... 57 
12.2.2 Analysis Plan ........................................................................................................................................................ 57 
12.3  
SAMPLE SIZE .................................................................................................................. 57 
12.3.1 Accrual estimates ............................................................................................................................................... 57 
12.3.2 Sample size justification .................................................................................................................................. 57 
12.3.3 Effect size justification ..................................................................................................................................... 58 
12.4 
CRITERIA FOR FUTURE STUDIES ..................................................................................... 58 
13. 
REFERENCES ........................................................................................................... 59 
APPENDICES ............................................................................................................................. 62 
APPENDIX A: PARTICIPANT ELIGIBILITY CHECKLIST .......................................................... 62 
APPENDIX B: DEFINITION OF TUMOR RESPONSE USING IRRC ............................................. 66 
APPENDIX C: ECOG PERFORMANCE STATUS ..................................................................... 68 
APPENDIX D:   LIST OF P450 INHIBITORS AND INDUCERS .................................................... 69 
APPENDIX E: CONTRACEPTION GUIDELINES  
 
 
 
 
        ? 
 


Protocol for Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
IRB-36750 
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PROTOCOL SYNOPSIS 
TITLE 
Intratumoral Injection of SD-101, an 
Immunostimulatory CpG, in combination with 
Ibrutinib and Local Radiation in Relapsed or 
Refractory Low-Grade Follicular Lymphoma 
STUDY PHASE 
Phase 1b/2 
INDICATION 
Relapsed/Refractory Low grade Follicular 
Lymphoma, Mantle cell Lymphoma, Marginal 
Zone Lymphoma 
INVESTIGATIONAL PRODUCT OR 
PROCEDURE 
Intratumoral SD-101 plus low-dose local 
radiotherapy plus oral ibrutinib 
PRIMARY OBJECTIVE(S) 
Phase 1b:   
1) To determine the recommended phase 2 dose 
(RP2D) of intratumoral SD-101 in combination 
with ibrutinib and radiation in subjects with 
relapsed or refractory B-cell lymphoma  
2) To determine the safety and tolerability of 
SD-101 in combination with ibrutinib and 
radiation in subjects with relapsed or refractory 
B-cell lymphoma  
Phase 2:   
1) To evaluate the efficacy of intratumoral SD-101 
in combination with ibrutinib and radiation in 
subjects with relapsed or refractory 
B-cell lymphoma by assessing overall response 
rate 
SECONDARY OBJECTIVE(S) 
Phase 2: 
1)   To evaluate progression-free survival after 
treatment with intratumoral SD-101 in 
combination with ibrutinib and radiation in 
subjects with relapsed or refractory 
B-cell lymphoma 
2)   To evaluate the induction of tumor-specific 
immune responses by treatment with 
intratumoral SD-101 in combination with 
ibrutinib and radiation in patients with relapsed 
or refractory B-cell lymphoma 


Protocol for Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
IRB-36750 
Page 8 of 70 
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TREATMENT SUMMARY 
Local low-dose radiation therapy to a single site of 
disease combined with intratumoral injections to 
the same single site. 
SD-101 (CpG) – Intratumoral injection on Day 2, 
then once every week x 4 successive weeks for a 
total of 5 injections at a dose of 3 mg per dose in 
cohort 1 or 1 mg per dose in cohort -1. 
Ibrutinib orally at a dose of 560 mg daily starting 
on Day 10 until progression of disease or for 
96 weeks, whichever comes first. 
In the safety portion of the study, a starting dose of 
3 mg SD-101 and 560 mg ibrutinib will be studied 
and will follow a 6+3 dose de-escalation design.  In 
the first cohort of 6 subjects, if ≤ 1 subjects 
experiences a DLT, then that dose level will be 
chosen as the recommended phase 2 dose.  If 
2 subjects experience a DLT, then an additional 
3 subjects will be enrolled at the same dose level.  
If 3 or more of 6 to 9 subjects experience a DLT, 
dose de-escalation will occur with a new cohort of 
6 subjects at a dose of 1 mg SD-101 and 560 mg 
ibrutinib. 
Based on the data from dose de-escalation cohorts, 
a dose of SD-101 will be chosen and an additional 
cohort of 15 subjects will be treated at that dose in 
order to assess the clinical response rate.  
Immune monitoring and follow-up will occur over 
the following 24 weeks.  
Subjects without PD will be followed for immune 
and clinical response every 12 weeks until Week 96 
or progression, whichever comes first. 
SAMPLE SIZE  
This research study is looking for a total of up to 
30 subjects with low-grade follicular lymphoma, 
marginal zone lymphoma, or mantle cell 
lymphoma.  All subjects will be enrolled at 
Stanford University.  A total of 6 to 15 subjects will 
be enrolled in the phase 1B 6 x 3 dose de-escalation 
portion.  An additional 15 subjects will be enrolled 
in the expanded phase 2 cohort. 
If ≤ 1 of 6 subjects experience a DLT at a dose of 
intratumoral SD-101 of 3 mg, we will proceed to the 
expansion phase.  If 2 of 6 subjects experience a DLT
at 3 mg, then an additional 3 subjects will be enrolled 
in the same dosing cohort.  If ≥ 3 of 6 to 9 subjects 


Protocol for Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
IRB-36750 
Page 9 of 70 
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experience a DLT, then a dose de-escalation 
cohort -1 of 6 subjects will be opened. 
STATISTICAL CONSIDERATIONS 
The sample size of 15 subjects in the expanded 
phase 2 cohort (with resulting total number of 
21 to 24 subjects at the RP2D in the combined 
1b/2 phases) allows estimation of the response rate 
+/- 0.21 with 90% confidence.  The chance of 
obtaining three or fewer responses out of 15 is only 
2.1% if the true response rate is 49%, with 49% 
ORR being a historical benchmark for response rate 
in this population.  
 


Protocol for Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
IRB-36750 
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SCHEMA
Treatment Week 1 
 
Day 1:   
• 
Radiation (2 Gy) 
 
Day 2:   
• 
Radiation (2 Gy) 
• 
SD-101 Inj no. 1 
 
Day 4: 
• 
FNA (optional) 
Screening and 
Registration 
• 
Consult with 
Medical Oncology 
• 
Consult with 
Radiation Oncology 
and  Radiotherapy 
Planning 
• 
Consult with 
Surgical Oncology 
and Biopsy (if 
necessary) 
• 
Fine needle 
aspiration biopsy (if 
excision biopsy not 
performed) 
• 
Baseline imaging 
assessment (CT) 
• 
Apheresis (if 
excisional biopsy is 
obtained at 
screening) and 
routine safety labs 
 
Treatment Day 9 
• 
SD-101 intratumoral injection no. 2 
• 
Research blood draws  
• 
Safety labs 
• 
FNA (optional) accessible tumor(s) 
• 
Ibrutinib dispensed to start the 
next day 
Treatment Day 16 
• 
SD-101 intratumoral injection no. 3 
• 
Continue ibrutinib daily dosing 
• 
Research blood draw 
Treatment Day 23 
• 
SD-101 intratumoral injection no. 4 
• 
Continue ibrutinib daily dosing 
• 
Research blood draws 
• 
Safety labs 
Treatment Day 30 
• 
SD-101 intratumoral injection no. 5 
• 
Continue ibrutinib daily dosing 
Treatment Day 37  
• 
FNA (optional) accessible tumor 
• 
Apheresis  
• 
Safety labs 
• 
Continue ibrutinib daily dosing 
• 
Research blood draws 
Week 12 and every 12 weeks thereafter 
• 
Response assessment (CTs) 
• 
Research blood draw 
• 
Safety labs 
• 
Continue ibrutinib until disease 
progression or week 96 


Protocol Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
IRB-36750 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
BID 
Twice daily 
CBC 
Complete blood count 
CNS 
Central nervous system 
CpG 
Cytosine-phosphate-Guanine 
CRF 
Case report/Record form 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T lymphocyte 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPF 
High-power field  
HTN 
Hypertension 
IRB 
Institutional Review Board 
ISS 
Immunostimulatory sequence 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal  
MTD 
Maximum Tolerated Dose 
ODN 
Oligonucleotide 
OS 
Overall survival  
PBL 
Peripheral blood leukocytes 
PLT 
Platelet 
PD 
Progressive disease 
PFS 
Progression free survival  
PQC 
Product Quality Complaint 
PR 
Partial response 
QD 
Once daily 
RECIST 
Response evaluation criteria in solid tumors 
RP2D 
Recommended phase 2 dose 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Stable disease 
SD-101 
Immunostimulant CpG injection (Dynavax) 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
WBC 
White blood cell 
WHO 
World Health Organization 


Protocol Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
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1. 
OBJECTIVES 
1.1. 
Primary Objectives  
Phase 1b:   
1) To determine the recommended phase 2 dose (RP2D) of intratumoral SD-101 in 
combination with ibrutinib and radiation in subjects with relapsed or refractory B cell 
lymphoma 
2) To determine the safety and tolerability of SD-101 in combination with ibrutinib and 
radiation in subjects with relapsed or refractory B cell lymphoma  
Phase 2: 
1) To evaluate the efficacy of intratumoral SD-101 in combination with ibrutinib and 
radiation in subjects with relapsed or refractory B-cell lymphoma by assessing overall 
response rate 
1.2. 
Secondary Objectives 
 
Phase 2: 
1) To evaluate progression-free survival after treatment with intratumoral SD-101 in 
combination with ibrutinib and radiation in subjects with relapsed or refractory 
B-cell lymphoma 
2) To evaluate the induction of tumor-specific immune responses by treatment with 
intratumoral SD-101 in combination with ibrutinib and radiation in patients with relapsed 
or refractory B-cell lymphoma 
2. 
BACKGROUND 
2.1 
Non-Hodgkin’s lymphoma 
Non-Hodgkin’s lymphoma (NHL) is a group of histologically and biologically distinct lymphoid 
malignancies.  80 to 90% of NHLs are B-cell lymphomas, and the great majority of the rest are 
T-cell lymphomas.  It is estimated that there will be 71,850 cases of NHL diagnosed in the US in 
2015, representing 4% of all cancers diagnosed in the United States.(1)  An estimated 19,790 
deaths will result from NHL in 2015.  Reporting from the US Surveillance, Epidemiology, and 
End Results (SEER) program indicates that the incidence of NHL has increased substantially in 
recent years, from 10.2 per 100,000 in 1973 to 18.5 in 1990, an increase of 81% overall and 
about 3.6% per year.  The rapid increase in NHL incidence in the 1970s and 1980s has been 
surpassed only by the increases in lung cancer in women and malignant melanomas in both 
sexes.(2) 
Non-Hodgkin’s lymphomas encompass many histological types.  The Revised 
European-American Classification of Lymphoid Neoplasms (REAL) developed in 1994 is the 
currently accepted classification.  This was further refined by the World Health Organization 
(WHO) classification of hematologic malignancies in 1997.  Based on this classification, NHLs 
are grouped into indolent (low-grade), aggressive and highly aggressive lymphomas based on the 
clinical behavior of each entity.  Low-grade lymphomas (indolent lymphomas) can be further 
subdivided into B-cell and T-cell types.  The low-grade B-cell lymphomas include follicular 


Protocol for Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
IRB-36750 
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lymphoma (FL), B-chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 
lymphoplasmacytoid lymphoma and marginal zone lymphoma (MZL).  Mantle cell 
lymphoma (MCL) is an intermediate grade lymphoma.  The T-cell group includes T-CLL and 
mycosis fungoides.   
Follicular lymphoma is the most common type of low-grade B-cell lymphoma, and represents 
20% of all non-Hodgkin’s lymphomas.  It is characterized by an indolent clinical course, but 
with a potential to transform to a more aggressive form of lymphoma.  Follicular lymphoma is 
most often disseminated at diagnosis, and is rarely cured.  Although the disease is sensitive to 
chemotherapy, radiotherapy and immunotherapy, subjects eventually exhaust all options and 
succumb to progression of disease.  The median survival of all subjects with follicular lymphoma 
is approximately 10 years.  The prognosis of follicular lymphoma subjects can be estimated by a 
constellation of clinical parameters, described as FLIPI (follicular lymphoma international 
prognostic index), determined at disease presentation.  FLIPI includes one “point” for each of:  
stage III/IV disease;  number of nodal sites involved ≥ 5;  LDH > normal;  age ≥ 60;  and 
Hb < 12.  Subjects with 0 to 1;  2;  or ≥ 3 risk factors belong to good, intermediate and poor-risk 
groups.  The 10-year overall survival is 70%, 51% and 36% for the good, intermediate and poor 
risk groups, respectively (3).   
Because FL, MZL, and MCL are generally incurable, the principal of treatment is palliation.  In 
advanced-stage low-grade lymphoma subjects, the Stanford group showed no advantage in 
survival between watchful waiting and early intervention.(4)  Thus, therapy is instituted only 
when subjects develop symptoms from their lymphoma.  Follicular lymphoma, marginal zone 
lymphoma and mantle cell lymphoma are sensitive to many treatment modalities, including 
chemotherapy, radiotherapy and immunotherapy.  However, the response is generally not 
durable and subjects eventually succumb to the disease.  Therefore, novel therapies are needed to 
improve the outcome of subjects with FL, MZL, and MCL. 
2.2 Investigational Agents 
2.2.1 SD-101 
SD-101 is an investigational agent which requires an Investigational New Drug application 
(IND).   
Toll-like receptor 9 (TLR9) ligands have multiple mechanisms of action that modulate the 
immune system including both direct and indirect anti-tumor effects.  The natural ligands for 
TLR9 are unmethylated CpG oligonucleotide sequences that are rare in vertebrate genomes but 
prevalent in pathogen genomes including bacteria and viruses.  A synthetic CpG product SD-101 
is available to us for clinical use from DynaVax Technologies.  DynaVax is supplied as a GMP 
material.  SD-101, a Class C CpG, induces an IFN-α signature in both human PBMCs in vitro 
and non-human primates in vivo.  There is considerable experience with SD-101 in normal 
subjects and in subjects with lymphoma.  Based on single-agent studies in healthy volunteers and 
an ongoing trial of previously untreated low-grade lymphoma subjects, it is safe and well 
tolerated up to a dose of 5 mg per injection.  IND 111985 is held by Stanford Investigator, 
Robert Lowsky, MD (listed on the title page of this protocol) and will be cross-referenced and 
used in this study. 


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Mechanism of Action  
CpG-ODN, such as SD-101, are optimized for immune stimulation by substituting sulfur for 
phosphorus between nucleotide subunits to provide increased resistance to nuclease-mediated 
degradation.  The nucleotide sequences are recognized by TLR-9, a receptor for innate immune 
recognition of microbial and viral DNA (5).  Two principal types of human PBMCs express 
TLR-9 and respond directly to SD-101 in vitro or in vivo:  PDCs (peripheral dendritic cells) and 
B lymphocytes (6-10).  Immune activation by CpG results from specific binding to B-cells and 
plasmacytoid dendritic cells (pDC), with subsequent activation of lymphocyte, macrophage, 
monocyte, natural killer (NK) and T-cell populations.  The intracellular receptor for CpGs is 
TLR-9.  Both innate (non-specific) and adaptive (antigen-specific) immune responses are 
affected by CpGs.  The net result is increased secretion of antibodies from B-cells, cytokines 
from a variety of cells and increased NK activity as well as improved antigen presentation and 
T-help that can augment both humoral and cell-mediated immune responses.  See Figure 1 
below. 
 
Figure 1.  CpG Cellular Mechanism of Action 
Metabolism of SD-101 
As with other phosphorothioate oligodeoxyribonucleotides, SD-101 is metabolized by 
exonucleases present in plasma and tissues. 
Human Experience with SD-101 
Two phase 1 trials of a total of 60 subjects have been completed with SD-101 demonstrating 
safety up to a dose of 5 mg.  Additionally there are 2 ongoing trials of SD-101 in combination 
with local radiation in low-grade non-Hodgkin’s lymphomas. 


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Dosing rationale 
SD-101 will be dosed intratumoral at a starting dose of 3 mg.  This dose has been shown to be 
safe in prior phase 1 trials and PD studies in these trial have shown activity at this dose.   
2.2.2  Ibrutinib 
Ibrutinib has been approved by the FDA for the treatment of relapse/refractory mantle cell 
lymphoma, chronic lymphocytic leukemia, and Waldenstrom’s Macroglobulinemia, but not for 
the treatment of relapsed/refractory follicular lymphoma as proposed here.   
Ibrutinib is a first-in-class, potent, orally administered covalently-binding inhibitor of Bruton’s 
tyrosine kinase (BTK).  Inhibition of BTK blocks downstream B-cell receptor (BCR) signaling 
pathways and thus prevents B-cell proliferation.  In vitro, ibrutinib inhibits purified BTK and 
selected members of the kinase family with 10-fold specificity compared with non-BTK kinases.  
Ibrutinib (Imbruvica) is approved by the US Food and Drug Administration (FDA) for the 
treatment of subjects with chronic lymphocytic leukemia or mantle cell lymphoma who have 
received at least one prior therapy, subjects with CLL with 17p deletion regardless of prior 
treatment, and subjects with Waldenstrom’s macroglobulinemia.  Ibrutinib is currently being 
studied in various additional indications including multiple subtypes of non-Hodgkins 
lymphoma.   
Mechanism of Action 
Ibrutinib is a small-molecule inhibitor of BTK.  Ibrutinib forms a covalent bond with a cysteine 
residue in the BTK active site, leading to inhibition of BTK enzymatic activity.  BTK is a 
signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways.  BTK’s 
role in signaling through the B-cell surface receptors results in activation of pathways necessary 
for B-cell trafficking, chemotaxis, and adhesion.  Nonclinical studies show that ibrutinib inhibits 
malignant B-cell proliferation and survival in vivo as well as cell migration and substrate 
adhesion in vitro.  
Pharmacokinetics 
Absorption:  Ibrutinib is absorbed after oral administration with a median Tmax of 1 to 2 hours.  
Ibrutinib exposure increases with doses up to 840 mg.  The steady-state AUC (mean ± standard 
deviation) observed in subjects at 560 mg is 953 ± 705 ng⋅h/mL and in subjects at 420 mg is 
680 ± 517 ng⋅h/mL.  Administration with food increased ibrutinib Cmax and AUC by 
approximately 2 to 4- and 2-fold, respectively, compared with administration of ibrutinib after 
overnight fasting.  Distribution:  Reversible binding of ibrutinib to human plasma protein in vitro 
was 97.3% with no concentration dependence in the range of 50 to 1000 ng/mL.  The volume of 
distribution at steady state (Vd,ss) was 683 L, and the apparent volume of distribution at steady 
state (Vd,ss/F) was approximately 10000 L.  
Metabolism:  Metabolism is the main route of elimination for ibrutinib.  It is metabolized to 
several metabolites primarily by cytochrome P450, CYP3A, and to a minor extent by CYP2D6.  
The active metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards 
BTK approximately 15 times lower than that of ibrutinib.  The range of the mean 
metabolite to parent ratio for PCI-45227 at steady-state is 1 to 2.8.  


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Elimination:  Intravenous clearance was 62 and 76 L/h in fasted and fed conditions, respectively.  
In line with the high first-pass effect, the apparent oral clearance is approximately 2000 and 
1000 L/h in fasted and fed conditions, respectively.  The half-life of ibrutinib is 4 to 6 hours.  
Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces.  After a single oral 
administration of radiolabeled [14C]-ibrutinib in healthy subjects, approximately 90% of 
radioactivity was excreted within 168 hours, with the majority (80%) excreted in the feces and 
less than 10% accounted for in urine.  Unchanged ibrutinib accounted for approximately 1% of 
the radiolabeled excretion product in feces and none in urine, with the remainder of the dose 
being metabolites.  
Renal Impairment:  Ibrutinib is not significantly cleared renally; urinary excretion of metabolites 
is < 10% of the dose.  Creatinine clearance > 25 mL/min had no influence on the exposure to 
ibrutinib.  There are no data in subjects with severe renal impairment (CLcr < 25 mL/min) or in 
subjects on dialysis.   
Hepatic Impairment:  Ibrutinib is metabolized in the liver.  In a hepatic impairment trial, a single 
dose of 140 mg of ibrutinib was administered in non-cancer subjects.  Ibrutinib AUC increased 
2.7-, 8.2- and 9.8-fold, respectively, in subjects with mild (n = 6), moderate (n = 10) and severe 
(n = 8) hepatic impairment relative to subjects with normal liver function.  Ibrutinib Cmax 
increased 5.2-, 8.8- and 7.0-fold, respectively, in subjects with mild, moderate and severe hepatic 
impairment relative to subjects with normal liver function.   
Drug Interactions 
Coadministration of Ibrutinib with CYP3A Inhibitors:  In a sequential design trial of 18 healthy, 
fasted volunteers, a single dose of 120 mg of ibrutinib was administered alone on Day 1 and a 
single dose of 40 mg of ibrutinib was administered on Day 7 in combination with 400 mg of 
ketoconazole (given daily on Days 4 to 9).  Ketoconazole increased ibrutinib dose-normalized 
Cmax and AUC 29-fold and 24-fold, respectively.  Simulations using fasted conditions indicate 
that moderate CYP3A inhibitors diltiazem and erythromycin may increase AUC of ibrutinib by 
5- to 8-fold. 
Coadministration of Ibrutinib with CYP3A Inducers:  PK data from a dedicated drug interaction 
trial showed that rifampin (a strong CYP3A inducer) decreases ibrutinib Cmax and AUC by 
more than 13- and 10-fold.  Simulations using PBPK suggested that a moderate CYP3A inducer 
(efavirenz) may decrease the AUC of ibrutinib by up to 3-fold. 
Efficacy of Ibrutinib in Follicular Lymphoma 
Ibrutinib has been studied in the treatment of subjects with low-grade follicular lymphoma.  In a 
phase 1 study of subjects with relapsed or refractory B-cell malignancies, 13 subjects with 
follicular lymphoma were evaluated for response to ibrutinib, with 7/13 subjects showing a 
>50% decrease in sum of the largest diameter of each target lesion (11).  The MTD in this study 
was 560 mg daily and this dose showed full-target occupancy.  Preliminary results from a 
phase 2 trial of ibrutinib monotherapy in relapsed/refractory follicular lymphoma showed an 
overall response rate of 30% in 40 subjects on the intention-to-treat analysis.  An additional 
14 subjects had reduction of tumor size not meeting response criteria (12).   


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Efficacy of Ibrutinib in Marginal Zone Lymphoma 
In the PCYC-1121-CA study of 63 patients with marginal zone lymphoma(13), ibrutinib was 
shown to be active, with an overall response rate of 48% with a median duration of response not 
reached.  Response rates were similar across all marginal zone subtypes (MALT, nodal, splenic).  
On the basis of this trial, ibrutinib received accelerated approval for adult patients with marginal 
zone lymphoma after at least one prior anti-CD20-based therapy.   
Efficacy of Ibrutinib in Mantle Cell Lymphoma 
Ibrutinib is FDA-approved for the treatment of relapsed/refractory treatment of mantle cell 
lymphoma.  This is based on an overall response rate of 65.8% with median duration of response 
of 17.5 months seen in the PCYC-1104-CA trial of 111 patients (14).  Ibrutinib is now frequently 
used in the treatment of relapsed mantle cell lymphoma and is being study as a front-line therapy 
for MCL.   
Dosing rationale 
Dosing of ibrutinib will be 560 mg daily, based on the proven safety at this level and efficacy in 
follicular lymphoma as discussed above.  This is also the FDA-approved dose for treatment of 
mantle cell lymphoma and marginal zone lymphoma.  
2.2.3 Radiotherapy 
Pre-clinical and Clinical Studies 
Animal studies of subcutaneous tumors have demonstrated that tumor cells undergo apoptosis 
upon irradiation.  Furthermore, it has been shown that dendritic cells migrate towards irradiated 
tumor (15).   
The purpose of using low-dose radiation to a single tumor site in our study is to induce tumor 
necrosis and/or apoptosis, which in turn releases tumor antigens locally.  These tumor antigens 
will be processed by antigen presenting cells to mount a tumor- specific immune response.  This 
immune response will be augmented by intratumoral injection of SD-101, which is a potent 
immunostimulant.   
Low-dose (2 Gy x 2) radiotherapy has been studied in recurrent follicular lymphoma (16).  The 
overall local tumor response rate is estimated at 80 to 90%.  The reason for choosing a low-dose 
radiation is that the low-dose therapy is sufficient to induce tumor cell death and will not 
jeopardize subjects’ opportunity to receive standard radiotherapy at the same anatomic site in the 
future.  Another potential advantage of using a low-dose radiation regimen is to minimize the 
possibility that the radiation will inhibit tumor-infiltrating dendritic cell functions. 
Radiotherapy:  Dosage 
All subjects will receive 2 Gy radiation to a single tumor site on each of two consecutive days 
(Day 1 and Day 2).   
2.3 
Rationale 
Research Hypothesis:  Ibrutinib can be safely and feasibly combined with intratumoral 
injections of SD-101 and local radiation therapy.   


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The combination of low-dose local external beam radiotherapy and intratumoral injection of 
SD-101 to a single site of disease can induce an immune response leading to systemic objective 
responses in lymphoma subjects.  The addition of ibrutinib may have an additive or synergistic 
effect, prolonging anti-tumor response. 
Product Development Rationale 
Ibrutinib 
 
Figure 2.  Bruton's Tyrosine Kinase and the B-cell receptor pathway. 
Bruton’s Tyrosine Kinase (BTK) is part of the B-cell receptor (BCR) signaling pathway.  There 
is strong evidence that lymphoma survival requires BCR signaling.  In lymphoma cells, a 
functional B-cell receptor is conserved, even as the non-expressed immunoglobulin heavy chain 
(IgH) is typically involved in oncogenic translocations(17).  In trials of anti-idiotype directed 
therapies, subjects whose tumor cells developed resistance to treatment did not produce 
BCR-negative tumor populations as a resistance strategy, indicating that the BCR provides 
important survival signals for lymphoma cells(18).  Selective knockdown of BCR components 
by siRNA causes apoptosis in B-cell lymphoma cell lines(19).  Some large cell lymphomas have 
low-level tonic activation of the kinases downstream of the BCR; inhibition of this signaling also 
results in apoptosis(20).  Primary follicular lymphoma cells have enhanced BCR pathway 
signaling when compared with normal B-cells(21).  Because of cellular dependency on BCR 
signaling and the restricted expression of the BCR components in B-cell lineages, the BCR 
pathway has become an attractive target for lymphoma therapies. 
Ibrutinib (PCI-32765) is a selective, small molecule irreversible inhibitor of BTK.  In vitro 
studies showed that ibrutinib binds covalently to a cysteine-481 residue (Cys-481) near the BTK 
active site and inhibits the enzymatic activity with half maximal inhibitory concentration (IC50) 
of 0.5 nM (22, 23).  Preclinical and clinical data indicate that B-cell receptor (BCR) signaling is 
effectively inhibited by ibrutinib, leading to highly selective cytotoxicity in malignant B-cells.   


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The inhibitory effect of ibrutinib against other related kinases has been characterized in 
biochemical assays.  Only a small subset of kinases is predicted to contain a modifiable cysteine 
residue homologous to Cys-481 in BTK, and thus have the potential to be irreversibly modified 
by ibrutinib.  The other Cys-481 containing kinases include EGFR (IC50 = 12 nM);  
HER2 (IC50 = 22 nM);  HER4 (IC50 = 0.6 nM);  ITK (IC50 = 12nM);  BMX (IC50 = 1nM);  
JAK3 (IC50 = 22nM);  and BLK (IC50 = 1nM).   
While the direct cytotoxic function of ibrutinib on lymphoma appears to be driven by inhibition 
of BTK and therefore interruption of BCR signaling, there is evidence to suggest an independent 
effect of ibrutinib on non-malignant components of the immune system.  BTK is expressed on 
multiple hematopoietic cells including antigen presenting cells (APCs) such as monocytes, 
macrophages and dendritic cells (DCs).  Dendritic cells derived from btk-/- mice appear to have 
superior T-cell stimulatory function, suggesting that BTK inhibition by ibrutinib may promote 
T-cell stimulation by APCs(24).  Additionally, ibrutinib has been shown to promote Th1 immune 
responses through an off-target effect on ITK(25).  In mouse models of colon cancer, triple 
negative breast cancer, and ibrutinib-insensitive lymphoma, ibrutinib enhanced the therapeutic 
activity of the immune checkpoint blockage with antibodies targeting PD1-L (26).  These data 
suggest a potential beneficial role of ibrutinib as an immunomodulatory molecule in the 
treatment of malignancy.   
Dendritic cells and Immunostimulatory Agents 
The potential to harness the power and specificity of the immune system is of growing interest in 
cancer immunotherapy.  The main challenge of a successful immunotherapy strategy is to 
overcome tolerance to tumor antigens and to induce an immune response against the tumor.  One 
such approach uses DCs, and their ability to induce potent T-cell-dependent antigen-specific 
immune responses to generate tumor- specific immunity.  Support for this strategy comes from 
animal studies that demonstrated that ex vivo loading of DCs with tumor lysates, tumor 
antigen-derived proteins, synthetic major histocompatibility complex (MHC) class I-restricted 
peptides or whole protein has generated tumor-specific immune responses and anti-tumor 
activity (27, 28).  Our group has shown that the injection of DCs into a single tumor site, in 
combination with systemic chemotherapy, can completely eradicate metastatic lymphoma in an 
animal model and induce a systemic CD8+ immune response (29).  Dendritic-cell based 
vaccination methods have shown some success in clinical trials in subjects with lymphoma, 
melanoma and prostate cancer (27-35).  However, these DC-vaccine trials involve expensive and 
cumbersome ex vivo manipulation of dendritic cells. 
Radiotherapy combined with CpG 
Radiotherapy combined with CpG has been shown to enhance tumor regression.  Studies 
investigating the use of RT in combination with CpG and DC administration demonstrated 
significant enhancement of tumor regression in murine sarcoma and melanoma models (36-38).  
Our group has identified that the combination of intratumoral injection of CpG and local RT was 
more efficacious in tumor regression than each modality alone as demonstrated in a murine 
lymphoma model (39).  Radiation induces tumor necrosis and apoptosis, which results in the 
release of tumor antigens.  The tumor antigens are processed by antigen presenting cells and 
generate a tumor-specific immune response that can be augmented by the immunomodulatory 
effects of CpG injections (37).   


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In order to circumvent the need for collecting and processing dendritic cells ex vivo, we 
developed a novel approach to combine low-dose radiotherapy with intratumoral injection of a 
CpG-oligodeoxynucleotide (CpG-ODN), a TLR9 agonist, such as CpG-7909, PF-03512676 or 
SD-101, to elicit an immune response to the tumor.  The rationale is that radiotherapy triggers 
tumor necrosis, apoptosis and inflammatory responses.  These events, in turn, act as “danger 
signals” that recruit dendritic cells to sites of inflammation (40, 41).  At the site of inflammation, 
dendritic cells process tumor antigens (provided by necrotic and/ or apoptotic tumor cells), 
undergo maturation and migrate to draining lymph nodes, where they generate immune response 
to tumor-antigens.  Intratumoral injection of CpG can augment the immune response by 
recruiting dendritic cells to the tumor site.  Furthermore, CpG enhances the antigen presentation 
property of dendritic cells (9, 10, 42-46).   
Rationale for combination of intratumoral CpG and systemic ibrutinib 
The in situ vaccination approach we developed previously uses intratumoral CpG injection to 
trigger immune responses at a site of disease which can then spread systemically yielding 
abscopal responses.  Effective antigen presentation requires the release of tumor antigens from 
tumor cells which can then be presented by professional antigen presenting cells such as 
dendritic cells.  Previously we have used low-dose local radiation to induce tumor death at the 
site of the in situ vaccination.  As opposed to alternative cytotoxic treatment such as 
chemotherapy, local radiation minimally affects the systemic immune response.  We 
hypothesized that the use of a targeted anti-lymphoma agent such as ibrutinib could similarly 
induce cell death at the site of CpG injection.  Ibrutinib produces minimal detrimental effect on 
the immune system, and potentially could augment immune responses.  In an animal model of an 
ibrutinib-sensitive lymphoma, we found striking synergy between ibrutinib and intratumoral 
CpG (26).  This effect was seen with doses of ibrutinib and CpG that had minimal single-agent 
activity.  The effect was only produced in immunocompetent animals, and adoptive T-cell 
transfer from animals treated with this combination could prevent tumor growth in naïve mice 
without treatment.  These data suggest that the antitumor effect of the combination of ibrutinib 
and CpG is driven by induced immune responses rather than direct effects of these agents on 
tumor cells.  Indeed, in additional mouse models of ibrutinib-insensitive tumors including colon 
and breast cancer, treatment with ibrutinib and intratumoral CpG produced the same synergistic 
effect (47). 
2.4 
Study Design 
This is a single-arm, single-group, non-randomized, open-label, treatment study of intratumoral 
SD-101 and local low-dose radiation plus oral ibrutinib.  This will be a phase 1b dose 
de-escalation study followed by a phase 2 expanded cohort at a chosen dose of intratumoral 
SD-101 designed to evaluate safety (phase 1b) and efficacy (phase 2).  The study will be a 
single-center trial conducted at Stanford University Medical Center.   
2.5 
Correlative Studies Background 
2.5.1  CTL activity against autologous tumor (performed if adequate tumor 
sample): 
The mechanism of immune response to concurrent treatment with CpG and ibrutinib is 
hypothesized to be mediated at least in part through CTL cells (26).  We will test the induction of 


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CTL immune responses in this correlate.  PBLs will be collected before and after treatment and 
co-cultured with autologous tumor to assess for tumor-specific immune responses.  
Immunophenotyping will identify lymphocyte populations associated with response or 
resistance. 
2.5.2 Immunophenotyping of treated and untreated tumor sites: 
Intratumoral injection of CpG has been shown to break tolerance against lymphoma by altering 
the local tumor microenvironment.  Resistance to intratumoral CpG is hypothesized to be 
mediated via T regulatory cells and potentially other leukocyte populations.  This correlative will 
investigate the cell populations altered at the treatment site and potential abscopal responses by 
sampling treated and untreated lymph nodes before and after treatment.  Multiparameter flow 
will be performed at the various time points to define immune populations including CD4 and 
CD8 T-cells, regulatory T-cells, follicular helper T-cells, B-cells (including the malignant 
B-cells), natural killer cells, dendritic cells and macrophages.  The extent of immunophenotyping 
will depend on the availability of cells from each biopsy.  
2.5.3. Anti-tumor antibody response (performed if adequate tumor sample): 
Humoral responses against follicular lymphoma have been shown to be associated with clinical 
benefit in prior idiotype vaccine studies (48).  The induction of humoral responses by 
intratumoral injection of CpG and/or treatment with ibrutinib has not been studied but may 
correlate with clinical benefit.  In this correlate, we will test for the development of humoral 
immunity after treatment. 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 
Refer to the Participant Eligibility Checklist in Appendix A.   
3.1 
Inclusion Criteria 
3.1.1 Biopsy-confirmed Grade 1 or 2, or 3A follicular lymphoma;  mantle cell lymphoma;  or 
marginal zone lymphoma.  Subjects must have relapsed from or are refractory to prior 
therapy.   
3.1.2 Subjects must have at least one site of disease that is accessible for intratumoral injection 
of SD-101 (diameter ≥ 10mm), percutaneously. 
3.1.3 Subjects must have at least one site of measurable disease (see Section 10.2.2 for 
definition of measurable disease) other than the injection site which is not included in the 
radiation field. 
3.1.4 ECOG Performance Status of 0 or 1 
3.1.5 Subjects must be 18 years of age or older. 
3.1.6 Required values for initial laboratory tests: 
a) Absolute neutrophil count (ANC) ≥ 1000/mm3 independent of growth factor support 
b) Platelets:  ≥ 100,000/mm3 or ³50,000/mm3 if bone marrow involvement independent of 
transfusion support in either situation 
c) Hemoglobin:  ≥ 8 g/dL (may be transfused) 


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d) Creatinine:  Creatinine clearance > 25 mL/min 
e) AST/ALT:  ≤ 3 x ULN  
f) Bilirubin:  ≤ 1.5 x ULN (except for subjects with Gilbert’s Syndrome or of non-hepatic 
origin) 
3.1.7 Must be at least 4 weeks since treatment with standard or investigational chemotherapy, 
biochemotherapy, major surgery, radiation, cytokine therapy, and 8 weeks since any 
monoclonal antibodies or immunotherapy, and recovered from any clinically significant 
toxicity experienced during treatment.   
3.1.8 Women of childbearing potential and men who are sexually active must be practicing a 
highly effective method of birth control during and after the study (see Appendix E) 
consistent with local regulations regarding the use of birth control methods for subjects 
participating in clinical trials.  Men must agree to not donate sperm during and after the 
study.  For females, these restrictions apply for 1 month after the last dose of study drug.  
For males, these restrictions apply for 3 months after the last dose of study drug. 
3.1.9 Women of childbearing potential must have a negative serum (beta-human chorionic 
gonadotropin [b-hCG]) or urine pregnancy test at Screening.  Women who are pregnant 
or breastfeeding are ineligible for this study. 
3.1.10 Life expectancy greater than 4 months. 
3.1.11 Able to comply with the treatment schedule. 
3.1.12 Ability to understand and the willingness to sign a written informed consent document. 
3.2 
Exclusion Criteria 
3.2.1 Autoimmune disease requiring treatment within the last 5 years including systemic lupus 
erythematosus, rheumatoid arthritis, multiple sclerosis, Sjӧgren’s syndrome, autoimmune 
thrombocytopenia, uveitis, or other if clinically significant 
3.2.2 Major surgery or a wound that has not fully healed within 4 weeks of enrollment. 
3.2.3 History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
3.2.4 Requires anticoagulation with warfarin or equivalent vitamin K antagonists. 
3.2.5 Requires chronic treatment with strong CYP3A inhibitors. 
3.2.6 Vaccinated with live, attenuated vaccines within 4 weeks of enrollment. 
3.2.7 Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or 
active Hepatitis B Virus infection or any uncontrolled active systemic infection. 
3.2.8 Known CNS lymphoma. 
3.2.9 Subjects with a history of prior malignancy with the exception of non-melanoma skin 
cancer, carcinoma in situ of the cervix, in situ carcinoma of the bladder, stage 1 prostate 
cancer that does not require treatment, or other malignancy that has undergone potentially 
curative therapy with no evidence of disease for the last > 2 years and that is deemed by 
the investigator to be a low risk for recurrence.   


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3.2.10 History of allergic reactions attributed to compounds of similar composition to SD-101 or 
ibrutinib 
3.2.11 Treatment with an immunosuppressive regimen of corticosteroids or other 
immunosuppressive medication (eg, methotrexate, rapamycin) within 30 days of study 
treatment.  Note:  subjects may take up to 5 mg of prednisone or equivalent daily.  
Topical and inhaled corticosteroids in standard doses are allowed. 
3.2.12 Significant cardiovascular disease (ie, NYHA class 3 congestive heart failure; myocardial 
infarction with the past 6 months; unstable angina; coronary angioplasty with the past 
6 months; uncontrolled atrial or ventricular cardiac arrhythmias). 
3.2.13 Pregnant or breast feeding.   
3.2.14 Any other medical history, including laboratory results, deemed by the investigator to be 
likely to interfere with their participation in the study, or to interfere with the 
interpretation of the results.   
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.  Participants must 
sign the IRB approved informed consent prior to participation in any study-specific  procedure.  
The participant must receive a copy of the signed and dated consent document.  The original 
signed copy of the consent document must be retained in the medical record or research file.   
3.4 
Randomization Procedures 
This is a non-randomized trial. 
3.5 
Study Timeline 
Primary Completion: 
The study will reach primary completion 60 months from the time the study opens to accrual. 
Study Completion: 
The study will reach study completion 60 months from the time the study opens to accrual. 
4. 
TREATMENT PLAN 
4.1 
Dose de-escalation Study Design 
The study will use a 6+3 design with a goal of determining the recommended phase 2 dose.  We 
will enroll a cohort of 6 subjects, with a 3 mg dose of intratumoral SD-101 and 560 mg dose of 
oral ibrutinib.  The proposed initial dose of SD-101 is below the maximum tolerated dose as 
determined in previous trials, and there is extensive data regarding the safety of treatment with 
ibrutinib at the FDA-approved dose of 560 mg.  Because no additional toxicity is anticipated 
with combination therapy of SD-101 and ibrutinib, the 6+3 dose de-escalation design will be 
employed, permitting rapid confirmation of the safety of the combination therapy and selection 
of the recommended phase 2 dose while still allowing detection of any unanticipated toxicity.   
If 0 or 1 subjects out of the initial 6 subjects experience a DLT, we will chose this dosing as the 
recommended phase 2 dose level.  If 2 out of 6 subjects experience a DLT, we will expand the 


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cohort and enroll an additional 3 subjects at the same dose level.  If 3 out of 6-9 subjects in the 
initial dose cohort experience a DLT, then the dose de-escalation cohort -1 will accrue.  This 
dose de-escalation cohort will be treated with 1 mg intratumoral SD-101 and 560 mg ibrutinib.  
If ≤ 2 out of 6 subjects in the dose de-escalation cohort experience a DLT, then this dose will be 
considered the RP2D.  If 3 or more subjects in the de-escalation cohort experience a DLT, the 
study will be stopped.   
Table 1.  Dose Escalation Plan 
Cohort 
Dose ( mg) 
Total 
Enrollment 
per Cohort 
Dose Escalation Rules 
-1 
1 mg SD-101 
560 mg ibrutinib 
6 
1 of 6 or 2 of 6 DLT, RP2D is established 
3 of 6 DLT, trial is stopped 
1 
3 mg SD-101 
560 mg ibrutinib 
6-9 
0 of 6 or 1 of 6 DLT, RP2D is established at 
this level 
2 of 6 DLT, expand cohort to 9 subjects 
2 of 9 DLT, RP2D is established at this level 
3 of 6-9 DLT, decrease to dose level -1 
Phase 2 
Expansion 
RP2D 
15 
If the incidence of study drug-related DLTs 
as defined previously equals or exceeds 33% 
of treated subjects at RP2D dose level 1, 
enrollment will be stopped for dose level 1, 
and enrollment of 15 subjects will begin at 
dose level -1.  If the incidence of study 
drug-related DLTs equals or exceeds 33% of 
treated subjects at RP2D dose level -1, then 
the trial is stopped 
Phase 2 (SD-101 dose Cohort Expansion):  Once the safety profile and tolerability of all doses 
tested has been characterized and the RP2D of SD-101 has been defined during the dose 
de-escalation phase of this trial, the RP2D dose cohort will be expanded by an additional 
15 subjects.  This will enable further characterization of the immunoregulatory activity and 
preliminary antitumor effects of this treatment regimen.  The treatment schema for SD-101, RT 
and ibrutinib will remain the same as previously described. 
Clinical safety monitoring of subjects enrolled during this additional Cohort Expansion  portion 
of the study will be the same as conducted during the dose escalation portion of the study 
(ie, part 1).  If the chosen RP2D is dose level 1 (3 mg SD-101) and the combined incidence of 
study drug-related DLTs of any kind (ie, Grade 3 injection site reaction, hematologic or 
non-hematologic DLT) is equal to or exceeds 33% of treated subjects at any point during 
treatment, this will prompt a halt in enrollment at that dose level.  Enrollment of 15 subjects will 
then begin at the lower dose level of 1 mg SD-101.  If the incidence of DLTs in the lower dose 
cohort equals or exceeds 33%, the trial will be stopped. 


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4.2 
Informed Consent and Screening Period 
Subjects who may be eligible for the trial will be approached by the Investigator and offered 
participation in the trial.  The Investigator or co-Investigator will explain the study to the 
potential subject verbally, providing all pertinent information (purpose, procedures, risks, 
benefits, alternatives to participation, etc.), and will allow the potential subject ample opportunity 
to ask questions.  Following this verbal explanation, the potential subject will be provided with 
the IRB approved informed consent form and will be afforded sufficient time to consider 
whether or not to participate in the research.  After allowing the potential subject time to read the 
consent form, the investigator or approved designee (study coordinator) will answer any 
additional questions the potential subject may have and will obtain the subject’s signature on the 
consent form.  The investigator or designee will also sign the consent form.  A signed copy of the 
consent form will be given to the subject, scanned into the medical record and distributed to the 
pharmacy and CTRU as per Stanford Cancer Clinical Trials Office (CCTO) Standard Operating 
Procedures.  Before any protocol-specified procedures are conducted, each prospective 
participant must provide informed consent.   
The screening period will take place up to 4 weeks prior to first dosing.  Studies to evaluate the 
extent of tumor burden may be performed up to 6 weeks prior to dosing. 
Subjects will undergo the following procedures during the screening period: 
• Written informed consent  
• Medical history and complete physical exam 
• Obtain vital signs / ECOG performance status   
• Monitoring of concomitant medications 
• Hematology:  CBC, differential, platelet count 
• Chemistry:  comprehensive metabolic panel 
• LDH  
• Urine pregnancy test (for females of childbearing potential) 
• Determination of extent of disease with CT scans or PET/CT to evaluate all areas of 
known or suspected neoplastic disease.  Procedures performed prior to subject entry into 
the trial, but within 6 weeks of first dosing, will fulfill the screening requirements. 
• Infectious disease screening- HIV antibody testing, Hepatitis B surface antigen, Hepatitis 
B core antibody and Hepatitis C antibody testing 
• Fine needle aspiration of planned treatment site (if no tissue from excisional biopsy is 
available for correlative studies).  If additional sites of disease are safely accessible via 
fine needle aspiration, these may be biopsied as well. 
• An excisional biopsy may be performed to confirm that the tumor has not transformed to 
a more aggressive form (optional).  Tissue/cells not required for clinical diagnostic 
assessment may be collected and stored for immune correlative studies. 
• Collection of 1 purple top tube for research correlates 
• Only for subjects with sufficient material from an excisional biopsy or, optionally, for 
patients with circulating lymphoma cells:  Apheresis for collection of peripheral blood 


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mononuclear cells (PBMC) (approximately 2 hours) to provide adequate sample for 
immune assays  
• Only for subjects not undergoing apheresis:  7 additional green top tubes of peripheral 
blood will be collected for research correlates 
 
4.3 
Treatment Period: 
The treatment schema and study visit schedule is the same for both the dose de-escalation 
cohorts and the expanded, phase 2 cohort.   
SD-101 will be administered within 12 hours of the completion of radiotherapy during Day 2.   
The study agent SD-101 at a dose of either 1 mg or 3 mg will be injected intratumorally on 
Day 2.  Subsequent weekly injections will be administered on days 9, 16, 23 and 30 for a total of 
5 intratumoral injections. 
Ibrutinib will be taken PO daily starting on Day 10.  Dosing will be continuous 560 mg daily 
throughout the course of the trial.  Subjects will continue to take ibrutinib until disease 
progression or for a total of 96 weeks of therapy, whichever comes first.   
All intratumoral SD-101 injections will be carried out at the Clinical Translational Research Unit 
(CTRU) and/or oncology clinic infusion treatment area (ITA).  Vital signs, including weight, will 
be taken prior to each injection.  Subjects will be monitored for at least 30 minutes after each 
injection with repeat vital signs before being discharged home. Vital signs (blood pressure, heart 
rate, temperature, respiratory rate and oxygen saturation via pulse oximetry) should be obtained 
at the end of the monitoring period, within a -5/+15 minute window. 
 
All subjects will be evaluated as described below. The first day of treatment is Day 1, which is 
the first day of Week 1. Subsequent days or weeks listed are with reference to his landmark. 
4.3.1  Day 1: 
• First treatment of radiotherapy (2 Gy) 
4.3.2 Day 2:   
• Obtain vital signs/ ECOG performance status   
• Assessment of adverse events and toxicity grading according the CTCAE v4.0 
• Monitoring of concomitant medications 
• Second treatment of radiotherapy (2 Gy) 
• Administration of intratumoral injection no. 1 of SD-101 within 12 hours of radiotherapy 
4.3.3 Day 4 (+/- 1 day):   
• Optional (encouraged but not mandatory) FNA of accessible tumor for research studies. 
If additional (untreated) sites of disease are safely accessible via fine needle aspiration, 
these may be biopsied as well. 
 


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4.3.4 Day 9 (+/- 2 days) 
• Obtain vital signs/ ECOG performance status   
• Assessment of adverse events and toxicity grading according the CTCAE v4.0 
• Monitoring of concomitant medications 
• CBC with Differential and platelet count 
• Comprehensive Metabolic panel 
• FNA of accessible tumor for research studies.  To be performed prior to intratumoral 
injection no. 2.  If additional (untreated) sites of disease are safely accessible via fine 
needle aspiration, these may be biopsied as well. 
• Collection of 1 purple top tube for research correlates.  Collection should occur before 
SD-101 injection no. 2.   
• Administration of SD-101 intratumoral injection no. 2 at the same site as previously 
• Collection of 7 peripheral blood green top tubes for research correlates 
• Distribution of 1 month supply of ibrutinib.  Administration of first dose of ibrutinib 
560 mg orally will occur the next day.  Ibrutinib will be self-administered by the subject 
daily from this point until progression of disease or for 96 weeks, whichever comes first. 
4.3.5 Day 16 (+/- 2 days) 
• Obtain vital signs/ ECOG performance status   
• Assessment of adverse events and toxicity grading according the CTCAE v4.0 
• Monitoring of concomitant medications 
• Collection of 7 green top tubes for research correlates 
• Administration of SD-101 intratumoral injection no. 3  
4.3.6 Day 23 (+/- 2 days); Day 30 (+/- 2 days)  
• Obtain vital signs/ ECOG performance status   
• Assessment of adverse events and toxicity grading according the CTCAE v4.0 
• Monitoring of concomitant medications 
• CBC with Differential and platelet count at Day 23 visit 
• Comprehensive Metabolic panel at Day 23 visit 
• Administration of SD-101 intratumoral injection no. 4 (Day 23), no. 5 (Day 30) at the 
same injection site as previously 
• Collection of 1 purple top tube for research correlates (Day 23 visit only) 
4.3.7 Day 37 (+/-7 days) 
• Obtain vital signs/ ECOG performance status  
• Monitoring of concomitant medications 
•  Assessment of adverse events and toxicity grading according the CTCAE v4.0 
• CBC with Differential, and platelet count  
• Comprehensive metabolic panel  
• Distribution of a 6-week supply of ibrutinib.  Ibrutinib will be self-administered by 
subject daily. 
• FNA of accessible tumor, if available, for research studies.  If additional sites of disease 
are safely accessible via fine needle aspiration, these may be biopsied as well. 
• Collection of 1 purple top tube for research correlates 


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• Only for subjects with sufficient material from an excisional biopsy:  Apheresis for 
collection of peripheral blood mononuclear cells (PBMC) (approximately 2 hours) to 
provide adequate sample for research studies (+/- 10 days).   
• Only for subjects not undergoing apheresis:  Collection of 7 additional green top tubes of 
peripheral blood for research correlates (+/- 10 days).   
 
4.3.8 Weeks 12, 24, 36, 48, 60, 72, 84 (+/- 10 days): 
• History and physical examination 
• Obtain vital signs/ ECOG performance status  
• Monitoring of concomitant medications 
• Assessment of adverse events and toxicity grading according the CTCAE v4.0 
• Routine CBC, differential, and platelet count 
• Routine Comprehensive metabolic panel 
• LDH 
• Distribution of ibrutinib.  Ibrutinib will be self-administered by subject daily. 
• Weeks 12, 24, 48, 72 only - Determination of response to treatment with CT scans of the 
chest/ abdomen/ pelvis or other medically appropriate imaging modality to evaluate all 
areas of disease followed by calculation of response by the Cheson Criteria (49) for 
lymphoma subjects (draining lymph nodes of the injected region will be excluded from 
this assessment, since SD-101 injections may cause transient enlargement of the draining 
lymph nodes).  CT scan is the preferred mode of imaging, however, if a CT scan is 
contraindicated or if it is felt by the Sponsor Investigator that a PET/CT will be a better 
modality to assess a particular subject, a PET/CT may be used for evaluation. 
• Collection of 1 purple top tube for research correlates 
• Optional:  If there is no evidence of disease on CT scan, a bone marrow biopsy will be 
obtained to document whether a complete response is achieved. 
• At Week 12 only, 7 additional green top tubes of peripheral blood will be collected  
4.3.9 Final Study Visit  
Subjects who withdraw from treatment due to progressive disease will be seen within 4 weeks of 
the determination of progressive disease for a final visit.  Subjects who withdraw due to 
intolerance of treatment should be followed weekly until all toxicities have reverted to Grade ≤ 2 
or have stabilized in the opinion of the Investigator, at which point they will undergo the final 
visit.  All subjects who withdraw for any reason other than progressive disease will be seen 
within 4 weeks of withdrawal for a final visit. 
At the Final Study Visit, the following procedures will be performed: 
• History and physical examination 
• Obtain vital signs/ ECOG performance status  
• Monitoring of concomitant medications 
• Hematology:  CBC with differential and platelet count 
• Chemistry:  comprehensive metabolic panel 
• LDH 
• Collection of 1 purple top tube for research correlates 


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• If not already radiologically documented within 4 weeks, determination of extent of 
disease with CT scans, or any other radiographic procedures determined appropriate by 
the investigator, followed by calculation of response by the Cheson criteria (49).   
• If progressive disease, obtain an FNA of accessible tumor(s), if available, for research 
studies (optional). 
• Collection of 7 green top tubes of peripheral blood for research correlates 
 4.4 
Follow-Up Period   
After Week 96, subjects will be evaluated every 3 to 6 months with CTs at intervals per standard 
practice at our institution, until disease progression or subject withdrawal.   
4.5 
Duration of Therapy 
The planned duration of study for each subject is approximately 96 weeks, after which time the 
primary evaluation of safety, efficacy and immune response will be performed.  Subjects will 
remain on study until development of disease progression, intolerable toxicity or any of the 
conditions outlined in Section 4.10 (Criteria for removal from study).  Treatment toxicity will be 
evaluated at each study visit during the treatment period and at the final visit in Week 96.  After 
Week 96, low-grade B-cell lymphoma subjects will be followed every 3 to 6 months as part of 
routine care until disease progression or subject withdrawal from the study. 
4.6  
Duration of Follow Up 
After Week 96, subjects will be followed every 3 to 6 months as part of routine care until disease 
progression or subject withdrawal from the study.  Subjects who withdraw from treatment due to 
progressive disease will be seen within 4 weeks of the determination of progressive disease for a 
final visit.  Subjects who withdraw due to intolerance of treatment should be followed weekly 
until all toxicities have reverted to Grade ≤ 2 or have stabilized in the opinion of the Investigator, 
at which point they will undergo the final visit.  All subjects who withdraw for any reason other 
than progressive disease will be seen within 4 weeks of withdrawal for a final visit. 
4.7 
Radiotherapy Administration 
All subjects will receive 2 Gy radiation to a single tumor site on each of 2 consecutive days 
(Day 1 and Day 2).   
4.8 
Investigational Agent Administration:  SD-101 
The first injection of SD-101 will be performed on Day 2, within 12 hours of the radiation 
treatment.  Subsequent injections of SD-101 will begin approximately one week later (Day 9), to 
be administered once per week for 3 weeks, for a total of five injections over a 4-week period.  
SD-101 is supplied in individual vials at a concentration of 5 mg/mL or 16 mg/mL.  Per 
instruction from Dynavax Pharmacy Manual (Dynavax Study DV3-MEL-01) below, SD-101 at 
16 mg/mL will be diluted to a concentration of 5 mg/mL in normal saline prior to pharmacy 
dispensation.  


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SD-101 drug product should be removed from storage at 2° to 8°C and placed at ambient 
temperature prior to preparation for administration per the equilibration protocol below.  Each 
vial of SD-101 drug product and prepared dose are for single-use only. 
NOTE: SD-101 drug product or diluted SD-101 drug product is stable at room temperature for 
8 hours.  The SD-101 drug product or corresponding diluted SD-101 drug product must be used 
within 8 hours of removal of the SD-101 drug product vial from refrigerated storage.  Prior to 
any drug preparation, prepare a clean working surface.  Use aseptic technique to reduce the 
possibility of contamination, eg, wear gloves, use isopropyl alcohol to wipe down all vials 
(including rubber stopper area), etc.  All syringes and sterile empty vials are for single-use;  
use only unopened syringes, needles, and/or vials for each step. 
4.8.1.  SD-101 DRUG PRODUCT EQUILIBRATION PROTOCOL: 
Remove SD-101 drug product vial(s) from refrigerated storage.  Allow SD-101 drug product to 
come to ambient temperature for 20 minutes.  Gently mix SD-101 drug product by completely 
inverting vial(s) by hand and repeating 10 times.  
NOTE:  If diluent has been stored under refrigerated conditions, it must be allowed to come to 
ambient temperature for 20 minutes prior to preparation of the dosing solution.  
4.8.2.  PREPARATION OF SD-101 DOSING SOLUTION 
All vials (SD-101 drug product, diluted SD-101 drug product, and diluent) are for single-use 
only.  Prepare the appropriate dosing solution as specified below.  
4.8.2.1  DILUTION & DOSE PREPARATION 
Note:  This section requires the use of 1 vial of 16 mg/mL SD-101 drug product. Draw 1.1 mL 
of 0.9% sodium chloride diluent in a 3 mL syringe and transfer into an empty sterile mixing vial 
(2 or 5 mL capacity).  
Note:  While injecting the 0.9% sodium chloride diluent into the empty vial, ensure that pressure 
does not build up in the vial by equalizing the pressure recurrently.  Draw 0.50 mL from the 
SD-101 drug product vial (16 mg/mL) in a 1 mL syringe attached with a 20-25G needle, and 
transfer into the same sterile mixing vial containing the 1.1 mL diluent.  Mix the solution by 
gently inverting the vial completely 10 times.  This mixing vial will contain a 5 mg/mL solution 
of SD-101.  
FOR 3 mg DOSE:  Using a 20-25G needle, draw 0.60 mL of the diluted SD-101 drug product 
from the mixing vial into a 1 mL syringe for the administration of a 3 mg fixed dose of SD-101.  
A 25-30G needle must be used to administer the dose of SD-101.  
FOR 1 mg DOSE:  Using a 20-25G needle, draw 0.20 mL of the diluted SD-101 drug product 
from the mixing vial into a 1 mL syringe for the administration of a 1 mg fixed dose of SD-101. 
A 25-30G needle must be used to administer the dose of SD-101.  
The site of injection will be into an accessible enlarged lymph node or subcutaneous tumor site.  
Injections will be prepared and administered by a person designated by the principal investigator 
(eg, sub-investigators, study nurses) in response to written orders from the investigators. 


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4.9 
Investigational Agent Administration:  Ibrutinib 
Subjects will begin treatment with ibrutinib on Day 10 of study treatment.   
Ibrutinib is supplied as white opaque 140 mg capsules marked with “ibr 140” in black ink.  
Subjects will take 4 capsules daily for a total dose of 560 mg PO.  The capsules should be 
swallowed intact and subjects should not attempt to open capsules or dissolve them in water.  
The use of strong CYP3A inhibitors/inducers, and grapefruit and Seville oranges should be 
avoided for the duration of the study. 
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day 
with a return to the normal schedule the following day.  The subject should not take extra 
capsules to make up the missed dose. 
Ibrutinib will be dispensed to subjects in bottles at designated visits.  Unused ibrutinib dispensed 
during previous visits must be returned to the site and drug accountability records updated at 
each visit.  Returned capsules must not be re-dispensed to anyone. 
4.10 
General Concomitant Medication and Supportive Care Guidelines 
4.10.1 Prohibited Therapies 
Subjects may not use any of the following therapies during the study: 
• Any non-study anti-cancer agent (investigational or non-investigational) 
• Immunosuppressive agents 
• Chronic systemic corticosteroids above a dose of 5mg prednisone daily 
• Any non-oncology live vaccine therapies used for the prevention of infectious diseases 
(for up to 30 days prior to or after any dose of study drug). 
• Chronic (more than 7 days) therapy with a strong CYP3A inhibitor (see Appendix D). 
• Chronic (more than 7 days) therapy with a strong CYP3A inducer (see Appendix D) 
4.10.2 Restricted Therapies 
CYP3A Inhibitors 
Use of a strong CYP3A inhibitor for more than 7 days is prohibited.  If a moderate CYP3A 
inhibitor must be used, the dose of ibrutinib will be reduced by 140 mg daily.  Avoid grapefruit 
and Seville oranges during ibrutinib treatment, as these contain moderate inhibitors of CYP3A.  
Subjects taking concomitant strong or moderate CYP3A inhibitors should be monitored more 
closely for signs of ibrutinib toxicity. 
Surgeries and Procedures 
The following guidance should be applied during the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving ibrutinib: 
For any planned surgery or invasive procedure requiring sutures or staples for closure, ibrutinib 
should be held at least 7 days prior to the intervention and should be held at least 7 days after the 
procedure, and restarted at the discretion of the investigator when the surgical site is reasonably 
healed without serosanguineous drainage or the need for drainage tubes.   
For planned minor procedures (such as a central line placement, lymph node biopsy (not 
including fine needle biopsy), thoracentesis, or paracentesis) ibrutinib should be held for at least 


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3 days prior to the procedure and should not be restarted for at least 3 days after the procedure.  
For bone marrow biopsies that are performed while the subject is on ibrutinib, it is not necessary 
to hold ibrutinib for these procedures. 
For emergency procedures, ibrutinib should be held after the procedure until the surgical site is 
reasonably healed, for at least 7 days after the urgent surgical procedure, or at the discretion of 
the investigator 
4.11 
Criteria for Removal from Study 
Subjects may withdraw from the study at any time and for any reason.  Possible reasons for 
withdrawal include the following:   
• DLT 
• Progressive neoplastic disease 
• Development of an intercurrent medical condition or need for concomitant treatment that 
precludes further participation in the trial 
• Subject withdraws consent to continue participation 
• An adverse event which in the opinion of the Investigator precludes further participation 
in the trial 
• The Investigator removes the subject from the trial in the best interests of the subject 
• Study termination  
• The Investigator removes the subject from the trial due to non-compliance 
• The subject is lost to follow-up.   
• Female subjects who become pregnant during this study. 
If a subject withdraws from the trial, attempts should be made to contact the subject to determine 
the reason(s) for discontinuation.  All procedures and evaluations required by the Final Study 
Visit should be completed in the event of early withdrawal.  All subjects who discontinue the 
trial secondary to an adverse event must be followed until resolution or stabilization of the 
adverse event.   
This trial is subject to continuing approval of IRB at Stanford University and drug and funding 
under a cross-filed IND from the drug companies, DynaVax and Janssen Scientific Affairs, LLC.  
Reasons for early trial discontinuation may include, but are not limited to, unacceptable toxicity 
of study drug, a request to discontinue the trial from a regulatory authority, protocol violations, 
or poor enrollment.   
4.12 
Alternatives 
Alternative therapies for this subject population will be discussed with each subject and would 
include standard chemotherapy regimens, radiotherapy, monoclonal antibodies, other 
investigational treatments (if available), or watchful waiting.   
5. 
INVESTIGATIONAL AGENT INFORMATION 
5.1 
 SD-101 
Toll-like receptor 9 (TLR9) ligands have multiple mechanisms of action that modulate the 
immune system including both direct and indirect anti-tumor effects.  The natural ligands for 
TLR9 are unmethylated CpG oligonucleotide sequences that are rare in vertebrate genomes but 


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prevalent in pathogen genomes including bacteria and viruses.  A synthetic CpG product SD-101 
is available for clinical use from DynaVax Technologies.  DynaVax is supplied as a GMP 
material.  SD-101, a Class C CpG, induces an IFN-α signature in both human PBMCs in vitro 
and non-human primates in vivo.  There is considerable experience with SD-101 in normal 
subjects and in subjects with lymphoma.  Based on single-agent studies in healthy volunteers and 
an ongoing trial of previously untreated low-grade lymphoma subjects, it is safe and well 
tolerated up to a dose of 5 mg per injection.  IND 111985 is held by Stanford Investigator, Dr.  
Robert Lowsky (listed on the title page of this protocol) and will be cross referenced and used in 
this study. 
Mechanism of Action  
CpG-ODN, such as SD-101, are optimized for immune stimulation and sulfur for phosphorus 
between nucleotide subunits to provide increased resistance to nuclease-mediated degradation.  
The nucleotide sequences are recognized by TLR-9, a receptor for innate immune recognition of 
microbial and viral DNA (5).  Two principal types of human PBMCs express TLR-9 and respond 
directly to SD-101 in vitro or in vivo:  PDCs (peripheral dendritic cells) and B lymphocytes (6-
10).  Immune activation by CpG results from specific binding to B-cells and plasmacytoid 
dendritic cells (pDC), with subsequent activation of lymphocyte, macrophage, monocyte, natural 
killer (NK) and T-cell populations.  The intracellular receptor for CpGs is TLR-9.  Both innate 
(non-specific) and adaptive (antigen-specific) immune responses are affected by CpGs.  The net 
result is increased secretion of antibodies from B-cells, cytokines from a variety of cells and 
increased NK activity as well as improved antigen presentation and T-help that can augment both 
humoral and cell-mediated immune responses.  (see Figure 1). 
.  Human Experience with SD-101 
In a phase 1, randomized single-blind, placebo controlled study of SD-101 in 26 healthy 
volunteers, 0.1 mg;  1 mg;  3 mg;  and 5 mg dose cohorts were analyzed.  Secondary outcome 
pharmacodynamics measures included level of serum cytokines and levels of blood biomarkers 
(interferon-alpha inducible genes).  A dose-dependent induction of IFN-inducible genes was 
observed, which reached a plateau at the 3 mg level.  A trial of SD-101 in 34 subjects with 
chronic HCV infection tested doses up to 5 mg with or without ribavirin.  In both trials, 
influenza-like symptoms including headache, chills, fatigue, and fever were common as well as 
local injection site reactions including erythema, induration and pain.  In the trial of healthy 
volunteers, there was one DLT of headache, neck pain, and local induration at the 5 mg dose.  In 
the trial of subjects with chronic HCV, there was one SAE of hyperthyroidism which was 
considered to probably be related to SD-101.   
We are currently participating in a phase 1 clinical trial of SD-101 in lymphoma subjects who 
have relapsed after allo-transplantation (NCT01745354).  In that study, subjects receive 
low-dose radiation to one site of disease (as in the current proposed trial) followed by 
intratumoral injection of SD-101 at doses of 0.1 mg, 1 mg and 3 mg in successive cohorts.  We 
have observed no significant toxicity, and we have observed abscopal tumor responses in 
all subjects.  In addition, there is an ongoing trial of intratumoral SD-101 in combination with 
local radiation in untreated low-grade Hodgkin’s lymphomas.  This trial has completed 
enrollment of the first 3 cohorts of 1 mg, 2 mg, and 4 mg and is currently treating subjects on the 
final dose cohort of 8 mg.  No DLT has been observed in the first 3 cohorts.   


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Stanford CpG 6 mg Protocol (IRB-13956) 
Our group reported results from a phase 1-2 study of in situ vaccination with CpG TLR9 agonist 
PF-3512676 in subjects with relapsed low-grade lymphoma (50).  15 subjects were enrolled on 
study, and received low-dose RT (4 Gy over 2 days) to a solitary tumor site, and 6 mg of 
PF-3512676 by intratumoral injection to the same tumor site immediately before the first RT 
dose, after the second RT dose, and weekly for 8 consecutive weeks.  This vaccination strategy 
was well tolerated with no Grade 3 toxicities.  One subject had a complete clinical response, 
3 subjects had partial responses, and 2 subjects had stable disease.  Induction of tumor-reactive 
memory CD8+ T-cells was demonstrated.  Low-dose RT was selected for use in this protocol 
since the dose was adequate to induce tumor cell death, but did not affect the ability for subjects 
to receive higher treatment doses to the same sites in the future and potentially minimized 
radiation-induced inhibition the induced immune response.   
A similar in situ vaccination strategy was explored in cutaneous T-cell lymphoma (CTCL), 
specifically mycosis fungoides (MF) (50).  Subjects with MF stages IA-IVA who failed standard 
therapy were eligible.  The immunization site was treated with low-dose RT (2 Gy x 2), 
bracketed by intratumoral injection of PF-3512676 followed by weekly intratumoral 
PF-3512676 x 8.  15 subjects were included.  After the initial 6 subjects, a second immunization 
site was added at Week 4 to enhance systemic response.  A total of 5 partial responses were 
observed (30% OR);  2 of 6 treated with single immunization and 3 of 9 with dual immunization.  
Median time to response was 8 weeks, duration of response 7 weeks, and time to progression 
20+ weeks.  Common toxicities were injection site and flu-like symptoms; mostly Grade 1 to 2 
and all transient. 
The treated immunization sites had significant reduction of CD25+, Foxp3+ T-cells (p < 0.01).  
Similar reduction in S100+, CD1a+ DCs was observed post immunization (p < 0.025).  A 
qualitative analysis suggested more remarkable reduction of CD25+ T-cells and skin DCs in 
clinical responders vs non-responders (p = 0.058, 0.121).  PF-3512676 dose-responsive 
activation of peripheral blood PDCs was observed in vitro.  This novel in situ vaccination 
strategy is feasible in CTCL/MF with acceptable toxicities.  Depletion of tissue T-regs may be 
observed at immunized sites, and reduction of skin DCs may suggest cross-priming and 
migration of DCs to regional lymph nodes.  These Stanford preclinical and clinical studies using 
CpG intratumorally demonstrated a toxicity profile similar to that obtained using SC injection. 
Stanford CpG 18 mg Protocol (IRB 14820) 
In our clinical trial using intratumoral injection of CpG (PF-03512676, Pfizer, Inc.) at a dose 
level of 18 mg combined with 2 x 2 Gy radiation, 15 subjects with previously treated and 
15 subjects with previously untreated B-cell lymphoma were evaluated.  The treatments were 
well tolerated, with mild-to-moderate injection site reaction, flu-like symptoms, fever and 
headache being the most common adverse events.  There were no SAEs in this Stanford trial.  
Clinical regressions were observed in both treatment arms, but the rate was no higher than in our 
previous trial of 6 mg of CpG. 
Adverse Events in Stanford Clinical Studies with CpG 
Local injection reactions have consisted of pain, erythema, edema, inflammation and induration.  
Although these reactions are common, they usually resolve within 2 days.  Flu-like symptoms 


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including fever, myalgia, arthralgia, fatigue, headaches, rigors and/or musculoskeletal pain have 
often been observed in subjects treated with CpG.   
Among the subjects treated on the Stanford study (Protocol 13956), the treatment was 
well-tolerated as anticipated.  There were mild-to-moderate injection site reactions such as 
erythema, induration, swelling, warmth, pain.  Injections were discontinued early at the 
discretion of the investigator in one MF subject due to Grade 2 injection site reaction.  The 
systemic adverse events included mild-to-moderate flu-like symptoms, fevers, chills, myalgia, 
arthralgia, headaches and fatigue.  One subject also reported cough, decreased appetite, 
rhinorrhea and sore throat although this was felt to be not-related.  There was one report of 
dizziness.  All adverse events were grades 1 and 2.   
Out of the 30 subjects treated in the study using 18 mg of CpG (Protocol 14820), the most 
commonly reported adverse events were injection site reaction, flu-like symptoms, fatigue, and 
headache.  All adverse reactions were Grade 1 or 2 and most resolved within 2 days.  2 subjects 
required interruption of injections (one subject received 7 of 10 and one subject received 8 of 10) 
due to Grade 2 injection site reactions.  Another subject had Grade 2 pleural effusion that 
contained reactive T-cells and the fluid did not recur after drainage. 
5.2 
Ibrutinib 
Ibrutinib is a first-in-class, potent, orally administered covalently-binding inhibitor of Bruton’s 
tyrosine kinase (BTK).  Inhibition of BTK blocks downstream B-cell receptor (BCR) signaling 
pathways and thus prevents B-cell proliferation.  In vitro, ibrutinib inhibits purified BTK and 
selected members of the kinase family with 10-fold specificity compared with non-BTK kinases.  
Ibrutinib (Imbruvica) is approved by the US Food and Drug Administration (FDA) for the 
treatment of subjects with chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia, 
mantle cell lymphoma, and marginal zone lymphoma who have received at least 1 prior therapy, 
as well as subjects with CLL with 17p deletion regardless of prior treatment.  Ibrutinib is 
currently being studied in various additional indications including multiple subtypes of 
non-Hodgkins lymphoma.  Ibrutinib is not FDA-approved for the treatment of follicular 
lymphoma as proposed in this trial. 
Mechanism of Action 
Ibrutinib is a small-molecule inhibitor of BTK.  Ibrutinib forms a covalent bond with a cysteine 
residue in the BTK active site, leading to inhibition of BTK enzymatic activity.  BTK is a 
signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways.  BTK’s 
role in signaling through the B-cell surface receptors results in activation of pathways necessary 
for B-cell trafficking, chemotaxis, and adhesion.  Nonclinical studies show that ibrutinib inhibits 
malignant B-cell proliferation and survival in vivo as well as cell migration and substrate 
adhesion in vitro. 
Pharmacokinetics 
Absorption:  Ibrutinib is absorbed after oral administration with a median Tmax of 1 to 2 hours.  
Ibrutinib exposure increases with doses up to 840 mg.  The steady-state AUC (mean ± standard 
deviation) observed in subjects at 560 mg is 953 ± 705 ng⋅h/mL and in subjects at 420 mg is 
680 ± 517 ng⋅h/mL.  Administration with food increased ibrutinib Cmax and AUC by 


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approximately 2 to 4- and 2-fold, respectively, compared with administration of ibrutinib after 
overnight fasting. 
Distribution:  Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with 
no concentration dependence in the range of 50 to 1000 ng/mL.  The volume of distribution at 
steady state (Vd,ss) was 683 L, and the apparent volume of distribution at steady state (Vd,ss/F) 
was approximately 10000 L.   
Metabolism:  Metabolism is the main route of elimination for ibrutinib.  It is metabolized to 
several metabolites primarily by cytochrome P450, CYP3A, and to a minor extent by CYP2D6.  
The active metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards 
BTK approximately 15 times lower than that of ibrutinib.  The range of the mean 
metabolite-to-parent ratio for PCI-45227 at steady-state is 1 to 2.8.   
Elimination:  Intravenous clearance was 62 and 76 L/h in fasted and fed conditions, respectively.  
In line with the high first-pass effect, the apparent oral clearance is approximately 2000 and 1000 
L/h in fasted and fed conditions, respectively.  The half-life of ibrutinib is 4 to 6 hours.  Ibrutinib, 
mainly in the form of metabolites, is eliminated primarily via feces.  After a single oral 
administration of radiolabeled [14C]-ibrutinib in healthy subjects, approximately 90% of 
radioactivity was excreted within 168 hours, with the majority (80%) excreted in the feces and 
less than 10% accounted for in urine.  Unchanged ibrutinib accounted for approximately 1% of 
the radiolabeled excretion product in feces and none in urine, with the remainder of the dose 
being metabolites.   
Renal Impairment:  Ibrutinib is not significantly cleared renally; urinary excretion of metabolites 
is < 10% of the dose.  Creatinine clearance > 25 mL/min had no influence on the exposure to 
ibrutinib.  There are no data in subjects with severe renal impairment (CLcr < 25 mL/min) or in 
subjects on dialysis.   
Hepatic Impairment:  Ibrutinib is metabolized in the liver.  In a hepatic impairment trial, a single 
dose of 140 mg of ibrutinib was administered in non-cancer subjects.  Ibrutinib AUC increased 
2.7-, 8.2- and 9.8-fold, respectively, in subjects with mild (n = 6), moderate (n = 10) and severe 
(n = 8) hepatic impairment relative to subjects with normal liver function.  Ibrutinib Cmax 
increased 5.2-;  8.8-;  and 7.0-fold, respectively, in subjects with mild, moderate and severe 
hepatic impairment relative to subjects with normal liver function.   
Drug Interactions 
Co-administration of Ibrutinib with CYP3A Inhibitors:  In a sequential design trial of 18 healthy, 
fasted volunteers, a single dose of 120 mg of ibrutinib was administered alone on Day 1 and a 
single dose of 40 mg of ibrutinib was administered on Day 7 in combination with 400 mg of 
ketoconazole (given daily on Days 4 to 9).  Ketoconazole increased ibrutinib dose-normalized 
Cmax and AUC 29-fold and 24-fold, respectively.  Simulations using fasted conditions indicate 
that moderate CYP3A inhibitors diltiazem and erythromycin may increase AUC of ibrutinib by 
5- to 8-fold. 
Co-administration of Ibrutinib with CYP3A Inducers:  PK data from a dedicated drug interaction 
trial showed that rifampin (a strong CYP3A inducer) decreases ibrutinib Cmax and AUC by 
more than 13- and 10-fold.  Simulations using PBPK suggested that a moderate CYP3A inducer 
(efavirenz) may decrease the AUC of ibrutinib by up to 3-fold. 


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Clinical Safety with Ibrutinib 
Mantle Cell Lymphoma:  The data described below reflect exposure to ibrutinib in a clinical trial 
that included 111 subjects with previously treated MCL treated with 560 mg daily with a median 
treatment duration of 8.3 months.  The most commonly occurring adverse reactions (≥ 20%) 
were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral 
edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal 
pain, vomiting and decreased appetite (see Tables 1 and 2).  The most common Grade 3 or 4 
non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, 
diarrhea, fatigue, and skin infections.  Fatal and serious cases of renal failure have occurred with 
ibrutinib therapy.  Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% 
of subjects.  Adverse reactions from the MCL trial (N = 111) using single-agent ibrutinib 560 mg 
daily occurring at a rate of ≥ 10% are presented in Table 1. 
Table 2:  Non-Hematologic Adverse Reactions in ≥ 10% of Subjects with MCL (N = 111) 
System Organ Class 
Preferred Term 
All Grades (%) 
Grade 3 or 4(%) 
Gastrointestinal disorders 
Diarrhea  
Nausea  
Constipation  
Abdominal pain  
Vomiting  
Stomatitis  
Dyspepsia 
51 
31 
25 
24 
23 
17 
11 
5 
0 
0 
5 
0 
1 
0 
Infections and infestations 
Upper respiratory tract infection 
Urinary tract infection 
Pneumonia  
Skin infections  
Sinusitis
34 
14 
14 
14 
13
0 
3 
7 
5 
1
General disorders and 
administrative site 
Fatigue 
Peripheral edema 
Pyrexia 
Asthenia 
41 
35 
18 
14 
5 
3 
1 
3 
Skin and subcutaneous tissue 
disorders 
Bruising  
Rash  
Petechiae 
30 
25 
11 
0 
3 
0 
Musculoskeletal and connective 
tissue disorders 
Musculoskeletal pain 
Muscle spasms 
Arthralgia 
37 
14 
11 
1 
0 
 
Respiratory, thoracic and 
mediastinal disorders 
Dyspnea 
Cough 
Epistaxis 
27 
19 
11 
40 
0 
0 
Metabolism and nutrition 
disorders 
Decreased appetite 
Dehydration 
21 
12 
2 
4 
Nervous system disorders 
Dizziness 
Headache 
14 
13 
0 
0 


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Table 3:  Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils  
in Subjects with MCL (N = 111) 
 
Percent of Subjects (N = 111) 
All Grades (%) 
Grade 3 or 4(%) 
Platelets Decreased 
57 
17 
Neutrophils Decreased 
47 
29 
Hemoglobin Decreased 
41 
9 
Hemoglobin Decreased 
41 
9 
*  Based on laboratory measurements and adverse reactions 
Chronic Lymphocytic Leukemia:   
The data described below reflect exposure to ibrutinib in a randomized clinical trial that included 
391 randomized subjects with previously treated CLL or SLL.  The most commonly occurring 
adverse reactions (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, 
musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia.  Approximately 
5% of subjects in the ibrutinib arm discontinued treatment due to adverse events.  These included 
infections, subdural hematomas and diarrhea.  Adverse events leading to dose reduction occurred 
in approximately 6% of subjects. 
Efficacy of Ibrutinib in Follicular Lymphoma 
Ibrutinib has been studied in the treatment of subjects with low-grade follicular lymphoma.  In a 
phase 1 study of subjects with relapsed or refractory B-cell malignancies, 13 subjects with 
follicular lymphoma were evaluated for response to ibrutinib, with 7/13 subjects showing a 
>50% decrease in sum of the largest diameter of each target lesion (11).  The MTD in this study 
was 560 mg daily and this dose showed full-target occupancy.  Preliminary results from a 
phase 2 trial of ibrutinib monotherapy in relapsed/refractory follicular lymphoma showed an 
overall response rate of 30% in 40 subjects on the intention-to-treat analysis.  An additional 
14 subjects had reduction of tumor size not meeting response criteria (12).   


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Table 4:  Non-Hematologic Adverse Reactions ≥ 10% Reported in CLL 
System Organ Class 
ADR Term  
IMBRUVICA (N = 195)  
Ofatumumab (N = 191)  
 
All Grades (%) Grade 3 or 4(%) All Grades (%) Grade 3 or 4(%) 
Gastrointestinal disorders  
 
Diarrhea  
48 
4 
18 
2 
Nausea  
26 
2 
18 
0 
Stomatitis*  
17 
1 
6 
1 
Constipation  
15 
0 
9 
0 
Vomiting  
14 
0 
6 
1 
General disorders and 
admin site conditions  
 
Fatigue  
28 
2 
30 
2 
Pyrexia  
24 
2 
15 
1 
Infections and infestations  
 
Upper respiratory tract 
infection  
16 
1 
11 
2 
Pneumonia*  
15 
10 
13 
9 
Sinusitis*  
11 
1 
6 
0 
Urinary tract infection  
10 
4 
5 
1 
Skin and subcutaneous 
tissue disorders  
 
Rash*  
24 
3 
13 
0 
Petechiae  
14 
0 
1 
0 
Bruising*  
12 
0 
1 
0 
 
 
 
 
 
Musculoskeletal and 
connective tissue 
disorders  
 
Musculoskeletal Pain*  
28 
2 
18 
1 
Arthralgia  
17 
1 
7 
0 
Nervous system disorders  
 
Headache  
14 
1 
6 
0 
Dizziness  
11 
0 
5 
0 
Injury, poisoning and 
procedural complications  
 
Contusion  
11 
0 
3 
0 
Eye disorders  
 
Vision blurred  
10 
0 
3 
0 
Subjects with multiple events for a given ADR term are counted once only for each ADR term.   
The system organ class and individual ADR terms are sorted in descending frequency order in 
the IMBRUVICA arm.   
* Includes multiple ADR terms  
 


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Table 5:  Treatment-Emergent Decrease of Hemoglobin, Platelets, or Neutrophils in CLL 
Sys 
IMBRUVICA (N = 195)  
Ofatumumab (N = 191)  
 
All Grades (%) Grade 3 or 4(%) All Grades (%) Grade 3 or 4(%) 
Neutrophils Decreased 
51 
23 
57 
26 
Platelets Decreased 
52 
5 
45 
10 
Hemoglobin Decreased 
36 
0 
21 
0 
5.3 
Radiotherapy 
Pre-clinical and Clinical Studies 
Animal studies of subcutaneous tumors have demonstrated that tumor cells undergo apoptosis 
upon irradiation.  Furthermore, it has been shown that dendritic cells migrate towards irradiated 
tumor (15).   
The purpose of using low-dose radiation to a single tumor site in our study is to induce tumor 
necrosis and/or apoptosis, which in turn releases tumor antigens locally.  These tumor antigens 
will be processed by antigen presenting cells to mount a tumor- specific immune response.  This 
immune response will be augmented by intratumoral injection of SD-101, which is a potent 
immunostimulant.   
Low-dose (2 Gy x 2) radiotherapy has been studied in recurrent follicular lymphoma (16).  The 
overall local tumor response rate is estimated at 80 to 90%.  The reason for choosing a low-dose 
radiation is that the low-dose therapy is sufficient to induce tumor cell death and will not 
jeopardize subjects’ opportunity to receive standard radiotherapy at the same anatomic site in the 
future.  Another potential advantage of using a low-dose radiation regimen is to minimize the 
possibility that the radiation will inhibit tumor-infiltrating dendritic cell functions. 
Radiotherapy:  Dosage 
All subjects will receive 2 Gy radiation to a single tumor site on each of 2 consecutive days 
(Day 1 and Day 2).   
5.4 
Availability 
SD-101 will be supplied by DynaVax Technologies Corporation.  Ibrutinib will be supplied by 
Janssen Scientific Affairs, LLC. 
5.5 
Agent Ordering 
Describe how the agent will be requested and provide mailing address and phone number.   
SD-101 will be requested and ordered directly from:   
Dynavax Technologies 
2929 Seventh Street, Suite 100 
Berkeley, CA 94710 
Ibrutinib will be requested by the study site investigational pharmacy.   


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5.4 
Agent Accountability 
Supplies of the SD-101 and ibrutinib will be stored in the Stanford University Medical Center 
Investigational Pharmacy in a secure location with restricted access.  The Investigational 
Pharmacist will maintain drug accountability records. 
6. 
DOSE MODIFICATIONS 
6.1 
Dose/ Schedule Modifications of SD-101 
The SD-101 dose of will not be reduced except by the rules listed in the study design.  In the 
case of adverse events affecting the feasibility or safety of injection, as judged by the 
investigator, injections may be delayed or omitted until resolution of the adverse event to Grade 
≤1 or baseline and after re-assessment by investigator. When doses are delayed, all five 
intratumoral injections may still be delivered, provided all five are given within a span of 8 
weeks and there is a minimum interval of 3 days between injections. In the case of local injection 
site reactions that cause dose delays or modifications and are not DLTs, the Investigators are 
asked to avoid administering subsequent injections near to this site and to document the reaction 
with a photograph  when possible.   
6.2 
Re-Treatment after Hypersensitivity Reaction (HSR) for SD-101 
All subjects must be observed for at least 30 minutes after administration of SD-101 for onset of 
acute hypersensitivity reactions.  All hypersensitivity should be appropriately managed 
according to standard local practice.   
Following treatment-related anaphylaxis (any grade) or grade 3-4 non-anaphylactic 
hypersensitivity reaction (urticaria, serum sickness, Stevens-Johnson Syndrome, or Toxic 
Epidermal Necrolysis) occurring after intratumoral treatments, all study agents will be 
permanently discontinued for that patient. Following a Grade 2 treatment-related 
non-anaphylactic hypersensitivity reaction, re-treatment may be considered following discussion 
and with an explicit agreement from the Investigator and the patient.  Premedication with 
antihistamines and acetaminophen with or without a corticosteroid is recommended for 
subsequent treatments. 
6.3 
Dose Modifications for Ibrutinib 
Ibrutinib dose modifications may occur starting on Day 31.  Interrupt ibrutinib therapy for any 
Grade 3 or greater non-hematological, Grade 3 or greater neutropenia with infection or fever, or 
Grade 4 hematological toxicities.  Once the symptoms of the toxicity have resolved to Grade 1 or 
baseline (recovery), ibrutinib therapy may be reinitiated at the starting dose.  If the toxicity 
reoccurs, reduce dose by one capsule (140 mg per day).  A second reduction of dose by 140 mg 
may be considered as needed.  If these toxicities persist or recur following two dose reductions, 
this will be considered a DLT.  Doses of ibrutinib may be held for surgeries or procedures as 
listed below in Section 4.9.2.  Dose of ibrutinib will be reduced by 140 mg daily if chronic 
treatment with a moderate CYP3A inhibitor is required (see Section 4.9.2).   


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7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1  
Overview: 
As the sponsor of the Study, the Sponsor Investigator shall be solely responsible for complying, 
within the required timelines, any safety reporting obligation to competent Health Authorities, 
IRB/ECs and any participating (co or sub) investigators, as defined in applicable laws and 
regulations.  Safety data includes adverse events, product quality complaints (PQCs), and special 
situations including pregnancies. 
7.2 
Management of Safety Data: 
All adverse events regardless of causality and special situations and product quality complaints 
with or without an adverse event will be reported from the time a subject has signed and dated an 
Informed Consent Form (ICF) until completion of the subject’s last study-related procedure 
(which may include contact for follow-up safety).  Serious adverse events will be recorded and 
reported starting from when the subject signs the informed consent form and will continue until 
30 days after the last dose of study drug. 
Definitions: 
Adverse Events (AEs):  An adverse event is any untoward medical occurrence in a clinical study 
subject administered a medicinal (investigational or non-investigational) product.  An adverse 
event does not necessarily have a causal relationship with the treatment.  An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational or non- investigational) 
product, whether or not related to that medicinal (investigational or non-investigational) product.   
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
Serious Adverse Event (SAE):  An adverse event which meets one or more the following criteria 
is considered serious. 
• Results in death 
• Is life-threatening (The subject was at risk of death at the time of the event.  It does not 
refer to an event that hypothetically might have caused death if it were more severe.) 
• Requires or prolongs insubject hospitalization 
• Is disabling 
• Is a congenital anomaly/birth defect 
• Is a suspected transmission of any infectious agent via a medicinal product 
• Is medically significant or requires medical or surgical intervention to prevent one of the 
outcomes listed above. 
• Is medically important  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 


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or may require intervention to prevent one of the other outcomes listed in the definition above.  
These should usually be considered serious. 
NOTE:  DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS ADVERSE 
EVENT. 
Hospitalization: 
For reports of hospitalization, details of the sign, symptom or diagnosis which led to the 
hospitalization must be provided. 
Any event requiring hospitalization or prolongation of hospitalization that occurs during the 
study must be reported as a serious adverse event, except hospitalizations for the following: 
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such as 
pending placement in long-term care facility) 
Surgery or procedure planned before entry into the study.  [Note:  Hospitalizations that were 
planned before the start of data collection and where the underlying condition for which the 
hospitalization was planned has not worsened will not be considered serious adverse events.  
Any adverse event that results in a prolongation of the originally planned hospitalization is to be 
reported as a new serious adverse event.] 
Life-threatening Conditions: 
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition. 
Adverse Events of Special Interest: 
Adverse events of special interest are events that Janssen Scientific Affairs, LLC  is actively 
monitoring as a result of a previously identified signal (even if non-serious).  These adverse 
events are: 
• Major Hemorrhage 
Major hemorrhage is defined as any hemorrhagic event that is Grade 3 or greater in 
severity or that results in 1 of the following:  intraocular bleeding causing loss of vision, 
the need for a transfusion of 2 or more units of red cells or an equivalent amount of whole 
blood, hospitalization, or prolongation of hospitalization. 
• Intracranial Hemorrhage 
Any intracranial hemorrhage adverse event, including subdural hematoma/hemorrhage, 
epidural hematoma/hemorrhage and intracerebral hemorrhage, of any grade severity, will 
be captured as an event of special interest. 
• Other Malignancies 
In addition to all routine AE reporting, all new malignant tumors, including solid tumors, 
skin malignancies and hematologic malignancies, are to be reported for the duration of 
study treatment and during any protocol-specified follow-up periods including 
post-progression follow-up for overall survival. 


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Unanticipated (Unlisted) Problem Involving Risks to Participants or Others (UPs): 
Adverse Event that is: 
Unexpected:  Not in the consent form, investigator brochure, protocol, package insert, or label, 
or unexpected in its specificity, severity or frequency AND 
Related to the research:  Caused by, or probably caused by research activity.  Events caused by 
progression of underlying disease are NOT related.  If a device is involved;  the event was 
caused by, or associated with the device AND caused harm or increased risk of harm:  Involves 
harm to participants or others, or places participants or others at increased risk of harm. 
Unlisted adverse events related to the drug ibrutinib: 
An adverse event will be considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information.  The expectedness of an adverse event will be 
determined by whether or not it is listed in the applicable product information. 
http://www.imbruvica.com/  
Product Quality Complaint (PQC): 
A product quality compliant is defined as any suspicion of a product defect related to a potential 
quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product, or delivery system.  Not all PQCs involve a 
subject.  Lot and batch numbers are of high significance and need to be collected whenever 
available. 
Examples of PQC include but not limited to: 
• Functional Problem:  eg, altered delivery rate in a controlled release product 
• Physical Defect:  eg, abnormal odor, broken or crushed tablets/capsules 
• Potential Dosing Device Malfunction:  eg, autoinjector button not working, needle 
detaching from syringe 
• Suspected Contamination 
• Suspected Counterfeit 
7.3 
Assessing Adverse Events: 
Events must be assessed by the investigator as to whether they are unexpected, related to the 
research procedures, and/or harmful.  To qualify as an unanticipated problem involving risks to 
participants or others (UP), an event must be Unexpected and Related and Harmful.   
7.4 
Adverse Event Reporting Requirements 
7.4.1 Adverse Events 
Adverse events will be graded according to CTCAE v4.03.  Both Serious and Non-Serious 
Adverse Events will be clearly noted in source documentation and listed on study-specific Case 
Report Forms (CRFs).  The Protocol Director (PD) or designee will assess each 
Adverse Event (AE) to determine whether it is unexpected according to the Informed Consent, 
Protocol Document, or Investigator’s Brochure, and related to the investigation.  All Serious 


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Adverse Events (SAEs) will be tracked until resolution, or until 30 days after the last dose of the 
study treatment.   
Adverse events, which are not serious, should be captured in the CRF.  The research team will 
meet regularly to discuss AEs being experienced by the participants.  
7.4.2 Serious Adverse Events 
SAEs CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to the 
Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the 
study-specific  CRF regardless of the event’s relatedness to the investigation.  Following review 
by the DSMC, events meeting the IRB definition of ‘Unanticipated Problem’ will be reported to 
the IRB using eProtocol within 10 working days of DSMC review, or within 5 working days for 
deaths or life-threatening experiences.  Deaths within 30 days of a subject being treated with the 
study drug will be reported within 5 days, all other SAEs will be reported within 10 days of the 
SI becoming aware of the event.  All SAEs which are possibly or definitely related to the study 
will be reported to DynaVax using the MedWatch 3500a form within 24 hours of the SI being 
informed of the event.   
7.4.3 Requirements related to reporting to Janssen Scientific Affairs, LLC 
In addition to the above reporting, the SI will use the following guidelines in reporting adverse 
events and product quality complaints to Janssen Scientific, LLC.   
Maintenance of Safety Information 
All safety data will be maintained in a clinical database in a retrievable format.  The Sponsor 
Investigator shall provide all adverse events, both serious and non-serious, in report format.  
However, in certain circumstances more frequent provision of safety data may be necessary, 
eg, to fulfill a regulatory request, and as such the data shall be made available within a 
reasonable timeframe at Janssen Scientific Affairs, LLC request.   
Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for Janssen 
Medicinal Products to the COMPANY 
All adverse events and special situations, whether serious or non-serious, related or not related, 
following exposure to a Janssen medicinal product are to be documented by the investigator and 
recorded in the CRF and in the subject’s source records.  Investigators will record in the CRF 
their opinion concerning the relationship of the adverse event to a Janssen medicinal product.   
All (serious and non-serious) adverse events reported for a Janssen medicinal product should be 
followed-up in accordance with clinical practice. 
SAEs and Special Reporting Situations 
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs: 


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• The event resolves 
• The event stabilizes 
• The event returns to baseline, if a baseline value/status is available 
• The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
• It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts 
The Sponsor Investigator will transmit all SAEs and special situations following exposure to a 
Janssen product under study in a form provided by Janssen Scientific Affairs, LLC in accordance 
with Section Transmission Methods, in English within 24-hours of becoming aware of the 
event(s). 
All follow-up information for serious adverse events that are not resolved at the end of the study 
or by the time of subject withdrawal must be reported directly by the Sponsor Investigator, 
within 24 hours becoming aware, to Janssen Scientific Affairs, LLC using the Janssen Scientific 
Affairs, LLC Serious Adverse Event Report . 
All available clinical information relevant to the evaluation of a related SAE, serious ADR or 
special situation is required. 
The Sponsor Investigator is responsible for ensuring that these cases are complete and if not are 
promptly followed-up.  A safety report is not considered complete until all clinical details needed 
to interpret the case are received.  Reporting of follow-up information should follow the same 
timeline as initial reports. 
Non-Serious AEs 
All non-serious adverse events should be reported to Janssen Scientific Affairs, LLC according 
to the timeframe outlined in the Research Funding Agreement section entitled Reporting of Data. 
PQC Reporting 
A PQC may have an impact on the safety and efficacy of the product.  Timely, accurate, and 
complete reporting and analysis of PQC information from studies are crucial for the protection of 
subjects, investigators, and Janssen Scientific Affairs, LLC, and are mandated by regulatory 
agencies worldwide.  Janssen Scientific Affairs, LLC has established procedures in conformity 
with regulatory requirements worldwide to ensure appropriate reporting of PQC information.  
Lot and/or Batch no. s shall be collected or any reports failure of expected pharmacological 
action (ie, lack of effect).  The product should be quarantined immediately and if possible, take a 
picture. 
All initial PQCs involving a Janssen medicinal product under study must be reported to Janssen 
Scientific Affairs, LLC by the Sponsor Investigator within 24 hours after being made aware of 
the event.  The Janssen contact will provide additional information/form to be completed. 
If the defect for a Janssen medicinal product under study is combined with either a serious 
adverse event or non-serious adverse event, the Sponsor Investigator must report the PQC to 
Janssen Scientific Affairs, LLC according to the serious adverse event reporting timelines.  A 


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sample of the suspected product should be maintained for further investigation if requested by 
Janssen Scientific Affairs, LLC. 
Reporting Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for 
Non-Janssen Medicinal Products  
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen medicinal 
product under study, the Sponsor Investigator should notify the appropriate regulatory/competent 
authority or the manufacturer of that medicinal product (in the absence of appropriate local 
legislation) as soon as possible. 
Transmission Methods 
The following methods are acceptable for transmission of safety information to Janssen 
Scientific Affairs, LLC: 
• Electronically via Janssen SECURE Email service (preferred) 
• For business continuity purposes, if SECURE Email is non-functional: 
• Facsimile (fax), receipt of which is evidenced in a successful fax transmission report 
• Telephone (if fax is non-functional). 
Please use the contact information and process information provided by Janssen Scientific 
Affairs, LLC  
8. 
CORRELATIVE/SPECIAL STUDIES  
8.1 
Blood and tissue acquisition 
Research blood draws will be processed within the laboratory of Ronald Levy at Stanford 
University and stored as cryopreserved peripheral blood mononuclear cells (green top tubes) and 
plasma (purple top tubes). 
Excisional lymph node biopsy prior to first dosing, which will be processed and stored as single 
cell suspensions within the laboratory of Ronald Levy at Stanford University. 
FNA biopsies will be processed within the laboratory of Ronald Levy at Stanford University and 
stored as single cell suspensions. 
Leukapheresis to obtain peripheral blood mononuclear cells (PBMC) may be performed during 
the screening period (prior to Day 1) and at Day 37, if excisional biopsy is obtained at screening.   
8.2 
Storage of blood and tissue samples 
Samples will be stored as viable single cells suspensions in liquid nitrogen and cell-depleted 
serum at -80°C within the laboratory of Ronald Levy at Stanford University.  Remaining unused 
samples will be stored for potential future correlative studies including flow cytometric studies 
with additional potential biomarkers, gene expression analysis, and high-throughput sequencing 
of immunoglobulin and T-cell receptors.   
Access to samples will be limited only to research personnel involved in performing the 
correlative studies.  Samples will be labeled with a unique subject identification code and  
all sample consent, acquisition, handling, storage and processing will be in accordance with  


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HIPAA and any other state or federal laws or regulations concerning the use or storage of human 
tissue for research purposes.  
8.3 
Lymphocyte activity against autologous tumor (performed if adequate tumor 
sample):   
PBL and/or PBMCs will be obtained from all subjects, as described above, cryopreserved, and 
thawed, then used to for detection of tumor-specific T-cell responses by flow cytometry.   
Autologous tumors undergo negative selection with antibody-bound paramagnetic beads and are 
then activated for 72 hours with CpG.  These activated tumor B-cells are irradiated to 50 Gy in a 
Cesium-137 irradiator then used as stimulator cells in 24 hour co-culture with autologous subject 
PBMCs collected at the specified time points.  Negative controls run in parallel include PBMC 
incubated with media alone.  Positive controls for lymphocyte functional capacity will include 
anti-CD3 plus anti-CD28 stimulation.  After co-culture, PBMC are stained for CD4;  CD8;  and a 
panel of T cell activation associated markers.  Tumor-specific immune responses are calculated 
as the increase in percentage of activated T-cell subsets (CD4 or CD8) specifically in response to 
co-culture with autologous tumor at post-treatment time points compared to pre-treatment time 
points. 
8.4 
Immunophenotyping of treated and untreated tumor sites 
Cells recovered from fine needle aspiration of treated and any easily accessible untreated sites 
will be processed for analysis by flow cytometry.  Multiparameter flow will be performed at the 
various time points to define immune populations including CD4 and CD8 T-cells, regulatory 
T-cells, follicular helper T-cells, B-cells (including the malignant B-cells), natural killer cells, 
dendritic cells and macrophages.  The extent of immunophenotyping will depend on the 
availability of cells from each biopsy.   
8.5 
Anti-tumor antibody response (performed if adequate tumor sample): 
For IgM expressing lymphomas, pre – and post – treatment serum will be incubated with 
autologous tumor cells, followed by staining with FITC-labeled anti-human IgG antibodies and 
detection by flow cytometry.  Additionally, Western blotting of tumor cell lysate using sera 
followed by anti-human IgG detectors may be performed and anti-idiotypic humoral responses 
may be assayed. 


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9. 
STUDY CALENDAR 
Procedures 
Screen 
Day 1 
Week 1 
RT 
Day 2 
Week 1 
RT 
IT SD-
101 
Day 4 
Week 1 
FNA 
(optional) 
Day 9 
Week 2 
FNA 
IT SD-101 
Ibrutinib 
Day 16 
Week 3 
IT SD-101 
Day 23 and 30 
Week 4 and 5 
IT SD-101 
Day 37 
Week 6 
Safety 
Assessment 
Weeks 12, 24, 36, 48, 60, 72, 84 
Safety and Response 
Evaluation 
Final 
Study 
Visit 
Visit Windows 
 
 
 
+/- 1 day 
+/- 2 days 
+/- 2 days 
+/- 2 days 
+/-7 days 
+/- 10 days 
 
Written Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
History and Physical 
Exam 
X 
 
 
 
 
 
 
 
X 
X 
Adverse Event 
Evaluation 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Vital Signs and 
Performance Status 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
X 1 
 
 
 
 
 
 
 
 
 
Tumor Biopsy 2 
(optional) 
X 2 
 
 
 
 
 
 
 
 
 
Fine needle aspiration 
X 3 
 
 
X 3 
X 3 
 
 
X 3 
 
X3 
Research Blood 
Samples 4 
X 
 
 
 
X 
 
X 5 
X  
X 
X 
CBC with differential 
X 
 
 
 
X 
 
X 6 
X  
X 
X 
Comprehensive 
Metabolic Panel 
X 
 
 
 
X 
 
X 6 
X  
X 
X 
HIV and hepatitis testing 
X 7 
 
 
 
 
 
 
 
 
 
LDH 
X 
 
 
 
 
 
 
 
X 
X 
Radiation 
 
X(2 Gy) 
X (2 Gy) 
 
 
 
 
 
 
 
SD-101 Injection 
 
 
X 8 
 
X 8 
X 8 
X 8 
 
 
 
Ibrutinib supply dispensed 
 
 
 
 
X 
 
 
X 9 
X 9 
 
Imaging Studies 
(CT) 
X 
 
 
 
 
 
 
 
X 14 
X 10 
Bone Marrow Biopsy 
(conditional) 11 
 
 
 
 
 
 
 
 
X 11 (optional) 
X 11 
(optional) 
Apheresis 12 
(conditional) 
X 12 
 
 
 
 
 
 
X 12 
 
 
Additional Research 
Peripheral Blood 13 
(conditional) 
X 13 
 
 
 
X 13 
X 13 
 
X 13 
X 13 
X 13 


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1  
Pregnancy test - for women of childbearing potential only 
2  
Tumor excisional biopsy (optional) to be done during screening if indicated to rule out transformation.  Tissue not needed for clinical 
diagnostics may be collected for use in correlative studies 
3  
Fine needle aspiration of the tumor site chosen for treatment at screening, Day 9 (prior to second SD-101 injection) and Day 37.  Optional 
FNA on Day 4.  Fine needle aspiration of additional tumor (outside of the radiation field) to be done concurrently if amenable to biopsy. 
4  
Consisting of 1 purple top tube.   
5  The indicated research labs are collected on Day 23 and not Day 30  
6  
CBCD and CMP monitoring to be done at Day 23 and not Day 30  
7  
Hepatitis and HIV testing to include hepatitis B surface antigen, anti-HBc antibody, anti-HCV antibody, and anti-HIV antibody 
8  
Subjects must be monitored at least 30 minutes after all injections of SD-101 before discharge  
9  Ibrutinib to be self-administered by subject starting on Day 10 and continuing daily until Week 96, disease progression, or removal from 
study.  Event indicates dispensing of supply. 
10  Imaging performed at final study visit only if there has not been interval imaging within the last 4 weeks 
11  Bone marrow biopsy (conditional) only if subject achieves a complete response by imaging to confirm complete response 
12  Apheresis (conditional) only if subject had excisional biopsy prior to treatment with sufficient sample to perform immune assay correlative 
study or, optionally, if patient has circulating lymphoma cells. 
13  7 green top tubes to be collected: This collection will occur for all patients at Day 9, Day 16, Week 12, and final study visit.  Additionally, 
7 green top tubes (conditional) will be collected for patients not undergoing apheresis at the following timepoints:  screening and Day 37.   
14  CT scans to be performed on Weeks 12;  24;  48;  72 
 


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10. 
MEASUREMENTS 
10.1 
Phase 1B - Primary Outcome Measure 
The primary outcome measure for the phase 1b portion will be the observation of dose-limiting 
toxicity.  This outcome measure assesses a safety issue.  The outcome will be measured at each 
visit during the trial. 
10.1.1 Dose-Limiting Toxicity Definition 
DLTs are defined as: 
Days 1-30: 
• Any Grade 4 treatment-related toxicity; 
• Any Grade ≥ 3 treatment related toxicity persisting despite adequate/maximal medical 
therapy and/or prophylaxis.  [NOTE:  Grade 3 or lower treatment related skin rash not 
requiring systemic steroid therapy or other immunosuppressive therapy or Severe 
(Grade 3) flu-like symptoms are not considered DLTs.  Grade 3 rash may be treated by 
withholding ibrutinib and/or systemic corticosteroids for up to 7 days.  If rash resolves or 
improves to Grade 1, subjects may be restarted at the same dose of ibrutinib.  If Grade 3 
rash recurs upon restarting ibrutinib, then this will be considered a DLT]; 
• Any Grade ≥ 3 non-hematologic study drug-related toxicity will be considered a 
dose-limiting toxicity 
• Any Grade ≥ 3 hematological study drug-related toxicity 
• Grade ≥ 3 treatment related clinical autoimmune reaction involving major organs, which 
are defined as liver, pancreas, lung, heart, kidney, bowel, bone marrow and CNS 
(including the eye) which does not resolve to baseline or Grade 1 within 6 weeks; 
• Grade ≥ 3 Injection Site Reaction; 
Days 31-731: 
• Any Grade 4 treatment related non-hematologic toxicity; 
• Any Grade ≥ 3 treatment related toxicity persisting despite adequate/maximal medical 
therapy and/or prophylaxis.  [NOTE:  Grade 3 or lower treatment related skin rash not 
requiring systemic steroid therapy or other immunosuppressive therapy or Severe 
(Grade 3) flu-like symptoms are not considered DLTs]; 
• Grade ≥ 3 treatment related clinical autoimmune reaction involving major organs, which 
are defined as liver, pancreas, lung, heart, kidney, bowel, bone marrow and CNS 
(including the eye) which does not resolve to baseline or Grade 1 within 6 weeks 
• Any Grade ≥ 3 hematologic toxicity that persists despite protocol-defined 
dose-modification of ibrutinib. (see Section 4.1) 
10.1.2 Measurement Methods 
Dose-limiting toxicity will be assessed using CTCAE v4.0.   
10.1.3 Measurement Time Points 
Dose-limiting toxicity will be assessed continuously throughout the trial.  Adverse event 
information will be collected at each visit.  Safety labs will be collected on Days 9; 23;  37;  
week 12;  and every 12 weeks thereafter until the final study visit.   


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10.2 
Phase 2 - Primary Outcome Measure 
The primary outcome measure for the phase 2 portion will be to evaluate the response rate of 
intratumoral SD-101 in combination with ibrutinib and radiation in subjects.   
10.2.1 Relevant Subset 
This outcome will be measured on any individual who has received at least one intratumoral 
injection of SD-101 at the recommended phase 2 dose level.  This will include any subjects 
treated during the phase 1B portion who were treated at the recommended phase 2 dose level.   
10.2.2 Response Definition 
Tumor response rates (CR, PR) will be calculated based on the Lugano classification (51) for 
low-grade B-cell lymphomas.   
Definition of Measurable and Non-Measurable Lesions 
Measurable Lesions are lesions that can be accurately measured in two perpendicular diameters, 
with at least one diameter ≥ 20 mm and the other dimension ≥ 10 mm (10 mm x 10 mm for spiral 
CT).  The area will be defined as the product of the largest diameter with its perpendicular.  Skin 
lesions can be considered measurable. 
Non-Measurable (evaluable) Lesions are all other lesions, including unidimensionally 
measurable disease and small lesions (lesions without at least one diameter ≥ 20 mm), and any of 
the following: 
- Lesions occurring in a previously irradiated area (unless they are documented as new 
lesions since the completion of radiation therapy), bone lesions, leptomeningeal disease, 
ascites, pleural or pericardial effusion, lymphangitis cutis/pulmonis, abdominal masses 
that are not pathologically/cytologically confirmed and followed by imaging techniques 
and cystic lesions. 
- All measurable and non-measurable lesions should be measured at screening and at the 
defined tumor assessment time points.  Extra assessments may be performed, as clinically 
indicated, if there is a suspicion of progression. 
Definition of Index/Non-Index Lesions 
All measurable lesions, up to a maximum of 5 lesions per organ and 10 lesions in total, should 
be identified as index lesions to be measured and recorded on the medical record at Screening.  
The index lesions should be representative of all involved organs.  In addition, index lesions 
should be selected based on their size (lesions with the longest diameters), their suitability for 
accurate repeat assessment by imaging techniques, and how representative they are of the 
subject’s tumor burden.  At Screening, a sum of the products of diameters (SPD) for all index 
lesions will be calculated and considered the baseline sum of the products of diameters.  
Response criteria to be followed are listed below.  The baseline sum will be used as the reference 
point to determine the objective tumor response of the index lesions at tumor assessment (TA). 
Measurable lesions, other than index lesions, and all sites of non-measurable disease, will be 
identified as non-index lesions.  Non-index lesions will be recorded on the medical record and 
should be evaluated at the same assessment time points as the index lesions.  In subsequent 


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assessments, non-index lesions will be recorded as “stable or decreased disease,” “absent,” or 
“progression.” 
Definition of Response 
Response will be based upon the Lugano Classification (Table 6).  To better assess systemic 
responses, an additional response assessment will be reported which will exclude any index 
lesions which were within the irradiation field.  Overall response will include both complete and 
partial responses. 
Table 6.  IRB-36750 response based upon the Lugano Classification 
Response and Site 
CT-Based Response 
Complete 
Complete radiologic response (all of the following) 
    Lymph nodes and 
extralymphatic sites 
Target nodes/nodal masses must regress to ≤ 1.5 cm in LDi 
No extralymphatic sites of disease 
    Nonmeasured lesion 
Absent 
    Organ enlargement 
Regress to normal 
    New lesions 
None 
    Bone marrow 
Normal by morphology; if indeterminate, IHC negative 
Partial 
Partial remission (all of the following) 
    Lymph nodes and 
extralymphatic sites 
≥ 50% decrease in SPD of up to 6 target measurable nodes and 
extranodal sites 
  
When a lesion is too small to measure on CT, assign 5 mm × 5 mm as 
the default value 
  
When no longer visible, 0 × 0 mm 
  
For a node > 5 mm × 5 mm, but smaller than normal, use actual 
measurement for calculation 
    Nonmeasured lesions 
Absent/normal, regressed, but no increase 
    Organ enlargement 
Spleen must have regressed by > 50% in length beyond normal 
    New lesions 
None 
    Bone marrow 
Not applicable 
No response or stable disease 
Stable disease 
    Target nodes/nodal masses, 
extranodal lesions 
< 50% decrease from baseline in SPD of up to 6 dominant, measurable 
nodes and extranodal sites; no criteria for progressive disease are met 
    Nonmeasured lesions 
No increase consistent with progression 
    Organ enlargement 
No increase consistent with progression 
    New lesions 
None 
    Bone marrow 
Not applicable 
Progressive disease 
Progressive disease requires at least 1 of the following 
    Individual target 
nodes/nodal masses 
PPD progression: 


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Table 6.  IRB-36750 response based upon the Lugano Classification 
Response and Site 
CT-Based Response 
    Extranodal lesions 
An individual node/lesion must be abnormal with: 
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the splenic length must increase by 
> 50% of the extent of its prior increase beyond baseline (eg, a 15-cm 
spleen must increase to > 16 cm).  If no prior splenomegaly, must 
increase by at least 2 cm from baseline 
New or recurrent splenomegaly 
    Nonmeasured lesions 
New or clear progression of preexisting nonmeasured lesions 
    New lesions 
Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and must be attributable to lymphoma 
Assessable disease of any size unequivocally attributable to lymphoma 
    Bone marrow 
New or recurrent involvement 
 
10.2.3 Measurement Methods 
Response assessment will be performed based on CT imaging.  CT scan is the preferred mode of 
imaging, however, if a CT scan is contraindicated or if it is felt by the Sponsor Investigator that a 
PET/CT will be a better modality to assess a particular subject, a PET/CT may be used for 
evaluation. 
10.2.4 Measurement Time Points 
Subjects will undergo imaging studies at screening, and at the 12 Week visit.  Imaging will be 
performed at Week 24 as part of routine follow-up and to assess safety and response.  
Subsequent imaging as part of routine follow-up will be done every 3 to 6 months.   
10.3 
Phase 2 - Secondary Outcome Measure – Progression free survival 
The secondary outcome measure for the phase 2 portion will be progression-free survival.   
Table 3. LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; 
PET, positron emission tomography; PPD, cross product of the LDi and perpendicular 
diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the 
perpendicular diameters for multiple lesions 


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10.3.1 Relevant Subset 
This outcome will be measured on any individual who has received at least one intratumoral 
injection of SD-101 at the recommended phase 2 dose level.  This will include any subjects 
treated during the phase 1B portion who were treated at the recommended phase 2 dose level.   
10.3.2 Progression-free Survival Definition 
Progression-free Survival is defined as the time elapsed between treatment initiation (Day 1) and 
tumor progression or death from any cause.  Progression will be defined using the Lugano 
Classification (Section 10.2.2, Table 6).  It is recommended in difficult cases to confirm PD by 
serial imaging.  If it is felt by the Sponsor Investigator that a participant may be experiencing 
immune-related pseudoprogression resulting in PD, then at the discretion of the Sponsor 
Investigator, that participant may continue on study until the next response assessment.  
Participants who meet the definition for PD on two consecutive response assessments will be 
assessed as PD and treatment must be discontinued 
10.3.3 Measurement Methods 
Progression will be assessed based on CT imaging.  CT scan is the preferred mode of imaging, 
however, if a CT scan is contraindicated or if it is felt by the Sponsor Investigator that a PET/CT 
will be a better modality to assess a particular subject, a PET/CT may be used for evaluation. 
10.3.4 Measurement Time Points 
Subjects will undergo imaging studies at screening, and at the 12 Week visit.  Imaging will be 
performed at Week 24 as part of routine follow-up and to assess safety and response.  
Subsequent imaging as part of routine follow-up will be done every 3 to 6 months.   
10.4 
Phase 2 - Secondary Outcome Measure – Induction of tumor-specific immune 
responses 
An additionally exploratory secondary outcome measure for the phase 2 portion will be the 
induction of tumor-specific immune responses.   
10.4.1 Relevant Subset 
This outcome will be measured on any individual who has received at least one intratumoral 
injection of SD-101 at the recommended phase 2 dose level.  This will include any subjects 
treated during the phase 1B portion who were treated at the recommended phase 2 dose level.  
This analysis will be limited to individuals with adequate research samples collection to perform 
the required assays.  
10.4.2 Tumor-specific Immune Response Definition 
Tumor-specific immune responses will be defined as lymphocyte activity against autologous 
tumor over the baseline of activity against media only. 
10.4.3 Measurement Methods 
Tumor-specific immune responses will be assayed as in section 8.3, Lymphocyte activity against 
autologous tumor. 
10.4.4 Measurement Time Points 
Tumor-specific immune responses are calculated as the increase in percentage of activated T-cell 
subsets (CD4 or CD8) specifically in response to co-culture with autologous tumor at 


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post-treatment time points compared to pre-treatment time points. All post-treatment time points 
will be evaluated, but the primary timepoint for analysis will be from Day 37 samples.   
11. 
REGULATORY CONSIDERATIONS 
11.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to 
the study (eg, advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes 
made to the protocol will be submitted as a modification and will be approved by the IRB prior 
to implementation.  The Protocol Director will disseminate the protocol amendment information 
to all participating investigators. 
11.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study.  The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  This may include review of the 
following types of documents participating in the study:  regulatory binders, case report forms, 
eligibility checklists, and source documents.  In addition, the DSMC will regularly review 
serious adverse events and protocol deviations associated with the research to ensure the 
protection of human subjects.  Results of the DSMC audit will be communicated to the IRB and 
the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. 
11.3 
Data Management Plan 
The Protocol Director and Coordinator will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Case Report Forms 
(CRFs) are printed to record all protocol-related information on each trial participant.  CRFs will 
summarize the clinical findings and observations necessary to ensure safety of participants on the 
study.  CRF design and creation will be completed prior to enrollment of the first participant.  
The plan is to work with the OnCore Team CCTO-OnCore@stanford.edu for CRF design and 
storage as well as in all subject binders that will include same CRFs to be kept locked in the 
lymphoma research area. 
These study-specific Case Report Forms (CRFs) will document treatment outcomes for data 
analysis.  Case report forms will be developed using the above mentioned OnCore database 
system and will be maintained by the OnCore team, Research Coordinator and Protocol Director.  
CRFs will be kept in a locked office, only accessible to the research team. 
11.4 Confidentiality  
Subject records will be kept in a secure location at Stanford University Medical Center, 
accessible only to research authorized personnel.  The subject identity will be kept as 
confidential as possible as required by law.  Except as required by law, the subject will not be 
identified by name, social security number, address, telephone number, or any other  direct 
personal identifier.  Study subjects will be assigned an ID code that will consist of a three digit 
number.  Information about the code will be kept in a secure location and access limited to 
research study personnel.  The results of this research study may be presented at scientific or 


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medical meetings or published in scientific journals.  However, the subject identity will not be 
disclosed.  The subject's personal data which may be included in the investigator’s database shall 
be treated in compliance with all applicable laws and regulations. 
12. 
STATISTICAL CONSIDERATIONS 
12.1 
Statistical Design 
The phase 1B portion of this trial is designed to allow preliminary assessments of safety and 
biological activity.  No pre-specified hypothesis testing will be performed. 
The phase 2 portion of this trial will be powered to detect an improvement in response equal to 
the combined overall response rate of each intervention alone (SD-101 and ibrutinib) 
12.2 
Primary Analysis  
12.2.1 Analysis Population 
Phase 1B – Safety 
The safety population will consist of all enrolled subjects who received at least one dose of any 
study treatment.  The safety population will be used for the analysis of safety data. 
Phase 2 – Efficacy 
The response-evaluable population is defined as all enrolled subjects who received at least one 
dose of study treatment (ibrutinib or SD-101) and provided at least one post-baseline response 
(or disease) assessment.  The response-evaluable population will be used as the primary 
population for analyses based on overall response. 
12.2.2 Analysis Plan 
The phase 1B portion of this trial is designed to allow preliminary assessments of safety and 
biological activity.  No pre-specified hypothesis testing will be performed. 
The phase 2 portion of this trial will be powered to detect an improvement in response equal to 
the combined overall response rate (ORR) of each intervention alone (SD-101 and ibrutinib). 
12.3  Sample Size 
12.3.1 Accrual estimates  
Sample Size – Dose Escalation Cohorts 
6 to 15 subjects may be enrolled in the dose de-escalation cohorts in a 6+3 study design. 
Sample Size – Phase 2 Expanded Cohort 
15 subjects will be enrolled in the phase 2 expanded cohort. 
We estimate accruing an average of 10 subjects per year based on prior experience with this 
subject population.  The Stanford STRIDE database reports 40 subjects with BOTH an ICD9 
diagnosis of nodular lymphoma (202.0) AND encounter for antineoplastic chemotherapy and 
immunotherapy (V58.1) occurring in the year 2015 – indicating the number of subjects with this 
diagnosis who required treatment in the prior calendar year. 
12.3.2 Sample size justification 
The reported overall response rate with single-agent ibrutinib in a similar population of 
relapsed/refractory low-grade follicular lymphoma has been 30% (12 of 40 subjects) (12), and 


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we previously reported an ORR of 27% to intratumoral CpG (4 of 15 subjects) (50).  We will 
therefore expect overall response rate of >57% (ie, a 27% improvement over ibrutinib alone). 
This trial design will enroll a minimum of 21 subjects at the recommended phase 2 dose (a 
minimum of 6 subjects in phase 1b and 15 subjects in the phase 2 expansion).  For a true 
response rate of 57%, this sample size will provide 83.6% power to detect a significantly 
improved (95% confidence interval) response rate as compared to the previously reported ORR 
of 30% with ibrutinib alone.   
A total of 6 to 15 subjects will be enrolled in the phase 1B 6 x 3 dose de-escalation portion.  An 
additional 15 subjects will be enrolled in the expanded phase 2 cohort. 
If ≤ 1/6 subjects experience a DLT at a dose of intratumoral SD-101 of 3 mg, we will proceed to 
the expansion phase.  If 2/6 subjects experience a DLT at 3 mg, then an additional 3 subjects will 
be enrolled in the same dosing cohort.  If ≥ 3 of 6 to 9 subjects experience a DLT, then a dose 
de-escalation cohort -1 of 6 subjects will be opened. 
The sample size of 15 subjects in the expanded phase 2 cohort (with resulting total number of 
21 to 24 subjects at the RP2D in the combined 1b/2 phases) allows estimation of the response 
rate +/- 0.21 with 90% confidence.  The chance of obtaining three or fewer responses out of 15 is 
only 2.1% if the true response rate is 49%, with 49% ORR being a historical benchmark for 
response rate in this population.   
12.3.3 Effect size justification 
The reported overall response rate with single-agent ibrutinib in a similar population of 
relapsed/refractory low-grade follicular lymphoma has been 30% (12/40 subjects) (12), and we 
previously reported an ORR of 27% to intratumoral CpG (4/15 subjects) (50).   
12.4 
Criteria for future studies 
If the results are promising, we will also consider future trials, broadening the selection criteria 
to include other types of lymphoma.  If we do not detect at least 6  responses in this first trial we 
will consider designing a new trial with a different dose and/or schedule of SD-101 and ibrutinib, 
depending on what is learned from the immune response evaluations.  We will also consider 
initiating a different trial testing another immune stimulant, depending on the results of our 
pre-clinical animal models. 


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13. 
REFERENCES 
1. 
, A. C. Society, Ed. (American Cancer Society, Atlanta, 2015 ). 
2. 
E. M. Ries LAG, Kosary Cl, et al., SEER Cancer Statistics Review, 1973-1999. National 
Cancer Institute (2002). 
3. 
P. e. a. Solal-Celigny, Internationa Prognostic Index (PI) for Follicular Lymphoma (FL). 
ASCO Annual Meetng   Abstract No: 1121,  (2002). 
4. 
S. J. Horning, S. A. Rosenberg, The natural history of initially untreated low-grade non-
Hodgkin's lymphomas. N Engl J Med 311, 1471-1475 (1984). 
5. 
H. Hemmi et al., A Toll-like receptor recognizes bacterial DNA. Nature 408, 740-745 
(2000). 
6. 
Y. J. Liu, IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic 
cell precursors. Annu Rev Immunol 23, 275-306 (2005). 
7. 
N. L. Bernasconi, N. Onai, A. Lanzavecchia, A role for Toll-like receptors in acquired 
immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive 
expression in memory B cells. Blood 101, 4500-4504 (2003). 
8. 
D. M. Klinman, A. K. Yi, S. L. Beaucage, J. Conover, A. M. Krieg, CpG motifs present 
in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and 
interferon gamma. Proc Natl Acad Sci U S A 93, 2879-2883 (1996). 
9. 
G. Hartmann, G. J. Weiner, A. M. Krieg, CpG DNA: a potent signal for growth, 
activation, and maturation of human dendritic cells. Proc Natl Acad Sci U S A 96, 9305-
9310 (1999). 
10. 
T. Sparwasser et al., Bacterial DNA and immunostimulatory CpG oligonucleotides 
trigger maturation and activation of murine dendritic cells. Eur J Immunol 28, 2045-2054 
(1998). 
11. 
R. H. Advani et al., Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant 
activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 31, 88-94 
(2013). 
12. 
N. L. Bartlett et al., in American Society of Hematology Annual Meeting. (San 
Franscisco, 2014 ), vol. 124, pp. abstract 800. 
13. 
A. Noy et al., Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory 
marginal zone lymphoma. Blood 129, 2224-2232 (2017). 
14. 
M. L. Wang et al., Targeting BTK with ibrutinib in relapsed or refractory mantle-cell 
lymphoma. N Engl J Med 369, 507-516 (2013). 
15. 
C. Labratories, A 3-week Intravenous Pilot Study in Cynomolgus Monkeys. 
0433SC77.001. 
16. 
R. L. Haas et al., High response rates and lasting remissions after low-dose involved field 
radiotherapy in indolent lymphomas. J Clin Oncol 21, 2474-2480 (2003). 
17. 
R. Küppers, Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 5, 251-262 
(2005). 
18. 
T. Meeker et al., Emergence of idiotype variants during treatment of B-cell lymphoma 
with anti-idiotype antibodies. N Engl J Med 312, 1658-1665 (1985). 
19. 
M. Gururajan, C. D. Jennings, S. Bondada, Cutting edge: constitutive B cell receptor 
signaling is critical for basal growth of B lymphoma. J Immunol 176, 5715-5719 (2006). 
20. 
L. Chen et al., SYK-dependent tonic B-cell receptor signaling is a rational treatment 
target in diffuse large B-cell lymphoma. Blood 111, 2230-2237 (2008). 
21. 
J. M. Irish, D. K. Czerwinski, G. P. Nolan, R. Levy, Altered B-cell receptor signaling 


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IRB-36750 
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kinetics distinguish human follicular lymphoma B cells from tumor-infiltrating 
nonmalignant B cells. Blood 108, 3135-3142 (2006). 
22. 
L. A. Honigberg et al., The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell 
activation and is efficacious in models of autoimmune disease and B-cell malignancy. 
Proc Natl Acad Sci U S A 107, 13075-13080 (2010). 
23. 
Z. Pan et al., Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. 
ChemMedChem 2, 58-61 (2007). 
24. 
Y. Kawakami et al., Regulation of dendritic cell maturation and function by Bruton's 
tyrosine kinase via IL-10 and Stat3. Proc Natl Acad Sci U S A 103, 153-158 (2006). 
25. 
J. A. Dubovsky et al., Ibrutinib is an irreversible molecular inhibitor of ITK driving a 
Th1-selective pressure in T lymphocytes. Blood 122, 2539-2549 (2013). 
26. 
I. Sagiv-Barfi, H. E. Kohrt, L. Burckhardt, D. K. Czerwinski, R. Levy, Ibrutinib enhances 
the antitumor immune response induced by intratumoral injection of a TLR9 ligand in 
mouse lymphoma. Blood 125, 2079-2086 (2015). 
27. 
L. Fong et al., Dendritic cell-based xenoantigen vaccination for prostate cancer 
immunotherapy. J Immunol 167, 7150-7156 (2001). 
28. 
F. J. Hsu et al., Vaccination of patients with B-cell lymphoma using autologous antigen-
pulsed dendritic cells. Nat Med 2, 52-58 (1996). 
29. 
J. D. Geiger et al., Vaccination of pediatric solid tumor patients with tumor lysate-pulsed 
dendritic cells can expand specific T cells and mediate tumor regression. Cancer Res 61, 
8513-8519 (2001). 
30. 
L. Fong, C. L. Ruegg, D. Brockstedt, E. G. Engleman, R. Laus, Induction of tissue-
specific autoimmune prostatitis with prostatic acid phosphatase immunization: 
implications for immunotherapy of prostate cancer. J Immunol 159, 3113-3117 (1997). 
31. 
L. Fong et al., Altered peptide ligand vaccination with Flt3 ligand expanded dendritic 
cells for tumor immunotherapy. Proc Natl Acad Sci U S A 98, 8809-8814 (2001). 
32. 
B. Schuler-Thurner et al., Rapid induction of tumor-specific type 1 T helper cells in 
metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded 
monocyte-derived dendritic cells. J Exp Med 195, 1279-1288 (2002). 
33. 
B. Thurner et al., Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived 
dendritic cells expands specific cytotoxic T cells and induces regression of some 
metastases in advanced stage IV melanoma. J Exp Med 190, 1669-1678 (1999). 
34. 
J. M. Timmerman et al., Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: 
clinical and immune responses in 35 patients. Blood 99, 1517-1526 (2002). 
35. 
A. E. Chang et al., A phase I trial of tumor lysate-pulsed dendritic cells in the treatment 
of advanced cancer. Clin Cancer Res 8, 1021-1032 (2002). 
36. 
S. Teitz-Tennenbaum et al., Radiotherapy potentiates the therapeutic efficacy of 
intratumoral dendritic cell administration. Cancer Res 63, 8466-8475 (2003). 
37. 
L. Milas et al., CpG oligodeoxynucleotide enhances tumor response to radiation. Cancer 
Res 64, 5074-5077 (2004). 
38. 
K. A. Mason et al., CpG oligodeoxynucleotides are potent enhancers of radio- and 
chemoresponses of murine tumors. Radiother Oncol 80, 192-198 (2006). 
39. 
J. Li et al., Lymphoma immunotherapy with CpG oligodeoxynucleotides requires TLR9 
either in the host or in the tumor itself. J Immunol 179, 2493-2500 (2007). 
40. 
E. J. Friedman, Immune modulation by ionizing radiation and its implications for cancer 
immunotherapy. Curr Pharm Des 8, 1765-1780 (2002). 


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IRB-36750 
Page 61 of 70 
 24 January 2020 
41. 
E. Y. Nikitina, D. I. Gabrilovich, Combination of gamma-irradiation and dendritic cell 
administration induces a potent antitumor response in tumor-bearing mice: approach to 
treatment of advanced stage cancer. Int J Cancer 94, 825-833 (2001). 
42. 
T. L. Warren et al., APC stimulated by CpG oligodeoxynucleotide enhance activation of 
MHC class I-restricted T cells. J Immunol 165, 6244-6251 (2000). 
43. 
M. Bauer et al., Bacterial CpG-DNA triggers activation and maturation of human 
CD11c-, CD123+ dendritic cells. J Immunol 166, 5000-5007 (2001). 
44. 
T. Sparwasser, R. M. Vabulas, B. Villmow, G. B. Lipford, H. Wagner, Bacterial CpG-
DNA activates dendritic cells in vivo: T helper cell-independent cytotoxic T cell 
responses to soluble proteins. Eur J Immunol 30, 3591-3597 (2000). 
45. 
S. Behboudi, D. Chao, P. Klenerman, J. Austyn, The effects of DNA containing CpG 
motif on dendritic cells. Immunology 99, 361-366 (2000). 
46. 
R. E. Tascon, S. Ragno, D. B. Lowrie, M. J. Colston, Immunostimulatory bacterial DNA 
sequences activate dendritic cells and promote priming and differentiation of CD8+ T 
cells. Immunology 99, 1-7 (2000). 
47. 
I. Sagiv-Barfi et al., Therapeutic antitumor immunity by checkpoint blockade is enhanced 
by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci U S A 112, E966-972 
(2015). 
48. 
R. Levy et al., Active Idiotypic Vaccination Versus Control Immunotherapy for 
Follicular Lymphoma. J Clin Oncol,  (2014). 
49. 
B. D. Cheson et al., Report of an international workshop to standardize response criteria 
for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin 
Oncol 17, 1244 (1999). 
50. 
J. D. Brody et al., In situ vaccination with a TLR9 agonist induces systemic lymphoma 
regression: a phase I/II study. J Clin Oncol 28, 4324-4332 (2010). 
51. 
B. D. Cheson et al., Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol 32, 3059-3068 (2014). 
 


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APPENDICES 
APPENDIX A: 
Participant Eligibility Checklist  
A Participant Eligibility Checklist must be completed in its entirety for each subject prior to 
registration.  The completed, signed, and dated checklist must be retained in the subject’s study 
file and the study’s Regulatory Binder.   
The study coordinator, treating physician and an independent reviewer must verify that the 
participant’s eligibility is accurate, complete, and legible in source records.  A description of the 
eligibility verification process should be included in the EPIC or other Electronic Medical 
Record progress note.   
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory 
CpG, in combination with Ibrutinib and Local Radiation in 
Low-Grade Follicular Lymphoma 
Protocol Number: 
IRB-36750  /  LYMNHL0135 
Principal Investigator: 
Ronald Levy, MD 
II.  Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III.  Study Information: 
SRC Approved 
 IRB Approved 
 Contract signed 
 
IV.  Inclusion/Exclusion Criteria 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Biopsy-confirmed Grade 1 or 2, or 3A follicular 
lymphoma;  mantle cell lymphoma;  or marginal 
zone lymphoma.  Subjects must have relapsed 
from or are refractory to prior therapy. 
 
 
      
2. Subjects must have at least one site of disease that 
is accessible for intratumoral injection of SD-101 
(diameter ≥ 10mm), percutaneously. 
 
 
      
3. Subjects must have at least one site of measurable 
disease other than the injection site which is not 
included in the radiation field. 
 
 
      
4. ECOG Performance Status of 0 or 1 
 
 
      
5. Subjects must be 18 years of age or older. 
 
 
      


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6. Required values for initial laboratory tests:  
a) Absolute neutrophil count (ANC) ≥ 1000/mm3 
independent of growth factor support 
b) Platelets:  ≥ 100,000/mm3 or ³50,000/mm3 if 
bone marrow involvement independent of 
transfusion support in either situation 
c) Hemoglobin:  ≥ 8 g/dL (may be transfused) 
d) Creatinine:  Creatinine clearance > 25 mL/min 
e) AST/ALT:  ≤ 3 x ULN  
f) Bilirubin:  ≤ 1.5 x ULN (except for subjects 
with Gilbert’s Syndrome or of non-hepatic 
origin) 
 
 
      
7. Must be at least 4 weeks since treatment with 
standard or investigational chemotherapy, 
biochemotherapy, major surgery, radiation, 
cytokine therapy, and 8 weeks since any 
monoclonal antibodies or immunotherapy, and 
recovered from any clinically significant toxicity 
experienced during treatment.   
 
 
      
8. Women of childbearing potential and men who are 
sexually active must be practicing a highly 
effective method of birth control during and after 
the study consistent with local regulations 
regarding the use of birth control methods for 
subjects participating in clinical trials.  Men must 
agree to not donate sperm during and after the 
study.  For females, these restrictions apply for 
1 month after the last dose of study drug.  For 
males, these restrictions apply for 3 months after 
the last dose of study drug. 
 
 
      
9. Women of childbearing potential must have a 
negative serum (beta-human chorionic 
gonadotropin [b-hCG]) or urine pregnancy test at 
Screening.  Women who are pregnant or 
breastfeeding are ineligible for this study 
 
 
      
10. Life expectancy greater than 4 months. 
 
 
      
11. Able to comply with the treatment schedule. 
 
 
      
12. Ability to understand and the willingness to sign a 
written informed consent document. 
 
 
      


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Exclusion Criteria 
(From IRB approved protocol) 
 
1. Autoimmune disease requiring treatment within 
the last 5 years including systemic lupus 
erythematosus, rheumatoid arthritis, multiple 
sclerosis, Sjӧgren’s syndrome, autoimmune 
thrombocytopenia, uveitis, or other if clinically 
significant 
 
 
      
2. Major surgery or a wound that has not fully healed 
within 4 weeks of enrollment. 
 
 
      
3. History of stroke or intracranial hemorrhage 
within 6 months prior to enrollment. 
 
 
      
4. Requires anticoagulation with warfarin or 
equivalent vitamin K antagonists. 
 
 
      
5. Requires chronic treatment with strong CYP3A 
inhibitors. 
 
 
      
6. Vaccinated with live, attenuated vaccines within 
4 weeks of enrollment. 
 
 
      
7. Known history of human immunodeficiency virus 
(HIV) or active Hepatitis C Virus or active 
Hepatitis B Virus infection or any uncontrolled 
active systemic infection. 
 
 
      
8. Known CNS lymphoma. 
 
 
      
9. Subjects with a history of prior malignancy with 
the exception of non-melanoma skin cancer, 
carcinoma in situ of the cervix, in situ carcinoma 
of the bladder, stage 1 prostate cancer that does not 
require treatment, or other malignancy that has 
undergone potentially curative therapy with no 
evidence of disease for the last > 2 years and that 
is deemed by the investigator to be a low risk for 
recurrence.   
 
 
      
10. History of allergic reactions attributed to 
compounds of similar composition to SD-101 or 
ibrutinib 
 
 
      


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11. Treatment with an immunosuppressive regimen of 
corticosteroids or other immunosuppressive 
medication (eg, methotrexate, rapamycin) within 
30 days of study treatment.  Note:  subjects may 
take up to 5 mg of prednisone or equivalent daily.  
Topical and inhaled corticosteroids in standard 
doses are allowed. 
 
 
      
12. Significant cardiovascular disease (ie, NYHA 
class 3 congestive heart failure; myocardial 
infarction with the past 6 months; unstable angina; 
coronary angioplasty with the past 6 months; 
uncontrolled atrial or ventricular cardiac 
arrhythmias). 
 
 
      
13. Pregnant or breast feeding.   
 
 
      
14. Any other medical history, including laboratory 
results, deemed by the investigator to be likely to 
interfere with their participation in the study, or to 
interfere with the interpretation of the results. 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  
The method of confirmation can include, but is not limited to, laboratory test results, 
radiology test results, subject self-report, and medical record review.   
 
IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study.  This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
 
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
 
Study Coordinator Signature: 
Date: 
Printed Name: 


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APPENDIX B: 
Definition of Tumor Response Using irRC 
The sum of the products of diameters at tumor assessment using the immune-related response 
criteria (irRC) for progressive disease incorporates the contribution of new measurable lesions.  
Each net Percentage Change in Tumor Burden per assessment using irRC criteria accounts for 
the size and growth kinetics of both old and new lesions as they appear. 
Definition of Index Lesions Response Using irRC 
• irComplete Response (irCR):  Complete disappearance of all index lesions.  This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
• irPartial Response (irPR):  Decrease, relative to baseline, of 50% or greater in the sum of the 
products of the two largest perpendicular diameters of all index and all new measurable 
lesions (ie, Percentage Change in Tumor Burden).  Note:  the appearance of new measurable 
lesions is factored into the overall tumor burden, but does not automatically qualify as 
progressive disease until the SPD increases by ≥ 25% when compared to SPD at nadir. 
• irStable Disease (irSD):  Does not meet criteria for irCR or irPR, in the absence of 
progressive disease. 
• irProgressive Disease (irPD):  At least 25% increase Percentage Change in Tumor Burden 
(ie, taking sum of the products of all index lesions and any new lesions) when compared to 
SPD at nadir. 
Definition of Non-Index Lesions Response Using irRC 
• irComplete Response (irCR):  Complete disappearance of all non-index lesions.  This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria. 
• irPartial Response (irPR) or irStable Disease (irSD):  non-index lesion(s) are not considered 
in the definition of PR, these terms do not apply. 
• irProgressive Disease (irPD):  Increases in number or size of non-index lesion(s) does not 
constitute progressive disease unless/until the Percentage Change in Tumor Burden increases 
by 25% (ie, the SPD at nadir of the index lesions increases by the required amount). 
Impact of New Lesions on irRC 
New lesions in and by themselves do not qualify as progressive disease.  However their 
contribution to total tumor burden is included in the SPD which in turn feeds into the irRC 
criteria for tumor response.  Therefore, new non-measurable lesions will not discontinue any 
subject from the study. 
Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria: 
• Immune-Related Complete Response (irCR):  Complete disappearance of all tumor lesions 
(index and non-index together with no new measurable/unmeasurable lesions) for at least 
4 weeks from the date of documentation of complete response.   
• Immune-Related Partial Response (irPR):  The sum of the products of the two largest 
perpendicular diameters of all index lesions is measured and captured as the SPD baseline.  


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At each subsequent tumor assessment, the sum of the products of the two largest 
perpendicular diameters of all index lesions and of new measurable lesions are added 
together to provide the Immune Response Sum of Product Diameters (irSPD).  A decrease, 
relative to baseline of the irSPD compared to the previous SPD baseline, of 50% or greater is 
considered an immune Partial Response (irPR).   
• Immune-Related Stable Disease (irSD):  irSD is defined as the failure to meet criteria for 
immune complete response or immune partial response, in the absence of progressive 
disease.   
• Immune-Related Progressive Disease (irPD):  It is recommended in difficult cases to confirm 
PD by serial imaging.  Any of the following will constitute progressive disease: 
- At least 25% increase in the sum of the products of all index lesions over baseline SPD 
calculated for the index lesions. 
- At least a 25% increase in the sum of the products of all index lesions and new 
measurable lesions (irSPD) over the baseline SPD calculated for the index lesions. 
Table 7: Immune-Related Response Criteria Definitions 
Index 
Lesion 
Definition 
Non-Index 
Lesion 
Definition 
New 
Measurable 
Lesions 
New 
Unmeasurable 
Lesions 
% change in tumor burden 
(including measurable new 
lesions when present) 
Overall 
irRC 
Response 
Complete 
Response 
Complete 
Response 
No 
No 
-100% 
irCR 
Partial 
Response 
Any 
Any 
Any 
≥ -50% 
irPR 
< -50% to < +25% 
irSD 
>+25% 
irPD 
Stable 
Disease 
Any 
Any 
Any 
< -50% to < +25% 
irSD 
> +25% 
irPD 
Progressive 
Disease 
Any 
Any 
Any 
≥ +25% 
irPD 
 
Immune-Related Best Overall Response Using irRC (irBOR)  
irBOR is the best confirmed irRC overall response over the study as a whole, recorded between 
the date of first dose until the last tumor assessment before subsequent therapy (except for local 
palliative radiotherapy for painful bone lesions) for the individual subject in the study.  For the 
assessment of irBOR, all available assessments per subject are considered. 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a second 
(confirmatory) evaluation meeting the criteria for response and performed no less than 4 weeks 
after the criteria for response are first met. 


Protocol for Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
IRB-36750 
Page 68 of 70 
 24 January 2020 
APPENDIX C: 
ECOG Performance Status 
ECOG PERFORMANCE STATUS* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
5 
Dead 


Protocol for Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
IRB-36750 
Page 69 of 70 
 24 January 2020 
APPENDIX D:   
List of P450 inhibitors and inducers 
A comprehensive list of inhibitors, inducers, and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/   
 
This website is continually revised and should be checked frequently for updates. 
 


Protocol for Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and Local 
Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
IRB-36750 
Page 70 of 70 
 24 January 2020 
APPENDIX E: Contraception Guidelines 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
Highly effective methods of contraception have a failure rate of < 1% when used consistently 
and correctly.  WOCBP and female partners of male subjects who are WOCBP are expected to 
use one of the highly effective methods of contraception listed below.  Male subjects must 
inform their female partners who are WOCBP of the contraceptive requirements of the protocol 
and are expected to adhere to using contraception with their partner.  Male subjects are expected 
to use a condom, in addition to a highly effective method as noted in the list below: 
1.  Progestogen only hormonal contraception associated with inhibition of ovulation 
2.  Hormonal methods of contraception including oral contraceptive pills containing combined 
estrogen and progesterone, vaginal ring, injectables, implants, and hormonal intrauterine 
devices (IUDs), such as Mirena 
3.  Nonhormonal IUDs, such as ParaGard 
4.  Bilateral tubal occlusion 
5.  Vasectomized partner with documented azoospermia 90 days after procedure 
• Vasectomy is a highly effective birth control method provided that the partner is the sole 
sexual partner of the WOCBP trial participant and that the vasectomized partner has received 
medical assessment of the surgical success. 
6.  Intrauterine hormone-releasing system 
7.  Complete abstinence 
• Complete abstinence is defined as the complete avoidance of heterosexual intercourse 
• Complete abstinence is an acceptable form of contraception and must be used throughout 
the duration of the study treatment plus an additional 160 days 
• No additional method of contraception is required when complete abstinence is elected. 
• Participant WOCBP who choose complete abstinence must continue to have pregnancy 
tests at screening and within 72 hours prior to each study treatment. 
• Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the subject chooses to forego complete abstinence. 
• The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject. 
8.  Use a condom in male subjects with female partners. 
UNACCEPTABLE METHODS OF CONTRACEPTION 
1) Periodic abstinence (calendar, symptothermal, and/or post-ovulation methods) 
2) Withdrawal (coitus interruptus) 
3) Spermicide only 
4) Lactation amenorrhea method 
5) Diaphragm with spermicide 
6) Cervical cap with spermicide 
7) Vaginal sponge with spermicide 
8) Male or female condom with or without spermicide* 
9) Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action. 
* A male and a female condom must not be used together. 
 

ICF_000.pdf: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 1 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
Are you participating in any other research studies _____ Yes ______ No 
 
PURPOSE OF RESEARCH 
 
You are invited to participate in a research study of SD-101 (an immuno-
stimulatory drug), Ibrutinib (an anti-Lymphoma drug) and radiation therapy to 
treat your lymphoma. 
 
 
You were selected as a possible participant in this study because you have been 
diagnosed with either Follicular Lymphoma, Marginal Zone Lymphoma or Mantle Cell 
Lymphoma and have either been treated without improvement in your disease or 
your previous treatment worked, but now your Lymphoma is now growing once 
again.   
 
We hope to learn about the safety and tolerability of different doses of SD-101 
when directly injected into your lymphoma when combined with ibrutinib to treat 
your lymphoma.  In addition, this study aims to discover what the outcomes (good 
or bad) will be in combination with the other treatments mentioned above, 
(ibrutinib and radiation therapy).  SD-101 is a drug currently being studied for the 
treatment of B-cell lymphomas, and the efficacy of this drug for the treatment of 
follicular lymphoma, marginal zone lymphoma, and mantle cell lymphoma is not 
yet known.  Ibrutinib is a drug which has been approved by the FDA for the 
treatment of certain subtypes of B-cell lymphoma, including chronic lymphocytic 
leukemia, mantle cell lymphoma, marginal zone lymphoma and Waldenstrom’s 
macroglobulinemia.  Ibrutinib has not been approved for the treatment of follicular 
lymphoma.  
 
If you decide to terminate your participation in this study, you should notify Dr. 
Ronald Levy at (650) 725-6452.   
 
This research study is looking for a total of up to 30 patients with B cell 
lymphoma. Up to 15 patients will be enrolled in Phase I of the study; an additional 
up to 15 patients will be enrolled in Phase II, the expansion of the study. All 
patients will be enrolled at Stanford University. 
 
VOLUNTARY PARTICIPATION  
 
Your participation in this study is entirely voluntary.  Your decision not to 
participate will not have any negative effect on you or your medical care.  You 
can decide to participate now, but withdraw your consent later and stop being in 
the study without any loss of benefits or medical care to which you are entitled. 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 2 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
DURATION OF STUDY INVOLVEMENT  
 
This research study is expected to take approximately 96 weeks with follow up 
until definite progression of disease or withdrawal by you or at the Protocol 
Director’s discretion. 
 
PROCEDURES 
 
You will be screened at Stanford Cancer Center to see if you are a suitable 
candidate and meet all research criteria.  You will be given this consent to look 
over and to share with your family and/or health advocates to go over with you. 
You will be asked if you have any questions regarding the study calendar below 
and any of the events within that calendar.  You are strongly encouraged to take 
all the time you need to understand all the contents of this consent form.  This is 
a 96-week study which includes injections over a 4 week period in combination 
with local radiation to a single lymph node region site on days 1 and 2 of the 
study.  In addition, there will be a follow up period every 3-6 months which is 
standard of care to manage your disease with CTs at intervals per standard 
practice at Stanford, until disease progression or if you decide to withdraw from 
the study.  This follow up will be ongoing and you will be considered part of this 
study unless you decide to withdraw or the Principal Investigator, Dr. Ronald 
Levy, removes you from the study at his discretion.  
 
The experimental part of this study includes the following: monitored maximum 
tolerated dose of SD-101 in combination with ibrutinib and radiation therapy.  
If you withdraw from treatment due to progressive disease, you will be seen 
within four weeks of the determination of progressive disease for a final visit.  If 
you withdraw due to intolerance of treatment you will be followed weekly until all 
toxicities have stabilized in the opinion of the Investigator, at which point you will 
undergo the final visit.  If you withdraw for any reason other than progressive 
disease, you will be seen within 4 weeks of withdrawal for a final visit. 
If you choose to participate, Dr. Ronald Levy and his research study staff will 
follow this schedule of study events. 
 
Pretreatment: 
• Complete physical exam including vital signs, weight, and performance 
status (your ability to perform basic daily activities) 
• Collection of medical history 
• Monitoring of concomitant medications 
• Research blood draw and LDH 
• HIV, hepatitis B, and hepatitis C testing 
• Urine pregnancy test 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 3 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
• Safety blood labs 
• Fine needle aspiration of designated tumor lesion in the treatment site 
(Lesion A).  Fine needle aspiration biopsies of additional lesions may be 
performed if accessible to needle biopsy 
• Meeting with Radiation Oncologist 
• Imaging by CT scan or PET/CT scan to assess extent of disease as 
indicated by study protocol 
• A surgical biopsy may be performed, to exclude the possibility of a more 
aggressive type of lymphoma, if medically necessary.  In this case, or 
potentially in the case that you have lymphoma cells in your blood, we 
would also collect blood cells by a procedure called apheresis. 
 
Day 1: 
• First treatment of radiotherapy (2 Gy) to the designated tumor lesion 
(lesion A) 
 
Day 2:  
• Obtain vital signs  
• Assessment of adverse events 
• Monitoring of concomitant medications (medications currently being 
taken) 
• Second treatment of radiotherapy (2 Gy) 
• Intratumoral injection of SD-101 to lesion A (within 12 hours of 
radiotherapy) 
 
Day 4 (+/- 1 day) 
• Fine needle aspiration of accessible tumor may be performed (optional)  
 
Day 9 (+/- 2 days) 
• Obtain vital signs  
• Assessment of adverse events and toxicity  
• Monitoring of concomitant medications (medications currently being 
taken) 
• Routine safety labs 
• Fine needle aspiration of accessible tumor for research studies. If 
additional (untreated) sites of disease are safely accessible by fine needle 
aspiration, an untreated tumor lesion may be biopsied also (optional). To 
be performed prior to intratumoral injection #2 
• Intratumoral injection of SD101 to lesion A 
• Collection of 8 research blood draw tubes 
• Distribution of first month supply of ibrutinib 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 4 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
Day 16 (+/- 2 days)  
• Obtain vital signs  
• Assessment of adverse events and toxicity  
• Monitoring of concomitant medications (medications currently being 
taken) 
• Collection of 7 research blood draw tubes 
• Intratumoral injection of SD101 to lesion A 
 
Day 23 (+/- 2 days), Day 30 (+/- 2 days)  
• Obtain vital signs  
• Assessment of adverse events and toxicity  
• Monitoring of concomitant medications (medications currently being 
taken) 
• Intratumoral injection of SD101 to lesion A (both week 4 and 5) 
• Routine safety labs (week 4 only) 
• Collection of 1 research blood draw tube (week 4 only) 
 
Day 37 (+/- 7 days) 
• Obtain vital signs 
• Assessment of adverse events and toxicity  
• Monitoring of concomitant medications (medications currently being 
taken) 
• Routine safety labs  
• Fine needle aspiration of the treated site (lesion A) for research studies, if 
lesion A remains after treatment.  In addition, if other untreated sites of 
disease are safely accessible via fine needle aspiration, these may be 
biopsied.  
• Collect of 8 research blood draw tubes 
• Distribution of six week supply of ibrutinib  
• If a surgical biopsy was performed before treatment, apheresis will be 
repeated 
 
Week 12 and every 12 weeks thereafter until week 96 (+/- 10 days 
for each timepoint): 
• Physical exam to assess clinical response to treatment  
• Obtain vital signs 
• Assessment of adverse events and toxicity  
• Monitoring of concomitant medications (medications currently being taken) 
• Routine safety labs and LDH 
• Collect of 1 or 8 research blood draw tubes 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 5 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
• Determination of response to treatment with CT scans of the chest/ 
abdomen/ pelvis (and neck, if needed); CT scans will be performed weeks 
12, 24, 48, 72. 
• Distribution of ibrutinib supply  
• If there is no evidence of disease on the CT scan, a bone marrow biopsy 
will be obtained to document whether a complete response is achieved. 
• If participant has progressive disease, FNA of accessible tumor may be 
performed (optional). 
 
Final study visit: 
• Physical exam to assess clinical response to treatment  
• Obtain vital signs 
• Assessment of adverse events and toxicity  
• Monitoring of concomitant medications (medications currently being taken) 
• Routine safety labs and LDH 
• Collect of 8 research blood draw tubes 
• If there has not been a recent CT scan, then response to treatment will be 
assessed with CT scans of the chest/ abdomen/ pelvis (and neck if 
needed) 
• If progressive disease, FNA will be performed on an accessible tumor site 
for research studies – (optional). 
• If there is no evidence of disease on the CT scan, a bone marrow biopsy 
will be obtained to document whether a complete response is achieved. 
 
Dosing of Ibrutinib: 
All participants will take 560mgs of ibrutinib daily, in the form of during the ibrutinib 
treatment period, which starts at day 10 and ends at week 96 or until progression or 
treatment is ended for other reasons before week 96. 
 
Dosing of SD101: 
Phase I participants: The first 6 participants will receive 3mgs of SD-101.  If a less 
than a third of these first 6 participants experience a serious side effect, then no 
additional participants will be enrolled in Phase I, and Phase II participants will 
receive 3mgs of SD 101. 
 
Phase II participants: The dose of this group of 15 participants will receive 3mgs or 
1 mg of SD101, based on the best dosage determined from Phase I. 
 
Other procedures: 
CT (computerized tomography) scans: create pictures of the inside of your 
body. CT scans use an x-ray machine together with a special dye injected into a vein 
in your arm before the scan. CT scans will occur at the Screening visit, and 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 6 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
approximately every 3-6 months after your first study treatment, for the rest of the 
study or at time if your doctor suspects your Lymphoma is getting worse. CT scans 
are standard of care for lymphoma.   
 
Bone marrow aspiration and biopsy: First, an area of the hip is numbed, then a 
needle is inserted into the hip bone to collect the sample. This procedure is done to 
determine if your lymphoma has spread to the bone marrow.  This may be required 
if your CT scan shows no evidence of residual lymphoma to determine whether 
there is still lymphoma within the bone marrow. 
 
Localized Low-dose Radiation Therapy: is a procedure that uses high energy 
radiation like x-rays to kill cancer cells. Low dose radiation (locally to the area of one 
site of one lesion; 2 Gy** x 2) is being given to help SD-101 to increase your 
immune system to fight your lymphoma.  You will receive 2 treatments of low dose 
radiation at Day 1 and Day 2.  In addition, the injection of SD-101 will be given on 
Day 2 within 12 hours of radiotherapy. As this injection will be in a different location 
in the Cancer Center from where you receive your radiotherapy at Stanford, we 
hope at best to have your wait be less than 2 hours. 
**2 Gray (Gy) has the equivalent radiation dose of approximately 10000 
x-rays. This radiation is localized only to the treatment area. 
 
Apheresis (only for patients with pre-treatment biopsy): This procedure is 
similar to donating blood but allows certain parts of your blood to be collected while 
the red blood cells are returned to you.  A needle is placed in each arm and you will 
spend 3-5 hours resting in a chair while the blood is collected from one arm and 
returned to the other arm.  (Patients usually watch a movie or two during the 
procedure). 
 
Specimens Collection: Blood and Tissue (Lymph Node samples) 
• Blood samples (up to 6 tablespoons) will be taken from a vein in your arm at 
each study visit. 
• Fine needle aspirates (FNA) involves the insertion of a needle into the tumor 
to collect a sample. We will do this from the tumor that we treat and, if 
possible from a tumor that we do not treat at screening and weeks 2, 8 and at 
the end of the study if there is residual tumor. 
• If you are able to become pregnant, you will be asked to have a pregnancy 
test done before beginning this research study. 
 
 
HIV/Hepatitis/HCV You will have a blood tests for HIV, Hepatitis B and Hepatitis 
C during screening.  Positive results will be reported to the local health agency. If 
you test positive for HIV, counseling will be provided. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 7 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
Tissue Sampling for Research: The investigators would like to include your 
tissues in research on lymphoma and they want to save the samples for future 
research.  There are several things you should know before allowing your tissues to 
be studied.   
 
You have the right to refuse to allow your tissues to be studied now or saved for 
future study. If you withdraw your permission, the investigators might retain the 
samples as part of your routine clinical care, but not for additional research.  
In order to protect your identity, your study doctor will assign you a unique code, 
such as a series of numbers and/or letters. Your tissue will be stored under this 
code.  Your study doctor will keep a confidential list linking your name or medical 
record number to your code number and only authorized persons will have access to 
this list.  
 
You will be told the results of tests that are part of your clinical care, but you will not 
be told the results of the research tests, including any future research tests. Any of 
your samples which are used in research may result in new products, tests or 
discoveries. In some instances, these may have potential commercial value and may 
be developed and owned by the Investigators, Stanford University, Dynavax 
Technologies Corporation, Janssen Scientific Affairs, LLC and/or others.  Donors of 
samples do not retain any property rights to the materials.  Therefore, you would 
not share in any financial benefits from these products, tests or discoveries.  Please 
mark one of the following statements with your initial.   
 
 
_____ I consent to my samples being saved for future research 
 
Initial  
 
_____ I do not consent to my samples being saved for future research 
 
Initial 
 
Women of Childbearing Potential (see risks below) 
If you are a woman who is able to become pregnant, it is expected that you will 
use an effective method of birth control to prevent exposing a fetus to a 
potentially dangerous agent with unknown risk.  If you are pregnant or currently 
breast feeding, you may not participate in this study.  You understand that if you 
are pregnant, if you become pregnant, or if you are breast-feeding during this 
study, you or your child may be exposed to an unknown risk.  
 
To confirm to the extent medically possible that you are not pregnant, you agree 
to have a urine pregnancy test done before beginning this research study.  You 
must agree to avoid sexual intercourse or use a birth control method judged to be 
effective by the investigator and which will not interfere with the proposed 
investigation.  You must accept the risk that pregnancy could still result despite 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 8 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
the responsible use of reliable method of birth control.  You agree to notify the 
investigator as soon as possible of any failure of proper use of your birth control 
method, or if you become pregnant, either of which may result in your being 
withdrawn from the study. 
 
If you are a man participating in this study and your partner is able to become 
pregnant, you and your partner must use adequate contraception while you are 
participating in the study.  Your doctor will discuss with you what methods of 
birth control are considered adequate.  You should inform your study doctor if 
your partner becomes pregnant. Men must agree to not donate sperm during 
and after the study. 
 
PARTICIPANT RESPONSIBILITIES           
 
As a participant, your responsibilities include:  
• Follow the instructions of the Protocol Director and study staff. 
• Ask questions at your visits and/or by contacting the study 
staff/research coordinator 
• Keep your study appointments.  If it is necessary to miss an appointment, 
please contact the Protocol Director or research study staff to reschedule 
as soon as you know you will miss the appointment. 
• Tell the Protocol Director or research study staff about any side effects, 
doctor visits, or hospitalizations that you may have. 
• Tell the Protocol Director or research staff if you believe you might be 
pregnant or gotten your partner pregnant. 
• Take the study drug as instructed. 
• Keep the study drug in a safe place, away from children and for your use 
only. 
• Ask questions as you think of them. 
• Tell the Protocol Director or research staff if you change your mind about 
staying in the study. 
 
WITHDRAWAL FROM STUDY 
 
Participation in the study is entirely your choice. If you first agree to participate and 
then you change your mind, you are free to withdraw your consent and discontinue 
your participation at any time.  Your decision will not affect your ability to receive 
medical care for your disease and you will not lose any benefits to which you would 
otherwise be entitled.  
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 9 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
If you decide to withdraw from this study, you should notify the study staff at (650) 
725-8589. You may also want to speak directly with the Dr. Ronald Levy at 650- 
725-6452. 
 
If you choose to withdraw, or are withdrawn from the study, you will be asked to 
return to the study clinic for at least one final visit assessment as part of the study’s 
ongoing safety evaluations. All study-related supplies, including unused study drug, 
must be returned to the study personnel. 
 
The Protocol Director may also withdraw you from the study without your 
consent for one or more of the following reasons:   
o Failure to follow the instructions of the Protocol Director and 
study staff. 
o The Protocol Director decides that continuing your participation 
could be harmful to you. 
o Pregnancy  
o You need treatment not allowed in the study. 
o The study is cancelled.  
o Other administrative reasons. 
o Unanticipated circumstances. 
 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
 
There are risks, discomforts, and inconveniences associated with any research study.  
These deserve careful thought.  You should talk with the Protocol Director, Dr. 
Ronald Levy if you have any questions. 
 
Drugs may have side effects. The drug used in this study may cause some or all of 
the side effects listed below.  There may also be side effects that we cannot predict at 
this time. 
 
SD-101   
As of July 12th, 2019, SD-101 has been tested in 358 subjects, including healthy 
volunteers, patients with chronic hepatitis C, and patients with cancer. In most of 
these patients, the SD-101 was given with other experimental or approved therapies. 
In all these studies, the SD-101 was injected either under the skin or into a tumor 
(intratumoral). 
 
Side effects that have been reported in people who have received SD-101 injections 
include the following: 
• Fatigue 
• Fever, Chills 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 10 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
• Malaise 
• Headache 
• Redness, pain, itching or swelling at injection site 
• Nausea and/or vomiting 
• Diarrhea or constipation 
• Muscle aches 
• Joint pains, neck pain, back pain 
• Rash, itching 
• Other flu-like symptoms 
• Anemia, low neutrophils, low platelets 
• Decreased appetite, dehydration 
• Abdominal discomfort 
• Cough, nasal congestion 
• Mouth pain, throat pain 
• Night sweats 
• Bruising 
• Dizziness 
• Shortness of breath 
• Ankle/leg swelling 
• Infections 
• Changes in laboratory values without clinical signs or symptoms 
 
Other side effects, which were uncommon (occurred in one patient each), included 
hyperthyroidism (overactive thyroid gland), pneumonitis (lung inflammation), 
pituitary dysfunction, atrial fibrillation (abnormal heart rhythm), septic shock and 
hypothyroidism (low thyroid function). These all occurred in patients also receiving 
another treatment at the same time. 
 
There also may be changes in other blood characteristics and components. You 
will be monitored for any of these changes.   
 
Ibrutinib  
The side effects listed below have been reported by patients who have received 
ibrutinib in clinical trials:  
 
The most common side effects, occurring in at least 1 of every 5 patients ( 20%),, 
have been:  
Occurrence or increase in frequency of loose or watery stools (Diarrhea)  
Muscle and bone pain (Musculoskeletal pain) 
Nausea 
Low white blood cell count (cells that help fight infection) (Neutropenia) 
Bleeding (Haemorrhage) 
Rash 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 11 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
Fever (Pyrexia) 
Low platelet count (cells that help blood to clot) (Thrombocytopenia) 
Common cold (Upper Respiratory Tract Infection) 
 
 
Side effects that have been seen in at least 1 of every 10 ( 10%) patients include:  
Pneumonia 
Constipation 
Swelling of the hands or feet (Oedema peripheral)  
Muscle spasms  
Vomiting 
Joint aches (Arthralgia) 
Sores in mouth (Stomatitis) 
Headache 
High Blood pressure (Hypertension) 
Skin infection 
Weakness, tingling, numbness, and pain from nerve damage, usually in the hands and 
feet (Peripheral neuropathy) 
Urinary tract infection 
Dizziness 
 
Side effects that have been seen in at least 1 of every 100 ( 1%) patients include:  
Sinus infection (Sinusitis) 
Increased level of uric acid in the blood (Hyperuricemia) 
Abnormal heart rhythm (Atrial fibrillation) 
Non-melanoma skin cancer 
Blurry vision (Vision blurred)  
Low white blood cell counts with fever (Febrile neutropenia) 
Severe infection throughout the body (Sepsis) 
Redness of the skin (Erythema) 
Increase in specific white blood cell counts (Leukocytosis, Lymphcytosis) 
Breaking of the nails (Onychoclasis)  
Inflammation within the lungs that may lead to permanent damage (Interstitial lung 
disease)  
Increased level of “creatinine” in the blood (blood creatinine increased) 
 
Side effects that have been seen in less than 1 of every 100 (<1%) patients 
include: 
Unusual levels of chemicals in the blood caused by the fast breakdown of cancer 
cells, which may lead to changes in kidney function, abnormal heartbeat, or 
seizures. (Tumor lysis syndrome) 
Itchy rash (Urticaria)  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 12 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
Inflammation of the fatty tissue underneath the skin (Panniculitis) 
Swollen face, lip, mouth, tongue, or throat (Angioedema)  
High WBC count with abnormal clumping that can lead to bleeding (Leukostasis 
syndrome) 
Severe rash with blisters and peeling skin, particularly around the mouth, nose, 
eyes, and genitals (Stevens-Johnson syndrome)  
Liver failure (Hepatic failure) 
Abnormal rapid and/or irregular heart rhythm that starts from the lower chambers 
(ventricles) of the heart (Ventricular tachyarrhythmias). 
Temporary or permanent decrease of brain or nerve function due to reduced blood 
flow to the brain (mini-stroke or stroke) 
 
Most of these side effects listed above have been mild to moderate in severity; 
however severe side effects have occurred. Some side effects have been severe 
enough to lead to study drug discontinuation, dose modification or reduction, 
hospitalization, disability, and sometimes death.  
 
You should tell your study doctor or medical team about any side effects you are 
having. Your study doctor may be able to give you medications to help treat the side 
effects and prevent them from becoming worse. Your study doctor may also choose 
to stop ibrutinib for a short time or reduce its dose to allow you to recover from any 
side effects.  
  
Bleeding 
You may experience bruising or nosebleeds during treatment with IMBRUVICA. 
Rarely, serious internal bleeding, such as bleeding in your stomach, intestine, or brain 
may occur, sometimes resulting in death. If you take other medicines or supplements 
that increase your risk of bleeding, such as aspirin, non-steroidal anti-inflammatory 
drugs (NSAIDs) or medicines used to prevent or treat blood clots or stroke, ibrutinib 
may increase this risk. Blood thinners such as warfarin or other vitamin K antagonists 
should not be taken together with ibrutinib. Supplements such as fish oil and vitamin 
E preparations should be avoided while taking ibrutinib. Call your study doctor if you 
have signs or symptoms of serious bleeding, such as blood in your stools or urine or 
bleeding that lasts for a long time or that you cannot control. 
 
Effects on the heart 
Abnormal heartbeats (atrial fibrillation and/or atrial flutter with some fatal events) 
have been reported in patients treated with ibrutinib, especially when they also have 
heart conditions, increased blood pressure, acute infections, or had abnormal 
heartbeat in the past. Atrial fibrillation/flutter is a common type of abnormal 
heartbeat. The heartbeat may be fast or irregular causing symptoms such as a 
pounding or racing heart, dizziness, weakness, feeling light-headed or shortness of 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 13 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
breath. You should tell your study doctor immediately if you develop any of these 
symptoms while on the study drug.  
 
 
 
Infections 
You may experience viral, bacterial, or fungal infections during treatment with 
ibrutinib. Some of these infections have led to hospitalization and death. Contact your 
study doctor immediately if you have fever, chills, weakness, confusion, body aches, 
cold or flu symptoms, vomiting, jaundice, feel tired or feel short of breath - these 
could be signs of an infection. Your study doctor may start or continue medication to 
help prevent or treat an infection. 
 
A rare and usually fatal viral disease in the brain, Progressive Multifocal 
Leukoencephalopathy (PML), has been reported in patients treated with ibrutinib in 
combination with rituximab and in patients who were previously treated with 
rituximab. If you experience symptoms such as weakness, paralysis, vision loss and/or 
impaired speech, you should tell your study doctor immediately. 
 
Lymphocytosis and leukostasis 
You may experience an increase in the number of lymphocytes, which is a specific 
type of white blood cell, in your blood (lymphocytosis). This may occur in the first few 
weeks of treatment and you should not assume that this increase in white blood cells 
means that your disease is worsening. This increase may last for several weeks to 
months. In rare cases, increased number of white blood cells in your bloodstream 
may alter blood flow resulting in bleeding or clotting (leukostasis). Isolated cases of 
these events have been reported in patients treated with ibrutinib. Your study doctor 
will monitor your blood counts and may administer additional therapy as needed. Talk 
to your study doctor about what your test results mean.  
 
Decreased blood counts  
Severe decreases in white blood cells, red blood cells, and platelets (neutropenia, 
anemia, and thrombocytopenia) were reported in subjects treated with ibrutinib. If 
you experience symptoms such as fever, weakness, or easy bruising and/or bleeding, 
you should tell your study doctor immediately. 
 
Allergic reactions  
Sometimes people have allergic reactions to drugs. Serious allergic reactions can be 
life-threatening. If you have an allergic reaction to ibrutinib, you might develop a 
rash, difficulty breathing, wheezing when you breathe, sudden low blood pressure 
with light-headedness, swelling around the mouth, throat or eyes, a racing heartbeat, 
and/or sweating.  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 14 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
 
Before starting the study drug, you must tell your study doctor about any drug 
allergies. You should tell the study doctor right away if you have any allergy 
symptoms listed above.  
 
Rash 
A maculopapular rash (flat, red areas on the skin with small bumps) has been 
commonly reported in patients treated with ibrutinib alone or in combination with 
other drugs. Most rashes are mild to moderate in severity and begin 2 to 3 weeks or 
longer after starting ibrutinib.  
 
There have been rare reports of severe skin reactions (known as severe cutaneous 
adverse reaction or “SCAR”, involving more than 50% of the body) or rash with 
blisters and peeling skin, which may include open ulcers or sores in the mouth and 
other areas of the body (Stevens-Johnson Syndrome). These skin rashes could be life-
threatening. You should notify your study doctor immediately if you develop a rash 
that spreads quickly, or if you notice peeling of your skin, with or without ulcers or 
sores in your mouth. 
 
Non Melanoma Skin Cancer and Other Cancers 
Non melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma of the 
skin) have been reported with more frequency and maybe related to the use of 
ibrutinib. Other cancers have been reported such as solid tumors and blood cancers 
the relationship to the use of ibrutinib is unknown.  You should tell your study doctor 
if you develop a new cancer while in the study.  
 
Tumor Lysis Syndrome (TLS) 
Unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells 
have happened during treatment of cancer and sometimes even without treatment. 
This may lead to changes in kidney function, abnormal heartbeat, or seizures. Your 
study doctor may do blood tests to check for TLS. 
 
Hypertension 
Hypertension is also called high blood pressure, and has been commonly reported 
in subjects treated with ibrutinib. Sometimes, people with high blood pressure may 
have headaches, dizziness, nervousness, sweating, difficulty in sleeping, facial 
flushing or nosebleeds, but in some cases, there may be no symptoms and it may 
go undetected. After starting ibrutinib, your doctor may measure your blood 
pressure regularly. You should let your study doctor know if you have any of the 
symptoms of high blood pressure which may mean that you have developed 
hypertension or that your hypertension is getting worse. Your study doctor may 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 15 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
adjust existing anti-hypertensive medications and/or initiate anti-hypertensive 
treatment as appropriate. 
 
Stroke 
Cases of stroke, with and without changes in heartbeat rhythm and/or hypertension 
have been reported with the use of ibrutinib.  Some of these cases have led to death. 
Seek immediate medical attention if you notice or someone notices in you: sudden 
numbness or weakness in the limbs (especially on one side of the body), sudden 
confusion, trouble speaking or understanding speech, sight loss, difficulty walking, 
loss of balance or lack of coordination, sudden severe headache with no known cause. 
These may be signs and symptoms of stroke. 
 
Liver Failure 
Rare cases of liver failure have been reported in patients treated with ibrutinib. 
Symptoms of liver failure include yellowing of the eyes and skin (Jaundice), itching of 
the skin, dark colored urine, gray or clay-colored stools, confusion, nausea , loss of 
appetite, fatigue or diarrhea,. You should tell your study doctor immediately if you 
have any of these symptoms which may suggest liver disease. Your study doctor may 
be able to diagnose and provide you required medical care. 
 
Interstitial lung disease 
Interstitial lung disease is a group of lung disorders in which the tissues become 
inflamed and may become damaged. Interstitial lung disease is not associated with 
infections (e.g, bacteria, viruses, fungi) and has been reported in patients treated 
with ibrutinib. You should report to your physician if you have cough, any signs of 
new or worsening respiratory symptoms such as shortness of breath or difficulty 
breathing.  
 
Interference with other drugs  
Some foods like grapefruit juice and Seville oranges, as well as some medications, 
may interfere with the way your body processes ibrutinib. This interference could 
cause the amount of ibrutinib in your body to be higher or lower than expected. It is 
also possible that taking the study drug with your regular medications or supplements, 
including fish oil, Vitamin E, or other vitamins, may change how your regular 
medications, or your regular supplements, work. It is very important that you avoid 
grapefruit juice and Seville oranges and tell the study doctor about all medications, 
supplements, or herbal medicine like St. John’s wort that you are taking during the 
study. You should notify your study doctor immediately about any side effects to 
avoid possible harm.  
 
Drug interruption for any surgical procedures  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 16 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
Ibrutinib may increase the risk of bleeding with any surgical procedure. Ibrutinib 
should be held at least 3 to 7 days before and after surgery depending upon the type 
of surgery and the risk of bleeding. Please contact your study doctor if you have any 
planned surgical procedures. For emergency surgical procedures, ibrutinib should be 
discontinued (stopped) after the procedure until the surgical site is reasonably healed 
(not oozing fluid). 
 
Please contact your study doctor as soon as possible and your study doctor will tell 
you when to stop ibrutinib and when to restart it following a surgical procedure. 
 
In addition to the risks listed above, there could be unknown or unexpected side 
effects associated with the use of ibrutinib. You will be told in a timely manner, 
verbally and in writing, of any new information, findings, or changes to the way the 
research will be done that might influence your willingness to continue your 
participation in this study.  
 
You may have all, some, or none of the listed side effects of ibrutinib. Your study 
doctors and nurses will check you closely for side effects. You may receive medicines 
or other treatments to prevent or reduce some of these effects. Please tell the study 
doctor or study staff right away if you have any side effects. Please tell them if you 
have any other problems with your health or the way you feel during the study, 
whether or not you think they are related to the study drug.  
 
You should get medical help and contact the study doctor or study staff if you have 
any of these or any other side effects during the study.  
 
Reproductive effects  
The effects of ibrutinib on a developing baby are unknown; therefore women who are 
pregnant or nursing are not allowed to be in this study. Nobody knows what these 
risks are right now. Some drugs cause women to have their babies prematurely 
(early) or to have babies with birth defects.  
 
Women: If you are able to have children, you must use a highly effective method of 
birth control and a barrier method while taking study treatment, as well as for 1 
month after you stop taking study treatment, to prevent pregnancy in either you or 
your partner. A “highly effective method of birth control” is defined as a method that 
has a low failure rate (ie, less than 1% per year) when used consistently and correctly 
and includes implants, injectables, birth control pills with 2 hormones, some 
intrauterine devices (IUDs), sexual abstinence (which is defined as refraining from all 
aspects of sexual activity) or a sterilized partner. If you are using hormonal 
contraceptives such as birth control pills or devices, a second barrier method of 
contraception (eg, condoms) must be used.  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 17 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
 
Men: You must use a barrier method while on treatment with ibrutinib and for 3 
months after the last dose of treatment to prevent pregnancy of your partner. 
 
Note: Some birth control pills may not work when you are taking certain drugs. If you 
have any questions about this, please discuss this with the study doctor.  
 
Be aware that you can still become pregnant even if you use a highly effective 
method of birth control.  
 
Men: If your partner becomes pregnant while you are on study treatment, or within 3 
months of your last dose of ibrutinib, you must notify the study staff. The study staff 
will discuss this with you further. You should not donate sperm while you are taking 
the study drug and for 3 months after you stop taking the study drug.  
 
Women: If you become pregnant while you are on study treatment or within 1 month 
of your last dose of ibrutinib you must notify the study staff. If you become pregnant 
on the study, you must immediately stop taking the study treatment. The protocol 
director will continue to collect information about your pregnancy and the birth of 
your baby even after study treatment is stopped. 
 
Breast-feeding 
It is not known whether ibrutinib or its metabolites are excreted in human milk. 
Because many drugs are excreted in human milk and because of the potential for 
serious adverse reactions in nursing infants from ibrutinib, breast-feeding should be 
discontinued during ibrutinib treatment. 
 
As with any drug, you may experience an allergic reaction or may have other 
reactions that are not expected or have not been seen before.  Symptoms of an 
allergic reaction include a rash, hives, itching, and/or difficulty breathing, closing of 
the throat, swelling of the lips, tongue or face, and rarely, death.  You will be 
monitored carefully at the study site for signs of an allergic reaction after all study 
injections. Trained medical personnel and emergency equipment are available at the 
study site to treat you in the event of an allergic reaction.  If you have a significant 
allergic to the drug, the drug may be discontinued permanently for your safety. If the 
doctors feel the reaction was not significant enough to require discontinuation, they 
will discuss this with you and obtain your explicit consent again prior to re-starting 
treatment. If you think you are having a severe allergic reaction after you 
leave the study center, call 9-1-1 and seek medical attention immediately. 
 
Blood Sample Collection 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 18 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
We will collect up to 6 tablespoons of blood for testing at each study visit over the 
course of the trial.  Blood collection may cause pain and bruising at the site of vein 
puncture, inflammation of the vein, and infection; care will be taken to avoid these 
complications. Collection can also cause redness, temporary pain and sometimes 
bruising. Fainting or infection may also occur, however these side effects from blood 
collections are rare.   
 
Fine Needle Aspirate (FNA) Lymph node aspirate may cause pain, bruising and/or 
bleeding at site of biopsy, infection, inflammation and swelling; care will be taken to 
avoid these complications. 
 
Standard radiological test (CT) 
 
For a CT scan, a dye is injected into your vein before the scan.  Most patients 
feel a sensation of warmth, a funny metallic taste in their throat, nausea and a feeling 
of warmth. Some patients develop hives and itching, but this rarely needs to be 
treated with antihistamines. 1 in 500 patients may develop a severe reaction which 
may have to be treated with medications. These reactions may involve tightness in 
the throat, facial swelling, difficulty breathing, drop in blood pressure, or even a 
seizure. Medical personnel who perform the scans are trained to treat you if any bad 
reaction occurs.  
 
Localized radiation therapy (RT): Radiation therapy is painless. Side effects from 
radiation are usually limited to the area of the patient's body that is under treatment. 
The main side effects are fatigue and skin irritation, like a mild to moderate sun burn. 
The fatigue can last for weeks after treatment ends. The irritated skin will heal, but 
may not be as elastic as it was before. With the low dose of radiation used in this 
study we do not expect any of these side effects. 
 
Bone marrow aspiration and biopsy: This biopsy may cause pain and bruising at 
the site of puncture, inflammation, pain, and infection; care will be taken to avoid 
these complications. Other side effects may include bleeding at the biopsy site. If you 
have bleeding problems, pressure will be put on the biopsy site to stop the bleeding. 
 
Pregnancy Risks: There is no information about the risks of SD-101 on pregnancy 
or to the developing baby; therefore it is important that during the study, you do not 
get pregnant. If you are pregnant or currently breast-feeding, you may not participate 
in this study. In addition to pregnancy tests you will be asked to take before 
beginning the study and during the study, you must agree to avoid sexual intercourse 
or use birth control methods judged to be effective by the investigator and which will 
not interfere with the proposed investigation.  You must accept the risk that 
pregnancy could still result despite the responsible use of reliable method of birth 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 19 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
control.  You agree to notify the investigator as soon as possible if you do not use 
your birth control method, or if you become pregnant, either of which may result in 
your being withdrawn from the study. By agreeing to participate in this study, you are 
also allowing the study staff to ask follow-up questions and request medical records 
about your pregnancy and its outcome (for example, type of birth, number of babies 
and health of baby[ies]) 
 
POTENTIAL BENEFITS                              
 
This research study is being conducted to understand the safety, and potential good 
effect of SD-101 in combination with Ibrutinib and Radiation therapy for low-grade B-
cell lymphoma.  Knowledge gained from this study may also help to develop this 
therapy for other people with Lymphoma. 
 
The investigational drug SD-101 in combination with Ibrutinib may stimulate your 
immune system to fight your lymphoma. However, there is no assurance that this will 
happen.  There is a chance that your health could get worse or stay the same while 
you are participating in the study.  
 
We cannot and do not guarantee or promise that you will receive any benefits from 
this study. 
 
ALTERNATIVES 
 
You do not have to participate in this study to receive treatment for your lymphoma. 
If you choose not to participate in this study, there may be other treatments available 
to you. You may discuss alternative treatments and their risks and benefits with your 
study doctor. 
 
PARTICIPANT’S RIGHTS 
 
You should not feel obligated to agree to participate.  Your questions should be 
answered clearly and to your satisfaction.  If you decide not to participate, tell the 
Protocol Director.   
 
You will be told of any important new information that is learned during the course 
of this research study, which might affect your condition or your willingness to 
continue participation in this study. 
 
ClinicalTrials.gov 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 20 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law.  This Web site will not include information that can 
identify you.  At most, the Web site will include a summary of the results.  You can 
search this Web site at any time. 
 
 
 
CONFIDENTIALITY 
 
The purpose of this research study is to obtain data or information on the safety 
and effectiveness of CpG SD-101 in combination with ibrutinib and local radiation 
therapy; the results will be provided to the trial supporters Janssen Scientific 
Affairs, LLC, Dynavax Technologies Corporation, the NIH, the Food and Drug 
Administration and other federal and regulatory agencies as required. 
 
The results of this research study may be presented at scientific or medical 
meetings or published in scientific journals.  Your identity and/or your personal 
health information will not be disclosed except as authorized by you or as required 
by law.  However, there is always some risk that even de-identified information 
might be re-identified.  
 
Patient information may be provided to the trial supporters, Dynavax Technologies 
Corporation and Janssen Scientific Affairs, LLC, Federal and other regulatory 
agencies as required.  The Food and Drug Administration (FDA), for example, may 
inspect research records and learn your identity if this study falls within its 
jurisdiction. 
 
CERTIFICATE OF CONFIDENTIALITY 
This research is covered by a Certificate of Confidentiality from the National 
Institutes of Health. The researchers with this Certificate may not disclose or use 
information, documents, or biospecimens that may identify you in any federal, 
state, or local civil, criminal, administrative, legislative, or other action, suit, or 
proceeding, or be used as evidence, for example, if there is a court subpoena, 
unless you have consented for this use. Information, documents, or biospecimens 
protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that 
requires disclosure (such as to report child abuse or communicable diseases but 
not for federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings, see below); if you have consented to the disclosure, including for 
your medical treatment; or if it is used for other scientific research, as allowed by 
federal regulations protecting research subjects. 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 21 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
The Certificate cannot be used to refuse a request for information from personnel 
of the United States federal or state government agency sponsoring the project 
that is needed for auditing or program evaluation by the NIH which is funding this 
project or for information that must be disclosed in order to meet the requirements 
of the federal Food and Drug Administration (FDA). You should understand that a 
Certificate of Confidentiality does not prevent you from voluntarily releasing 
information about yourself or your involvement in this research. If you want your 
research information released to an insurer, medical care provider, or any other 
person not connected with the research, you must provide consent to allow the 
researchers to release it. 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 22 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
Authorization To Use Your Health Information For Research 
Purposes 
Because information about you and your health is personal and 
private, it generally cannot be used in this research study without 
your written authorization.  If you sign this form, it will provide that 
authorization.  The form is intended to inform you about how your 
health information will be used or disclosed in the study.  Your 
information will only be used in accordance with this authorization 
form and the informed consent form and as required or allowed by 
law.  Please read it carefully before signing it.   
 
What is the purpose of this research study and how will my 
health information be utilized in the study? 
We hope to learn about the safety and tolerability of dose levels of 
intratumoral injections (into your tumor site) of SD-101 in combination 
with Ibrutinib and local radiation to treat your low-grade, B-cell 
lymphoma.  In addition, this study has been designed to discover what 
the outcomes (good or bad) will be in combination with the other 
treatments mentioned above, (ibrutinib and radiation therapy). Your 
information will be kept in a secure location at Stanford University 
Medical Center, accessible only to research authorized personnel. The 
patient identity will be kept as confidential as possible as required by 
law. Except as required by law, the patient will not be identified by 
name, social security number, address, telephone number, or any 
other  direct personal identifier. Study patients will be assigned an ID 
code that will consist of a three digit number. Information about the 
code will be kept in a secure location and access limited to research 
study personnel. The results of this research study may be presented 
at scientific or medical meetings or published in scientific journals. 
However, the patient identity will not be disclosed. Your personal data 
which may be included in the investigator’s database shall be treated 
in compliance with all applicable laws and regulations. 
 
Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, 
you will not be able to participate in this research study, including 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 23 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
receiving any research-related treatment.  Signing the form is not a 
condition for receiving any medical care outside the study. 
 
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your 
authorization regarding the use and disclosure of your health 
information (and to discontinue any other participation in the study) 
at any time.  After any revocation, your health information will no 
longer be used or disclosed in the study, except to the extent that 
the law allows us to continue using your information (e.g., necessary 
to maintain integrity of research).  If you wish to revoke your 
authorization for the research use or disclosure of your health 
information in this study, you must write to:  
Dr. Ronald Levy at 269 Campus Drive, CCSR 1105, Stanford, CA 
94305  
 
What Personal Information Will Be Obtained, Used or 
Disclosed? 
PHI that may be used and disclosed in connection with this research  
study will include but not be limited to, information on the past 
treatment of your disease and any future, tests, examinations, and 
treatment that you receive as part of this study. This may include 
blood and urine tests, physical examinations, measurements of your 
tumor, results of analysis of your tumor samples, study drugs that 
are administered and side effects. This health information may 
include identifiers such as name, date of birth, geographical location, 
medical record number, and participant number. 
 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your 
health information in connection with this research study: 
• The Protocol Director Ronald Levy, MD  
• The Stanford University Administrative Panel on Human 
Subjects in Medical Research and any other unit of Stanford 
University as necessary 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 24 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
• Research Staff which may include lab staff, study coordinators, 
research nurses, data mangers, pharmacists, and the radiology 
department. 
 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your 
health information to the following persons and organizations for 
their use in connection with this research study:  
• The Office for Human Research Protections in the U.S. 
Department of Health and Human Services 
• National Institutes of Health (NIH) 
• The U.S. Food and Drug Administration (FDA) 
• Dynavax Technologies Corporation 
• Janssen Scientific Affairs, LLC 
 
Your information may be re-disclosed by the recipients described 
above, if they are not required by law to protect the privacy of the 
information. 
 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health 
information will end on December 31, 2050 or when the research 
project ends, whichever is earlier. 
 
Will access to my medical record be limited during the study? 
To maintain the integrity of this research study, you may not have 
access to any health information developed as part of this study until 
it is completed.  At that point, you would have access to such health 
information if it was used to make a medical or billing decision about 
you (e.g., if included in your official medical record).  
 
 
________________________________             
______________ 
Signature of Adult Participant                                   Date 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 25 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
 
________________________________________ 
Printed Name of Adult Participant                                           
 
 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 26 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
FINANCIAL CONSIDERATIONS 
 
Payment 
You can receive partial or full reimbursement for your time and expenses (car 
travel and hotel stays only) as a result of taking part in this study. Receipts for 
your hotel stay must be provided to the Study Coordinator to receive this 
reimbursement at each visit.  
 
Payments may only be made to U.S. citizens, legal resident aliens, and those 
who have a work eligible visa. You may need to provide your social security 
number to receive payment. 
 
 
Costs 
If you participate in this study, the study will pay for those services, supplies, 
procedures, and care associated with the study that are not a part of your 
routine medical care.  However, there may be additional costs to you.  These 
include basic expenses like transportation and the personal time it will take to 
come to the study visits.  You and/or your health insurance must pay for 
services, supplies, procedures, and care that are required during this study for 
routine medical care.  You will also be responsible for any co-payments and/or 
deductibles as required by your insurance.  Participation in this study is not a 
substitute for health insurance. 
 
Supporters 
Dynavax Technologies Corporation and Janssen Scientific Affairs, LLC 
are providing the 2 drugs for this study.  Dynavax Technologies Corporation will 
be providing the SD-101 and Janssen Scientific Affairs LLC will provide the 
Ibrutinib and funding.    
 
The National Institutes of Health is providing financial support and material 
for this study and some financial support for the facility and staff where part or 
all of the study is taking place. 
 
Leukemia & Lymphoma Foundation and Rising Tide Foundation For 
Clinical Cancer Research also provide funding for the study. 
 
COMPENSATION for Research-Related Injury 
 
All forms of medical diagnosis and treatment – whether routine or experimental 
– involve some risk of injury.  In spite of all precautions, you might develop 
medical complications from participating in this study.  If such complications 
arise, the Protocol Director and the research study staff will assist you in 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 27 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
obtaining appropriate medical treatment.  In the event that you have an injury or 
illness that is directly caused by your participation in this study, reimbursement 
for all related costs of care first will be sought from your insurer, managed care 
plan, or other benefits program.  You will be responsible for any associated 
co-payments or deductibles as required by your insurance. 
 
If costs of care related to such an injury are not covered by your insurer, 
managed care plan or other benefits program, you may be responsible for these 
costs.  If you are unable to pay for such costs, the Protocol Director will assist 
you in applying for supplemental benefits and explain how to apply for patient 
financial assistance from the hospital. 
 
You do not waive any liability rights for personal injury by signing this form. 
 
CONTACT INFORMATION  
 
Questions, Concerns, or Complaints:  If you have any questions, concerns or 
complaints about this research study, its procedures, risks and benefits, or 
alternative courses of treatment, you should ask the Protocol Director, Dr. Ronald 
Levy.  You may contact him now or later at 650-725-6452  
 
Injury Notification:  If you feel you have been hurt by being a part of this study, 
please contact the Protocol Director, Dr. Ronald Levy at 650-725-6452.  
 
Independent Contact:  If you are not satisfied with how this study is being 
conducted, or if you have any concerns, complaints, or general questions about 
the research or your rights as a participant, please contact the Stanford 
Institutional Review Board (IRB) to speak to someone independent of the 
research team at 650-723-5244 or toll free at 1-866-680-2906.  You can also 
write to the Stanford IRB, Stanford University, 1705 El Camino Real, Palo Alto, 
CA 94306. 
 
Appointment Contact: If you need to change your appointment, please contact 
the research coordinator at 650-498-6000 
 
Alternate Contact:  If you cannot reach the Protocol Director, please contact the 
research coordinator at 650-498-6000 
 
 
 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 28 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
 
As a research participant you have the following rights.  These rights include but 
are not limited to the participant's right to: 
• 
be informed of the nature and purpose of the experiment;  
• 
be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized;  
• 
be given a description of any attendant discomforts and risks reasonably 
to be expected;  
• 
be given an explanation of any benefits to the subject reasonably to be 
expected, if applicable;  
• 
be given a disclosure of any appropriate alternatives, drugs or devices 
that might be advantageous to the subject, their relative risks and 
benefits; 
• 
be informed of the avenues of medical treatment, if any available to the 
subject after the experiment if complications should arise;  
• 
be given an opportunity to ask questions concerning the experiment or 
the procedures involved;  
• 
be instructed that consent to participate in the medical experiment may 
be withdrawn at any time and the subject may discontinue participation 
without prejudice;  
• 
be given a copy of the signed and dated consent form; and  
• 
be given the opportunity to decide to consent or not to consent to a 
medical experiment without the intervention of any element of force, 
fraud, deceit, duress, coercion or undue influence on the subject's 
decision. 
 
May we contact you about future studies that may be of interest to you?   Yes   No 
 
Signing your name means you agree to be in this study and that you were given 
a copy of this signed and dated consent form.  
 
 
_____________________________________                ____________ 
Signature of Adult Participant 
 
 
 
   
   Date 
 
 
______________________________________________________ 
Printed name of Adult Participant                                           
 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
RONALD LEVY, MD 
Protocol Title: 
Intratumoral Injection of SD-101, an Immunostimulatory CpG, in combination with Ibrutinib and 
Local Radiation in Relapsed or Refractory Low-Grade Follicular Lymphoma 
 
Page 29 of 29 
 
NCT: NCT02927964 
IRB Use Only 
Approval Date:   May 18, 2021 
Expiration Date: May 18, 2022  
Participant ID: 
 
_____________________________________                ____________  
Signature of Person Obtaining Consent  
 
   
  Date 
 
 
______________________________________________________ 
Printed name of Person Obtaining Consent                                           
 
The following witness line is to be signed only if the consent is provided as a summary 
form and accompanied by a short form foreign language consent. 
 
 
_____________________________________                ____________  
Signature of witness                              
 
     
  Date 
 
 
 
_____________________________________                 
Printed name of witness    
 
(e.g., staff, translator/interpreter, family member) 
• Translated short form must be signed and dated by both the participant (or their 
LAR) AND the witness. 
• The English consent form (referred to as the "Summary Form" in the regulations): 
o Must be signed by the witness AND the Person Obtaining Consent (POC). 
o The non-English speaking participant/LAR does not sign the English consent. 
o The non-English speaking participant/LAR should not sign the HIPAA participant line 
o If the participant or the LAR is non-English speaking, the Person Obtaining Consent 
(POC) must ensure that 1) the LAR's Description of Authority is completed and 2) 
that any questions or options presented by the consent form are documented and 
initialed by the POC on the Summary Form, per the participant's wishes, as they are 
understood during the consent process.