Clinical trial NCT02501473
Conditions: Follicular Low Grade Non-Hodgkin's Lymphoma
Keywords: follicular lymphoma FL low-grade lymphoma Non-Hodgkin's Lymphoma follicular NHL Marginal Zone
Sponsor: Immune Design, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Start date: 2016-02-03; Completion date: 2019-08-01
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1/2 open label trial of G100 in participants with low grade Non-Hodgkin's Lymphoma (NHL). G100 is composed of glucopranosyl lipid A in a stable emulsion and is a potent TLR4 (toll-like receptor-4) agonist. G100 will be administered by direct injection (intratumorally) into tumors of low grade NHL with or without standard low dose radiation therapy. Preclinical models and clinical studies in other cancers such as Merkel cell carcinoma have demonstrated that G100 administered in this manner can alter the tumor microenvironment, activate dendritic cells, T cells and other immune cells and induce systemic anti-tumor immune responses. In this trial, the safety, immunogenicity, and preliminary clinical efficacy of G100 will be examined alone or with pembrolizumab.

Detailed description:
This is a multi-center Phase 1/2 open label trial of intratumoral G100 in participants with low grade NHL. Eligible participants with NHL will be enrolled and receive G100 to an accessible tumor mass. Clinical response will be evaluated in the injected tumor and systemic (abscopal) responses will be evaluated in distal areas involved with tumor.

The study will be conducted in 5 parts. In Part 1, Dose Escalation, 2 sequentially enrolled cohorts of participants will be treated at one of 2 dose levels of G100 using a standard escalation design. In this portion of the study, both follicular and marginal zone NHL will be eligible. In Part 2, 2 groups of participants with follicular NHL may be examined. One group will be randomly assigned to receive either single agent G100 intratumorally at the maximum safe dose determined in Part 1 following local radiation or will receive the same treatment regimen sequentially administered with pembrolizumab. A second treatment group may be explored if the safety profile in Part 1 is acceptable. In this optional group, participants with injectable tumors of 4 cm or greater would be enrolled and treated with a higher dose of G100. In Part 3, expansion of a higher dose (20µg of G100) in participants with follicular NHL will be enrolled to receive local radiation therapy and intratumoral G100. In Part 4, Dose Escalation and Expansion, a dose of 20µg of G100 will be examined as a treatment of 1 or more tumors (up to 4) with pembrolizumab in order to establish safety and examine clinical and biomarker responses in participants receiving increasing total systemic doses of G100 and Part 5, will evaluate standard induction therapy with rituximab (anti-CD20) in combination of escalating doses of intratumoral G100 in single tumors.

The primary goal of this study is to determine the safety and tolerability of different doses of G100 when administered by intratumoral injection. The development of anti-tumor immune responses and preliminary evidence of clinical responses in local and distal tumor sites will also be examined.

Arms: arm 1: Part 1: Local radiation and G100 \[glucopyranosyl lipid A stable emulsion, GLA-SE\] at 5μg/tumor administered intratumorally (IT) into accessible tumors for up to 8 weeks. arm 2: Part 1: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks. arm 3: Part 2: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks. arm 4: Part 2: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks; pembrolizumab 200mg intravenously (IV) administered every 3 weeks (Q3W) IV for up to 2 years. arm 5: Part 2: Local radiation and G100 at 20 μg/tumor administered IT into accessible large tumors \[injectable lymphoma mass(es) ≥ 4 cm in total size\] for up to 8 weeks. arm 6: Part 3: Local radiation and G100 at 20μg/tumor administered IT into accessible tumors for up to 8 weeks. arm 7: Part 4: G100 at 20μg/tumor administered IT into accessible tumors for up to 8 weeks and pembrolizumab 200mg IV and administered Q3W for up to 2 years. arm 8: Part 5: G100 at 20, 40, 60, or 80μg/tumor administered IT for up to 6 weeks and rituximab administered as an IV infusion at 375mg/m\^2 on Day 0 and then QW for up to 3 weeks.
Interventions: intervention 1: G100 intervention 2: Pembrolizumab intervention 3: Rituximab
Intervention descriptions: intervention 1: GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist intervention 2: PD-1 Inhibitor intervention 3: Rituximab (anti-CD20 antibody)

Protocol documents:
Prot_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT02501473
15-Nov-2018
Document Date: 
Phase 1/2 Study of Intratumoral G100 With Or Without 
Pembrolizumab or Rituximab In Patients With Follicular Non-
Hodgkin’s Lymphoma


CLO-30.002 V04B 
Page 1 of 177 
 
 
 
CLINICAL PROTOCOL 
Phase 1/2 Study Of Intratumoral G100 With Or Without Pembrolizumab or 
Rituximab In Patients With Follicular Non-Hodgkin’s Lymphoma 
 
Protocol Number: 
IMDZ-G142 
Investigational Agent(s): 
G100 (glucopyranosyl lipid A stable emulsion, GLA-SE) 
and Pembrolizumab and Rituximab 
Sponsor’s Name: 
Immune Design 
1616 Eastlake Ave. E, Suite 310 
Seattle, WA 98102 
Version and Date: 
Version 04B  
November 15, 2018 
IND Number: 
BB-IND 15708 
 
CONFIDENTIALITY STATEMENT: 
This document contains confidential and proprietary information belonging to Immune 
Design.  Except as otherwise agreed to in writing by Immune Design, by accepting or 
reviewing this document, you agree to hold this information in confidence and to use it for 
authorized purposes only.  You further agree not to copy or disclose it to others except as 
required by applicable law.   
 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 2 of 177 
INVESTIGATOR’S SIGNATURE PAGE 
 
Investigator: 
 
 
 
 
____________________ 
Study Number:  
 
IMDZ-G142 
Product Name(s): 
G100 and Pembrolizumab or Rituximab 
Study Title: 
Phase 1/2 Study Of Intratumoral G100 With Or Without Pembrolizumab 
or Rituximab In Patients With Follicular Non-Hodgkin’s Lymphoma 
Document Date: 
November 15, 2018 
As Principal Investigator, I agree to: 
1. Keep all documentation supplied to me or developed by me concerning this study, and 
that has not been previously published, in the strictest confidence. This documentation 
includes, but is not limited to, the Investigator’s Brochure and Case Report Forms (CRFs) 
2. That the study will not commence without prior written approval of a properly 
constituted Institutional Review Board. No changes will be made to the study Protocol 
without prior written approval of Immune Design and the Institutional Review Board, 
except where necessary to eliminate an immediate hazard to patients 
3. Implement and conduct the study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations 
4. Accurately transfer all required data from each patient’s source document to the CRFs. 
The original CRFs will be submitted to the Sponsor in a timely manner at the completion 
of the trial, or as otherwise specified by the Sponsor 
5. Keep a complete and accurate accounting during and at the completion of the trial of all 
procedures performed with the drug provided by the Sponsor 
6. Allow authorized representatives of Immune Design or regulatory authority 
representatives to conduct on-site visits to review, audit and copy trial documents. I will 
personally meet with these representatives at mutually convenient times to answer any 
trial-related questions 
7. Provide the Sponsor with an investigator’s summary within 90 days of completion of the 
final trial visit for the last patient enrolled, or as designated by Sponsor 
8. Maintain all information supplied by the Sponsor in confidence and, when this 
information is submitted to an Institutional Review Board (IRB), Ethical Review 
Committee, or another group, it will be submitted with a designation that the material is 
confidential. 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 3 of 177 
This protocol was designed and will be conducted, recorded, and reported in compliance with the 
principles of Good Clinical Practice (GCP) guidelines. These guidelines are stated in U.S. federal 
regulations as well as “Guidance for Good Clinical Practice,” International Council on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. 
I have read this protocol in its entirety, including the preceding statements, and I agree to comply 
with all aspects of this trial. 
 
 
 
 
 
Investigator Printed Name 
 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
Institution Name 
 
 
 
 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
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1.0 
TABLE OF CONTENTS  
CLINICAL PROTOCOL ..............................................................................................................1 
INVESTIGATOR’S SIGNATURE PAGE ..................................................................................2 
1.0 
TABLE OF CONTENTS ..................................................................................................4 
LIST OF TABLES .........................................................................................................................9 
LIST OF FIGURES .......................................................................................................................9 
LIST OF APPENDICES .............................................................................................................10 
2.0 
GENERAL INFORMATION .........................................................................................11 
2.1 
Sponsor Information ..............................................................................................11 
2.2 
Protocol Revision History ......................................................................................12 
2.3 
List of Abbreviations and Glossary of Terms ........................................................15 
3.0 
TRIAL SYNOPSIS AND SCHEDULE OF EVENTS ..................................................18 
3.1 
Trial Synopsis ........................................................................................................18 
3.2 
Schedule of Events: Part 1, Dose Escalation and Part 2, Patient Expansion 
(G100 alone) and Large Tumor Groups.................................................................43 
3.3 
Schedule of Events:  Part 2, Sequential Administration of G100 and anti-PD-1 ..45 
3.4 
Schedule of Events:  Part 3, G100 Expansion of 20 µg Dose Group ....................47 
3.5 
Schedule of Events:  Part 4, G100 at 20µg/lesion Into Single Or Multiple 
Tumor Masses Plus Pembrolizumab ......................................................................49 
3.6 
Schedule of Events:  Part 5, G100 Plus Rituximab ...............................................51 
3.7 
Schedule of Events:  Optional Retreatment / Second Course ................................53 
4.0 
INTRODUCTION AND RATIONALE .........................................................................55 
4.1 
Study Overview .....................................................................................................58 
4.2 
G100: Glucopyranosyl Lipid A Stable Emulsion, GLA-SE ..................................63 
4.3 
Summary of Known and Potential Risks to Human Patients ................................64 
4.3.1 
Safety Profile of G100 in Follicular Lymphoma ..................................66 
4.4 
Rationale for G100 Therapy ..................................................................................66 
4.4.1 
Rationale for G100 Dose .......................................................................67 
4.4.2 
Rationale for Radiotherapy with Intratumoral G100 ............................69 
4.4.3 
Rationale for Proposed G100 Schedule Selection ................................69 
4.5 
Rationale for anti-PD-1 Therapy and Proposed Schedule .....................................70 
4.5.1 
Pembrolizumab Background and Clinical Trials ..................................71 
4.5.2 
Pharmaceutical and Therapeutic Background .......................................72 
4.5.3 
Pre-clinical and Clinical Trials..............................................................73 
4.5.4 
Justification for Dose ............................................................................73 
4.6 
Rationale for Rituximab Therapy and Proposed Schedule ....................................74 


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4.7 
Safety Monitoring ..................................................................................................77 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................80 
5.1 
Primary Objective ..................................................................................................80 
5.2 
Secondary Objectives.............................................................................................81 
5.3 
Exploratory Objective ............................................................................................81 
5.4 
Primary Endpoint ...................................................................................................81 
5.5 
Secondary Endpoints .............................................................................................81 
5.6 
Exploratory Endpoints ...........................................................................................82 
6.0 
INVESTIGATIONAL PLAN .........................................................................................82 
6.1 
Overall Trial Design and Plan................................................................................82 
6.2 
Dose-Limiting Toxicities .......................................................................................91 
6.3 
Stopping Rules .......................................................................................................93 
6.4 
Maximum Tolerated Dose/Maximum Safe Dose ..................................................93 
6.5 
Dosing Delays / Dose Modifications .....................................................................93 
7.0 
SELECTION OF PATIENTS .........................................................................................93 
7.1 
Inclusion Criteria ...................................................................................................94 
7.2 
Exclusion Criteria ..................................................................................................95 
8.0 
TRIAL REGIMENS ........................................................................................................97 
8.1 
G100 Investigational Drug .....................................................................................97 
8.1.1 
G100 Packaging and Labeling ..............................................................97 
8.1.2 
Storage and Disposition of the G100 Investigational Drug Product .....97 
8.1.3 
G100 Preparation ..................................................................................97 
8.1.4 
G100 Administration .............................................................................98 
8.1.5 
Pembrolizumab Background ...............................................................100 
8.1.5.1 
Pembrolizumab Dose Selection (Preparation) .............................100 
8.1.5.2 
Pembrolizumab Investigational Product ......................................100 
8.1.5.3 
Timing of Dose Administration ...................................................101 
8.1.5.4 
Pembrolizumab Administration ...................................................101 
8.1.5.5 
Dose Modification for Pembrolizumab .......................................101 
8.1.5.6 
Other allowed dose interruptions for Pembrolizumab .................105 
8.1.6 
Rescue Medications & Supportive Care for Pembrolizumab .............105 
8.1.7 
Dose modification and toxicity management of infusion-reactions 
related to Pembrolizumab ...................................................................105 
8.1.8 
Rituximab Background .......................................................................107 
8.1.8.1 
Rituximab Dose ...........................................................................107 
8.1.8.2 
Rituximab Investigational Product ..............................................107 


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8.1.8.3 
Rituximab Administration ...........................................................107 
8.1.8.4 
Dose Modification, Warning and Precuations for Rituximab .....107 
8.1.9 
Contraception ......................................................................................110 
8.1.10 
Use in Pregnancy.................................................................................111 
8.1.11 
Use in Nursing Women .......................................................................111 
8.2 
Subject Withdrawal/Discontinuation Criteria ......................................................111 
8.2.1 
Discontinuation of Study Therapy after Complete Response (CR) ....111 
8.2.2 
Investigational Drug Accountability ...................................................112 
8.3 
Radiation ..............................................................................................................112 
8.4 
Prior and Concomitant Therapy ...........................................................................112 
8.4.1 
Prior Therapy ......................................................................................112 
8.4.2 
Prohibited Concomitant Therapy ........................................................113 
8.4.3 
Permitted Concomitant Therapy .........................................................114 
9.0 
ASSESSMENTS OF SAFETY AND EFFICACY ......................................................114 
9.1 
Safety Assessments ..............................................................................................114 
9.2 
Clinical Efficacy Assessments .............................................................................114 
9.3 
Tumor Response Based Upon irRC Criteria ........................................................115 
9.4 
International Working Group Response Criteria for Malignant Lymphoma or 
the Lugano Criteria and Disease Response Assessment ......................................115 
9.5 
Immune Response Assessments ..........................................................................115 
9.6 
Exploratory Biomarkers .......................................................................................115 
10.0 
STUDY PROCEDURES ...............................................................................................116 
10.1 
Visit Windows .....................................................................................................116 
10.2 
Registration ..........................................................................................................116 
10.3 
Study Procedures .................................................................................................117 
10.3.1 
Visit 1: Screening and Enrollment (Day -30 to Day -1) – Baseline 
Visit 1 ..................................................................................................117 
10.3.2 
Visit 2: Baseline Assessment 2 (Day -7 to -1 for Parts 1 and 2, and 
Day -14 to -1 for Part 3) ......................................................................118 
10.3.3 
Visit 3 and Visit 4: Radiation Therapy (Day 0 and Day 1) .................121 
10.3.4 
Visit 5: G100 Treatment #1 (Day 2) ...................................................121 
10.3.5 
Visit 6: G100 Dose #2 (Day 5-7) ........................................................121 
10.3.6 
Visits 7, 8, 9, 10: G100 Doses #3, 4, 5, 6 (Days 14, 21, 28, 35) .........122 
10.3.7 
Optional Visit 10A, 10B: G100 Doses # 7, 8 (Days 42, 49) ...............122 
10.3.8 
Visit 11: Clinical Assessment and Optional G100 Dose # 9 
(Day 56) ..............................................................................................123 


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G100 (GLA-SE) and Pembrolizumab or Rituximab 
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10.3.9 
Visit 12: Post-Immunization / End of Study Visit (Day 77) ...............124 
10.3.10 
Long-Term Follow-up Visits ..............................................................125 
10.3.10.1 
Visits Before Disease Progression (Day 112, then every 
8 weeks) .......................................................................................125 
10.3.10.2 
After Disease Progression (Every 8 to 12 Weeks) .......................125 
10.3.11 
Visits 7, 8, 9, 10:  G100 Doses #3, 4, 5, 6 (Days 14, 21, 28, 35) ........126 
10.3.12 
Optional Visit 10A, 10B:  G100 Doses # 7, 8 (Days 42, 49) ..............126 
10.3.13 
Visit 11:  Clinical Assessment and Optional G100 Dose # 9 
(Day 56) ..............................................................................................127 
10.3.14 
Visit 12: Post-Immunization / End of Safety Visit (Day 77) ..............128 
10.3.15 
Long-Term Follow-up Visits ..............................................................129 
10.3.15.1 
Visits For Anti-PD-1 Therapy and Before Disease Progression 
(Day 98, then every 3 weeks) ......................................................129 
10.3.15.2 
Visits After Disease Progression (Every 8 to 12 Weeks) ............130 
10.3.16 
Visit 3: G100 Treatment #1 (Day 0) ...................................................131 
10.3.17 
Visit 4: G100 Dose #2 (Day 5-7) ........................................................131 
10.3.18 
Visits 5, 6, 7, 8:  G100 Doses #3, 4, 5, 6 (Days 14, 21, 28, 35) ..........132 
10.3.19 
Optional Visit 8A, 8B:  G100 Doses # 7, 8 (Days 42, 49) ..................132 
10.3.20 
Visit 9:  Clinical Assessment and Optional G100 Dose # 9 (Day 56) 133 
10.3.21 
Visit 10:  Post-Immunization / End of Safety Visit (Day 77) .............134 
10.3.22 
Long-Term Follow-up Visits ..............................................................135 
10.3.22.1 
132BVisits For Anti-PD-1 Therapy and Before Disease Progression 
(Day 98, then every 3 weeks) ......................................................135 
10.3.22.2 
13Visits After Disease Progression (Every 8 to 12 Weeks) ............136 
10.3.23 
Visit 3: Rituximab Treatment #1 (Day 0) ...........................................137 
10.3.24 
Visit 4: G100 Dose #1 (Day 1) ...........................................................137 
10.3.25 
Visits 5, 6, 7:  G100 Doses #2, 3, 4  (Days 7, 14, 21) and Rituximab 
Doses #2, 3, 4 (Days 7, 14, 21) ...........................................................138 
10.3.26 
Visits 8, 8A and 8B (Days 28, 35, 42):  Visit and Optional G100 
Doses # 5, 6 (Days 28, 35) ..................................................................138 
10.3.27 
Visit 9:  Clinical Assessment (Day 56) ...............................................140 
10.3.28 
Visit 10: Post-Immunization / End of Safety Visit (Day 112) ............140 
10.3.29 
Long-Term Follow-up Visits ..............................................................141 
10.3.29.1 
Visits Before Disease Progression (Day 168, then every 
8 weeks) .......................................................................................141 
10.3.29.2 
Visits After Disease Progression (Every 8 to 12 Weeks) ............142 
10.4 
Optional Retreatment / Second Course with G100 (Parts 1, 2, 3, 4 and 5) .........142 


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G100 (GLA-SE) and Pembrolizumab or Rituximab 
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10.4.1 
Visit 1: Baseline Evaluation Days -14 to -1 ........................................143 
10.4.2 
Visit 2: G100 Treatment #1 (Day 0) ...................................................144 
10.4.3 
Visit 3: G100 Dose #2 (Day 5-7) ........................................................144 
10.4.4 
Visits 4, 5, 6, 7: G100 Doses #3, 4, 5, 6 (Days 14, 21, 28, 35) ...........144 
10.4.5 
Optional Visit 7A, 7B: G100 Doses # 7, 8 (Days 42, 49) ...................145 
10.4.6 
Visit 8: Clinical Assessment and Optional G100 Dose # 9 (Day 56) .145 
10.4.7 
Visit 9: Post-Immunization / End of Study Visit (Day 77) .................145 
10.4.8 
Long-Term Follow-up Visits ..............................................................145 
10.4.9 
Additional Biomarker Testing.............................................................146 
11.0 
PATIENT WITHDRAWAL .........................................................................................146 
12.0 
ADVERSE EVENTS .....................................................................................................147 
12.1 
Definitions............................................................................................................148 
12.2 
Adverse Event Severity........................................................................................149 
12.3 
Relationship to Investigational Drug ...................................................................150 
12.4 
Adverse Event Collection Period .........................................................................151 
12.5 
Adverse Event Reporting .....................................................................................152 
12.6 
Serious Adverse Event Reporting ........................................................................152 
12.7 
Pregnancy .............................................................................................................153 
12.8 
Events of Clinical Interest /Medical Events of Interest .......................................154 
12.9 
Data Monitoring Committee ................................................................................155 
13.0 
PROTOCOL DEVIATIONS ........................................................................................155 
14.0 
STATISTICAL CONSIDERATIONS .........................................................................156 
14.1 
Study Endpoints ...................................................................................................156 
14.2 
Sample Size ..........................................................................................................156 
14.3 
Definition and Analysis of Primary and Secondary Endpoints ...........................158 
14.3.1 
Safety...................................................................................................158 
14.3.2 
Immunogenicity ..................................................................................158 
14.3.3 
Tumor Response .................................................................................158 
14.3.4 
Pharmacokinetic and Pharmacodynamic ............................................159 
14.4 
Interim Analysis ...................................................................................................159 
15.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................159 
16.0 
DATA QUALITY ASSURANCE .................................................................................160 
17.0 
ETHICS ..........................................................................................................................160 
17.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) .......160 
17.2 
Ethical Conduct of the Study ...............................................................................160 


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17.3 
Patient Information and Consent .........................................................................161 
17.4 
Patient Confidentiality .........................................................................................161 
18.0 
DATA HANDLING AND RECORD KEEPING ........................................................161 
18.1 
Source Documents ...............................................................................................161 
18.2 
Case Report Forms ...............................................................................................162 
18.3 
Record Retention .................................................................................................162 
19.0 
FINANCING AND COMPENSATION .......................................................................162 
20.0 
PROTOCOL AMENDMENTS ....................................................................................163 
21.0 
PUBLICATION POLICY .............................................................................................163 
 
LIST OF TABLES 
Table 1: 
Total Subjects Treated and Total Doses of GLA Administered to Human 
Subjects Through August 2014 ..............................................................................64 
Table 2: 
Product Descriptions ............................................................................................101 
Table 3: 
Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab ..................................................................103 
Table 4: 
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ............................................................................................................106 
Table 5: 
Adverse Event Severity Assessment ....................................................................150 
Table 6: 
Assessment of Relationship .................................................................................150 
 
LIST OF FIGURES 
Figure 1: 
Toll-like Receptor (TLR) Ligands And Signaling .................................................56 
Figure 2:  
Intratumoral G100 in non-Hodgkin’s lymphoma (NHL) Model ...........................57 
Figure 3: 
Part 2, Patient Expansion With Or Without Pembrolizumab ................................60 
Figure 4: 
Treatment Schema for Part 1, Part 2 Patient Expansion G100 Alone, Part 2 
Large Tumor Group, and Part 3, G100 Expansion of 20 µg Dose Group .............61 
Figure 5: 
Treatment Schema for Part 2, Sequential G100 and Pembrolizumab ...................61 
Figure 6: 
Dose Escalation And Expansion Of Part 4: G100 at 20µg/dose Into Single Or 
Multiple Tumor Lesions Plus Pembrolizumab Group ...........................................61 
Figure 7: 
Part 4, G100 at 20µg/lesion Into Single Or Multiple Tumor Lesions Plus 
Pembrolizumab Group ...........................................................................................62 
Figure 8: 
Part 5, G100 Plus Rituximab .................................................................................62 
Figure 9: 
Part 5, G100 Plus Rituximab .................................................................................63 
Figure 10: 
For Parts 1 to 5, Optional Retreatment / Second Course .......................................63 
Figure 11: 
Structure of GLA ...................................................................................................64 


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G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
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Figure 12: 
Intratumoral Injection Of 50µg G100 Is More Potent Than 10 µg Of G100 In 
A20 Lymphoma. ....................................................................................................68 
Figure 13: 
Intratumoral G100 Plus Check Point Inhibitors In The B16 Melanoma Model ....71 
Figure 14: 
G100 Increases NK Cells In The Tumor Microenvironment ................................75 
Figure 15: 
G100 Induces Genes Related To NK Cell Function In FL Patients ......................75 
Figure 16: 
GLA Enhances Rituximab-Mediated ADCC.........................................................76 
 
LIST OF APPENDICES 
Appendix A: ECOG Performance Status ..................................................................................164 
Appendix B: Immune-Related Response Criteria (irRC) ..........................................................165 
Appendix C: Revised International Working Group Response Criteria for Malignant 
Lymphomas..........................................................................................................168 
Appendix D: Follicular Lymphoma International Prognostic Index (FLIPI) ............................169 
Appendix E: Serious Adverse Event Contact Information .......................................................170 
Appendix F: Contraception .......................................................................................................171 
Appendix G: References ............................................................................................................173 
 


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G100 (GLA-SE) and Pembrolizumab or Rituximab 
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2.0 
GENERAL INFORMATION 
2.1 
Sponsor Information 
Trial Sponsor: 
Immune Design  
1616 Eastlake Ave. E, Suite 310 
Seattle, WA 98102 
Sponsor’s Medical Monitor: 
Sergey Yurasov, M.D., Ph.D 
Immune Design 
601 Gateway Blvd., Suite 250 
South San Francisco, CA 94080 
1-650-392-8351 
sergey.yurasov@immunedesign.com 
 


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2.2 
Protocol Revision History 
 
Version 
Date 
Comment 
01 
12 March 2015 
Initial Release 
02 
05 November 2015 
This amendment adds a treatment arm to Part 2 Patient Expansion to 
examine the sequential addition of the anti-PD1 antibody 
pembrolizumab to intratumoral G100. The new Patient Expansion 
treatment group will randomize 12 patients each to receive either G100 
or G100 with sequentially administered pembrolizumab. The title has 
been modified to reflect this. Other changes include the addition of 
new objectives/endpoints for the analysis of G100 with sequentially 
administered pembrolizumab; background, safety information, dose 
and dose modifications for the use of pembrolizumab; added marginal 
zone B cell lymphomas as potentially eligible indications for Part 1 
Dose Escalation and changed NHL description from “follicular” to 
“low-grade” NHL to clarify the expanded population in Part 1 
objective/endpoints ; additional exclusion criteria for patients with the 
potential to be randomized and treated with pembrolizumab; addition 
of thyroid function tests as part of safety analyses for patients receiving 
pembrolizumab; added a baseline beta-2-microglobulin test; revision of 
the G100 study drug description section; addition of clinical response 
assessment by International Working group criteria for NHL; 
clarification that PD will be assessed by irRC criteria; clarification that 
FLIPI criteria will be collected and evaluated; added information about 
the International Working group criteria and FLIPI as new Appendices; 
clarification in the Synopsis that patients achieving CR, PR or SD will 
be followed as long as feasible to assess long term outcome; added that 
photographic documentation should be considered for visually 
accessible lesions; correction of a visit 10 blood draw for TCR analysis 
in Section 10.0; modification of the DLT criteria to exclude moderate 
grade 3 injection site reactions if they improve within 14 days; 
clarification of DLT criteria for patients receiving pembrolizumab and 
role of DMC safety reviews of pembrolizumab adverse events; 
changed the follow up of G100 patients who withdraw early to 30 days 
to match pembrolizumab treated patients; in the Schedule of Events for 
pembrolizumab therapy clarified that all AEs/SAEs and events of 
clinical interest experienced from time of enrollment through 30 days 
following cessation of treatment would be reported and that all SAEs 
would be collected up to 90 days following the last dose of 
pembrolizumab. Based on the consensus guidelines from the 
Cardiovascular and Interventional Radiology Society of Europe, 
clarified that for low risk injection/biopsies such as a superficial lymph 
node or subcutaneous mass, non-steroidal anti-inflammatory drugs 
(NSAIDs), aspirin, or clopidogrel may be used by the patient and do 
not have to be withheld. 


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Version 
Date 
Comment 
02.1 
23 March 2016 
UK specific Amendment.  In this version, an abbreviation list has been 
included, the investigators and sites have been updated.  The 
contraception sections have been updated to reflect the recommended 
types of contraception and definitions.  Updated contraception language 
has been added to Inclusion criteria #7 and #8, Section 8.1.6 and in the 
new Appendix F.  The Schedule Events in Sections 3 and 10 have been 
updated to include at least monthly pregnancy testing for female patients 
while receiving study drug.  The SAE reporting language has been 
clarified such that only serious events that are considered at least possibly 
related and are considered unexpected will be expedited as reports to 
regulatory agencies. 
03 
05 January 2017 
Updated list of all current investigators and sites. Added Part 3 G100 
20µg Dose Expansion arm and language inserted throughout the protocol 
to allow treatment of up to 25 subjects at the 20 µg dose using the same 
tumor size entrance criteria as the other non-Large Tumor arms.  Added 
new Schedule of Events table 3.4 for Part 3.  Corrected changes addressed 
by Administrative letter dated 17June2016: DLT definition by adding a 
“not” and corrected inconsistent criteria language in Section 10.3.12 and 
10.3.13 where required tumor shrinkage was listed as 50% instead of 
75%.  The requirement for 75% or less shrinkage has now been removed 
and now states if the lesion has not “regressed completely”.  The 
requirement to receive a second course of G100 has been modified to 
allow patients with PD who do not require immediate therapy to be 
eligible for a second course. Clarified treatment windows. Added 
potential assessments of PFS and OS.  Changed follow-up radiology 
assessments to every 3-4 months in the second year and to at least every 6 
months during year 3 and subsequent years to match current practice for 
this indication. Updated contraceptive language to be more specific in the 
Inclusion Criteria and added detailed information about contraception in 
Appendix F.  Removed egg lecithin as a possible allergen since it is not 
part of the G100 product used in this study. Added UK specific language 
regarding contraceptives and pregnancy testing.  Updated information in 
Appendix B regarding IrRC tumor measurements.  Added the ability to 
potentially request and collect additional blood and/or tumor samples for 
biomarkers studies.  Additional administrative changes were made 
throughout the document to ensure clarity and consistency throughout the 
protocol. 


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Version 
Date 
Comment 
04 
31 July 2018 
Added Part 4, a new dose escalation and expansion arm to examine G100 in 
combination with pembrolizumab in relapsed or refractory FL.  This arm will 
investigate the effect of 20µg  of G100 in combination with pembrolizumab 
without radiation therapy in single and multiple tumor lesions on safety, 
clinical effect and changes in immune biomarkers and permit an assessment 
of activity that will permit the design of future studies of G100 and 
pembrolizumab. 
Added Part 5, a new dose escalation and expansion to examine the safety and 
preliminary clinical efficacy of G100 in combination with rituximab in FL.  
This arm will first examine the safety of escalating doses of G100 
administered into a single lesion in combination with rituximab administered 
at a standard induction regimen.  After establishing the maximum safe dose in 
a single lesion and systemic exposure, a Patient Expansion will then be 
performed by injecting single or multiple tumor masses with G100 at 
20µg/lesion to provide additional data on safety, clinical efficacy, and 
biomarker changes associated with the new combination regimen.  This study 
will provide an assessment of activity that will permit the design of future 
studies of G100 and rituximab. 
An updated Investigator Brochure and Safety language was received from 
Merck for pembrolizumab and this new safety language has been 
incorporated throughout this protocol. 
04A 
31 August 2018 
Revised the Inclusion criteria for Part 4 to only include patients with relapsed 
or refractory disease after ≥3 prior therapies, reduced the number of patients 
to be enrolled, and revised the statistical section and general treatment 
sections to reflect this. Part 5 was revised to limit the intratumoral G100 
treatment to a single tumor mass during Patient Expansion with either the 
highest dose determined to be safe during Dose Escalation or the most 
biologically active and safe dose if determined to be different than the MTD.  
In addition, the number of patients was reduced, the statistical section and 
general treatment sections were revised to reflect this.  Corrected formatting 
errors, spelling and added minor word and sentence changes throughout.  
These corrections included the numbering of Exclusion criteria to be 
continuous, correction of minor issues with figures, window of pregnancy 
testing in Section 12.7 and clarifications to the procedures to be followed for 
Parts 4 and 5. 
04B 
15 November 
2018 
An exploratory objective of evaluating Pharmacokinetics and 
Pharmacodynamic properties of G100 and appropriate sample collection were 
added. DLT criteria for Parts 4 and 5 were updated and are now consistent for 
G100, pembrolizumab and rituximab.  For Part 4 and Part 5, retreatment 
criteria timing were clarified.  For Part 5, patient eligibility criteria were 
updated to include patients who have relapsed or refractory CD20+ follicular 
NHL and who have received at least 1, but not more than 2 prior systemic 
therapy.  Exclusion criteria have been updated to exclude prior G100 therapy.  
Addition of the use of the Lugano criteria for lymphoma (Cheson 2014) to 
evaluate clinical response as an additional analysis was clarified at the 
Sponsor level.  A provision to collect radiographic images for central storage 
and independent radiology review was added. 


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2.3 
List of Abbreviations and Glossary of Terms  
Abbreviation 
Description 
ADCC 
antibody dependent cellular cytotoxicity 
AE 
adverse event 
AF 
aqueous formulation  
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CD 
cluster of differentiation 
CFR 
code of federal regulations 
CRF 
case report form 
CR 
complete response 
CpG 
C-G motifs 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DC 
dendritic cell 
DCF 
Data Clarification Form 
DKA 
diabetic ketoacidosis 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
ECI 
event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
EOS 
End of Study 
EU 
European Union 
FLIPI 
Follicular Lymphoma International Prognostic Index 
G-CSF 
granulocyte-colony stimulating factor 
GCP 
Good Clinical Practice 
GM-CSF 
granulocyte-macrophage colony stimulating factor 
GVHD 
graft versus host disease 
FCBP 
female of child bearing potential 
FDA 
Food and Drug Administration 
Hgb 
Hemoglobin 
HIPAA  
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH  
International Council on Harmonization  
IEC 
independent ethics committee 
IgG 
immunoglobin G 
IHC 
immunohistochemistry 
IL 
interleukin  


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Abbreviation 
Description 
INR 
international normalised ratio 
IRB 
institutional review board 
irCR 
immune-related complete response  
irPD 
immune-related progressive disease 
irPR 
immune-related partial response 
irRC 
immune related response criteria 
irSD 
immune-related stable disease 
IT 
Intratumoral 
IV 
intravenous(ly) 
mAb 
monoclonal antibody 
MHC 
major histocompatibility complex 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute  
NHL 
non-Hodgkin’s lymphoma 
NSAID 
non-steroidal anti-inflammatory drug 
NSCLC 
non-small-cell lung cancer  
NYHA 
New York Heart Association 
ORR 
overall response rate  
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed death receptor-1 
PDL 
programmed death ligand 
PFS 
progression-free survival 
PI 
principal investigator 
PK 
Pharmacokinetics 
PR 
partial response 
PTT 
partial thromboplastin time 
q2W 
every 2 weeks 
q3W 
every 3 weeks 
qd 
every day 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SC 
subcutaneous  
SD 
stable disease 
SE 
stable emulsion 
SGOT 
serum glutamic oxaloacetic transaminase  
SGPT 
serum glutamic pyruvic transaminase  
SOP 
standard operating procedure 


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Abbreviation 
Description 
SPD 
sum of the products of the two largest perpendicular diameters 
TILs 
tumor infiltrating lymphocytes  
TLR 
toll-like receptor 
TNF 
tumor necrosis factor 
TSH 
thyroid-stimulating hormone 
TTP 
time-to-progression 
UK 
United Kingdom 
ULN 
upper limit of normal 
WBC 
leukocyte count 
WHO 
World Health Organization 


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3.0 
TRIAL SYNOPSIS AND SCHEDULE OF EVENTS 
3.1 
Trial Synopsis 
Title: 
Phase 1/2 Study Of Intratumoral G100 With Or Without Pembrolizumab or 
Rituximab In Patients With Follicular Non-Hodgkin’s Lymphoma 
Sponsor:  
Immune Design 
Trial Site(s): 
US sites: 
Augusta University, Augusta, GA. 
City of Hope, Duarte, CA. 
Emory University, Atlanta, GA, 
Greenville Health System, Greenville, SC. 
Moffitt, Tampa, FL. 
Northwest Medical Specialties, Tacoma, WA. 
Oregon Health Sciences University (OHSU), Portland, OR. 
UCSF, San Francisco, CA  
University of Utah/Huntsman Cancer Center, Salt Lake City, UT. 
Washington University, St. Louis, MO. 
Yale University, New Haven, CT.  
 
European Sites: 
Royal Marsden Hospital, London, UK 
The Christie NHS Trust – Christie Hospital, Manchester, UK. 
Hopital Ponchaillou – CHU de Rennes, Rennes, FR 
Clínica Universidad de Navarra, Pamplona, ESP 
Hospital Universitario Virgen Macarena, Seville, ESP 
Hospital De La Santa Creu I Sant Pau.Barcelona, ESP 
(Sites may be added or removed) 
Principal 
Investigator(s): 
Weiyun Ai, M.D. PhD., UCSF 
Nancy Bartlett, M.D., Washington University 
Locke Bryan M.D., Augusta University 
Jorge Chaves, M.D. Northwest Medical Specialties 
Elizabeth Cull, M.D., Greenville Health System 
Christopher Flowers, M.D., Emory University 
Ahmad Halwani, M.D., University of Utah 
Alex Herrera, M.D., City of Hope  
Iris Isufi, M.D., Yale University 
Bela Kis, M.D. PhD., Moffitt 
Craig Okada, M.D. Ph.D., OHSU 
Ian Chau, M.D., Royal Marsden Hospital 
Kim Linton, M.D., Christie Hospital, Manchester, UK 
Roch Houot, M.D. PhD., CHU Rennes, FR 
Javier Briones, M.D. PhD., Hospital De La Santa Creu I Sant Pau.Barcelona, 
ESP 
Luis de la Cruz, M.D. PhD, Hospital Universitario Virgen Macarena, ESP  
Carlos Panizo, M.D., Clínica Universidad de Navarra, Pamplona, ESP 


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Start Date: 
June 2015 
Trial Phase: 
Phase 1/2 
Investigational Drug 
Product(s): 
G100 (glucopyranosyl lipid A stable emulsion, GLA-SE) and 
Pembrolizumab or Rituximab 
Objectives: 
Primary: 
 
In Part 1:  Evaluate the safety and tolerability of ascending doses of 
intratumoral G100 in patients with low-grade non-Hodgkin’s 
lymphoma (NHL) receiving local radiation 
 
In Part 2:  Assess the safety and tolerability of intratumoral G100 or 
sequential intratumoral G100 and anti-programmed cell death protein 
1 (PD-1) therapy in patients with follicular NHL receiving local 
radiation 
 
In Part 3:  Evaluate the safety and tolerability of 20 µg/dose of 
intratumoral G100 in patients with low-grade NHL receiving local 
radiation 
 
In Part 4:  Evaluate safety and preliminary clinical efficacy of  
intratumoral G100 at 20µg/lesion in single or multiple tumor lesions 
and pembrolizumab (anti-PD-1) therapy in patients with relapsed or 
refractory follicular NHL who have received at least 3 prior systemic 
treatments, one of which was or included an anti-CD20 antibody 
 
In Part 5:  Evaluate safety and preliminary clinical efficacy of 
standard induction therapy with rituximab (anti-CD20) in 
combination with escalating doses of intratumoral G100 in single 
tumor lesions in patients with follicular NHL who have received at 
least one or two prior treatment(s)  
Secondary: 
 
Assess clinical responses by Immune-related Response Criteria 
(irRC) using bi-dimensional measurements and time to progression 
(TTP) as a preliminary indication of efficacy For comparison, 
clinical responses will also be assessed by the International Working 
Group response criteria and Lugano criteria for lymphomas 
(Cheson 2014). 
 
Assess abscopal tumor responses in non-treated, distal tumor sites  
Exploratory: 
 
Evaluate pre- and post-regimen tumor tissue and blood for 
exploratory biomarkers of immunologic and tumor response  


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 
Part 4 and Part 5, explore pharmacokinetic and pharmacodynamic 
properties of G100 
 
Assess clinical responses by Immune-related Response Criteria 
(irRC) and Lugano criteria for lymphomas using independent 
radiology review 
Endpoints: 
Primary:  
 
Part 1:  The nature, frequency and severity of adverse events (AEs) 
and laboratory abnormalities up through Study Day 28 in patients 
with low-grade NHL receiving intratumoral G100 and local radiation 
 
Part 2:  The nature, frequency and severity of AEs and laboratory 
abnormalities occurring in patients with follicular NHL receiving 
local radiation and either intratumoral G100 alone or sequential 
intratumoral G100 and anti-PD-1 therapy  
 
Part 3:  The nature, frequency, and severity of AEs and laboratory 
abnormalities occurring in patients with follicular NHL receiving 
local radiation and G100 at 20 µg/dose 
 
Part 4:  The nature, frequency and severity of AEs and laboratory 
abnormalities and the frequency of clinical responses occurring in 
patients with follicular NHL receiving intratumoral G100 at 20 
µg/lesion in single or multiple tumor masses and pembrolizumab 
therapy 
 
Part 5:  The nature, frequency and severity of AEs and laboratory 
abnormalities and the frequency of clinical responses occurring in 
patients with follicular NHL receiving rituximab therapy in 
combination with escalating doses of intratumoral G100 in single 
tumor lesions  
Secondary: 
 
The nature, frequency and severity of AEs and laboratory 
abnormalities until 21 days after G100 regimen is completed or 
discontinued 
 
Clinical responses by irRC using bi-dimensional measurements and 
expressed as partial response (PR), complete response (CR), stable 
disease (SD), or progressive disease (PD), time-to-progression (TTP) 
and/or progression-free survival (PFS) as a preliminary indication of 
efficacy  
 
As an exploratory comparison, assess clinical responses by the 
International Working Group response criteria for lymphomas (For 
determining PD, the irRC criteria will be used). Sponsor will assess 
for clinical responses by the Lugano criteria for lymphomas 
(Cheson  2014).  
 
Abscopal tumor responses in non-treated, distal tumor sites  


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Exploratory: 
 
Assessment of blood and tumor samples for exploratory biomarkers 
of immunologic and tumor response 
 
For Part 4 and 5, explore the pharmacokinetic and pharmacodynamic 
properties of IT G100 
Patient Population: 
Patients with follicular low-grade NHL with tumor masses accessible for 
intratumoral injection and, if enrolled on Parts 1, 2, or 3, local radiation 
therapy.  
Sample Size: 
In Part 1, Dose Escalation, up to 12 evaluable patients  
In Part 2,  
 
Patient Expansion group: up to 24 additional patients randomly 
assigned to receive G100 or sequential administration of G100 and 
pembrolizumab 
 
Large Tumor group: up to 4 evaluable patients (Optional) to receive 
G100 at 20 µg/dose 
In Part 3, 
 
G100 Expansion 20 µg Dose group:  up to 25 evaluable patients to 
receive G100 at 20 µg/dose 
In Part 4, 
 
G100 at 20μg/dose Into Single Or Multiple Tumor Lesions Plus 
Pembrolizumab: 22 efficacy evaluable patients as defined in the 
Statistical Section will be enrolled 
In Part 5,  
 
G100 Plus Rituximab: During Dose Escalation 12-24 patients and 
during Patient Expansion 20 efficacy evaluable patients as defined in 
the Statistical Section will be enrolled  
Inclusion Criteria: 
1) Follicular low-grade NHL (grades 1, 2, 3A): either treatment naïve or 
relapsed or refractory following at least one prior treatment. For France, 
patients with either relapsed or refractory only. In Part 1 Dose Escalation 
only, in addition to follicular NHL, marginal zone B cell lymphomas: 
either treatment naïve or relapsed or refractory following at least one 
prior treatment.   
 
In Part 4, enrollment is limited to relapsed or refractory follicular 
NHL patients who have received at least 3 prior systemic treatments, 
one of which was or included an anti-CD20 antibody.   
 
In Part 5, enrollment will include relapsed or refractory CD20+ 
follicular NHL following at least one but not more than 2 prior 
treatments.   


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2) Tumor mass(es) accessible for intratumoral injection and are being 
considered for local radiation therapy and at least one additional site of 
disease outside the radiation field for assessment of distal (abscopal) 
response (imaging assisted injections are allowed following approval by 
Medical Monitor) 
 
For Parts 4 and 5, radiation therapy is omitted.  Measurable tumor 
mass(es) accessible for intratumoral injection must be present for 
treatment and assessment of response.     
3) ≥18 years of age 
4) Life expectancy of ≥6 months per the investigator 
5) Eastern Cooperative Oncology Group (ECOG) performance status of 
0 or 1 
6) Electrocardiogram (ECG) without evidence of clinically significant 
arrhythmia or ischemia 
7) If female of childbearing potential (FCBP), willing to undergo pregnancy 
testing and agrees to use two methods of birth control or is considered 
highly unlikely to conceive during the dosing period and for three 
months after last study treatment, or if receiving pembrolizumab, four 
months after last treatment (See Section 8.1.9 and Appendix F for 
details) 
8) If male and sexually active with a FCBP, must agree to use effective 
contraception such as latex condom or is sterile (e.g., following a 
surgical procedure) during the dosing period and for three months after 
last study treatment, or if receiving pembrolizumab, four months after 
last treatment (See Section 8.1.9 and Appendix F for details) 
Exclusion Criteria: 
1) Cancer therapies, including chemotherapy, radiation (non-study regimen 
related), biologics or kinase inhibitors, granulocyte-colony stimulating 
factor (G-CSF) or granulocyte-macrophage colony stimulating factor 
(GM-CSF) within 4 weeks prior to the first scheduled G100 dose 
2) Investigational therapy within 4 weeks prior to G100 dosing 
3) Prior administration of G100 or other intratumoral immunotherapeutics 
4) Inadequate organ function including: 
a. Marrow: Peripheral blood leukocyte count (WBC) <3000/mm3, 
absolute neutrophil count ≤1500/mm3, platelets <75000/mm3, or 
hemoglobin <10 gm/dL 
b. Hepatic: alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) >2.5 × the upper limit of normal (ULN), 
total serum bilirubin >1.5 × ULN (patients with Gilbert’s Disease 
may be included if their total bilirubin is ≤3.0 mg/dL) 
c. Renal: Creatinine >1.5 × ULN 


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d. Other: international normalised ratio (INR) or partial thromboplastin 
time (PTT) >1.5 × ULN 
5) Significant immunosuppression from: 
a. Concurrent, recent (≤4 weeks ago) or anticipated treatment with 
systemic corticosteroids at any dose, or 
b. Other immunosuppressive medications such as methotrexate, 
cyclosporine, azathioprine or conditions such as common variable 
hypogammaglobulinemia 
6) Pregnant or nursing 
7) Myocardial infarction within 6 months of study initiation, active cardiac 
ischemia or New York Heart Association (NYHA) Grade III or IV heart 
failure 
8) History of other cancer within 2 years (except non-melanoma cutaneous 
malignancies and cervical carcinoma in situ) 
9) Recent (<1 week ago) clinically significant infection, active tuberculosis 
or evidence of active hepatitis B, hepatitis C or human 
immunodeficiency virus (HIV) infection 
10) Central nervous system involvement with lymphoma, including 
parenchymal and leptomeningeal disease.  In Parts 4 and 5, any 
involvement with lymphoma in a closed or confined space such as the 
retroorbital area will need to be pre-approved by the Medical Monitor. 
11) Significant autoimmune disease, including active non-infectious 
pneumonitis, with the exception of alopecia, vitiligo, hypothyroidism or 
other conditions that have never been clinically active or were transient 
and have completely resolved and require no ongoing therapy.  
(Replacement therapy for hypothyroidism or diabetes is allowed.) 
12) Psychiatric, other medical illness or other condition that in the opinion of 
the principle investigator (PI) prevents compliance with study procedures 
or ability to provide valid informed consent 
13) History of significant adverse or allergic reaction to any component of 
G100, if enrolled in Part 2 or Part 4, pembrolizumab and/or any of its 
excipients, and if enrolled in Part 5, anti-CD20 antibodies including 
rituximab and/or any of its excipients 
14) Use of anti-coagulant agents or history a significant bleeding diathesis. 
{If a superficial lymph node or subcutaneous (SC) mass is to be injected, 
patients on agents such as non-steroidal anti-inflammatory drugs 
(NSAIDs), aspirin, or clopidogrel are eligible and these agents do not 
have to be withheld.  For procedures with moderate or significant risk of 
bleeding, long-acting agents such as aspirin or clopidogrel should be 
discussed with the Medical Monitor and may need to be discontinued 
before G100 therapy.} 


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For patients enrolled in Part 2 or Part 4 with the potential to receive 
pembrolizumab: 
15) Has a history of (non-infectious) pneumonitis that required steroids or 
has current pneumonitis or interstitial lung disease 
16) Has received a live vaccine within 30 days prior to the first dose of study 
drug (Applies to patients who may receive either pembrolizumab or 
rituximab).  Examples of live vaccines include, but are not limited to, the 
following:  measles, mumps, rubella, varicella/zoster (chicken pox), 
yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid 
vaccine.  Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines 
(e.g., FluMist®) are live attenuated vaccines and are not allowed. 
17) Has undergone prior allogeneic hematopoietic stem cell transplantation 
within the last 5 years. (Subjects who have had a transplant greater than 
5 years ago are eligible as long as there are no symptoms of graft versus 
host disease [GVHD].) 
18) Has had an allogeneic tissue/solid organ transplant 
19) Has received prior therapy with an anti-PD-1, anti-programmed death 
ligand (PD-L)1, or anti-PD-L2 agent or if the patient has previously 
participated in Merck MK-3475 clinical trials or was previously treated 
with an agent directed to another stimulatory or co-inhibitory T-cell 
receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that 
treatment due to a Grade 3 or higher immune-related adverse event. 


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Trial Design: 
This is a Phase 1/2, open label, trial of G100 in patients with low grade 
follicular NHL. G100 is composed of glucopyranosyl lipid A formulated in a 
stable emulsion (GLA-SE).  GLA is a fully synthetic toll-like receptor 
(TLR)-4 agonist that is a potent stimulator of innate immune responses.  In 
this study, G100 will be administered intratumorally into tumors of follicular 
NHL patients in order to generate anti-tumor immune responses.  GLA in 
either the stable emulsion (SE) formulation or an aqueous formulation 
(GLA-AF) has been examined in >1000 patients as an adjuvant for various 
infectious agent and cancer vaccines as well as in 2 ongoing clinical studies 
involving patients with Merkel Cell carcinoma or sarcoma where it has been 
administered intratumorally, either alone or in combination with local 
radiation therapy.  G100 has demonstrated the ability to stimulate immune 
responses with an acceptable safety profile. 
In Part 1, Dose Escalation, patients with accessible tumors that are being 
considered for radiation therapy will receive standard local radiation 
followed by intratumoral injections of G100 into the irradiated mass(es).  
Two dose levels will be examined and a 3+3 sequential dose escalation 
design will be used.  All patients will receive a regimen consisting of 
standard low dose radiation (2 Gy every day [qd] x2, 4 Gy total) to the target 
tumor mass(es). G100 will be injected intratumorally beginning 1 day 
following completion of radiation therapy (Study Day 2), a second dose will 
be administered 3-5 days later (Study Day 5 to 7) and then dosing will 
continue weekly for up to 4 additional doses (6 total) as long as the tumor 
remains of sufficient size for injection.  A single lesion within the radiation 
field will be targeted to receive each dose of G100. If the lesion regresses, 
another lesion within the radiation field will be chosen for treatment 
(as described in the protocol).  If the tumor mass has not regressed 
completely from baseline, dosing may continue for 3 additional weekly 
intratumoral doses (9 total). 
Two dose levels of G100 are planned: 
 
Cohort 1:  5 µg  
 
Cohort 2:  10 µg  
Initially, three patients will be scheduled to receive G100 at the first dose 
level. Dose escalation will be contingent upon acceptable safety data 
obtained during the first 28 days of observation following initiation of the 
regimen.  A dose level cohort will be expanded from three to six if one of the 
first three patients experiences a dose-limiting toxicity (DLT).  Further 
patient accrual into that dose level cohort (or higher) will be suspended as 
soon as ≥2 patients in that cohort experience DLT, or when otherwise 
deemed clinically appropriate by the investigator or Sponsor medical 
monitor.  After the 28-day DLT observation period for the final patient in a 
cohort is complete, if less than one third of the patients enrolled in that cohort 
developed a DLT, advancement to the next dose-level cohort can begin.  


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Patients will be considered evaluable if they have received at least three 
G100 injections and have completed Day 28 safety monitoring OR have 
experienced DLT.  Patients who experienced DLT during the safety period 
will not be replaced.  All other patients who have not received at least three 
G100 injections and/or do not complete the Day 28 safety monitoring period 
for reasons other than treatment-related toxicity will be replaced.  
Following completion of the dose escalation stage of the trial, the maximum 
tolerated dose (MTD) or maximum safe dose (highest dose level examined in 
the study) will be defined as the highest dose reached in which less than one 
third of the patients in the cohort experienced a DLT. 
In Part 2, depending on the results of Part 1 and the MTD/maximum safe 
dose, two groups of patients may be examined, Patient Expansion With or 
Without Pembrolizumab and (optional) Large Tumor groups.  
Part 2, Patient Expansion With or Without Pembrolizumab group:  
Up to 24 patients will be randomly assigned and treated with single-agent 
intratumoral G100 or with the sequential administration of intratumoral G100 
and pembrolizumab at the MTD or maximum safe dose of G100 determined 
in Part 1.  This portion of the study is designed to be exploratory. Data 
indicate that inhibitory immune checkpoint pathways are up-regulated in the 
tumor microenvironment and that interfering with these regulatory pathways 
can lead to improved tumor responses in preclinical models.  Treatment will 
follow the same dose regimen as in Part 1 and consist of G100 at the MTD or 
maximum safe dose and local radiation therapy.  If the tumor mass has not 
regressed completely following 6 doses, treatment may continue for 
3 additional weekly intratumoral doses (9 total).  For patients randomized to 
anti-PD-1 therapy, on Day 14, pembrolizumab treatment will be initiated at a 
standard dose of 200 mg intravenously (IV) and then administered every 
3 weeks (Q3W) IV for up to 2 years or until disease progression or 
unacceptable toxicity.  For pembrolizumab, dose modification for AEs 
attributed to the drug will follow the guidelines as recommended for the 
product and as outlined in the protocol.  The main goal of Part 2, Patient 
Expansion With Or Without Pembrolizumab, is to gain safety information, 
immunologic data and early clinical experience with these regimens to allow 
planning for future studies with these agents.  
Part 2, Large Tumor group: If the G100 dose consisting of 10 µg of the GLA 
component is determined to be the maximal safe dose and the Data 
Monitoring Committee (DMC) agrees, an optional treatment group for Large 
Tumor patients will be treated. Preclinical data indicates a dose response to 
G100 and this will be explored in these patients. In this group, up to 
4 patients with injectable lymphoma mass(es) 4 cm or greater in total size 
(based on the sum of the measurements of the single greatest dimension of 
each the tumor(s) within the planned radiation field) will be enrolled and will 
receive G100 consisting of 20 µg of the GLA component per dose.  This will 
allow greater distribution of the G100 within the large tumor mass(es) and 


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the examination of safety and dose effect.  Treatment would be administered 
on the same treatment schedule as in Part 1 except that the G100 dose would 
be 20 µg of the GLA component.  The dose will be administered to a single 
large target lesion or distributed among 2 or more lesions within the radiation 
field.  If the target lesion(s) regresses, a different lesion within the radiation 
field will be chosen for treatment, if available.  If the tumor mass has not 
regressed completely following 6 doses, treatment may continue for 
3 additional weekly intratumoral doses (9 total). 
Part 3, G100 Expansion of 20 µg Dose group:  Following completion of 
enrollment of the Part 2 Patient Expansion With or Without Pembrolizumab 
group (as determined by Sponsor), and when at least 3 patients are enrolled 
in the Large Tumor Group with follow-up to at least Day 28, and contingent 
upon determining an acceptable safety profile following a review of G100 
alone data, commencement of Part 3 will begin.  Up to 25 patients with 
follicular NHL will be enrolled to receive local radiation therapy and 
intratumoral G100 at 20 µg/dose following the same treatment schedule as in 
Part 1 and Part 2 where G100 was administered alone.  Large tumors are not 
required, and patients with any injectable tumor mass regardless of size may 
participate.  Data from another study in sarcoma and early data from this trial 
have not demonstrated any safety concerns with the 20-µg dose level, and to 
date, all reported events considered at least possibly related to the study agent 
have only been grade 1 or 2.  Compared to baseline, post-treatment tumor 
biopsies have demonstrated significant increases in immune infiltrates within 
the tumor of some patients suggesting that this dose level should be explored 
further.  The dose will be administered to a single target lesion or distributed 
among 2 or more lesions within the radiation field.  If the target lesion(s) 
regresses, a different lesion within the radiation field will be chosen for 
treatment, if available.  If the tumor mass has not regressed completely 
following 6 doses, treatment may continue for 3 additional weekly 
intratumoral doses (9 total).  Data will be monitored continuously for safety, 
clinical effect, and exploratory biomarkers.  
Part 4, G100 at 20µg/lesion Into Single Or Multiple Tumor Masses Plus 
Pembrolizumab:  Data from Parts 1-3 of this study demonstrate that 
intratumoral G100 at the highest dose examined (20µg) has been well-
tolerated with only grade 1 or 2 related AEs and no DLTs reported with its 
use.  This higher dose has been associated with increased numbers of 
infiltrating CD8 T cells into the tumor (TILs), and greater numbers of CD8 
TILs have been statistically associated with the development of objective 
clinical responses.  In Part 2, the combination of G100 (10 µg) and 
pembrolizumab was well-tolerated without new or unexpected toxicities, and 
the addition of pembrolizumab resulted in more clinical responses, deeper 
abscopal tumor shrinkage, and a higher number of tumor infiltrating CD8 
T cells.  Therefore Part 4 will examine the 20µg dose of G100 in 1 or more 
tumor lesions (up to 4 lesions) plus pembrolizumab in order to establish 
safety and examine clinical and biomarker responses in patients receiving 
increasing total systemic doses of G100.   


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Part 4 will consist of a Dose Escalation group to evaluate and establish the 
safety of injecting 20µg of G100 into multiple lesions (up to 4 lesions) in 
combination with pembrolizumab and a Patient Expansion group to assess 
clinical responses with this regimen.  At least 22 relapsed or refractory 
follicular NHL patients who received ≥3 prior systemic therapies will be 
treated in Part 4.  Twenty-two efficacy evaluable patients as defined in the 
Statistical Section will be enrolled. 
During Dose Escalation, safety will be assessed using a 3+3 design where 
sequential cohorts of patients will be treated with intratumoral G100 at 
20µg/lesion in 1, 2, 3, or 4 tumor lesions corresponding to systemic G100 
exposure of 20, 40, 60 or 80µg G100.  Once the 20 µg systemic dose level 
cohort (20 µg injected in 1 lesion) has been established to be reasonably safe, 
patients who do not qualify to enroll on the next dose level cohort due to 
insufficient numbers of potentially injectable lesions may enter Patient 
Expansion at that single lesion dose level.  As each higher systemic dose 
level (40 µg, 60 µg, 80 µg) in multiple lesions is established to be well-
tolerated, additional patients who otherwise qualify for the study but are 
unable to be treated on Dose Escalation due to insufficient numbers of 
injectable lesions will be allowed to enroll into the Patient Expansion portion 
of the study at the established safe dose levels.  If complete enrollment of 
22 efficacy evaluable patients is reached before Dose Escalation is complete, 
the Sponsor may choose to continue enrollment into just the Dose Escalation 
cohorts with up to 12 patients to fill all or some of the remaining cohort(s). 
Treatment will follow a similar dose regimen as in "Part 2, Patient Expansion 
With or Without Pembrolizumab" group, except that radiation therapy has 
been omitted.  G100 will be injected intratumorally beginning on Day 0, a 
second dose will be administered 5-7 days later (Study Day 5-7) and then 
dosing will continue weekly for up to 4 additional doses (6 total) as long as 
the tumor remains of sufficient size for injection.  At least 1 lesion will be 
targeted to receive each dose of G100.  If the lesion regresses, another lesion 
will be chosen for treatment (as described in the protocol).  If the patient is 
entered in a cohort where more than one lesion is injected (cohorts 2 to 4), as 
many easily accessible tumors will be targeted and treated as specified for 
the cohort.  Imaging assisted injections are allowed but the feasibility and 
safety of these treatments must be discussed first and approved by the 
Medical Monitor.  If the tumor mass has not regressed completely from 
baseline, dosing may continue for 3 additional weekly intratumoral doses 
(9 total).  On Day 14, pembrolizumab treatment will be initiated at a standard 
dose of 200 mg intravenously (IV) and then be administered every 3 weeks 
(q3W) IV for up to 2 years or until disease progression or unacceptable 
toxicity. 
Part 4 Dose Escalation 
In the Dose Escalation portion, safety will be assessed using a 3+3 design 
where 12 to 24 patients will be assigned to sequential cohorts of escalating 


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number of G100 injected lesions in combination with standard dose 
pembrolizumab (Figure 6).  Four cohorts are planned: 
 
Cohort 1: G100 20 µg/lesion in 1 tumor  
 
Cohort 2: G100 20 µg/lesion in 2 tumor lesions (40 µg total) 
 
Cohort 3: G100 20 µg/lesion in 3 tumor lesions (60 µg total) 
 
Cohort 4: G100 20 µg/lesion in 4 tumor lesions (80 µg total)  
Once a Cohort dose level is established to be safe, patients who do not meet 
the criteria of sufficient numbers of injectable tumors to enter the next dose 
Cohort will be enrolled in a Patient Expansion group at a systemic dose level 
that has already been established as safe.   
Initially, three patients will be scheduled to receive G100 at the first dose 
level.  Dose escalation will be contingent upon acceptable safety data 
obtained during the first 28 days of observation following initiation of the 
regimen.  A dose level cohort will be expanded from three to six if one of the 
first three patients experiences a dose-limiting toxicity (DLT).  Further 
patient accrual into that dose level cohort (or higher) will be suspended as 
soon as ≥2 patients in that cohort experience DLT, or when otherwise 
deemed clinically appropriate by the investigator or Sponsor Medical 
Monitor.  After the 28-day DLT observation period for the final patient in a 
cohort is complete, if less than one third of the patients enrolled in that cohort 
developed a DLT, advancement to the next dose-level cohort can begin.  
During Dose Escalation, patients will be considered evaluable for 
determination of safety and dose-level cohort advancement if they have 
received at least three complete G100 treatments and 1 dose of 
pembrolizumab and have completed Day 28 safety monitoring OR have 
experienced DLT.  Patients who experienced DLT during the safety period 
will not be replaced.  All other patients who have not received at least three 
G100 treatments and 1 dose of pembrolizumab and/or do not complete the 
Day 28 safety monitoring period for reasons other than treatment-related 
toxicity will be replaced.  
Following completion of the Dose Escalation portion of Part 4, the maximum 
tolerated dose or maximum safe dose (highest dose level examined in the 
study) will be defined as the highest dose reached in which less than one 
third of the patients in the cohort experienced a DLT. 
Potential Dose Modification During Dose Escalation 
G100 is a local therapy with systemic immune responses.  Therefore, the 
safety profile may differ from that of systemically administered agents.  In 
order to further investigate this, if 2 or more DLTs are observed in the initial 
cohort at 20 µg of G100, the Sponsor, in agreement with the independent 
DMC may choose to examine a new cohort of patients to better understand 
whether or not the DLTs associated with the injection of a single lesion 


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might be abrogated by decreasing the dose and administering the lower 
single lesion dose of 10 µg into multiple lesions.  Intratumoral G100 10µg in 
a single lesion in combination with pembrolizumab was established to be 
well-tolerated in Part 2 of this study.  Thus, this new cohort would examine 
the safety of G100 10µg administered into 2 injectable lesions and would use 
the same 3+3 design described above.  Based on a review of the safety 
profile of this new cohort and in agreement with the independent DMC, 
further dose escalation cohorts may be investigated using this lower dose of 
10 µg/lesion and a similar dose escalation schema as described above where 
up to 4 lesions may be potentially treated.   
For pembrolizumab, dose modification for AEs attributed to the drug will 
follow the guidelines as recommended for the product and as outlined in the 
protocol.  
Part 4 Patient Expansion  
Once the G100 20 µg systemic dose level has been established to have an 
acceptable safety profile, patients who otherwise qualify for the study but do 
not have the requisite number of injectable tumor masses to enroll on the 
dose cohort currently under evaluation may be enrolled into a Patient 
Expansion group.  The Patient Expansion group will begin to evaluate 
clinical response (ORR) and biomarker changes of G100 plus 
pembrolizumab combination.  An exploratory analysis will also be 
performed in those who are considered TLR4high.   
The per lesion dose during Patient Expansion will be 20µg/lesion.  The total 
administered dose of G100 will depend on the safety established with each 
dose cohort.  Determination of the number of potential injectable lesions will 
be made by the investigator in consultation with Medical Monitor. 
As the safety of each dose cohort is established, the number of allowed 
injectable lesions in Patient Expansion will be as follows: 
Established Safe Systemic Dose 
Treatment In Patient Expansion 
20 µg dose level  
20 µg in 1 lesion 
40 µg dose level  
20 µg in up to 2 lesions 
60 µg dose level  
20 µg in up to 3 lesions 
80 µg dose level  
20 µg in up to 4 lesions 
Patient enrollment will be monitored.  It is planned that 22 efficacy evaluable 
patients will be treated with intratumoral G100 and IV pembrolizumab in 
Part 4 in order to provide sufficient data for evaluation of efficacy (see 
Statistical Section).  Patients who received G100 20µg/lesion during Dose 
Escalation in Part 4 may be included in the clinical response analysis. 
Part 5, G100 Plus Rituximab:  Studies have demonstrated the potential for 
additive or synergistic effects of the combination of G100 and rituximab.  
G100 has been shown to increase the number of inflammatory and activated 


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immune cells within the tumor microenvironment, including T cells, NK 
cells, macrophage and dendritic cells.  Rituximab can potentially increase the 
loading/pulsing of dendritic cells with tumor antigen, leading to more 
effective antigen presentation of rare tumor antigens.  Rituximab and other 
similar antibodies that bind to tumor cells and debris have been previously 
shown to facilitate the uptake and processing of tumor antigens by dendritic 
cells through opsonization/phagocytosis.  In addition, a known mechanism of 
action of rituximab is through antibody dependent cellular cytotoxicity 
(ADCC).  In preclinical work, the combination of G100 with rituximab 
demonstrated enhanced ADCC.  Therefore, G100 in combination with 
rituximab can increase the amount of tumor antigen processed by dendritic 
cells potentially leading to greater T cell stimulation/activity; in addition, the 
combination could enhance tumor cytotoxicity by activating and increasing 
the number of ADCC effector cells. 
In this study, a Dose Escalation will be performed first followed by Patient 
Expansion. During Dose Escalation 12-24 patients and during Patient 
Expansion 20 efficacy evaluable patients as defined in the Statistical Section 
will be enrolled.  Patient enrollment will be monitored.  Patients who 
received G100 during Dose Escalation in Part 5 may be included in clinical 
response analysis. 
Data from the G142 study indicate that the G100 intratumoral dose of 20µg 
is relatively safe with only grade 1 or 2 related AEs reported and no DLTs 
and that this higher dose appears to induce greater numbers of infiltrating 
CD8 T cells into the tumor.  Recent preclinical data indicate that G100 doses 
greater than 20 µg can lead to improved survival of animals in tumor models, 
further supporting that additional dose exploration may be warranted.  
Therefore, this arm will examine escalating doses of G100 plus rituximab in 
a single tumor site utilizing a 3+3 design in order to establish safety and 
examine clinical and biomarker responses.  Once the highest safe 
dose/systemic exposure is determined from the Dose Escalation portion of 
the study, all safety, efficacy and biomarker data will be reviewed by the 
Sponsor (in collaboration with the independent DMC) and either the highest 
dose determined to be safe or the most biologically active and safe dose (if 
different than the MTD) will be chosen for further investigation.  A Patient 
Expansion group would then begin.  Details of Dose Escalation and Patient 
Expansion are described below. 
Part 5, Dose Escalation 
In the Dose Escalation portion, safety and efficacy of G100 injected into a 
single tumor lesion without radiation will be assessed using a 3+3 design 
where patients will be assigned to sequential cohorts of escalating doses of 
intratumoral G100 in combination with standard dose induction therapy with 
rituximab (Figure 8 and Figure 9).  Treatment will begin on Day 0 with 
rituximab 375mg/m2 IV and continue weekly for a total of 4 doses.  If there 
are no DLTs or significant safety events after the first dose of rituximab, 
G100 will be injected intratumorally beginning on Day 1, and then dosing 


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will continue weekly for 3 additional doses (4 total) on a visit schedule that 
coincides with rituximab treatments as long as the tumor remains of 
sufficient size for injection.  One lesion will be targeted to receive each dose 
of G100. If the lesion regresses, another lesion will be chosen for treatment. 
Imaging assisted injections are allowed but the feasibility and safety of these 
treatments must be discussed first and approved by the Medical Monitor.  If 
the tumor lesion has not regressed completely after the first 4 doses of G100, 
dosing may continue for 2 additional weekly intratumoral doses (6 total).  
Following restaging, the patient may be eligible for a second course of G100.  
Four cohorts G100 plus rituximab are planned and will be enrolled 
sequentially: 
 
Cohort 1: G100 20 µg in single tumor lesion 
 
Cohort 2: G100 40 µg in a single tumor lesion 
 
Cohort 3: G100 60 µg in a single tumor lesion 
 
Cohort 4: G100 80 µg in a single tumor lesion 
Initially, 3 patients will be scheduled to receive G100 at the first dose level. 
Dose escalation will be contingent upon acceptable safety data obtained 
during the first 28 days of observation following initiation of the regimen.  
A dose level cohort will be expanded from 3 to 6 if one of the first 3 patients 
experiences a dose-limiting toxicity (DLT).  Further patient accrual into that 
dose level cohort (or higher) will be suspended as soon as ≥2 patients in that 
cohort experience DLT, or when otherwise deemed clinically appropriate by 
the investigator or Sponsor Medical Monitor.  After the 28-day DLT 
observation period for the final patient in a cohort is complete, if less than 
one third of the patients enrolled in that cohort developed a DLT, 
advancement to the next dose-level cohort can begin.  
During Dose Escalation, patients will be considered evaluable for 
determination of safety and dose-level cohort advancement if they have 
received at least 3 complete G100 treatments and 3 doses of rituximab and 
have completed Day 28 safety monitoring OR have experienced DLT.  
Patients who experienced DLT during the safety period will not be replaced. 
All other patients who have not received at least 3 G100 treatments and 
3 doses of rituximab and/or do not complete the Day 28 safety monitoring 
period for reasons other than treatment-related toxicity will be replaced.  
Based on ongoing evaluation of study data, the Sponsor may decide to 
complete fewer than the planned 4 dose cohorts and proceed directly to the 
Patient Expansion portion of the study. 
Following completion of the dose escalation stage of the trial, the MTD will 
be defined as the highest dose reached in which less than one third of the 
patients in the cohort experienced a DLT.  If no DLTs are experienced in the 
first 3 patients enrolled at highest dose of 80µg, the 80µg dose per lesion will 
be determined to be the “maximum safe dose” examined in this study and 


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dose escalation will be considered complete.  An additional 3 patients may 
then be enrolled for a total of 6 patients at that dose level and safety stopping 
rules will be followed.  If after the Sponsor and DMC review all safety data it 
is determined that there are no safety issues requiring the separation of the 
first dose of rituximab and G100, the regimen may be modified to administer 
both on Day 0 during Patient Expansion. 
Part 5, Patient Expansion  
Once the MTD/maximum safe dose has been established, all safety, clinical 
and biomarker data will be reviewed and a recommended dose for further 
exploration will be made.  The Patient Expansion would then begin and 
would enroll patients to receive G100 IT at the recommended dose into a 
single tumor mass in combination with rituximab.  Patients enrolled on Part 5 
Patient Expansion will be analyzed on the basis of the ORR.  An exploratory 
analysis will also be performed in those who are considered TLR4high.   
Patients will be enrolled with the intent of obtaining data from at least 20 
efficacy evaluable patients as defined in the Statistical Section.  Patients who 
received G100 at the recommended dose during Dose Escalation in Part 5 
may be included in clinical response analysis. 
G100 is a local therapy with systemic immune responses.  Therefore, the 
safety profile may differ from that of systemically administered agents.  In 
order to further investigate this, after establishment of an MTD, the Sponsor 
in agreement with the independent DMC may choose to examine one 
additional cohort of patients to better understand whether or not the DLTs 
associated with the injection of a single lesion might be abrogated by 
splitting the dose and administering into two separate lesions.  The data from 
this cohort may help determine if the tolerability of G100 was limited due to 
the injection of a single tumor mass or to the total systemic exposure.  In this 
additional cohort, 3-6 patients would be treated at the total systemic dose 
level associated with DLTs but divided and distributed into two tumor 
masses instead of one.  For example, if the MTD in a single tumor mass were 
determined to be 40µg due to DLTs occurring at 60µg/lesion, the dose of this 
cohort would be 30µg/lesion injected separately into 2 tumor masses.  In the 
event that the 20µg dose level (Cohort 1) experiences DLTs, a cohort of 
10µg/lesion administered into 2 lesions may be explored.  The information 
from this additional cohort could help the design of future studies.  The 
decision whether or not to open this cohort would be made when the Dose 
Escalation data is reviewed following the determination of the MTD.  No 
additional treatment cohorts are planned beyond this one group.  Following 
this evaluation, patients would be enrolled into the Patient Expansion group 
and would receive G100 injected into a single lesion at the recommended 
dose. 


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For rituximab, dose modification for AEs attributed to the drug will follow 
the guidelines as recommended for the product and as outlined in the 
protocol.  
For All Parts (1 to 5) 
Retreatment / Second Course:  Following the G100 course of treatment, if a 
patient is determined to have achieved SD or better or has PD that does not 
require immediate therapy, has an additional site of disease outside of the 
prior radiation field (Parts 1, 2, or 3) that is amenable to injection, and has 
not had significant treatment emergent AEs (including events that would be 
considered a DLT) as determined by the investigator and the Sponsor, the 
patient may be eligible to receive a second course of G100.  For patients 
enrolled on Parts 4 or 5, the same previously injected tumor site(s) may be 
targeted or a replacement site(s) may be chosen.   
Six weeks or more after completion of the first course of G100 treatment, the 
second course would begin and consist of G100 alone (no radiation and no 
additional rituximab for patients enrolled on Part 5) at the same dose 
received during the first course of therapy.  Treatment would be administered 
on a similar weekly schedule as the first course except without radiation 
therapy (or rituximab therapy).  G100 will be injected intratumorally 
beginning on Day 0, a second dose will be administered 5 to 7 days later and 
then dosing will continue weekly for up to 4 additional doses (6 total) as long 
as the tumor remains of sufficient size for injection.  For Parts 1 to 3, a single 
lesion will be targeted to receive each dose of G100.  If the lesion regresses, 
another lesion will be chosen for treatment.  If the tumor mass has not 
regressed completely, dosing may continue for 3 additional weekly 
intratumoral doses (9 total).  If the patient had been receiving pembrolizumab 
as part of their therapy, the anti-PD-1 antibody would continue as scheduled 
during the second course.  For Part 4, dosing may continue into multiple 
lesions as selected for their initial course; for Part 5, the number of G100 
doses is limited to 6 treatments of a single lesion. 
Dose regimen interruption in a single patient may be made by the clinical 
investigator if it is deemed in the best interest of patient safety.  The study 
Medical Monitor should be consulted prior to or immediately upon the 
decision to interrupt therapy.  Safety will be reviewed on a regular basis by 
an independent DMC and the Sponsor.  These reviews may lead to 
modification or stopping of the treatment program. 
Tumor imaging will be performed during the screening visit (baseline) and 
then approximately every 8 weeks thereafter for the first year, every 3 to 4 
months for the second year, and then at least every 6 months for the third and 
subsequent years until disease progression as defined by the irRC.  Pre- and 
post-treatment tumor biopsies (e.g., core biopsies) will be obtained for 
histologic review and exploratory immune analyses, including cell 
phenotype, tumor expression of TLR4, and genomic analyses of T cells.  
Post-treatment biopsies will be performed in patients with accessible tumors 


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within 3 weeks after the last planned G100 injection.  Peripheral blood will 
be drawn for immune assays and biomarker tests at time points listed in the 
Study Procedures.  
Duration of Patient 
Participation: 
Patients will continue with clinical assessments every 8 weeks and will have 
imaging assessments every 8 weeks for the first year, every 3 to 4 months for 
the second year, and then at least every 6 months for the third and subsequent 
years until disease progression as defined by the irRC.  If the patient 
experiences PD, the expected duration of a patient’s participation and follow-
up in the trial is approximately 1 year (or longer if the patient agrees) to 
determine clinical status and time to next treatment. 
Dosing Limiting 
Toxicity: 
DLTs will be used to establish safety parameters for stopping dose escalation 
and will follow a standard 3+3 study design.  AE severity assessments will 
be performed using National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) v4.03 or newer.  Unacceptable toxicity 
is defined when two or more subjects in a dose level cohort develop DLTs 
considered at least possibly related to the study regimen.  Further dosing at 
that level will be discontinued.  Hospitalizations primarily intended to 
expedite diagnostic evaluations or for elective surgery will not be considered 
as serious adverse events (SAEs) for the purpose of ascertaining DLT. 
The occurrence of any of the following toxicities during the first 28 days will 
be considered a DLT, if assessed by the investigator to be possibly, probably, 
or definitely related to any component of study treatment (G100, 
pembrolizumab, or rituximab):  
1. Grade 4 nonhematologic toxicity (not laboratory). 
2. Grade 4 hematologic toxicity lasting ≥7 days, except 
thrombocytopenia: 
 
Grade 4 thrombocytopenia of any duration 
 
Grade 3 thrombocytopenia associated with clinically significant 
bleeding 
3. Any nonhematologic AE ≥Grade 3 in severity should be considered 
a DLT, with the following exceptions: Grade 3 fatigue lasting 
≤3 days; Grade 3 diarrhea, nausea, or vomiting without use of anti-
emetics or anti-diarrheals per standard of care; Grade 3 rash without 
use of corticosteroids or anti-inflammatory agents per standard of 
care. 
4. Any Grade 3 or Grade 4 non-hematologic laboratory value if: 
 
Clinically significant medical intervention is required to treat the 
subject, or 


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 
The abnormality leads to hospitalization, or 
 
The abnormality persists for >1 week. 
 
The abnormality results in a Drug-induced Liver Injury (DILI)  
 
Exceptions: Clinically nonsignificant, treatable, or reversible 
laboratory abnormalities including liver function tests, uric acid, 
etc. 
5. Febrile neutropenia Grade 3 or Grade 4: 
 
Grade 3 is defined as ANC <1000/mm3 with a single temperature 
of >38.3 degrees C (101 degrees F) or a sustained temperature of 
≥38 degrees C (100.4 degrees F) for more than 1 hour 
 
Grade 4 is defined as ANC <1000/mm3 with a single temperature 
of >38.3 degrees C (101 degrees F) or a sustained temperature of 
≥38 degrees C (100.4 degrees F) for more than 1 hour, with life-
threatening consequences and urgent intervention indicated. 
6. Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-
related toxicity. 
7. Any treatment-related toxicity that causes the participant to 
discontinue treatment during Cycle 1. 
8. Grade 5 toxicity. 
9. Missing >25% of study drug doses as a result of treatment-related 
AE(s) during the first cycle. 
Maximum Tolerated 
Dose/ Maximum Safe 
Dose Examined: 
The MTD will be defined as the highest G100 dose level studied in which 
less than one third of patients in a cohort experience DLT.  If the MTD is 
declared at the final dose level, the highest dose will be considered the 
maximum safe dose examined in the trial. 
Progressive Disease: 
The irRC using bi-dimensional measurements will be used to determine 
disease progression.  Immunomodulatory agents can induce tumor size 
changes due to immune inflammatory reactions and do not represent true 
tumor progression.  To help mitigate false determinations of tumor growth, 
irRC requires a confirmation of PD at least 4 weeks later with imaging and/or 
by direct tumor measurement.  In addition, the appearance of new lesions 
does not define disease progression but their size measurements are added to 
the tumor burden calculation.  


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 37 of 177 
Stopping Rules 
During the initial 28-day treatment period, dosing will be suspended at any 
dose level (and higher) if DLTs are observed in 2 or more patients during 
Part 1 or during Dose Escalation of Part 4 or Part 5.  During patient 
expansion of Parts 2, 3, 4 and 5, dosing will be suspended if DLT considered 
at least possibly related to the study medications are observed during the first 
28 days in one third or more patients within a group receiving the same 
treatment (assuming a minimum of 6 patients receiving the same dose and 
treatment regimen and would represent the initial denominator:  In Parts 2 
and 3, G100 alone; in Parts 2 and 4, G100/pembrolizumab, in Part 5, 
G100/rituximab)  
All AEs and DLTs observed during dose escalation of any treatment arm 
and/or patient expansion meeting the criteria of a stopping rule will be 
reviewed by the DMC.  If there is disagreement between the DMC and the 
investigator’s assessment regarding the relationship of the event to study 
agent or to the clinical relevance (e.g., lab abnormality), the Sponsor in 
consultation with the DMC may determine to stop the treatment or continue.  
In the later case, the AE may become a medical event of interest and be 
tracked closely for additional events occurring in the future with intratumoral 
G100. 
Safety Monitoring: 
G100 safety will be monitored by evaluating both solicited and 
spontaneously reported AEs, including reactogenicity, symptoms, physical 
examination findings, vital signs, laboratory findings, ECGs and 
discontinuations for AEs.  Monitoring will be continuous. An independent 
DMC will operate in accord with a signed charter, will consist of 
2 oncologists, and will provide independent review/assessment of all safety 
data on a regular basis to minimize risks to study patients.  The DMC and 
Sponsor will review all DLTs and SAEs considered at least possibly related 
to the study regimen as they are reported on an ongoing basis.  In addition, 
the DMC and Sponsor will review all safety data for any trends at least once 
every 3 months.  SAE reports considered at least possibly related to the study 
regimen and are unexpected will be expedited to regulatory authorities, 
investigators and DMC members.  These reviews may lead to modification 
of the treatment program.  
In Part 2, two groups of patients are planned: Patient Expansion (G100 alone 
and sequential G100 and pembrolizumab) and Large Tumor groups 
(optional).  The Patient Expansion With Or Without Pembrolizumab group 
will begin once the MTD / maximum safe dose is determined from Part 1.  
Based on the results of Part 1 and the safety profile of the highest dose level, 
the DMC will recommend whether or not to open the optional Large Tumor 
treatment group.  The Large Tumor group will only be possible if the 
10 µg/dose level is determined to be safe.  
In Part 3, G100 Expansion of 20 µg Dose Group, treatment may begin after 
enrollment into Part 2 Patient Expansion (G100 alone and sequential G100 
and pembrolizumab) has been completed (as determined by Sponsor), at least 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 38 of 177 
3 patients have been enrolled in the Large Tumor group and observed to at 
least Day 28, and an acceptable safety profile has been determined.  The 
Sponsor in consultation with the DMC will review the safety profile of G100 
alone data from Part 1 and 2.  Commencement of Part 3 will be contingent 
upon determination of an acceptable safety profile of G100 alone data at that 
evaluation timepoint.  In Part 3, up to 25 patients will be enrolled to receive 
local radiation therapy and intratumoral G100 at 20 µg/dose following the 
same treatment schedule as in Part 1 and Part 2 where G100 was 
administered alone.  
In Part 4, G100 at 20µg/lesion Into Single Or Multiple Tumor Masses Plus 
Pembrolizumab Group, treatment may begin after enrollment into Part 3 has 
been completed (as determined by Sponsor), and an acceptable safety profile 
has been determined by the Sponsor in consultation with the DMC.  In Part 
4, at least 22 evaluable patients will be enrolled to receive sequential IT 
G100 at 20 µg/lesion and pembrolizumab at 200mg IV every 3 weeks 
following the same treatment schedule as in Part 2 where G100 was 
administered with pembrolizumab, except without radiation therapy.  During 
dose escalation, sequential cohorts of patients will be treated with 
intratumoral G100 at 20µg/lesion in 1, 2, 3, or 4 tumor masses corresponding 
to local and systemic G100 exposure of 20, 40, 60 or 80µg of the GLA 
component.  Patient Expansion will be allowed to begin at each dose level as 
safety is established for each cohort and agreed upon with the DMC.  
Twenty-two efficacy evaluable patients as defined in the Statistical Section 
will be enrolled. 
In Part 5, G100 Plus Rituximab, treatment may begin after enrollment into 
Part 3 has been completed (as determined by Sponsor), and an acceptable 
safety profile has been determined by the Sponsor in consultation with the 
DMC.  In Part 5, patients will be enrolled to receive IT G100 and standard 
induction rituximab without radiation therapy.  During Dose Escalation, 
sequential cohorts of 3-6 patients will be treated with intratumoral G100 at 
20, 40, 60 or 80 µg/dose into a single tumor mass.  Once the highest safe 
dose/systemic exposure is determined from the Dose Escalation portion of 
the study, all safety, efficacy and biomarker data will be reviewed by the 
Sponsor (in collaboration with the independent DMC) and either the highest 
dose determined to be safe or the most biologically active and safe dose (if 
different than the MTD) will be chosen for further investigation.  The Patient 
Expansion would then begin and would treat patients with G100 at the 
recommended dose in a single lesion in combination with rituximab.  
Overall, 20 efficacy evaluable patients as defined in the Statistical Section 
will be enrolled 
In addition to the stopping rules (DLTs within the initial 28 days), these 
DMC safety reviews may lead to modification or stopping of the treatment 
program if related, treatment-emergent AEs indicate a safety profile that is 
inconsistent or significantly worse than reported with the use of G100 alone 
or pembrolizumab alone or rituximab alone.  


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 39 of 177 
During Part 2 and based on the continuous review of safety events, if the 
dose of 10 μg G100 is used during Patient Expansion and subsequently 
determined to have an increased safety risk, the DMC may recommend and 
the Sponsor may choose to reduce the dose of G100 to 5 μg or they may 
recommend stopping the G100 treatment.  If the 5 μg dose level is 
determined not to be safe by the independent DMC, treatment with G100 will 
be stopped.  Following evaluation by the DMC and the Sponsor, a further 
modification to the dose/treatment schedule could be recommended.   
During Part 4 and based on the continuous review of safety events, if the 
dose of 20 μg/lesion G100 plus pembrolizumab is subsequently determined 
to have an increased safety risk, the DMC may recommend and the Sponsor 
may choose to reduce the dose of G100 to 10μg or they may recommend 
stopping the G100 treatment.  
Similarly during Part 5, if G100 plus rituximab is subsequently determined 
to have an increased safety risk, the DMC may recommend and the Sponsor 
may choose to reduce the dose of G100 or they may recommend stopping the 
G100 treatment.  As described in the Part 5 design, an optional cohort may 
be examined where the dose level associated with a DLT is split in two 
lesions in order to help determine if the lack of tolerability of the dose was 
due to the treatment of a single lesion or was limited due to the total systemic 
G100 exposure.  Following evaluation by the DMC and the Sponsor, a 
further modification to the dose/treatment schedule could be recommended.   
All patients treated with one or more injections of G100 will be considered 
part of the safety data set.  Patients will be followed every 8 weeks until 
disease progression as defined by the irRC.  Patients with disease progression 
by irRC (or symptomatic deterioration) will be followed thereafter every 
8-12 weeks by telephone or clinical visit for up to one year (or longer if the 
patient agrees) after first study injection as long as they are able to engage in 
follow-up.  Follow-up will ascertain vital status (survival status) as well as 
cancer status (e.g., lymphoma transformation), post-treatment anti-cancer 
therapy (including time to next treatment, treatment details, and clinical 
response), and any SAE that might be possibly related to G100 treatment.  
Patients followed on this study have developed delayed objective tumor 
responses occurring >18 months from study start.  If patients develop late 
responses after initial IrRC progression but have not received additional 
therapy, they may be asked to consent to additional follow-up of clinical 
response and biomarker analyses. 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 40 of 177 
Data Analysis: 
An interim analysis will be performed on the first 6 to 12 evaluable subjects 
in Part 1 who have completed the Day 77 assessment or completed an end of 
study evaluation.  
Safety: 
Tabulation, summarization and descriptive statistics will be performed for all 
safety information including AEs, SAEs, laboratory findings and 
discontinuations of patients at all data collection time points.  No formal 
statistical hypothesis will be tested. 
Immunogenicity: 
Tabulation, summarization and descriptive statistics will be performed 
describing the baseline and post G100 administration peripheral blood 
lymphocyte subsets.  Analyses will be performed to determine if there are 
any statistically significant changes from baseline values.  An exploratory 
analysis will be performed to examine TLR4 expression in baseline tumor 
cells and will be investigated to understand if there is an association between 
baseline TLR4 expression levels and clinical outcome.  Association between 
other pre-existing/post treatment immunogenicity biomarkers and clinical 
outcome will also be explored. 
Tumor Response: 
Anti-tumor activity as defined by irRC using bidimensional measurements 
will be reported.  The primary analysis will be based on investigator’s 
assessment.  Independent radiology review will be supportive.  As a 
comparison, tumor response using the International Working Group and 
Lugano (Cheson 2014) criteria for lymphoma will also be analyzed. IrRC 
will be used to determine PD.  The main differences between the criteria are 
that the IrRC requires confirmatory restaging to determine if tumor size 
increase is due to true progression instead of immune inflammation and that 
new lesions add to tumor size calculations are not determinants of PD by 
themselves.  Please see Appendix B for details.  Progression-free survival 
and/or TTP will be plotted as a Kaplan-Meier curve.  Disease control rate 
(CR, PR, and SD) and overall response rate (ORR or CR + PR) will be 
reported.  Time to next treatment, overall survival (OS), and the Follicular 
Lymphoma International Prognostic Index (FLIPI) may also be examined as 
exploratory analyses. 
Independent radiology review of tumor assessments: 
The Sponsor may request at any time that radiographic images of tumor 
assessments for all or select patients be submitted to central storage facility 
for the purpose of an independent radiology assessment of tumor responses.  
All patients starting with protocol version 4B will be required to provide an 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 41 of 177 
informed consent for such central storage and independent radiology review 
prior to study treatment. 
Part 4 
In Part 4, G100 plus pembrolizumab, at least 22 evaluable patients will be 
enrolled and treated as part of a Dose Escalation group or a Patient 
Expansion group with intratumoral G100 in combination with 
pembrolizumab.  The purpose of this treatment regimen will be to explore the 
safety and preliminary clinical efficacy and biomarker changes of patients 
treated with G100 at a dose of 20 µg/lesion injected in single or multiple 
lesions.  The administered dose of G100 will depend on the number of 
potentially injectable lesions and whether the MTD has been established 
during Dose Escalation.  One or more lesions will be targeted for injection 
and each lesion would receive 20µg of G100 intratumorally (or 10 µg G100 
if 20 µg/lesion in a single lesion is not tolerated) as long as the total number 
of treated tumor lesions and total systemic dose does not exceed the MTD (if 
established) or 80 µg total dose (20 µg injected in 4 lesions).  This analysis is 
designed to be exploratory and will evaluate safety, clinical outcome and 
exploratory biomarkers to guide further clinical development.  Clinical 
efficacy including ORR and DOR will be evaluated in relapsed or refractory 
follicular NHL patients who received ≥3 prior systemic therapies. 
For this analysis, 22 efficacy evaluable patients will be required. Efficacy 
evaluable patients are patients who received at least 3 doses of G100 at 
20 µg/lesion and at least 1 dose of pembrolizumab, had at least one post 
baseline tumor assessment, and had no major protocol deviations that impact 
the efficacy of the study treatment or the assessment of response.  Patients 
who received G100 20µg/lesion during Dose Escalation in Part 4 may be 
included in clinical response analysis.  With a target ORR of 40%, if ≤5 
responders are observed among 22 evaluable patients, we will conclude 
futility with 7.2% error rate.  The Sponsor will use this analysis to decide 
whether to continue further clinical development of this regimen.  Early 
acceptance of treatment at the end of the 22 evaluable patients is not 
permitted.  If the true ORR for this group is 20% and 20% ORR is 
considered not clinically meaningful, the probability of observing ≤5/22 
responders and stopping the study is 73.3%.  
Part 5 
In Part 5, G100 Plus Rituximab, after Dose Escalation has been completed, 
patients will be treated with intratumoral G100 at the recommended dose 
level in combination with rituximab.  The purpose of this Patient Expansion 
group will be to explore the safety and clinical outcome of patients treated at 
a biologically active and safe G100 dose level administered into single tumor 
lesion in combination with rituximab.  This analysis is designed to be 
exploratory and will evaluate safety, clinical outcome and exploratory 
biomarkers.  


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 42 of 177 
An exploratory analysis will be performed on 20 efficacy evaluable relapsed 
or refractory FL patients and will include analyses of the frequency and 
duration of CRs.  Efficacy evaluable patients are patients who received at 
least 3 injections of G100 at the recommended dose and 3 doses of 
rituximab, had at least one post baseline tumor assessment, and had no major 
protocol deviations that impact the efficacy of the study treatment or the 
assessment of response.  Five or more CRs in 20 patients treated with G100 
plus rituximab will signal an improvement of CR rate over 10%.  Patients 
who received G100 at the recommended dose during Dose Escalation in Part 
5 may be included in clinical response analysis.  With 20 efficacy evaluable 
patients, and a historical CR rate of 10%, assuming a true CR rate of 32% in 
the G100 plus rituximab, this subgroup analysis has 82% power to detect a 
signal of an improvement in CR rate from 10% at a 1-sided alpha of 0.05.  


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 43 of 177 
3.2 
Schedule of Events: Part 1, Dose Escalation and Part 2, Patient Expansion (G100 alone) and Large Tumor Groups 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
10A 10B 
11 
12 
Follow-up  
LT Follow-
up after PD 
Timeline – weeks 
-4 to 0 
-1 
0 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
11 
Day 112 
then every 
8 weeksh 
Every 8-12 
weeks 
Timeline – days 
-30 to -1 
-7 to -1 
0 
1 
2 
5 to 7 
14 
21 
28 
35 
42 
49 
56 
77 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent / HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics / Medical  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of cancer therapy  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
Report all AEs and SAEs 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
 
 
Report possibly-related SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Record any previous / concomitant 
medications 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
Vital signs 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exama 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG (12-Lead) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Tumor staging, including CT, MRI, 
and/or other modalities 
X 
 
 
 
 
 
 
 
 
 
 
 
Xb 
Xb 
Xh 
 
ECOG  
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV, HepB, and HepC (5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beta-2-microglobulin (5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for phenotyping/profiling 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
Blood for safety labs (10 mL)   
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid function testsf  (5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for T cell gene profiling 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Local Radiation 2Gy qd x2 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 44 of 177 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
10A 10B 
11 
12 
Follow-up  
LT Follow-
up after PD 
Timeline – weeks 
-4 to 0 
-1 
0 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
11 
Day 112 
then every 
8 weeksh 
Every 8-12 
weeks 
Timeline – days 
-30 to -1 
-7 to -1 
0 
1 
2 
5 to 7 
14 
21 
28 
35 
42 
49 
56 
77 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
G100 dosing 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Tumor biopsy  
X 
 
 
 
 
 
 
 
 
 
 
 
Xd 
Xd 
 
 
Clinical Status, treatment history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
Blood volume per visit (mL) 
 
38 
0 
0 
10 
10 
10 
10 
10 
23 
10 
10 
23 
10 
10 
 
Total blood volume 
 
38 
38 
38 
48 
58 
68 
78 
88 
111 
121 
131 
154 
164 
174 
 
a 
Physical exam also includes tumor measurements of treated and any untreated lesions measurable by exam. If appropriate, photographs should be taken to 
document lesions. 
b 
Day 56 restaging CT or MRI scans should be performed if the optional treatment #9 is not given. If a PET CT is used, a standard high resolution CT series 
should be obtained rather than low resolution scans for tumor measurements. However, PET scans should not be used to determine disease progression since 
it is expected that PET avidity will increase with the type of inflammation induced by this treatment and may lead to false positive results.  Confirmation of 
disease progression by CT or MRI must be performed 4 or more weeks later per IrRC.  If the 9th dose is given, then CT/MRI should be delayed to Day 63 to 
77. Photographs:  if the tumor can be measured and assessed visually, photographic documentation with measurements should be considered in order to keep 
a record and help assess any response to treatment (may be performed at any time during study) 
c    
Pregnancy test should only be performed on FCBP. Urine pregnancy test is recommended and must be performed (and negative) within 7 days prior to 
starting study treatment and on day 77. Site may use serum pregnancy test if part of their procedures.  For patients in the UK and France, urine pregnancy 
tests must also be performed every month or sooner while the patient is receiving G100. 
d 
Post-treatment biopsy should be done on Day 56 +/- 7 days for patients not receiving optional treatment #9. If the 9th dose is given, biopsy should be 
delayed to Day 63 to 77.    
e 
Patients should have all AEs reported for at least 30 days following the last dose of the G100 study agent. This includes those who withdraw early before 
completion of the study. 
f 
Thyroid function tests (including TSH) should be performed at screening in those patients being evaluated to participate and be randomized in Part 2 G100 
vs. G100 plus pembrolizumab. 
g 
Patients will receive telephone follow-up or clinic visit every 8 to 12 weeks after disease progression until 1 year after first study injection. Follow-up will 
include vital status (survival), cancer status (e.g., lymphoma transformation), and post-treatment anti-cancer therapy including time to next treatment, 
treatment details, and clinical response. If the patient agrees, the site may periodically (e.g. every 2 to 4 months) contact the patient beyond 1 year to check 
on vital and cancer status.   
h 
Imaging studies during Follow-up will occur on Day 112, every 8 weeks thereafter for the first year, every 3 to 4 months for the second year, and then at 
least every 6 months for the third and subsequent years. 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 45 of 177 
3.3 
Schedule of Events:  Part 2, Sequential Administration of G100 and anti-PD-1 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
10A 
10B 
11 
12 
Follow-
up 
LT Follow-up 
after PD 
Timeline – weeks 
-4 to 0 
-1 
0 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
11 
14+ 
Every 8-12 
weeks 
Timeline – days 
-30 to -1 
-7 to -1 
0 
1 
2 
5 to 7 
14 
21 
28 
35 
42 
49 
56 
77 
D98… 
q21d  
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent / HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics / Medical  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of cancer therapy  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
Report all AEs and SAEs 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
Xe 
Report possibly-related SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
Record any previous / 
concomitant medications 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
Vital signs 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exama 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG (12-Lead) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Tumor staging, including CT, 
MRI, and/or other modalityf 
X 
 
 
 
 
 
 
 
 
 
 
 
Xi 
Xi 
Xh 
 
ECOG  
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid function tests (5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Xb 
 
HIV, HepB, and HepC (5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beta-2-microglobulin (5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for cell phenotyping / 
profiling 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
Blood for safety labs (10 mL) 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood for T cell gene profiling 
and biomarkers 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testc 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Local Radiation 2Gy qd x2 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
G100 dosing 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 46 of 177 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
10A 
10B 
11 
12 
Follow-
up 
LT Follow-up 
after PD 
Timeline – weeks 
-4 to 0 
-1 
0 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
11 
14+ 
Every 8-12 
weeks 
Timeline – days 
-30 to -1 
-7 to -1 
0 
1 
2 
5 to 7 
14 
21 
28 
35 
42 
49 
56 
77 
D98… 
q21d  
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab dosing 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Tumor biopsy 
Xd 
 
 
 
 
 
 
 
 
 
 
 
Xd 
Xd 
 
 
Clinical Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
Blood volume per visit (mL) 
 
38 
0 
0 
10 
10 
10 
10 
10 
23 
10 
10 
28  
10 
 
 
Total blood volume 
 
38 
38 
38 
48 
58 
68 
78 
88 
111  
121 
131  
159  
169  
 
 
a Physical exam also includes tumor measurements of treated and any untreated lesions measurable by exam. If appropriate, photographs should be taken to document lesions. 
b  Thyroid function tests (including TSH) should be performed at screening and then every 6 weeks (following initiation of pembrolizumab) or as indicated by patient symptoms during pembolizumab 
therapy to screen for immune mediated thyroid changes. 
c Pregnancy test should only be performed on FCBP. Urine pregnancy test is recommended and must be performed (and negative) within 7 days prior to starting study treatment, Day 14 prior to the 
first dose of pembrolizumab, and day 77. Site may use serum pregnancy test if part of their procedures.  For patients in the UK and France, urine pregnancy tests must also be performed every month 
or sooner while the patient is receiving G100. 
d  For the pre-treatment tumor biopsy, baseline excisional or core biopsy should be obtained from the treatment target lesion or non-target lesion (preferably near the target lesion).  Post-treatment tumor 
biopsy should be performed on Day 56 +/- 7 days for patients not receiving optional treatment #9. If a 9th dose is given, then biopsy should be delayed to Day 63 to 77.  The biopsies should be 
performed on the treated tumor if feasible. If the primary treated site is not available, a different site should be chosen.  The biopsy site location and whether or not it was treated with G100, 
radiation, or was an abscopal site must be recorded/documented.   
e  For patients enrolled on the pembrolizumab arm, all adverse events experienced from the time of enrollment through 30 days following cessation of treatment will be reported by the investigator. Any 
event of clinical interest (ECI) experienced through 30 days following cessation of treatment should be reported within 24 hours to the Sponsor. Any SAE due to any cause other than progression of 
the cancer under study that occurs through 90 days following cessation of pembrolizumab treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported within 24 hours to the Sponsor. After the 90-day reporting period, any SAE that comes to the attention of the site staff that may be causally related to study drug 
(i.e., the event is considered possibly, probably or definitely caused by the drug) must be reported to Sponsor regardless of time elapsed. 
f Assessment of disease should include CT or MRI of chest, abdomen, pelvis. Other assessments such as CT scan of head or bone marrow biopsy should be performed if indicated for the individual 
patient.  However, PET scans should not be used to determine disease progression since it is expected that PET avidity will increase with the type of inflammation induced by this treatment 
and may lead to false positive results.   For this reason, PET scans are not recommended.  If a PET CT is used, a standard high resolution CT series should be obtained rather than low resolution 
scans and only the CT imaging should be used to determine tumor measurements. Confirmation of disease progression by CT or MRI must be performed 4 or more weeks later per IrRC.  In addition 
to restaging scans, if the tumor can be measured and assessed visually, photographic documentation with measurements should be considered in order to keep a record and help assess any response to 
treatment (may be performed at any time during study).     
g Patients will receive telephone follow-up or clinic visit every 8 to 12 weeks after disease progression until 1 year after first study injection. Follow-up will include vital status (survival), cancer status 
(e.g., lymphoma transformation), and post-treatment anti-cancer therapy including time to next treatment, treatment details, and clinical response. If the patient agrees, the site may periodically (e.g. 
every 2 to 4 months) contact the patient beyond 1 year to check on vital and cancer status.   
h Imaging studies during Follow-up will occur, on Day 112 to 119, every 8 weeks thereafter for the first year, every 3 to 4 months for the second year, and then at least every 6 months for the third and 
subsequent years. 
 i  Day 56 restaging CT or MRI scans should be performed if the optional treatment #9 is not given. If a PET CT is used, a standard high resolution CT series should be obtained rather than low 
resolution scans and only the CT imaging should be used to determine tumor measurements. PET scans should not be used to determine disease progression.  Confirmation of disease progression by 
CT or MRI must be performed 4 or more weeks later per IrRC.  If the 9th dose is given, then CT/MRI should be delayed to Day 63 to 77. Photographs:  if the tumor can be measured and assessed 
visually, photographic documentation with measurements should be considered to keep a record and help assess any response to treatment (may be performed at any time during study. 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 47 of 177 
3.4 
Schedule of Events:  Part 3, G100 Expansion of 20 µg Dose Group 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
10
A 
10B 
11 
12 
Follow-up  
LT Follow-
up after PD 
Timeline – weeks 
-4 to 0 
-2 
0 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
11 
Day 112 
then every 
8 weeksj 
Every 8-12 
weeks 
Timeline – days 
-30 to -1 
-14 to -1 
0 
1 
2 
5 to 7 
14 
21 
28 
35 
42 
49 
56 
77 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent / HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics / Medical  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of cancer therapy  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
Report all AEs and SAEs 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
 
 
Report possibly-related SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xg 
Record any previous / concomitant 
medications 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
Vital signs 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exama 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG (12-Lead) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Tumor staging, including CT, MRI, 
and/or other modalitiesh 
X 
 
 
 
 
 
 
 
 
 
 
 
Xb 
Xb 
Xj 
 
ECOG  
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV, HepB, and HepC (5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beta-2-microglobulin (5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for safety labs (10 mL) 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid function testsf  (5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for T cell gene profiling 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Local Radiation 2Gy qd x2 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
G100 dosing 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 48 of 177 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
10
A 
10B 
11 
12 
Follow-up  
LT Follow-
up after PD 
Timeline – weeks 
-4 to 0 
-2 
0 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
11 
Day 112 
then every 
8 weeksj 
Every 8-12 
weeks 
Timeline – days 
-30 to -1 
-14 to -1 
0 
1 
2 
5 to 7 
14 
21 
28 
35 
42 
49 
56 
77 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy  
Xi 
 
 
 
 
 
 
 
 
 
 
 
Xd 
Xd 
 
 
Clinical Status, treatment history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
Blood volume per visit (mL) 
 
33 
0 
0 
10 
10 
10 
10 
10 
18 
10 
10 
18 
10 
10 
 
Total blood volume 
 
33 
33 
33 
43 
53 
63 
73 
83 
101 111 121 139 149 
159 
 
a Physical exam also includes tumor measurements of treated and any untreated lesions measurable by exam. If appropriate, photographs should be taken to document 
lesions. 
b Day 56 restaging CT scans should be performed if the optional treatment #9 is not given. If the 9th dose is given, then CT should be delayed to Day 63 to 77. Photographs:  
if the tumor can be measured and assessed visually, photographic documentation with measurements should be considered in order to keep a record and help assess any 
response to treatment (may be performed at any time during study) 
c Pregnancy test should only be performed on FCBP and must be performed (and negative) within 7 days prior to starting study treatment and on Day 77. Urine pregnancy 
test is recommended. Site may use serum pregnancy test if part of their procedures. For patients in the UK and France, urine pregnancy tests must also be performed 
every month or sooner while the patient is receiving G100. 
d Post-treatment biopsy should be done on Day 56 +/- 7 days for patients not receiving optional treatment #9. If the 9th dose is given, biopsy should be delayed to Day 63 
to 77.  If the primary treated site is not available, a different site should be chosen.  The biopsy site location and whether or not it was treated with G100, radiation 
or was an abscopal site must be documented.   
e Patients should have all AEs reported for at least 30 days following the last dose of the G100 study agent. This includes those who withdraw early before completion of 
the study. 
f Thyroid function tests should include TSH  
g   Patients will receive telephone follow-up or clinic visit every 8 to 12 weeks after disease progression until 1 year after first study injection. Follow-up will include vital 
status (survival), cancer status, and post-treatment anti-cancer therapy including time to next treatment, treatment details, and clinical response. If the patient agrees, the 
site may periodically (e.g. every 2 to 4 months) contact the patient beyond 1 year to check on vital and cancer status.   
h  Assessment of disease should include CT or MRI of chest, abdomen, pelvis. Other assessments such as CT scan of head or bone marrow biopsy should be performed if 
indicated for the individual patient.  However, PET scans should not be used to determine disease progression since it is expected that PET avidity will increase 
with the type of inflammation induced by this treatment and may lead to false positive results.   For this reason, PET scans are not recommended.  If If a PET CT is 
used, a standard high resolution CT series should be obtained rather than low resolution scans and only the CT imaging should be used to determine tumor measurements.  
Confirmation of disease progression by CT or MRI must be performed 4 or more weeks later per IrRC.   
i For pre-treatment tumor biopsy, baseline excisional or core biopsy should be obtained from the treatment target lesion or non-target lesion (preferably near the target 
lesion).   
j Imaging studies during Follow-up will occur on Day 112 and every 8 weeks thereafter for the first year, every 3 to 4 months for the second year, and then at least every 
6 months for the third and subsequent years. 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 49 of 177 
3.5 
Schedule of Events:  Part 4, G100 at 20µg/lesion Into Single Or Multiple Tumor Masses Plus Pembrolizumab  
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
8A 
8B 
9 
10 
Follow-up 
LT Follow-
up after PD 
Timeline – weeks 
-4 to 
0 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
11 
14+ 
Every 8-12 
weeks 
Timeline – days 
-30 
to -1 
-14 to -1 
0 
5 to 7 
14 
21 
28 
35 
42 
49 
56 
77 
D98  q21d  
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent / HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics / Medical  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
History of cancer therapy  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Xg 
Report all AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
Xe 
Report possibly-related SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
Record any previous / concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exama 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG (12-Lead) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Tumor staging, including CT, MRI, and/or other 
modalityf 
X 
 
 
 
 
 
 
 
 
 
Xi 
Xi 
Xh 
 
ECOG  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid function tests (5 mL) 
TSH, T3 or Free T3, Free T4b 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
HIV, HepB, and HepC (5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Beta-2-microglobulin (5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for safety labs (10 mL) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood for Pharmacokinetics/ Pharmacodynamics 
(10 mL)j 
 
 
Xj 
 
Xj 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testc 
 
X 
 
 
X 
 
 
 
 
 
 
X 
Xc 
 
G100 dosing 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pembrolizumab dosing 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Tumor biopsy 
Xd 
 
 
 
 
 
 
 
 
 
Xd 
Xd 
 
 
Clinical Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
Blood volume per visit (mL) 
 
25 
30 
10 
30 
10 
10 
10 
10 
10 
15 
10 
 
 
Total blood volumej 
 
25 
55 
65 
95 
105 
115 
125 
135 
145 
160 
170 
 
 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 50 of 177 
a 
Physical exam also includes tumor measurements of treated and any untreated lesions measurable by exam. If appropriate, photographs should be taken to document 
lesions. 
b  
Thyroid function tests (including TSH) should be performed at screening and then every 6 weeks (following initiation of pembrolizumab) or as indicated by patient 
symptoms during pembolizumab therapy to screen for immune mediated thyroid changes. 
c 
Pregnancy test should only be performed on FCBP. Urine pregnancy test is recommended and must be performed (and negative) within 72 hours (3 days) prior to 
starting G100 and then before pembrolizumab on Day 14, and on day 77. Site may use serum pregnancy test if part of their procedures.  In  UK and France, urine 
pregnancy tests must also be performed every month or sooner while receiving G100 and/or pembrolizumab. 
d  
For the pre-treatment tumor biopsy, baseline excisional or core biopsy should be obtained from the treatment target lesion or non-target lesion (preferably near the 
target lesion).  Post-treatment tumor biopsy should be performed as close to 2 weeks following the last dose of G100 as possible: on Day 42 to 56 for patients 
receiving 6 doses if G100 or, if a 9th dose is given, then biopsy should be delayed to Day 63 to 77.  The biopsies should be performed on the treated tumor if feasible. 
If the primary treated site is not available, a different site should be chosen.  The location of the biopsy site and whether or not it was treated with G100 or was 
an abscopal site must be recorded/documented.  If the patient has both treated and untreated tumor sites amenable to biopsy, separate biopsies of each site 
should be performed. 
e  
For patients receiving pembrolizumab, all adverse events experienced from the time of enrollment through 30 days following cessation of treatment will be reported 
by the investigator. Any event of clinical interest (ECI) experienced through 30 days following cessation of treatment should be reported within 24 hours to the 
Sponsor. Any SAE due to any cause other than progression of the cancer under study that occurs through 90 days following cessation of pembrolizumab treatment, 
or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported within 24 hours to the Sponsor. 
After the 90-day reporting period, any SAE that comes to the attention of the site staff that may be causally related to study drug (i.e., the event is considered 
possibly, probably or definitely caused by the drug) must be reported to Sponsor regardless of time elapsed. 
f 
Assessment of disease should include CT or MRI of chest, abdomen, pelvis. Other assessments such as CT scan of head or bone marrow biopsy should be performed 
if indicated for the individual patient.  However, PET scans should not be used to determine disease progression since it is expected that PET avidity will 
increase with the type of inflammation induced by this treatment and may lead to false positive results.  If a PET CT is used, a standard high resolution CT 
series should be obtained rather than low resolution scans and only the CT imaging should be used to determine tumor measurements. Confirmation of disease 
progression by CT or MRI must be performed 4 or more weeks later per IrRC.  In addition to restaging scans, if the tumor can be measured and assessed visually, 
photographic documentation with measurements should be considered in order to keep a record and help assess any response to treatment (may be performed at any 
time during study).     
g 
Patients will receive telephone follow-up or clinic visit every 8 to 12 weeks after disease progression until 1 year after first study injection.  Follow-up will include 
vital status (survival), cancer status (e.g., lymphoma transformation), and post-treatment anti-cancer therapy including time to next treatment, treatment details, and 
clinical response. If the patient agrees, the site may periodically (e.g., every 2 to 4 months) contact the patient beyond 1 year to check on vital and cancer status.   
h 
Imaging studies during Follow-up will occur on Day 112 to 119 for patients receiving 6 doses of G100 or on Day133 to 140 for patients receiving 9 doses of G100.  
Imaging studies should then occur every 8 weeks thereafter for the first year, every 3 to 4 months for the second year, and then at least every 6 months for the third 
and subsequent years. 
 i  
Day 56 restaging CT or MRI scans should be performed if the optional treatment #9 is not given.  If a PET CT is used, a standard high resolution CT series should be 
obtained rather than low resolution scans and only the CT imaging should be used to determine tumor measurements.  PET scans should not be used to determine 
disease progression since it is expected that PET avidity will increase with the type of inflammation induced by this treatment and may lead to false positive results.  
Confirmation of disease progression by CT or MRI must be performed 4 or more weeks later per IrRC.  If the 9th dose is given, then CT/MRI should be delayed to 
Day 63 to 77.  Photographs:  if the tumor can be measured and assessed visually, photographic documentation with measurements should be considered to keep a 
record and help assess any response to treatment (may be performed at any time during study) 
j 
A plasma sample for Pharmacokinetics/Pharmacodynamics analysis will be drawn within 2 hours prior to the first administration of G100 and 6 hours after the first 
administration of G100 or pembrolizumiab, if applicable. 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 51 of 177 
3.6 
Schedule of Events:  Part 5, G100 Plus Rituximab  
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
8A 
8B 
9 
10 
Follow-up 
LT Follow-up 
after PD 
Timeline – weeks 
-4 to 0 
-2 
0 
 
1 
2 
3 
4 
5 
6 
8 
16 
24+ every 
8 weeks 
Every 8-12 
weeks 
Timeline – days 
-30 to -1 
-14 to -1 
0 
1 
7 
14 
21 
28 
35 
42 
56 
112 
D168  
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent / HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics / Medical  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
History of cancer therapy  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Xg 
Report all AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
Xe 
Report possibly-related SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xg 
Record any previous / concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
Vital signs 
 
X 
X 
(Xb) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exama 
 
X 
X 
(Xb) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG (12-Lead) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Tumor staging, including CT, MRI, 
and/or other modalityf 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Xh 
 
ECOG  
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV, HepB, and HepC (5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Beta-2-microglobulin (5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for safety labs (10 mL) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood for Pharmacokinetics/ 
Pharmacodynamics (10 mL)j 
 
 
Xj 
Xj 
 
 
 
 
 
 
 
 
 
 
Blood for T cell gene profiling and 
biomarkers 
 
Xi 
 
 
 
 
 
Xk 
 
Xk 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testc 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
G100 dosing 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Rituximab dosing 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
Tumor biopsy 
Xd 
 
 
 
 
 
 
Xd 
 
Xd 
 
 
 
 
Clinical Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
Blood volume per visit (mL)i 
 
36 
20 
30 
10 
10 
10 
18 or 26 
10 
18 or 26 
10 
10 
 
 
Total blood volumei 
 
36 
56 
76 
86 
96 
106 
124 or 132 134 or 142 
160 
170 
180 
 
 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 52 of 177 
a 
Physical exam also includes tumor measurements of treated and any untreated lesions measurable by exam. If appropriate, photographs should be taken to 
document lesions. 
b 
Physical exam and vital signs should be done if the patient reports adverse events following their first rituximab dose. 
c 
Pregnancy test should only be performed on FCBP. Urine pregnancy test is recommended and must be performed (and negative) within 72 hours (3 days) 
prior to starting study treatment and day 56. Site may use serum pregnancy test if part of their procedures.  In  UK and France, urine pregnancy tests must 
also be performed every month or sooner while receiving G100. 
d  
For the pre-treatment tumor biopsy, baseline excisional or core biopsy should be obtained from the treatment target lesion or non-target lesion (preferably 
near the target lesion).  Post-treatment tumor biopsy should be performed as close to 2 weeks following the last dose of G100 as possible: on Day 28 to 35 
for patients receiving 4 doses and, if 6 doses are given, then the biopsy should be delayed to Day 42 to 56.  The biopsies should be performed on the treated 
tumor if feasible. If the primary treated site is not available, a different site should be chosen.  The location of the biopsy site and whether or not it was 
treated with G100 or was an abscopal site must be recorded/documented.  If the patient has both treated and untreated tumor sites amenable to 
biopsy post G100, separate biopsies of each site should be performed. 
e  
All adverse events experienced from the time of enrollment through 30 days following cessation of treatment (including those patients who withdraw early) 
will be reported by the investigator. Any adverse event designated as a Clinical/Medical Event of Interest experienced through 30 days following cessation 
of treatment should be reported within 24 hours to the Sponsor. Any SAE due to any cause other than progression of the cancer under study that occurs 
through 30 days following cessation of treatment must be reported within 24 hours to the Sponsor. After the reporting period, any SAE that comes to the 
attention of the site staff that may be causally related to study drug (i.e., the event is considered possibly, probably or definitely caused by the drug) must be 
reported to Sponsor regardless of time elapsed. 
f 
Assessment of disease should include CT or MRI of chest, abdomen, pelvis. Other assessments such as CT scan of head or bone marrow biopsy should be 
performed if indicated for the individual patient.  However, PET scans should not be used to determine disease progression since it is expected that 
PET avidity will increase with the type of inflammation induced by this treatment and may lead to false positive results.  If a PET CT is used, a 
standard high resolution CT series should be obtained rather than low resolution scans and only the CT imaging should be used to determine tumor 
measurements. Confirmation of disease progression by CT or MRI must be performed 4 or more weeks later per IrRC.  In addition to restaging scans, if the 
tumor can be measured and assessed visually, photographic documentation with measurements should be considered in order to keep a record and help 
assess any response to treatment (may be performed at any time during study).     
g 
Patients will receive telephone follow-up or clinic visit every 8 to 12 weeks after disease progression until 1 year after first study injection. Follow-up will 
include vital status (survival), cancer status (e.g., lymphoma transformation), and post-treatment anti-cancer therapy including time to next treatment, 
treatment details, and clinical response. If the patient agrees, the site may periodically (e.g. every 2 to 4 months) contact the patient beyond 1 year to check 
on vital and cancer status.   
h 
Imaging studies during Follow-up will occur, on Day 168, every 8 weeks thereafter for the first year, every 3 to 4 months for the second year, and then at 
least every 6 months for the third and subsequent years. 
i 
Patients treated on Part 5 will have an additional 8ml drawn for T cell gene and biomarker analyses on Day 0 
j 
Pharmacokenetics/Pharmacodynamics plasma samples will be drawn within 2 hours prior to first rituximab administration, within 2 hours prior to the first 
G100 administration, and 6 hours after the first G100 administration. 
 k 
Patients treated on Part 5 will have an additional 8ml drawn for T cell gene and biomarker analyses on either Day 28 or 42 depending whether or not the 
patient received 4 or 6 G100 injections (see Lab Manual for details).  The additional blood is reflected as the larger blood volume collection beginning on 
either Day 28 or 42. 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 53 of 177 
3.7 
Schedule of Events:  Optional Retreatment / Second Course 
Visit 
1 
2 
3 
4 
5 
6 
7 
7A 
7B 
8 
9 
Follow-up  
LT Follow-
up after 
PD 
Timeline – weeks 
6+ wks after 
last restaging 
 
1 
2 
3 
4 
5 
6 
7 
8 
11 
Day 112 
then every 
8 weeks9 
*(3 weeks 
if receiving 
pembro) 
Every 8-12 
weeks 
Timeline – days 
-14 to -1 
0 
5 to 7 
14 
21 
28 
35 
42 
49 
56 
77 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Report all AEs and SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
X6 
X6,7 
Report possibly-related SAEs 
 
 
 
 
 
 
 
 
 
 
 
X6 
X6,7 
Record any previous / concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X7 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG (12-Lead) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Tumor staging, including CT, MRI, and/or 
other modalities8 
X2 
 
 
 
 
 
 
 
 
X3 
X3 
X9 
 
ECOG  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood for cell phenotyping / profiling10 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
Blood for safety labs (10 mL) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood for T cell gene profiling and 
biomarkers 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
Pregnancy test4 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
G100 dosing* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Tumor biopsy  
X5 
 
 
 
 
 
 
 
 
X5 
X5 
 
 
Clinical Status, treatment history 
 
 
 
 
 
 
 
 
 
 
 
 
X7 
Blood volume per visit (mL) 
23 
10 
10 
10 
10 
10 
15 
10 
10 
23 
10 
10 
 
Total blood volume 
23 
33 
43 
53 
63 
73 
88 
98 
108 
131 
141 
151 
 
1 
Physical exam also includes tumor measurements of treated and any untreated lesions measurable by exam. If appropriate, photographs should be taken to document lesions. 


Immune Design 
G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
Page 54 of 177 
2  
CT scan should be repeated if last CT was done 8 or more weeks prior to planned starting date of second course of therapy.  If the last scan indicated tumor regression that 
might now be an objective PR or CR, the scan should be repeated. 
3  
Day 56 restaging CT scans should be performed if the optional treatment #9 is not given. If the 9th dose is given, then CT should be delayed to Day 63 to 77. 
4 
Pregnancy test should only be performed on FCBP. Urine pregnancy test is recommended and must be performed (and negative) within 7 days prior to starting study 
treatment and repeated on Day 77.  Site may use serum pregnancy test if part of their procedures. For patients in UK and France, urine pregnancy tests must also be performed 
every month or sooner while the patient is receiving G100. 
5  
For Parts 1, 2 and 3, pre-treatment biopsy should be performed if one was not collected after the first course of G100 or if it has been ≥ 3 months from the last G100 
treatment; otherwise it is optional.  For Parts 4 and 5, new biopsies should be obtained pre- and post- G100 from the planned new treatment site. For pre-treatment biopsy, 
baseline excisional samples should be obtained from the treatment target lesion or non-target lesion (near the target lesion).  Post-treatment tumor biopsy should be performed 
as close to 2 weeks following the last dose of G100 as possible: on Day 42 to 56 for patients receiving 6 doses if G100 or, if a 9th dose is given, then biopsy should be delayed 
to Day 63 to 77.  The biopsies should be performed on the treated tumor if feasible. If the primary treated site is not available, a different site should be chosen.  The biopsy 
site location and whether or not it was treated with G100, radiation, or was an abscopal site must be recorded / documented. For Parts 4 and 5, patients who have 
both treated and untreated tumor sites amenable to biopsy post treatment should have collections done on both sites. 
6 
Patients receiving G100 alone who complete or withdraw early before completion of the study should have all AEs reported for at least 30 days following the last dose of the 
G100 study agent. For pembrolizumab patients, all AEs experienced from the time of enrollment through 30 days following cessation of treatment will be reported by the 
investigator. Any ECI experienced through 30 days following cessation of treatment should be reported within 24 hours to the Sponsor. Any SAE due to any cause other than 
progression of the cancer under study that occurs through 90 days following cessation of pembrolizumab treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, must be reported within 24 hours to the Sponsor. After the 90-day reporting period, Any SAE that comes to the attention 
of the site staff that may be causally related to study drug must be reported to Sponsor regardless of time elapsed.  For patients receiving G100 alone or with rituximab (Parts 
1, 2, 3, 5), after the End of Study Visit (Day77) or 30 days after the last dose of study agent whichever is longer, patients receiving G100 alone or G100 plus rituximab will be 
followed for possibly related SAEs only, and any SAE that comes to the attention of the site staff that may be causally related to study drug (i.e., the event is considered 
possibly, probably or definitely caused by the drug) must be reported to Sponsor regardless of time elapsed. 
7  
Patients will receive telephone follow-up or clinic visit every 8 to 12 weeks after disease progression until 1 year after first study injection. Follow-up will include vital status 
(survival), cancer status (e.g., lymphoma transformation), and post-treatment anti-cancer therapy including time to next treatment, treatment details, and clinical response. If 
the patient agrees, the site may periodically (e.g. every 2 to 4 months) contact the patient beyond 1 year to check on vital and cancer status.   
8  
Assessment of disease should include CT or MRI of chest, abdomen, pelvis. Other assessments such as CT scan of head or bone marrow biopsy should be performed if 
indicated for the individual patient.  However, PET scans should not be used to determine disease progression since it is expected that PET avidity will increase with 
the type of inflammation induced by this treatment and may lead to false positive results.  If a PET CT is used, a standard high resolution CT series should be obtained 
rather than low resolution scans and only the CT imaging should be used to determine tumor measurements. Confirmation of disease progression by CT or MRI must be 
performed 4 or more weeks later per IrRC.  In addition to restaging scans, if the tumor can be measured and assessed visually, photographic documentation with 
measurements should be considered in order to keep a record and help assess any response to treatment (may be performed at any time during study).     
9 
Imaging studies during Follow-up will occur on Day 112 to 119 for patients receiving 6 doses of G100 or on Day133 to 140 for patients receiving 9 doses of G100.  Imaging 
studies should then occur every 8 weeks (± 14 days) thereafter for the first year, every 3 to 4 months for the second year, and then at least every 6 months for the third and 
subsequent years. 
10  
Cell phenotyping will not be done in patients on Parts 3, 4, or 5. 
*
Patients on Parts 2 or 4 who receive pembrolizumab will continue on their every 3-week schedule while receiving this course of G100. Thyroid function tests should continue 
every 6 weeks and for Part4 include TSH, T3 or FT3, and FT4. If possible the treatment with pembrolizumab should be synched with this schedule; if not, then continue to 
follow Part 2: Section 10.3.15.1 or Part 4: Section 10.3.22.1 on pembrolizumab treatment days.  Patients on Part 5 G100 plus rituximab may receive up to 6 doses of G100.


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4.0 
INTRODUCTION AND RATIONALE 
Follicular low grade non-Hodgkin’s lymphomas (NHL) are typically sensitive to many different 
anti-cancer modalities including chemotherapy, biologics, and radiation, but despite this, remain 
incurable (Friedberg 2011).  Lymphomas are responsive to passive immunotherapy with agents 
such as monoclonal antibodies (mAbs) and adoptive cell therapy and to active immunotherapy 
approaches with agents that stimulate the host’s own immune system to fight their own cancer. 
Active immunotherapy holds particular promise in that it has the potential to provide lifelong 
lasting protection against these malignancies and their recurrence through immunologic memory. 
In NHL, active immunotherapy approaches have led to significant tumor reduction and long-
lasting disease-free intervals in some patients.  
B cell NHL are unique in that they harbor a recognized tumor-specific antigen, the idiotype 
protein (B cell antigen receptor), which is genetically different from any other B cell in the host 
and is expressed at high levels.  In small clinical studies where patient specific idiotype proteins 
were manufactured and provided in the form of a protein-adjuvant vaccine or protein pulsed 
dendritic cells (DCs), immune response were induced that in some patients that led to tumor 
responses lasting several years (Hsu 1996; Hsu 1997; Timmerman 2002).  However, challenges 
of manufacturing of patient-specific idiotype proteins have not allowed wide use of these 
antigens.  
Newer approaches have focused on using the tumor itself to provide a source of both recognized 
“specific” antigens like the idiotype protein and unidentified “endogenous” antigens present 
within the tumor. In preclinical studies, intratumoral injection of DCs in combination with 
systemic chemotherapy could completely eradicate established and metastatic lymphoma in 
animal models (Tong 2001; Song 2005).  In these studies, the injected DCs were able to ingest 
and process antigens released from the dying or apoptotic tumor cells and induced a systemic 
immune response against the tumor that was mediated by cluster of differentiation (CD)8 T cells. 
Although promising, DC manufacturing was required.  Alternatively, a more convenient method 
would to activate DC directly in situ and avoid the requirement of ex vivo cell production.  
The activation of immune responses in cancer patients has been challenging because DCs at the 
tumor site are often dysfunctional and unable to prime T cells efficiently.  Several biological 
agents, such as CD40L, 4-1BBL, tumor necrosis factor (TNF), oligodeoxynucleotides containing 
certain unmethylated C-G motifs (CpG) (Li 2007) and toll-like receptor (TLR)-4 agonists 
activate DCs and B cells by inducing their expression of costimulatory molecules and by 
triggering cytokine production. TLR4 agonists are particularly suited for this approach. 
(Figure 1).  TLR4 is a cell surface receptor that is critical for the recognition of 
lipopolysaccharide (LPS), an integral component of gram-negative bacteria.  TLR4 reside on the 
cell surface as opposed to TLR 9, a common target of CpGs, which is mainly expressed in the 
endosomal compartment.  TLR4 agonists activate antigen-presenting cells (APCs) and induce 
acute inflammatory responses including production of chemokines and cytokines that mediate 
inflammatory reactions.  Activation of TLR4 induces two distinct signaling pathways controlled 


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by (i) myeloid differentiation primary response gene 88 (MyD88)/myeloid differentiation 
primary response gene 88-adapter-like (MAL) which results in activation of nuclear factor 
(NF)-kB for induction of a number of NF-kB- dependent genes and inflammatory cytokines, and 
(ii) TIR-domain-containing adapter-inducing interferon-β (TRIF)/TIR-domain-containing 
adapter-inducing interferon-β-related adaptor molecule (TRAM) which induces production of 
type I interferons (IFN) (Coler 2011).  TLR4 also plays a non-redundant role in eliciting DC 
maturation, which is of key importance for effective priming naive T cells and initiating potent 
immune responses.  Recent studies have demonstrated that both MyD88 and TRIF synergize for 
maximal DC activation.  
Figure 1: 
Toll-like Receptor (TLR) Ligands And Signaling 
 
Toll-like receptors (TLRs) recognize bacterial and viral components. TLR ligands induce TLRs homodimer or 
heterodimer to trigger the activation of signaling molecules.  TLR4 recognizes LPS to form a homodimer. 
TLR3, TLR7, and TLR9 localize in intracellular compartment and recognize pathogen-derived nucleotides like 
double-strand RNA, single- strand RNA, and CpG-containing DNA, respectively.  TLR1/TLR2, TLR2/TLR6, 
and TLR4 activate MyD88 pathway through TIRAP, which is a membrane-association molecule, to induce 
inflammatory cytokines.  In addition, TLR4 activates TRAM and TRIF to induce type I interferon through 
activating IRF3. (from Saitoh, Chapter 4, Innate Immune Regulation and Cancer Immunotherapy, Springer, 
Editor Wang, Saitoh 2012)  
 
Immune Design’s G100 agent is a potent TLR4 agonist. G100 is composed of glucopyranosyl 
lipid A (GLA) formulated in a stable emulsion (SE). GLA a fully synthetic TLR4 agonist that is 
a potent stimulator of innate immune responses.  GLA improves the immunogenicity of a wide 
variety of antigens by increasing the magnitude of the T helper (Th)1 immune response marked 
by a high antigen-specific immunoglobin G (IgG)2a:IgG1 ratio and increased production of 
IFN-γ, TNFα, and interleukin (IL)-12 compared to IL-4, IL-5, and IL-13.  In preclinical models 


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of lymphoma and other cancers, injections of G100 intratumorally alone has led to tumor 
regression and slowing of tumor progression (Figure 2). 
Figure 2:  
Intratumoral G100 in non-Hodgkin’s lymphoma (NHL) Model 
 
A20 tumor cells (5x106) were injected subcutaneously at sites on both the right and left abdomen. G100 was injected 
into the right abdominal site only on days 6, 8, and 11 with the indicated dose of 2 µg or 10 µg of G100. 
Panel A, Treated Tumor, demonstrates the effect of G100 compared to SE vehicle alone or no treatment in the 
treated right abdominal lesion. Panel B, Untreated Tumor, demonstrates the distal (abscopal) effect of this 
treatment on the left side, untreated abdominal lesion. (Barfi and Levy, Stanford, unpublished data) 
 
GLA has been extensively evaluated in human subjects formulated in stable oil-in-water 
emulsion or in an aqueous formulation and has been examined in over 1000 patients as an 
adjuvant for various infectious agent and cancer vaccines.  G100 has been examined in 
2 ongoing clinical studies involving patients with Merkel Cell carcinoma or sarcoma where it has 
been administered intratumorally either alone or in combination with local radiation therapy.  It 
has demonstrated the ability to stimulate immune responses with an acceptable safety profile. 
In this study, Immune Design’s G100 agent will be administered intratumorally in patients with 
follicular NHL and evaluated for safety, tolerability and for its ability to stimulate local and 
distal tumor responses following standard local radiation.  


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4.1 
Study Overview 
The overall goal of this study is to evaluate the safety and immunogenicity of repeat-dose 
intratumoral G100 administration in patients with NHL following standard local radiation 
therapy. In Part 1: Dose Escalation, two dose levels of G100 will be examined, 5 µg and 10 µg, 
using a standard 3+3 dose escalation design.  
In Part 2, two groups of patients will be examined. In the first group, Patient Expansion With Or 
Without Pembrolizumab, up to 24 patients will be treated with G100 at the maximum tolerated 
dose (MTD) or maximum safe dose determined in Part 1 (Figure 3).  In this portion of the study, 
patients will be randomized to receive either intratumoral G100 alone (Figure 4), or intratumoral 
G100 and sequential anti-programmed death receptor-1 (PD-1) antibody therapy (Figure 5). This 
portion of the study is designed to be exploratory.  The main goal of Part 2, Patient Expansion 
With Or Without Pembrolizumab, is to gain safety information regarding these approaches to 
allow planning for future studies with these agents.  The G100 treatment regimen will be 
identical to that used in Part 1, Dose Escalation (Figure 4).  For patients randomized to receive 
pembrolizumab, the anti-PD-1 antibody begins on day 14 and follows a standard every 3-week 
schedule (Figure 5).  
In the second group, Part 2, Large Tumors, a higher dose of G100 may be examined. If the G100 
dose consisting of 10 µg of the GLA component is determined to be the maximal safe dose and 
the Data Monitoring Committee (DMC) agrees, an optional treatment group for Large Tumor 
patients will be treated.  In this group, up to 4 patients with injectable lymphoma mass(es) >4 cm 
in total size (based on the sum of the measurements of the single greatest dimension of each the 
tumor(s) within the planned radiation field) will be enrolled and will receive G100 consisting of 
20 µg of the GLA component per dose (Figure 4).  This will allow greater distribution of the 
G100 within the large tumor mass(es) and the examination of safety and dose effect.   
In Part 3, G100 Expansion of 20 µg Dose Group, treatment may begin after enrollment into 
Part 2 Patient Expansion (G100 alone and sequential G100 and pembrolizumab) has been 
completed (as determined by Sponsor), at least 3 patients in the Large Tumor group have been 
enrolled and observed to at least Day 28, and an acceptable safety profile has been determined.  
The Sponsor in consultation with the DMC will review the safety profile of G100 alone data 
from Part 1 and 2.  Commencement of Part 3 will be contingent upon determination of an 
acceptable safety profile of G100 alone data at that evaluation timepoint.  In Part 3, up to 
25 patients will be enrolled to receive local radiation therapy and intratumoral G100 at 
20 µg/dose following the same treatment schedule as in Part 1 and Part 2 where G100 was 
administered alone. 
In Part 4, G100 at 20µg/lesion Into Single Or Multiple Tumor Masses Plus Pembrolizumab 
Group, treatment may begin after enrollment into Part 3 has been completed (as determined by 
Sponsor), and an acceptable safety profile has been determined.  The goal of Part 4 is to obtain 
safety information, immunologic data and clinical response data with this higher G100 dose 


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regimen in combination with pembrolizumab in relapsed or refractory FL patients who have 
received at least 3 prior systemic therapies.  In Part 4, at least 22 evaluable patients will be 
enrolled to receive IT G100 at 20 µg/lesion and pembrolizumab at 200mg IV every 3 weeks 
following the same treatment schedule as in Part 2 where G100 was administered with 
pembrolizumab, except without radiation therapy.  In this dose escalation arm, sequential cohorts 
of patients will be treated with intratumoral G100 at 20µg/lesion in 1, 2, 3, or 4 tumor masses 
corresponding to local and systemic G100 exposure of 20, 40, 60 or 80µg of the GLA 
component (Figure 6).  If the tumor mass(es) has not regressed completely following the initial 
6 weekly doses, treatment may continue for 3 additional weekly intratumoral doses (9 total) 
(Figure 7).  On Day 14, pembrolizumab treatment will be initiated at a standard dose of 200 mg 
intravenously (IV) and then administered every 3 weeks (q3W) IV for up to 2 years or until 
disease progression or unacceptable toxicity. For pembrolizumab, dose modification for AEs 
attributed to the drug will follow the guidelines as recommended for the product and as outlined 
in the protocol.  
Once the 20 µg systemic dose level cohort (20 µg injected in 1 lesion) has been established to be 
reasonably safe, patients who do not qualify to enroll on the next dose level cohort due to 
insufficient numbers of potentially injectable lesions may enter Patient Expansion at that single 
lesion dose level.  As each higher systemic dose level (40 µg, 60 µg, 80 µg) in multiple lesions is 
established to be well-tolerated, additional patients who otherwise qualify for the study but are 
unable to be treated on Dose Escalation due to insufficient numbers of injectable lesions will be 
allowed to enroll into the Patient Expansion portion of the study at the established safe dose 
levels (Figure 6).  Patient enrollment will be monitored.  It is planned that 22 efficacy evaluable 
patients will be treated with intratumoral G100 and IV pembrolizumab in Part 4 in order to 
provide sufficient data for evaluation of efficacy (see Statistical Section).  Patients who received 
G100 20µg/lesion during Dose Escalation in Part 4 may be included in the clinical response 
analysis. 
If complete enrollment of 22 evaluable patients is reached before Dose Escalation is complete, 
the Sponsor may choose to continue enrollment into just the Dose Escalation cohorts with up to 
12 patients to fill all or some of the remaining cohort(s).  The main goal of Part 4, is to obtain 
safety information, immunologic data and clinical response data with this higher G100 dose 
regimen in combination with pembrolizumab and to determine if further studies are warranted. 
In Part 5, G100 Plus Rituximab, treatment may begin after enrollment into Part 3 has been 
completed (as determined by Sponsor), and an acceptable safety profile has been determined by 
the Sponsor in consultation with the DMC.  The goal of Part 5 is to obtain safety information, 
immunologic data and clinical response data with this higher G100 dose regimen in combination 
with rituximab in FL patients.  In Part 5, patients will be enrolled to receive IT G100 and 
standard induction rituximab without radiation therapy.  During dose escalation, sequential 
cohorts of 3-6 patients will be treated with intratumoral G100 at 20, 40, 60 or 80 µg/dose into a 
single tumor mass in combination with a standard induction regimen of rituximab 375mg/m2 IV 


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weekly x4 (Figure 8).  Treatment will begin with rituximab on Day 0, and after evaluation of 
rituximab related adverse events, G100 would begin on Day 1 (See Figure 9).  If there are no 
significant toxicities, treatment with rituximab and G100 would continue and subsequent 
administrations would be given during the same visits.  Once the highest safe dose/systemic 
exposure is determined from the Dose Escalation portion of the study, all safety, efficacy and 
biomarker data will be reviewed by the Sponsor (in collaboration with the independent DMC) 
and either the highest dose determined to be safe or the most biologically active and safe dose 
(if different than the MTD) will be chosen for further investigation.  The Patient Expansion 
portion of the study would then begin and patients would receive G100 at this recommended 
dose level into a single tumor mass in combination with rituximab.  Patient enrollment will be 
monitored with the goal of enrolling 20 efficacy evaluable patients as defined in the Statistical 
Section.  Patients who received G100 during Dose Escalation in Part 5 may be included in 
clinical response analysis. 
For All Parts (1 to 5) 
Retreatment / Second Course:  Following the G100 course of treatment, if a patient is determined 
to have achieved stable disease (SD) or better or has progressive disease (PD) that does not 
require immediate therapy, has an additional site of disease outside of the prior radiation field 
(Parts 1, 2, or 3) that is amenable to injection and the patient has not had significant treatment 
emergent adverse events (AE) (including events that would be considered a dose-limiting 
toxicity [DLT]) as determined by the investigator and the Sponsor, the patient may be eligible to 
receive a second course of G100 (Figure 10).  For patients enrolled on Parts 4 or 5, the same 
previously injected tumor sites may be targeted or a replacement site(s) may be chosen.  Six 
weeks or more after completion of the first course of G100 treatment, the second course would 
begin and consist of G100 alone (no radiation and no additional rituximab) at the same dose 
received during the first course of therapy.  Treatment would be administered on a similar 
weekly schedule as the first course except without radiation therapy (or rituximab therapy) . 
Figure 3: 
Part 2, Patient Expansion With Or Without Pembrolizumab 
 
 


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Figure 4: 
Treatment Schema for Part 1, Part 2 Patient Expansion G100 Alone, Part 2 
Large Tumor Group, and Part 3, G100 Expansion of 20 µg Dose Group 
 
 
 
Figure 5: 
Treatment Schema for Part 2, Sequential G100 and Pembrolizumab 
 
 
 
Figure 6: 
Dose Escalation And Expansion Of Part 4: G100 at 20µg/dose Into Single Or 
Multiple Tumor Lesions Plus Pembrolizumab Group 
 


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Figure 7: 
Part 4, G100 at 20µg/lesion Into Single Or Multiple Tumor Lesions Plus 
Pembrolizumab Group 
 
 
 
Figure 8: 
Part 5, G100 Plus Rituximab 
 
 


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Figure 9: 
Part 5, G100 Plus Rituximab 
 
 
 
Figure 10: 
For Parts 1 to 5, Optional Retreatment / Second Course 
 
 
4.2 
G100: Glucopyranosyl Lipid A Stable Emulsion, GLA-SE  
In this study, G100 will be administered intratumorally in order to generate an immune response 
against endogenous tumor antigens. G100 consists of a SE formulation of GLA, or 
glucopyranosyl lipid A, a fully synthetic glycolipid acyl component of endotoxin lipid A with the 
molecular formula of C96H184N3O22P and a molecular weight of 1,762.31 (Figure 11 ).  G100 is 
manufactured by high-pressure micro-fluidization followed by filter-sterilization. It contains 
squalene (oil), glycerol, tocopherol (vitamin E), synthetic dimyristoylphosphatidylcholine, 
surfactant (poloxamer) and ammonium phosphate buffer.  The emulsion is filled aseptically into 
vials and appears as a milky-white liquid. 


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Figure 11: 
Structure of GLA 
 
 
4.3 
Summary of Known and Potential Risks to Human Patients 
Over 1000 human subjects have been injected with GLA in either the SE formulation (GLA-SE) 
or a second aqueous formulation (AF), with or without antigen.  Dosing has ranged from 0.5 to 
10 μg with repeat dosing and has primarily been given subcutaneous (SC) or intramuscular (IM).  
Eleven patients have received up to 7 doses of 5 µg G100 intratumorally with or without local 
radiation.  More than 270 human subjects treated with GLA in different regimens (with or 
without antigen and via different dosing methods) have had 1 year of systematic post-vaccination 
follow-up, and there have been no long latency AEs or autoimmune or inflammatory AEs 
(Table 1). 
Table 1: 
Total Subjects Treated and Total Doses of GLA Administered to Human 
Subjects Through August 2014 
Study Treatment 
Exposure  
N 
Any GLA Product 
Total doses administered 
2299 
 
Total subjects treated  
1065 
 
GLA 0.5 µg  
6 
 
GLA 1.0 µg  
274 
 
GLA 2.0 µg  
332 
 
GLA 2.5 µg  
63 
 
GLA 5.0 µg  
349 
 
GLA 10.0 µg  
41 
GLA-AF 
Total doses administered 
576 
 
Total subjects treated 
255 
GLA-SE 
Total doses administered 
1723 
 
Total subjects treated 
810 


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The majority of the human experience to date with GLA has been as an adjuvant with infectious 
agent or cancer associated protein antigens.  The most commonly observed AEs have been 
injection site reactions of mild to moderate severity using the conservative “2007 FDA Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials.”  The only laboratory abnormalities of note have been transient increases in acute 
phase reactants (C-reactive protein [CRP] and fibrinogen) and peripheral blood neutrophils. 
The safety findings across multiple studies including different formulations of GLA suggest that 
the dose response for GLA safety will vary with different co-administered antigens.  The 5 μg 
dose of GLA-SE administered with a complex and highly immunogenic influenza (Fluzone®) 
split virus resulted in 3 of 4 subjects developing Grade 2 AEs (2007 Preventive Vaccine Grading 
Scale above) of arthralgia, myalgia, fatigue, and chills.  However, an investigator-initiated study 
performed in Brazil has indicated that 50 μg of recombinant hookworm protein administered 
with a 10 μg dose of GLA-SE 3 times over 2 months was well tolerated.  Fewer than 4% of AEs 
reported in association with GLA containing vaccines have been considered Grade 3 or higher in 
severity. 
The AEs considered expected include injection site reactions, fever, fatigue, chills, myalgia, and 
arthralgia. There are insufficient data to date to establish that the safety profile is substantially 
different when GLA-SE is administered by either the IM or SC route of administration or as the 
SE or AF formulation. 
Twenty-five serious adverse events (SAEs) have been reported from all GLA-SE clinical trials to 
date, most temporally dissociated from vaccination and no reports considered possibly, probably 
or definitely related to GLA treatment.  The majority of these events were elective 
hospitalizations for surgical procedures.  One SAE has been reported within 2 weeks of vaccine 
administration:  A 37-year-old female was enrolled and vaccinated, with 3.8 μg investigational 
recombinant avian influenza protein + 1.0 μg GLA-SE and eight days later was observed 
overnight in a hospital setting, where cardiac enzymes and electrocardiogram (ECG) were 
normal.  The patient was discharged with ibuprofen 800 mg, aspirin 325 mg, and omeprazole 
40 mg with a discharge diagnosis of costochondritis. 
In separate pilot studies, intratumoral injections of 5 µg G100 have been administered to patients 
with Merkel cell carcinoma and to patients with advanced sarcoma.  As of 05 February 2015, 
11 patients have been enrolled and treated in these ongoing studies.  Six patients have received 
G100 treatment before, during and after radiation therapy.  No grade 3 or higher AEs have been 
reported and the majority of events have consisted of grade 1 or 2 local reaction, pain and 
fatigue. In early results, 1 patient with biopsy proven, locoregional Merkel cell carcinoma was 
found to have a pathologic complete response (CR) following resection of the treated lesion.  
Tumor-specific cytotoxic T cells were found in a draining lymph node adjacent to the tumor 
mass, supporting the concept that clinically meaningful induction of anti-tumor immune activity 
can be achieved by this approach. 


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4.3.1 
Safety Profile of G100 in Follicular Lymphoma 
As of August 2018, 50 pts have been enrolled and treated on Parts 1, 2 and 3 of the G142 study.  
Some of this data was presented at ASCO 2017 and ASH 2017.  Safety was evaluated using 
CTCAE version 4.03 and was reviewed by an independent Data Monitoring Committee 
following completion of each cohort and then at least quarterly.  During G100 Dose Escalation, 
no related SAEs or dose limiting toxicity (DLT) were reported at dose levels of 5, 10 and 
20µg/dose.  Of all patients who received G100 as a single agent, all AEs considered at least 
possibly related to G100 were CTCAE Grade 1 or 2. 
To date, the most common AEs considered related to G100 were injection site reactions 
(34%: includes terms of injection site:  reactions, discomfort, pain, tenderness, erythema, 
bruising), nausea (10%), lymphocyte count decreased (10%), white blood cell count decreased 
(10%), fatigue (8%), chills (6%), fever (6%), myalgias (6%), abdominal discomfort/pain (6%), 
alkaline phosphatase increased (6%) and anemia (6 %).  
Overall, the addition of pembrolizumab to G100 did not result in unexpected or worsening 
toxicity than has been reported with pembrolizumab alone.  In the G100 and pembrolizumab 
group, two subjects experienced immune mediated toxicities considered related to 
pembrolizumab consisting of colitis/adrenal insufficiency or grade 2 hypothyroidism.  The 
patient with adrenal insufficiency initially experienced grade 3 colitis and was treated with 
prolonged steroids.  During steroid withdrawal, the patient experienced an SAE of grade 3 
adrenal insufficiency with fatigue/weakness, hyponatremia, and hypocalcemia that required 
hospitalization.  The event has completely resolved and was considered not related to G100 but 
probably related to pembrolizumab and to the prolonged steroid use and withdrawal.   
4.4 
Rationale for G100 Therapy  
Intratumoral administration of TLR4 agonists can activate local DCs and other immune cells to 
react to local cancer cells despite the immunosuppressive nature of the tumor microenvironment. 
This approach has the potential to stimulate immune responses against known “specific” as well 
as previously unrecognized “endogenous” tumor antigens.  This locally generated anti-tumor 
response would be expected to result in a systemic immunity and lead to regression of distal 
untreated lesions (abscopal response).  In preclinical models and in ongoing clinical studies of 
Merkel cell carcinoma and sarcoma patients, intratumoral G100 has demonstrated early evidence 
of clinical activity with a reasonable safety profile.  In this trial, intratumoral G100 therapy of 
patients with follicular NHL will be examined.  These malignancies are known to contain tumor-
specific antigens and have demonstrated responsiveness to active immunotherapy approaches 
with idiotype vaccines, with intratumoral DCs and with intratumoral CpGs.  This may indicate 
that NHL are an ideal indication to investigate this approach. 
This study will be performed in multiple parts.  In Part 1, Dose Escalation, the safety and 
tolerability of 5 µg or 10 µg of G100 will be investigated following standard local radiation 


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therapy.  Based on the safety profile, the MTD or maximal safe dose will be determined and used 
to treat additional patients.  In Part 2, two groups of patients will be examined. In the first group, 
Patient Expansion with or without pembrolizumab, up to 24 patients will be treated with G100 at 
the MTD or maximum safe dose determined in Part 1.  In this portion of the study, patients will 
be randomized to receive either intratumoral G100 alone or intratumoral G100 and sequential 
anti-PD-1 antibody therapy.  This portion of the study is designed to be exploratory.  In the 
second group, Part 2 Large Tumors, a higher dose of G100 may be examined.  If the G100 dose 
consisting of 10 µg of the GLA component is determined to be the maximal safe dose and the 
DMC agrees, an optional treatment group for Large Tumor patients will be treated, where up to 
4 patients with injectable lymphoma mass(es) 4 cm or greater in total size (based on the sum of 
the measurements of the single greatest dimension of each the tumor(s) within the planned 
radiation field) will be enrolled and will receive G100 consisting of 20 µg of the GLA 
component per dose.  Following completion of enrollment into Part 2 Patient Expansion (G100 
alone and sequential G100 and pembrolizumab) as determined by Sponsor, when at least 
3 patients in the Large Tumor group have been enrolled and observed to at least Day 28 and an 
acceptable safety profile has been determined, Part 3 may begin.  In Part 3, up to 25 patients will 
be enrolled to receive local radiation therapy and intratumoral G100 at 20 µg/dose following the 
same treatment schedule as in Part 1 and Part 2 where G100 was administered alone.  Data from 
another study in sarcoma and early data from this trial have demonstrated no safety concerns 
with the 20 µg dose level, and to date, all reported events considered at least possibly related to 
the study agent have only been grade 1 or 2.  Compared to baseline, post-treatment tumor 
biopsies have demonstrated significant increases in immune infiltrates within the tumor of some 
patients suggesting that this dose level should be explored further.  In Parts 4 and 5, higher doses 
of G100 in combination with pembrolizumab or rituximab will be examined.  Both arms will 
begin after Part 3 has completed and established safety with G100 at 20 µg/lesion and both will 
start with Dose Escalation to establish the safety of the total systemic dose of G100 administered.  
4.4.1 
Rationale for G100 Dose 
In preclinical models, there has been a suggestion of a dose response for intratumoral G100 when 
doses up to 10 µg were used.  In Part 1, two dose levels of G100 will be examined.  The starting 
dose of 5 µg G100 was selected because it has demonstrated acceptable safety in prior clinical 
studies of product candidates containing GLA involving over 300 patients when given IM or SC 
and can be administered in small volumes of the most extensively studied 2% oil/water SE 
formulation to facilitate intratumoral administration.  Multiple injections of this dose level have 
been administered intratumorally in 11 patients with Merkel cell carcinoma or sarcoma both with 
and without accompanying radiation therapy and a reasonable safety profile has emerged.  The 
higher dose of 10 µg GLA has also been used clinically in over 40 patients as an adjuvant for IM 
and SC vaccine treatments in both healthy volunteers and cancer patients.  Reasonable safety 
profiles have been observed at this dose level in the past, and if this dose demonstrates 
reasonable safety in Part 1, it will be used to treat subjects in the Patient Expansion group.  If the 
10 µg dose of G100 is determined to be the maximal safe dose and if the DMC agrees, an 


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optional treatment group for Large Tumor patients will be treated.  In this group, up to 4 patients 
with injectable lymphoma mass(es) 4 cm or greater in total size will be enrolled and will receive 
G100 consisting of 20 µg of the GLA component per dose.  This will allow greater distribution 
of the G100 within the large tumor mass(es) and the examination of safety and dose effect.  
A new treatment arm, G100 Expansion of 20 µg Dose Group, was added to expand the 
experience with G100 at 20 µg/dose.  This higher dose has been examined in over 3 patients with 
sarcoma where each patient has received 12 doses of intratumoral G100.  Principle investigator 
(PI) reported patient safety events were minimal and were only grade 1 or 2.  There were no 
grade 3 or serious events considered at least possibly related to the study agent.  The profile was 
similar to that of patients treated with G100 at 5 µg or 10 µg/dose in the same study.  At the time 
of this amendment, 4 patients have been treated in the Large Tumor Group and 14 patients in 
Part 3 with 20 µg/dose.  The emerging safety profile has been similar to that of 10 µg/dose 
treated patients.  Therefore, there does not appear to be any new safety concerns.   
In preclinical studies using the A20 lymphoma model, a side-by-side comparison of GLA-SE at 
10ug/dose vs. 50ug/dose showed that higher dose (50 ug) has more potent anti-tumor effects and 
resulted in significantly better overall survival (Figure 12).  Early exploratory data from sarcoma 
patients treated with the 20 µg dose indicate an increase in tumor immune infiltrates compared 
with lower treatment doses.  Therefore, exploration of the higher dose level appears warranted.   
Figure 12: 
Intratumoral Injection Of 50µg G100 Is More Potent Than 10 µg Of G100 In 
A20 Lymphoma.  
 
Balb/c mice received A20 cell inoculation on Day 0 on both flanks.  After the tumor became palpable (Day 5), treatment 
was initiated.  G100 (10 ug or 50ug in 2%SE and diluted in 50uL of PBS) or control PBS of the same volume was 
injected into the tumor on the right side.  Tumor growth on both treated and untreated tumors were monitored by 
caliper measurement.  Results shown are combined data from three independent studies (N=25 mice per group). 


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The original concentration of G100 would have required a 2-mL volume to deliver a 20 µg dose.  
Highly concentrated formulations of G100 have been prepared and all patients on the G142 study 
have received G100 using these preparations.  Doses of G100 >20 µg can be delivered in small 
volumes, and therefore, dose escalation beyond 20 µg as proposed for Parts 4 and 5 is feasible.  
4.4.2 
Rationale for Radiotherapy with Intratumoral G100 
Recent studies with CpGs (a TLR9 agonist) administered intratumorally plus local radiation 
therapy have been associated with tumor responses at local and distant sites, both in mycosis 
fungoides (Kim 2012) and B cell lymphoma (Brody 2010).  Local radiation therapy is thought to 
increase tumor immunogenicity by inducing tumor cell apoptosis and death and thereby releasing 
endogenous tumor antigens for cross-presentation by local DCs.  In addition, radiation can 
increase tumor major histocompatibility complex (MHC) Class I expression and help facilitate 
DC migration to regional lymph nodes (Lugade 2005).  
As discussed, G100 is a very potent TLR4 agonist that can promote the stimulation of DCs and 
immune effector cells.  The combination of intratumoral G100 and radiation would be expected 
to augment the release of tumor antigens and enhance cross-presentation by DCs and the 
effective stimulation of anti-tumor immunity.  TLR4 agonists may have an advantage over TLR9 
agonists such as CpGs in this approach.  TLR4 reside and are accessible on the cell surface as 
opposed to TLR 9, which is mainly expressed in the endosomal compartment.  TLR4 agonists 
also stimulate both the MyD88 and TRIF pathways leading to broad immune stimulation through 
NF-kB and induction of type I INF (Figure 1).   
For Part 4, the G100 regimen will examine the use of higher doses of G100 without radiation 
therapy to see if the increased dose can compensate for any benefit from radiation.  This could 
potentially simplify the regimen by eliminating this portion of the treatment.  Similarly, in Part 5, 
G100 plus Rituximab, radiation will not be used. 
4.4.3 
Rationale for Proposed G100 Schedule Selection 
G100 will be administered by intratumoral injection into tumor mass(es) within the local 
radiation treatment field once on Day 2, with a second dose on Day 5 to 7 and then weekly for a 
total of 6 doses (Figure 4).  At the end of the 6 doses, if the tumor has not regressed completely, 
3 additional intratumoral weekly doses may be given.  Non-clinical studies suggest that multiple 
injections 1 to 2 times per week generate the most durable and highest magnitude responses. 
NHL tends to be very responsive to local radiation therapy, and 6 doses of G100 may be the 
optimal number of doses that can be applied before significant tumor regression occurs.  Three 
additional G100 doses are an option for those patients with potentially slower responding 
disease. 


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4.5 
Rationale for anti-PD-1 Therapy and Proposed Schedule 
High levels of the programmed death ligand (PD-L)-1 molecule are expressed on a wide variety 
of cancer cells or on histiocytes and other cells within the tumor microenvironment.  The binding 
of the PD-1 on tumor-infiltrating T cells to its ligand PD-L1 leads to an inhibition of anti-tumor 
immune activity.  The PD-1/L1 axis is an immune checkpoint inhibitor that when activated 
negatively affects the ability of T cells to proliferate, generate cytokines, and kill cancer cells 
(Mellman 2011; Pardoll 2012).  Blocking the interaction of PD-1 with its ligands, PD-L1 and 
PD-L2, with a mAb against PD-1 can restore immune function, increase migration of T cells 
from the invasive margin into the tumor, and enhance anti-tumor immune responses.  The 
proliferation of intratumoral CD8 T cells was recently shown to directly correlate with reduction 
in tumor size (Tumeh 2014).  Several checkpoint inhibitor mAbs are undergoing clinical 
evaluation; pembrolizumab (Keytruda, Merck) was recently approved and is the first anti-PD-1 
antibody available in the United States (US).  In its approved indication, unresectable or 
metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 
mutation positive, a BRAF inhibitor, pembrolizumab has demonstrated an overall response rate 
of 24% (FDA 2014; Keytruda product label 2018).  
Clinically, anti-PD-1/L1 blocking antibodies are active as a single agent but are limited in their 
ability to induce objective responses (CR and partial response [PR]).  For this treatment to have a 
clinical effect, it is hypothesized that tumor-reactive T cells are present, but are being suppressed 
by this pathway.  Blocking this axis would restore anti-tumor immunity.  One theory that can 
explain why anti-PD1/L1 blocking antibodies do not result in higher response rates is that non-
responding patients do not have pre-existing effective anti-tumor T cells present that are being 
suppressed (Tumeh 2014).  As a corollary, if more patients had pre-existing anti-tumor immune 
responses, then these anti-PD-1/L1 agents could potentially be more effective.  
In patients with cancer, the PD-1/L1 pathway would be expected to diminish any anti-tumor 
immune response, and it stands to reason that CD8 T cells generated by the immune response to 
G100 would eventually be affected by this pathway.  Therefore, G100 activity might be 
enhanced by blocking the PD-1/L1 pathway, especially in the presence of tumor or cells within 
the tumor microenvironment expressing PD-L1.  This effect can be demonstrated in tumor-
bearing animals, where blocking PD-1 in combination with active immunization with G100 
controlled tumor growth significantly better than animals treated with G100 alone (Figure 13). 


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Figure 13: 
Intratumoral G100 Plus Check Point Inhibitors In The B16 Melanoma 
Model 
 
On Day 0, B6 mice were injected with 5 x 105 B16F10 cells, footpad. On Day 4 and every 3-4 days thereafter, G100 
(5 µg GLA/2% SE) was administered intratumorally either with or without anti-PD-1, anti-PD-L1, anti-CTLA4 
(2 antibody clones) or control (100 µg intraperitoneal injection).  The anti-tumor effect of anti-PD-1, anti-PD-
L1 and anti-CTLA4 antibodies were additive or synergistic when combined with G100. 
 
There is reasonable rationale that an optimal dose schedule of an active immune approach with 
an anti-PD-1/L1 may require that a T-cell response be induced before introducing PD-1/L1 
blockade.  Therefore, the dose regimen for this study administers two doses of G100 before 
initiating an anti-PD-1 blocking antibody.  In this regimen (Figure 5), G100 is first administered 
on Day 2 and a second dose is given on Day 5 to 7.  Then beginning on Day 14, anti-PD-1 
therapy is given around the time of the 3rd dose of G100 and is continued every 3 weeks (Q3W) 
for up to 2 years or until disease progression or unacceptable toxicity.  The separation of each 
agent in time is expected to allow an assessment of the benefit of adding each agent toward the 
development of anti-tumor immune responses and help distinguish the contribution of each agent 
to any safety events that might be observed. 
4.5.1 
Pembrolizumab Background and Clinical Trials 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies. 
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications. For more details on specific indications refer to the Investigator’s Brochure. 


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Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on MK-3475. 
4.5.2 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (Disis 2010).  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such 
as melanoma (Dudley 2005; Hunder 2008). 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2) (Greenwald 2005; 
Okazaki 2001). 
The structure of murine PD-1 has been resolved (Zhang 2004).  PD-1 and its family members are 
type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch 
motif.  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, 
to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade (Okazaki 2001; Chemnitz 2004; Sheppard 2004; Riley 2009). The mechanism 
by which PD-1 down-modulates T-cell responses is similar to, but distinct from, that of CTLA-4, 
because both molecules regulate an overlapping set of signaling proteins (Parry 2005; 
Francisco 2010).  As a consequence, the PD-1/PD-L1 pathway is an attractive target for 
therapeutic intervention in non-Hodgkins lymphomas.  


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4.5.3 
Pre-clinical and Clinical Trials 
Therapeutic studies in mouse models have shown that administration of antibodies blocking PD-
1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads to 
tumor rejection, either as a monotherapy or in combination with other treatment modalities 
(Hirano 2005; Blank 2004;Weber 2010; Strome 2003; Spranger 2014; Curran 2010; 
Pilon-Thomas 2010).  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
antitumor responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, 
acute myeloid leukemia and colorectal carcinoma (Strome 2003; Curran 2010; 
Pilon-Thomas 2010; Nomi 2007; Zhang 2004).  In such studies, tumor infiltration by CD8+ T 
cells and increased IFN-γ, granzyme B and perforin expression were observed, indicating that 
the mechanism underlying the antitumor activity of PD-1 checkpoint inhibition involved local 
infiltration and activation of effector T cell function in vivo (Curran 2010).  Experiments have 
confirmed the in vivo efficacy of anti-mouse PD-1 antibody as a monotherapy, as well as in 
combination with chemotherapy, in syngeneic mouse tumor models (see the Investigator’s 
Brochure [IB]). 
4.5.4 
Justification for Dose  
The planned dose of Pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of Pembrolizumab for adults across all indications and regardless of tumor type. 
As outlined below, this dose is justified by: 
 Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
 Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
 Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and 
KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, 
KN001 Cohort F2 and KN006).  All of these studies demonstrated flat dose- and exposure-
response relationships across the doses studied representing an approximate 5- to 7.5-fold 
difference in exposure.  The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to 
the highest doses studied.  Subsequently, flat dose-exposure-response relationships were also 


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observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer and 
classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of 
the tumor type. These findings are consistent with the mechanism of action of Pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression.  This evaluation concluded that Pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of Pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all Pembrolizumab protocols. 
4.6 
Rationale for Rituximab Therapy and Proposed Schedule 
Rituximab either as a single agent or in combination with other agent(s) has become an essential 
treatment and a backbone of therapies used to treat follicular lymphomas and other B cell 
malignancies.  The clinical anti-tumor activity of this anti-CD20 antibody appears to derive from 
its ability to facilitate antibody-dependent cellular cytotoxicity (ADCC), directly inducing 
apoptosis of lymphoma cells (studies with cross-linked antibody), and activating complement 
dependent cytotoxicity. (Rituximab label 2010; Hsu 2002) 
The mechanism of action of G100 complements that of rituximab.  ADCC requires the presence 
of activated NK cells, macrophages and other phagocytic cells.  G100 releases cytokines and can 
attract and increase the number of activated NK and other phagocytic cells in the tumor 
microenvironment (Figure 14).  In clinical studies of intratumoral G100 in patients with sarcoma, 
G100 was associated with an increase of inflammatory macrophages of M1 phenotype, 
indicating an increased activity (Seo 2017).  Preliminary nanostring gene expression analysis 
using tumor biopsy collected from FL patients before or after G100 treatment showed induction 
of genes associated with NK cell function, including FcgR2A, FcgR3A, 2B4, Granzyme A, etc.  
As shown in Figure 15, heatmap analysis of genes from two representative patients shows higher 
levels of genes expression of multiple NK cell receptors.  This data would support the potential 
synergy between G100 and rituximab.  Further testing using PBMC from healthy donors and 
rituximab-coated target Raji cells showed that pre-incubation of PBMC with GLA (0.2 or 1 
µg/mL for 48hr) significantly enhanced the lysis of target cells at different concentrations of 
rituximab (Figure 16). 


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Figure 14: 
G100 Increases NK Cells In The Tumor Microenvironment 
 
Balb/c mice with established A20 tumors received 2 intratumoral G100 injection.  Tumors were collected at 2 hours 
after the last injection and tumor infiltrating lymphocytes (TIL) were isolated by Ficoll gradient centrifugation 
and stained with antibodies for CD4, CD8, CD3, CD19, and NKp46.  Shown are the percentages of NK cells 
out of total CD3- lymphocytes (non-T cells).  Each dot represents an individual mouse.  *, p<0.05.  The 
percentages of NK cells was also evaluated in splenocytes, and there was a trend of decreasing numbers in 
splenocytes, suggesting the possibility that increased NK cells in TIL may be due to increased trafficking of NK 
cells from periphery to tumor. 
 
Figure 15: 
G100 Induces Genes Related To NK Cell Function In FL Patients 
 
Pre-G100 and post-G100 biopsies from FL patients were collected.  RNA from these tumors was isolated and then 
200ng of total RNA was used for nanostring gene expression analyses using the panCancer Immune Profiling 
panel.  The results were analyzed using nSolver software after normalization.  The heatmap shows unsupervised 
clustering of 13 genes related to NK cell function in two pre-G100 samples (106006TP, 109003TP) and two 
post-G100 samples (106006TO, 109003TO).  Blue color indicates low gene expression levels; Orange color 
indicates high gene expression levels.  Specific genes are labeled and identified to the right of the heatmap. 


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Figure 16: 
GLA Enhances Rituximab-Mediated ADCC 
 
Fresh PBMC were isolated from healthy donors.  PBMC were incubated with medium alone or with GLA-AF (0.2 
or 1 ug/mL) for 48hr.  Raji cells were stained with CFSE and mixed with PBMC at an Effector to Target ratio 
of 50:1 in combination in media containing increasing concentrations of rituximab.  After incubation at 37°C 
for 4hr, the percentage of dead target cells (CFSE+PI+) and live target cells (CFSE+PI-) were measured by flow 
cytometry and the percentage of cell lysis was calculated. 
 
Another important aspect of rituximab is its ability to induce tumor apotosis and facilitate 
phagocytosis and tumor antigen presentation by dendritic cells.  Tumor-specific antigens that can 
be recognized by the immune system represent a small proportion of all proteins in the 
surrounding environment available for processing by dendritic cells.  Therefore, methods that 
facilitate targeting and increase the loading of dendritic cells with tumor-specific antigens would 
be expected to increase the stimulation, development, and activity of cytolytic T cells.  In studies 
using autologous tumor, T cells and dendritic cells obtained from patients previously immunized 
with patient specific idiotype proteins, rituximab coated tumor cells were rapidly opsonized and 
processed by dendritic cells.  These tumor-pulsed dendritic cells could then be used to stimulate 
and expand previously primed cytotoxic T cells that were capable of specifically killing tumor 
cells (Hsu 2002).  Similar preclinical studies using mouse models have demonstrated a survival 
advantage to animals immunized with rituximab coated or anti-Id antibody coated autologous 
tumor (Manzur 2012, Franki 2008).  These studies indicated that coating tumor cells with 
opsonizing antibodies could direct these relatively rare tumor antigens to be taken up/loaded and 
processed by dendritic cells, thereby increasing the potential anti-tumor activity of 
immunotherapy approaches such as G100 that use autologous tumor as a source of antigen. 
Rituximab for the treatment of NHL is well established and the primary treatment (induction) 
regimen (375 mg/m2 IV weekly x4 doses) has not changed since its original approval in 1997.  
Although extended / maintenance therapy has been examined in multiple large studies, its use 
has remained controversial and can lead to increased side effects including infections and low 
white blood counts (Rituxan label 2010).  In low tumor burden patients, maintenance therapy did 
not result in improvement in time to treatment failure compared to retreatment at time of 
3 0
6
1 .2
0 .2 4
0 .0 4 8
0 .0 0 9 6
0 .0 0 1 9 2
0
0
2 0
4 0
6 0
8 0
D o n o r 1
R itu x im a b  (µ g /m L )
%  o f L y s is  o f R a ji C e lls
M e d iu m
G L A  0 .2  u g /m L
G L A  1 u g /m L
3 0
6
1 .2
0 .2 4
0 .0 4 8
0 .0 0 9 6
0 .0 0 1 9 2
0
0
2 0
4 0
6 0
8 0
1 0 0
D o n o r 2
R itu x im a b  (µ g /m L )
%  o f L y s is  o f R a ji C e lls
M e d iu m
G L A  0 .2  u g /m L
G L A  1 u g /m L


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progression with rituximab (Kahl 2014).  Therefore, for this study, the standard induction 
therapy of rituximab without maintenance will be used in combination with G100. 
4.7 
Safety Monitoring 
G100 safety will be monitored by evaluating both solicited and spontaneously reported AEs, 
including reactogenicity, symptoms, physical examination findings, vital signs, laboratory 
findings, ECGs and discontinuations for AEs.  Subjects will be encouraged to call and/or return 
to the site if they have any significant concerns regarding AEs. 
The independent DMC will operate in accord with a signed charter and be advisory to the 
Sponsor. In Part 1, the DMC will review all DLTs and SAEs considered at least possibly related 
to study agent on an ongoing basis and will review all safety data for any trends at least once 
every 3 months.  SAE reports considered at least possibly related to the study regimen and are 
unexpected will be expedited to regulatory authorities, investigators and DMC members.  All 
patients treated with one or more doses of G100 will be considered part of the safety data set.  
The independent DMC will review all safety data and make recommendations regarding safety 
concerns, determination of DLTs, and the conduct of the study. Modifications to the treatment 
program may arise out of such reviews.  
In Part 2, two groups of patients are planned, Patient Expansion With Or Without 
Pembrolizumab and (optional) Large Tumor patients.  The Patient Expansion group will receive 
intratumoral G100 or sequential intratumoral G100 and pembrolizumab and will begin once the 
MTD / maximum safe dose is determined from Part 1.  Based on the results of Part 1 and safety 
profile of the highest dose level, the DMC will recommend whether or not to open the optional 
Large Tumor treatment group.  Enrollment in the Large Tumor group will only be possible if the 
10 µg/dose level is determined to be safe.  
During Part 2 and based on the continuous review of safety events, if the dose of 10 μg G100 is 
used during Patient Expansion and subsequently determined to have an increased safety risk, the 
DMC may recommend and the Sponsor may choose to reduce the dose of G100 to 5 μg or they 
may recommend stopping the G100 treatment.  If the 5 μg dose level is determined not to be safe 
by the independent DMC, treatment with G100 will be stopped.  Following evaluation by the 
DMC and the Sponsor, a further modification to the dose/treatment schedule could be 
recommended. 
In Part 3, G100 Expansion of 20 µg Dose Group, treatment may begin after enrollment into 
Part 2 Patient Expansion (G100 alone and sequential G100 and pembrolizumab) has been 
completed (as determined by Sponsor), at least 3 patients in the Large Tumor group have been 
enrolled and observed to at least Day 28, and an acceptable safety profile has been determined.  
The Sponsor in consultation with the DMC will review the safety profile of G100 alone data 
from Part 1 and 2.  Commencement of Part 3 will be contingent upon determination of an 
acceptable safety profile of G100 alone data at that evaluation timepoint.  In Part 3, up to 


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25 patients will be enrolled to receive local radiation therapy and intratumoral G100 at 
20 µg/dose following the same treatment schedule as in Part 1 and Part 2 where G100 was 
administered alone. 
In Part 4, Sequential G100 at 20µg/lesion Into Single Or Multiple Tumor Masses Plus 
Pembrolizumab Group, treatment may begin after enrollment into Part 3 has been completed (as 
determined by Sponsor), and an acceptable safety profile has been determined by the Sponsor in 
consultation with the DMC.  In Part 4, at least 22 evaluable patients will be enrolled to receive 
sequential IT G100 at 20 µg/lesion and pembrolizumab at 200mg IV every 3 weeks following 
the same treatment schedule as in Part 2 where G100 was administered with pembrolizumab, 
except without radiation therapy (Figure 7).  In this dose escalation arm, sequential cohorts of 
patients will be treated with intratumoral G100 at 20 µg/lesion in 1, 2, 3, or 4 tumor masses 
corresponding to local and systemic G100 exposure of 20, 40, 60 or 80 µg of the GLA 
component.  Patient Expansion will be allowed to begin at each dose level as safety is 
established for each cohort and agreed upon with the DMC (Figure 6).  Twenty-two efficacy 
evaluable patients as defined in the Statistical Section will be enrolled. 
In Part 5, G100 Plus Rituximab, treatment may begin after enrollment into Part 3 has been 
completed (as determined by Sponsor), and an acceptable safety profile has been determined by 
the Sponsor in consultation with the DMC.  In Part 5, patients will be enrolled to receive IT 
G100 and standard induction rituximab without radiation therapy.  During dose escalation, 
sequential cohorts of 3-6 patients will be treated with intratumoral G100 at 20, 40, 60 or 80 
µg/dose into a single tumor mass.  Once the MTD/maximum safe dose has been established, all 
safety, clinical and biomarker data will be reviewed and a recommended dose for further 
exploration will be made.  The Patient Expansion would then begin and would treat patients with 
G100 at the recommended dose in a single lesion in combination with rituximab.  Overall, 
20 efficacy evaluable patients as defined in the Statistical Section will be enrolled. 
Potential Dose Modification During Dose Escalation: 
During Part 4 and based on the continuous review of safety events, if the dose of 20 μg/lesion 
G100 is subsequently determined to have an increased safety risk, the DMC may recommend 
and the Sponsor may choose to reduce the dose of G100 to 10μg and potentially to re-examine 
escalation with this lower dose/lesion regimen or they may recommend stopping the G100 
treatment.  
G100 is a local therapy with systemic immune responses.  Therefore, the safety profile may 
differ from that of systemically administered agents.  In order to further investigate this, if 2 or 
more DLTs are observed in the initial cohort at 20 µg of G100, the Sponsor, in agreement with 
the independent DMC may choose to examine a new cohort of patients to better understand 
whether or not the DLTs associated with the injection of a single lesion might be abrogated by 
decreasing the dose and administering the lower single lesion dose of 10 µg  into multiple 


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lesions.  Intratumoral G100 10 µg in a single lesion in combination with pembrolizumab was 
established to be well-tolerated in Part 2 of this study.  Thus, this new cohort would examine the 
safety of G100 10 µg administered into 2 injectable lesions and would use the same 3+3 design 
described above.  Based on a review of the safety profile of this new cohort and in agreement 
with the independent DMC, further dose escalation cohorts may be investigated using this lower 
dose of 10 µg/lesion and a similar dose escalation schema as described above where up to 
4 lesions may be potentially treated.   
Similarly during Part 5, if G100 plus rituximab is subsequently determined to have an increased 
safety risk, the DMC may recommend and the Sponsor may choose to reduce the dose of G100 
or they may recommend stopping the G100 treatment.  In order to further investigate this, after 
establishment of an MTD, the Sponsor in agreement with the independent DMC may choose to 
examine one additional cohort of patients to better understand whether or not the DLTs 
associated with the injection of a single lesion might be abrogated by splitting the dose and 
administering the lower single lesion dose into two lesions.  The data from this cohort may help 
determine if the tolerability of G100 was limited due to the injection of a single tumor mass or to 
the total systemic exposure with this agent.  In this additional cohort, 3-6 patients would be 
treated at the total systemic dose level associated with DLTs but divided and distributed into two 
tumor masses instead of one.  For example, if the MTD in a single tumor mass were determined 
to be 40 µg due to DLTs occurring at 60 µg/lesion, the dose of this cohort would be 30 µg/lesion 
injected separately into 2 tumor masses.  In the event that the 20 µg dose level (Cohort 1) 
experiences DLTs, a cohort of 10 µg/lesion administered into 2 lesions may be explored.  The 
information from this additional cohort could help the design of future studies.  The decision 
whether or not to open this cohort would be made when the Dose Escalation data is reviewed 
following the determination of the MTD.  No additional treatment cohorts are planned beyond 
this one group.  Following this evaluation, patients would be enrolled into the Patient Expansion 
group and would receive G100 injected into a single lesion at the recommended dose. 
Following each safety evaluation by the DMC and the Sponsor, a further modification to the 
dose/treatment schedule could be recommended.  For all treatment groups, the DMC and 
Sponsor will review all events meeting the criteria for DLTs and all SAEs considered at least 
possibly related to the study regimen as they are reported on an ongoing basis. In addition, the 
DMC and Sponsor will review all safety data for any trends at least once every 3 months. SAE 
reports considered at least possibly related to the study regimen and are unexpected will be 
expedited to regulatory authorities, investigators, and DMC members.  In addition to the 
stopping rules (DLTs within the initial 28 days), these reviews may lead to modification or 
stopping of the treatment program if related, treatment-emergent AEs indicate a safety profile 
that is inconsistent or significantly worse than previously reported with the use of either G100 or 
pembrolizumab alone or rituximab alone.  
All AEs and DLTs observed during dose escalation of any treatment arm and/or patient 
expansion meeting the criteria of a stopping rule will be reviewed by the DMC.  If there is 


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disagreement between the DMC and the investigator’s assessment regarding the relationship of 
the event to study agent or to the clinical relevance (e.g., lab abnormality), the Sponsor in 
consultation with the DMC may determine to stop the treatment or continue.  In the later case, 
the AE may become a medical event of interest and be tracked closely for additional events 
occurring in future with IT G100 
All patients treated with one or more injections of G100 will be considered part of the safety data 
set.  Patients will be followed every 8 weeks until disease progression as defined by the irRC.  
Patients with disease progression by irRC (or symptomatic deterioration) will be followed 
thereafter every 8-12 weeks by telephone or clinical visit for up to one year (or longer if the 
patient agrees) after first study injection as long as they are able to engage in follow-up.  Follow-
up will ascertain vital status (survival status) as well as cancer status (e.g., lymphoma 
transformation), post-treatment anti-cancer therapy (including time to next treatment, treatment 
details, and clinical response), and any SAE that might be possibly related to G100 treatment.   
Patients with disease progression by the immune-related Response Criteria (irRC) 
(Wolchok 2009) will be followed thereafter every three months by telephone or clinic visit for up 
to one year after first study treatment to ascertain clinical status. 
5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Primary Objective 
 In Part 1:  Evaluate the safety and tolerability of ascending doses of intratumoral G100 in 
patients with low-grade NHL receiving local radiation 
 In Part 2:  Assess the safety and tolerability of intratumoral G100 or sequential 
intratumoral G100 and anti-PD-1 therapy in patients with follicular NHL receiving local 
radiation 
 In Part 3:  Evaluate the safety and tolerability of 20 µg/dose of intratumoral G100 in 
patients with low-grade NHL receiving local radiation  
 
In Part 4:  Evaluate safety and preliminary clinical efficacy of intratumoral G100 at 
20µg/lesion in single or multiple tumor lesions and pembrolizumab (anti-PD-1) therapy 
in patients with relapsed or refractory follicular NHL who have received at least 3 prior 
systemic treatments, one of which was or included an anti-CD20 antibody 
 In Part 5:  Evaluate safety and preliminary clinical efficacy of standard induction therapy 
with rituximab (anti-CD20) in combination with escalating doses of intratumoral G100 in 
single tumor lesions in patients with follicular NHL who have received at least one or 
two prior treatment(s) 


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5.2 
Secondary Objectives 
 Assess clinical responses by irRC using bi-dimensional measurements and 
time-to-progression (TTP) as a preliminary indication of efficacy 
For comparison, clinical responses will also be assessed by the International Working 
Group response criteria and Lugano criteria for lymphomas (Cheson 2014). 
 Assess abscopal tumor responses in non-treated, distal tumor sites  
5.3 
Exploratory Objective 
 For Part 4 and 5, explore pharmacokinetic and pharmacodynamic properties of G100 
 Evaluate pre- and post-regimen tumor tissue and blood for exploratory biomarkers of 
immunologic and tumor response 
 To assess clinical responses by Immune-related Response Criteria (irRC) and Lugano 
criteria for lymphomas using independent radiology review 
5.4 
Primary Endpoint 
 Part 1:  The nature, frequency and severity of AEs and laboratory abnormalities up 
through Study Day 28 in patients with low-grade NHL receiving intratumoral G100 and 
local radiation 
 Part 2:  The nature, frequency and severity of AEs and laboratory abnormalities occurring 
in patients with follicular NHL receiving local radiation and either intratumoral G100 
alone or sequential intratumoral G100 and anti-PD-1 therapy  
 Part 3:  The nature, frequency, and severity of AEs and laboratory abnormalities 
occurring in patients with follicular NHL receiving local radiation and G100 at 
20 µg/dose 
 Part 4: The nature, frequency and severity of AEs and laboratory abnormalities and the 
frequency of clinical responses occurring in patients with follicular NHL receiving 
intratumoral G100 at 20 µg/lesion in single or multiple tumor masses and pembrolizumab 
therapy 
 Part 5:  The nature, frequency and severity of AEs and laboratory abnormalities and the 
frequency of clinical responses occurring in patients with follicular NHL receiving 
rituximab therapy in combination with escalating doses of intratumoral G100 in single 
tumor lesions  
5.5 
Secondary Endpoints 
 The nature, frequency and severity of AEs and laboratory abnormalities until 21 days 
after G100 regimen is completed or discontinued 


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 Clinical responses by irRC using bi-dimensional measurements and expressed as PR, CR, 
SD, or PD, and TTP and/or progression-free survival (PFS) as a preliminary indication of 
efficacy 
 As an exploratory comparison, assess clinical responses by the International Working 
Group response criteria for lymphomas. (For determining PD, the irRC criteria will be 
used.)  Sponsor will assess for clinical responses by the Lugano criteria for lymphomas 
(Cheson 2014). 
 Abscopal tumor responses in non-treated, distal tumor sites  
5.6 
Exploratory Endpoints 
 For Part 4 and 5, Explore pharmacokinetic and pharmacodynamic properties of G100 
 Assess blood and tumor samples for exploratory biomarkers of immunologic and tumor 
response 
6.0 
INVESTIGATIONAL PLAN 
6.1 
Overall Trial Design and Plan 
This is a Phase 1/2, open label, trial of G100 in patients with low grade follicular NHL. G100 is 
composed of GLA formulated in a SE.  GLA is a fully synthetic TLR4 agonist that is a potent 
stimulator of innate immune responses.  In this study, G100 will be injected into tumors of 
follicular NHL patients in order to generate anti-tumor immune responses.  GLA in either the SE 
formulation or an AF has been examined in >1000 patients as an adjuvant for various infectious 
agent and cancer vaccines as well as in 2 ongoing clinical studies involving patients with Merkel 
Cell carcinoma or sarcoma where it has been administered intratumorally either alone or in 
combination with local radiation therapy.  It has demonstrated the ability to stimulate immune 
responses with an acceptable safety profile. 
In Part 1, Dose Escalation, patients with accessible tumors that are being considered for 
radiation therapy will receive standard local radiation followed by intratumoral injections of 
G100 into the irradiated mass(es).  Two dose levels will be examined and a 3+3 sequential dose 
escalation design will be used. All patients will receive a regimen consisting of standard low 
dose radiation (2Gy every day [qd] x2, 4 Gy total) to the target tumor mass(es).  G100 will be 
injected intratumorally beginning 1 day following completion of radiation therapy 
(Study Day 2), a second dose will be administered 3-5 days later (Study Day 5 to 7) and then 
dosing will continue weekly for up to 4 additional doses (6 total) as long as the tumor remains of 
sufficient size for injection.  A single lesion within the radiation field will be targeted to receive 
each dose of G100. If the lesion regresses, another lesion within the radiation field will be chosen 
for treatment (as described in Section 8.1.3.2).  If the tumor mass has not regressed completely 
dosing may continue for 3 additional weekly intratumoral doses (9 total). 


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Two dose levels of G100 are planned: 
 Cohort 1: 5 µg  
 Cohort 2: 10 µg  
Initially, three patients will be scheduled to receive G100 at the first dose level. Dose escalation 
will be contingent upon acceptable safety data obtained during the first 28 days of observation 
following initiation of the regimen.  A dose level cohort will be expanded from three to six if one 
of the first three patients experiences a DLT.  Further patient accrual into that dose level cohort 
(or higher) will be suspended as soon as ≥2 patients in that cohort experience DLT, or when 
otherwise deemed clinically appropriate by the investigator or Sponsor medical monitor.  After 
the 28-day DLT observation period for the final patient in a cohort is complete, if less than one 
third of the patients enrolled in that cohort developed a DLT, advancement to the next dose-level 
cohort can begin.  
Patients will be considered evaluable if they have received at least three G100 injections and 
have completed Day 28 safety monitoring OR have experienced DLT.  Patients who experienced 
DLT during the safety period will not be replaced.  All other patients who have not received at 
least three G100 injections and/or do not complete the Day 28 safety monitoring period for 
reasons other than treatment-related toxicity will be replaced.  
Following completion of the dose escalation stage of the trial, the maximum tolerated dose 
(MTD) or maximum safe dose (highest dose level examined in the study) will be defined as the 
highest dose reached in which less than one third of the patients in the cohort experienced a 
DLT. 
In Part 2, depending on the results of Part 1 and the MTD/maximum safe dose, two groups of 
patients may be examined, Patient Expansion With Or Without Pembrolizumab and (optional) 
Large Tumor groups. 
In the first group, Patient Expansion With or Without Pembrolizumab: Up to 24 patients will be 
randomly assigned and treated with single agent intratumoral G100 or with the sequential 
administration of intratumoral G100 and pembrolizumab at the MTD or maximum safe dose of 
G100 determined in Part 1.  This portion of the study is designed to be exploratory.  Data 
indicate that inhibitory immune checkpoint pathways are up-regulated in the tumor 
microenvironment and that interfering with these regulatory pathways can lead to improved 
tumor responses in preclinical models.  Treatment will follow the same dose regimen as in Part 1 
(Figure 4) and consist of G100 at the MTD or maximum safe dose and local radiation therapy.  
For patients randomized to anti-PD-1 therapy, on Day 14, pembrolizumab treatment will be 
initiated at a standard dose of 200 mg intravenously (IV) and then administered Q3W IV for up 
to 2 years or until disease progression or unacceptable toxicity (Figure 5).  For pembrolizumab, 
dose modification for AEs attributed to the drug will follow the guidelines as recommended for 
the product and as outlined in the protocol.  The main goal of Part 2, Patient Expansion With Or 


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Without Pembrolizumab, is to gain safety information, immunologic data and early clinical 
experience with these regimens to allow planning for future studies with these agents.  
In the second group, Part 2, Large Tumors: a higher dose of G100 may be examined.  If  G100 
at the 10 µg/dose is determined to be the maximal safe dose and the DMC agrees, an optional 
treatment group for Large Tumor patients will be treated.  Preclinical data indicates a dose 
response to G100 and this will be explored in these patients.  In this group, up to 4 patients with 
injectable lymphoma mass(es) 4 cm or greater in total size (based on the sum of the 
measurements of the single greatest dimension of each the tumor(s) within the planned radiation 
field) will be enrolled and will receive G100 at 20 µg/dose.  This will allow greater distribution 
of the G100 within the large tumor mass(es) and the examination of safety and dose effect.  
Treatment would be administered on the same treatment schedule as in Part 1 except that the 
G100 dose be at 20 µg.  The dose would be administered to a single large target lesion or 
distributed among 2 or more lesions within the radiation field.  If the target lesion(s) regresses, a 
different lesion within the radiation field will be chosen for treatment, if available.  If the tumor 
mass has not regressed completely following 6 doses, treatment may continue for 3 additional 
weekly intratumoral doses (9 total). 
In Part 3, G100 Expansion of 20 µg Dose Group, up to 25 patients with follicular NHL will be 
enrolled to receive local radiation therapy and intratumoral G100 at 20 µg/dose.  Part 3 would 
begin following: (a) completion of enrollment of the Part 2 Patient Expansion With or Without 
Pembrolizumab group (as determined by Sponsor), (b) enrollment of at least 3 patients on the 
Large Tumor Group with follow-up to at least Day 28, and (c) determination of an acceptable 
safety profile following a review of G100 alone data.  Large tumors are not required, and 
patients with any injectable tumor may participate.  Data from another study in sarcoma and 
early data from this trial have not demonstrated any safety concerns with the 20-µg dose level, 
and to date, all reported events considered at least possibly related to the study agent have only 
been grade 1 or 2.  Compared to baseline, post-treatment tumor biopsies have demonstrated 
significant increases in immune infiltrates within the tumor of some patients suggesting that this 
dose level should be explored further.  The dose will be administered to a single target lesion or 
distributed among 2 or more lesions within the radiation field. If the target lesion(s) regresses, a 
different lesion within the radiation field will be chosen for treatment, if available.  If the tumor 
mass has not regressed completely following 6 doses, treatment may continue for 3 additional 
weekly intratumoral doses (9 total).  Data will be monitored continuously for safety, clinical 
effect and exploratory biomarkers.  
Part 4, G100 at 20µg/lesion Into Single Or Multiple Tumor Masses Plus Pembrolizumab:  Data 
from Parts 1-3 of this study demonstrate that intratumoral G100 at the highest dose examined 
(20 µg) has been well-tolerated with only grade 1 or 2 related AEs and no DLTs reported with its 
use.  This higher dose has been associated with increased numbers of infiltrating CD8 T cells 
into the tumor (TILs), and greater numbers of CD8 TILs have been statistically associated with 
the development of objective clinical responses.  In Part 2, the combination of G100 (10 µg) and 


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pembrolizumab was well-tolerated without new or unexpected toxicities, and the addition of 
pembrolizumab resulted in more clinical responses, deeper abscopal tumor shrinkage, and a 
higher number of tumor infiltrating CD8 T cells.  Therefore Part 4 will examine the 20 µg dose 
of G100 in 1 or more tumor lesions (up to 4 lesions) plus pembrolizumab in order to establish 
safety and examine clinical and biomarker responses in patients receiving increasing total 
systemic doses of G100.   
Part 4 will consist of a Dose Escalation group to evaluate and establish safety of injecting 20µg 
of G100 into multiple lesions (up to 4 lesions) in combination with pembrolizumab and a Patient 
Expansion group to assess clinical responses with this regimen.  At least 22 relapsed or 
refractory follicular NHL patients who received ≥3 prior systemic therapies will be treated in 
Part 4.  Twenty-two efficacy evaluable patients as defined in the Statistical Section will be 
enrolled. 
During Dose Escalation, safety will be assessed using a 3+3 design where sequential cohorts of 
patients will be treated with intratumoral G100 at 20µg/lesion in 1, 2, 3, or 4 tumor lesions 
corresponding to systemic G100 exposure of 20, 40, 60 or 80 µg G100.  Once the 20 µg systemic 
dose level cohort (20 µg injected in 1 lesion) has been established to be reasonably safe, patients 
who do not qualify to enroll on the next dose level cohort due to insufficient numbers of 
potentially injectable lesions may enter Patient Expansion at that single lesion dose level.  
As each higher systemic dose level (40 µg, 60 µg, 80 µg) in multiple lesions is established to be 
well-tolerated, additional patients who otherwise qualify for the study but are unable to be 
treated on Dose Escalation due to insufficient numbers of injectable lesions will be allowed to 
enroll into the Patient Expansion portion of the study at the established safe dose levels.  
If complete enrollment of 22 efficacy evaluable patients is reached before Dose Escalation is 
complete, the Sponsor may choose to continue enrollment into just the Dose Escalation cohorts 
with up to 12 patients to fill all or some of the remaining cohort(s). 
Treatment will follow a similar dose regimen as in "Part 2, Patient Expansion With or Without 
Pembrolizumab" group, except that radiation therapy has been omitted.  G100 will be injected 
intratumorally beginning on Day 0, a second dose will be administered 5-7 days later 
(Study Day 5-7) and then dosing will continue weekly for up to 4 additional doses (6 total) as 
long as the tumor remains of sufficient size for injection.  At least 1 lesion will be targeted to 
receive each dose of G100.  If the lesion regresses, inject around the area where the lesion was 
until the course is complete.  If the patient is entered in a cohort where more than one lesion is 
injected (cohorts 2 to 4), as many easily accessible tumors will be targeted and treated as 
specified for the cohort.  Imaging assisted injections are allowed but the feasibility and safety of 
these treatments must be discussed first and approved by the Medical Monitor.  If the tumor 
mass has not regressed completely from baseline, dosing may continue for 3 additional weekly 
intratumoral doses (9 total).  On Day 14, pembrolizumab treatment will be initiated at a standard 
dose of 200 mg intravenously (IV) and then be administered every 3 weeks (Q3W) IV for up to 
2 years or until disease progression or unacceptable toxicity.  


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Part 4 Dose Escalation 
In the Dose Escalation portion, safety will be assessed using a 3+3 design where 12 to 24 
patients will be assigned to sequential cohorts of escalating number of G100 injected lesions in 
combination with standard dose pembrolizumab (Figure 6).  Four cohorts are planned: 
 Cohort 1: G100 20 µg/lesion in 1 tumor  
 Cohort 2: G100 20 µg/lesion in 2 tumor lesions (40µg total) 
 Cohort 3: G100 20 µg/lesion in 3 tumor lesions (60µg total) 
 Cohort 4: G100 20 µg/lesion in 4 tumor lesions (80µg total) 
Once a Cohort dose level is established to be safe, patients who do not meet the criteria of 
sufficient numbers of injectable tumors to enter the next dose Cohort will be enrolled in a Patient 
Expansion group at a systemic dose level that has already been established as safe.   
Initially, three patients will be scheduled to receive G100 at the first dose level.  Dose escalation 
will be contingent upon acceptable safety data obtained during the first 28 days of observation 
following initiation of the regimen.  A dose level cohort will be expanded from three to six if one 
of the first three patients experiences a dose-limiting toxicity (DLT).  Further patient accrual into 
that dose level cohort (or higher) will be suspended as soon as ≥2 patients in that cohort 
experience DLT, or when otherwise deemed clinically appropriate by the investigator or Sponsor 
Medical Monitor.  After the 28-day DLT observation period for the final patient in a cohort is 
complete, if less than one third of the patients enrolled in that cohort developed a DLT, 
advancement to the next dose-level cohort can begin.  
During Dose Escalation, patients will be considered evaluable for determination of safety and 
dose-level cohort advancement if they have received at least three complete G100 treatments and 
1 dose of pembrolizumab and have completed Day 28 safety monitoring OR have experienced 
DLT.  Patients who experienced DLT during the safety period will not be replaced.  All other 
patients who have not received at least three G100 treatments and 1 dose of pembrolizumab 
and/or do not complete the Day 28 safety monitoring period for reasons other than treatment-
related toxicity will be replaced.  
Following completion of the Dose Escalation portion of Part 4, the maximum tolerated dose 
(MTD) or maximum safe dose (highest dose level examined in the study) will be defined as the 
highest dose reached in which less than one third of the patients in the cohort experienced a 
DLT. 
Potential Dose Modification During Dose Escalation: 
G100 is a local therapy with systemic immune responses.  Therefore, the safety profile may 
differ from that of systemically administered agents.  In order to further investigate this, if 2 or 


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more DLTs are observed in the initial cohort at 20 µg of G100, the Sponsor, in agreement with 
the independent DMC may choose to examine a new cohort of patients to better understand 
whether or not the DLTs associated with the injection of a single lesion might be abrogated by 
decreasing the dose and administering the lower single lesion dose of 10 µg  into multiple 
lesions.  Intratumoral G100 10 µg in a single lesion in combination with pembrolizumab was 
established to be well-tolerated in Part 2 of this study.  Thus, this new cohort would examine the 
safety of G100 10 µg administered into 2 injectable lesions and would use the same 3+3 design 
described above.  Based on a review of the safety profile of this new cohort and in agreement 
with the independent DMC, further dose escalation cohorts may be investigated using this lower 
dose of 10 µg/lesion and a similar dose escalation schema as described above where up to 
4 lesions may be potentially treated.   
For pembrolizumab, dose modification for AEs attributed to the drug will follow the guidelines 
as recommended for the product and as outlined in the protocol.  
Part 4 Patient Expansion:  
Once the G100 20 µg systemic dose level has been established to have an acceptable safety 
profile, patients who otherwise qualify for the study but do not have the requisite number of 
injectable tumor masses to enroll on the dose cohort currently under evaluation may be enrolled 
into a Patient Expansion group.  The Patient Expansion group will begin to evaluate clinical 
response (ORR) and biomarker changes of G100 plus pembrolizumab combination.  An 
exploratory analysis will also be performed in those who are considered TLR4high. 
The per lesion dose during Patient Expansion will be 20 µg/lesion.  The total administered dose 
of G100 will depend on the safety established with each dose cohort.  Determination of the 
number of potential injectable lesions will be made by the investigator in consultation with 
Medical Monitor. 
As the safety of each dose cohort is established, the number of allowed injectable lesions in 
Patient Expansion will be as follows: 
Established Safe Systemic Dose 
Treatment In Patient Expansion 
20 µg dose level  
20 µg in 1 lesion 
40 µg dose level  
20 µg in up to 2 lesions 
60 µg dose level  
20 µg in up to 3 lesions 
80 µg dose level  
20 µg in up to 4 lesions 


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Patient enrollment will be monitored.  It is planned that 22 efficacy evaluable patients will be 
treated with intratumoral G100 and IV pembrolizumab in Part 4 in order to provide sufficient 
data for evaluation of efficacy (see Statistical Section).  Patients who received G100 20 µg/lesion 
during Dose Escalation in Part 4 may be included in the clinical response analysis. 
Part 5, G100 Plus Rituximab:  Studies have demonstrated the potential for additive or synergistic 
effects of the combination of G100 and rituximab.  G100 has been shown to increase the number 
of inflammatory and activated immune cells within the tumor microenvironment, including T 
cells, NK cells, macrophage and dendritic cells.  Rituximab can potentially increase the 
loading/pulsing of dendritic cells with tumor antigen, leading to more effective antigen 
presentation of rare tumor antigens.  Rituximab and other similar antibodies that bind to tumor 
cells and debris have been previously shown to facilitate the uptake and processing of tumor 
antigens by dendritic cells through opsonization/phagocytosis.  In addition, a known mechanism 
of action of rituximab is through antibody dependent cellular toxicity (ADCC).  In preclinical 
work, the combination of G100 with rituximab demonstrated enhanced ADCC.  Therefore, G100 
in combination with rituximab can increase the amount of tumor antigen processed by dendritic 
cells potentially leading to greater T cell stimulation/activity; in addition, the combination could 
enhance tumor cytotoxicity by activating and increasing the number of ADCC effector cells. 
In this study, a Dose Escalation will be performed first followed by Patient Expansion.  During 
Dose Escalation 12-24 patients and during Patient Expansion 20 efficacy evaluable patients as 
defined in the Statistical Section will be enrolled.  Patient enrollment will be monitored.  Patients 
who received G100 during Dose Escalation in Part 5 may be included in clinical response 
analysis. 
Data from the G142 study indicate that the G100 intratumoral dose of 20 µg is relatively safe 
with only grade 1 or 2 related AEs reported and no DLTs and that this higher dose appears to 
induce greater numbers of infiltrating CD8 T cells into the tumor.  Recent preclinical data 
indicate that G100 doses greater than 20 µg can lead to improved survival of animals in tumor 
models, further supporting that additional dose exploration may be warranted.  Therefore this 
arm will examine escalating doses of G100 plus rituximab in a single tumor site utilizing a 3+3 
design in order to establish safety and examine clinical and biomarker responses.  Once the 
highest safe dose/systemic exposure is determined, from the Dose Escalation portion of the 
study, all safety, efficacy and biomarker data will be reviewed by the Sponsor (in collaboration 
with the independent DMC) and either the highest dose determined to be safe or the most 
biologically active and safe dose (if different than the MTD) will be chosen for further 
investigation.  A Patient Expansion group would then begin.  Details of Dose Escalation and 
Patient Expansion are described below. 
Part 5, Dose Escalation : 
In the Dose Escalation portion, safety and efficacy of G100 injected into a single tumor lesion 
without radiation will be assessed using a 3+3 design where patients will be assigned to 


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sequential cohorts of escalating doses of intratumoral G100 in combination with standard dose 
induction therapy with rituximab. (Figure 8)  Treatment will begin on Day 0 with rituximab 
375mg/m2 IV and continue weekly for a total of 4 doses.  If there are no DLTs or significant 
safety events after the first dose of rituximab, G100 will be injected intratumorally beginning on 
Day 1, and then dosing will continue weekly for 3 additional doses (4 total) on a visit schedule 
that coincides with rituximab treatments as long as the tumor remains of sufficient size for 
injection.  One lesion will be targeted to receive each dose of G100.  If the lesion regresses, 
another lesion will be chosen for treatment.  Imaging assisted injections are allowed but the 
feasibility and safety of these treatments must be discussed first and approved by the Medical 
Monitor.  If the tumor lesion has not regressed completely after the first 4 doses of G100, dosing 
may continue for 2 additional weekly intratumoral doses (6 total).  Following restaging, the 
patient may be eligible for a second course of G100.  
Four cohorts G100 plus rituximab are planned and will be enrolled sequentially: 
 Cohort 1: G100 20 µg in single tumor lesion 
 Cohort 2: G100 40 µg in a single tumor lesion 
 Cohort 3: G100 60 µg in a single tumor lesion 
 Cohort 4: G100 80 µg in a single tumor lesion 
Initially, 3 patients will be scheduled to receive G100 at the first dose level. Dose escalation will 
be contingent upon acceptable safety data obtained during the first 28 days of observation 
following initiation of the regimen.  A dose level cohort will be expanded from 3 to 6 if one of 
the first 3 patients experiences a dose-limiting toxicity (DLT).  Further patient accrual into that 
dose level cohort (or higher) will be suspended as soon as ≥2 patients in that cohort experience 
DLT, or when otherwise deemed clinically appropriate by the investigator or Sponsor.  After the 
28-day DLT observation period for the final patient in a cohort is complete, if less than one third 
of the patients enrolled in that cohort developed a DLT, advancement to the next dose-level 
cohort can begin.  
During Dose Escalation, patients will be considered evaluable for determination of safety and 
dose-level cohort advancement if they have received at least 3 complete G100 treatments and 
3 doses of rituximab and have completed Day 28 safety monitoring OR have experienced DLT.  
Patients who experienced DLT during the safety period will not be replaced.  All other patients 
who have not received at least 3 G100 treatments and 3 doses of rituximab and/or do not 
complete the Day 28 safety monitoring period for reasons other than treatment-related toxicity 
will be replaced.  Based on ongoing evaluation of study data, the Sponsor may decide to 
complete fewer than the planned 4 dose cohorts and proceed directly to the Patient Expansion 
portion of the study. 
Following completion of the dose escalation stage of the trial, the maximum tolerated dose 
(MTD) will be defined as the highest dose reached in which less than one third of the patients in 


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the cohort experienced a DLT.  If no DLTs are experienced in the first 3 patients enrolled at 
highest dose of 80 µg, the 80 µg dose per lesion will be determined to be the “maximum safe 
dose” examined in this study and dose escalation will be considered complete.  An additional 
3 patients may then be enrolled for a total of 6 patients at that dose level and safety stopping 
rules will be followed.  If after the Sponsor and DMC review all safety data it is determined that 
there are no safety issues requiring the separation of the first dose of rituximab and G100, the 
regimen may be modified to administer both on Day 0 during Patient Expansion. 
Part 5, Patient Expansion: 
Once the MTD/maximum safe dose has been established, all safety, clinical and biomarker data 
will be reviewed and a recommended dose for further exploration will be made.  The Patient 
Expansion would then begin and would enroll patients to receive G100 IT at the recommended 
dose into a single tumor mass in combination with rituximab.  Patients enrolled on Part 5 Patient 
Expansion will be analyzed on the basis of the ORR.  An exploratory analysis will also be 
performed in those who are considered TLR4high. 
G100 is a local therapy with systemic immune responses.  Therefore, the safety profile may 
differ from that of systemically administered agents.  In order to further investigate this, after 
establishment of an MTD, the Sponsor in agreement with the independent DMC may choose to 
examine one additional cohort of patients to better understand whether or not the DLTs 
associated with the injection of a single lesion might be abrogated by splitting the dose and 
administering into two separate lesions.  The data from this cohort may help determine if the 
tolerability of G100 was limited due to the injection of a single tumor mass or to the total 
systemic exposure.  In this additional cohort, 3-6 patients would be treated at the total systemic 
dose level associated with DLTs but divided and distributed into two tumor masses instead of 
one.  For example, if the MTD in a single tumor mass were determined to be 40 µg due to DLTs 
occurring at 60 µg/lesion, the dose of this cohort would be 30 µg/lesion injected separately into 
2 tumor masses.  In the event that the 20 µg dose level (Cohort 1) experiences DLTs, an optional 
cohort of 10 µg/lesion administered into 2 lesions may be explored.  The information from this 
optional cohort could help the design of future studies.  The decision whether or not to open this 
cohort would be made when the Dose Escalation data is reviewed following the determination of 
the MTD.  No additional treatment cohorts are planned beyond this one group.  Following this 
evaluation, patients would be enrolled into the Patient Expansion group and would receive G100 
injected into a single lesion at the recommended dose. 
For rituximab, dose modification for AEs attributed to the drug will follow the guidelines as 
recommended for the product and as outlined in the protocol.  
For All Parts (1 to 5) 
Retreatment / Second Course:  Following the G100 course of treatment, if a patient is determined 
to have achieved SD or better or has PD that does not require immediate therapy, has an 


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additional site of disease outside of the prior radiation field (Parts 1, 2, or 3) that is amenable to 
injection, and has not had significant treatment emergent AEs (including events that would be 
considered a DLT) as determined by the investigator and the Sponsor, the patient may be eligible 
to receive a second course of G100.  For patients enrolled on Parts 4 or 5, the same previously 
injected tumor site(s) may be targeted or a replacement site(s) may be chosen.   
Six weeks or more after completion of the first course of G100 treatment, the second course 
would begin and consist of G100 alone (no radiation and no additional rituximab for patients 
enrolled on Part 5) at the same dose received during the first course of therapy.  Treatment would 
be administered on a similar weekly schedule as the first course except without radiation therapy 
(or rituximab therapy).  G100 will be injected intratumorally beginning on Day 0 (instead of 
Study Day 2), a second dose will be administered 5 to 7 days later and then dosing will continue 
weekly for up to 4 additional doses (6 total) as long as the tumor remains of sufficient size for 
injection.  For Parts 1 to 3, a single lesion will be targeted to receive each dose of G100. If the 
lesion regresses, another lesion will be chosen for treatment.  If the tumor mass has not regressed 
completely, dosing may continue for 3 additional weekly intratumoral doses (9  total).  If the 
patient had been receiving pembrolizumab as part of their therapy, the anti-PD-1 antibody would 
continue as scheduled during the second course.  For Part 4, dosing may continue into multiple 
lesions as selected for their initial course; for Part 5, the number of G100 doses is limited to 6 
treatments of a single lesion. 
Dose regimen interruption in a single patient may be made by the clinical investigator if it is 
deemed in the best interest of patient safety.  The study Medical Monitor should be consulted 
prior to or immediately upon the decision to interrupt therapy.  Safety will be reviewed on a 
regular basis by an independent DMC and the Sponsor.  These reviews may lead to modification 
or stopping of the treatment program. 
Tumor imaging will be performed during the screening visit (baseline) and then approximately 
every 8 weeks thereafter for the first year, every 3 to 4 months for the second year, and then at 
least every 6 months for the third and subsequent years until disease progression as defined by 
the irRC.  Pre- and post-treatment tumor biopsies (e.g., core biopsies) will be obtained for 
histologic review and exploratory immune analyses, including cell phenotype, tumor expression 
of TLR4, and genomic analyses of T cells.  Post-treatment biopsies will be performed in patients 
with accessible tumors within 3 weeks after the last planned G100 injection.  Peripheral blood 
will be drawn for immune assays and biomarker tests at time points listed in the Study 
Procedures. 
6.2 
Dose-Limiting Toxicities 
DLTs will be used to establish safety parameters for stopping dose escalation and will follow a 
standard 3+3 study design. AE severity assessments will be performed using National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 or newer.  
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considered at least possibly related to the study regimen Further dosing at that level will be 
discontinued.  Hospitalizations primarily intended to expedite diagnostic evaluations or for 
elective surgery will not be considered as SAEs for the purpose of ascertaining DLT.The 
occurrence of any of the following toxicities during the first 28 days will be considered a DLT, if 
assessed by the investigator to be possibly, probably, or definitely related to any component of 
study treatment (G100, pembolizumab, or rituximab).  
1. 
Grade 4 nonhematologic toxicity (not laboratory) 
2. 
Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia: 
 Grade 4 thrombocytopenia of any duration 
 Grade 3 thrombocytopenia associated with clinically significant bleeding 
3. 
Any nonhematologic AE ≥Grade 3 in severity should be considered a DLT, with the 
following exceptions: Grade 3 fatigue lasting ≤3 days; Grade 3 diarrhea, nausea, or vomiting 
without use of anti-emetics or anti-diarrheals per standard of care; Grade 3 rash without use of 
corticosteroids or anti-inflammatory agents per standard of care. 
4. 
Any Grade 3 or Grade 4 nonhematologic laboratory value if: 
 Clinically significant medical intervention is required to treat the subject, or 
 The abnormality leads to hospitalization, or 
 The abnormality persists for >1 week. 
 The abnormality results in a Drug induced Liver Injury (DILI)  
 Exceptions: Clinically nonsignificant, treatable, or reversible laboratory abnormalities 
including liver function tests, uric acid, etc. 
5. 
Febrile neutropenia Grade 3 or Grade 4: 
 Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C 
(101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for 
more than 1 hour 
 Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C 
(101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for 
more than 1 hour, with life-threatening consequences and urgent intervention 
indicated. 
6. 
Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity. 
7. 
Any treatment-related toxicity that causes the participant to discontinue treatment during 
Cycle 1. 
8. 
Grade 5 toxicity. 
9. 
Missing >25% of study drug doses as a result of treatment-related AE(s) during the first 
cycle.   


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6.3 
Stopping Rules 
During the initial 28-day treatment period, dosing will be suspended at any dose level (and 
higher) if DLTs are observed in 2 or more patients during Part 1 or during Dose Escalation of 
Part 4 or Part 5.  During patient expansion of Parts 2, 3, 4 and 5, dosing will be suspended if 
DLTs considered at least possibly related to any study medication are observed during the first 
28 days in one third or more patients within a group receiving the same treatment (assuming a 
minimum of 6 patients receiving the same dose and treatment regimen and would represent the 
initial denominator:  In Parts 2 and 3, G100 alone; in Parts 2 and 4, G100/pembrolizumab, in Part 
5, G100/rituximab)  
All AEs and DLTs observed during dose escalation of any treatment arm and/or patient 
expansion meeting the criteria of a stopping rule will be reviewed by the DMC.  If there is 
disagreement between the DMC and the investigator’s assessment regarding the relationship of 
the event to study agent or to the clinical relevance (e.g., lab abnormality), the Sponsor in 
consultation with the DMC may determine to stop the treatment or continue.  In the later case, 
the AE may become a medical event of interest and be tracked closely for additional events 
occurring in the future with intratumoral G100. 
6.4 
Maximum Tolerated Dose/Maximum Safe Dose 
The MTD will be defined as the highest G100 dose level studied in which less than one third of 
patients in a cohort experience DLT.  If the MTD is declared at the final dose level, the highest 
dose will be considered the maximum safe dose examined in the study. 
6.5 
Dosing Delays / Dose Modifications 
There are no adjustments for dose delay for a given patient, and treatment delays of >14 days 
from the treatment plan will not be allowed.  If a patient experiences a DLT, treatment of that 
patient will be suspended.  A subject may be considered for receiving further injections of the 
G100 investigational drug product on a case-by-case basis after the PI and medical monitor, in 
consultation with the independent DMC, have evaluated the risk/benefit ratio for a subject.  As 
an example, for subjects who have experienced a tumor response and had a non-life- and 
non-organ-threatening DLT, continuation of treatment as per protocol may be considered.  
7.0 
SELECTION OF PATIENTS 
This study plans to enroll patients with follicular NHL and other indolent lymphomas.  In Part 1, 
Dose Escalation, up to 12 evaluable patients may be enrolled.  In Part 2, for the Patient 
Expansion With or Without Pembrolizumab group, up to 24 additional patients and for the 
optional Large Tumor Group up to 4 evaluable patients will be enrolled.  In Part 3, G100 
Expansion of 20 µg Dose Group, up to 25 patients may be enrolled.  In Part 4, Sequential G100 
at 20 µg/lesion Into Single Or Multiple Tumor Masses Plus Pembrolizumab Group, 22 efficacy 


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evaluable patients will be enrolled.  In Part 5, G100 Plus Rituximab, 12-24 patients will be 
enrolled during Dose Escalation and 20 efficacy evaluable patients, during Patient Expansion. 
7.1 
Inclusion Criteria 
In order to be enrolled in the study, patients must meet all of the following inclusion criteria:  
1) Follicular low-grade NHL (grades 1, 2, 3A): either treatment naïve or relapsed or refractory 
following at least one prior treatment.  For France, patients with either relapsed or refractory 
only.  In Part 1 Dose Escalation only, in addition to follicular NHL, marginal zone B cell 
lymphomas: either treatment naïve or relapsed or refractory following at least one prior 
treatment.   
 In Part 4, enrollment is limited to relapsed or refractory follicular NHL patients who 
have received at least 3 prior systemic treatments, one of which was or included an anti-
CD20 antibody.   
 In Part 5, enrollment will include relapsed or refractory CD20+ follicular NHL 
following at least one but not more than 2 prior treatments.   
2) Tumor mass(es) accessible for intratumoral injection and are being considered for local 
radiation therapy and at least one additional site of disease outside the radiation field for 
assessment of distal (abscopal) response.  (Imaging assisted injections are allowed following 
approval by Medical Monitor) 
 For Parts 4 and 5, radiation therapy is omitted.  Measurable tumor mass(es) accessible 
for intratumoral injection must be present for treatment and assessment of response.  
3) ≥18 years of age 
4) Life expectancy of ≥6 months per the investigator 
5) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
6) ECG without evidence of clinically significant arrhythmia or ischemia 
7) If female of childbearing potential (FCBP), willing to undergo pregnancy testing and agrees 
to use two methods of birth control or is considered highly unlikely to conceive during the 
dosing period and for three months after last study treatment, or if receiving pembrolizumab, 
four months after last treatment (See Section 8.1.9 and Appendix F:  References for details) 
8) If male and sexually active with a FCBP, must agree to use effective contraception such as 
latex condom or is sterile (e.g., following a surgical procedure) during the dosing period and 
for three months after last study treatment, or if receiving pembrolizumab, four months after 
last treatment (See Section 8.1.9 and Appendix F:  References for details) 


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7.2 
Exclusion Criteria 
If any of the following are met, the patient will not be eligible for the study: 
1) Cancer therapies, including chemotherapy, radiation (non-study regimen related), biologics 
or kinase inhibitors, granulocyte-colony stimulating factor (G-CSF) or granulocyte-
macrophage colony stimulating factor (GM-CSF) within 4 weeks prior to the first scheduled 
G100 dose 
2) Investigational therapy within 4 weeks prior to G100 dosing 
3) Prior administration of G100 or other intratumoral immunotherapeutics 
4) Inadequate organ function including: 
a. Marrow: Peripheral blood leukocyte count (WBC) <3000/mm3, absolute neutrophil 
count ≤1500/mm3, platelets <75000/mm3, or hemoglobin <10 gm/dL 
b. Hepatic: alanine aminotransferase (ALT), and aspartate aminotransferase (AST) 
>2.5 × the upper limit of normal (ULN), total serum bilirubin >1.5 × ULN (patients 
with Gilbert’s Disease may be included if their total bilirubin is ≤3.0 mg/dL) 
c. Renal: Creatinine >1.5 × ULN 
d. Other: international normalized ratio (INR) or partial thromboplastin time (PTT) 
>1.5 × ULN 
5) Significant immunosuppression from: 
a. Concurrent, recent (≤4 weeks ago) or anticipated treatment with systemic 
corticosteroids at any dose, or 
b. Other immunosuppressive medications such as methotrexate, cyclosporine, 
azathioprine or conditions such as common variable hypogammaglobulinemia 
6) Pregnant or nursing 
7) Myocardial infarction within 6 months of study initiation, active cardiac ischemia or New 
York Heart Association (NYHA) Grade III or IV heart failure 
8) History of other cancer within 2 years (except non-melanoma cutaneous malignancies and 
cervical carcinoma in situ) 
9) Recent (<1 week ago) clinically significant infection, active tuberculosis or evidence of 
active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection 
10) Central nervous system involvement with lymphoma, including parenchymal and 
leptomeningeal disease.  In Parts 4 and 5, any involvement with lymphoma in a closed or 
confined space such as the retroorbital area will need to be pre-approved by the Medical 
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11) Significant autoimmune disease, including active non-infectious pneumonitis, with the 
exception of alopecia, vitiligo, hypothyroidism or other conditions that have never been 
clinically active or were transient and have completely resolved and require no ongoing 
therapy.  (Replacement therapy for hypothyroidism or diabetes is allowed.) 
12) Psychiatric, other medical illness or other condition that in the opinion of the PI prevents 
compliance with study procedures or ability to provide valid informed consent 
13) History of significant adverse or allergic reaction to any component of G100, and if enrolled 
in Part 2 or Part 4, pembrolizumab and/or any of its excipients, and if enrolled in Part 5, anti-
CD20 antibodies including rituximab and/or any of its excipients 
14) Use of anti-coagulant agents or history a significant bleeding diathesis. {If a superficial 
lymph node or subcutaneous mass is to be injected, patients on agents such as non-steroidal 
anti-inflammatory drugs (NSAIDs), aspirin, or clopidogrel are eligible and these agents do 
not have to be withheld.  For procedures with moderate or significant risk of bleeding, long-
acting agents such as aspirin or clopidogrel should be discussed with the Medical Monitor 
and may need to be discontinued before G100 therapy.} 
For patients enrolled in Part 2 or Part 4 with the potential to receive pembrolizumab: 
15) Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis or interstitial lung disease 
16) Has received a live vaccine within 30 days prior to the first dose of study drug (Applies to 
patients who may receive either pembrolizumab or rituximab).  Examples of live vaccines 
include, but are not limited to, the following:  measles, mumps, rubella, varicella/zoster 
(chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; 
however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are 
not allowed. 
17) Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 
5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as 
there are no symptoms of graft versus host disease [GVHD].) 
18) Has had an allogeneic tissue/solid organ transplant 
19) Has received prior therapy with an anti-PD-1, anti-programmed death ligand (PD-L)1, or 
anti-PD-L2 agent or if the patient has previously participated in Merck MK-3475 clinical 
trials or was previously treated with an agent directed to another stimulatory or co-inhibitory 
T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due 
to a Grade 3 or higher immune-related adverse event. 


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8.0 
TRIAL REGIMENS 
8.1 
G100 Investigational Drug  
GLA, glucopyranosyl lipid A, is a TLR4 agonist that activates specific cells of the immune 
system.  TLR4 agonists activate DCs and induce acute inflammatory responses including 
production of chemokines and cytokines that mediate leukocyte infiltration, stimulation of DC 
maturation and induction of adaptive immune responses.  Several completed clinical studies with 
vaccines containing GLA administered to healthy subjects have shown that GLA is generally 
well tolerated and is associated with heightened immune responses. 
G100 (GLA-SE) is a stable oil-in-water emulsion and will be used in this study in NHL. G100 is 
formulated in a high-pressure microfluidizer and appears as a milky white liquid.  It is composed 
of GLA with the SE vehicle which includes excipients squalene (oil), glycerol, tocopherol, 
synthetic dimyristoylphosphatidylcholine, surfactant (poloxamer) and buffer (ammonium 
phosphate).  G100 is filter-sterilized and the emulsion is filled aseptically into each vial. 
8.1.1 
G100 Packaging and Labeling 
G100 (GLA-SE) will be supplied in 3 mL single use vials and will be packaged according to 
current GMP guidelines and applicable national laws and regulations.  Detailed information and 
instructions for the preparation of G100 product for the specific Study Part/Cohort will be 
included in the Study Pharmacy Manual.   
8.1.2 
Storage and Disposition of the G100 Investigational Drug Product 
G100 (GLA-SE) should be stored at 2 - 8°C. Specific instructions for the admixture and 
administration of G100 are provided in the Study Pharmacy Manual.  G100 Dose Preparation for 
Administration to the Patient 
8.1.3 
G100 Preparation 
The GLA-SE vial is single use.  Specific instructions for the appropriate dose concentration, 
preparation and administration will be provided in the Pharmacy Manual.  
For intratumoral administration into the lymphoma lesions, the dose of GLA will be fixed based 
on the dose cohort and will consist of 5, 10 or 20 µg/dose/lesion in Parts 1 to 4 and up to 80 
µg/lesion in Part 5.  The maximum total dose of drug that can be injected in one patient on a 
given day will be determined by the dose cohort the patient is assigned to and the outcome of the 
MTD/maximal safe dose determination.  Details on the preparation of the study agent and dose 
concentration and volume will be provided in the Pharmacy Manual. 


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8.1.4 
G100 Administration 
For Parts 1, 2, or 3, patients with follicular NHL with at least one tumor mass that is being 
considered for radiation therapy that is also accessible and assessed to be safe for intratumoral 
injection are eligible for enrollment.  In Part 4 and Part 5, similar patients are eligible for 
enrollment except that radiation therapy has been omitted.  All patients must also have a second 
site where tumor response can be assessed.  For example, the second untreated, abscopal site 
could be a measurable tumor lesion or involvement of skin.  For Parts 4 and 5, the G100 treated 
site(s) and a non-injected site (unless not available and prior approval is provided by Medical 
Monitor) must be measurable (Index) lesions and be followed by imaging studies and recorded.  
Skin lesions and other lesions measured by exam are acceptable if lesions can be measured by 
reproducible methods and preferably if photographically documented. 
Parts 1, 2 or 3: For Parts 1, 2 or 3, target tumor lesions will be treated with local radiation 
therapy at a standard dose (2Gy x2).  The day after radiation therapy is complete, for Part 1 Dose 
Escalation and Part 2 Patient Expansion, the target tumor lesion will be injected with either 5, 
10 or 20 μg of GLA depending on the assigned dose level.  Although more than one tumor mass 
may receive radiation, injections of each dose should be administered completely to one 
superficial radiated tumor when feasible.  The ability to inject tumors with G100 is dependent on 
the elasticity or fibrotic nature of the tumor mass and can be quite variable. In general, lesions >1 
cm in diameter will be able to accommodate 0.5 mL and lesions closer to 2 cm can accommodate 
1.0 or more mL injections of G100.  If not, adjacent masses within the radiation field may be 
targeted and as much of the full dose should be given.  Based on the clinical trial experience with 
other intratumoral approaches in NHL, it should be expected that there will be peritumoral 
administration of G100 from either direct or extravasation following injection; this has not 
changed the clinical safety, immunologic or clinical results of those agents (personal 
communication, Stanford University).  Based on the >1000 subjects receiving GLA by either IM, 
SC or intradermal (ID) routes of administration, there is no expectation of any safety issues for 
peritumoral administration of G100.  If during therapy, the G100 treated target lesion regresses 
significantly and cannot be injected, any other remaining lesions within the radiation field may 
be chosen for therapy, or if not possible due to technical issues, the dose may be distributed 
among 2 or more lesions.  The total dose of G100 administered should be recorded for each 
treatment.  Skin overlying the lesion should be prepped and sterilized using standard methods; 
the use of local anesthesia will be at the discretion of the treating physician.  It is expected that 
the injected tumor mass will regress during G100 treatment due to the radiation therapy.  At the 
discretion of the investigator, should the lesion(s) within the radiation treatment field become too 
small or inaccessible for injection, G100 therapy will stop and the patient will continue to be 
followed for tumor response at distal sites and for long-term clinical status.   
In the optional treatment group for Large Tumor patients, up to 4 patients with injectable 
lymphoma mass(es) 4 cm or greater in total size will be enrolled and receive G100 consisting of 
20 µg of the GLA component per dose.  In Part 3, G100 Expansion of 20 µg Dose Group, up to 


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25 patients will be enrolled and treated with 20 µg/dose.  Treatment with G100 would be 
administered on the same treatment schedule as in Part 1 except that the dose would be higher 
(See Figure 4).  Depending on the treatment volume, the dose should be administered to a single 
large target lesion or distributed among 2 or more lesions within the radiation field.  If the target 
lesion(s) regresses, a different lesion(s) within the radiation field will be chosen for treatment, if 
available. 
Parts 4 and 5:  In Part 4, patients will be treated with G100 at 20 µg/lesion in combination with 
pembrolizumab, and the treatment schedule will follow that in Figure 7.  Overall, 22 efficacy 
evaluable patients as defined in the Statistical Section will be enrolled.  In Part 5, 12-24 patients 
will be treated during Dose Escalation and 20 efficacy evaluable patients as defined in the 
Statistical Section will be enrolled following the treatment schedule in Figure 9.  For Parts 4 and 
5, radiation therapy has been omitted.  Once identified, easily accessible lesion(s) will be 
targeted to receive each dose of G100.  If the initially injected lesion(s) regresses before 
completion of therapy, another site may be chosen for treatment.  If the patient is entered in a 
cohort where more than one lesion is injected (Part 4, cohorts 2 to 4 or expansion group), as 
many easily accessible tumors will be targeted and treated as specified for the cohort treatment 
group.  Imaging assisted injections are allowed but the feasibility and safety of these treatments 
must be discussed first and approved by the Medical Monitor. 
As much of the full dose as possible should be given and the total dose of G100 administered 
should be recorded for each administration.  As noted above, it should be expected that there will 
be peritumoral administration of G100 from either direct or extravasation following injection.  In 
Parts 1 to 4, if the tumor mass has not regressed completely following 6 doses, treatment may 
continue for 3 additional weekly intratumoral doses (9 total).  At the discretion of the 
investigator, should the G100 treated lesion(s) become too small or inaccessible for injection, 
G100 therapy will stop and the patient will continue to be followed for tumor response at distal 
sites and for long-term clinical status.  In Part 5, up to 6 doses will be administered. 
For All Parts (1 to 5) 
Retreatment / Second Course:  Patients may be eligible to receive a second course of G100 if 
they achieved SD or better or have PD that does not require immediate therapy, have accessible 
and injectable lesions outside the prior radiation field, and have not had significant treatment 
emergent AEs (including events that would be considered a DLT) as determined by the 
investigator and the Sponsor.  For patients enrolled on Parts 4 or 5, the same previously injected 
tumor sites may be targeted or a replacement site(s) may be chosen.   
Six weeks or more after completion of the first course of G100 treatment, the second course 
would begin and consist of G100 alone (no radiation and no additional rituximab) at the same 
dose received during the first course of therapy.  Treatment would be administered on a similar 
weekly schedule as the first course except without radiation therapy (or rituximab therapy).  
G100 will be injected intratumorally beginning on Day 0 (instead of Study Day 2), a second dose 


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will be administered 5 to 7 days later and then dosing will continue weekly for up to 4 additional 
doses (6 total) as long as the tumor remains of sufficient size for injection.  For Parts 1 to 3, a 
single lesion will be targeted to receive each dose of G100.  If the lesion regresses, another lesion 
will be chosen for treatment.  If the tumor mass has not regressed completely, dosing may 
continue for 3 additional weekly intratumoral doses (9 total).  If the patient had been receiving 
pembrolizumab as part of their therapy, the anti-PD-1 antibody would continue as scheduled 
during the second course.  For Part 4, dosing may continue into multiple lesions as selected for 
their initial course; for Part 5, the number of G100 doses is limited to 6 treatments of a single 
lesion. 
If the patient has any grade 3 toxicity, either attributable to the treatment or affecting the area of 
the injections, G100 injections will be held until toxicity resolves to grade 2 or lower.  For 
grade 2 local toxicities, treatments should continue.  However if the investigator has concerns, 
treatment may be held and a delay should be discussed with the Sponsor.  Delays of greater than 
2 weeks will not be allowed. 
8.1.5 
Pembrolizumab Background 
In Part 2, Patient Expansion With Or Without Pembrolizumab and Part 4, Sequential G100 plus 
Pembrolizumab, patients will receive this anti-PD-1 antibody sequentially following G100 as an 
investigational agent for the treatment of follicular lymphoma.  The study agent will be provided 
by Merck, the manufacturer of pembrolizumab. 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies. 
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications.  For more details on specific indications refer to the Investigator’s Brochure. 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on MK-3475. 
8.1.5.1 
Pembrolizumab Dose Selection (Preparation) 
The rationale for selection of dose of pembrolizumab to be used in this trial is provided in 
Section 4.5.4, Rationale for Pembrolizumab Dose Selection.  Details on preparation and 
administration of pembrolizumab are provided in the Pharmacy Manual. 
8.1.5.2 
Pembrolizumab Investigational Product  
Clinical Supplies will be provided by the Sponsor as summarized in Table 2.  


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Table 2: 
Product Descriptions 
Product Name & Potency 
Dosage Form 
MK-3475 50 mg 
Lyophilized Powder for Solution for Infusion 
MK-3475 100 mg/ 4mL 
Solution for Infusion 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations. 
8.1.5.3 
Timing of Dose Administration 
Following the End of Study (EOS) Visit on Day 77, trial treatment of pembrolizumab may be 
administered up to 5 days before or after the scheduled dosing day of each cycle due to 
administrative reasons. 
Note: Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons (i.e., elective surgery, unrelated medical events, patient vacation, holidays) not related to 
study therapy.  Patients should be placed back on study therapy within 3 weeks of the scheduled 
interruption.  The reason for interruption should be documented in the subject's study record. 
8.1.5.4 
Pembrolizumab Administration 
For patients randomized or assigned to receive pembrolizumab, treatment will be administered 
beginning on Study Day 14 after all procedures and assessments have been completed.  
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window between -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of infusion solution. 
8.1.5.5 
Dose Modification for Pembrolizumab 
AEs associated with Pembrolizumab exposure may represent an immunologic etiology.  These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of Pembrolizumab treatment and may affect more than on body system simultaneously.  
Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based 
on existing clinical study data, most irAEs were reversible and could be managed with 


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interruptions of Pembrolizumab, administration of corticosteroids and/or other supportive care.  
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes.  
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation.  Based on the severity of irAEs, withhold or permanently discontinue 
Pembrolizumab and administer corticosteroids.  Dose modification and toxicity management 
guidelines for irAEs associated with Pembrolizumab are provided in Table 3. 
 


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Table 3: 
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with 
Pembrolizumab  
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where Pembrolizumab has been withheld, Pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. 
Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent 
per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be initiated if irAEs cannot 
be controlled by corticosteroids. 
Immune-related 
AEs 
Toxicity grade or 
conditions (CTCAEv4.0) 
Action taken to Pembrolizumab 
irAE management with corticosteroid and/or 
other therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
Administer corticosteroids (initial dose of 
1-2  mg/kg prednisone or equivalent) followed 
by taper 
Monitor participants for signs and symptoms of 
pneumonitis 
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment 
Add prophylactic antibiotics for opportunistic 
infections 
Grade 3 or 4, or recurrent 
Grade 2 
Permanently discontinue 
 
 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
Administer corticosteroids (initial dose of 
1-2  mg/kg prednisone or equivalent) followed 
by taper 
Monitor participants for signs and symptoms of 
enterocolitis (i.e., diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (i.e., peritoneal signs and 
ileus). 
Participants with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis.  
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids.  
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion. 
Grade 4 
Permanently discontinue 
AST / ALT 
elevation or 
Increased bilirubin 
Grade 2 
Withhold 
Administer corticosteroids (initial dose of 
0.5-1 mg/kg prednisone or equivalent) followed 
by taper 
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable 
Grade 3 or 4  
Permanently discontinue 
Administer corticosteroids (initial dose of 
1-2  mg/kg prednisone or equivalent) followed 
by taper 


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Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
Newly onset T1DM or 
Grade 3 or 4 
hyperglycemia associated 
with evidence of β-cell 
failure 
Withhold 
Initiate insulin replacement therapy for 
participants with T1DM  
Administer anti-hyperglycemic in participants 
with hyperglycemia  
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids and initiate hormonal 
replacements as clinically indicated.   
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)  
Grade 3 or 4  
Withhold or permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
Treat with non-selective beta-blockers (e.g., 
propranolol) or thionamides as appropriate  
Monitor for signs and symptoms of thyroid 
disorders.  
Grade 3 or 4  
Withhold or  
permanently discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
Initiate thyroid replacement hormones (e.g., 
levothyroxine or liothyronine) per standard of 
care 
Monitor for signs and symptoms of thyroid 
disorders.  
Nephritis and 
Renal dysfunction 
Grade 2 
Withhold  
Administer corticosteroids (prednisone 
1-2 mg/kg or equivalent) followed by taper. 
Monitor changes of renal function 
Grade 3 or 4  
Permanently discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 3 or 4 
Permanently discontinue 
All other immune-
related AEs 
Intolerable/ persistent 
Grade 2 
Withhold 
Based on type and severity of AE administer 
corticosteroids  
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 3 
Withhold or discontinue based 
on the type of event.  Events that 
require discontinuation include 
and not limited to:  Guillain-
Barre Syndrome, encephalitis 
Grade 4 or recurrent 
Grade 3  
Permanently discontinue 
1 Withhold or permanently discontinue Pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE: For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of Pembrolizumab is required, Pembrolizumab may be resumed when AE resolves to ≤Grade 
2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   


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8.1.5.6 
Other allowed dose interruptions for Pembrolizumab  
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays).  Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor.  The reason for interruption 
should be documented in the patient's study record. 
8.1.6 
Rescue Medications & Supportive Care for Pembrolizumab 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 8.1.5.5, Table 3.  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids.  Note that several courses of steroid tapering may 
be necessary as symptoms may worsen when the steroid dose is decreased.  For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care.  The treatment guidelines are intended 
to be applied when the investigator determines the events to be related to Pembrolizumab.  
Note: If after the evaluation of the event, it is determined not to be related to Pembrolizumab, the 
investigator does not need to follow the treatment guidance.  Refer to Table 3 in Section 8.1.5.5 
for guidelines regarding dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
Note:  In addition to Table 3, supportive and treatment information may be found in the 
investigator brochure in the “Warnings and Precautions” section of the company core data 
sheet provided in the Appendix of that document and also provided in the product label. 
8.1.7 Dose modification and toxicity management of infusion-reactions related to 
Pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion.  Dose 
modification and toxicity management guidelines on Pembrolizumab associated infusion 
reaction are provided in Table 4. 


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Table 4: Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at  
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment  
(e.g., antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
 Stop Infusion. 
 Additional appropriate medical therapy may include 
but is not limited to: 
 IV fluids 
 Antihistamines 
 NSAIDs 
 Acetaminophen 
 Narcotics 
 Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
 If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g., from 100 mL/hr. to 50 
mL/hr.).  Otherwise dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
Participant may be 
premedicated 1.5h  
(± 30 minutes) prior to 
infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of analgesic). 
Grades 3 or 4 
 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae  
(e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilator support indicated 
 Stop Infusion. 
 Additional appropriate medical therapy may include 
but is not limited to: 
 Epinephrine** 
 IV fluids 
 Antihistamines 
 NSAIDs 
 Acetaminophen 
 Narcotics 
 Oxygen 
 Pressors 
 Corticosteroids 
 Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
 Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used 
immediately. 
Participant is permanently discontinued from further 
study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration. For further information, please refer to the Common Terminology Criteria for 
Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov 


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8.1.8 
Rituximab Background 
In Part 5, patients will receive this anti-CD20 antibody in combination with G100 as an 
investigational agent for the treatment of follicular lymphoma.  Rituximab is an approved 
standard treatment for follicular lymphoma patients: approved regulatory labeling and 
institutional guidelines for dose, administration including premedication, contraindications, 
warnings and precautions should be followed.  Rationale for addition of rituximab and details of 
Part 5 design are described in Section 4.1 and 6.1.  Treatment regimen is presented in Figure 9.  
Brief summary of administration, warnings and precautions is summarized below. 
8.1.8.1 
Rituximab Dose 
Rituximab dose is 375 mg/m2 as an IV infusion administered on Day 0 and then continued once 
weekly for 4 doses on a schedule as described in Section 4.1 and 6.1 and Figure 9.  No 
maintenance therapy will be used in this study. 
8.1.8.2 
Rituximab Investigational Product  
Commerically available rituximab will be used as the standard of care therapy for follicular 
lymphoma unless institutional or regional regulations request otherwise. 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations. 
8.1.8.3 
Rituximab Administration 
For patients in Part 5, treatment will be administered beginning on Study Day 0 after all 
procedures and assessments have been completed.  
Rituximab will be administered as a dose of 375 mg/m2 IV infusion. Premedicate before each 
infusion with acetaminophen and an antihistamine or other appropriate premedication regimen as 
specified by local institutional guidelines.  First Infusion:  Initiate infusion at a rate of 50 mg/hr. 
In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 
minutes, to a maximum of 400 mg/hr.  Subsequent Infusions: Initiate infusion at a rate of 
100 mg/hr.  In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 
30-minute intervals, to a maximum of 400 mg/hr.  Interrupt the infusion or slow the infusion rate 
for infusion reactions.  Continue the infusion at one-half the previous rate upon improvement of 
symptoms. 
8.1.8.4 
Dose Modification, Warning and Precuations for Rituximab 
Approved regulatory rituximab labeling and institutional guidelines for contraindications, 
warnings and precautions should be followed.  Some of them are briefly summarized below.  


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Infusion Reaction 
Rituxan can cause severe, including fatal, infusion reactions.  Severe reactions typically occurred 
during the first infusion with time to onset of 30−120 minutes.  Rituxan-induced infusion 
reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, 
pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular 
fibrillation, cardiogenic shock, anaphylactoid events, or death.  
 Premedicate patients with an antihistamine and acetaminophen prior to dosing.  Institute medical 
management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion 
reactions as needed.  Depending on the severity of the infusion reaction and the required 
interventions, temporarily or permanently discontinue rituximab.  Resume infusion at a 
minimum 50% reduction in rate after symptoms have resolved.  Closely monitor the following 
patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior 
cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells 
(≥25,000/mm3). 
Tumor Lysis Syndrome 
Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from 
tumor lysis, some fatal, can occur within 12−24 hours after he first infusion of rituximab in 
patients with NHL.  A high number of circulating malignant cells ( ≥25,000/mm3) or high tumor 
burden, confers a greater risk of TLS.  Administer aggressive intravenous hydration and anti-
hyperuricemic therapy in patients at high risk for TLS.  Correct electrolyte abnormalities, 
monitor renal function and fluid balance, and administer supportive care, including dialysis as 
indicated.  
Severe Mucocutaneous Reactions 
Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab.  
These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid 
dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis.  The onset of these 
reactions has varied from 1−13 weeks following rituximab exposure.  Discontinue rituximab in 
patients who experience a severe mucocutaneous reaction.  The safety of readministration of 
rituximab to patients with severe mucocutaneous reactions has not been determined. 


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Progressive Multifocal Leukoencephalopathy (PML) 
JC virus infection resulting in PML and death can occur in rituximab-treated patients with 
hematologic malignancies or with autoimmune diseases.  The majority of patients with 
hematologic malignancies diagnosed with PML received rituximab in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant.  The patients with autoimmune 
diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were 
diagnosed within 12 months of their last infusion of rituximab.  
 Consider the diagnosis of PML in any patient presenting with new-onset neurologic 
manifestations.  Evaluation of PML includes, but is not limited to, consultation with a 
neurologist, brain MRI, and lumbar puncture.  Discontinue rituximab in patients who develop 
PML. 
Hepatitis B Virus (HBV) Reactivation 
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can 
occur in patients with hematologic malignancies treated with rituximab.  The median time to the 
diagnosis of hepatitis was approximately 4 months after the initiation of rituximab and 
approximately one month after the last dose.  
Screen patients at high risk of HBV infection before initiation of rituximab.  Closely monitor 
carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several 
months following rituximab therapy.  Discontinue rituximab and any concomitant chemotherapy 
in patients who develop viral hepatitis, and institute appropriate treatment including antiviral 
therapy. 
Infections 
Serious, including fatal, bacterial, fungal, and new or reactivated viral infections  can occur 
during and up to one year following the completion of rituximab-based therapy.  New or 
reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, 
varicella zoster virus, West Nile virus, and hepatitis B and C.  Discontinue rituximab for serious 
infections and institute appropriate anti-infective therapy. 
Cardiovascular 
Discontinue rituximab infusions for serious or life-threatening cardiac arrhythmias.  Perform 
cardiac monitoring during and after all infusions of rituximab for patients who develop clinically 
significant arrhythmias, or who have a history of arrhythmia or angina. 


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Renal 
Severe, including fatal, renal toxicity can occur after rituximab administration in patients with 
NHL.  Renal toxicity has occurred in patients who experience tumor lysis syndrome and in 
patients with NHL administered concomitant cisplatin therapy during clinical trials.  Monitor 
closely for signs of renal failure and discontinue rituximab in patients with a rising serum 
creatinine or oliguria. 
Immunization 
The safety of immunization with live viral vaccines following Rituxan therapy has not been 
studied and vaccination with live virus vaccines is not recommended. 
Laboratory Monitoring 
In patients with lymphoid malignancies, during treatment with rituximab, obtain complete blood 
counts (CBC) and platelet counts prior to each rituximab course.   
Further details regarding the safety, dose, and dose adjustments of rituximab are reviewed in the 
product label (Rituximab PI 2018) 
8.1.9 
Contraception 
G100, rituximab and/or pembrolizumab may have adverse effects on a fetus in utero.  
Furthermore, it is not known if G100 and/or pembrolizumab have transient adverse effects on the 
composition of sperm.   
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  Therefore, non-pregnant, non-
breast-feeding FCBP may only be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  Abstinence is only acceptable as “true abstinence” when it is 
in line with the preferred and usual lifestyle of the patient and not a periodic occurrence (see 
Appendix F).  The two birth control methods can be either two barrier methods or a barrier 
method plus a hormonal method to prevent pregnancy.  Subjects should start using birth control 
from study Visit 1 throughout the study period up to 120 days after the last dose of study therapy 
if receiving pembrolizumab or at least 90 days if only receiving G100.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide as per local regulations or 
guidelines.  Appropriate hormonal contraceptives will include any registered and marketed 
contraceptive agent that contains an estrogen and/or a progestational agent (including oral, SC, 


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intrauterine, or IM agents).  See Appendix F for additional details and definitions of highly 
effective agents. 
For male patients, acceptable contraception includes documented sterility such as what is 
achieved following surgical sterilization (vasectomy or orchiectomy) or use of male condom.  
If the partner is a woman of childbearing potential, supplemental contraception with hormonal or 
barrier methods should be considered. 
In order to participate in the study, subjects must adhere to the contraception requirement 
(described above) for the duration of the study and during the follow-up period defined in 
Section 12.7.  If there is any question that a subject will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 
8.1.10 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with G100, rituximab and/or 
pembrolizumab, the subject will immediately be removed from the study.  The site will contact 
the subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor without 
delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor.  If a 
male subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and followed as described above and in 
Section 12.7. 
8.1.11 
Use in Nursing Women 
It is unknown whether G100, rituximab and/or pembrolizumab is excreted in human milk.  Since 
many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, subjects who are breast-feeding are not eligible for enrollment.  
8.2 
Subject Withdrawal/Discontinuation Criteria 
8.2.1 
Discontinuation of Study Therapy after Complete Response (CR) 
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR 
that have been treated for at least 24 weeks with pembrolizumab and had at least 2 treatments 
with pembrolizumab beyond the date when the initial CR was declared.   
For patients receiving pembrolizumab who experience grade 2 pneumonitis, the patient should 
be discontinued from study treatment but continued to be monitored. 


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8.2.2 
Investigational Drug Accountability 
Under no circumstances is it permitted to use study supplies for any purposes other than those 
specified in this Protocol. 
The investigator or medically qualified, authorized delegate will be provided with forms to 
enable accurate recording of all study doses at the study facility at all times.  The investigator, or 
designee, must sign a statement that he/she has received the investigational product intended for 
the study.  At all times, the accountability of supplied, used and remaining doses of study drug 
must match.  At the end of the study, it must be possible to reconcile delivery records with those 
of used and unused stocks.  Account must be given of any discrepancies.  
8.3 
Radiation 
Patients will receive local palliative radiation to their tumor masses as part of normal cancer care. 
For this study, a standard short 2-day course of therapy of 2Gy qd × 2 is recommended as the 
optimal dose to allow G100 treatment to begin shortly after starting radiation and to minimize 
any immune suppressive effects from the treatment.  Other details and planning are at the 
discretion of the radiation therapist.  Modifications to the dose should be discussed with Immune 
Design.  Although steroids are sometimes used for radiation treatment related effects, use of 
concomitant or prophylactic steroids are not allowed on this study due to their potential 
immunosuppressive effects.   
As part of this study, the injected lesion is followed for local effect, and untreated, abscopal 
lesions are followed for systemic treatment effect.  Therefore the G100 treated / irradiated lesion 
should be one of the Index (target) lesions followed for response.  In addition, the radiation 
treatment field should be reviewed by the radiation therapist to confirm the identity of all 
irradiated lesions and untreated “abscopal” lesions to be used to follow treatment response. 
Patients in Parts 4 and 5 will not receive radiation.  
8.4 
Prior and Concomitant Therapy 
8.4.1 
Prior Therapy 
Any investigational agent or therapy is prohibited during the 28 days prior to enrollment.  Cancer 
therapies, including chemotherapy, radiation, biologic, or kinase inhibitors or immunotherapy, 
G-CSF or GM-CSF are not allowed within 4 weeks prior to the first scheduled G100 dosing.  
Systemic corticosteroid use and live vaccines are not permitted within four weeks prior to 
dosing.  Patients who have previously received intratumoral therapies are not permitted.  


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8.4.2 
Prohibited Concomitant Therapy 
The following treatments will be prohibited during study until the EOS visit or tumor 
progression: 
 Any investigational drug other than G100, rituximab or pembrolizumab if 
enrolled on that study arm, is prohibited during the study  
 Any systemic corticosteroid (including prednisone of any dose) within four weeks 
of first study treatment and during the study period (Intermittent use of inhaled or 
topical steroids is acceptable but chronic use or high doses where systemic 
absorption is expected should be discussed and approved by the Sponsor).  For 
patients receiving pembrolizumab, systemic glucocorticoids may be used to 
modulate symptoms from an event of suspected immunologic etiology.  However, 
the event should be discussed with the Medical Monitor before continuing 
therapy. 
 Other concurrent immunosuppressive medications such as methotrexate, 
cyclosporine, azathioprine  
 Concomitant chemotherapy, immunotherapy not specified in this protocol, or 
biologic therapy 
 Except as given per protocol regimen, radiotherapy 
 Anti-coagulation therapy – due to the increased risk of bleeding at the site of 
injection.  Based on the consensus guidelines from the Cardiovascular and 
Interventional Radiology Society of Europe, if a patient is to have a superficial 
lymph node or subcutaneous mass injected, NSAIDs, aspirin, or clopidogrel may 
be used and do not have to be withheld (Patel 2012; Patel 2013).  For procedures 
with moderate or significant risk of bleeding, long-acting agents such as aspirin or 
clopidogrel should be discussed with the Medical Monitor and may need to be 
discontinued before beginning G100 therapy. 
 Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited 
to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, 
BCG, and typhoid vaccine.  Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza 
vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.  
Due to the potential increase risk of bleeding following intratumoral injection, it is recommended 
that drugs that might increase bleeding be avoided (example: aspirin, clopidogrel, etc.).  For 
similar reasons, injections involving deeper structures such as organs and those requiring 
imaging guided injection assistance must be reviewed and pre-approved by the Medical Monitor. 


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8.4.3 
Permitted Concomitant Therapy 
The following medications will be permitted: 
 Antihistamines 
 Anti-emetics 
 Anti-diarrheals 
 If a patient is to have a superficial lymph node or subcutaneous mass injected, 
NSAIDs, aspirin, or clopidogrel are acceptable and do not have to be withheld.  
For procedures with moderate or significant risk of bleeding, long-acting agents 
such as aspirin or clopidogrel should be discussed with the Medical Monitor and 
may need to be discontinued before G100 therapy. 
9.0 
ASSESSMENTS OF SAFETY AND EFFICACY 
9.1 
Safety Assessments 
The investigator is responsible for the appropriate medical care and safety of patients who have 
entered this study.  The investigator must notify the Sponsor within 24 hours if either of the 
following events occurs: 
 Any event meeting the criteria for an SAE 
All patients will be evaluated at baseline and at regular intervals as presented in the Schedule of 
Events in Section 3.2 through Section 3.7, and Section 10.0.  Safety assessments will include 
solicited and unsolicited symptoms, physical examination findings, vital signs, documentation of 
AEs, ECGs as applicable, clinical laboratory evaluations, and deviations or discontinuations 
attributed to AEs.  
9.2 
Clinical Efficacy Assessments 
Clinical responses will be examined using the irRC criteria and the International Working Group 
response criteria for lymphomas.  Immunotherapeutic agents may cause tumor size increases due 
to inflammation and not due to true tumor growth.  Therefore, confirmation of PD is important to 
help rule out inflammatory processes.  The irRC criteria using bidimensional measurements 
attempts to do this by requiring confirmation of PD findings at least 4 weeks after the initial PD 
finding(s).  In addition, new lesions contribute to the overall tumor burden measurements and do 
not automatically signal PD.  The irRC is based on World Health Organization (WHO) 
bi-dimensional response criteria.  However, the more commonly used method to measure NHL 
responses is the International Working Group response criteria for malignant lymphoma 
(Cheson 2007).  Therefore, for this study, tumor response will be examined both by the irRC and 
the International Working group criteria for lymphomas.  The irRC will be used in the 
determination of PD (see Appendix B for details). 


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9.3 
Tumor Response Based Upon irRC Criteria 
Patients will be evaluated for tumor response per the modified irRC measurement criteria 
(Wolchok 2009) and expressed as PR, CR or SD every 8 weeks (Appendix B).  As noted above, 
the irRC requires that PD be confirmed by repeat imaging studies or tumor measurements at least 
4 weeks following the initial question of tumor size increase and any new lesion is not 
automatically counted as disease progression.  
9.4 
International Working Group Response Criteria for Malignant Lymphoma or the 
Lugano Criteria and Disease Response Assessment 
Lymphoma response assessment by computerized tomography (CT) is based on the International 
Working Group response criteria for malignant lymphoma (positron emission tomography [PET] 
is not required for follicular NHL) (Cheson 2007) or the Lugano criteria (Cheson 2014).  Local 
reading (investigator assessment with site radiology reading) will be used to determine subject 
eligibility and for subject management.  The Sponsor may request radiologic images for a 
retrospective analysis of subject eligibility and treatment response to be performed by a central 
vendor.  Assessment of lymphoma B symptoms should occur with each lymphoma disease 
response assessment.  
For this IT G100 treatment, PET or PET-CT scans must not be used for determination of disease 
progression.  G100 will induce inflammation within the tumor and will cause false positive PET 
scan results.  This has been observed in patients.  Therefore CT or MRI imaging or direct exam 
measurements must be used for the determination of suspected disease progression.  (Note:  
accurate tumor measurements obtained from CT scans using standard high resolution and 
standard image spacing obtained as part of a PET-CT study are acceptable) 
9.5 
Immune Response Assessments 
The following immune monitoring will be conducted: 
 Evaluation of immune cell profiling in tumor samples pre- and post-therapy  
 Evaluation of immune cell phenotyping of blood (Parts 1 and 2 only) 
 T cell receptor profiling of tumor and blood from baseline and over the course of 
the trial  
Details for sample handling will be provided in the Study Manual.  
9.6 
Exploratory Biomarkers 
Pre- and post- treatment blood and/or tumor samples will be collected for exploratory analyses of 
potential biomarkers of G100 immunogenicity and clinical tumor response.  A number of 
exploratory analyses are being investigated but the predictive value of such tests is not known.  It 
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that might be used in future studies to help define the ability of G100 to stimulate anti-tumor 
immune responses, to help stratify patients who might respond to this treatment and/or to 
determine a minimum therapeutic dose.  Exploratory blood tests may include profiling of 
immune cells during the course of treatment by phenotyping, evaluation of TLR4 expression on 
tumor cells, and by evaluation of T cell receptor repertoires by gene sequence analyses.  Tumor 
samples will be examined for evidence of anti-tumor cellular immunity (e.g., CD8 T cell or NK 
cell infiltration, tumor necrosis, etc.) by immunohistochemistry (IHC) and for evidence of 
immune suppression within the tumor microenvironment.  Any blood or tumor samples will only 
be used to examine the patient’s immune response, their cancer, or to help evaluate any potential 
toxicity arising in the study.  The samples will not be examined for unrelated research or to 
examine unrelated genes or diseases. 
10.0 
STUDY PROCEDURES 
The schedule of events/study procedures is presented in Section 3.2 through Section 3.7. 
10.1 
Visit Windows  
The treatment windows below apply unless otherwise specified in the study procedures that there 
is a different event window.  For Visit 1, in Parts 1, 2, 3, 4, and 5 all screening procedures will 
have the windows of Days -30 to -1.  For Visit 2, in Parts 1 and 2, screening procedures will 
have windows of Days -7 to -1; for Visit 2, in Part 3, 4, and 5 a window of Days -14 to -1 will 
apply, except as otherwise specified in the procedures.  All dosing-treatment visits will have a 
window of ± 2 days from the day specified.  After completion of G100 treatment, follow-up 
visits will have a window of ±1 week (7 days).  Following the Day 77 EOS Visit, patients 
receiving pembrolizumab will have a window of ±5 days for pembrolizumab dose administration 
and will have a window of ±14 days for restaging radiographic studies.  If a dose interruption 
beyond the windows listed above is required, this should be discussed and approved by the 
medical monitor; treatment delays of >14 days from the treatment plan will not be allowed. 
10.2 
Registration  
Once patients have been properly consented, and all inclusion/exclusion criteria have been 
documented as being met, patients will be registered into the trial.  Patients should be registered 
within 30 days prior to their anticipated dosing start date (Day 0).  This is an open-label trial.  
Patients enrolled into the Part 2, Patient Expansion With Or Without Pembrolizumab group will 
be randomly assigned to receive either intratumoral G100 alone or intratumoral G100 and 
sequential pembrolizumab.  Patients enrolled into Part 4, Sequential G100 at 20µg/lesion Into 
Single Or Multiple Tumor Masses Plus Pembrolizumab will be assigned at the time of 
enrollment to a Dose Escalation cohort or Expansion group (See Figure 6).  Patients enrolled into 
Part 5, G100 Plus Rituximab will be assigned at the time of enrollment to a Dose Escalation 
cohort or to an Expansion group (See Figure 8).   


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No trial-specific staging or biopsy procedures will be undertaken prior to completion of the 
consenting process.  However, if a patient has had tests performed prior to providing informed 
consent as part of “standard of care” (considered standard for the patient and routine medical 
practice, based upon their presentation at the time), and these tests are required for study entry 
and all of the following conditions are met, then these data may be allowed as part of the study 
data: 
 The tests fulfill all requirements of the study; i.e., are complete and follow the 
procedures outlined in the study;  
 The tests have been completed within the specified number of days to perform pre-
treatment assessments; and  
 It is medically unwise to repeat a test/procedure or it poses undue additional risk to the 
patient.  
10.3 
Study Procedures  
Patients receiving pembrolizumab will follow Visit 1 to 6 (Sections 10.3.1 to 10.3.5).  For Part 2, 
patients will then follow Sections 10.3.11 to 10.3.15 for the remainder of their treatment.  For 
Part 4, patients will follow Visit 1 and 2 (Sections 10.3.1 to 10.3.2) and then Sections 10.3.16 to 
10.3.22.2.  For Part 5, patients will follow Visit 1 and 2 (Sections 10.3.1 to 10.3.2) and then 
Sections 10.3.23 to 10.3.29.2. 
10.3.1 
Visit 1: Screening and Enrollment (Day -30 to Day -1) – Baseline Visit 1 
Patients will undergo the following screening and enrollment procedures within 1 to 30 days 
prior to Study Day 0:  
1) Informed consent/Health Insurance Portability and Accountability Act (HIPAA) 
authorization. 
 Before inclusion into the study, each patient will receive complete information, both 
verbally and in writing, about the nature of the study, the anticipated risks and 
discomfort associated with the study, and also about the right to interrupt participation in 
the study at any time.  Prior to participation in the study, each patient (or representative) 
will have signed the written, institutional review board (IRB)- or ethics committee (EC)-
approved informed consent form (ICF) and HIPAA form if applicable.  


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2) Determination of patient eligibility. 
 Compliance with Inclusion/Exclusion criteria as presented in Section 7.0 above will be 
confirmed. 
3) Demographics. 
4) Medical History. (Any changes to Medical History from initial collection of data to Day -1 
should be updated to the records). 
 To include a review of systems, general medical and surgical history, concomitant 
illnesses, and previous/concomitant medications 
 Tumor-specific therapy history - Oncologic baseline disease characteristics/history/ prior 
treatment/recent tumor growth will be recorded (diagnosis and stage of disease) 
5) 12-Lead ECG 
6) Assessment of diagnosis and stage of disease, including CT or magnetic resonance imaging 
(MRI) of chest, abdomen, pelvis.  Other assessments such as CT scan of head, a body PET 
CT, or bone marrow biopsy should be performed if indicated for the individual patient.  If a 
PET CT is used, a standard high resolution CT series should be obtained rather than low 
resolution scans.  However, PET scans should not be used to determine disease progression 
since it is expected that PET avidity will increase with the type of inflammation induced by 
this treatment and may lead to false positive results. 
7) Photographs:  if the tumor can be measured and assessed visually, photographic 
documentation with measurements should be considered in order to keep a record and help 
assess any response to treatment (may be performed at any time during study) 
8) Pre-treatment tumor biopsy.  Baseline excisional or core biopsy should be obtained from the 
treatment target lesion or a non-target lesion (preferably near the target lesion).   
10.3.2 
Visit 2: Baseline Assessment 2 (Day -7 to -1 for Parts 1 and 2, and Day -14 to -1 
for Part 3) 
Patients will undergo the following evaluations within 1 to 7 days prior to Day 0.  For patients 
enrolled in Parts 3, 4, and 5, the window for assessments is Day -14 to -1, except where 
otherwise indicated. 
1) Demographics: confirm and update as needed. 
2) Medical History: confirm and update as needed. 
3) Review of AEs and SAEs. Note: During the Screening Period, new SAEs experienced by 
patients should be reported to Immune Design only if the events are considered related to 
study procedures.  From Day 0 to the End-of-Treatment Visit, any new SAE should be 
reported to Immune Design.  
4) Recording of any previous / concomitant medications.  


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5) Vital signs. To include temperature, pulse, and resting systolic and diastolic blood pressure 
measurements 
6)  Physical examination. 
a. To include height and weight 
b. Tumor measurements with specific measurements and location description of the lesions 
to be treated with G100 and disease sites to be followed for untreated distal tumor 
responses 
7) ECOG performance status 
8) Hepatitis B (e.g., hepatitis B surface antigen [HBsAg]) and C testing (e.g., hepatitis C virus 
[HCV] RNA qualitative). 
a. HIV testing. 
9) For patients in Part 1 and Part 2 (not collected in Parts 3, 4, or 5), blood sample draw for 
baseline cell phenotyping / profiling. Instructions will be outlined in the Study Manual.   
10) For patients in Parts 1, 2, 3, and 5 (not Part 4), blood sample draw for baseline T cell receptor 
gene profiling. Instructions will be outlined in the Study Manual. 
11) Safety Labs - Hematology 
a. WBC with differential count 
b. Absolute neutrophil count (ANC) 
c. Red blood cell (RBC) count 
d. Hemoglobin (Hgb) 
e. Hematocrit 
f. Platelet count 
g. If not already performed for screening of inclusion/exclusion criteria, prothrombin time 
(PT)/PTT and INR (for baseline only) 
12) Safety labs - Clinical chemistry 
a. Sodium 
b. Chloride 
c. Potassium 
d. Random glucose 
e. Blood urea nitrogen (BUN) 
f. Creatinine 
g. Calcium 


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h. AST/serum glutamic oxaloacetic transaminase (SGOT) 
i. ALT/serum glutamic pyruvic transaminase (SGPT) 
j. Total bilirubin 
k. Alkaline phosphatase 
l. Lactic acid dehydrogenase 
m. Total protein 
n. Albumin 
13) Serum Beta-2-microglobulin (Baseline only) 
14) Urinalysis (Baseline Only). Urine samples will be analyzed by dipstick for:  
a. Protein 
b. Glucose 
c. Blood 
d. Leukocytes 
e. Nitrites 
f. Urobilinogen 
g. Bilirubin 
h. pH 
i. Specific gravity 
j. Ketones 
15) Urine pregnancy test for FCBP. (Serum pregnancy test may be performed for any urine 
pregnancy assay if site standard operating procedure [SOP] allows this test.  (For treatment 
groups, Parts 1, 2, 3 and Large Tumor, all pregnancy testing must be performed {and be 
negative} within Days -7 to -1 and for Parts 4 and 5, within 72 hours of prior to starting study 
treatment).  Note:  For patients in the United Kingdom (UK) and France, urine pregnancy 
tests must also be performed every month or sooner while the patient is receiving G100 
and/or pembrolizumab. 
16) If enrolled or potentially could be randomized and enrolled onto the pembrolizumab arm:  
Baseline thyroid function tests, which at a minimum should include thyroid-stimulating 
hormone (TSH).  For patients on Part 4, tests should include TSH, Triiodothyronine (T3) or 
Free Triiodothyronine (FT3), Free thyroxine (FT4):  Patients randomized to receive 
pembrolizumab should be monitored for changes in thyroid function every 6 weeks after 
starting pembrolizumab treatment and as indicated based on clinical signs and symptoms of 
thyroid disorders. 


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10.3.3 
Visit 3 and Visit 4: Radiation Therapy (Day 0 and Day 1) 
Patients receive local radiation therapy to tumor mass identified for intratumoral treatment. 
Standard 2Gy each day × 2 is recommended.  Treatment plan will be determined by the treating 
radiation therapist.  Changes in doses should be discussed with Immune Design. 
As part of this study, the injected lesion(s) is followed for local effect, and untreated, abscopal 
lesions are followed for systemic treatment effect.  Therefore the G100 treated / irradiated lesion 
should be one of the Index (target) lesions followed for response.  In addition, the radiation 
treatment field should be reviewed by the radiation therapist to confirm the identity of all 
irradiated lesions and untreated “abscopal” lesions to be used to follow treatment response. 
(For the purpose of this study, abscopal tumor site refers to a lesion that is not irradiated or 
injected / treated that can be followed for shrinkage that would indicate a systemic immune 
effect) 
10.3.4 
Visit 5: G100 Treatment #1 (Day 2) 
Patients will return for initiation of G100 the day after radiation therapy.  Note that on each 
immunization day, all procedures and blood draws must be done before.  The following will be 
completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor to be treated with G100 and measureable untreated 
distal tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2– Hematology, Clinical chemistry 
8) G100 administration 
10.3.5 
Visit 6: G100 Dose #2 (Day 5-7) 
Patients will return for the second dose of G100 on either Day 5, 6, or 7.  Note that on each 
immunization day, all procedures and blood draws must be done before dosing. The following 
will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 


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5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
8) G100 administration 
10.3.6 
Visits 7, 8, 9, 10: G100 Doses #3, 4, 5, 6 (Days 14, 21, 28, 35) 
Patients will return for their G100 doses #3, 4, 5, and 6.  Note that on each immunization day, all 
procedures and blood draws must be done before dosing.  The following will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
8) On Day 35, Visit 10 only, blood for cell phenotyping / profiling (collected from patients in 
Parts 1 and 2; not collected in Part 3) and for T cell gene profiling (collected for Parts 1, 2, 
and 3) 
9) G100 administration (Note: If the tumor regressed and is no longer of sufficient size for 
injection per evaluation by the investigator and there are no alternate lesions within the 
irradiated area, the remaining G100 treatments and treatment visits may be cancelled. The 
patient should then continue with Clinical Assessment visits beginning on Day 56) 
10.3.7 
Optional Visit 10A, 10B: G100 Doses # 7, 8 (Days 42, 49) 
For patients in Parts 2 and 3 whose treated tumor has not regressed completely, dosing may 
continue for 3 additional weekly intratumoral treatments (9 total) with doses #7 and 8 given on 
these visits.  Note that on each immunization day, all procedures and blood draws must be done 
before dosing.  The following will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 


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5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
8) Optional G100 administration of Doses #7, 8 in qualified patients. (Note: If the tumor 
regressed and is no longer of sufficient size for injection per evaluation by the investigator 
and there are no alternate lesions within the irradiated area, the remaining G100 treatments 
and treatment visits may be cancelled.  The patient should then continue with Clinical 
Assessment visits beginning on Day 56) 
10.3.8 
Visit 11: Clinical Assessment and Optional G100 Dose # 9 (Day 56) 
This is a mandatory Clinical Assessment visit.  For patients whose treated tumor has not 
regressed completely, 3 optional treatments may continue and the final dose #9 may be given on 
this visit.  Note that on each immunization day, all procedures and blood draws must be done 
before dosing. The following will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2– Hematology, Clinical chemistry 
8) For patients in Part 1 and Part 2, blood for cell phenotyping / profiling (not collected in 
Part 3) 
9) Blood for T cell gene profiling 
10) For patients in the UK, urine pregnancy test  
11) Assessment of disease including CT or MRI of chest, abdomen, pelvis. Other assessments 
such as CT of the head, body PET CT, or bone marrow biopsy should be performed if 
indicated. Day 56 (+/- 7 days) restaging CT or MRI scans should be performed if the optional 
treatment #9 is not given.  If the 9th dose is given, then imaging studies should be delayed to 
Day 63 to 77.  If a PET CT is used, a standard high resolution CT series should be obtained 
rather than low resolution scans for tumor measurements.  However, PET scans should not be 
used to determine disease progression since it is expected that PET avidity will increase with 
the type of inflammation induced by this treatment and may lead to false positive results. 


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12) Photographs:  if the tumor can be measured and assessed visually, photographic 
documentation with measurements should be considered in order to keep a record and help 
assess any response to treatment (may be performed at any time during study) 
13) Post Treatment tumor biopsy. Post-treatment tumor biopsy of available tumor (treated or 
untreated tumor to investigate systemic response) should be performed on Day 56 +/- 1 week 
for patients not receiving optional treatment #9.  If the 9th dose is given, then the biopsy 
should be delayed to Day 63 to 77.  The biopsies should be performed on the treated tumor if 
feasible; if not available, a different site should be chosen.  The location from where the 
sample was obtained (treated, non-treated, irradiated or non-irradiated, untreated distal site) 
must be recorded.  
14) Optional G100 administration of Dose #9 in qualified patients 
10.3.9 
Visit 12: Post-Immunization / End of Study Visit (Day 77) 
The following will be completed:  
1) Review of AEs and SAEs (Note: Patients should have all AEs reported for at least 30 days 
following the last dose of the G100 study agent.  This includes those who withdraw early 
before completion of the study.) 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
8) 12-lead ECG 
9) Urine pregnancy test for FCBP. (Serum pregnancy test may be performed for any urine 
pregnancy assay if site SOP allows this test.) 
10) If the optional 9th dose was given, then imaging studies should be delayed to Day 63 to 77.  
Assessment of disease including CT or MRI of chest, abdomen, and pelvis should be 
performed.  Other assessments such as CT of the head, body PET CT, or bone marrow 
biopsy should be completed if indicated.  If a PET CT is used, a standard high resolution CT 
series should be obtained rather than low resolution scans for tumor measurements.  
However, PET scans should not be used to determine disease progression since it is expected 
that PET avidity will increase with the type of inflammation induced by this treatment and 
may lead to false positive results.   


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Protocol IMDZ-G142; Version 04B, November 15, 2018 
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11) Photographs:  if the tumor can be measured and assessed visually, photographic 
documentation with measurements should be considered in order to keep a record and help 
assess any response to treatment (may be performed at any time during study) 
12) If the optional 9th dose was given, then the post-treatment tumor biopsy of available tumor 
(treated or untreated tumor to investigate systemic response) should be performed Day 63 
to 77.  The biopsies should be performed on the treated tumor if feasible; if not available, a 
different site should be chosen.  The location from where the sample was obtained (treated, 
non-treated, irradiated or non-irradiated, untreated distal site) must be recorded.  
10.3.10 
Long-Term Follow-up Visits  
10.3.10.1 
 Visits Before Disease Progression (Day 112, then every 8 weeks)  
1) Any SAE that comes to the attention of the site staff that may be causally related to study 
drug must be reported to Immune Design regardless of time elapsed. 
2) Recording of any previous / concomitant medications. 
3) Vital signs 
4) Symptom-directed physical examination 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG performance status 
7) Assessment of disease including CT or MRI (chest, abdomen, pelvis) (to be repeated 4 weeks 
later to confirm disease progression as defined by irRC). Other assessments such as a CT of 
head, body PET CT, or bone marrow biopsy should be performed if indicated.  If a PET CT 
is used, a standard high resolution CT series should be obtained rather than low resolution 
scans for tumor measurements.  However, PET scans should not be used to determine disease 
progression since it is expected that PET avidity will increase with the type of inflammation 
induced by this treatment and may lead to false positive results.  Imaging studies will occur 
on Day 112, every 8 weeks thereafter for the first year, every 3 to 4 months for the second 
year, and then at least every 6 months for the third and subsequent years. 
8) Photographs:  if the tumor can be measured and assessed visually, photographic 
documentation with measurements should be considered in order to keep a record and help 
assess any response to treatment (may be performed at any time during study) 
9) Safety labs as in Section 10.3.2– Hematology, Clinical chemistry 
10.3.10.2 After Disease Progression (Every 8 to 12 Weeks)  
Patients will receive telephone follow-up or clinic visit every 8 to 12 weeks after disease 
progression until 1 year after first study injection.  Follow-up will include vital status (survival 
status), cancer status, and post-treatment anti-cancer therapy including time to next treatment, 
treatment details, and clinical response.  If the patient agrees, the site may periodically 


Immune Design 
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Protocol IMDZ-G142; Version 04B, November 15, 2018 
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(e.g., every 2 to 4 months) contact the patient beyond 1 year to check on vital and cancer status 
(e.g., lymphoma transformation).  In addition, any SAE and that comes to the attention of the site 
staff that may be causally related to study drug must be reported to Immune Design, regardless 
of time elapsed. 
Note: Sections 10.3.11 to 10.3.15 apply only to patients randomized to receive pembrolizumab 
on Part 2, Patient Expansion With Or Without Pembrolizumab  
10.3.11 
Visits 7, 8, 9, 10:  G100 Doses #3, 4, 5, 6 (Days 14, 21, 28, 35) 
Patients will return for their G100 doses #3, 4, 5, and 6.  Note that on each immunization day, all 
procedures and blood draws must be done before dosing.  The following will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2– Hematology, Clinical chemistry 
8) On Day 35, Visit 10 only, blood for cell phenotyping / profiling and for T cell gene profiling 
9) G100 administration (Note: If the tumor regressed and is no longer of sufficient size for 
injection per evaluation by the investigator and there are no alternate lesions within the 
irradiated area, the remaining G100 treatments and G100 only treatment visits may be 
cancelled.  The patient should then continue with pembrolizumab and Clinical Assessment 
visits) 
10) Urine pregnancy test on Day 14 prior to pembrolizumab.  Note:  For patients in the UK and 
France, urine pregnancy tests must also be performed every month or sooner while the 
patient is receiving G100 and/or pembrolizumab. 
11) On Day 14 and 35, administer pembrolizumab 
10.3.12 
Optional Visit 10A, 10B:  G100 Doses # 7, 8 (Days 42, 49) 
For patients whose treated tumor has not regressed completely dosing may continue for 
3 additional weekly intratumoral treatments (9 total) with doses #7 and 8 given on these visits. 
Note that on each immunization day, all procedures and blood draws must be done before 
dosing. The following will be completed:  
1) Review of AEs and SAEs 


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2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
8) Optional G100 administration of Doses #7, 8 in qualified patients. (Note: If the tumor 
regressed and is no longer of sufficient size for injection per evaluation by the investigator 
and there are no alternate lesions within the irradiated area, the remaining G100 treatments 
and G100 only treatment visits may be cancelled.  The patient should then continue with 
pembrolizumab and Clinical Assessment visits) 
10.3.13 
Visit 11:  Clinical Assessment and Optional G100 Dose # 9 (Day 56) 
This is a mandatory visit for Clinical Assessment.  For patients whose treated tumor has not 
regressed completely, 3 optional treatments may continue and the final dose #9 may be given on 
this visit.  Note that on each immunization day, all procedures and blood draws must be done 
before dosing.  The following will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
8) Thyroid function tests (including TSH) 
9) Blood for cell phenotyping /profiling 
10) Blood for T cell gene profiling 
11) For patients in the UK, urine pregnancy test 


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Protocol IMDZ-G142; Version 04B, November 15, 2018 
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Page 128 of 177 
12) Assessment of disease including CT or MRI of chest, abdomen, pelvis (Day 56 +/- 7 days).  
Other assessments such as CT of the head, body PET CT, or bone marrow biopsy should be 
performed if indicated.  If a PET CT is used, a standard high resolution CT series should be 
obtained rather than low resolution scans for tumor measurements.  However, PET scans 
should not be used to determine disease progression since it is expected that PET avidity will 
increase with the type of inflammation induced by this treatment and may lead to false 
positive results. 
13) Photographs:  if the tumor can be measured and assessed visually, photographic 
documentation with measurements should be considered in order to keep a record and help 
assess any response to treatment (may be performed at any time during study)  
14) Post Treatment tumor biopsy.  Post-treatment tumor biopsy of available tumor (treated or 
untreated tumor) should be performed (Day 56 +/- 1 week) on patients not receiving optional 
treatment #9 to investigate systemic response.  If the 9th dose is given, then the biopsy 
should be delayed to Day 63 to 77.  The biopsies should be performed on the treated tumor if 
feasible; if not available, a different site should be chosen.  The location from where the 
sample was obtained (treated, non-treated, irradiated or non-irradiated, untreated distal site) 
must be recorded.  
15) Optional G100 administration of Dose #9 in qualified patients   
16) Administer pembrolizumab 
10.3.14 
Visit 12: Post-Immunization / End of Safety Visit (Day 77) 
The following will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
8) 12-lead ECG 
9) Urine pregnancy test for FCBP. (Serum pregnancy test may be performed for any urine 
pregnancy assay if site SOP allows this test.)  Note:  For patients in the UK and France, urine 
pregnancy tests must also be performed every month or sooner while the patient is receiving 
G100 and/or pembrolizumab. 
10) Administer pembrolizumab 


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10.3.15 
Long-Term Follow-up Visits 
10.3.15.1 Visits For Anti-PD-1 Therapy and Before Disease Progression (Day 98, then 
every 3 weeks)   
1) Any SAE that comes to the attention of the site staff that may be causally related to G100 
must be reported to Immune Design regardless of time elapsed. 
2) All AEs experienced from the time of enrollment through 30 days following cessation of 
pembrolizumab treatment will be reported by the investigator.  Any event of clinical interest 
(ECI) experienced through 30 days following cessation of treatment should be reported 
within 24 hours to the Sponsor.  Any SAE due to any cause other than progression of the 
cancer under study that occurs through 90 days following cessation of pembrolizumab 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, must be reported within 24 hours to the Sponsor.  After the 
90-day reporting period, any SAE that comes to the attention of the site staff that may be 
causally related to pembrolizumab must be reported to Sponsor regardless of time elapsed. 
3) Recording of any previous / concomitant medications. 
4) Vital signs 
5) Symptom-directed physical examination 
6) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
7) ECOG performance status 
8) Beginning on Day 112 to 119 and then repeat every 8 weeks: Assessment of disease 
including CT or MRI (chest, abdomen, pelvis) (to be repeated 4 or more weeks later to 
confirm disease progression as defined by irRC).  Other assessments such as a CT of head, 
body PET CT, or bone marrow biopsy should be performed if indicated.  If a PET CT is 
used, a standard high resolution CT series should be obtained rather than low resolution 
scans for tumor measurements.  However, PET scans should not be used to determine disease 
progression since it is expected that PET avidity will increase with the type of inflammation 
induced by this treatment and may lead to false positive results.  Imaging studies will occur 
every 8 weeks for the first year, every 3 to 4 months for the second year and then at least 
every 6 months for the third and subsequent years. 
9) Photographs:  if the tumor can be measured and assessed visually, photographic 
documentation with measurements should be considered in order to keep a record and help 
assess any response to treatment (may be performed at any time during study) 
10) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry.  For patients in France 
and the UK, urine pregnancy tests must also be performed every month or sooner while the 
patient is receiving G100 and/or pembrolizumab. 


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Protocol IMDZ-G142; Version 04B, November 15, 2018 
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11) For patients in the UK, urine pregnancy tests must also be performed every month or sooner 
while the patient is receiving G100 and/or pembrolizumab. 
12) Beginning Day 98, thyroid function tests (including TSH).  Tests should then be repeated 
every 6 weeks to monitor for changes in thyroid function during treatment and as indicated 
based on clinical signs and symptoms of thyroid disease. 
13) Administer pembrolizumab. Continue Q3W until disease progression or unacceptable 
toxicity for up to a total of 2 years.  Discontinuation of treatment may be considered for 
subjects who have attained a confirmed CR that have been treated for at least 24 weeks with 
pembrolizumab and had at least 2 treatments with pembrolizumab beyond the date when the 
initial CR was declared.  
10.3.15.2 Visits After Disease Progression (Every 8 to 12 Weeks)  
Patients will receive telephone follow-up or clinic visit every 8 to 12 weeks after disease 
progression until 1 year after first study injection.  Follow-up will include vital status (survival 
status), cancer status (e.g., lymphoma transformation), and post-treatment anti-cancer therapy 
including time to next treatment, treatment details, and clinical response.  If the patient agrees, 
the site may periodically (e.g., every 2 to 4 months) contact the patient beyond 1 year to check 
on vital and cancer status.  In addition, any SAE that comes to the attention of the site staff that 
may be causally related to G100 must be reported to Immune Design, regardless of time elapsed.  
All AEs experienced from the time of enrollment through 30 days following cessation of 
pembrolizumab (and/or G100, whichever is longer) treatment will be reported by the 
investigator.  Any ECI experienced through 30 days following cessation of treatment should be 
reported within 24 hours to the Sponsor.  Any SAE due to any cause other than progression of 
the cancer under study that occurs through 90 days following cessation of pembrolizumab 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, must be reported within 24 hours to the Sponsor.  After the 90-day 
reporting period, any SAE that comes to the attention of the site staff that may be causally related 
to pembrolizumab must be reported to Sponsor regardless of time elapsed. 
 


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Note: Sections 10.3.16 to 10.3.22.2 apply only to patients enrolled to receive G100 and  
pembrolizumab on Part 4, Sequential G100 at 20µg/lesion Into Single Or Multiple Tumor 
Masses Plus Pembrolizumab  
10.3.16 
Visit 3: G100 Treatment #1 (Day 0) 
For Part 4, patients will be assigned to a treatment cohort or cohort expansion and the number of 
lesions to be injected and location will be agreed upon before initiation of therapy.  Note for 
Part 4, radiation therapy has been omitted, and that on each immunization day, all procedures 
and blood draws must be done before dosing except for the pharmacokinetics/ 
pharmacodynamics 6 hours pose the first G100 treatment or pembrolizumab, if applicable.  The 
following will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor to be treated with G100 and measureable untreated 
distal tumor lesions by exam 
6) ECOG status 
7) Safety labs and pharmacokinetics/ pharmacodynamic labs as in Section 10.3.2– Hematology, 
Clinical chemistry 
8) G100 administration 
10.3.17 
Visit 4: G100 Dose #2 (Day 5-7) 
Patients will return for the second dose of G100 on either Day 5, 6, or 7.  Note that on each 
immunization day, all procedures and blood draws must be done before dosing. The following 
will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
8) G100 administration 


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10.3.18 
Visits 5, 6, 7, 8:  G100 Doses #3, 4, 5, 6 (Days 14, 21, 28, 35) 
Patients will return for their G100 doses #3, 4, 5, and 6. Note that on each immunization day, all 
procedures and blood draws must be done before dosing.  The following will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2– Hematology, Clinical chemistry 
8) Pharmacokinetics and Pharmacodynamic labs (Visit 5 Day 15 only)  
9) G100 (20 µg/lesion) administration (Note: If the injected tumor(s) regressed and is no longer 
of sufficient size for injection (either intra- or peritumoral) per evaluation by the investigator 
and there are no easily accessable alternate lesions – i.e., There are no longer any injectable 
lesions, the remaining G100 treatments and G100 only treatment visits may be cancelled.  
The patient should then continue with pembrolizumab and Clinical Assessment visits) 
10) Urine pregnancy test on Day 14 prior to pembrolizumab.  Note:  For patients in UK and 
France, urine pregnancy tests must also be performed every month or sooner while the 
patient is receiving G100 and/or pembrolizumab. 
11) On Day 14 and 35, administer pembrolizumab 
10.3.19 
Optional Visit 8A, 8B:  G100 Doses # 7, 8 (Days 42, 49) 
For patients whose treated tumor(s) has not regressed completely dosing may continue for 
3 additional weekly intratumoral treatments (9 total) with doses #7 and 8 given on these visits. 
Note that on each immunization day, all procedures and blood draws must be done before 
dosing.  The following will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG status 


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Protocol IMDZ-G142; Version 04B, November 15, 2018 
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7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
8) Optional G100 (20µg/lesion) administration of Doses #7, 8 in qualified patients. (Note: If the 
injected tumor(s) regressed and is no longer of sufficient size for injection (either intra- or 
peritumoral) per evaluation by the investigator and there are no easily accessable alternate 
lesions – i.e., There are no longer any injectable lesions, the remaining G100 treatments and 
G100 only treatment visits may be cancelled.  The patient should then continue with 
pembrolizumab and Clinical Assessment visits.  
10.3.20 
Visit 9:  Clinical Assessment and Optional G100 Dose # 9 (Day 56) 
This is a mandatory visit for Clinical Assessment.  For patients whose treated tumor has not 
regressed completely, the three optional treatments may continue and the final dose #9 may be 
given on this visit.  Note that on each immunization day, all procedures and blood draws must be 
done before dosing.  The following will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
8) Thyroid function tests including TSH, T3 or FT3, and FT4 
9) For patients in UK and France, urine pregnancy tests must also be performed every month or 
sooner while the patient is receiving G100 and/or pembrolizumab. 
10) Assessment of disease including CT or MRI of chest, abdomen, pelvis. Other assessments 
such as CT of the head, body PET CT, orbone marrow biopsy should be performed if 
indicated. Day 56 (+/- 7 days) restaging CT or MRI scans should be performed if the optional 
treatment #9 is not given.  If the 9th dose is given, then imaging studies should be delayed to 
Day 63 to 77.  If a PET CT is used, a standard high resolution CT series must be obtained 
rather than low resolution scans and only the CT imaging should be used for tumor 
measurements.  PET scans should not be used to determine disease progression since it is 
expected that PET avidity will increase with the type of inflammation induced by this 
treatment and may lead to false positive results. 
11) Photographs:  if the tumor can be measured and assessed visually, photographic 
documentation with measurements should be considered in order to keep a record and help 
assess any response to treatment (may be performed at any time during study)  


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12) Post Treatment tumor biopsy.  Post-treatment tumor biopsy of available tumor (treated or 
untreated tumor) should be performed as close to 2 weeks after last G100 dose as possible: 
Day 42 to 56 for patients receiving 6 doses of G100 or, if the 9th dose is given, then the 
biopsy should be delayed to Day 63 to 77.  The biopsies should be performed on the treated 
tumor if feasible and if available; in addition, a second abscopal site should also be biopsied 
if feasible.  The location from where the sample was obtained (treated, non-treated, irradiated 
or non-irradiated, untreated distal site) must be recorded.  
13) Optional G100 administration of Dose #9 in qualified patients   
14) Administer pembrolizumab 
10.3.21 
Visit 10:  Post-Immunization / End of Safety Visit (Day 77) 
The following will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
8) 12-lead ECG 
9) Urine pregnancy test for FCBP. (Serum pregnancy test may be performed for any urine 
pregnancy assay if site SOP allows this test.)  Note:  For patients in UK and France, urine 
pregnancy tests must also be performed every month or sooner while the patient is receiving 
G100 and/or pembrolizumab. 
10) If the 9th dose is given, then imaging studies should be performed Day 63 to 77 instead of 
Day 56.  Assessment of disease including CT or MRI of chest, abdomen, pelvis should be 
performed.  Other assessments such as CT of the head, body PET CT, or bone marrow 
biopsy should be performed if indicated.  If a PET CT is used, a standard high resolution CT 
series must be obtained rather than low resolution scans and only the CT imaging should be 
used for tumor measurements.  PET scans should not be used to determine disease 
progression since it is expected that PET avidity will increase with the type of inflammation 
induced by this treatment and may lead to false positive results. 


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G100 (GLA-SE) and Pembrolizumab or Rituximab 
Protocol IMDZ-G142; Version 04B, November 15, 2018 
CLO-30.002 V04B 
 
Page 135 of 177 
11) Post Treatment tumor biopsy. If the 9th dose is given, then the biopsy should be peformed as 
close to 2 weeks after the last G100 dose as possible (Day 63 to 77).  Post-treatment tumor 
biopsy of available tumor (treated or untreated tumor) should be performed to investigate 
systemic response.  The biopsies should be performed on the treated tumor if feasible and if 
available; in addition, a second abscopal site should also be biopsied if feasible.  The location 
from where the sample was obtained (treated, non-treated, irradiated or non-irradiated, 
untreated distal site) must be recorded.  
12) Administer pembrolizumab 
10.3.22 
Long-Term Follow-up Visits 
10.3.22.1 
132BVisits For Anti-PD-1 Therapy and Before Disease Progression (Day 98, then 
every 3 weeks)   
1) Any SAE that comes to the attention of the site staff that may be causally related to G100 
must be reported to Immune Design regardless of time elapsed. 
2) All AEs experienced from the time of enrollment through 30 days following cessation of 
pembrolizumab treatment will be reported by the investigator.  Any event of clinical interest 
(ECI) experienced through 30 days following cessation of treatment should be reported 
within 24 hours to the Sponsor.  Any SAE due to any cause other than progression of the 
cancer under study that occurs through 90 days following cessation of pembrolizumab 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, must be reported within 24 hours to the Sponsor.  After the 
90-day reporting period, any SAE that comes to the attention of the site staff that may be 
causally related to pembrolizumab must be reported to Sponsor regardless of time elapsed. 
3) Recording of any previous / concomitant medications. 
4) Vital signs 
5) Symptom-directed physical examination 
6) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
7) ECOG performance status 
8) Beginning on Day 112 to 119 for patients receiving 6 doses of G100 or on Day133 to 140 for 
patients receiving 9 doses of G100 and then repeat every 8 weeks (±14 days):  Assessment of 
disease including CT or MRI (chest, abdomen, pelvis) (to be repeated 4 or more weeks later 
to confirm disease progression as defined by irRC).  Other assessments such as a CT of head, 
body PET CT, or bone marrow biopsy should be performed if indicated.  However, PET 
scans should not be used to determine disease progression since it is expected that PET 
avidity will increase with the type of inflammation induced by this treatment and can lead to 
false positive results.  For this reason, PET scans are not recommended.  If a PET CT is used, 
a standard high resolution CT series must be obtained rather than low resolution scans and 


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Protocol IMDZ-G142; Version 04B, November 15, 2018 
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Page 136 of 177 
only the CT imaging should be used for tumor measurements.  Imaging studies will occur 
every 8 weeks for the first year, every 3 to 4 months for the second year and then at least 
every 6 months for the third and subsequent years. 
9) Photographs:  if the tumor can be measured and assessed visually, photographic 
documentation with measurements should be considered in order to keep a record and help 
assess any response to treatment (may be performed at any time during study) 
10) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry.   
11) For patients in UK and France, urine pregnancy tests must also be performed every month or 
sooner while the patient is receiving G100 and/or pembrolizumab. 
12) Beginning Day 98, thyroid function tests including TSH, T3 or FT3, and FT4.  Tests should 
then be repeated every 6 weeks to monitor for changes in thyroid function during treatment 
and as indicated based on clinical signs and symptoms of thyroid disease. 
13) Administer pembrolizumab.  Continue Q3W until disease progression or unacceptable 
toxicity for up to a total of 2 years.  Discontinuation of treatment may be considered for 
subjects who have attained a confirmed CR that have been treated for at least 24 weeks with 
pembrolizumab and had at least 2 treatments with pembrolizumab beyond the date when the 
initial CR was declared.  
10.3.22.2 
13Visits After Disease Progression (Every 8 to 12 Weeks)  
Patients will receive telephone follow-up or clinic visit every 8 to 12 weeks after confirmed 
disease progression (or symptomatic deterioration with therapy) for at least 1 year after first 
study injection.  Follow-up will include vital status (survival status), cancer status, and post-
treatment anti-cancer therapy including time to next treatment, treatment details, and clinical 
response.  If the patient agrees, the site may periodically (e.g., every 2 to 4 months) contact the 
patient beyond 1 year to check on vital and cancer status.  Delayed objective responses have 
been observed on this study at >18 months from Day 0.  Therefore, if the patient should 
experience a clinical regression and has not received any additional therapy, the patient may be 
asked for consent to collect clinical information such as imaging studies and biomarkers.   
Any SAE that comes to the attention of the site staff that may be causally related to G100 must 
be reported to Immune Design, regardless of time elapsed.  All AEs experienced from the time of 
enrollment through 30 days following cessation of pembrolizumab (and/or G100, whichever is 
longer) treatment will be reported by the investigator.  Any ECI experienced through 30 days 
following cessation of treatment should be reported within 24 hours to the Sponsor.  Any SAE 
due to any cause other than progression of the cancer under study that occurs through 90 days 
following cessation of pembrolizumab treatment, or 30 days following cessation of treatment if 
the subject initiates new anticancer therapy, whichever is earlier, must be reported within 
24 hours to the Sponsor.  After the 90-day reporting period, any SAE that comes to the attention 


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of the site staff that may be causally related to pembrolizumab must be reported to Sponsor 
regardless of time elapsed. 
Note: Sections 10.3.23 to 10.3.29.2 apply only to patients enrolled on Part 5, G100 Plus 
Rituximab  
10.3.23 
Visit 3: Rituximab Treatment #1 (Day 0) 
For Part 5, patients will be assigned to a Dose Escalation treatment cohort or to a Patient 
Expansion arm at the time of study enrollment.  The treatment dose and the single lesion to be 
injected and its location will be agreed upon with the Medical Monitor before initiation of 
therapy.  Note for Part 5, radiation therapy has been omitted, and that on each immunization day, 
all procedures and blood draws must be done before dosing except for the pharmacokinetics/ 
pharmacodynamic blood draw 6 hours post the G100 first treatment.  The following will be 
completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor to be treated with G100 and measureable untreated 
distal tumor lesions by exam 
6) ECOG status 
7) Safety labs and Pharmacokinetics/Pharmacodynamics labs as in Section 10.3.2– Hematology, 
Clinical chemistry 
8) Rituximab administration 
10.3.24 
Visit 4: G100 Dose #1 (Day 1) 
Patients will return the next day for their first dose of G100. Note that on each immunization 
day, all procedures and blood draws must be done before dosing.  The following will be 
completed:  
1) Review of AEs and SAEs, including those associated with the first dose of rituximab 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam if indicated by adverse events 
5) Safety labs and Pharmacokinetics/ Pharmacodynamics labs as in Section 10.3.2 – 
Hematology, Clinical chemistry 


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6) G100 administration 
Note:  Following completion of the Dose Escalation portion of the study, if after a review of all 
safety, and with agreement of the independent DMC, it is determined that there are no safety 
concerns (e.g., significant rituximab first dose infusion reactions or potential of overlap of 
toxicities) that would prevent the administration of both G100 and rituximab on Day 0, the 
Sponsor may choose to administer G100 following rituximab on Day 0 and eliminate Visit 4. 
10.3.25 
Visits 5, 6, 7:  G100 Doses #2, 3, 4  (Days 7, 14, 21) and Rituximab Doses #2, 3, 4 
(Days 7, 14, 21) 
Patients will return for their G100 doses #2, 3, 4 and rituximab doses #2, 3, 4.  Note that on each 
immunization day, all procedures and blood draws must be done before dosing.  The following 
will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated, non-
injected distal tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2– Hematology, Clinical chemistry 
8) G100 administration (Note: If the injected tumor(s) regressed and is no longer of sufficient 
size for injection (either intra- or peritumoral) per evaluation by the investigator and there are 
no easily accessable alternate lesions – i.e., There are no longer any injectable lesions, the 
remaining G100 treatments and G100 only treatment visits may be cancelled.  The patient 
should then continue with rituximab and Clinical Assessment visits) 
9) On Days 7, 14 and 21, administer rituximab 
10.3.26 
Visits 8, 8A and 8B (Days 28, 35, 42):  Visit and Optional G100 Doses # 5, 6 
(Days 28, 35) 
At the discretion of the PI, patients whose injected or observed tumor(s) have not regressed 
completely may continue G100 dosing for 2 additional weekly intratumoral treatments (6 total) 
with doses #5 and 6 given on Visits 8 and 8A (Days 28 and 35).  These patients should follow 
the Schedule of Events for Visits 8, 8A, and 8B. 
Patients who will only receive 4 doses of G100 must follow the Schedule of Events for Visit 8 
and should not return for Visits 8A or 8B. 


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Note that on each immunization day, all procedures and blood draws must be done before 
dosing.  The following will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated, non-
injected distal tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
8) For patients who will receive 6 doses of G100, optional G100 administration of Doses #5, 6 
in qualified patients are given on Visits 8 and 8A (Days 28 and 35). (Note: If the injected 
tumor(s) regressed and is no longer of sufficient size for injection (either intra- or 
peritumoral) per evaluation by the investigator and there are no easily accessable alternate 
lesions – i.e., There are no longer any injectable lesions, the remaining G100 treatments and 
G100 only treatment visits may be cancelled.  The patient should then continue with Clinical 
Assessment visits. 
9) On Visit 8 (Day 28), patients who only receive 4 or fewer doses of G100, blood for T cell 
gene profiling and biomarkers (see Lab Manual for collection guidelines) and tumor biopsy 
should be obtained as close to 2 weeks following the last dose of G100 as possible (Biopsy 
window: Day 28 to 35) 
On Visit 8B (Day 42), patients who received 5 or 6 doses of G100, blood for T cell gene profiling 
and biomarkers and tumor biopsy should be obtained as close to 2 weeks following the last dose 
of G100 as possible (Biopsy window, Day 42 to 56)  
Note:  Patients treated on Part 5 will have an additional 8ml drawn for T cell gene and biomarker 
analyses on either Day 28 or 42 depending whether or not the patient received 4 or 6 G100 
injections (see Lab Manual for details).  The additional blood is reflected as the larger blood 
volume collection beginning on either Day 28 or 42. 
Post Treatment Tumor Biopsies should be performed on the treated tumor if feasible and if 
available; in addition, a second non-injected site should also be biopsied if feasible.  The location 
where the sample was obtained (injected or non-injected distal site) must be recorded. 
10) For patients in UK and France, urine pregnancy tests must also be performed every month 
(Day 28) or sooner while the patient is receiving G100. (Otherwise, urine pregnancy test on 
Day 77)  


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10.3.27 
Visit 9:  Clinical Assessment (Day 56) 
This is a mandatory visit for Clinical Assessment. The following will be completed:  
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated, non-
injected distal tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
8) Urine pregnancy test for FCBP (Serum pregnancy test may be performed for any urine 
pregnancy assay if site SOP allows this test.)  Note:  For patients in the UK, urine pregnancy 
tests must also be performed every month or sooner while the patient is receiving G100 
9) 12-lead ECG 
10) Assessment of disease including CT or MRI of chest, abdomen, pelvis (Day 56 ±7 days).  
Other assessments such as CT of the head or bone marrow biopsy should be performed if 
indicated.  However, PET scans should not be used to determine disease progression 
since it is expected that PET avidity will increase with the type of inflammation induced 
by this treatment and can lead to false positive results.  For this reason, PET scans are not 
recommended.  If a PET CT is used, a standard high resolution CT series must be obtained 
rather than low resolution scans and only the CT imaging should be used for tumor 
measurements.   
11) Photographs:  if the tumor can be measured and assessed visually, photographic 
documentation with measurements should be considered in order to keep a record and help 
assess any response to treatment (may be performed at any time during study)  
10.3.28 
Visit 10: Post-Immunization / End of Safety Visit (Day 112) 
The following will be completed:  
1) Review of AEs and SAEs: All AEs experienced from the time of enrollment through 30 days 
following cessation of G100 treatment will be reported by the investigator. Any event of 
clinical/medical interest experienced through 30 days following cessation of treatment should 
be reported within 24 hours to the Sponsor.  Any SAE that comes to the attention of the site 
staff that may be causally related to G100 must be reported to Sponsor regardless of time 
elapsed 
2) Recording of any previous / concomitant medications 


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3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) Assessment of disease including CT or MRI of chest, abdomen, pelvis (Day 112 ±7 days).  
Other assessments such as CT of the head or bone marrow biopsy should be performed if 
indicated.  However, PET scans should not be used to determine disease progression 
since it is expected that PET avidity will increase with the type of inflammation induced 
by this treatment and can lead to false positive results.  For this reason, PET scans are not 
recommended.  If a PET CT is used, a standard high resolution CT series must be obtained 
rather than low resolution scans and only the CT imaging should be used for tumor 
measurements.   
7) ECOG status 
8) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
10.3.29 
Long-Term Follow-up Visits 
10.3.29.1 Visits Before Disease Progression (Day 168, then every 8 weeks) 
1) Any SAE that comes to the attention of the site staff that may be causally related to G100 
must be reported to Immune Design regardless of time elapsed. 
2) Recording of any previous / concomitant medications. 
3) Vital signs 
4) Symptom-directed physical examination 
5) Assessment and measurements of tumor treated with G100 and measureable untreated distal 
tumor lesions by exam 
6) ECOG performance status 
7) Beginning on Day 168 ± 7 days and then repeat every 8 weeks ±14 days: Assessment of 
disease including CT or MRI (chest, abdomen, pelvis) (to be repeated 4 or more weeks later 
to confirm disease progression as defined by irRC).  Other assessments such as a CT of head 
or bone marrow biopsy should be performed if indicated.  However, PET scans should not 
be used to determine disease progression since it is expected that PET avidity will increase 
with the type of inflammation induced by this treatment and can lead to false positive results.  
For this reason, PET scans are not recommended.  If a PET CT is used, a standard high 
resolution CT series must be obtained rather than low resolution scans and only the CT 
imaging should be used for tumor measurements.  Imaging studies will occur every 8 weeks 
for the first year, every 3 to 4 months for the second year and then at least every 6 months for 
the third and subsequent years. 


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8) Photographs:  if the tumor can be measured and assessed visually, photographic 
documentation with measurements should be considered in order to keep a record and help 
assess any response to treatment (may be performed at any time during study) 
9) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry.   
10.3.29.2 Visits After Disease Progression (Every 8 to 12 Weeks)  
Patients will receive telephone follow-up or clinic visit every 8 to 12 weeks after confirmed 
disease progression (or symptomatic deterioration with therapy) for at least 1 year after first 
study injection.  Follow-up will include vital status (survival status), cancer status (e.g., 
lymphoma transformation), and post-treatment anti-cancer therapy including time to next 
treatment, treatment details, and clinical response.  If the patient agrees, the site may periodically 
(e.g., every 2 to 4 months) contact the patient beyond 1 year to check on vital and cancer status.  
Delayed objective responses have been observed on this study at >18 months from Day 0.  
Therefore, if the patient should experience a clinical regression and has not received any 
additional therapy, the patient may be asked for consent to collect clinical information such as 
imaging studies and biomarkers.   
Any SAE that comes to the attention of the site staff that may be causally related to G100 must 
be reported to Immune Design, regardless of time elapsed.  All AEs experienced from the time of 
enrollment through 30 days following cessation of G100 will be reported by the investigator. 
Any clinical/medical event of interest experienced through 30 days following cessation of 
treatment should be reported within 24 hours to the Sponsor.  
10.4 
Optional Retreatment / Second Course with G100 (Parts 1, 2, 3, 4 and 5) 
Following the initial G100 course of treatment, if a patient is determined to have achieved SD or 
better or has PD that does not require immediate therapy (requires Medical Monitor pre-
approval), has an additional site of disease outside of the prior radiation field that is amenable to 
injection (Parts 1, 2, or 3) and the patient has not had significant treatment emergent AEs 
(including events that would be considered a DLT) as determined by the investigator and the 
Sponsor, the patient may be eligible to receive a second course of G100.  For patients enrolled on 
Parts 4 or 5, the same previously injected tumor site(s) may be targeted or a replacement site(s) 
may be chosen.   
Six weeks or more after completion of the first course of G100 treatment the second course 
would begin and consist of G100 alone (no radiation or additional rituximab) at the same dose 
received during the first course of therapy.  Treatment would be administered on a similar 
weekly schedule as the first course except without radiation therapy (or rituximab).  Most of the 
visit procedures are identical to the initial G100 treatment schedule (except Visit numbers) and 
sections are referred to below.  


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For patients receiving pembrolizumab, treatment with the anti-PD-1 antibody would continue on 
its schedule during the second course of G100.  In addition, all recurring safety bloods specific to 
pembrolizumab including thyroid function should continue.  For reference, the treatment 
schedule for the initial set of visits are listed/linked below.  If possible the treatment with 
pembrolizumab should be synched with this schedule in order to collect and examine safety 
bloods on the same schedule as G100. If not, then continue to follow the Q3W schedule as 
outlined in Section 10.3.15.1 for Part 2 and 10.3.22.1 for Part 4 patients, “Visits For Anti-PD-1 
Therapy and Before Disease Progression”.  
10.4.1 
Visit 1: Baseline Evaluation Days -14 to -1 
1) Review of AEs and SAEs 
2) Recording of any previous / concomitant medications 
3) Vital signs 
4) Symptom-directed physical exam 
5) Assessment and measurements of tumor treated with G100 and measureable untreated, non-
injected distal tumor lesions by exam 
6) ECOG status 
7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry 
8) For patients in Part 1 and Part 2, blood for cell phenotyping / profiling (not collected in Part 
3, 4, or 5) 
9) Blood for T cell gene profiling and biomarkers (Not collected in Part 4) 
10) Assessment of disease including CT or MRI of chest, abdomen, pelvis. Other assessments 
such as CT of the head or bone marrow biopsy should be performed if indicated. (CT scan or 
MRI should be repeated if the last study was done 8 or more weeks prior to planned starting 
date of second course of therapy.  If the last scan indicated tumor regression that might now 
be an objective PR/CR, the imaging studies should be repeated.)  PET scans should not be 
used to determine disease progression since it is expected that PET avidity will increase 
with the type of inflammation induced by this treatment and can lead to false positive 
results.  For this reason, PET scans are not recommended.  If a PET CT is used, a standard 
high resolution CT series must be obtained rather than low resolution scans and only the CT 
imaging should be used for tumor measurements.  Imaging studies will occur every 8 weeks 
for the first year, every 3 to 4 months for the second year and then at least every 6 months for 
the third and subsequent years. 
11) Tumor biopsy:  For Parts 1, 2 and 3, pre-second course treatment biopsy should be performed 
if one was not collected after the first course of G100 or if the last G100 treatment was 
>3 months prior to the start of the second course.  For pre-treatment biopsy, baseline 
excisional samples should be obtained from the treatment target lesion or non-target lesion 
(near the target lesion).  For Parts 4 and 5, new biopsies are mandatory unless collected 


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within 2 weeks of planned start of second course and should be obtained from the planned 
new treatment site.  Both the treated and untreated sites post G100 should be biopsied if 
feasible. 
12) Urine pregnancy test for FCBP must be performed (and negative) within 7 days prior to
study treatment. (Serum pregnancy test may be performed for any urine pregnancy assay if
site allows this test).  Note:  For patients in the UK and France, urine pregnancy tests must
also be performed every month or sooner while the patient is receiving G100 and/or
pembrolizumab.
10.4.2 
Visit 2: G100 Treatment #1 (Day 0) 
Patients will return for initiation of G100. Note that on each immunization day, all procedures 
and blood draws must be done before dosing.  The following will be completed:  
1) Review of AEs and SAEs
2) Recording of any previous / concomitant medications
3) Vital signs
4) Symptom-directed physical exam
5) Assessment and measurements of tumor to be treated with G100 and measureable untreated
distal tumor lesions by exam
6) ECOG status
7) Safety labs as in Section 10.3.2 – Hematology, Clinical chemistry
8) G100 administration.  For Part 4, if multiple lesions were injected initially, the choice of
lesions to inject for the second course must be discussed and agreed upon with the Medical
Monitor and could include previously treated lesions based on availability of lesions or
technical issues.
10.4.3 
Visit 3: G100 Dose #2 (Day 5-7) 
Follow procedures outlined in Section 10.3.5, G100 Dose #2 (Day 5-7). 
10.4.4 
Visits 4, 5, 6, 7: G100 Doses #3, 4, 5, 6 (Days 14, 21, 28, 35) 
Follow procedures outlined in Section 10.3.6, G100 Doses #3, 4, 5, 6 (Days 14, 21, 28, 35) or if 
receiving pembrolizumab, Section 10.3.11 for patients on Part 2, or Section 10.3.18 for patients 
on Part 4 (see Section 10.3.22.1 for description of timing of pembrolizumab dosing).  Patients on 
Part 5 are limited to 6 doses of G100. 


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10.4.5 
Optional Visit 7A, 7B: G100 Doses # 7, 8 (Days 42, 49)  
Follow procedures outlined in Section 10.3.7, Optional G100 Doses #7, 8 (Days 42, 49) or if 
receiving pembrolizumab, Section 10.3.12 for patients on Part 2 or Section 10.3.19 for patients 
on Part 4.  
10.4.6 
Visit 8: Clinical Assessment and Optional G100 Dose # 9 (Day 56)  
Follow procedures outlined in Section 10.3.8, Clinical Assessment and Optional G100 Dose # 9 
(Day 56) or if receiving pembrolizumab, Section 10.3.13 for patients on Part 2 or Section 10.3.20 
for patients on Part 4. Day 56 (± 7 days) restaging CT or MRI scans should be performed if the 
optional treatment #9 is not given.  PET scans should not be used to determine disease 
progression since it is expected that PET avidity will increase with the type of inflammation 
induced by this treatment and can lead to false positive results.  For this reason, PET scans 
are not recommended.  If a PET CT is used, a standard high resolution CT series must be 
obtained rather than low resolution scans and only the CT imaging should be used for tumor 
measurements.  If the 9th dose is given, then scans should be delayed to Day 63 to 77.  
Post-treatment tumor biopsy should be performed as close to 2 weeks following the last dose of 
G100 as possible: on Day 42 to 56 for patients receiving 6 doses of G100 or, if the 9th dose is 
given, then biopsy should be delayed to Day 63 to 77.  The biopsies should be performed on the 
treated tumor if feasible; if not available, a different site should be chosen.  The location from 
where the sample was obtained (treated, non-treated, irradiated or non-irradiated, untreated distal 
site) must be recorded.  For Parts 4 and 5, patients should have injected and non-injected lesions 
biopsied if feasible. 
10.4.7 
Visit 9: Post-Immunization / End of Study Visit (Day 77) 
Follow procedures outlined in Section 10.3.9, Post-Immunization / EOS Visit (Day 77) or if 
receiving pembrolizumab, Section 10.3.14 for patients on Part 2 or Section 10.3.21 for patients 
on Part 4. If the 9th dose is given, then restaging CT or MRI scans and biopsy should be delayed 
to Day 63 to 77. 
10.4.8 
Long-Term Follow-up Visits 
Follow procedures outlined in Section 10.3.10.1 for Visits Before Disease Progression (Day 112, 
then every 8 weeks) or Section 10.3.29.1 for patients on Part 5 or if receiving pembrolizumab, 
Section 10.3.15.1 for patients on Part 2 or Section 10.3.22.1 for patients on Part 4. (Day 98, then 
Q3W).    
Note for Part 4, imaging studies during Follow-up will occur on Day 112 to 119 for patients 
receiving 6 doses of G100 or on Day133 to 140 for patients receiving 9 doses of G100.  Imaging 
studies should then occur every 8 weeks (±14 days) thereafter for the first year, every 3 to 4 
months for the second year, and then at least every 6 months for the third and subsequent years. 


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Follow procedures outlined in Section 10.3.10.2 for Visits After Disease Progression (every 
8 weeks) or Section 10.3.29.2 for patients on Part 5 or if receiving pembrolizumab, 
Section 10.3.15.2 for patients on Part 2 or Section 10.3.22.2 for patients on Part 4.   
10.4.9 
Additional Biomarker Testing 
For patients in any treatment group (and at any time), if a patient develops progression, a tissue 
biopsy should be obtained.  The biopsies should be performed on the treated tumor if feasible; if 
not available, a different site should be chosen.  The location from where the sample was 
obtained (treated, non-treated, irradiated or non-irradiated, untreated distal site) must be 
recorded.  
In addition, for patients who are having a change in clinical outcome or immune response or on 
the basis of emerging data, additional tests for exploratory biomarkers may be extremely 
important to help investigate their response.  Of note, on this study, very delayed objective tumor 
responses have occurred >18 months after study initiation.  These additional tests may require 
additional blood or tumor (and may be requested at any time).  For example, a patient may be 
demonstrating a significant tumor response and additional blood may be required to fully 
investigate the patient’s anti-tumor immune response or a fine needle aspirate (FNA) might be 
requested to examine a gene signature at a specific timepoint after study therapy.  Patients be 
may be asked to provide baseline blood (or tumor) and/or post-treatment samples to be used for 
these type of analysis.  In these cases, the patient may be asked permission for additional blood 
or tumor samples to be collected for these exploratory assays. 
11.0 
PATIENT WITHDRAWAL 
While patients will be encouraged to continue on study for safety follow-up, patients MUST be 
discontinued from receiving further study agent for the following reasons: 
1) Withdrawal of informed consent (patient’s decision to withdraw for any reason). 
2) Pregnancy [NOTE: All FCBP should be instructed to contact the investigator immediately if 
they suspect they might be pregnant (e.g., missed or late menstrual period) at any time during 
study participation]. 
3) Termination of the study for safety or other reasons. 
4) Imprisonment or the compulsory detention for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness. 
5) Any clinical AE, laboratory abnormality or intercurrent illness that, in the opinion of the 
investigator, indicates that continued dosing on the study is not in the best interest of the 
patient. 
6) Patients who cannot tolerate G100 or outpatient study procedures.  


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Unless consent is withdrawn and the patient is unwilling to continue with safety follow-up, the 
patient is lost to follow-up, or the study is terminated, all efforts should be made to continue 
safety monitoring of all patients who received G100 as outlined in Sections 10.3.10, 10.3.15, 
10.3.22, 10.3.29, or 10.4.8.  In addition, the procedures described in Sections 10.3.9, 10.3.14, 
10.3.21, 10.3.28, or 10.4.7 should be done at the last site visit if feasible.  
Patients who withdraw from the study prior to the EOS Visit should be followed for new AEs for 
at least 30 days after their last dose of G100.  If the subject withdraws prematurely and is 
unwilling to continue safety follow-up, any subsequent SAE that may be causally related to 
G100 that comes to the attention of the site staff should be reported to Immune Design. 
For patients receiving pembrolizumab, all AEs experienced from the time of enrollment through 
30 days following cessation of pembrolizumab and/or G100 treatment, whichever is later, will be 
reported by the investigator.  Any ECI experienced through 30 days following cessation of 
treatment should be reported within 24 hours to the Sponsor.  Any SAE due to any cause other 
than progression of the cancer under study that occurs through 90 days following cessation of 
pembrolizumab treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, must be reported within 24 hours to the Sponsor.  After 
the 90-day reporting period, any SAE that comes to the attention of the site staff that may be 
causally related to pembrolizumab or to G100 must be reported to Sponsor regardless of time 
elapsed.  
12.0 
ADVERSE EVENTS 
All patients who receive at least one study injection or another study-related procedure will be 
considered evaluable for safety parameters.  This includes any untoward signs (including 
abnormal laboratory findings) or symptoms experienced by the patient from the time of 
enrollment until the EOS / Post Vaccination Safety Visit (i.e., last study visit before long-term 
follow-up).  For patients enrolled on the pembrolizumab arm, all AEs experienced from the time 
of enrollment through 30 days following cessation of treatment will be reported by the 
investigator.  Safety will be evaluated for all treated patients using the NCI CTCAE v.4.03 or 
newer.  Safety assessments will be based on medical review of both solicited and spontaneously 
reported AEs, including symptoms, physical examination findings, vital signs, laboratory 
findings, ECGs, and discontinuations for AEs.  The nature, severity, and frequency of AEs will 
be monitored on an ongoing basis for risk assessment and to determine if risk management 
interventions are warranted (i.e., expedited notification of safety findings to investigators, IRBs 
or regulators; update of IB and ICF risks and re-consenting study patients; revision of safety 
monitoring procedures; revision of eligibility criteria or other study procedures; etc.).  
Progression of the cancer under study is not considered an AE unless it is considered to be drug-
related by the investigator. 


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All SAEs that are unexpected and considered possibly, probably or definitely related to study 
regimen will be reported to the FDA and IRB in accordance with the requirements in 21 code of 
federal regulations (CFR) §312.32.  
12.1 
Definitions 
Adverse Event (AE) - Any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product, medical treatment or procedure and which does 
not necessarily have to have a causal relationship with this regimen.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, medical 
treatment or procedure whether or not considered possibly, probably or definitely related to the 
medicinal product.  
Unexpected Adverse Event – An AE is “unexpected” when its nature (specificity), severity, or 
frequency are not consistent with the known or foreseeable risk of AE associated with the 
research procedures described in the protocol, informed consent form, or the investigator 
brochure. 
Serious Adverse Event (SAE) – Any AE occurring that results in any of the following 
outcomes: 
1) Death. 
2) A life-threatening AE.  
3) Inpatient hospitalization or prolongation of existing hospitalization.   
Note: Hospitalizations not to be reported as SAEs include admissions for planned 
medical/surgical procedure (such as scheduled tumor excision or debulking surgery) or 
routine health assessment requiring admission for baseline/trending of health status 
documentation (e.g., routine colonoscopy) or admission for social purposes such as lack of 
housing, economic inadequacy, care-giver respite, or family circumstances. 
4) A persistent or significant disability/incapacity. 
5) Results in a congenital anomaly/birth defect. 
6) Is a medically important condition which is judged by a health care professional as serious. 
The term “life-threatening” refers to an event in which the subject was at risk of death at the time 
of the event, and it does not refer to an event that hypothetically might have caused death if it 
were more severe.  
Disability refers to a substantial disruption of a person’s ability to conduct normal life function.  
Medical and scientific judgment will be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 


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life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the outcomes listed in the definition above.  These may also be 
considered serious.  Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm; or blood dyscrasias or convulsions that do not result in 
hospitalization.  
When there is doubt regarding an AE meeting the criteria for an SAE, the investigator should 
default to reporting the AE as an SAE.  
There are special circumstances in which an SAE reporting form is used to communicate 
important clinical trial safety observations that may not constitute an SAE.  
1) Pregnancy: Although pregnancy is not considered an SAE and is instead a normal human 
experience, all pregnancies reported in the month before or month after last G100 
investigational injection must be reported to Sponsor.  If enrolled onto the pembrolizumab 
arm, pregnancies and lactations that occur through 120 days following cessation of 
pembrolizumab or 30 days if the subject initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator. (See Section 12.7) 
2) Overdose: As defined for this study, an overdose is defined as the accidental or intentional 
administration of any dose of the G100 product that is considered both excessive and 
medically important.  For reporting purposes, an overdose will be considered, regardless of 
adverse outcome, as an important medical event.  All cases of overdose must be reported 
immediately to the Sponsor.  
3) Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor for 
Pembrolizumab. For this trial, an overdose will be defined as ≥1000 mg (5 times the dose) of 
pembrolizumab.  No specific information is available on the treatment of overdose of 
pembrolizumab.  In the event of overdose, the subject should be observed closely for signs of 
toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
12.2 
Adverse Event Severity 
All AEs will be evaluated according to the NCI CTCAE v4.03 or newer (2010) 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.  For 
AEs not listed in this reference scale, severity will be assessed by the investigator according to 
the criteria in Table 5. 


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Table 5: 
Adverse Event Severity Assessment 
Grade 1 (Mild) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.  
Grade 2 (Moderate) 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*. 
Grade 3 (Severe) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living (ADL)**.  
Grade 4  
(Life threatening) 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 (Death) 
Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
 
Changes in the severity of an AE should be documented to enable an assessment of the duration 
of the event at each level of intensity.  Adverse events characterized as intermittent require 
documentation of onset and duration of each episode.  
12.3 
Relationship to Investigational Drug 
The investigator will report his or her interpretation of the relationship between an AE and the 
study treatment on the basis of their clinical judgment and the definitions in Table 6.  
Table 6: 
Assessment of Relationship 
Definitely related 
AEs clearly attributable to study regimen administration  
Probably related 
AEs for which there is a reasonable possibility of causal association to study 
regimen  
Possibly related 
AEs for which there is confounding by comorbidities, medications or other 
considerations but for which it is not unreasonable that the AE may have been 
caused by study regimen. Note that it is not appropriate to invoke “you can’t 
rule it out.” 
Not related 
AEs that are considered clearly not causally related to study regimen, or for 
which there is a clear alternative explanation 
AE = adverse event 
 


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If there is any question whether or not an AE is possibly, probably or definitely related, the 
investigator should default to conservatism in categorization.  Similarly, the investigator should 
default to conservatism by calling an AE an SAE if there is doubt regarding the serious nature of 
an AE, if it meets one of the definitions described above.  
12.4 
Adverse Event Collection Period 
All enrolled patients in Parts 1, 2, 3, 4, and 5 will have periodic assessment of clinical and 
laboratory AEs. All AEs will be collected at the EOS / Post-Vaccination Safety Visit and for 
30 days after the last dose of study agent whichever is longer (if receiving pembrolizumab, see 
below).  Thereafter, any SAE that comes to the attention of the site staff that may be causally 
related to study drug (i.e., the event is considered possibly, probably or definitely caused by the 
drug) must be reported to Sponsor regardless of time elapsed.  
Patients who withdraw from the study prior to the EOS Visit should be followed for new AEs for 
at least 30 days after their last dose of G100.  If the subject withdraws prematurely and is 
unwilling to continue safety follow-up, any subsequent SAE that may be causally related to 
G100 that comes to the attention of the site staff should be reported to Immune Design. 
For patients receiving pembrolizumab, any serious AE, or follow up to a serious AE, including 
death due to any cause other than progression of the cancer under study that occurs through 
90 days following cessation of treatment, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported within 24 hours to 
the Sponsor either by electronic media or paper.  In addition, any event of clinical interest (ECI) 
experienced through 30 days following cessation of treatment should be reported within 24 hours 
to the Sponsor. 
For Pembrolizumab: 
 All AEs or ECIs (Events of Clinical Interest) from the time of treatment/ allocation 
through 30 days following cessation of study treatment must be reported by the 
investigator.  
 All AEs meeting serious criteria, from the time of treatment/ allocation through 90 days 
following cessation of study treatment, or 30 days following cessation of study treatment 
if the participant initiates new anticancer therapy, whichever is earlier must be reported 
by the investigator  
 All pregnancies and exposure during breastfeeding, from the time of treatment/ allocation 
through 120 days following cessation of study treatment, or 30 days following cessation 
of study treatment if the participant initiates new anticancer therapy must be reported by 
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 Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered to be drug-related. 
12.5 
Adverse Event Reporting 
At each study visit (including unscheduled visits), the investigator, or designee, will determine 
whether any AEs have occurred.  AEs will be reported in the patient’s medical record and on the 
AE case report form (CRF) page and each will be classified according to the criteria in 
Section 12.1 and Section 12.2.  If known, the diagnosis should be recorded, in preference to the 
listing of individual signs and symptoms.  Any pre-existing conditions that are detected as part of 
the initial screening procedures will need to be reported in the medical history and not as an AE.  
However, pre-existing conditions that worsen enrollment should be reported as an AE.  
Adverse events will be reported to FDA in accordance with the requirements outlined in 21 CFR 
§312.32.  Deaths due to cancer progression will not be reported as expedited events.  The 
Investigator will continue to monitor the patient until any new, changed, or worsened AE 
resolves, returns to baseline, or until the Investigator and Immune Design agree that follow-up is 
no longer necessary.  AEs must be followed until resolution whenever possible. 
12.6 
Serious Adverse Event Reporting 
If an SAE occurs, Immune Design must be notified within 24 hours of awareness of the event by 
the investigator. If the SAE is fatal or life-threatening, Immune Design must be notified 
immediately, irrespective of the extent of available AE information.  In the rare event that the 
investigator or designee does not become aware of the occurrence of a SAE immediately, the 
investigator or designee must report the event within 24 hours of their awareness and document 
the time of when his/her first awareness occurred.  For all SAEs, the investigator or designee is 
obligated to pursue and provide information to Immune Design in accordance with the 
timeframes for reporting specified above.  In addition, an investigator may be requested to obtain 
specific additional follow-up information in an expedited fashion.  This information may be 
more detailed than that captured on the AE CRF. In general, this will include a description of the 
AE in sufficient detail to allow for a complete medical assessment of the case and independent 
determination of causality.  
New SAEs experienced by patients during the Screening Period (pre-study treatment) will be 
reported to Immune Design if the events are considered related to study procedures.  New SAEs 
determined to be related to study tests or procedures (not including cancer-related events) and 
any hospitalizations that are experienced by patients from the time of signing the informed 
consent until Day 0 (start of G100 treatment) will be noted on the SAE form and CRF.  From 
Day 0 until the EOS / Post Vaccination Safety Visit, any new SAE will be noted on the SAE 
form and CRF.  After the EOS / Post Vaccination Safety Visit, any SAE that comes to the 


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attention of the site staff that may be causally related to study drug (i.e., there is a reasonable 
possibility that the event may have been caused by the drug) will be reported to Immune Design. 
For patients receiving pembrolizumab, any SAE, or follow up to an SAE, including death due to 
any cause other than progression of the cancer under study that occurs through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, must be reported within 24 hours to the Sponsor either 
by electronic media or paper.  
SAEs will be monitored until they have resolved, returned to baseline, or they are not clinically 
significant, stable, or do not require additional follow-up, as judged by the Investigator and 
Immune Design. 
The SAE contact and reporting information are provided in Appendix E. 
12.7 
Pregnancy 
Sexually active men and FCBP must use an effective method of birth control during the course 
of the study, in a manner such that risk of failure is minimized.  Before enrolling FCBP in this 
clinical trial, all FCBP must be advised of the importance of avoiding pregnancy during trial 
participation and the potential risk factors for an unintentional pregnancy.  All patients (men and 
women) must sign an informed consent form documenting this discussion. (See conception 
warnings for pembrolizumab, Sections 8.1.9 – 8.1.11) 
All FCBP must have a negative pregnancy test within 7 days for Parts 1, 2, or 3 and within 
72 hour for Parts 4 and 5 prior to the study regimen initiation.  If the pregnancy test is positive, 
the subject must not be enrolled in the study.  
In addition, all FCBP should be instructed to contact the investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. 
If following initiation of study dosing, it is subsequently discovered that a trial subject is 
pregnant or may have been pregnant within one month before or after study regimens will be 
permanently discontinued and the patient will be followed as possible by the investigator or 
designated health care professional to determine pregnancy outcomes for both mother and baby.  
If a male patient enrolled in study has a female sexual partner who becomes pregnant after 
initiation of study, then the study subject should be asked permission for the investigator (or 
designated health care professional) to approach his partner for permission to follow-up with the 
pregnant partner to determine outcomes for both mother and baby.  
For patients receiving pembrolizumab, it is the responsibility of investigators or their designees 
to report any pregnancy or lactation in a subject (spontaneously reported to them) that occurs 
during the trial or within 120 days of completing the trial or 30 days following cessation of 


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treatment if the subject initiates new anticancer therapy, whichever is earlier.  All subjects who 
become pregnant must be followed to the completion/termination of the pregnancy.  Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events).  If the pregnancy continues to term, the outcome (health of infant) 
must also be reported. Such events must be reported within 24 hours to the Sponsor either by 
electronic media or paper.  
12.8 
Events of Clinical Interest /Medical Events of Interest  
Selected non-serious and serious AEs that may be associated with G100 or pembrolizumab are 
also known as ECI / MEOI and must be reported to the Sponsor. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, or is 
the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 30 days following 
cessation of treatment, any ECI, or follow up to an ECI, whether or not related to the Sponsor’s 
product, must be reported within 24 hours to the Sponsor, either by electronic media or paper. 
Electronic reporting procedures can be found in the electronic data capture (EDC) data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent). 
For G100, ECI / MEOIs may be added to the Investigator Brochure as clinical experience with 
G100 increases and will be used to capture additional information on these events of interest. 
For Pembrolizumab, Events of clinical interest for this trial include: 
1) an overdose of Sponsor's product, as defined in Section 12.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2) an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents.  The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology.  The trial site guidance for assessment and 


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follow up of these criteria can be made available.  It may also be appropriate to conduct 
additional evaluation for an underlying etiology in the setting of abnormalities of liver blood 
tests including AST, ALT, bilirubin, and alkaline phosphatase that do not meet the criteria 
noted above. In these cases, the decision to proceed with additional evaluation will be made 
through consultation between the study investigators and the Sponsor Clinical Director.  
However, abnormalities of liver blood tests that do not meet the criteria noted above are not 
ECIs for this trial. 
12.9 
Data Monitoring Committee 
A DMC will be established to provide independent review of safety data and to assure that the 
risk to patients is minimized.  The DMC will be composed of 2 oncologists.  The DMC will 
review all related and unexpected (i.e., expedited) SAEs and DLTs as individual cases arise and 
will perform periodic reviews of all AEs, laboratory results, and patient discontinuations.  
Safety data will be collected and monitored on an ongoing basis throughout the study.  Immune 
Design will summarize all available safety and laboratory data on all patients at regular intervals 
(at least every 3 months) during the study, as specified in the DMC charter.  Immune Design and 
the DMC will conduct separate reviews of these data for any safety trends that might impact the 
treatment of patients. Safety issues that arise out of such ongoing reviews could lead to 
modifications of the treatment program. 
The DMC may convene on an ad-hoc basis to evaluate any urgent safety issues.  Upon request, 
the DMC will be granted access to any available data pertinent to the issues under evaluation. 
Immune Design will provide cumulative data, as specified in the DMC charter, to the DMC for 
review, including clinical laboratory values, AEs, SAEs, medical events of interest, and patient 
discontinuations. 
13.0 
PROTOCOL DEVIATIONS  
A protocol deviation is any change, divergence or departure from the study design or procedures 
defined in the protocol.  
Important protocol deviations are a subset of protocol deviations that might significantly affect 
the completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
subject’s rights, safety or wellbeing such as enrolling subjects in violation of key eligibility 
criteria or failing to collect data necessary to interpret primary endpoints, the PI prescribing or 
administering the wrong dose, or the study subject being scheduled to return for follow-up 
intervention outside the protocol-dictated window as a convenience to the patient or study staff.   
There will be unforeseen circumstances that are beyond the investigator’s control (e.g., a patient 
not attending a scheduled follow-up visit).  Prior approval will not be granted in these situations, 
but the investigator should report these events upon determining that a deviation has occurred. 


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The investigator is responsible for complying with and adhering to IRB procedures for reporting 
protocol deviations and violations.  All protocol deviations should be documented and forwarded 
to Immune Design or its authorized representative. 
Protocol deviations will be collected during the study, and reported by Immune Design or its 
authorized representative to the FDA and IRBs yearly in the annual report.  Participating 
investigators will receive regular updates regarding their site’s deviations.  
14.0 
STATISTICAL CONSIDERATIONS 
14.1 
Study Endpoints 
The study endpoints include both clinical safety and immunogenicity.  Where possible, 
parameters will be quantified for direct comparisons among the five study groups; however, due 
to the small sample size and the primary objective to evaluate vaccine safety and 
immunogenicity, all analyses will be exploratory in nature.  
14.2 
Sample Size 
In Part 1, Part 2, and Part 3, up to 65 evaluable patients will be enrolled. In Part 1, Dose 
Escalation, a total of two pre-defined dose levels will be studied (see Section 4.1).  For cohort 1, 
each patient will receive a total of 6 planned injections and up to 3 additional injections 
depending on the treated tumor response.  A conventional “3+3” design will be used during 
Part 1 for dose assessment and escalation.  The first cohort of 3 patients will be enrolled at the 
lowest dose level.  If 0/3 patients experience DLT, the next cohort will be enrolled into the next 
higher dose.  If 1/3 patients experience DLT, the current dose level will be expanded to a total of 
6 patients.  If 1/6 patients experience DLT, dose escalation may occur.  If 2 or more patients in 
dose cohort experience DLT at any time, the MTD has been exceeded.  The MTD or maximum 
safe dose (if at the highest dose level) is defined as the highest dose in which less than one third 
of patients in the cohort experienced a DLT.  
Once the MTD or maximum safe dose examined in the study has been determined, Part 2 will 
begin. In the optional Large Tumor group, up to 4 patients will be treated and safety will be 
examined.  
In Part 2, Patient Expansion, up to 24 patients (12 per treatment group) will be randomly 
assigned to receive treatment with either G100 alone or the sequential administration of G100 
and pembrolizumab.  The dose of G100 will be the MTD / maximum safe dose determined in 
Part 1.  This portion of the study will provide additional safety, immunogenicity and early 
efficacy data of G100 at the MTD / maximum safe dose and provide initial data on the sequential 
administration of G100 and pembrolizumab.  This analysis is designed to be exploratory but will 
provide important data to guide further development.  While the sample size is not based on 
formal power calculations, it is expected to provide adequate preliminary data to inform 
subsequent trials and to reject an indication should no clinical benefit occur.  For example, if the 


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true ORR is 20%, we will conclude futility with a 6.9% error rate if 0 response is observed in 12 
patients.  In that case, the Sponsor would terminate that study arm for development.  
In Part 3, G100 Expansion of 20 µg Dose Group, up to 25 patients will be enrolled and treated 
with intratumoral G100 at 20 µg/dose following radiation therapy.  The purpose of this group 
would be to explore the safety and potential clinical responses at the higher dose level.  The 
number of patients was chosen to provide a similar cohort treated with G100 alone in Parts 1 and 
2 for descriptive comparison.  In those portions of the study, 18 patients (3 at 5 µg/dose; 15 at 
10 µg/dose) may receive intratumoral G100 alone following radiation therapy.   
In Part 4, G100 Plus Pembrolizumab, at least 22 evaluable patients will be enrolled and treated as 
part of a Dose Escalation group or a Patient Expansion group with intratumoral G100 in 
combination with pembrolizumab.  The purpose of this treatment regimen will be to explore the 
safety and preliminary clinical efficacy and biomarker changes of patients treated with G100 at a 
dose of 20 µg/lesion injected in single or multiple lesions.  The administered dose of G100 will 
depend on the number of potentially injectable lesions and whether the MTD has been 
established during Dose Escalation.  One or more lesions will be targeted for injection and each 
lesion would receive 20µg of G100 intratumorally (or 10 µg G100 if 20 µg/lesion in a single 
lesion is not tolerated) as long as the total number of treated tumor lesions and total systemic 
dose does not exceed the MTD (if established) or 80 µg total dose (20 µg injected in 4 lesions).  
This analysis is designed to be exploratory and will evaluate safety, clinical outcome and 
exploratory biomarkers to guide further clinical development.  Clinical efficacy including ORR 
and DOR will be evaluated in relapsed or refractory FL patients who received ≥3 prior systemic 
therapies. 
For this analysis, 22 efficacy evaluable patients will be required.  Efficacy evaluable patients are 
patients who received at least 3 doses of G100 at 20 µg/lesion and at least 1 dose of 
pembrolizumab, had at least one post baseline tumor assessment, and had no major protocol 
deviations that impact the efficacy of the study treatment or the assessment of response.  Patients 
who received G100 20µg/lesion during Dose Escalation in Part 4 may be included in clinical 
response analysis. With a target ORR of 40%, if ≤5 responders are observed among 22 evaluable 
patients, we will conclude futility with 7.2% error rate.  The Sponsor will use this analysis to 
decide whether to continue further development of this regimen.  Early acceptance of treatment 
at the end of the 22 evaluable patients is not permitted.  If the true ORR for this group is 20% 
and 20% ORR is considered not clinically meaningful, the probability of observing ≤5/22 
responders and stopping the study is 73.3%.  
In Part 5, G100 Plus rituximab, after Dose Escalation has been completed, patients will be 
treated with intratumoral G100 at the recommended dose level in combination with 
rituximab.  The purpose of this Patient Expansion group will be to explore the safety and clinical 
outcome of patients treated at a biologically active and safe G100 dose level administered into 
single tumor lesion in combination with rituximab.  This analysis is designed to be 
exploratory and will evaluate safety, clinical outcome and exploratory biomarkers.  


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An exploratory analysis will be performed on 20 efficacy evaluable relapsed or refractory FL 
patients and will include analyses of the frequency and duration of CRs.  Efficacy evaluable 
patients are patients who received at least 3 injections of G100 at the recommended dose and 
3 doses of rituximab, had at least one post baseline tumor assessment, and had no major protocol 
deviations that impact the efficacy of the study treatment or the assessment of response.  Five or 
more CRs in 20 patients treated with G100 plus rituximab will signal an improvement of CR rate 
over 10%.  For reference, the probability of observing ≤4 CRs in 20 patients is 5.1% if the true 
CR rate is 40% (the targeted CR rate).  Patients who received G100 at the recommended dose 
during Dose Escalation in Part 5 may be included in clinical response analysis.  With 20 efficacy 
evaluable patients, and a historical CR rate of 10%, assuming a true CR rate of 32% in the G100 
plus rituximab, this subgroup analysis has 82% power to detect a signal of an improvement in 
CR from 10% at a 1-sided alpha of 0.05.  
14.3 
Definition and Analysis of Primary and Secondary Endpoints  
14.3.1 
Safety 
All enrolled patients who receive at least one injection of study drug or undergo a study-related 
procedure will be included in the safety analysis.  The highest toxicity grades per patient will be 
tabulated for AEs and laboratory measurements, and the number and percent of patients 
reporting AEs will be quantified.  Listings will be required for all on-study deaths, SAEs, DLT, 
and AEs that lead to withdrawal from study. Narratives for all SAEs and deaths on-study will be 
required.  
14.3.2 
Immunogenicity 
All enrolled patients who receive at least one injection of study drug and have an 
immunogenicity sample will be included in the exploratory immunogenicity analysis.  
Tabulation, summarization and descriptive statistics will be performed describing the baseline 
and post G100 peripheral blood and tumor lymphocyte subsets.  Analyses will be performed to 
determine if there are any statistically significant changes from baseline values.  Association 
between pre-existing and post treatment immunogenicity biomarkers (e.g., baseline TLR4 
expression) and clinical outcome will be explored. 
14.3.3 
Tumor Response 
Anti-tumor activity as defined by irRC using bi-dimensional tumor measurement will be 
reported.  The primary analysis will be based on investigator’s assessment.  Independent 
radiology review will be supportive.  As a comparison, clinical responses will also be examined 
by the International Working Group and by Lugano criteria for lymphomas (Cheson 2014)).  
Progression-free survival and/or TTP will be evaluated and will be plotted as a Kaplan-Meier 
curve.  Disease control rate (CR, PR, and SD) and ORR (or CR + PR) will be reported.  As 
exploratory analyses, time to next treatment, overall survival (OS), and Follicular Lymphoma 


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International Prognostic Index (FLIPI) scores may be examined (Frederico 2009; 
Solar-Celigny 2004).  
Independent radiology review of tumor assessments 
The Sponsor may request at any time that radiographic images of tumor assessments for all or 
select patients be submitted to central storage facility for the purpose of an independent 
radiology assessment of tumor responses.  All patients starting with protocol version 4B will be 
required to provide an informed consent for such central storage and independent radiology 
review prior to study treatment. 
14.3.4 
Pharmacokinetic and Pharmacodynamic 
All enrolled patients who receive at least one injection of study drug and have a 
pharmacokinetics/ pharmacodynamics sample will be included in the exploratory 
pharmacokinetics/ pharmacodynamics analysis.  Tabulation and summarization will be 
performed to describe the baseline and post G100 results by timepoint.  Data permitting, 
statistical analysis will be performed to characterize the pharmacokinetics/ pharmacodynamics 
profile of G100. 
14.4 
Interim Analysis 
An analysis will be performed once the MTD or maximum safe dose examined in the study is 
established in Part 1 Dose Escalation.  All data from the relevant subjects through Day 77 EOS 
evaluation will be monitored, cleaned, and reconciled to create an interim analysis SAS dataset. 
Part 2 Patient Expansion is designed to be exploratory.  Data will be assessed for each patient as 
it becomes available.  Based on the statistical considerations described above, an interim analysis 
of responses observed in the first 12 patients in Part 2 will be performed to determine whether or 
not the study should continue or be terminated early. 
15.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Information on the CRF will be verifiable to source documents. Other records that will be 
considered source documents include, but are not limited to, hospital records, clinic charts, 
radiographic data, laboratory reports and pathology reports. Copies of source documents that 
should be sent to Immune Design or its authorized representative, if requested, include hospital 
or clinic records, radiographic data, laboratory reports, pathology reports, operative summaries 
and discharge reports.  Other source documents may include hospital discharge summaries, if 
available, or information in lieu of a discharge summary, such as discharge orders or progress 
notes; any relevant notes pertaining to AEs, additional surgical procedures, or deaths and autopsy 
reports.  Any documentation sent from the site should be redacted to exclude patient identifying 
information. 


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16.0 
DATA QUALITY ASSURANCE  
Immune Design performs quality assurance checks on all clinical studies that it sponsors.  Before 
the enrollment of any patient in this study, Immune Design or its authorized representative and 
the investigator will review the Protocol, the Investigator Brochure, the CRFs and instructions 
for completing them, the procedure for obtaining informed consent and the procedure for 
reporting AEs/SAEs.  Site monitoring visits will be performed by Immune Design or its 
authorized representative on a regular basis pursuant to its Monitoring Plan.  During these visits, 
information recorded on the CRFs will be verified against source documents.  After the CRFs are 
received by Immune Design or its authorized representative, they will be reviewed for safety 
information, legibility, completeness, accuracy and logical consistency.  The data will be entered 
into a database.  Additional computer programs that identify selected Protocol deviations, out-of-
range data, and other data errors may be used to help monitor the study.  As necessary, requests 
for clarification or correction will be sent to the investigator.  
Independent auditors from Immune Design or its authorized representative will be allowed by 
the investigator to audit data and records for GCP compliance  In addition, inspections may be 
conducted by appropriate regulatory authorities.  
Data entered in the CRF will be source verified for accuracy and completeness.  In addition, 
protocol compliance and compliance with FDA regulations and International Conference on 
Harmonization (ICH) Good Laboratory Practices (GCP) guidelines will be verified.  
17.0 
ETHICS 
17.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
The Protocol and the ICFs must have the approval of a properly constituted IRB responsible for 
approving clinical studies.  The signed IRB approval letter must specify the date of Protocol and 
ICF approval and identify the documents approved including the investigator's name, the 
Protocol version, date and title.  Any patient materials or advertisements used to recruit 
volunteers should also be reviewed and approved by the IRB.  Clinical supplies will not be 
shipped until a signed approval letter from the IRB has been received and a contractual 
agreement has been signed by Immune Design or its authorized representative and the clinical 
site.  
17.2 
Ethical Conduct of the Study 
All investigators on the protocol must have received formal training in the ethical conduct of 
human research.  The study will be conducted in accordance with the ethical principles that have 
their origins in the Declaration of Helsinki.  All CRFs, compliance with the protocol, compliance 
with GCP, and compliance with the FDA’s Code of Federal Regulations (21 CFR, as applicable) 
and ICH GCP will be monitored by an independent monitor routinely at each institution 


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participating in this trial.  This process, as well as the process for the documentation of the 
monitoring, will be documented in detail in the Clinical Monitoring Plan.  
17.3 
Patient Information and Consent 
Written informed consent must be obtained from the patient prior to performing any 
study-related procedures, including Screening assessments.  The investigator or investigator’s 
designee will provide background information on the study, including the benefits and risks of 
the investigative regimen.  The investigator or investigator’s designee will also encourage the 
prospective patient to ask questions about the study and will provide the prospective patient with 
sufficient opportunity to consider whether or not to participate.  
Original signed ICFs must be filed in the patient records at the site.  A copy of the signed consent 
must also be provided to the patient. 
The patient ICF template that has been provided for this study may be revised by an investigator 
or an IRB based on the institution’s requirements.  However, all changes requested by an 
investigator or an IRB, even those that are not substantial and/or do not affect the rights, safety 
or welfare of a patient, must be approved by Immune Design.  If Immune Design determines that 
the revisions are substantial and/or affect the rights, safety or welfare of a patient, the ICF must 
be reviewed and approved by both Immune Design and local IRB before the ICF can be utilized. 
17.4 
Patient Confidentiality 
Patient names shall not be revealed to Immune Design or its authorized representative.  Only the 
patient identifier will be recorded in the CRF, and if the patient’s name appears on any other 
document, it must be redacted and replaced with the patient identifier before a copy of the 
document is supplied to Immune Design or its authorized representatives.  Study findings stored 
on a computer will be stored in accordance with local data protection laws.  In the event of 
accidental communication of such information, immediate steps to redact the information from 
all study files will be implemented, with appropriate documentation in the patient study file.  
18.0 
DATA HANDLING AND RECORD KEEPING 
18.1 
Source Documents 
Information on the CRF should be verifiable to source documents.  Other records that will be 
considered source documents include, but are not limited to, hospital records, clinic charts, 
radiographic data, laboratory reports and pathology reports.  Copies of source documents that 
should be sent to Immune Design or its authorized representative, if requested, include operative 
summaries and discharge reports.  Other source documents may include hospital discharge 
summaries, if available, or information in lieu of a discharge summary, such as discharge orders 
or progress notes; any relevant notes pertaining to AEs, additional surgical procedures, or deaths 
and autopsy reports.  


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18.2 
Case Report Forms 
The investigator is responsible for maintaining adequate and accurate medical records from 
which information will be transferred into the study database.  The CRFs should be completed by 
the investigator or delegated personnel. In the context of this protocol, CRF will refer to either 
paper form or electronic data or both. 
CRFs will be provided to the Sponsor for each patient.  No data will be recorded directly on the 
CRF without source documentation.  Data/corrections entered will be signed or initialed by the 
study personnel undertaking that procedure.  
For corrections that become necessary after in-house data verification procedures, Data 
Clarification Forms (DCFs) will be used.  
Only complete CRFs, reviewed and signed by the investigator indicating his/her assurance of the 
accuracy of all recorded data, will be accepted.  It is expected that the Investigator and his/her 
staff will cooperate with the monitoring team and provide any missing data or data clarifications 
in a timely manner.  
18.3 
Record Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an agreement 
with Immune Design.  It is the responsibility of Immune Design to inform the Investigator/ 
institution as to when these documents no longer need to be retained. 
Essential documents are those documents, which individually and collectively, permit evaluation 
of the conduct of a trial and the quality of the data produced.  These documents serve to 
demonstrate the compliance of the Investigator, Sponsor, and monitor with the standards of GCP 
and with all applicable regulatory requirements.  Any or all of the documents should be available 
for audit by the Sponsor’s auditor and inspection by the regulatory authorities. 
Immune Design or its authorized representative will maintain all records related to this 
investigational study, according to 21 CFR §312.32 and any other local regulatory requirements. 
In addition, paragraph 4.9.5 of the ICH E6 (GCP) guideline applies.  
19.0 
FINANCING AND COMPENSATION  
The financial aspects of the trial are documented in an agreement between the Sponsor and the 
investigator/institution.  Details regarding Sponsor-provided insurance/indemnity, subject 
compensation and costs to patients are documented in an agreement between the Sponsor and the 


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investigator/the institution.  A summary of this information for the subject is also provided in the 
informed consent.  
20.0 
PROTOCOL AMENDMENTS 
Any amendment to the study protocol must be approved by Immune Design.  A protocol 
amendment may not be implemented until after it has been submitted to the FDA and approved 
by the IRB, unless immediate implementation of the change is necessary for patient safety.  In 
this case, the protocol change must be documented in an amendment and reported to the IRB 
within five working days.  Once a protocol amendment has received approval from Immune 
Design, the investigator will submit it to the IRB for written approval.  The approval letter, 
signed by the IRB Chair, must refer specifically to the investigator, the protocol title, the 
protocol amendment number, and the date of the protocol amendment.  Immune Design is 
responsible for submitting all protocol amendments to the FDA.  
21.0 
PUBLICATION POLICY 
It is expected that the results of this study will be published in a peer-reviewed journal.  A 
publication plan for the primary results will be discussed with the investigators and established 
before the start of the trial.  Any manuscripts reporting the results of this clinical trial must be 
provided to the Sponsor by the Principal Investigator for review and comment prior to 
submission for publication.  Immune Design will have 30 days from the date of receipt for 
review, and shall have the right to request that publication be delayed for up to an additional 
30 days in order to ensure that the Sponsor’s confidential and proprietary data, in addition to the 
Sponsor’s intellectual property rights, are protected.  Abstracts, press releases, and other media 
presentations must also be forwarded to the Sponsor prior to release.  No publication, 
manuscript, or other form of public disclosure shall contain any of the Sponsor’s confidential/ 
proprietary information.  Co-authorship of subsequent publications with Immune Design 
personnel will be discussed and mutually agreed upon before submission of a manuscript to a 
publisher. 


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APPENDIX A: ECOG Performance Status 
ECOG PERFORMANCE STATUS* 
Grade 
Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all 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 
*As published in Oken et al. (Oken 1982)  
 


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APPENDIX B: 
IMMUNE-RELATED RESPONSE CRITERIA (irRC)  
Immune based therapies pose a challenge for response measurements because the inflammatory 
response of an immune reaction can mimic disease progression.  For this reason, the irRC was 
created to help evaluate and prevent the incorrect assignment of progressive disease to these 
situations, primarily by requiring confirmation of PD and by not immediately concluding that 
new lesions represent PD.  The irRC was originally based on WHO bi-dimensional 
measurements and will be used for this study.  A RECIST based irRC has been evaluated and 
commonly used for solid cancers. At this time, a similar NHL-specific irRC does not exist.  For 
this reason, the irRC based on bi-dimensional measurements as well as the more commonly used 
International Working Group Criteria for Lymphomas will both be examined to determine 
response in this study. 
The irRC was originally developed to systematically characterize additional patterns of response 
in patients with advanced melanoma.  Underlying WHO criteria were evolved into irRC 
(Wolchok 2009).  The definitions of the irRC and guidelines on how they can be used in clinical 
practice are detailed below.  
Anti-tumor response based on total measurable tumor burden:  For the irRC, only index and 
measurable new lesions are taken into account (in contrast to conventional WHO criteria, which 
do not require the measurement of new lesions, nor do they include new lesion measurements in 
the characterization of evolving tumor burden).  At the baseline tumor assessment, the sum of the 
products of the two largest perpendicular diameters (SPD) of all index lesions is calculated.  At 
each subsequent tumor assessment, the SPD of the index lesions and of new, measurable lesions  
are added together to provide the total tumor burden: 
Tumor Burden = SPDindex lesions + SPDnew, measurable lesions 
The WHO criteria were developed for solid cancer indications and have not been adapted yet for 
lymphomas.  In WHO solid cancer criteria, abnormal new lesions are counted if >5 × 5 mm and 
up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral lesions would be 
evaluated. 
For the purpose of this trial, the criteria for minimal lymph node / lymphoma tumor dimensions 
for determining an abnormal lesion will be >1.5cm in the longest axis, or if 1.1 to 1.5 cm in 
longest axis, the short axis must be 1 cm or more.  This follows that of standard international 
working group criteria for lymphomas.  A minimum of a 0.5cm increase will be required for a 
previously normal small node (i.e., <1cm in short axis) to be re-classified as a new lesion.  In 
addition, to allow a comparison to the Cheson International Working Group Criteria, up to 
6 dominant nodes / masses will be evaluated and followed for determination of response instead 
of the 5 lesions maximum for irRC (5 lesions per organ, 10 visceral lesions and 5 cutaneous).   


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A comparison of the use of SPD in WHO criteria versus the use of tumor burden in irRC is 
presented below. Comparison between WHO Criteria and the irRC 
 
WHO 
irRC 
New, measurable 
lesion  
(i.e., ≥5 x 5 mm) 
Always represent PD 
Incorporated into tumor burden 
New, nonmeasurable 
lesions  
(i.e., <5 x 5 mm) 
Always represent PD 
Do not define progression (but 
preclude irCR) 
Non-index lesions 
Changes contribute to defining best 
objective response of CR, PR, SD, 
and PD 
Contribute to defining irCR 
(complete disappearance required) 
CR 
Disappearance of all lesions in two 
consecutive observations not less 
than 4 wk apart 
Disappearance of all lesions in two 
consecutive observations not less 
than 4 wk apart 
PR 
≥50 percent decrease in SPD of all 
index lesions compared with baseline 
in two observations at least 4 wk 
apart, in absence of new lesions or 
unequivocal progression of non-
index lesions 
≥50 percent decrease in tumor burden 
compared with baseline in two 
observations at least 4 wk apart 
SD 
50 percent decrease in SPD 
compared with baseline cannot be 
established nor 25 percent increase 
compared with nadir, in absence of 
new lesions or unequivocal 
progression of non-index lesions 
50 percent decrease in tumor burden 
compared with baseline cannot be 
established nor 25 percent increase 
compared with nadir 
PD 
At least 25 percent increase in SPD 
compared with nadir and/or 
unequivocal progression of non-
index lesions and/or appearance of 
new lesions (at any single time point) 
At least 25 percent increase in tumor 
burden compared with nadir (at any 
single time point) in two consecutive 
observations at least 4 wk apart 
 
Time-point response assessment using irRC:  Percentage changes in tumor burden per 
assessment time point describe the size and growth kinetics of both conventional and new, 
measurable lesions as they appear.  At each tumor assessment, the response in index and new, 
measurable lesions is defined based on the change in tumor burden (after ruling out irPD).  
Decreases in tumor burden must be assessed relative to baseline measurements (i.e., the SPD of 
all index lesions at screening).  The irRC were derived from WHO criteria and, therefore, the 
thresholds of response remain the same.  However, the irRC response categories have been 
modified from those of WHO criteria as detailed in the table above. 


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Overall response using the irRC:  The overall response according to the irRC is derived from 
time-point response assessments (based on tumor burden) as follows: 
 Immune-related complete response (irCR), complete disappearance of all lesions 
(whether measurable or not, and no new lesions) 
 confirmation by a repeat, consecutive assessment no less than 4 wk from the date 
first documented 
 Immune-related partial response (irPR), decrease in tumor burden >50% relative to 
baseline confirmed by a consecutive assessment at least 4 wk after first documentation 
 Immune-related stable disease (irSD), not meeting criteria for irCR or irPR, in absence of 
irPD 
 Immune-related progressive disease (irPD), increase in tumor burden >25% relative to 
nadir (minimum recorded tumor burden) 
 confirmation by a repeat, consecutive assessment no less than 4 wk from the date 
first documented 
Patients are considered to have irPR or irSD even if new lesions are present, as long as they met 
the respective thresholds of response as described above.  Furthermore, patients are not 
considered to have irPD if new lesions are present and the tumor burden of all lesions did not 
increase by >25%. In contrast to irCR, irPR, and irPD, a response of irSD does not require 
confirmation.  It is important to note that irCR, irPR, and irSD include all patients with CR, PR, 
or SD by WHO criteria as well as those patients that shift to these irRC categories from WHO 
PD.  Patients with irSD, particularly those with slow-declining tumor burden >25% from 
baseline at the last tumor assessment, are considered clinically meaningful because they show an 
objectively measurable reduction in tumor burden without reaching the 50% threshold that 
defines irPR (it represented an objectively measured reduction not commonly observed in the 
natural history of advanced cancer patients). 
If a patient is classified as having irPD at a post-baseline tumor assessment, then confirmation of 
irPD by a second scan in the absence of rapid clinical deterioration is required.  The definition of 
confirmation of progression represents an increase in tumor burden >25% compared with the 
nadir at two consecutive time points at least 4 weeks apart.  It is recommended that this be done 
at the discretion of the investigator because follow-up with observation alone may not be 
appropriate for patients with a rapid decline in performance status.  Confirmation of irPD allows 
for the capture of all observed responses using the irRC, as most of these late-responding patients 
have a trend toward response within 4 weeks after initial irPD.  Whereas WHO criteria consider 
any new measurable lesion to indicate PD, determination of immune-related best overall 
response (irBOR) is based on changes in total tumor burden from the baseline (nadir, for irPD) 
tumor assessment, regardless of any initial increase in baseline lesions or the appearance of new 
lesions. 


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APPENDIX C: REVISED INTERNATIONAL WORKING GROUP RESPONSE 
CRITERIA FOR MALIGNANT LYMPHOMAS.  
At this time, an NHL-specific irRC does not exist.  For this reason, the irRC based on bi-
dimensional measurements as well as the more commonly used International Working Group 
Criteria for Lymphomas (Cheson 2007) will both be examined to determine response in this 
study. 
Details on the International Working Group Criteria for Lymphomas can be found in Cheson, 
et al., Journal of Clinical Oncology, 2007. 
 


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APPENDIX D: FOLLICULAR LYMPHOMA INTERNATIONAL PROGNOSTIC 
INDEX (FLIPI) 
FLIPI was developed to help evaluate and choose treatments for patients with follicular 
lymphomas.  FLIPI was originally described in 2004 (Solal-Celigny 2004). Characteristics at 
diagnosis were collected from 4167 patients with follicular lymphoma diagnosed between 1985 
and 1992.  A proposed index was then tested on a patient set and five adverse prognostic factors 
were selected:  age (>60 vs. ≤60 years old), Ann Arbor stage (III/IV vs. I/II), hemoglobin 
(<120g/L vs. ≥120g/L), number of nodal sites (>4 vs. ≤4) and serum lactate dehydrogenase 
(LDH; > normal vs. ≤normal).  A score is assigned based on the number of risk factors and place 
patients into low, intermediate or high risk groups that correlate with overall survival differences.  
Because FLIPI was based on patients treated prior to chemoimmunotherapy, a prospective study 
FLIPI2 study was conducted with n=1093 subjects (Frederico 2009).  Three prognostic factors 
were removed (stage, number of nodal sites, and LDH) and three were added (Beta-2-
microglobulin, largest involved node >6cm, and bone marrow involvement.  Differences in risk 
factor scores correlate with progression free survival differences.  FLIPI2 has not yet been 
widely used in studies.  
For this trial, data will be collected to examine both FLIPI1 (original) and FLIPI2 as exploratory 
analyses of enrolled patients. 
Adverse Factor 
FLIPI 1 
FLIPI 2 
Age 
>=60 years 
>60 years 
Ann Arbor Stage 
Stage III/IV 
NA 
Hemoglobin level 
<120 g/L 
<120 g/L 
Serum LDH level 
>ULN 
NA 
Number of nodal sites 
>4 
NA 
Bone marrow involvement 
NA 
+ 
Beta-2-microglobulin 
NA 
>ULN 
LoDLIN 
NA 
>6cm 
 
Outcome Based on FLIPI 1 (original Solal-Celigny 2004) 
Risk Group 
# Risk factors 
Percentage of patients  
5-year OS rate 
10-year OS rate 
Low 
0-1 
36% 
91% 
71% 
Intermediate 
2 
37% 
78% 
51% 
High 
>=3 
27% 
53% 
36% 
 
Outcome Based on FLIPI 2 (Federico 2009) 
Risk Group 
# Risk factors 
Percentage of patients  
3-year PFS rate 
5-year PFS rate 
Low 
0 
20% 
91% 
80% 
Intermediate 
1-2 
53% 
69% 
51% 
High 
3-5 
27% 
51% 
19% 


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APPENDIX E: 
SERIOUS ADVERSE EVENT CONTACT INFORMATION 
STUDY CONTACT FOR REPORTING 
SERIOUS ADVERSE EVENTS 
Everest Clinical Research Inc. 
Telephone: 
+1-905-752-5219 (office) or +1-416-997-0778 (mobile) 
Fax: 
+1-877-327-7733 
Email: 
SAE forms to datafax@ecrscorp.com  
Supplemental information to everestsafety@ecrscorp.com  
 


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APPENDIX F: 
CONTRACEPTION 
Acceptable contraception used in this study is described in Section 8.1.9.  For reference the 
definitions and recommended contraception agents are further described here.  
(Reference:  Clinical Trial Facilitation Group, CTFG, “Recommendations related to 
contraception and pregnancy testing in clinical trials”, 15Sept2014, www.hma.eu).   
For Women:   
As noted in Section 8.1.9, non-pregnant, non-breast-feeding women may only be enrolled if they 
are willing to use 2 methods of birth control or are considered highly unlikely to conceive.  
Acceptable combinations of birth control are described in Section 8.1.9.  Highly unlikely to 
conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years 
of age and has not had menses for greater than 1 year will be considered postmenopausal), 
or 3) not heterosexually active for the duration of the study.  Abstinence (#3) is only acceptable 
as “true abstinence” when it is in line with the preferred and usual lifestyle of the patient and not 
a periodic occurrence. 
Birth Control Methods Which May Be Considered As “Highly Effective” 
For the purpose of this guidance, methods that can achieve a failure rate of less than 1% per year 
when used consistently and correctly are considered as highly effective birth control methods. 
Such methods include: 
 Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation1:   
 Oral  
 Intravaginal  
 Transdermal 
 Progestogen-only hormonal contraception associated with inhibition of ovulation1:    
 Oral   
 Injectable   
 Implantable 2 
 Intrauterine device (IUD) 2 
 Intrauterine hormone-releasing system (IUS) 2 
 Bilateral tubal occlusion 2 
 Vasectomized partner 2,3 
 Sexual abstinence 4 
________________________________________________________________________ 
1 Hormonal contraception may be susceptible to interaction with the Investigational Medicinal Product (IMP), which 
may reduce the efficacy of the contraception method (see Section 4.3).  
2 Contraception methods that in the context of this guidance are considered to have low user dependency. 


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3 Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the FCBP trial participant and that the vasectomized partner has received medical assessment of the surgical 
success. 
4 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. 
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. 
Acceptable Birth Control Methods Which May Not Be Considered As Highly Effective 
Acceptable birth control methods that result in a failure rate of more than 1% per year include: 
 Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action  
 Male or female condom with or without spermicide  
 Cap, diaphragm or sponge with spermicide  
The combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier methods) are also considered acceptable forms of contraception, but they 
are not individually considered highly effective birth control methods.  
For Men: 
As noted in Section 8.1.9, acceptable contraception for male patients with partners who are 
FCBP includes documented sterility such would occur following surgical sterilization 
(vasectomy or orchiectomy) or use of male condom.  In addition, supplemental contraception 
with hormonal or barrier methods should be considered. 
Acceptable contraception includes: 
 Male condom 
 Documented Sterility (example from surgical vasectomy or orchiectomy) 
If a female partner is pregnant, use of a male condom is recommended. 
Birth Control Methods Which Are Considered Unacceptable In Clinical Trials 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable 
methods of contraception. Female condom and male condom should not be used together. 


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APPENDIX G: REFERENCES  
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the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. 
Cancer Res. 64(3): p. 1140-5. 
2. 
Brody JD, Ai WZ, Czerwinski DK, Torchia JA, Levy M, et al. (2010) In situ vaccination 
with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. Journal 
of clinical oncology: official journal of the American Society of Clinical Oncology. 
28:4324-32. 
3. 
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. (2004) SHP-1 and SHP-2 
Associate with Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 
upon Primary Human T Cell Stimulation, but Only Receptor Ligation Prevents T Cell 
Activation. The Journal of Immunology. 173: 945–954. 
4. 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, et al. (2007) Revised 
response criteria for malignant lymphoma. Journal of clinical oncology: official journal 
of the American Society of Clinical Oncology. 25:579-86. 
5. 
Cheson BD, Fisher RI, Barrinbgton SF, Cavalli F, Schwartz LH, et al. (2014) 
Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin 
and Non-Hodgkin Lymphoma: The Lugano Classification. Journal of Clinical Oncology. 
32 (27): 3059-3067. 
6. 
Coler RN, Bertholet S, Moutaftsi M, Guderian JA, Windish HP, et al. (2011) 
Development and characterization of synthetic glucopyranosyl lipid adjuvant system as a 
vaccine adjuvant. PloS one. 6:e16333. 
7. 
Curran MA, Montalvo W, Yagita H, Allison JP. (2010) PD-1 and CTLA-4 combination 
blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within 
B16 melanoma tumors. Proc Natl Acad Sci U S A. 107(9): p. 4275-80. 
8. 
Disis ML. (2010) Immune Regulation of Cancer. Journal of Clinical Oncology. 28 
(29):4531-4538. 
9. 
Dudley ME, Wunderlich JE, Yang JC, Sherry RM, Topalian SL, et al.(2005) Adoptive 
Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting 
Chemotherapy for the Treatment of Patients With Refractory Metastatic Melanoma. 
Journal of Clinical Oncology.0732-183. 
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FDA. (2014) FDA approves Keytruda for advanced melanoma First PD-1 blocking drug 
to receive agency approval. US Food and Drug Administration. September 4, 2014. 


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11. 
Federico M, Bellei M, Marcheselli L, Luminari S, Lopez-Guillermo A, et al. (2009) 
Follicular lymphoma international prognostic index 2: a new prognostic index for 
follicular lymphoma developed by the international follicular lymphoma prognostic 
factor project. Journal of clinical oncology: official journal of the American Society of 
Clinical Oncology. 27:4555-62. 
12. 
Francisco LM, Sage PT, and Sharpe AH. (2010) The PD-1 pathway in tolerance and 
autoimmunity. Immunological Reviews. 0105-2896. 
13. 
Franki SN, Steward KK, Betting DJ, Kafi K, Tamada RE, Timmerman JM. (2008) 
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Nature. 480:480-9. 
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therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
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29. 
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inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
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98(24):13866-71. 
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SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
NCT02501473
17-July-2019
Document Date: 
Phase 1/2 Study of Intratumoral G100 With Or Without 
Pembrolizumab or Rituximab In Patients With Follicular Non-
Hodgkin’s Lymphoma


1 
 
 
 
 
Statistical Analysis Plan 
Final  
 
Protocol Number: IMDZ-G142                                                             
Phase 1/2 Study of Intratumoral G100 With Or Without Pembrolizumab or Rituximab                 
In Patients With Follicular Non-Hodgkin’s Lymphoma 
 
 
7/17/2019 
                                                                                      
 
Confidential Statement 
Information contained in this document is proprietary to Immune Design Corp. The information is 
provided in confidence which is requested under an agreed upon and signed Confidentiality and 
Disclosure Agreement. Do not give this document or any copy or reveal any proprietary information 
contained to any third party other than those bound by the Confidentiality and Disclosure Agreement 
without the prior written permission of an authorized representative of Immune Design Corp. 
      


 
 
2 
 
 
Statistical Analysis Plan Approvals 
Protocol: IMDZ-G142 
 
 
 
_________________________________________________ DATE: _______________  
Michael M. Chen, M.Sc. 
Sr. Director, Biostatistics and Data Management 
Immune Design Corp. 
 
 
_________________________________________________ DATE: _______________  
Shanshan Zhao  
Lead Statistical Programmer  
Q2 Business Intelligence 
 
 
_________________________________________________ DATE: _______________  
Sergey Yurasov, M.D. Ph.D. 
Senior Vice President & Chief Medical Officer 
Immune Design Corp. 
  
 
 
 


 
 
3 
 
 
 
Statistical Analysis Plan Version Log 
 
 
SAP Version  
Protocol Version 
Cohorts  
Prepared by 
Signed Off 
SAP Draft 
Version 1.0, dated 
September 15, 
2016 
Protocol version 
02 dated 
November 5, 2015 
Cohort 1 & 2 
Aurelie Le Maitre, M.Sc. 
Manager, Statistical 
Operations Everest 
Clinical Research 
No 
SAP Final 
Version 
Protocol version 
04B dated 15 
November 2018 
Cohort 1, 2, 3, 
4, 5 
Michael Chen, M.Sc.          
Sr. Director, Biostatistics 
and Data Management  
Immune Design 
Yes 
 
   
 
 
 


 
 
4 
 
 
 
 
Table of Contents 
LIST OF ABBREVIATIONS ...................................................................................................... 6 
1 
INTRODUCTION ................................................................................................................. 8 
2 
STUDY OBJECTIVES ......................................................................................................... 8 
2.1 
Primary Objective .................................................................................................................................... 8 
2.2 
Secondary Objectives ............................................................................................................................... 8 
2.3 
Exploratory Objectives ............................................................................................................................ 8 
3 
STUDY DESIGN ................................................................................................................... 9 
3.1 
Study Design ............................................................................................................................................ 9 
3.2 
Duration of Patient Participation .......................................................................................................... 19 
3.3 
Schedule of Procedures .......................................................................................................................... 19 
3.4 
Sample Size Consideration .................................................................................................................... 32 
4 
ANALYSIS POPULATIONS ............................................................................................. 33 
4.1 
Enrolled Population ............................................................................................................................... 33 
4.2 
Safety Population ................................................................................................................................... 33 
4.3 
Efficacy Evaluable Population ............................................................................................................... 33 
5 
STATISTICAL ANALYSIS ............................................................................................... 33 
5.1 
Data Summaries and Conventions ........................................................................................................ 33 
5.2 
Missing Data .......................................................................................................................................... 34 
5.3 
Patient Disposition ................................................................................................................................. 34 
5.4 
Protocol Deviations ................................................................................................................................ 34 
5.5 
Demographics and Baseline Information .............................................................................................. 34 
5.5.1 
Demographics and Baseline Characteristics .............................................................................................. 34 
5.5.2 
Cancer History ........................................................................................................................................... 34 
5.5.3 
Medical and Surgical History ..................................................................................................................... 35 
5.5.4 
Prior Anti-Cancer Therapy ......................................................................................................................... 35 
5.6 
Efficacy Evaluation ................................................................................................................................ 35 
5.6.1 
Tumor Growth Rate ................................................................................................................................... 35 
5.6.2 
Overall Response Rate (ORR) and Clinical Benefit Rate (CBR)............................................................... 36 


 
 
5 
 
5.6.3 
Duration of Response (DOR) and Duration of Clinical Benefit................................................................. 37 
5.6.4 
Progression-free Survival (PFS) ................................................................................................................. 37 
5.6.5 
Overall Survival (OS) ................................................................................................................................ 38 
5.6.6 
Time to Response for CR or PR Patients ................................................................................................... 39 
5.6.7 
Time to Next Treatment and Duration of All Subsequent Therapies ......................................................... 39 
5.6.8 
Immune Response and Biomarker Analyses .............................................................................................. 40 
5.7 
Safety Evaluation ................................................................................................................................... 40 
5.7.1 
Treatment Exposure ................................................................................................................................... 41 
5.7.2 
Adverse Events .......................................................................................................................................... 41 
5.7.3 
Death .......................................................................................................................................................... 42 
5.7.4 
Clinical Laboratory Evaluation .................................................................................................................. 42 
5.7.5 
Vital Signs .................................................................................................................................................. 43 
5.7.6 
Electrocardiogram (ECG) .......................................................................................................................... 43 
5.7.7 
Physical Examination ................................................................................................................................. 43 
5.7.8 
Pregnancy Test ........................................................................................................................................... 43 
5.7.9 
ECOG Performance Status ......................................................................................................................... 43 
5.7.10 
Prior and Concomitant Medications ...................................................................................................... 44 
6 
INTERIM ANALYSIS AND DATA MONITORING ..................................................... 44 
7 
ADJUSTMENT FOR COVARIATES............................................................................... 44 
8 
MULTIPLICITY ................................................................................................................. 44 
9 
CHANGES IN THE PROTOCOL PLANNED ANALYSIS ........................................... 44 
10 REFERENCES .................................................................................................................... 44 
APPENDIX 1: NCI CTCAE V4.03 GRADES FOR LABORATORY PARAMETERS...... 46 
 


6 
 
List of Abbreviations 
 
Abbreviation  
Description  
ADCC  
antibody dependent cellular cytotoxicity  
AE  
adverse event  
AF  
aqueous formulation  
ALT  
alanine aminotransferase  
ANC  
absolute neutrophil count  
AST  
aspartate aminotransferase  
BUN  
blood urea nitrogen  
CD  
cluster of differentiation  
CFR  
code of federal regulations  
CRF  
case report form  
CR  
complete response  
CTCAE  
Common Toxicity Criteria for Adverse Events  
DC  
dendritic cell  
DCF  
Data Clarification Form  
DLT  
dose-limiting toxicity  
DMC  
data monitoring committee  
ECG  
electrocardiogram  
ECOG  
Eastern Cooperative Oncology Group  
EOS  
End of Study  
EU  
European Union  
FLIPI  
Follicular Lymphoma International Prognostic Index  
G-CSF  
granulocyte-colony stimulating factor  
GCP  
Good Clinical Practice  
GM-CSF  
granulocyte-macrophage colony stimulating factor  
FDA  
Food and Drug Administration  
Hgb  
Hemoglobin  
HIPAA  
Health Insurance Portability and Accountability Act  
HIV  
human immunodeficiency virus  
ICF  
informed consent form  
ICH  
International Council on Harmonization  
IEC  
independent ethics committee  
IgG  
immunoglobin G  
IHC  
immunohistochemistry  
IL  
interleukin  
irSD  
immune-related stable disease  
INR  
international normalised ratio  
IRB  
institutional review board  
irCR  
immune-related complete response  
irPD  
immune-related progressive disease  
irPR  
immune-related partial response  
irRC  
immune related response criteria  
irSD  
immune-related stable disease  


 
 
7 
 
 
 
 
 
  
  
               
               
             
 
 
 
IT  
Intratumoral  
IV  
intravenous(ly)  
mAb  
monoclonal antibody  
MHC  
major histocompatibility complex  
MRI  
magnetic resonance imaging  
MTD  
maximum tolerated dose  
NCI  
National Cancer Institute  
NHL  
non-Hodgkin’s lymphoma  
NSAID  
non-steroidal anti-inflammatory drug  
NSCLC  
non-small-cell lung cancer  
NYHA  
New York Heart Association  
ORR  
overall response rate  
OS  
overall survival  
PCR  
polymerase chain reaction  
PD  
progressive disease  
PD-1  
programmed death receptor-1  
PDL  
programmed death ligand  
PFS  
progression-free survival  
PI  
principal investigator  
PK  
Pharmacokinetics  
PR  
partial response  
PTT  
partial thromboplastin time  
RECIST  
Response Evaluation Criteria in Solid Tumors  
SAE  
serious adverse event  
SAP 
Statistical Analysis Plan 
SC  
subcutaneous  
SD  
stable disease  
SE  
stable emulsion  
SGOT  
serum glutamic oxaloacetic transaminase  
SGPT  
serum glutamic pyruvic transaminase  
SOP  
standard operating procedure 
SPD  
sum of the products of the two largest perpendicular diameters  
TILs  
tumor infiltrating lymphocytes  
TLR  
toll-like receptor  
TNF  
tumor necrosis factor  
TSH  
thyroid-stimulating hormone  
TTP  
time-to-progression  
ULN  
upper limit of normal  
WHO  
World Health Organization 


 
 
8 
 
1 
Introduction 
This Statistical Analysis Plan (SAP) documents the planned statistical methods for the analysis and 
display of data collected within the scope of Immune Design Corp. Protocol IMDZ-G142, version 04B 
dated 15 November 2018. The analysis of the data should allow changes in the plan to the extent that 
deviations from the original plan would provide a more reliable and valid analysis of the data.  As such, 
deviations from this SAP must be substantiated by a sound statistical rationale and documented in the 
clinical study report (CSR). 
This SAP details the analysis of the data collected in the study and the presentation of the results of the 
analyses. All TLFs will be generated based on ADaM datasets. ADaM dataset specifications will be 
developed to detail the programming specifications and mapping rules necessary to create the analysis 
datasets and the TLFs. 
All statistical analyses will be performed using SAS® version 9.4. 
2 
Study Objectives 
2.1 Primary Objective 
• 
In Part 1: Evaluate the safety and tolerability of ascending doses of intratumoral G100 in patients 
with low-grade non-Hodgkin’s lymphoma (NHL) receiving local radiation 
• 
In Part 2: Assess the safety and tolerability of intratumoral G100 or sequential intratumoral G100 
and anti-programmed cell death protein 1 (PD-1) therapy in patients with follicular NHL 
receiving local radiation 
• 
In Part 3: Evaluate the safety and tolerability of 20 μg/dose of intratumoral G100 in patients with 
low-grade NHL receiving local radiation 
• 
In Part 4: Evaluate safety and preliminary clinical efficacy of intratumoral G100 at 20μg/lesion in 
single or multiple tumor lesions and pembrolizumab (anti-PD-1) therapy in patients with relapsed 
or refractory follicular NHL who have received at least 3 prior systemic treatments, one of which 
was or included an anti-CD20 antibody 
• 
In Part 5: Evaluate safety and preliminary clinical efficacy of standard induction therapy with 
rituximab (anti-CD20) in combination with escalating doses of intratumoral G100 in single tumor 
lesions in patients with follicular NHL who have received at least one or two prior treatment(s) 
2.2 Secondary Objectives 
• 
To assess clinical responses by Immune-related Response Criteria (irRC) using bi-dimensional 
measurements and time to progression (TTP) as a preliminary indication of efficacy. 
For comparison, clinical responses will also be assessed by the International Working Group 
response criteria and Lugano criteria for lymphomas (Cheson 2014) for Part 4 & Part 5 patients. 
• 
To assess abscopal tumor responses in non-treated, distal tumor sites 
2.3 Exploratory Objectives 
• 
Evaluate pre- and post-regimen tumor tissue and blood for exploratory biomarkers of 
immunologic and tumor response. 


 
 
9 
 
• 
Part 4 and Part 5, explore pharmacokinetic and pharmacodynamic properties of G100 
• 
Assess clinical responses by Immune-related Response Criteria (irRC) and Lugano criteria for 
lymphomas using independent radiology review 
3 
Study Design 
3.1 
Study Design 
This is a Phase 1/2, open label, trial of G100 in patients with low grade follicular NHL. G100 is 
composed of GLA formulated in a stable emulsion (SE). GLA is a fully synthetic TLR4 agonist that is a 
potent stimulator of innate immune responses. In this study, G100 will be injected into tumors of 
follicular NHL patients in order to generate anti-tumor immune responses. GLA in either the SE 
formulation or an aqueous formulation (AF) has been examined in >1000 patients as an adjuvant for 
various infectious agent and cancer vaccines as well as in 2 ongoing clinical studies involving patients 
with Merkel Cell carcinoma or sarcoma where it has been administered intratumorally either alone or in 
combination with local radiation therapy. It has demonstrated the ability to stimulate immune responses 
with an acceptable safety profile. 
In Part 1, Dose Escalation, patients with accessible tumors that are being considered for radiation therapy 
will receive standard local radiation followed by intratumoral injections of G100 into the irradiated 
mass(es) (Figure 2). Two dose levels will be examined and a 3+3 sequential dose escalation design will 
be used. All patients will receive a regimen consisting of standard low dose radiation (2Gy qd x2, 4 Gy 
total) to the target tumor mass(es). G100 will be injected intratumorally beginning 1 day following 
completion of radiation therapy (Study Day 2), a second dose will be administered 3-5 days later (Study 
Day 5 to 7) and then dosing will continue weekly for up to 4 additional doses (6 total) as long as the 
tumor remains of sufficient size for injection. A single lesion within the radiation field will be targeted to 
receive each dose of G100. If the lesion regresses, another lesion within the radiation field will be chosen 
for treatment. If the tumor mass has not regressed at least 75%, dosing may continue for 3 additional 
weekly intratumoral doses (9 total). 
Two dose levels of G100 are planned: 
• 
Cohort 1: 5 μg of GLA component 
• 
Cohort 2: 10 μg of GLA component 
Initially, three patients will be scheduled to receive G100 at the first dose level. Dose escalation will be 
contingent upon acceptable safety data obtained during the first 28 days of observation following 
initiation of the regimen. A dose level cohort will be expanded from three to six if one of the first three 
patients experiences a DLT. Further patient accrual into that dose level cohort (or higher) will be 
suspended as soon as ≥ 2 patients in that cohort experience DLT, or when otherwise deemed clinically 
appropriate by the investigator or Sponsor medical monitor. After the 28 day DLT observation period for 
the final patient in a cohort is complete, if less than one third of the patients enrolled in that cohort 
developed a DLT, advancement to the next dose-level cohort can begin. 
Patients will be considered evaluable if they have received at least three G100 injections and have 
completed Day 28 safety monitoring OR have experienced DLT. Patients who experienced DLT during 
the safety period will not be replaced. All other patients who have not received at least three G100 
injections and/or do not complete the Day 28 safety monitoring period for reasons other than treatment-
related toxicity will be replaced. 


 
 
10 
 
Following completion of the dose escalation stage of the trial, the maximum tolerated dose (MTD) or 
maximum safe dose (highest dose level examined in the study) will be defined as the highest dose reached 
in which less than one third of the patients in the cohort experienced a DLT. 
In Part 2, depending on the results of Part 1 and the MTD/maximum safe dose, two groups of patients 
may be examined, Patient Expansion With Or Without Pembrolizumab and (optional) Large Tumor 
groups (Figure 1). 
Part 2, Patient Expansion With or Without Pembrolizumab group: Up to 24 patients will be randomly 
assigned and treated with single agent intratumoral G100 (Figure 2) or with the sequential administration 
of intratumoral G100 and pembrolizumab (Figure 3) at the MTD or maximum safe dose of G100 
determined in Part 1.  
This portion of the study is designed to be exploratory. Data indicate that inhibitory immune checkpoint 
pathways are up-regulated in the tumor microenvironment and that interfering with these regulatory 
pathways can lead to improved tumor responses in preclinical models. Treatment will follow the same 
dose regimen as in Part 1 and consist of G100 at the MTD or maximum safe dose and local radiation 
therapy (Figure 2). For patients randomized to anti-PD-1 therapy (Figure 3), on Day 14, pembrolizumab 
treatment will be initiated at a standard dose of 200mg IV and then administered every 3 weeks IV for up 
to 2 years or until disease progression or unacceptable toxicity. For pembrolizumab, dose modification for 
adverse events attributed to the drug will follow the guidelines as recommended for the product and as 
outlined in the protocol. The main goal of Part 2, Patient Expansion With Or Without Pembrolizumab, is 
to gain safety information, immunologic data and early clinical experience with these regimens to allow 
planning for future studies with these agents. 
Part 2, Large Tumor group: In the second group, Part 2, Large Tumors, a higher dose of G100 may be 
examined. If the G100 dose consisting of 10 μg of the GLA component is determined to be the maximal 
safe dose and the DMC agrees, an optional treatment group for Large Tumor patients will be treated. 
Preclinical data indicates a dose response to G100 and this will be explored in these patients. In this 
group, up to 4 patients with injectable lymphoma mass(es) 4 cm or greater in total size (based on the sum 
of the measurements of the single greatest dimension of each the tumor(s) within the planned radiation 
field) will be enrolled and will receive G100 consisting of 20 μg of the GLA component per dose. This 
will allow greater distribution of the G100 within the large tumor mass(es) and the examination of safety 
and dose effect. Treatment would be administered on the same treatment schedule as in Part 1 except that 
the G100 dose would be 20 μg of the GLA component. The dose would be administered to a single large 
target lesion or distributed among 2 or more lesions within the radiation field. If the target lesion(s) 
regresses, a different lesion within the radiation field will be chosen for treatment, if available. If the 
tumor mass has not regressed at least 75% following 6 doses, treatment may continue for 3 additional 
weekly intratumoral doses (9 total). 
Part 3, G100 Expansion of 20 μg Dose group: Following completion of enrollment of the Part 2 Patient 
Expansion With or Without Pembrolizumab group (as determined by Sponsor), and when at least 3 
patients are enrolled in the Large Tumor Group with follow-up to at least Day 28, and contingent upon 
determining an acceptable safety profile following a review of G100 alone data, commencement of Part 3 
will begin. Up to 25 patients with follicular NHL will be enrolled to receive local radiation therapy and 
intratumoral G100 at 20 μg/dose following the same treatment schedule as in Part 1 and Part 2 where 
G100 was administered alone. Large tumors are not required, and patients with any injectable tumor mass 
regardless of size may participate. Data from another study in sarcoma and early data from this trial have 
not demonstrated any safety concerns with the 20-μg dose level, and to date, all reported events 
considered at least possibly related to the study agent have only been grade 1 or 2. Compared to baseline, 
post-treatment tumor biopsies have demonstrated significant increases in immune infiltrates within the 
tumor of some patients suggesting that this dose level should be explored further. The dose will be 
administered to a single target lesion or distributed among 2 or more lesions within the radiation field. If 


 
 
11 
 
the target lesion(s) regresses, a different lesion within the radiation field will be chosen for treatment, if 
available. If the tumor mass has not regressed completely following 6 doses, treatment may continue for 3 
additional weekly intratumoral doses (9 total). Data will be monitored continuously for safety, clinical 
effect, and exploratory biomarkers. 
Part 4, G100 at 20μg/lesion Into Single Or Multiple Tumor Masses Plus Pembrolizumab: Data from Parts 
1-3 of this study demonstrate that intratumoral G100 at the highest dose examined (20μg) has been well-
tolerated with only grade 1 or 2 related AEs and no DLTs reported with its use. This higher dose has been 
associated with increased numbers of infiltrating CD8 T cells into the tumor (TILs), and greater numbers 
of CD8 TILs have been statistically associated with the development of objective clinical responses. In 
Part 2, the combination of G100 (10 μg) and pembrolizumab was well-tolerated without new or 
unexpected toxicities, and the addition of pembrolizumab resulted in more clinical responses, deeper 
abscopal tumor shrinkage, and a higher number of tumor infiltrating CD8 T cells. Therefore Part 4 will 
examine the 20μg dose of G100 in 1 or more tumor lesions (up to 4 lesions) plus pembrolizumab in order 
to establish safety and examine clinical and biomarker responses in patients receiving increasing total 
systemic doses of G100. 
Part 4 will consist of a Dose Escalation group to evaluate and establish the safety of injecting 20μg of 
G100 into multiple lesions (up to 4 lesions) in combination with pembrolizumab and a Patient Expansion 
group to assess clinical responses with this regimen (Figure 4, Figure 5). At least 22 relapsed or refractory 
follicular NHL patients who received ≥3 prior systemic therapies will be treated in Part 4. Twenty-two 
efficacy evaluable patients as defined in the Statistical Section will be enrolled. 
During Dose Escalation, safety will be assessed using a 3+3 design where sequential cohorts of patients 
will be treated with intratumoral G100 at 20μg/lesion in 1, 2, 3, or 4 tumor lesions corresponding to 
systemic G100 exposure of 20, 40, 60 or 80μg G100. Once the 20 μg systemic dose level cohort (20 μg 
injected in 1 lesion) has been established to be reasonably safe, patients who do not qualify to enroll on 
the next dose level cohort due to insufficient numbers of potentially injectable lesions may enter Patient 
Expansion at that single lesion dose level. As each higher systemic dose level (40 μg, 60 μg, 80 μg) in 
multiple lesions is established to be well-tolerated, additional patients who otherwise qualify for the study 
but are unable to be treated on Dose Escalation due to insufficient numbers of injectable lesions will be 
allowed to enroll into the Patient Expansion portion of the study at the established safe dose levels. If 
complete enrollment of 22 efficacy evaluable patients is reached before Dose Escalation is complete, the 
Sponsor may choose to continue enrollment into just the Dose Escalation cohorts with up to 12 patients to 
fill all or some of the remaining cohort(s). 
Treatment will follow a similar dose regimen as in "Part 2, Patient Expansion With or Without 
Pembrolizumab" group, except that radiation therapy has been omitted. G100 will be injected 
intratumorally beginning on Day 0, a second dose will be administered 5-7 days later (Study Day 5-7) and 
then dosing will continue weekly for up to 4 additional doses (6 total) as long as the tumor remains of 
sufficient size for injection. At least 1 lesion will be targeted to receive each dose of G100. If the lesion 
regresses, another lesion will be chosen for treatment (as described in the protocol). If the patient is 
entered in a cohort where more than one lesion is injected (cohorts 2 to 4), as many easily accessible 
tumors will be targeted and treated as specified for the cohort. Imaging assisted injections are allowed but 
the feasibility and safety of these treatments must be discussed first and approved by the Medical 
Monitor. If the tumor mass has not regressed completely from baseline, dosing may continue for 3 
additional weekly intratumoral doses (9 total). On Day 14, pembrolizumab treatment will be initiated at a 
standard dose of 200 mg intravenously (IV) and then be administered every 3 weeks (q3W) IV for up to 2 
years or until disease progression or unacceptable toxicity. 
Part 4 Dose Escalation: In the Dose Escalation portion, safety will be assessed using a 3+3 design where 
12 to 24 patients will be assigned to sequential cohorts of escalating number of G100 injected lesions in 
combination with standard dose pembrolizumab (Figure 6). Four cohorts are planned:  


 
 
12 
 
• 
Cohort 1: G100 20 μg/lesion in 1 tumor  
• 
Cohort 2: G100 20 μg/lesion in 2 tumor lesions (40 μg total)  
• 
Cohort 3: G100 20 μg/lesion in 3 tumor lesions (60 μg total)  
• 
Cohort 4: G100 20 μg/lesion in 4 tumor lesions (80 μg total)  
 
Once a Cohort dose level is established to be safe, patients who do not meet the criteria of sufficient 
numbers of injectable tumors to enter the next dose Cohort will be enrolled in a Patient Expansion group 
at a systemic dose level that has already been established as safe. 
Initially, three patients will be scheduled to receive G100 at the first dose level. Dose escalation will be 
contingent upon acceptable safety data obtained during the first 28 days of observation following 
initiation of the regimen. A dose level cohort will be expanded from three to six if one of the first three 
patients experiences a dose-limiting toxicity (DLT). Further patient accrual into that dose level cohort (or 
higher) will be suspended as soon as ≥2 patients in that cohort experience DLT, or when otherwise 
deemed clinically appropriate by the investigator or Sponsor Medical Monitor. After the 28-day DLT 
observation period for the final patient in a cohort is complete, if less than one third of the patients 
enrolled in that cohort developed a DLT, advancement to the next dose-level cohort can begin. 
During Dose Escalation, patients will be considered evaluable for determination of safety and dose-level 
cohort advancement if they have received at least three complete G100 treatments and 1 dose of 
pembrolizumab and have completed Day 28 safety monitoring OR have experienced DLT. Patients who 
experienced DLT during the safety period will not be replaced. All other patients who have not received 
at least three G100 treatments and 1 dose of pembrolizumab and/or do not complete the Day 28 safety 
monitoring period for reasons other than treatment-related toxicity will be replaced. 
Following completion of the Dose Escalation portion of Part 4, the maximum tolerated dose or maximum 
safe dose (highest dose level examined in the study) will be defined as the highest dose reached in which 
less than one third of the patients in the cohort experienced a DLT. 
Potential Dose Modification During Dose Escalation 
G100 is a local therapy with systemic immune responses. Therefore, the safety profile may differ from 
that of systemically administered agents. In order to further investigate this, if 2 or more DLTs are 
observed in the initial cohort at 20 μg of G100, the Sponsor, in agreement with the independent DMC 
may choose to examine a new cohort of patients to better understand whether or not the DLTs associated 
with the injection of a single lesion might be abrogated by decreasing the dose and administering the 
lower single lesion dose of 10 μg into multiple lesions. Intratumoral G100 10μg in a single lesion in 
combination with pembrolizumab was established to be well-tolerated in Part 2 of this study. Thus, this 
new cohort would examine the safety of G100 10μg administered into 2 injectable lesions and would use 
the same 3+3 design described above. Based on a review of the safety profile of this new cohort and in 
agreement with the independent DMC, further dose escalation cohorts may be investigated using this 
lower dose of 10 μg/lesion and a similar dose escalation schema as described above where up to 4 lesions 
may be potentially treated. 
For pembrolizumab, dose modification for AEs attributed to the drug will follow the guidelines as 
recommended for the product and as outlined in the protocol. 
Part 4 Patient Expansion: Once the G100 20 μg systemic dose level has been established to have an 
acceptable safety profile, patients who otherwise qualify for the study but do not have the requisite 
number of injectable tumor masses to enroll on the dose cohort currently under evaluation may be 
enrolled into a Patient Expansion group. The Patient Expansion group will begin to evaluate clinical 
response (ORR) and biomarker changes of G100 plus pembrolizumab combination. An exploratory 
analysis will also be performed in those who are considered TLR4high. 


 
 
13 
 
The per lesion dose during Patient Expansion will be 20μg/lesion. The total administered dose of G100 
will depend on the safety established with each dose cohort. Determination of the number of potential 
injectable lesions will be made by the investigator in consultation with Medical Monitor. 
As the safety of each dose cohort is established, the number of allowed injectable lesions in Patient 
Expansion will be as follows: 
Established Safe Systemic Dose 
Treatment In Patient Expansion 
20 μg dose level 
20 μg in 1 lesion 
40 μg dose level 
20 μg in up to 2 lesions 
60 μg dose level 
20 μg in up to 3 lesions 
80 μg dose level 
20 μg in up to 4 lesions 
 
Patient enrollment will be monitored. It is planned that 22 efficacy evaluable patients will be treated with 
intratumoral G100 and IV pembrolizumab in Part 4 in order to determine if it’s unlikely to reach the 
target ORR of 40%. Patients who received G100 20μg/lesion during Dose Escalation in Part 4 may be 
included in the clinical response analysis.  
Part 5, G100 Plus Rituximab: Studies have demonstrated the potential for additive or synergistic effects 
of the combination of G100 and rituximab. G100 has been shown to increase the number of inflammatory 
and activated immune cells within the tumor microenvironment, including T cells, NK cells, macrophage 
and dendritic cells. Rituximab can potentially increase the loading/pulsing of dendritic cells with tumor 
antigen, leading to more effective antigen presentation of rare tumor antigens. Rituximab and other 
similar antibodies that bind to tumor cells and debris have been previously shown to facilitate the uptake 
and processing of tumor antigens by dendritic cells through opsonization/phagocytosis. In addition, a 
known mechanism of action of rituximab is through antibody dependent cellular cytotoxicity (ADCC). In 
preclinical work, the combination of G100 with rituximab demonstrated enhanced ADCC. Therefore, 
G100 in combination with rituximab can increase the amount of tumor antigen processed by dendritic 
cells potentially leading to greater T cell stimulation/activity; in addition, the combination could enhance 
tumor cytotoxicity by activating and increasing the number of ADCC effector cells. 
In this study, a Dose Escalation will be performed first followed by Patient Expansion (Figure 6, Figure 
7). During Dose Escalation 12-24 patients and during Patient Expansion 20 efficacy evaluable patients as 
defined in the Statistical Section of the protocol will be enrolled. Patient enrollment will be monitored. 
Patients who received G100 during Dose Escalation in Part 5 may be included in clinical response 
analysis. 
Data from the G142 study indicate that the G100 intratumoral dose of 20μg is relatively safe with only 
grade 1 or 2 related AEs reported and no DLTs and that this higher dose appears to induce greater 
numbers of infiltrating CD8 T cells into the tumor. Recent preclinical data indicate that G100 doses 
greater than 20 μg can lead to improved survival of animals in tumor models, further supporting that 
additional dose exploration may be warranted. Therefore, this arm will examine escalating doses of G100 
plus rituximab in a single tumor site utilizing a 3+3 design in order to establish safety and examine 
clinical and biomarker responses. Once the highest safe dose/systemic exposure is determined from the 
Dose Escalation portion of the study, all safety, efficacy and biomarker data will be reviewed by the 
Sponsor (in collaboration with the independent DMC) and either the highest dose determined to be safe or 
the most biologically active and safe dose (if different than the MTD) will be chosen for further 
investigation. A Patient Expansion group would then begin. Details of Dose Escalation and Patient 
Expansion are described below. 


 
 
14 
 
Part 5, Dose Escalation: In the Dose Escalation portion, safety and efficacy of G100 injected into a single 
tumor lesion without radiation will be assessed using a 3+3 design where patients will be assigned to 
sequential cohorts of escalating doses of intratumoral G100 in combination with standard dose induction 
therapy with rituximab (Figure 8 and Figure 9). Treatment will begin on Day 0 with rituximab 375 mg/m2 
IV and continue weekly for a total of 4 doses. If there are no DLTs or significant safety events after the 
first dose of rituximab, G100 will be injected intratumorally beginning on Day 1, and then dosing will 
continue weekly for 3 additional doses (4 total) on a visit schedule that coincides with rituximab 
treatments as long as the tumor remains of sufficient size for injection. One lesion will be targeted to 
receive each dose of G100. If the lesion regresses, another lesion will be chosen for treatment. Imaging 
assisted injections are allowed but the feasibility and safety of these treatments must be discussed first and 
approved by the Medical Monitor. If the tumor lesion has not regressed completely after the first 4 doses 
of G100, dosing may continue for 2 additional weekly intratumoral doses (6 total). Following restaging, 
the patient may be eligible for a second course of G100. 
Four cohorts of G100 plus rituximab are planned and will be enrolled sequentially: 
• 
Cohort 1: G100 20 μg in single tumor lesion 
• 
Cohort 2: G100 40 μg in a single tumor lesion 
• 
Cohort 3: G100 60 μg in a single tumor lesion 
• 
Cohort 4: G100 80 μg in a single tumor lesion 
Initially, 3 patients will be scheduled to receive G100 at the first dose level. Dose escalation will be 
contingent upon acceptable safety data obtained during the first 28 days of observation following 
initiation of the regimen. A dose level cohort will be expanded from 3 to 6 if one of the first 3 patients 
experiences a dose-limiting toxicity (DLT). Further patient accrual into that dose level cohort (or higher) 
will be suspended as soon as ≥2 patients in that cohort experience DLT, or when otherwise deemed 
clinically appropriate by the investigator or Sponsor Medical Monitor. After the 28-day DLT observation 
period for the final patient in a cohort is complete, if less than one third of the patients enrolled in that 
cohort developed a DLT, advancement to the next dose-level cohort can begin.  
During Dose Escalation, patients will be considered evaluable for determination of safety and dose-level 
cohort advancement if they have received at least 3 complete G100 treatments and 3 doses of rituximab 
and have completed Day 28 safety monitoring OR have experienced DLT. Patients who experienced DLT 
during the safety period will not be replaced. All other patients who have not received at least 3 G100 
treatments and 3 doses of rituximab and/or do not complete the Day 28 safety monitoring period for 
reasons other than treatment-related toxicity will be replaced. Based on ongoing evaluation of study data, 
the Sponsor may decide to complete fewer than the planned 4 dose cohorts and proceed directly to the 
Patient Expansion portion of the study.  
Following completion of the dose escalation stage of the trial, the MTD will be defined as the highest 
dose reached in which less than one third of the patients in the cohort experienced a DLT. If no DLTs are 
experienced in the first 3 patients enrolled at highest dose of 80μg, the 80μg dose per lesion will be 
determined to be the “maximum safe dose” examined in this study and dose escalation will be considered 
complete. An additional 3 patients may then be enrolled for a total of 6 patients at that dose level and 
safety stopping rules will be followed. If after the Sponsor and DMC review all safety data it is 
determined that there are no safety issues requiring the separation of the first dose of rituximab and G100, 
the regimen may be modified to administer both on Day 0 during Patient Expansion.  
Part 5, Patient Expansion: Once the MTD/maximum safe dose has been established, all safety, clinical 
and biomarker data will be reviewed and a recommended dose for further exploration will be made. The 
Patient Expansion would then begin and would enroll patients to receive G100 IT at the recommended 
dose into a single tumor mass in combination with rituximab. ORR in patients enrolled on Part 5 Patient 


 
 
15 
 
Expansion will be analyzed. An exploratory analysis will also be performed in those who are considered 
TLR4high.  
Patients will be enrolled with the intent of obtaining data from at least 20 efficacy evaluable patients. 
Patients who received G100 at the recommended dose during Dose Escalation in Part 5 may be included 
in clinical response analysis.  
G100 is a local therapy with systemic immune responses. Therefore, the safety profile may differ from 
that of systemically administered agents. In order to further investigate this, after establishment of an 
MTD, the Sponsor in agreement with the independent DMC may choose to examine one additional cohort 
of patients to better understand whether or not the DLTs associated with the injection of a single lesion 
might be abrogated by splitting the dose and administering into two separate lesions. The data from this 
cohort may help determine if the tolerability of G100 was limited due to the injection of a single tumor 
mass or to the total systemic exposure. In this additional cohort, 3-6 patients would be treated at the total 
systemic dose level associated with DLTs but divided and distributed into two tumor masses instead of 
one. For example, if the MTD in a single tumor mass were determined to be 40μg due to DLTs occurring 
at 60μg/lesion, the dose of this cohort would be 30μg/lesion injected separately into 2 tumor masses. In 
the event that the 20μg dose level (Cohort 1) experiences DLTs, a cohort of 10μg/lesion administered into 
2 lesions may be explored. The information from this additional cohort could help the design of future 
studies. The decision whether or not to open this cohort would be made when the Dose Escalation data is 
reviewed following the determination of the MTD. No additional treatment cohorts are planned beyond 
this one group. Following this evaluation, patients would be enrolled into the Patient Expansion group 
and would receive G100 injected into a single lesion at the recommended dose. 
For rituximab, dose modification for AEs attributed to the drug will follow the guidelines as 
recommended for the product and as outlined in the protocol.  
For All Parts (1 to 5)  
Retreatment / Second Course: Following the G100 course of treatment, if a patient is determined to have 
achieved SD or better or has PD that does not require immediate therapy, has an additional site of disease 
outside of the prior radiation field (Parts 1, 2, or 3) that is amenable to injection, and has not had 
significant treatment-emergent AEs (including events that would be considered a DLT) as determined by 
the investigator and the Sponsor, the patient may be eligible to receive a second course of G100 (Figure 
8). For patients enrolled on Parts 4 or 5, the same previously injected tumor site(s) may be targeted or a 
replacement site(s) may be chosen.  
Six weeks or more after completion of the first course of G100 treatment, the second course would begin 
and consist of G100 alone (no radiation and no additional rituximab for patients enrolled on Part 5) at the 
same dose received during the first course of therapy. Treatment would be administered on a similar 
weekly schedule as the first course except without radiation therapy (or rituximab therapy). G100 will be 
injected intratumorally beginning on Day 0, a second dose will be administered 5 to 7 days later and then 
dosing will continue weekly for up to 4 additional doses (6 total) as long as the tumor remains of 
sufficient size for injection. For Parts 1 to 3, a single lesion will be targeted to receive each dose of G100. 
If the lesion regresses, another lesion will be chosen for treatment. If the tumor mass has not regressed 
completely, dosing may continue for 3 additional weekly intratumoral doses (9 total). If the patient had 
been receiving pembrolizumab as part of their therapy, the anti-PD-1 antibody would continue as 
scheduled during the second course. For Part 4, dosing may continue into multiple lesions as selected for 
their initial course; for Part 5, the number of G100 doses is limited to 6 treatments of a single lesion.  
Dose regimen interruption in a single patient may be made by the clinical investigator if it is deemed in 
the best interest of patient safety. The study Medical Monitor should be consulted prior to or immediately 
upon the decision to interrupt therapy. Safety will be reviewed on a regular basis by an independent DMC 
and the Sponsor. These reviews may lead to modification or stopping of the treatment program.  


 
 
16 
 
Tumor imaging will be performed during the screening visit (baseline) and then approximately every 8 
weeks thereafter for the first year, every 3 to 4 months for the second year, and then at least every 6 
months for the third and subsequent years until disease progression as defined by the irRC. Pre- and post-
treatment tumor biopsies (e.g., core biopsies) will be obtained for histologic review and exploratory 
immune analyses, including cell phenotype, tumor expression of TLR4, and genomic analyses of T cells. 
Post-treatment biopsies will be performed in patients with accessible tumors within 3 weeks after the last 
planned G100 injection. Peripheral blood will be drawn for immune assays and biomarker tests at time 
points listed in the Study Procedures.  
 
Figure 1:    Part 2, Patient Expansion With Or Without Pembrolizumab 
 
 
Figure 2:    Treatment Schema for Part 1, Part 2 Patient Expansion G100 Alone, Part 2 Large 
Tumor Group, and Part 3, G100 Expansion of 20 μg Dose Group 
 
 
Figure 3:    Treatment Schema for Part 2, Sequential G100 and Pembrolizumab 
 


 
 
17 
 
 
Figure 4:    Dose Escalation And Expansion Of Part 4: G100 at 20μg/dose Into Single Or 
Multiple Tumor Lesions Plus Pembrolizumab Group 
 
 
Figure 5:    Part 4, G100 at 20μg/lesion Into Single Or Multiple Tumor Lesions Plus 
Pembrolizumab Group 
 
 
 


18 
 
 
Figure 6:    Part 5, G100 Plus Rituximab 
 
 
Figure 7:    Part 5, G100 Plus Rituximab 
 
 
Figure 8:    For Parts 1 to 5, Optional Retreatment / Second Course 
 


 
 
19 
 
3.2 
Duration of Patient Participation 
Patients will continue with clinical assessments every 8 weeks and will have imaging assessments every 8 
weeks for the first year, every 3 to 4 months for the second year, and then at least every 6 months for the 
third and subsequent years until disease progression as defined by the irRC. If the patient experiences PD, 
the expected duration of a patient’s participation and follow-up in the trial is approximately 1 year (or 
longer if the patient agrees) to determine clinical status and time to next treatment. 
3.3 
Schedule of Procedures  
The detailed schedule of procedures are specified in Table 1, Table 2, Table 3, Table 4, Table 5, and 
Table 6 below. 
 
 


20 
 
 
Table 1   Schedule of Events: Part 1, Dose Escalation and Part 2, Patient Expansion (G100 alone) and Large Tumor Groups 
 


 
 
21 
 
 
 
 


22 
 
 
Table 2   Schedule of Events: Part 2, Sequential Administration of G100 and anti-PD-1 
 


 
 
23 
 
 
 
 


24 
 
 
Table 3   Schedule of Events: Part 3, G100 Expansion of 20 μg Dose Group 
 
 


 
 
25 
 
 
 


26 
 
 
Table 4   Schedule of Events: Part 4, G100 at 20μg/lesion Into Single Or Multiple Tumor Masses Plus Pembrolizumab 
 
 
 


 
 
27 
 
 


28 
 
 
Table 5   Schedule of Events: Part 5, G100 Plus Rituximab 
 
 


 
 
29 
 
 
 
 


 
 
30 
 
 
Table 6   Schedule of Events: Optional Retreatment / Second Course 
 
 


 
 
31 
 


32 
 
  
3.4 
Sample Size Consideration 
In Part 1, Part 2, and Part 3, up to 65 evaluable patients will be enrolled. In Part 1, Dose Escalation, a total 
of two pre-defined dose levels will be studied. A conventional “3+3” design will be used during Part 1 for 
dose assessment and escalation. The first cohort of 3 patients will be enrolled at the lowest dose level. If 
0/3 patients experience DLT, the next cohort will be enrolled into the next higher dose. If 1/3 patients 
experience DLT, the current dose level will be expanded to a total of 6 patients. If 1/6 patients experience 
DLT, dose escalation may occur. If 2 or more patients in dose cohort experience DLT at any time, the 
MTD has been exceeded. The MTD or maximum safe dose (if at the highest dose level) is defined as the 
highest dose in which less than one third of patients in the cohort experienced a DLT. 
Once the MTD or maximum safe dose examined in the study has been determined, Part 2 will begin. In 
the optional Large Tumor group, up to 4 patients will be treated and safety will be examined. 
In Part 2, Patient Expansion, up to 24 patients (12 per treatment group) will be randomly assigned to 
receive treatment with either G100 alone or the sequential administration of G100 and pembrolizumab. 
The dose of G100 will be the MTD / maximum safe dose determined in Part 1. This portion of the study 
will provide additional safety, immunogenicity and early efficacy data of G100 at the MTD / maximum 
safe dose and provide initial data on the sequential administration of G100 and pembrolizumab. This 
analysis is designed to be exploratory but will provide important data to guide further development. While 
the sample size is not based on formal power calculations, it is expected to provide adequate preliminary 
data to inform subsequent trials and to reject an indication should no clinical benefit occur. For example, 
if the true ORR is 20%, we will conclude futility with a 6.9% error rate if 0 response is observed in 12 
patients. In that case, the Sponsor would terminate that study arm for development. 
In Part 3, G100 Expansion of 20 μg Dose Group, up to 25 patients will be enrolled and treated with 
intratumoral G100 at 20 μg/dose following radiation therapy. The purpose of this group would be to 
explore the safety and potential clinical responses at the higher dose level. The number of patients was 
chosen to provide a similar cohort treated with G100 alone in Parts 1 and 2 for descriptive comparison.  
In Part 4, G100 Plus Pembrolizumab, at least 22 evaluable patients will be enrolled and treated as part of 
a Dose Escalation group or a Patient Expansion group with intratumoral G100 in combination with 
pembrolizumab. The purpose of this treatment regimen will be to explore the safety and preliminary 
clinical efficacy and biomarker changes of patients treated with G100 at a dose of 20 μg/lesion injected in 
single or multiple lesions. The administered dose of G100 will depend on the number of potentially 
injectable lesions and whether the MTD has been established during Dose Escalation. One or more 
lesions will be targeted for injection and each lesion would receive 20μg of G100 intratumorally (or 10 μg 
G100 if 20 μg/lesion in a single lesion is not tolerated) as long as the total number of treated tumor lesions 
and total systemic dose does not exceed the MTD (if established) or 80 μg total dose (20 μg injected in 4 
lesions). This analysis is designed to be exploratory and will evaluate safety, clinical outcome and 
exploratory biomarkers to guide further clinical development. Clinical efficacy including ORR and DOR 
will be evaluated in relapsed or refractory FL patients who received ≥3 prior systemic therapies. 
For this analysis, 22 efficacy evaluable patients will be required. Efficacy evaluable patients are patients 
who received at least 3 doses of G100 at 20 μg/lesion and at least 1 dose of pembrolizumab, had at least 
one post baseline tumor assessment, and had no major protocol deviations that impact the efficacy of the 
study treatment or the assessment of response. Patients who received G100 20μg/lesion during Dose 
Escalation in Part 4 may be included in clinical response analysis. With a target ORR of 40%, if ≤5 
responders are observed among 22 evaluable patients, we will conclude futility with 7.2% error rate. The 
Sponsor will use this analysis to decide whether to continue further development of this regimen. Early 
acceptance of treatment at the end of the 22 evaluable patients is not permitted. If the true ORR for this 


 
 
33 
 
group is 20% and 20% ORR is considered not clinically meaningful, the probability of observing ≤5/22 
responders and stopping the study is 73.3%. 
In Part 5, G100 Plus rituximab, after Dose Escalation has been completed, patients will be treated with 
intratumoral G100 at the recommended dose level in combination with rituximab. The purpose of this 
Patient Expansion group will be to explore the safety and clinical outcome of patients treated at a 
biologically active and safe G100 dose level administered into single tumor lesion in combination with 
rituximab. This analysis is designed to be exploratory and will evaluate safety, clinical outcome and 
exploratory biomarkers. 
An exploratory analysis will be performed on 20 efficacy evaluable relapsed or refractory FL patients and 
will include analyses of the frequency and duration of CRs. Efficacy evaluable patients are patients who 
received at least 3 injections of G100 at the recommended dose and 3 doses of rituximab, had at least one 
post baseline tumor assessment, and had no major protocol deviations that impact the efficacy of the 
study treatment or the assessment of response. Five or more CRs in 20 patients treated with G100 plus 
rituximab will signal an improvement of CR rate over 10%. For reference, the probability of observing ≤4 
CRs in 20 patients is 5.1% if the true CR rate is 40% (the targeted CR rate). Patients who received G100 
at the recommended dose during Dose Escalation in Part 5 may be included in clinical response analysis. 
With 20 efficacy evaluable patients, and a historical CR rate of 10%, assuming a true CR rate of 32% in 
the G100 plus rituximab, this subgroup analysis has 82% power to detect a signal of an improvement in 
CR from 10% at a 1-sided alpha of 0.05. 
4 
Analysis Populations 
4.1 
Enrolled Population 
The enrolled population includes all patients who have passed screening and are enrolled into the study. 
4.2 
Safety Population 
The Safety Population includes all enrolled patients who received at least one injection of G100 after 
standard local radiation.  Safety data analyses will be conducted on all patients in the Safety Population 
according to the treatment received. 
4.3 
Efficacy Evaluable Population 
The Efficacy Evaluable population includes all enrolled patients without major protocol deviations, who 
have received at least one injection of G100, and have had baseline and at least one post-baseline disease 
assessment.  
The Efficacy Evaluable population will be used for the tumor response analysis based on irRC, including 
overall tumor response and time to disease progression (TTP). 
5 
Statistical Analysis 
5.1 
Data Summaries and Conventions 
All data collected on case report forms will be provided in listings, except data collected only for 
confirmation of study entry criteria and for study administrative purposes. If any enrolled patient is found 
to not have valid documented informed consent, that patient’s data will be excluded from the report, 
except as necessary to document the error.  


 
 
34 
 
Except where specified all continuous variables will be summarized with descriptive statistics (the 
number of non-missing values, mean, standard deviation, median, minimum and maximum) and all 
categorical variables will be summarized with frequency counts and percentages, by part, treatment, and 
overall. 
5.2 
Missing Data 
For adverse events and concomitant medication, the imputation rule for start date and end date are defined 
in relevant sections (i.e, AE and subsequent therapies sections). For other analysis when necessary (e.g., 
OS analysis), dates without a specific day of the month (i.e., JAN2010) will be assigned the 15th day of 
the month and dates without a specific day or month (i.e., 2010) will be assigned the 15th day of June. 
5.3 
Patient Disposition 
Patient disposition and the incidence of treatment discontinuation and study discontinuation (and the 
reasons for discontinuation) will be tabulated for all enrolled patients by part, treatment, and overall. The 
number and percentages of patients in each category will be reported. Patient disposition listing will be 
provided. 
5.4 
Protocol Deviations 
The clinical study team will define CSR reportable protocol deviations and major protocol deviations that 
will exclude a patient from Efficacy Evaluable population. The clinical study team will review all 
potential protocol deviations at regular time interval during study conduct and prior to database lock.  
Protocol deviations will be categorized by deviation type. CSR reportable protocol deviation and major 
protocol deviations that will exclude a patient from Efficacy Evaluable population will be flagged. The 
patient incidence of CSR reportable protocol deviations will be summarized by deviation type based on 
Safety population.      
5.5 
Demographics and Baseline Information 
5.5.1 Demographics and Baseline Characteristics 
Patient demographic and baseline characteristics include Age, Sex, Childbearing Potential for Female, 
Race, Ethnicity, Height, Weight, and ECOG Performance Status will be summarized by part, treatment, 
and overall, for Safety and Efficacy Evaluable population. A separate summary by treatment will be 
provided. 
5.5.2 Cancer History 
Cancer history will be summarized by part, treatment, and overall, for Safety and Efficacy Evaluable 
population. The summary will include the following: 
• 
Type of Lymphoma 
• 
Histologic Type by WHO Classification at Diagnosis 
• 
Did the WHO Classification Change? 
• 
Histologic Type at Study Entry by WHO Classification 
• 
Ann Arbor Stage at Diagnosis 
• 
Did the Stage Change? 
• 
Ann Arbor Stage at Study Entry 


 
 
35 
 
• 
Number of Nodal Sites 
• 
Number of Index Lesions at Baseline 
• 
Disease Status 
• 
Tumor Growth / Progressive Disease at Study Entry 
5.5.3  Medical and Surgical History 
Medical and surgical history will be listed based on Safety population. 
5.5.4 Prior Anti-Cancer Therapy 
Prior anti-cancer therapy will be summarized by part, treatment, and overall, for Safety and Efficacy 
Evaluable population. A separate summary by treatment will be provided. The summary will include the 
following: 
• 
Any Prior Therapy (Radiotherapy, Immunotherapy, Systemic Therapy, Other Therapy) 
• 
Type of Therapy 
• 
Intent of Treatment 
• 
Number of Any Prior Therapy  
• 
Number of Patients with Stem Cell/Bone Marrow Transplant 
• 
Prior Systemic Therapy Regimen/Agents 
• 
Number of Prior Systemic Therapy 
• 
Best Response 
• 
Reason for Discontinuation from Prior Systemic Therapy Regimen 
In addition, demographic and baseline characteristics, cancer history and anti-cancer therapy data will be 
presented in listings. 
5.6 
Efficacy Evaluation 
Unless otherwise specified, efficacy analyses will be performed by part, treatment, and overall. A separate 
summary by treatment will be provided. Efficacy evaluation will be provided for the Efficacy Evaluable 
population. Efficacy evaluation based on the Safety population will be provided as a supportive analysis. 
5.6.1 Tumor Growth Rate   
At the baseline tumor assessment, the sum of the products of the two largest perpendicular diameters 
(SPD) of all index lesions is calculated. At each subsequent tumor assessment, the SPD of the index 
lesions and, new measurable lesions if any, are added to provide the total tumor burden: 
Tumor Burden = SPD index lesions + SPD new measurable lesions 
Post treatment initiation, spider plot (% change and change from baseline in SPD of index and new 
measurable lesions) for all visits will be presented for all lesion sites and abscopal sites. Waterfall plot 
(best % change and best change from baseline) will be presented for all lesion sites and abscopal sites. 
Best percentage change in sum of tumor bi-dimensional products for abscopal lesions will be summarized 
by part, treatment, and overall. 


 
 
36 
 
5.6.2 Overall Response Rate (ORR) and Clinical Benefit Rate (CBR)  
Overall response rate (ORR) using irRC will be defined as the number and percent of patients with best 
overall response of irCR or irPR. ORR with two-sided 95% Clopper-Pearson exact CI will be provided. 
Both unconfirmed and confirmed response using irRC criteria will be reported. The overall response 
using irRC is derived from time-point response assessments as follows: 
• 
Immune-related complete response (irCR), complete disappearance of all lesions (whether 
measurable or not, and no new lesions), confirmed by a repeat, consecutive assessment no less 
than 4 weeks from first documentation 
• 
Immune-related partial response (irPR), decrease in tumor burden >= 50% relative to baseline, 
confirmed by a consecutive assessment at least 4 weeks from first documentation 
• 
Immune-related stable disease (irSD), not meeting criteria for irCR or irPR, in absence of irPD 
• 
Immune-related progressive disease (irPD), increase in tumor burden >= 25% relative to nadir, 
confirmed by a repeat, consecutive assessment no less than 4 weeks from first documentation 
 
In confirmed ORR summary, patients with best response of unconfirmed irPR will be summarized as 
irSD. 
Overall response rate (ORR) using IWG will be defined as the number and percent of patients with best 
overall response of CR or PR.  
Clinical benefit rate (CBR) will be defined as the number and percent of patients with best overall 
response of complete response, partial response or stable disease. CBR using both irRC and IWG will be 
reported.  
In addition, abscopal tumor reduction will be summarized. 
Lesion assessment (lesion type, organ site, evaluation method, diameter, and lesion status), as well as 
patient overall response based on both irRC and IWG criteria for lymphomas at each visit and the best 
overall response, will be presented in a data listing. 
Overall tumor response using irRC criteria for all tumor lesions, irradiated sites, non-irradiated sites and 
abscopal sites, and overall tumor response using IWG criteria for all tumor lesions will be summarized. 
Overall tumor response for the following subgroups will also be provided: 
• 
Relapsed/Refractory Patients 
• 
Treatment Native Patients 
• 
Patients with MR (minor response) 
• 
Patients with MR (minor response) and Decrease in Abscopal Lesions 
• 
Patients with PD at Study Entry 
• 
Patients with Guided Injection of G100 
• 
Patients with Not Guided Injection of G100 
MR (minor response) is defined as more than 25% decrease in tumor burden but less than the 50% that 
would make it a PR.  


 
 
37 
 
5.6.3 Duration of Response (DOR) and Duration of Clinical Benefit 
Duration of response (DOR) is defined as the time interval between the date of the earliest qualifying 
confirmed/unconfirmed response using irRC and the date of disease progression (PD) or death for any 
cause, whichever occurs first. DOR in months is calculated as: (date of PD or death – date of first 
confirmed/unconfirmed irCR/CR or irPR/PR + 1)/30.4375. DOR analysis will include only patients with 
confirmed/unconfirmed response of irCR/irPR using irRC.   
For patients who are alive without documentation of disease progression following the qualifying 
response, duration of response will be censored following the same rule defined for PFS. 
Duration of clinical benefit is defined as the time interval between the date of the earliest qualifying 
confirmed/unconfirmed best response using irRC and the date of progression disease (PD) or death for 
any cause, whichever occurs first. Duration of clinical benefit in months is calculated as: (date of PD or 
death – date of first confirmed/unconfirmed irCR/irPR or irSD + 1)/30.4375. Duration of clinical benefit 
will include only patients with confirmed/unconfirmed response of irCR/irPR or irSD using irRC. 
For patients who are alive without documentation of disease progression following the qualifying 
response, duration of clinical benefit will be censored following the same rule defined for PFS. 
Median DOR and duration of clinical benefit with the corresponding two-sided 95% CI will be estimated 
using the Kaplan-Meier method in each treatment group. The Kaplan-Meier curves will be presented. 
DOR and duration of clinical benefit data will be presented in listing. 
5.6.4 Progression-free Survival (PFS) 
PFS is defined as time from date of first study treatment to date of first disease progression by irRC 
criteria, symptomatic deterioration, or death due to any cause, whichever occurs first. Progression-free 
survival (PFS) in months is calculated as: (date of first progression, symptomatic deterioration, or death 
(any reason) – date of first dose +1)/30.4375. The irRC modification requires a PD confirmation no less 
than 4 weeks from first documentation of progressive Disease (PD); once confirmed, the date of 
progression is defined as date of the first PD. In case of unconfirmed PD followed by symptomatic 
deterioration, the date of unconfirmed PD will be the date of progression. Patients without progression, 
symptomatic deterioration, or death are censored at the date of the last tumor assessment. If a patient 
begins a new anti-cancer therapy or has radiotherapy or surgery at a lesion site prior to confirmed 
progression (or death), the patient will be censored at the last assessment where the patient is documented 
as progression free prior to the intervention. Patients with two or more missing response assessments 
prior to a visit with progression (or death) will be censored at the last visit where the patient is 
documented to be progression free. Patients without disease assessment post-baseline will be censored at 
the first dose date. Table 7 below provides further details on how date of PFS event and date of PFS 
censoring are assigned.  
Table 7   Progression-Free Survival  
Situation 
Date of Progression or Censoring 
Outcome 
No baseline tumor assessments 
Date of first dose 
Censored 


 
 
38 
 
Situation 
Date of Progression or Censoring 
Outcome 
Progression documented between 
scheduled visits  
 
Date of last radiological assessment of measured 
lesions (if progression is based on increase in sum of 
measured lesions) 
Progressed 
Symptomatic deterioration before first 
PD assessment 
Date of Symptomatic deterioration 
Progressed 
Symptomatic deterioration between 
adequate assessment visits 
Date of Symptomatic deterioration 
Progressed 
Symptomatic deterioration after two 
or more missed visit 
Date of last tumor assessment 
Censored 
Death before first scheduled 
assessment 
Date of death 
Progressed 
Death between adequately scheduled 
assessment visits 
Date of death 
Progressed 
Death or progression after two or 
more missed visit  
Date of last tumor assessment 
Censored  
New anti-cancer therapy or 
radiotherapy or surgery at a lesion site 
prior to confirmed progression (or 
death) 
Date of last tumor assessment where the patient was 
documented as progression free prior to the intervention 
Censored 
No progression or death 
Date of last tumor assessment 
Censored  
 
Summary of PFS including median, 95% CI, 25th and 75th percentiles, range, PFS rate at 3-month, 6-
month, 9-month and 12-month will be estimated using the Kaplan-Meier method. The corresponding 95% 
CI for median will be calculated using the Brookmeyer and Crowley method. The Kaplan-Meier curve 
and swimmer plot will be displayed. 
PFS analysis for the following subgroups will be presented: 
• 
Relapsed/Refractory Patients 
• 
Treatment Naïve Patients 
• 
MR Patients 
• 
MR and Abscopal Decrease Patients 
PFS data will be presented in a data listing. 
5.6.5 Overall Survival (OS) 
Overall Survival (OS) is defined as the time from date of first study treatment to death due to any cause. 
Overall survival in months is calculated as: (date of death – date of first dose) +1)/30.4375. Patients who 
are alive at the end of study will be censored at the last date the patient is known to be alive or data 
analysis cutoff date, whichever is earlier. 
Summary of OS including median, 95% CI, 25th and 75th percentiles, and range will be estimated using 
the Kaplan-Meier method. The corresponding 95% CI for median will be calculated using the 
Brookmeyer and Crowley method. The Kaplan-Meier survival curve will be displayed.  
OS data will be presented in a data listing. 


 
 
39 
 
5.6.6 Time to Response for CR or PR Patients 
Time to Response for CR/PR Patients is defined as time from date of first study treatment to the date of 
CR or PR response first documented. Time to response in months is calculated as: (date of first CR or PR 
– date of first dose +1)/30.4375. 
Summary of Time to Response including median, 95% CI, 25th and 75th percentiles, and range will be 
estimated using Kaplan-Meier method. The Kaplan-Meier survival curve and swimmer plot will be 
displayed. 
5.6.7 Time to Next Treatment and Duration of All Subsequent Therapies 
Time to next treatment is defined as the time from the date of first study treatment to the start date of 
subsequent therapy after PD. Patients who did not receive subsequent therapy after PD are censored at the 
date of last contact or death. 
Duration of all subsequent therapies after PD in week is calculated as (date of subsequent therapies last 
administered – date of subsequent therapies first administered + 1)/7. If one patient has multiple 
consecutive systemic therapies, the duration will be summarized per patient. If the start and end dates of 
multiple systemic therapies overlap, then duration = (date of last systemic therapy last administered – date 
of first systemic therapy first administered + 1)/7. 
Summary of time to next treatment including median, 95% CI, 25th and 75th percentiles, and range will 
be estimated using the Kaplan-Meier method. The corresponding 95% CI for median will be calculated 
using the Brookmeyer and Crowley method. Descriptive statistics using PROC UNIVARIATE of time to 
next treatment and duration of all subsequent therapies including only patients with subsequent anti-
cancer therapies will also be reported. 
Partial Dates for Subsequent Therapy 
Incomplete subsequent therapy dates will be imputed. Imputed dates will be used to determine Study Day. 
Partial start dates will be imputed as follows:  
1. Only the year is reported, with month and day missing: If the subject’s last study treatment and 
subsequent therapy are in the same year, then the date of the last dose of study treatment will be 
used to impute the start date of the subsequent therapy.  
2. The month and year are reported, with day missing: The first day of the month will be used to 
impute the start of the subsequent therapy. 
Partial end dates will be imputed for non-ongoing therapies as follows:  
1. Only the year is reported, with month and day missing: the earlier of December 31 or analysis 
cut-off date will be used to impute the end of the therapy.  
2. The month and year are reported, with day missing: The last day of the month will be used to 
impute the end of the therapy. 
End dates for ongoing therapies will be imputed to analysis cut-off date. 


 
 
40 
 
If an imputation results in an imputed start date after the stop date, set the date with more imputation to 
the one with less imputation. 
Subsequent anti-cancer therapies will be summarized by part, treatment and will be presented in a listing. 
• 
Any subsequent anti-cancer therapy 
• 
Type of therapy 
• 
Subsequent systemic therapy regimen/agents 
• 
Best response 
• 
Reason for discontinuation 
Subsequent procedures and surgeries will be presented in a separate listing. 
5.6.8 Immune Response and Biomarker Analyses 
All patients who have received at least one injection of G100 and have available immunohistochemistry 
(IHC), nanostring, or T cell receptor (TCR) data will be included in the biomarker analysis.  
Anti-tumor cellular immunity (CD4, CD8 T cell, CD20, CD68, NKp46, FoxP3, CD8/CD4 ratio, 
CD8/FoxP3 ratio) by immunohistochemistry (IHC) will be explored. Post/pre treatment ratio will be 
summarized by treatment, and by subgroups of interest (irPR vs non-responder, pre-TLR4>=50% vs 
<50%, treatment naïve, relapsed/refractory patients, prior line of therapy 0-2 vs >=3). Post and pre 
treatment values will be compared using signed-rank test to identify significant changes post treatment. 
Association between clinical endpoints (irPR, irPR+MR, irPR+MR+SD, abscopal best % change better 
than -25%) and cellular immunity by immunohistochemistry will be explored using a logistic regression 
model for all dosed patients, and by treatment.  Association between response (irPR) and pre-treatment 
TLR4 using different cutoffs will be presented in 2x2 tables and the proportion of response will be 
compared between TLR4 high and TLR4 low patients using Barnard’s unconditional exact test. 
Comparison of post treatment change in immunohistochemistry will be explored between G100 
monotherapy 10 µg and G100 monotherapy 20 µg patients.   
Association between clinical response and nanostring genes (NK, M1 Markers, M2 Markers, and other 
genes of interest) using PBMC and tumor samples will be explored using a logistic regression model that 
includes log2 transformed nanostring data. Post/pre mean expression ratio (as antilogarithm of the means 
of (log2 post – log2 pre)) for responder and non-responder, odds ratio, and nominal and adjusted p-values 
will be presented. Adjusted p-value is adjusted using False Discovery Rate (FDR) method. Ten most 
upregulated and ten most downregulated immune-related genes will be presented, with post/pre mean 
expression ratio and p-value from signed-rank test. Further, ten most highly differentially induced 
immune-related genes in clinical responders versus non-responders will be explored. 
T cell receptor (TCR) clones not detectable at baseline in tumor/PBMC but become detectable or 
increased post-treatment in tumor/PBMC will be explored.     
5.7 
Safety Evaluation 
Safety evaluation will be based on safety population.  


 
 
41 
 
5.7.1 Treatment Exposure 
Local radiation therapy received will be summarized by frequency. Number of radiation doses (for Part 1, 
2, and 3), number of G100 doses in first course, number of G100 doses modification in first course, 
number of G100 doses in second course, number of G100 doses modification in second course,  
cumulative pembrolizumab dose (mg), treatment duration of pembrolizumab (weeks), and number of 
pembrolizumab infusion interruptions will be reported.  
Treatment duration of pembrolizumab (weeks) will be calculated as (date of last pembrolizumab dose 
administered – date of first pembrolizumab dose administered + 21) / 7. Pembrolizumab treatment 
interruption, if any, will be removed from treatment duration of pembrolizumab. 
In addition, duration from first course to second course in month, calculated as (first dose date of G100 in 
second course – last dose date of G100 in first course + 1)/30.4375, will be reported. Treatment site for 
irradiated lesions, type of imaging used for G100 injection will be reported. 
G100, pembrolizumab administration, and low dose radiation treatment (Part 1, 2, and 3) will be 
displayed in listings. 
5.7.2 Adverse Events 
A Treatment-Emergent Adverse Event (TEAE) is an AE with onset date on or after the initiation of study 
treatment, or a pre-existing condition that worsens after initiation of study treatment (i.e., increase in 
severity), up to 30 days after the date of last dose of study treatment. AEs that occur more than 30 days 
after last dose, if deemed as related to study treatment, will also be included as TEAEs.  
If the AE start date is partial or missing, then: 
- 
If AE start date is completely missing, then the AE is considered treatment-emergent. 
- 
If both AE start month and day are missing, if the year is in the same year as the first study 
treatment, then the AE is considered treatment-emergent. Otherwise, 01Jan will be used to impute 
month and day. If the imputed AE start day is more than 30 days after the date of last study 
treatment, then the AE will not be a TEAE. 
- 
If AE start day is missing and AE start year and month are the same or after the first dose year 
and month, then the AE is considered as treatment-emergent, unless the imputed AE start day   
using day 01 is more than 30 days after the date of last study drug. 
The summaries will be based on TEAEs by part, treatment, and overall. A separate summary by treatment 
will be provided. All adverse events will be included in patient listings. 
The incidence of a TEAE will be defined as the number and percent of patients experiencing an event. 
TEAEs will be summarized by system organ class, preferred term, and further by severity. Adverse events 
will be coded using Medical Dictionary for Regulatory Activities (MedDRA 20.1 or newer). A patient 
with more than one different adverse event in a system organ class (SOC) will be counted only once in 
the total number of patients experiencing adverse events in that particular SOC. A patient having 
experienced the same event (AE preferred term) more than once during the study will be counted only 
once under the worst grade or relationship.  
The following adverse events summaries will be reported: 


 
 
42 
 
- 
Overall summary of TEAEs, including TEAEs, treated-related TEAEs, serious TEAEs, 
treatment-related serious TEAEs, TEAEs of grade 3 and above, treatment-related TEAEs of grade 
3 and above, TEAEs leading to treatment interruption, TEAEs leading to treatment 
discontinuation, TEAEs leaing to treatment interruption or discontinuation, TEAEs leading to 
death reported during the study, dose limiting toxicities (DLTs) 
- 
Incidence of TEAEs by system organ class, preferred term, and severity 
- 
Incidence of TEAEs related to study drug by system organ class, preferred term, and severity  
- 
Incidence of TEAEs related to G100 by system organ class, preferred term, and severity  
- 
Incidence of TEAEs related to pembrolizumab by system organ class, preferred term, and 
severity  
- 
Incidence of TEAEs related to study drug by preferred term and severity  
- 
Incidence of TEAEs related to G100 by preferred term and severity  
- 
Incidence of TEAEs related to pembrolizumab by preferred term and severity  
- 
Incidence of dose limiting toxicities (DLTs) by system organ class, preferred term, and severity  
- 
Incidence of TEAEs leading to study drug discontinuation by system organ class, preferred term, 
and severity  
- 
Incidence of medical events of interest (MEOIs) by system organ class, preferred term, and 
severity  
- 
Incidence of TEAEs by system organ class and preferred term 
- 
Incidence of TEAEs related to study drug by system organ class and preferred term 
- 
Incidence of TEAEs related to G100 by system organ class and preferred term 
- 
Incidence of TEAEs related to pembrolizumab by system organ class and preferred term 
- 
Incidence of serious TEAEs by system organ class and preferred term 
- 
Incidence of serious TEAEs related to study drug by system organ class and preferred term 
- 
Incidence of serious TEAEs related to G100 by system organ class and preferred term 
- 
Incidence of serious TEAEs related to pembrolizumab by system organ class and preferred term 
- 
Incidence of TEAEs leading to study drug discontinuation by system organ class and preferred 
term 
- 
Incidence of TEAEs related to study drug leading to study drug discontinuation by system organ 
class and preferred term 
- 
Incidence of TEAEs related to G100 leading to study drug discontinuation by system organ class 
and preferred term 
- 
Incidence of TEAEs related to pembrolizumab leading to study drug discontinuation by system 
organ class and preferred term 
- 
Incidence of TEAEs leading to death by system organ class and preferred term 
- 
Incidence of TEAEs related to study drug leading to death by system organ class and preferred 
term 
5.7.3 Death 
Deaths (and cause of death) will be provided in table and listing. 
5.7.4 Clinical Laboratory Evaluation 
Hematology and blood chemistry are assessed at baseline visit (Visit 2), Visit 10 and Visit 11. Urinalysis 
is assessed at baseline visit (Visit 2). Laboratory assessments included the following: 
- 
Hematology: WBC with differential count, RBC count, hemoglobin, hematocrit, platelet count, 
PT, PTT and INR (PT, PTT and INR for baseline only) 
- 
Serum chemistry: sodium, chloride, potassium, random glucose, blood urea nitrogen (BUN), 
creatinine, calcium,  AST/SGOT, ALT/SGPT, total bilirubin, alkaline phosphatase, lactic acid 
dehydrogenase (LDH), total protein, albumin 


 
 
43 
 
- 
Urinalysis (baseline only): protein, glucose, blood, leukocytes, nitrites, urobilinogen, bilirubin, 
pH, specific gravity, ketones 
- 
Thyroid function (Visit 2 (Parts 1-4), Visit 11 (Part 2 - Pembro arm), Visit 9 (Part 4), FU (Parts 1-
4)): T3, T4 and TSH 
All local laboratory data will be stored in the database with the units in which they are originally reported.  
Laboratory data in summary tables and patient data listings will be presented in the SI Units. Laboratory 
data not reported in SI units will be converted to SI units before further processing or data analysis. 
Summary statistics (mean, median, standard deviation, and range) of laboratory values for hematology 
tests and chemistry tests and their changes from baseline values will be tabulated for each visit, by part, 
treatment, and overall. Baseline is defined as the last value prior to first study treatment dosing. 
Laboratory tests will be graded using NCI-CTCAE v4.03 toxicity grading (see Appendix 1).  
Worst change from baseline in toxicity grade for selected laboratory parameters will be presented in shift 
tables. For each patient, baseline grade will be cross-tabulated by the patient’s maximum post-baseline 
grade. Data from both scheduled and unscheduled visits will be used for maximum post-baseline NCI-
CTCAE grade of laboratory values. 
All laboratory measurements will be presented in a listing. 
5.7.5 Vital Signs 
Vital sign measurements include temperature, pulse (heart rate), respiratory rate, resting systolic and 
diastolic blood pressure, height and weight. Temperature, pulse (heart rate), respiratory rate, resting 
systolic and diastolic blood pressure will be collected from baseline visit (Visit 2) through end of study 
visit (Visit 12) and continued throughout follow-up visits. Height and weight will be collected at baseline 
visit only. 
Summary statistics (mean, median, standard deviation, and range) of baseline and post-baseline vital signs 
measurements (temperature, pulse, respiratory rate, resting systolic and diastolic blood pressure), as well 
as the changes from baseline, will be tabulated for each visit, by part, treatment, and overall. Baseline is 
defined as the last value prior to first study treatment dosing. 
All vital signs measurements will be presented in a listing. Clinically significant abnormalities in vital 
sign measurements will be flagged in listing. 
5.7.6 Electrocardiogram (ECG) 
12-Lead ECG measurements collected in both scheduled and unscheduled visits will be presented in data 
listings. 
5.7.7 Physical Examination 
Physical examination abnormalities will be included in the adverse event (abnormalities after the start of 
study drug) or medical history (abnormalities before the start of study drug) summaries and listings.  
5.7.8 Pregnancy Test 
Pregnancy test results will be presented in a listing. 
5.7.9 ECOG Performance Status 
ECOG performance status will be summarized by visit and presented in a listing. 


 
 
44 
 
5.7.10 Prior and Concomitant Medications 
Verbatim terms of prior and concomitant medications will be coded using the most current version of the 
World Health Organization (WHO) Drug Dictionary (3Q 2018 or newer). 
All concomitant medications will be summarized by ATC class and preferred name and all prior and 
concomitant medications will be presented in a listing. A patient with more than one medication in a 
medication class will be counted only once in the total number of patients in that medication class. A 
patient having the same medication more than once during the study will be counted only once in the 
number of patients with that medication.  
Prior medication is defined as any medication with start date on or before the first dose date, or 
medication with start date missing. 
Concomitant medication/treatment will be any medication/treatment with start date on or after the 
initial dosing of study treatment. Any medication/treatment that cannot be identified as prior or 
concomitant will be considered as prior and concomitant. 
Prior and concomitant medications will be presented in a listing. 
6 
Interim Analysis and Data Monitoring 
For the purposes of safety monitoring, key safety analyses are performed quarterly. The DMC have 
evaluated available data and made necessary recommendations to the study. Details are outlined in the 
DMC charter. 
7 
Adjustment for Covariates 
In exploratory analyses comparing post treatment change in immunohistochemistry immune infiltrate 
between G100 monotherapy 10 µg and G100 monotherapy 20 µg patients, pre-treatment TLR4 and pre- 
treatment CD8/CD4 ratio are included as covariates in the analysis of variance model.   
8 
Multiplicity 
In analysis of nanostring data, adjusted p-value using False Discovery Rate (FDR) method is presented, as 
footnoted on summary tables. Nominal p-values are presented otherwise in this early phase study of 
exploratory nature.   
9 
Changes in the Protocol Planned Analysis    
Clinical response by Lugano criteria for lymphomas (Cheson 2014), and independent radiology review of 
response by Immune-related Response Criteria (irRC) and Lugano criteria for Part 4 will not be assessed 
due to study termination by the sponsor. 
10 
References 
 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, et al. (2007) Revised response criteria for 
malignant lymphoma. Journal of clinical oncology: official journal of the American Society of Clinical 
Oncology. 25:579-86.  


 
 
45 
 
Cheson BD, Fisher RI, Barrinbgton SF, Cavalli F, Schwartz LH, et al. (2014) Recommendations for 
Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The 
Lugano Classification. Journal of Clinical Oncology. 32 (27): 3059-3067.  
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, et al. (1982) Toxicity and response criteria of 
the Eastern Cooperative Oncology Group. American journal of clinical oncology. 5:649-55.  
Saitoh S. (2012) Toll-like Receptors and Their Regulatory Mechanisms. In: Wang, ed. Innate Immune 
Regulation and Cancer Imunotherapy. New York: Springer. 39-50.  
Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, et al. (2009) Guidelines for the evaluation of 
immune therapy activity in solid tumors: immune-related response criteria. Clinical cancer research: an 
official journal of the American Association for Cancer Research. 15:7412-20. 


46 
 
Appendix 1: NCI CTCAE V4.03 Grades for Laboratory Parameters 
Panel: Chemistry 
Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Albumin 
g/L 
[30, LLN) 
[20, 30) 
[0, 20) 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Alkaline 
Phosphatase 
U/L 
(ULN, 2.5*ULN] (2.5*ULN, 5*ULN] 
(5*ULN, 
20*ULN] 
>20*ULN 
ALT (increased) U/L 
(ULN, 3.0*ULN] (3.0*ULN, 5.0*ULN] (5*ULN, 
20*ULN]; 
>20*ULN 
AST (increased) U/L 
(ULN, 3.0*ULN] (3.0*ULN, 5.0*ULN] (5*ULN, 
20*ULN]; 
>20*ULN 
Bilirubin 
umol/L (ULN, 1.5*ULN] (1.5*ULN, 3*ULN] 
(3*ULN, 
10*ULN] 
>10*ULN 
Calcium high 
(Hypercalcemia)  
mmol/L (ULN, 2.9] 
(2.9, 3.1] 
(3.1, 3.4] 
>3.4 
Calcium low 
(Hypocalcemia)  
mmol/L [2.0, LLN) 
[1.75, 2.0) 
[1.5, 1.75) ; 
hospitalization 
indicated 
[0, 1.5); life 
threatening 
consequences 
Creatinine 
(increased) 
umol/L (1 – 1.5*baseline]; 
(ULN, 1.5*ULN] 
(1.5 – 3.0* baseline]; 
(1.5*ULN, 3*ULN] 
>3.0*baseline; 
(3*ULN, 6*ULN] 
>6*ULN 
Glucose high 
(hyperglycemia) 
mmol/L (ULN, 8.9] 
(8.9, 13.9] 
(13.9, 27.8] ; 
hospitalization 
indicated 
>27.8; life 
threatening 
consequences 
Glucose low 
(hypoglycemia) 
mmol/L [3.0, LLN) 
[2.2, 3.0) 
[1.7, 2.2) 
[0, 1.7); life 
threatening 
consequences; 
seizures 
Potassium high 
(hyperkalemia)  
mmol/L (ULN, 5.5] 
(5.5, 6]  
(6, 7]; 
hospitalization 
indicated 
>7; life-
threatening 
consequences 
Potassium low 
(hypokalemia)  
mmol/L [3, LLN) 
[3, LLN); 
symptomatic; 
intervention indicated 
[2.5, 3) ; 
hospitalization 
indicated 
[0, 2.5); life-
threatening 
consequences 
Sodium high 
(hypernatraemia) 
mmol/L (ULN, 150] 
(150, 155] 
(155, 160]; 
hospitalization 
indicated 
>160; life-
threatening 
consequences 
Sodium low 
(hyponatraemia) 
mmol/L [130, LLN) 
UNDEFINED 
[120, 130) 
[0, 120); life-
threatening 
consequences 
 
 
 


 
 
47 
 
Panel: Hematology 
Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
(decreased) 
g/L 
[100, LLN) 
[80, 100) 
[0, 80); 
transfusion 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Platelet count 
(decreased) 
10^9/L 
[75, LLN) 
[50, 75) 
[25, 50) 
[0, 25) 
WBC (decreased) 
10^9/L 
[3, LLN) 
[2, 3) 
[1, 2) 
[0, 1) 
Lymphocytes 
(decreased) 
10^9/L 
[0.8, LLN)  
[0.5, 0.8) 
[0.2, 0.5) 
[0, 0.2) 
Neutrophil count 
(decreased) 
10^9/L 
[1.5, LLN) 
[1, 1.5) 
[0.5, 1) 
[0, 0.5) 
Activated Partial 
Thromboplastin 
Time 
sec 
(ULN, 
1.5*ULN] 
(1.5*ULN, 
2.5*ULN] 
>2.5*ULN; 
hemorrhage 
 
Prothrombin Intl. 
Normalized Ratio 
Ratio 
(ULN, 
1.5*ULN]; >1 - 
1.5 times above 
baseline if on 
anticoagulation 
(1.5*ULN, 
2.5*ULN]; >1.5 - 
2.5 times above 
baseline if on 
anticoagulation 
>2.5*ULN; >2.5 
times above 
baseline if on 
anticoagulation 
 
 
Reference: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf