Conditions: Metastatic Melanoma Head Neck Cancer
Keywords: Skin Cancer Skin Tumors Head and Neck Squamous Cell Carcinoma Cancer Immunotherapy
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 241
Healthy volunteers: no

Brief summary:
This is a phase 1b/2, open-label, multicenter trial designed to evaluate the safety, tolerability, biologic activity, and preliminary efficacy of intratumoral SD-101 injections in combination with intravenous pembrolizumab in patients with metastatic melanoma or recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).

This study will be conducted in 2 phases. Phase 1 evaluates SD-101 given in combination with pembrolizumab in melanoma populations (anti-PD-1/L1 naïve and anti-PD-1/L1 experienced with progressive disease) in up to 4 Dose Escalation cohorts to identify a recommended Phase 2 dose (RP2D) to be evaluated in up to 4 Dose Expansion cohorts in Phase 2. Phase 2 also includes up to 4 Dose Expansion cohorts of patients with HNSCC (anti-PD-1/L1 naïve and anti-PD-1/L1 experienced with progressive disease).

Detailed description:

Arms:
arm 1: Determine the maximum tolerated dose (MTD) of escalating doses of SD-101(1) administered in combination with pembrolizumab in patients with melanoma (anti-PD-1/L1 therapy naïve and experienced patients with progressive disease). arm 2: Determine the safety and efficacy of SD-101(2) and pembrolizumab in anti-PD-1/L1 therapy naïve patients with recurrent or metastatic melanoma. arm 3: Determine the safety and efficacy of SD-101(2) and pembrolizumab in anti-PD-1/L1 therapy progressing patients with recurrent or metastatic melanoma. arm 4: Determine the safety and efficacy of SD-101(2) and pembrolizumab in anti-PD-1/L1 therapy naïve patients with recurrent head and neck squamous cell carcinoma. arm 5: Determine the safety and efficacy of SD-101(2) and pembrolizumab in anti-PD-1/L1 therapy progressing patients with recurrent head and neck squamous cell carcinoma. arm 6: Determine the safety and efficacy of SD-101(3) and pembrolizumab in anti-PD-1/L1 therapy naïve patients with recurrent or metastatic melanoma. arm 7: Determine the safety and efficacy of SD-101(3) and pembrolizumab in anti-PD-1/L1 therapy naïve patients with recurrent head and neck squamous cell carcinoma. arm 8: Determine the safety and efficacy of SD-101(3) and pembrolizumab in anti-PD-1/L1 therapy refractory or resistant patients with recurrent head and neck squamous cell carcinoma. arm 9: Determine the safety and efficacy of SD-101(3) and pembrolizumab in anti-PD-1/L1 therapy refractory or resistant patients with recurrent or metastatic melanoma.

Interventions: intervention 1: SD-101(1) intervention 2: Pembrolizumab intervention 3: SD-101(2) intervention 4: Pembrolizumab intervention 5: SD-101(3) intervention 6: Pembrolizumab
Intervention descriptions: intervention 1: SD-101 administered intratumorally at escalating doses (up to 11 doses). intervention 2: Pembrolizumab administered intravenously, 200 mg Q3W for two years (up to 35 doses). intervention 3: Dose Q1W for 4 weeks followed by dose Q3W for 7 weeks, then 9 weeks off, then dose Q1W for 4 weeks followed by dose Q3W for 7 weeks (up to 22 total doses). intervention 4: Pembrolizumab administered intravenously, 200mg Q3W for two years (up to 35 doses). intervention 5: Dose Q1W for 4 weeks followed by dose Q3W for 16 additional weeks (up to 20 total doses). intervention 6: Pembrolizumab administered intravenously, 200mg Q3W for two years (up to 35 doses).

Protocol document:
Prot_000.pdf: 
Protocol Title: 
A Phase 1b/2, Open-label, Multicenter, Dose-escalation and Expansion Trial of Intratumoral 
SD-101 in Combination With Pembrolizumab in Patients With Metastatic Melanoma or 
Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma 
Protocol No.: 
DV3-MEL-01 (SYNERGY-001) 
Protocol Version & Date: 
Amendment 9.0 dated 20 November 2019 
NCT No.: 
NCT02521870 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 1 of 163 
Protocol Title: 
A Phase 1b/2, Open-label, Multicenter, Dose-escalation and Expansion Trial of 
Intratumoral SD-101 in Combination With Pembrolizumab in Patients With 
Metastatic Melanoma or Recurrent or Metastatic Head and Neck Squamous Cell 
Carcinoma 
Protocol No.: 
DV3-MEL-01 (SYNERGY-001)  
Investigational Product: 
SD-101 
Regulatory Filing Reference 
Numbers: 
US IND: 125878 
EudraCT: 2016-004461-47  
AUS: CT-2016-CTN-05177-1  
NZ: TT50-10123 (2077) 
Trial Phase: 
Phase 1b/2 
Sponsor: 
Dynavax Technologies Corporation 
2100 Powell Street, Suite 900 
Emeryville, CA 94608 
United States of America 
Study Medical Monitor: 
Global: 
Robert Janssen, MD, Senior Vice 
President and Chief Medical Officer, 
Clinical Development, Medical and 
Regulatory Affairs  
Dynavax Technologies Corporation 
Tel: (510) 665-0414   
Fax: (510) 848-9750 
E-mail: rjanssen@dynavax.com 
Regional: 
Jorge Martinez, MD 
Medical Director, 
Hematology/Oncology – Medical 
Affairs 
PRA Health Sciences 
Tel: +49 621-878-2696   
E-mail: martinezjorge@prahs.com 
Coordinating Investigators: 
Melanoma: 
Antoni Ribas, MD, PhD 
Jonsson Comprehensive Cancer Center 
University of California, Los Angeles 
10833 Le Conte Avenue  
Los Angeles, CA 90095 
Tel: (310) 206-3928 
E-mail: aribas@mednet.ucla.edu 
Head and Neck Squamous Cell 
Carcinoma: 
Ezra Cohen, MD 
Moores Cancer Center 
University of California, San Diego 
3855 Health Sciences Drive, #0658 
La Jolla, CA 92093 
Tel: (858) 534-6161 
E-mail: ecohen@ucsd.edu 
 
Germany: 
Thomas Tüting, MD 
Department of Dermatology 
University Hospital Magdeburg, 
Leipziger Straße 44 
39120 Magdeburg, Germany 
Tel: +49-391-6715249 
E-mail: thomas.tueting@med.ovgu.de 
 
Clinical Operations: 
Rochelle Brewer 
Senior Clinical Trial Manager, Clinical Operations 
Dynavax Technologies Corporation 
Tel: (510) 665-7242   
E-mail: rbrewer@dynavax.com 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 2 of 163 
Protocol Title: 
A Phase 1b/2, Open-label, Multicenter, Dose-escalation and Expansion Trial of 
Intratumoral SD-101 in Combination With Pembrolizumab in Patients With 
Metastatic Melanoma or Recurrent or Metastatic Head and Neck Squamous Cell 
Carcinoma 
 
 
 
Amendment #9: 
Amendment #8: 
Amendment #7: 
Amendment #6: 
Amendment #5: 
 
20 November 2019 
08 February 2019 
22 June 2018 
02 April 2018 
02 June 2017 
 
Amendment #4: 
Amendment #3: 
Amendment #2: 
Amendment #1: 
Original Protocol: 
23 September 2016 
30 March 2016 
18 December 2015 
07 May 2015 
27 March 2015 
 
This trial will be conducted in accordance with the International Council for Harmonisation (ICH) E6(R2) Good 
Clinical Practice (GCP) guidelines and applicable local legal and regulatory requirements. 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 3 of 163 
PROTOCOL APPROVAL PAGE 
Protocol Title: A Phase 1b/2, Open-label, Multicenter, Dose-escalation and Expansion 
Trial of Intratumoral SD-101 in Combination With Pembrolizumab in 
Patients With Metastatic Melanoma or Recurrent or Metastatic Head and 
Neck Squamous Cell Carcinoma 
Regulatory Filing 
Reference Numbers: 
US IND: 125878 
EudraCT: 2016-004461-47 
AUS: CT-2016-CTN-05177-1  
NZ: TT50-10123 (2077) 
Protocol No.: DV3-MEL-01 (SYNERGY-001) 
Amendment #9: 20 November 2019 
Amendment #8: 08 February 2019 
Amendment #7: 22 June 2018 
Amendment #6: 02 April 2018 
Amendment #5: 02 June 2017 
Amendment #4: 23 September 2016 
Amendment #3: 30 March 2016 
Amendment #2: 18 December 2015 
Amendment #1: 07 May 2015 
Original Protocol: 27 March 2015 
Sponsor: Dynavax Technologies Corporation 
2100 Powell Street, Suite 900 
Emeryville, CA 94608 
United States of America 
 
This protocol has been approved by Dynavax Technologies Corporation. The following signature 
documents this approval. 
 
 
 
 
 
Robert Janssen, MD 
Chief Medical Officer and Sr. Vice President, Clinical Development and 
Medical and Regulatory Affairs 
 
Date 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 4 of 163 
 
INVESTIGATOR SIGNATURE PAGE 
Protocol Title: A Phase 1b/2, Open-label, Multicenter, Dose-escalation and Expansion Trial 
of Intratumoral SD-101 in Combination With Pembrolizumab in Patients 
With Metastatic Melanoma or Recurrent or Metastatic Head and Neck 
Squamous Cell Carcinoma  
Regulatory Filing 
Reference Numbers: 
US IND: 125878 
EudraCT: 2016-004461-47 
AUS: CT-2016-CTN-05177-1  
NZ: TT50-10123 (2077) 
Protocol No.: DV3-MEL-01 (SYNERGY-001) 
Amendment #9: 20 November 2019 
Amendment #8: 08 February 2019 
Amendment #7: 22 June 2018 
Amendment #6: 02 April 2018 
Amendment #5: 02 June 2017 
Amendment #4: 23 September 2016 
Amendment #3: 30 March 2016 
Amendment #2: 18 December 2015 
Amendment #1: 07 May 2015 
Original Protocol: 27 March 2015 
Sponsor: Dynavax Technologies Corporation 
2100 Powell Street, Suite 900 
Emeryville, CA 94608 
United States of America 
 
DECLARATION OF INVESTIGATOR 
I confirm that I have read and understood this protocol and agree to conduct the trial as outlined in the 
protocol and other information supplied to me. I agree to conduct the trial in accordance with ICH 
E6(R2) GCP guidelines and applicable local legal and regulatory requirements. 
 
 
Investigator Name (Print) 
Investigator Signature 
 Date 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 5 of 163 
TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................5 
LIST OF TABLES .........................................................................................................................9 
LIST OF FIGURES .....................................................................................................................10 
LIST OF APPENDICES .............................................................................................................10 
PROTOCOL SYNOPSIS ............................................................................................................11 
1.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................36 
2.0 
INTRODUCTION AND RATIONALE .........................................................................39 
2.1 
Melanoma and Head and Neck Squamous Cell Carcinoma ..................................39 
2.1.1 
Melanoma ..............................................................................................39 
2.1.2 
Head and Neck Squamous Cell Carcinoma ..........................................41 
2.2 
Oligodeoxynucleotides With CpG Motifs in Cancer Immunotherapy ..................41 
2.3 
PD-1 Blockade With Anti-PD-1 Antibody ............................................................44 
2.4 
Combined Anti-PD-1 Therapy and Intratumoral CpG-ODN Treatment of 
Melanoma ..............................................................................................................45 
2.5 
SD-101 Alone and in Combination With Anti-PD-1 in Head and Neck 
Squamous Cell Carcinoma Preclinical Models......................................................46 
2.6 
Clinical Experience With SD-101 .........................................................................48 
2.7 
About Pembrolizumab ...........................................................................................50 
2.8 
Trial Rationale and Doses to be Evaluated ............................................................50 
3.0 
TRIAL OBJECTIVES.....................................................................................................52 
3.1 
Phase 1 (Dose Escalation: Metastatic Melanoma) .................................................52 
3.1.1 
Primary Objectives ................................................................................52 
3.1.2 
Exploratory Objectives..........................................................................52 
3.2 
Phase 2 (Dose Expansion: Metastatic Melanoma or Recurrent or Metastatic 
Head and Neck Squamous Cell Carcinoma) ..........................................................52 
3.2.1 
Primary Objectives ................................................................................52 
3.2.2 
Secondary Objectives ............................................................................53 
3.2.3 
Exploratory Objectives..........................................................................53 
4.0 
INVESTIGATIONAL PLAN .........................................................................................53 
4.1 
Trial Design ...........................................................................................................53 
4.1.1 
Phase 1 Dose Escalation: Melanoma (COMPLETE) ............................58 
4.1.2 
Phase 2 Dose Expansion – Cohorts (CLOSED) ....................................61 
4.1.3 
Phase 2 Dose Expansion – Dosing Schedule ........................................63 


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4.1.4 
Phase 1 and Phase 2 – Assessments ......................................................66 
4.2 
Duration of Trial ....................................................................................................68 
4.3 
Trial Endpoints.......................................................................................................68 
4.3.1 
Phase 1 – Dose Escalation.....................................................................68 
4.3.2 
Phase 2 – Dose Expansion ....................................................................68 
4.4 
Randomization .......................................................................................................69 
4.5 
Blinding..................................................................................................................69 
4.6 
Appropriateness of Measurements .........................................................................69 
4.7 
Trial Termination ...................................................................................................70 
5.0 
SELECTION OF PATIENTS .........................................................................................70 
5.1 
Inclusion Criteria ...................................................................................................71 
5.2 
Exclusion Criteria ..................................................................................................74 
5.2.1 
Contraception ........................................................................................77 
5.3 
Removal of Patients From the Trial .......................................................................78 
6.0 
TRIAL TREATMENT AND SUPPLIES ......................................................................78 
6.1 
Trial Treatments .....................................................................................................79 
6.1.1 
Pembrolizumab .....................................................................................79 
6.1.2 
SD-101 ..................................................................................................79 
6.2 
Instructions for Administration ..............................................................................79 
6.2.1 
Pembrolizumab .....................................................................................79 
6.2.2 
SD-101 ..................................................................................................80 
6.3 
Labeling .................................................................................................................83 
6.3.1 
Pembrolizumab .....................................................................................83 
6.3.2 
SD-101 ..................................................................................................83 
6.4 
Storage and Handling Instructions .........................................................................83 
6.4.1 
Pembrolizumab .....................................................................................84 
6.4.2 
SD-101 ..................................................................................................84 
6.5 
Control and Accountability of Investigational Medicinal Product ........................84 
6.6 
Treatment Compliance ...........................................................................................85 
7.0 
TREATMENT OF PATIENTS ......................................................................................85 
7.1 
Treatments Administered .......................................................................................85 
7.2 
Treatment Period ....................................................................................................86 
7.3 
Treatment Precaution .............................................................................................86 


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SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
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7.4 
Prohibited Treatments or Therapies .......................................................................87 
7.5 
Permitted Therapy ..................................................................................................88 
7.6 
Dose Modification, Dose Delays, and Missed Doses ............................................88 
7.7 
Dose Modification and Toxicity Management for Immune-Related Adverse 
Events Associated With Pembrolizumab ...............................................................91 
7.8 
Replacement of Patients .........................................................................................96 
8.0 
ASSESSMENT OF RESPONSE ....................................................................................96 
8.1 
Interferon-inducible Genes ....................................................................................96 
8.2 
Response Evaluation and Criteria ..........................................................................97 
8.2.1 
Response Criteria ..................................................................................98 
8.3 
Biomarker Analysis .............................................................................................100 
9.0 
MANAGEMENT OF TRIAL TREATMENT TOXICITIES....................................100 
9.1 
Dose-limiting Toxicity Definitions and Stopping Rules (COMPLETE) .............101 
9.1.1 
Staggered Dosing for Phase 1 (COMPLETE) .....................................103 
9.1.2 
Safety Review and Dose Escalation (COMPLETE) ...........................103 
9.2 
Reasons for Stopping a Patient From Receiving Additional Treatment ..............104 
9.3 
Management of Patient Safety .............................................................................106 
9.3.1 
Management of Injection-site Reactions .............................................106 
9.3.2 
Management of Infusion Reactions ....................................................106 
10.0 
TRIAL PROCEDURES ................................................................................................108 
10.1 
Informed Consent and Screening Log .................................................................108 
10.1.1 
Eligibility ............................................................................................109 
10.1.2 
Tumor Biopsy .....................................................................................109 
10.2 
Trial Visits ...........................................................................................................110 
10.3 
Safety Assessments ..............................................................................................111 
10.3.1 
Medical and Medication History .........................................................111 
10.3.2 
ECOG Performance Status Assessment ..............................................112 
10.3.3 
Vital Signs ...........................................................................................112 
10.3.4 
Physical Examinations ........................................................................112 
10.3.5 
Electrocardiogram ...............................................................................112 
10.3.6 
Safety Laboratory Assessments ..........................................................112 
10.3.7 
Pregnancy ............................................................................................113 
10.3.8 
Injection-site Reaction Assessments ...................................................113 


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SD-101 
 
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CONFIDENTIAL AND PROPRIETARY 
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10.3.9 
Adverse Events....................................................................................114 
10.3.10 
Serious Adverse Events.......................................................................114 
10.3.11 
Concomitant Medications ...................................................................114 
10.4 
Disease Assessments ............................................................................................115 
10.4.1 
Confirmation of Progressive Disease (Based on irRECIST) ..............115 
10.5 
Pharmacodynamic Assessments ..........................................................................115 
10.6 
Immunogenicity Assessments ..............................................................................115 
10.7 
Exploratory Assessments .....................................................................................116 
10.7.1 
Expression Profiling ............................................................................116 
10.7.2 
Neoantigen and DNA Mutational Analyses ........................................116 
10.7.3 
Human Papillomavirus Status .............................................................116 
10.8 
End-of-Study/Safety Follow-up Visit ..................................................................116 
10.9 
Unscheduled Visit for Safety or Disease Progression .........................................117 
10.10 Duration of Follow-up .........................................................................................117 
11.0 
INVESTIGATOR’S RESPONSIBILITIES ................................................................117 
11.1 
Injection-site Reactions ........................................................................................118 
11.2 
Adverse Events ....................................................................................................118 
11.2.1 
Events of Clinical Interest ...................................................................119 
11.2.2 
Overdoses ............................................................................................120 
11.2.3 
New Cancer (Not the Cancer Being Investigated Under the Study) ...120 
11.2.4 
Definition of Adverse Reaction ..........................................................120 
11.2.5 
Definition of Suspected Adverse Reaction .........................................120 
11.2.6 
Definition of Unexpected Adverse Event or Unexpected Suspected 
Adverse Reactions ...............................................................................120 
11.3 
Serious Adverse Events .......................................................................................121 
11.3.1 
Definition of Serious Adverse Events .................................................121 
11.3.2 
Serious Adverse Event Reporting Requirements ................................122 
11.4 
Adverse Event Severity and Relationship to Trial Treatment .............................123 
11.4.1 
Severity Grading of Adverse Events ...................................................123 
11.4.2 
Relationship of Adverse Events to Trial Treatment ............................124 
11.5 
Reporting and Documentation of Pregnancy .......................................................124 
12.0 
STATISTICAL METHODS .........................................................................................125 
12.1 
General .................................................................................................................125 


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SD-101 
 
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12.2 
Sample Size Considerations .................................................................................126 
12.3 
Analysis Endpoints ..............................................................................................127 
12.3.1 
Safety Endpoints .................................................................................127 
12.3.2 
Efficacy Endpoints ..............................................................................127 
12.3.3 
Exploratory Biomarker Endpoints ......................................................128 
12.4 
Trial Analysis Populations ...................................................................................128 
12.5 
Demographic and Baseline Characteristics .........................................................128 
12.6 
Pharmacodynamic Analyses ................................................................................128 
12.7 
Safety Analyses ....................................................................................................129 
12.8 
Response Analyses...............................................................................................129 
12.9 
Source Documents ...............................................................................................129 
12.10 Direct Access to Source Data/Documents ...........................................................130 
13.0 
DATA QUALITY ASSURANCE .................................................................................131 
14.0 
ETHICS ..........................................................................................................................131 
14.1 
Institutional Review Board/Independent Ethics Committee................................131 
14.2 
Ethical Conduct of the Trial .................................................................................131 
14.3 
Informed Consent.................................................................................................131 
14.4 
Patient Confidentiality .........................................................................................132 
15.0 
DATA HANDLING AND RECORD KEEPING ........................................................132 
15.1 
Case Report Forms ...............................................................................................132 
15.2 
Data Handling ......................................................................................................132 
15.3 
Coding of Adverse Events, Drugs, and Diseases .................................................133 
15.4 
Record Retention .................................................................................................133 
16.0 
USE OF INFORMATION AND PUBLICATION......................................................134 
17.0 
REFERENCES ...............................................................................................................136 
 
LIST OF TABLES 
Table 4-1: 
Status of Cohorts for DV3-MEL-01 Protocol at Amendment 9 ................57 
Table 4-2: 
Phase 1 Melanoma Dose Escalation Cohorts (COMPLETE) ....................58 
Table 4-3: 
Phase 2 Melanoma Dose Expansion Cohorts (CLOSED) .........................62 
Table 4-4: 
Phase 2 HNSCC Dose Expansion (CLOSED) ...........................................63 
Table 6-1: 
Dosage and Dose Administration for Phase 1 and Phase 2 Cohorts..........81 


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SD-101 
 
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CONFIDENTIAL AND PROPRIETARY 
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Table 7-1: 
Dose Modification and Toxicity Management Guidelines for 
Immune-related Adverse Events Associated with Pembrolizumab ...........92 
Table 9-1: 
Infusion Reaction Treatment Guidelines .................................................107 
Table 11-1: 
National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE, Version 4.03) ...............................................................123 
Table 11-2: 
Definitions for Relationship of Adverse Events to Trial Treatment ........124 
 
LIST OF FIGURES 
Figure 2-1: 
SD-101 Cellular Mechanism of Action .....................................................43 
Figure 2-2: 
Blocking PD-1/PD-L1 Pathway Mechanism of Action .............................45 
Figure 2-3: 
Intratumoral SD-101 Reduced Tumor Growth in Murine Models of 
HPV-Positive (A) and Negative (B) Head and Neck Squamous Cell 
Carcinoma ..................................................................................................47 
Figure 4-1: 
DV3-MEL-01 Study Design Schema at Amendment 9 – Phase 1 and 
Phase 2 .......................................................................................................55 
Figure 4-2: 
Trial Flow Diagram for Phase 1 Dose Escalation Cohorts 1 to 4 
(COMPLETE) ............................................................................................59 
Figure 4-3: 
Trial Flow Diagram for Dose Expansion Cohorts 1 and 3 (CLOSED) ......64 
Figure 4-4: 
Trial Flow Diagram for Dose Expansion Cohorts 2 and 4 (CLOSED) ......65 
Figure 4-5: 
Trial Flow Diagram for Dose Expansion Cohorts 5, 6, 7, and 8 
(CLOSED) ..................................................................................................66 
 
LIST OF APPENDICES 
Appendix 1: 
Schedule of Trial Events (Phase 1 Dose Escalation Cohorts 1-4) - 
COMPLETE .............................................................................................140 
Appendix 2: 
Schedule of Trial Events (Phase 2 Expansion Cohorts 1 and 3 – Anti-
PD-1/L1 Naïve) – CLOSED.....................................................................144 
Appendix 3: 
Schedule of Trial Events (Phase 2 Expansion Cohorts 2 and 4 – Anti-
PD-1/L1 Experienced) – CLOSED ..........................................................147 
Appendix 4: 
Schedule of Trial Events (Phase 2 Expansion Cohorts 5 and 6 [Anti-
PD-1/L1 NaÏve] and Cohorts 7 and 8 [Anti-PD-1/L1 Refractory or 
Resistant]) - CLOSED ..............................................................................150 
Appendix 5: 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials .......................................156 
Appendix 6: 
RECIST V1.1 and Immune-Related RECIST Response Definition ........157 
Appendix 7: 
Imaging Modalities ..................................................................................161 
Appendix 8: 
ECOG Performance Status Index ............................................................163 


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SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
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PROTOCOL SYNOPSIS 
Objectives: 
NOTE: As of Amendment 9, Phase 1 of the trial is complete. For Phase 2, efficacy 
and exploratory objectives will not be pursued. 
Phase 1 (Dose Escalation: Metastatic Melanoma) 
Primary Objectives  
• 
To assess the safety and tolerability of escalating doses of intratumoral SD-101 in 
combination with intravenous pembrolizumab in patients with metastatic melanoma 
• 
To evaluate the expression of interferon (IFN)-inducible genes in whole blood 
24 hours after intratumoral injection of SD-101 given with pembrolizumab in 
patients with metastatic melanoma as a pharmacodynamic marker of SD-101 
activity  
• 
To determine a recommended Phase 2 dose (RP2D) of SD-101 in combination with 
pembrolizumab to be evaluated in Phase 2 
Exploratory Objectives 
• 
To assess the preliminary response both locally and systemically including: 
• 
Treatment response of the injected Lesion A (local response) 
• 
Treatment response of the non-injected lesion(s) (systemic response) 
• 
Treatment response of all lesions 
• 
Time to response 
• 
To assess changes in tumor biomarkers 
Phase 2 (Dose Expansion: Metastatic Melanoma or Recurrent or Metastatic Head 
and Neck Squamous Cell Carcinoma) 
Primary Objectives 
• 
To assess the tumor response both locally and systemically including: 
• 
Treatment response of the injected lesion(s) (local response) 
• 
Treatment response of the non-injected lesion(s) (systemic response) 
• 
Treatment response of all lesions 
Secondary Objectives  
• 
To assess the safety and tolerability of SD-101 in combination with pembrolizumab 


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SD-101 
 
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CONFIDENTIAL AND PROPRIETARY 
Page 12 of 163 
• 
To assess the time frame of tumor responses: 
• 
Time to response 
• 
Duration of response 
• 
To assess progression-free survival (PFS)  
Exploratory Objectives 
• 
To assess changes in tumor biomarkers  
• 
To identify and assess changes in potential tumor neoantigens in patients with 
recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) 
• 
To evaluate the expression of IFN inducible genes in whole blood 24 hours after 
intratumoral injection of SD-101 given with pembrolizumab in patients with 
recurrent or metastatic HNSCC as a pharmacodynamic marker of SD-101 activity 
Trial Design:  
NOTE: As of Amendment 9, Phase 1 of the trial is complete. Phase 2 of the trial 
has been modified to continue dosing per protocol; however, efficacy and 
exploratory endpoints will no longer be collected.  
This is a phase 1b/2, open-label, multicenter trial designed to evaluate the safety, 
tolerability, biologic activity, and preliminary efficacy of intratumoral SD-101 
injections in combination with intravenous pembrolizumab in patients with metastatic 
melanoma or recurrent or metastatic HNSCC. 
This study will be conducted in 2 phases. Phase 1 evaluates SD-101 given in 
combination with pembrolizumab in melanoma populations (anti-PD-1/L1 naïve and 
anti-PD-1/L1 experienced with progressive disease) in up to 4 Dose Escalation cohorts 
to identify an RP2D to be evaluated in up to 4 Dose Expansion cohorts in Phase 2. 
Phase 2 also includes up to 4 Dose Expansion cohorts of patients with HNSCC (anti-
PD-1/L1 naïve and anti-PD-1/L1 experienced with progressive disease).  
The following schema presents the study design for melanoma Phase 1 and Phase 2 and 
for HNSCC Phase 2. 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 13 of 163 
DV3-MEL-01 Study Design Schema    
 
Anti-PD-1/L1 = anti-programmed death receptor-1/ligand 1; HNSCC = head and neck squamous cell carcinoma; 
RP2D = recommended Phase 2 dose. 
a 
1.0 mg of SD-101 was added at Amendment 4. 
b 
At Protocol Amendment 5, enrollment in Dose Escalation Cohorts 1-4 was CLOSED. Based on available data 
(including efficacy, safety, and pharmacodynamics biomarkers), the sponsor selected 8.0 mg in a single injectable 
lesion if 1 lesion is selected or 2.0 mg per lesion if 2 to 4 lesions are selected for injection as the RP2D to be evaluated 
in the Dose Expansion phase. 
c 
At Protocol Amendment 6 and based on available data (including efficacy, safety, and pharmacodynamics biomarkers), 
the sponsor selected a second Phase 2 dose of 2.0 mg per lesion in 1 to 4 injectable lesions to be evaluated in the 
Dose Expansion phase. Expansion Cohorts 1, 2, 3, and 4 in which patients were treated with 8.0 mg in a single 
injectable lesion were CLOSED to further enrollment. Cohort 5 (melanoma anti-PD-1/L1 –naïve), Cohort 6 (HNSCC 
anti-PD-1/L1 –naïve), and Cohort 7 (HNSCC anti-PD-1/L1 –refractory or resistant) were ADDED with patients 
receiving 2.0 mg per lesion in 1 to 4 injectable lesion(s). 
d 
At Protocol Amendment 7 and based on available data (including efficacy, safety, and pharmacodynamics biomarkers), 
Cohort 8 (melanoma anti-PD-1/L1–refractory or resistant) was ADDED with patients receiving 2.0 mg per injection in 
1 to 4 injectable lesions/regions. 
e 
For Protocol Amendment 8 and based on available data from the ongoing trial (including efficacy, safety, and 
pharmacodynamics biomarkers), Cohorts 5 and 6 were CLOSED. Additionally, Cohort 8 (melanoma 
anti-PD-1/L1-refractory or resistant) was expanded to approximately 50 patients.  
Note: For Protocol Amendment 9, enrollment is closed for all cohorts. Enrolled patients should continue to receive their 
assigned trial treatments as per the protocol. 
 
Expansion Cohort 7
Anti-PD-1/L1 refractory or 
resistant
Dose: 2.0 mg per lesion in 
1 to 4 lesions
Closed
PHASE 2 DOSE EXPANSION
Determine RP2D - COMPLETED
(Selected as 8.0 mg for Protocol Amendment 5)
Escalation Cohorts 1-4
Anti-PD-1/L1 naïve or experienced 
Doses:  2.0 mg, 4.0 mg, 8.0 mg, and 1.0 mg a
Modified 3 + 3 Study Design
Closed 
Expansion Cohort 1
Anti-PD-1/L1 naïve
Dose: 8.0 mg in a single lesion 
if 1 lesion is selected or 2.0 mg 
per lesion if 2 to 4 lesions are 
selected for injection
Closed b
Expansion Cohort 2
Anti-PD-1/L1 experienced
Dose: 8.0 mg in a single 
lesion
Closed b
PHASE 1 DOSE ESCALATION
Melanoma
Expansion Cohort 3
Anti-PD-1/L1 naïve
Dose: 8.0 mg in a single 
lesion 
Closed b
Expansion Cohort 4
Anti-PD-1/L1 
experienced
Dose: 8.0 mg in a 
single lesion
Closed b
HNSCC
Melanoma 
Expansion Cohort 5
Anti-PD-1/L1 naïve
Dose: 2.0 mg per lesion in
1 to 4 lesions
Closed e
Expansion Cohort 6
Anti-PD-1/L1 naïve
Dose: 2.0 mg per lesion 
in 1 to 4 lesions
Closed e
Expansion Cohort 8
Anti-PD-1/L1 refractory or 
resistant
Dose: 2.0 mg per injection 
in 1 to 4 lesions/regions
Closed 
2nd RP2D
(Selected as 2.0 mg for Protocol Amendments 6 and 7) c, d


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 14 of 163 
The status of cohorts for this DV3-MEL-01 protocol at Amendment 9 is as follows: 
 
Cohort 
Anti-PD-1 /L1 
Treatment 
Status 
Orig 
A 
1 
A 
2 
A 
3 
A 
4 
A 5 
A 6 
A 7 
A 8 
 
 
 
A9 
Ph 1 Mel – 1 
Naïve or 
experienced 
X 
X 
X 
X 
X 
Closed 
Closed 
Closed 
Closed 
Complete 
Ph 1 Mel – 2 
Naïve or 
experienced 
X 
X 
X 
X 
X 
Closed 
Closed 
Closed 
Closed 
Complete 
Ph 1 Mel – 3 
Naïve or 
experienced 
X 
X 
X 
X 
X 
Closed 
Closed 
Closed 
Closed 
Complete 
Ph 1 Mel – 4 
Naïve or 
experienced 
- 
- 
- 
- 
X 
Closed 
Closed 
Closed 
Closed 
Complete 
 
 
 
 
 
 
 
 
 
 
 
 
Ph 2 Mel – 1 
Naive 
- 
- 
X 
X 
X 
X 
Closed 
Closed 
Closed 
Closed 
Ph 2 Mel – 2 
Experienced 
- 
- 
X 
X 
X 
X 
Closed 
Closed 
Closed 
Closed 
Ph 2 Mel – 5 
Naive 
- 
- 
- 
- 
- 
- 
X 
X 
Closed 
Closed 
Ph 2 Mel – 8 
Refractory or 
resistant 
- 
- 
- 
- 
- 
- 
- 
X 
X 
Closed 
 
 
 
 
 
 
 
 
 
 
 
 
Ph 2 
HNSCC – 3  
Naive 
- 
- 
- 
- 
X 
X 
Closed 
Closed 
Closed 
Closed 
Ph 2 
HNSCC – 4  
Experienced 
- 
- 
- 
- 
X 
X 
Closed 
Closed 
Closed 
Closed 
Ph 2 
HNSCC – 6  
Naive 
- 
- 
- 
- 
- 
- 
X 
X 
Closed 
Closed 
Ph 2 
HNSCC – 7  
Refractory or 
resistant 
- 
- 
- 
- 
- 
- 
X 
X 
X 
Closed 
A = Amendment; Closed = Closed to enrollment; Complete = last patient last visit (LPLV) has been reached for all 
patients; HNSCC = head and neck squamous cell carcinoma; Mel = melanoma; Orig = original; Ph = phase; X = 
Open for enrollment 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 15 of 163 
 
Phase 1 Dose Escalation: Melanoma (COMPLETE) 
The Phase 1 will consist of up to 4 Dose Escalation cohorts to evaluate the safety and 
tolerability of SD-101 given in combination with pembrolizumab in melanoma 
populations (anti-PD-1/L1 naïve and anti-PD-1/L1 experienced with progressive 
disease) to identify an RP2D to be evaluated in Phase 2. 
Phase 1 employs a modified 3 + 3 study design, evaluating escalating dose levels of 
SD-101 (given with a fixed dose of pembrolizumab) in patients with metastatic 
melanoma. Cohorts of 3 to 6 patients will be enrolled at each dose level, and each 
patient will participate in only 1 cohort.  
Patients in Escalation Cohorts 1-4 will be administered 2.0 mg, 4.0 mg, 8.0 mg, and 
1.0 mg, respectively, of SD-101 in combination with 200 mg pembrolizumab per the 
Schedule of Trial Events. The melanoma Dose Escalation cohorts, patient populations, 
and treatment assignments are outlined in the table below. 
Phase 1 Melanoma Dose Escalation Cohorts (COMPLETE) 
 
Cohort 
Anti-PD-1/L1 
Experience 
SD-101 Dose 
n 
Dosing 
Schema  
1 
Naïve or 
experienced 
2.0 mg per lesion in 1 injectable 
lesion (Lesion A) 
3 - 6 
A 
2 
Naïve or 
experienced 
4.0 mg per lesion in 1 injectable 
lesion (Lesion A) 
3 - 6 
A 
3 
Naïve or 
experienced 
8.0 mg per lesion in 1 injectable 
lesion (Lesion A) 
3 - 6 
A 
4 
Naïve or 
experienced 
1.0 mg per lesion in 1 injectable 
lesion (Lesion A) 
3 - 6 
Aa 
a 
Anti-PD-1/L1 = anti-programmed death receptor-1/ligand 1.Dosing Schema: 
A: SD-101 and pembrolizumab dosing both start on Day 1 and patients receive 1 course of SD-101 
(4 weekly doses and then every 3 weeks on schedule with pembrolizumab for 7 additional doses) 
b 
1.0 mg was added in Protocol Amendment 4. 
 
As presented in the Trial Flow Diagram for Dose Escalation Cohorts 1-4, patients with 
metastatic melanoma will receive 4 weekly doses of SD-101 administered 
intratumorally on Days 1, 8, 15, 22, and then every 3 weeks on schedule with 
pembrolizumab for 7 additional doses. Pembrolizumab 200 mg will be administered 
intravenously every 3 weeks starting on Day 1 for up to 35 treatments (approximately 2 
years) or until disease progression. SD-101 will be administered before pembrolizumab 
on days when both drugs are scheduled to be used. 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 16 of 163 
Trial Flow Diagram for Dose Escalation Cohorts 1 to 4 (COMPLETE) 
 
DLT Assessment (COMPLETE) 
Phase 1 implements a staggered enrollment for a cohort in addition to enrolling 
3 to 6 patients as part of a modified 3 + 3 Dose Escalation design. Patients enrolled 
under staggered enrollment in Phase 1 are referred to as sentinel patients in the protocol. 
For sentinel patients in Phase 1, DLTs as defined in the protocol will be assessed during 
the first 72 hours of dosing prior to dosing of subsequent patients in a cohort as 
described herein. The DLT assessment period for all Phase 1 patients is 28 days. 
The starting dose of SD-101 will be 2.0 mg administered intratumorally and will be 
given to 1 sentinel patient. If the sentinel patient does not experience a DLT within 
72 hours, the second patient in the cohort may be dosed. If no DLT is experienced in the 
second patient after 72 hours, the third and subsequent patients may be dosed. If a DLT 
is experienced in the first sentinel patient within 72 hours of injection, a second sentinel 
patient may be dosed with SD-101 following a safety review and an evaluation of 
safe to proceed. If no DLT is observed after 72 hours in the second sentinel patient, the 
third and subsequent patients in the cohort may be enrolled. 
If there is no DLT observed in the group of 3 or more patients, the next cohort will be 
enrolled, and escalation will proceed to the next highest dose with a sentinel patient 
receiving SD-101 at least 72 hours prior to dosing of subsequent patients. 
If a DLT is observed in 1 patient in the first 3 patients enrolled in a cohort, enrollment 
will proceed and the cohort size will be increased up to 6 patients.  
Screening
EOS
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
Day:
-28
1
8
15
22
29
43
64
85 106 127 148 169 190 … Q21Days…
715
Week:
-4
0
1
2
3
4
6
9
12
15
18
21
24
27 … Q3Weeks…
102
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
DLT = dose limiting toxicity; EOS = end of study; Q = every; × = times.
Note:  SD-101 is administered intratumorally. SD-101 is administered prior to pembrolizumab on the days when patients receive 
both treatments.
Trial Treatment
Extended Pembrolizumab 
Treatment
SD-101
Dose Q1 week × 4 followed by dose Q3 weeks × 7
 (11 doses)
EOS visit 28 
days after 
last dose
DLT Assessment Period
Pembrolizumab
Dose Q3 weeks × 2 years (up to 35 doses)


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 17 of 163 
If only 1 DLT is observed in 6 patients in a cohort, escalation will proceed, and the next 
cohort may begin enrollment. 
A minimum of 3 patients will be enrolled in each cohort. The sponsor may also decide 
to enroll up to 6 patients initially into a cohort. The maximum allowed DLTs per cohort 
to allow subsequent Dose Escalation is 1 DLT observed in 6 patients. If ≥ 2 of 6 patients 
experience a DLT in any cohort, Dose Escalation will cease and the previous lower dose 
of SD-101 may be designated the maximum tolerated dose (MTD).  
The planned dose cohorts for SD-101 are 2.0 mg, 4.0 mg, and 8.0 mg. Dose Escalation 
will continue until an MTD is determined, or a maximum planned dose (ie, a total body 
dose of 8.0 mg) is reached. A 1.0 mg dose cohort, added in Amendment 4 of this 
protocol, will not require staggered enrollment with a sentinel patient and may be 
enrolled concurrently with the higher dose cohorts. Decisions to escalate the dose of 
SD-101 to the next highest level will be based on review of safety data from the time of 
the first injection (Day 1) through Day 29 (the DLT assessment period). If 1 DLT in 
6 patients or 2 Grade 2 adverse events (AEs) considered drug-related (except for 
malaise, headache, myalgia, fatigue, or chills) occur in 3 patients in a dose cohort, the 
Dose Escalation increment for the next dosing cohort will be decreased from 100% to 
50%. Intra-patient Dose Escalation is not permitted.  
The RP2D of SD-101 given in combination with pembrolizumab will be chosen based 
on all available data including efficacy, safety, and pharmacodynamic biomarkers (eg, 
IFN-inducible gene signature and tumor-infiltrating lymphocytes). The sponsor may 
also choose to investigate lower dose level(s) and enroll 3 or more additional patients 
prior to Phase 2. A minimum of 6 patients must have been dosed and cleared of DLT 
either at the identified RP2D or higher before Phase 2 is initiated. If no more than 1 
DLT in 6 total patients is observed at a dose level, then the dose will be declared as the 
RP2D for use in Phase 2 of this trial. Once the RP2D is determined, an additional 6 
patients may be enrolled to assess safety at this dose. The RP2D must not exceed the 
MTD. 
Phase 2 Dose Expansion (CLOSED) 
NOTE: As of Amendment 9, enrollment in Phase 2 of the trial is closed. Enrolled 
patients should continue receiving their assigned treatment per protocol. 
Study Cohorts 
Melanoma  
As described in the table below, melanoma Dose Expansion cohorts in Phase 2 will be 
treated with 8.0 mg or 2.0 mg of SD-101 in combination with 200 mg pembrolizumab 
every 3 weeks across 3 cohorts. Phase 2 Expansion Cohort 1 will enroll approximately 
60 and Cohort 5 will enroll approximately 25 anti-PD-1/L1 naïve patients with 
melanoma. Cohort 2 will enroll approximately 25 and Cohort 8 will enroll 
approximately 50 melanoma patients who have disease progression on anti-PD-1/L1 
therapy. In melanoma Dose Expansion Cohort 1, SD-101 dosing starts on Day 22 at the 
second dose of pembrolizumab; whereas, in Cohorts 2, 5, and 8, SD-101 and 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 18 of 163 
pembrolizumab dosing both start on Day 1 (See flow diagram below for dosing 
schedule). 
Phase 2 Melanoma Dose Expansion Cohorts (CLOSED) 
Cohort Anti-PD-1/L1 
Experience 
SD-101 Dose 
n 
Dosing 
Schemaa 
1 
Naïve 
8.0 mg in a single injectable lesion if 
1 lesion is selected (Lesion A) or 2.0 mg 
per lesion if 2 to 4 lesions are selected for 
injection (Lesion A, Lesion B, Lesion C, 
Lesion D) 
Approximately 
60 
B 
2 
Experiencedb 8.0 mg in a single injectable lesion 
(Lesion A) 
Approximately 
25 
A 
5 
Naïve 
2.0 mg per lesion in 1 to 4 injectable 
lesions (Lesion A, Lesion B, Lesion C, 
Lesion D) 
Approximately 
25 
A1 
8 
Refractory or 
resistantc 
2.0 mg in 1 ml per injection in 1 to 
4 separate lesions for lesions measuring up 
to 5 cm in the longest diameter; or for 
lesions larger than 5 cm, 2.0 mg in 1 ml per 
injection in 1 to 4 separate regions where 
the injections are ≥ 5 cm apart (maximum 
total dose is 8.0 mg)  
Approximately 
50 
A1 
Anti-PD-1/L1 = anti-programmed death receptor-1/ligand 1. 
a 
Dosing Schema: 
A: SD-101 and pembrolizumab dosing both start on Day 1 and patients receive 2 courses of SD-101 
(each course, separated by 9 weeks, is 4 weekly doses and then every 3 weeks on schedule with 
pembrolizumab for 7 additional doses) 
B: SD-101 dosing starts on Day 22 at the second dose of pembrolizumab and patients receive 
2 courses of SD-101 (each course, separated by 9 weeks, is 4 weekly doses and then every 3 weeks on 
schedule with pembrolizumab for 7 additional doses) 
A1: SD-101 and pembrolizumab dosing both start on Day 1 and patients receive 1 course of SD-101 
(4 weekly then every 3 weeks on schedule with pembrolizumab up to Week 51) 
b 
Received prior treatment regimen containing an anti-PD-1/L1 drug. 
c 
Received at least 2 doses of an anti-PD-1/L1 therapy and experienced PD within 3 months after last 
dose of anti-PD-1/L1 therapy. Anti-PD-1/L1 refractory or resistant patients must have documented 
PD per RECIST v.1.1, which has been confirmed by a second scan at least 4 weeks from the date of 
the first documented PD, in the absence of rapid clinical progression. 
 
HNSCC 
As described in the table below, HNSCC Dose Expansion cohorts in Phase 2 will be 
treated with 8.0 mg or 2.0 mg of SD 101 in combination with 200 mg pembrolizumab 
every 3 weeks across 4 cohorts. Phase 2 Expansion Cohorts 3 and 6 will each enroll 
approximately 25 anti-PD-1/L1 naïve patients. Cohorts 4 and 7 will each enroll 
approximately 25 HNSCC patients who have disease progression on anti-PD-1/L1 
therapy. In HNSCC Dose Expansion Cohort 3, SD-101 dosing starts on Day 22 at the 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 19 of 163 
second dose of pembrolizumab; whereas, in Cohorts 4, 6 and 7, SD-101 and 
pembrolizumab dosing both start on Day 1 (See flow diagram below for dosing 
schedule). 
Phase 2 HNSCC Dose Expansion (CLOSED) 
Cohor
t 
Anti-PD-
1/L1 
Experience 
SD-101 Dose 
n 
Dosing 
Schemaa 
3 
Naïve 
8.0 mg in a single injectable lesion 
(Lesion A)b  
Approximately 
25 
B 
4 
Experiencedc 8.0 mg in a single injectable lesion 
(Lesion A)b 
Approximately 
25 
A 
6 
Naïve 
2.0 mg per lesion in 1 to 4 
injectable lesions (Lesion A, Lesion 
B, Lesion C, Lesion D) 
Approximately 
25 
A1 
7 
Refractory or 
resistantd 
2.0 mg per lesion in 1 to 4 
injectable lesions (Lesion A, Lesion 
B, Lesion C, Lesion D) 
Approximately 
25 
A1 
Anti-PD-1/L1 = anti-programmed death receptor-1/ligand 1. 
a 
Dosing Schema: 
A: SD-101 and pembrolizumab dosing both start on Day 1 and patients receive 2 courses of 
SD-101 (each course, separated by 9 weeks, is 4 weekly doses and then every 3 weeks on 
schedule with pembrolizumab for 7 additional doses) 
B: SD-101 dosing starts on Day 22 at the second dose of pembrolizumab and patients 
receive 2 courses of SD-101 (each course, separated by 9 weeks, is 4 weekly doses and then 
every 3 weeks on schedule with pembrolizumab for 7 additional doses) 
A1: SD-101 and pembrolizumab dosing both start on Day 1 and patients receive 1 course of 
SD-101 (4 weekly then every 3 weeks on schedule with pembrolizumab up to Week 51) 
b 
Patients receive 8.0 mg per lesion in 1 lesion with the option of injecting into up to 4 
regions within the lesion in approximate equally divided volumes of an 8.0 mg dose. 
c 
Received prior treatment regimen containing an anti-PD-1/L1 drug. 
d 
Received at least 2 doses of an anti-PD-1/L1 therapy, where the last dose of anti-PD-1/L1 
therapy was within 6 months of study enrollment (Day 1) and have either refractory 
response (PD occurred within 3 months duration of the start of treatment on anti-PD-1/L1 
therapy) OR resistant response (PD occurred beyond 3 months duration of treatment on 
anti-PD-1/L1 therapy and within 6 months after the last dose of treatment on anti-PD-1/L1 
therapy). Anti-PD-1/L1 refractory or resistant patients must have documented PD per 
RECIST v.1.1, which has been confirmed by a second scan at least 4 weeks from the date of 
the first documented PD, in the absence of rapid clinical progression. 
 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 20 of 163 
Study Dosing Schedule  
As presented in the Trial Flow Diagrams for the Dose Expansion Cohorts 1 to 4, 
patients with metastatic melanoma or HNSCC will receive 2 courses of the SD-101 dose 
regimen, with 9 weeks off between the 2 courses. In Cohorts 1 and 3, patients will have 
a lead-in dose of pembrolizumab at Day 1 and start the treatment course on Day 22; 
whereas, in Cohorts 2 and 4, SD-101 and pembrolizumab treatments will both start on 
Day 1. 
Metastatic melanoma or HNSCC patients in Cohorts 5, 6, 7, and 8 will receive 1 course 
of SD-101 (4 weekly then every 3 weeks on schedule with pembrolizumab up to 
Week 51) and dosing with SD-101 and pembrolizumab will both start on Day 1. 
Pembrolizumab 200 mg will be administered intravenously every 3 weeks until disease 
progression or up to 2 years. SD-101 will be administered before pembrolizumab on 
days when both drugs are scheduled to be used. 
 
Trial Flow Diagram for Dose Expansion Cohorts 1 and 3 (CLOSED) 
 
Screening
EOS
↓↓
↓
↓↓↓↓↓↓↓↓↓↓
↓
↓↓↓↓↓↓↓
↓
↓
↓
Day:
-28
1
22
29
36
43
64
85
106
127
148
169
190
211
232
253
260
267
274
295
316
337
358
379
400
421
442
… Q21Days…
715
Week:
-4
0 3 4 5 6
9 12 15 18 21 24 27 30 33 36 37 38 39
42 45 48 51 54 57 60 63… Q3Weeks… 102
↑↑↑↑
↑↑↑↑↑↑↑
↑↑↑↑
↑↑↑↑↑↑↑
EOS = end of study; Q = every; × = times.
Note:  SD-101 is administered intratumorally. SD-101 is administered prior to pembrolizumab on the days when patients receive both treatments.
Pembrolizumab
Dose Q3 weeks × 2 years (up to 35 doses)
EOS visit 28 
days after 
last dose
SD-101
Dose Q1 week × 4 followed by dose Q3 weeks × 7, then 9 weeks off, and then Dose 
Q1 week × 4 followed by dose Q3 weeks × 7 (22 doses)
Trial Treatment
Extended 
Pembrolizumab 
Treatment


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 21 of 163 
Trial Flow Diagram for Dose Expansion Cohorts 2 and 4 (CLOSED)  
 
 
 
Trial Flow Diagram for Dose Expansion Cohorts 5, 6 , 7, and 8 (CLOSED) 
 
 
Phase 1 and Phase 2 - Disease Assessment 
NOTE: As of Amendment 9, the trial will stop collecting all efficacy endpoints. 
Assessments of disease response to treatment should be made per Investigator 
based on local standard of care. This section has been modified accordingly. 
Disease response and progression will be assessed by the investigator based on 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. If imaging 
Screening
EOS
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
Day:
-28
1
8
15
22
43
64
85
106
127
148
169
190
211
232
253
274
295
316
337
358
379
715
Week:
-4
0
1
2
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
102
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
SD-101 (Intra-tumoral)
Dose Q1 week × 4, followed by dose Q3 weeks × 16 (up to 20 doses)
EOS = end of study; Q = every; × = times.
Note:  SD-101 is administered intratumorally. SD-101 is administered prior to pembrolizumab on the days when patients receive both 
treatments.
EOS visit 28 
days after 
last dose
Trial Treatment
Extended 
Pembrolizumab 
Treatment
… Q21Days…
… Q3Weeks…
Pembrolizumab (Intravenous)
Dose Q3 weeks × 2 years (up to 35 doses)
Screening
EOS
↓
↓
↓↓↓↓↓↓↓↓↓↓
↓
↓↓↓↓↓↓↓↓
↓
↓
Day:
-28
1
8
15
22
43
64
85
106
127
148
169
190
211
232
239
246
253
274
295
316
337
358
379
400
421
… Q21Days…
715
Week:
-4
0 1 2 3
6 9 # # # # # # # # # # #
# # # # # # # # … Q3Weeks…102
↑↑↑↑
↑↑↑↑↑↑↑
↑↑↑↑
↑↑↑↑↑↑↑
Trial Treatment
Extended 
Pembrolizumab 
Treatment
Pembrolizumab
Dose Q3 weeks × 2 years (up to 35 doses)
SD-101
Dose Q1 week × 4 followed by dose Q3 weeks × 7, then 9 weeks off, and then 
Dose Q1 week × 4 followed by dose Q3 weeks × 7 (22 doses)
EOS = end of study; Q = every; × = times.
Note: SD-101 is administered intratumorally. SD-101 is administered prior to pembrolizumab on the days when patients receive both 
treatments.
EOS visit 28 
days after last 
dose


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 22 of 163 
performed per local standard of care indicates disease progression (PD), it is at the 
discretion of the investigator whether to repeat imaging for confirmation of PD as per 
local assessment guidelines. 
The protocol also allows patients who are clinically stable and have unconfirmed PD to 
continue on pembrolizumab and SD-101 per investigator decision. Patients must 
discontinue all study treatment for confirmed PD. 
Patients who discontinue pembrolizumab must discontinue SD-101. Pembrolizumab 
may be continued as a single agent if SD-101 is discontinued per investigator decision. 
Specific procedures to be performed during the trial are described in the Schedule of 
Trial Events. The statistical methods section of the protocol describes the analysis of 
data collected in the trial. 
Trial 
Population: 
The trial population includes a total of approximately 284 men and women with at least 
1 site of disease that qualifies as a target lesion per RECIST v1.1 and is accessible for 
intratumoral injection. 
Phase 1 Dose Escalation Cohorts 1-4 will include up to 24 patients with metastatic 
melanoma who are anti-PD-1 naïve or experienced. 
Phase 2 Dose Expansion will include approximately 160 patients with metastatic 
melanoma and approximately 100 patients with recurrent or metastatic HNSCC: 
1) Expansion Cohort 1 of approximately 60 melanoma patients who are anti-PD-1/L1 
naïve 
2) Expansion Cohort 2 of approximately 25 melanoma patients who have disease 
progression on anti-PD-1/L1 therapy  
3) Expansion Cohort 3 of approximately 25 HNSCC patients who are anti-PD-1 naïve 
4) Expansion Cohort 4 of approximately 25 HNSCC anti-PD-1/L1 who have disease 
progression on anti-PD-1/L1 therapy 
5) Expansion Cohort 5 of approximately 25 melanoma patients who are anti-PD-1/L1 
naïve 
6) Expansion Cohort 6 of approximately 25 HNSCC patients who are anti-PD-1/L1 
naïve 
7) Expansion Cohort 7 of approximately 25 HNSCC patients who are refractory or 
resistant on anti-PD-1/L1 therapy 
8) Expansion Cohort 8 of approximately 50 melanoma patients who are refractory or 
resistant to anti-PD-1/L1 therapy 
Trial Period: The total duration of patient participation in this trial is up to approximately 110 weeks. 
This includes a Screening period beginning up to 28 days prior to the first trial 
treatment, and a trial completion visit approximately 28 days after the last dose of trial 
treatment.  


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Safety 
Evaluation: 
NOTE: As of Amendment 9, Phase 1 of the trial is complete. Phase 2 of the trial 
has been modified to simplify collection of safety endpoints. This section has been 
updated accordingly. 
A number of measures will be taken to ensure the safety of patients participating in this 
trial. These measures will be addressed through inclusion/exclusion criteria and routine 
safety monitoring. In addition, safety data monitoring during Phase 1 will be reviewed 
by a Safety Review Team comprised of the Dynavax Medical Monitor, Phase 1 
coordinating investigator, and other key safety Dynavax personnel as described in the 
Cohort Safety Review Plan. 
In Phase 1, during the DLT assessment period, patients will undergo targeted physical 
examinations and laboratory assessments, which will include a complete blood count 
(CBC) with differential, platelet assessment, coagulation testing, thyroid function tests, 
and serum chemistry (including creatinine, liver function tests, and lactate 
dehydrogenase [LDH]). 
In Phase 1, after the DLT assessment period, safety will be evaluated through the 
monitoring of the results of all clinical and laboratory assessments. Safety assessments 
will include specified laboratory parameters (eg, CBC, thyroid function, serum 
chemistry). 
In Phase 1, standard safety monitoring will be employed for DLT assessment and 
dose-escalation decisions. Before Dose Escalation at each dose level of SD-101 and at 
any other time during Phase 1 or Phase 2 that warrants additional review due to 
emerging safety data, the investigators will discuss and review the safety data with the 
Dynavax Medical Monitor. 
Prior to the first 4 initial weekly injections of SD-101 in Phase 1, patients will receive a 
new Diary Card with instructions to measure and record local injection-site reactions 
and solicited AEs. The completed Diary Cards will be reviewed with patients at their 
next study visit. 
In Phase 2, safety assessments prior to dosing will be performed according to the local 
standard of care. The investigator will follow all related AEs observed during the trial 
until the AEs are considered resolved or until 28 days after the last dose of trial 
treatment and/or the patient begins new anti-cancer therapy (whichever is earlier). 
Serious adverse events (SAEs) will be evaluated from the time of consent through 
90 days following cessation of trial treatment or End of Study (EOS) (whichever is 


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Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
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later), or 28 days following cessation of trial treatment if the patient initiates new 
anti-cancer therapy. 
New cancers (not the cancer being investigated under the study), whether AEs or SAEs, 
will be collected. 
Events of clinical interest (eg, overdoses), whether AEs or SAEs, will be collected and 
followed per the AE and SAE reporting processes. 
Overdose of SD-101 or pembrolizumab is considered an Event of Clinical Interest (ECI) 
and will be collected and reported irrespective of the presence of an associated AE or 
SAE. 
Progression of the cancer under study is not considered an AE or an SAE and should not 
be reported as an AE or SAE. 
Other 
Assessments: 
NOTE: As of Amendment 9, Phase 1 of the trial is complete and enrollment in 
Phase 2 is closed. Phase 2 of the trial has been modified to continue dosing per 
protocol. The trial will stop collecting all efficacy endpoints. Assessments of disease 
response should be made per Investigator based on local standard of care and 
assessment guidelines. This section has been modified accordingly 
All patients will undergo safety assessments, pharmacodynamic testing, tumor response 
assessments, and tumor biopsies at specified trial visits, as indicated in the Schedule of 
Trial Events (Appendix 1 through Appendix 4). 
Disease Assessment Prior to Treatment 
After informed consent is obtained, disease assessments prior to treatment will include: 
• 
Complete physical examination including assessment of superficial lesions with 
photographic documentation 
• 
Radiographic imaging including computed tomography (CT) (preferred) or 
magnetic resonance imaging (MRI) scans of the brain, chest, abdomen, pelvis, and 
other areas, as clinically indicated. In addition, screening imaging for HNSCC 
patients requires imaging of the neck. 
• 
Laboratory assessments 
• 
Baseline confirmation of PD-L1 expression from a biopsy of the target lesion 
(Lesion A) that will be injected with SD-101 in Phase 2 Expansion patients. A 
baseline biopsy should be collected within 28 days prior to the initiation of study 
treatment. Archival tissue within 3 months of screening is acceptable.  
• 
Copy of pathology report confirming diagnosis 
Assessment of Disease Response to Treatment  
Disease assessment may include physical examination and CT scans (or MRI) as per 
local standard of care.  


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SD-101 
 
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Trial 
Treatments: 
Treatments 
• 
Pembrolizumab 
• 
SD-101 
Dosage and Administration 
In both Phase 1 and Phase 2, patients will receive 200 mg pembrolizumab intravenously 
for up to 35 doses. Intra-patient Dose Escalation or reduction is not permitted. Up to 
11 doses of SD 101 in Phase 1 and 22 doses in Phase 2 will be administered in 
combination with pembrolizumab. 
The table below presents the dosage and dose administration for each study cohort. 
Phase 1 Metastatic Melanoma  
In Phase 1 Escalation Cohorts 1-4, SD-101 is injected intratumorally into a target lesion 
(Lesion A), the same site used throughout the trial. If at any point during treatment, the 
lesion for injection has completely regressed and there is no other replacement lesion, 
SD-101 will be injected peritumorally for up to the next 3 doses of SD-101 within the 
dosing cycle.  
Phase 2  
In all Phase 2 cohorts, a lesion designated as Lesion A must be selected and must meet 
the requirement of being a target lesion as defined per RECIST v1.1 and amenable to 
multiple intratumoral injections of SD-101. If a selected lesion regresses and/or 
becomes inaccessible for injection, then a replacement lesion, which could be either a 
target, non-target, or new lesion per RECIST v1.1, may be chosen for injection at 
subsequent dosing time points. Injection into a new lesion may occur only after 
consultation with the Dynavax MM. 
If at any point during treatment, the lesion for injection has completely regressed and 
there is no other replacement lesion, SD-101 will be injected peritumorally for up to the 
next 3 doses of SD-101.  
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Approval from the Medical Monitor is required 
to inject a previously radiated lesion. 
 
 
 
 
 


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Dosage and Dose Administration for Phase 1 and Phase 2 Cohorts 
Cohort 
Anti-PD-1/L1 
Experience 
SD-101 Dose 
Maximum 
Total Per-
patient SD-101 
Dose 
Phase 1 Melanoma Dose Escalation Cohorts 
 
1 
Naïve or experienced 2.0 mg per lesion in 1 injectable lesion (Lesion A) 
2.0 mg 
2 
Naïve or experienced 4.0 mg per lesion in 1 injectable lesion (Lesion A) 
4.0 mg 
3 
Naïve or experienced 8.0 mg per lesion in 1 injectable lesion (Lesion A) 
8.0 mg 
4 
Naïve or experienced 1.0 mg per lesion in 1 injectable lesion (Lesion A) 
1.0 mg 
Phase 2 Melanoma Dose Expansion Cohorts 
 
1 
Naïve 
8.0 mg in a single injectable lesion if 1 lesion is selected 
(Lesion A) or 2.0 mg per lesion if 2 to 4 lesions are selected for 
injection (Lesion A, Lesion B, Lesion C, Lesion D) 
8.0 mg 
2 
Experienced 
8.0 mg in a single injectable lesion (Lesion A) 
8.0 mg 
5 
Naïve 
2.0 mg per lesion in 1 to 4 injectable lesions (Lesion A, 
Lesion B, Lesion C, Lesion D) 
8.0 mg 
8 
Refractory or resistant 
2.0 mg in 1 ml per injection in 1 to 4 separate lesions for 
lesions measuring up to 5 cm in the longest diameter; or for 
lesions larger than 5 cm, 2.0 mg in 1 ml per injection in 
1 to 4 separate regions where the injections are ≥ 5 cm apart 
(maximum total dose is 8.0 mg) 
8.0 mg 
Phase 2 HNSCC Dose Expansion Cohorts 
 
3 
Naïve 
8.0 mg per lesion in 1 lesion with the option of injecting into up 
to 4 regions within the lesion in approximate equally divided 
volumes of an 8.0 mg dose 
8.0 mg 
4 
Experienced 
8.0 mg per lesion in 1 lesion with the option of injecting into up 
to 4 regions within the lesion in approximate equally divided 
volumes of an 8.0 mg dose 
8.0 mg 
6 
Naïve 
2.0 mg per lesion in 1 to 4 injectable lesions (Lesion A, 
Lesion B, Lesion C, Lesion D) 
8.0 mg 
7 
Refractory or resistant 2.0 mg per lesion in 1 to 4 injectable lesions (Lesion A, 
Lesion B, Lesion C, Lesion D) 
8.0 mg 
Please refer to the Pharmacy Manual for additional details on dose administration. 
 


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Eligibility 
Criteria: 
 
CLOSED 
Inclusion Criteria (Phase 1) 
A patient must meet all of the following criteria to be eligible for enrollment (defined as 
receiving the first trial treatment [ie, pembrolizumab or SD-101]) in the trial: 
1) Willing and able to provide written informed consent for the trial 
2) Aged 18 years and older 
3) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 
4) Patient must have adequate organ function as indicated by the following laboratory 
values: 
Hematological 
• 
Absolute neutrophil count (ANC) ≥ 1,500 /mcL 
• 
Platelet count ≥ 100,000 /mcL 
• 
Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L 
Renal 
• 
Serum creatinine ≤ 1.5 × upper limit of normal (ULN) OR 
• 
Measured or calculated creatinine clearance (GFR can also be used in place 
of creatinine or CrCl) ≥ 60 mL/min for subject with creatinine levels > 
1.5 × institutional ULN 
Hepatic 
• 
Serum total bilirubin: 
• 
≤ 1.5 × ULN OR 
• 
< 3 × ULN for persons with Gilbert’s syndrome OR 
• 
Direct bilirubin ≤ ULN for patients with total bilirubin levels > 
1.5 × ULN 
• 
Aspartate transaminase (AST) and alanine transaminase (ALT) (also known 
as serum glutamic oxaloacetic transaminase and serum glutamic pyruvic 
transaminase) 
• 
≤ 2.5 × ULN OR 
• 
≤ 5 × ULN for patients with liver metastases 
Coagulation 
• 
International normalized ratio or prothrombin time (PT) ≤ 1.5 × ULN 
unless patient is receiving anticoagulant therapy, and as long as PT or 
partial thromboplastin time (PTT) is within therapeutic range of intended 
use of anticoagulants  


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• 
Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless patient is 
receiving anticoagulant therapy, and as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants 
5) Have provided 2 tissue biopsy samples taken of the target lesion (Lesion A) as a 
single biopsy split into 2 samples or 2 separate biopsies that meet the minimal 
sample size requirement per the study laboratory manual. One sample is for 
determining PD-L1 expression level by immunohistochemistry and can be an 
archival sample of the anticipated target lesion that has been collected within 
3 months of screening. The other sample is for RNA expression profiling and must 
be a fresh biopsy. 
6) Life expectancy of at least 6 months 
7) Female patients of childbearing potential, as defined in this protocol, must have a 
negative urine or serum pregnancy test within 72 hours prior to taking the first dose 
of trial treatment. If the urine test is positive or cannot be confirmed as negative 
then a serum test is required which must be negative for the patient to enroll. 
Women of childbearing potential (WOCBP) must be willing to use 2 medically 
acceptable methods of contraceptive from Day 1 through 120 days after the last 
dose of trial treatment. The 2 medically acceptable birth control methods can be 
either 2 barrier methods or a barrier method plus a hormonal method to prevent 
pregnancy. 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, subcutaneous, 
intrauterine, or intramuscular agents). 
Male patients of childbearing potential, as described in this protocol, must agree to 
use an adequate method of contraception from Day 1 through 120 days after the last 
dose of trial treatment. 
Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the patient. 
Inclusion Criteria (Phase 1 only: Melanoma) 
A patient must meet the following to be eligible for Phase 1: 
8) Histologically or cytologically confirmed unresectable or metastatic (stage IV) 
melanoma 
9) For Phase 1 Escalation Cohorts 1-4, must have at least 1 lesion that qualifies as a 
target lesion per RECIST v1.1 except for the minimum measurement of 10 mm in 
diameter for superficial lesions, is easily accessible (palpable or can be visualized 
by ultrasound), and is amenable to multiple intratumoral injections. If superficial, 
the target lesion must be documented photographically. 


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Inclusion Criteria (Phase 2 only: Melanoma) 
A patient must meet the following to be eligible for Phase 2 (as applicable to the 
expansion cohorts): 
10) Histologically or cytologically confirmed recurrent or unresectable or metastatic 
(stage IV) melanoma 
11) Must have at least 2 lesions that qualify as a target lesion per RECIST v1.1, and 1 of 
the qualifying lesions must be easily accessible (palpable or can be visualized by 
ultrasound) and amenable to multiple intratumoral injections. The target lesion 
should be of sufficient size such that the required tumor biopsies do not 
significantly affect tumor assessment per RECIST v1.1. If superficial, the target 
lesion must measure at least 10 mm in diameter, be measured by calipers, and be 
documented photographically. Tumor lesions situated in a previously irradiated 
area, or in an area subjected to other loco-regional therapy, are usually not 
considered measurable unless there has been demonstrated progression in the lesion. 
Approval from the Medical Monitor is required to inject a previously radiated 
lesion. 
12) Expansion Cohort 2: Must have documented PD per RECIST v1.1 on a prior 
treatment regimen containing an anti-PD-1/L1 drug (see Appendix 6 for definition 
of PD per RECIST v1.1) 
13) Expansion Cohort 8: Must have all of the following:  
a) Received at least 2 doses of an anti-PD-1/L1 therapy 
b) PD occurred within 3 months after last dose of anti-PD-1/L1 therapy 
c) Documented PD per RECIST v.1.1, which has been confirmed by a second 
assessment at least 4 weeks from the date of the first documented PD, in the 
absence of rapid clinical progression 
Inclusion Criteria (Phase 2 only: HNSCC) 
A patient must meet the following to be eligible for Phase 2 (as applicable to the 
expansion cohorts): 
14) Histologically or cytologically confirmed recurrent or metastatic HNSCC that could 
not be treated with curative intent. 
15) Must have at least 1 lesion that qualifies as a target lesion per RECIST v1.1, and 
which must be easily accessible (palpable or can be visualized by ultrasound) and 
amenable to multiple intratumoral injections. The target lesion should be of 
sufficient size such that the required tumor biopsies do not significantly affect tumor 
assessment per RECIST v1.1. Tumor lesions situated in a previously irradiated area, 
or in an area subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the lesion. Approval 
from the Medical Monitor is required to inject a previously radiated lesion. 


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16) Expansion Cohort 4: Must have documented PD per RECIST v1.1 on a prior 
treatment regimen containing an anti-PD-1/L1 drug (see Appendix 6 for definition 
of PD per RECIST v1.1) 
17) Expansion Cohort 7: Must have all of the following:  
a) Received at least 2 doses of an anti-PD-1/L1 therapy, where the last dose of 
anti-PD-1/L1 therapy was within 6 months of study enrollment (Day 1) 
b) Refractory response, ie, PD occurred within 3 months duration of the start of 
treatment on anti-PD-1/L1 therapy; OR resistant response, ie, PD occurred 
beyond 3 months duration of treatment on anti-PD-1/L1 therapy and within 
6 months after the last dose of treatment on anti-PD-1/L1 therapy 
c) Documented PD per RECIST v.1.1, which has been confirmed by a second 
assessment at least 4 weeks from the date of the first documented PD, in the 
absence of rapid clinical progression 
 
Exclusion Criteria (Phase 1 and Phase 2) 
A patient with any 1 of the following criteria is not eligible for enrollment in the trial: 
1) Received systemic chemotherapy or biological cancer therapy (except anti-PD-1/L1 
therapy) within 3 weeks prior to study enrollment 
2) Received prior radiotherapy within 2 weeks of start of study therapy. A shorter 
washout period may be permitted after approval by the Medical Monitor. 
3) Received small molecule inhibitor targeted therapy, such as tyrosine kinase 
inhibitors, within 2 weeks prior to study enrollment 
4) Has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 1 or better from the AEs due to cancer therapeutics prior to study enrollment 
NOTE: Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia or Grade 2 AEs 
that qualify as Grade 2 due to replacement hormonal or steroid therapy are 
exceptions to this criterion and may qualify for the study with approval by a 
Dynavax Medical Monitor.  
If a patient received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to enrollment. 
5) Received a transfusion of blood products (including platelets or red blood cells) or 
colony-stimulating factors (including G-CSF, GM-CSF or recombinant 
erythropoietin) within 4 weeks prior to study enrollment 
6) Is expected to require any other form of anti-cancer therapy while in the trial 
7) Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy (including immune modulators or 
systemic corticosteroids) within 7 days prior to study enrollment 


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8) Positive for active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) 
infection as determined by laboratory tests for HBsAg, anti-HBc, and anti-HBs; 
anti-HCV; and anti-HIV -1/2, respectively 
9) History of or current uveal or ocular or mucosal melanoma 
10) Active infection including cytomegalovirus 
11) Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial through 120 days after the last dose of trial treatment 
12) Active autoimmune disease requiring systemic treatment in the past 2 years or a 
disease that requires immunosuppressive medication including systemic lupus 
erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren’s syndrome, or 
autoimmune thrombocytopenia. Replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency) is not considered a form of systemic treatment. 
13) Current pneumonitis or history of (non-infectious) pneumonitis that required 
steroids 
14) An immune-related AE from a previous immunotherapeutic agent that has not 
resolved to Grade 1 or less prior to study enrollment. The exception is a Grade 2 AE 
which qualifies as Grade 2 due to replacement steroid therapy which may be 
allowed with approval by a Dynavax Medical Monitor. 
15) Known active central nervous system metastases or carcinomatous meningitis 
NOTE: Patients with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging [using the identical 
imaging modality for each assessment, either MRI or CT scan] for at least 4 weeks 
prior to the first dose of trial treatment and with any neurologic symptoms returned 
to baseline), have no evidence of new or enlarging brain metastases, and are not 
using steroids for at least 7 days prior to trial treatment. This exception does not 
include carcinomatous meningitis which is excluded regardless of clinical stability. 
16) Use of any investigational agent within the last 28 days prior to study enrollment 
17) Has received a live-virus vaccination within 30 days of planned treatment start. 
Seasonal flu vaccines that do not contain live virus are permitted. 
18) Any other significant medical or psychiatric condition, laboratory abnormality, or 
difficulty complying with protocol requirements that may increase the risk 
associated with trial participation or trial drug administration that may interfere with 
the interpretation of trial results and, in the judgment of the investigator, would 
make the patient inappropriate for this trial 
19) History of sensitivity to any component of SD-101 or hypersensitivity reaction to 
treatment with a monoclonal antibody and/or any of its excipients 
20) Any known additional malignancy that is progressing or requires active treatment. 
Exceptions are cutaneous melanoma or HNSCC under study per protocol, or basal 


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cell carcinoma of the skin, squamous cell carcinoma of the skin or in situ cervical 
cancer that has undergone potentially curative therapy. 
Exclusion Criteria (Phase 2, Melanoma Expansion Cohorts 1 and 5 only) 
21) Melanoma considered resectable with curative intent 
22) Prior therapy with an anti-PD-1/L1 agent  
23) Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its 
excipients 
Exclusion Criteria (Phase 2, Melanoma Expansion Cohorts 2 and 8 only) 
24) Melanoma considered resectable with curative intent 
25) Any prior combination therapy involving agents given by intratumoral injection that 
target the innate immune pathway or system such as oncolytic viral or microbial 
therapy (eg, T-VEC [talimogene laherparepvec]), toll-like receptors (TLR) agonists, 
STING or RIG-1 and an anti-PD-1/L1 inhibitor 
Exclusion Criteria (Phase 2, HNSCC Expansion Cohorts 3 and 6 only) 
26) HNSCC considered resectable with curative intent 
27) Prior therapy with an anti-PD-1/L1 agent 
28) Require anticoagulation therapy 
Exclusion Criteria (Phase 2, HNSCC Expansion Cohorts 4 and 7 only) 
29) HNSCC considered resectable with curative intent 
30) Any prior combination therapy involving agents given by intratumoral injection that 
target the innate immune pathway or system such as oncolytic viral or microbial 
therapy (eg, T-VEC), TLR agonists, STING or RIG-1 and an anti-PD-1/L1 inhibitor 
31) Require treatment on anticoagulation therapy 
Trial 
Endpoints: 
NOTE: As of Amendment 9, Phase 1 of the trial is complete. Phase 2 of the trial 
has been modified to continue dosing per protocol; however, efficacy and 
exploratory endpoints will no longer be collected. The collection of safety 
endpoints has been simplified. This section has been modified accordingly. 
 
Phase 1 
Primary Endpoints  
• 
Incidence of DLTs 
• 
Incidence of injection-site reactions, AEs, and SAEs 
• 
Changes in the expression of IFN-inducible genes in whole blood 


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Exploratory Endpoints 
• 
Objective response rate (ORR) per RECIST v1.1  
• 
Disease control rate (DCR) per RECIST v1.1  
• 
Time to response per RECIST v1.1  
• 
Changes in tumor-infiltrating lymphocytes, PD-L1 expression, and other gene 
expression in tumor biopsies 
Phase 2 
Primary Endpoints - No longer collected as of Amendment 9 
• 
ORR per RECIST v1.1  
Secondary Endpoints  
• 
Incidence of injection-site reactions, AEs, and SAEs 
The following Secondary Endpoints (Phase 2) will not be collected as of 
Amendment 9: 
• 
Time to response per RECIST v1.1 
• 
Duration of response per RECIST v1.1 
• 
Radiographic PFS per RECIST v1.1 
• 
Exploratory Endpoints - No longer collected as of Amendment 9Radiographic 
primary and secondary endpoints evaluated using irRECIST 
• 
Changes in correlative biomarkers including tumor-infiltrating lymphocytes and 
PD-L1 expression at baseline and after SD-101 treatment 
• 
Changes in potential tumor neoantigens in patients with recurrent or metastatic 
HNSCC  
• 
Changes in the expression of IFN-inducible genes in whole blood in patients with 
metastatic head and neck squamous cell carcinoma 
Statistical 
Methods 
Note: As of Amendment 9, Phase 1 of the trial is complete. Analyses of data 
collected from Phase 1 will be performed as specified below. For Phase 2, the trial 
will stop collecting efficacy and exploratory endpoints, and the collection of safety 
endpoints has been simplified. Thus, after study completion, only selected analyses 
as detailed in this section will be performed and exploratory objectives will not be 
pursued.  
Phase 1 portion of this trial is designed to allow preliminary assessments of safety and 
biological activity in approximately 24 patients. All analyses of demographics, safety, 
biological activity, and biomarkers will be descriptive. 


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Injection-site reactions, AEs, SAEs, and abnormal laboratory values will be summarized 
by the proportion of patients in the all-treated population who experience them.  
Phase 2 of this trial is designed to allow preliminary assessments of efficacy, safety, and 
changes in biomarkers in approximately 160 melanoma patients and approximately 
100 HNSCC patients. All analyses of demographics, efficacy, safety, and changes in 
biomarkers will be descriptive.  
Sample size estimates for metastatic melanoma expansion cohorts: Although the 
analyses will be descriptive, the sample sizes for the expansion cohorts were determined 
based on power analyses of hypothesis tests and/or confidence intervals.  
In Expansion Cohort 1, approximately 60 anti-PD-1/L1 naïve patients with metastatic 
melanoma will be enrolled. The null hypothesis that the response rate is < 35% will be 
tested against a 1-sided alternative at a significance level of 0.05. The design will 
provide > 90% power if the true response rate is > 55%. There will be no adjustments 
for multiplicity. 
An exploratory sub-group analysis will be performed for those Expansion Cohort 1 
patients with PD-L1 negative tumors (ie, < 1% positivity) at baseline. It was estimated 
that this subgroup will have approximately 30 subjects. The analysis will have 80% 
power to reject the null hypothesis that the response rate is <15% with a 1-sided test at a 
significance level of 0.05 when the true response rate is 35%. There will be no 
adjustments for multiplicity. 
In Expansion Cohort 2, approximately 25 metastatic melanoma patients who have 
disease progression on anti-PD-1/L1 therapy will be enrolled. The null hypothesis that 
the true response rate is 10% will be tested against a 1-sided alternative and will be 
rejected if 6 or more responses are observed. This design yields a type I error rate of 
0.05 and 80% power when the true response rate is 30%. There will be no adjustments 
for multiplicity. 
In Expansion Cohort 5, approximately 25 anti-PD-1/L1 naïve melanoma patients will be 
enrolled. This will allow preliminary estimate of the response rate associated with the 
dose and dosing schedule chosen for Expansion Cohort 5. If 14 or more responses are 
observed, the 95% exact confidence interval will yield a lower bound of no less than 
37%. 
In Expansion Cohort 8, approximately 50 metastatic melanoma patients who are 
refractory or resistant to anti-PD-1/L1 therapy will be enrolled. If 13 or more responses 
are observed, the 95% exact confidence interval will yield a lower bound of no less than 
15.0%.  
Sample size estimates for HNSCC expansion cohorts: In Expansion Cohort 3, 
approximately 25 anti-PD-1/L1 naïve patients will be enrolled. The null hypothesis that 
the response rate is < 20% will be tested against a 1-sided alternative at a significance 
level of 0.05. The design will provide greater than 80% power if the true response rate is 
> 40%. There will be no adjustments for multiplicity. 
In Expansion Cohort 4, approximately 25 HNSCC patients who have disease 
progression on anti-PD-1/L1 therapy will be enrolled. The null hypothesis that the true 


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response rate is 5% will be tested against a 1-sided alternative and will be rejected if 4 
or more responses are observed. This design yields a type I error rate of 0.05 and 80% 
power when the true response rate is 21%. There will be no adjustments for multiplicity. 
In Expansion Cohort 6, approximately 25 anti-PD-1/L1 naïve HNSCC patients will be 
enrolled. This will allow preliminary estimate of the response rate associated with the 
dose and dosing schedule chosen for Expansion Cohort 6. If 9 or more responses are 
observed, the 95% exact confidence interval will yield a lower bound of no less than 
20%. 
In Expansion Cohort 7, approximately 25 patients who are refractory or resistant to 
anti-PD-1/L1 therapy will be enrolled. This will allow preliminary estimate of the 
response rate associated with the dose and dosing schedule chosen for Expansion 
Cohort 7. If 4 or more responses are observed, the 95% exact confidence interval will 
yield a lower bound of no less than 5%. 
Analyses 
Based on measurements per RECIST v1.1, ORR will be presented as the proportion of 
patients who achieved complete response (CR) or partial response (PR). DCR will be 
presented as the proportion of patients with CR, PR, or stable disease. Summary 
statistics will be provided for time to response and duration of response. 
AEs, SAEs, deaths, and abnormal laboratory values will be summarized by the 
proportion of patients who experience them. 
Summary statistics will be provided for changes in number of tumor-infiltrating 
lymphocytes and in PD-L1 and other gene expression in tumors from baseline to 
protocol-specified time points during treatment. 


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1.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Definition 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
anti-PD-1/L1 
anti-programmed death receptor-1/ligand 1 
aPTT 
activated partial thromboplastin time 
AR 
adverse reaction 
AST 
aspartate transaminase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CpG 
cytidine phosphoguanosine 
CFR 
Code of Federal Regulations 
CR 
complete response 
CRF 
case report form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein  
CSR 
Clinical Study Report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECI 
event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group  
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
End-of-Study (visit) 
FDA 
United States Food and Drug Administration 


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Abbreviation or Term 
Definition 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HNSCC 
head and neck squamous cell carcinoma 
HPV 
human papillomavirus 
HR 
hazard ratio 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IFN 
Interferon 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
irRECIST 
immune-related Response Evaluation Criteria In Solid Tumors 
LDH 
lactate dehydrogenase 
MHC 
major histocompatibility complex 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NK 
natural killer 
NSCLC 
non-small cell lung cancer 
ODN 
Oligodeoxynucleotide 
ORR 
objective response rate 
OS 
overall survival 
PBMCs 
peripheral blood mononuclear cells 
PD 
progressive disease 
PD-1 
programmed death receptor-1 
pDC 
plasmacytoid dendritic cell 
PD-L1 
programmed death-ligand 1 
PFS 
progression-free survival 
PR 
partial response 
PS 
performance status 
PT 
prothrombin time 


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Abbreviation or Term 
Definition 
PTT 
partial thromboplastin time 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose  
SAE 
serious adverse event 
SAR 
suspected adverse reaction 
SOD 
sum of diameters 
SUSAR 
suspected unexpected serious adverse reaction 
TLR9 
Toll-like receptor 9 
TSH 
thyroid stimulating hormone 
T-VEC 
talimogene laherparepvec 
ULN 
upper limit of normal 
UNS 
unscheduled visit/safety follow-up visit 
WOCBP 
women of childbearing potential 
 
 


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2.0 
INTRODUCTION AND RATIONALE 
2.1 
Melanoma and Head and Neck Squamous Cell Carcinoma  
2.1.1 
Melanoma  
Melanoma is the most serious form of skin cancer and strikes adults of all ages. In the United 
States (US), melanoma incidence rates have been increasing for at least 30 years and it was 
estimated that in 2014, approximately 76,100 patients would be diagnosed with malignant 
melanoma, and that there would be an estimated 9,710 deaths from melanoma (American Cancer 
Society 2014). Melanoma is more frequent with increasing age with the highest incidence in 
individuals 65 years of age and older (Howlader, Noone et al. 2014). 
Treatment for melanoma includes removal of the primary growth and surrounding normal tissue 
and sentinel lymph node biopsy to determine stage. More extensive lymph node surgery may be 
done if lymph node metastases are present. Melanomas with deep invasion or that have spread to 
lymph nodes may be treated with immunotherapy, radiation therapy, and/or surgery and 
chemotherapy. Advanced cases of melanoma are treated with palliative surgery, immunotherapy, 
and/or chemotherapy, and sometimes radiation therapy.  
Melanoma is more likely than other skin tumors to metastasize to other parts of the body. The 
5-year relative survival rate for persons with melanoma is 91% and highest in disease that is 
localized at diagnosis. About 84% of melanomas are diagnosed at a localized stage. For localized 
melanoma, the 5-year survival rate is 98%. However, the 5-year survival rates for regional and 
distant stage diseases are 63% and 16%, respectively (Howlader, Noone et al. 2014). 
Historically, chemotherapeutic regimens approved for use in melanoma produce responses in 
10% to 20% of patients with Stage III or IV melanoma with no impact on the overall survival 
(OS) of these patients (approximately 7 months) (National Cancer Institute 2014). BRAF and 
MEK inhibitors have been approved for melanoma with an improvement in OS but have median 
duration of responses less than 1 year (Flaherty, Robert et al. 2012, Sosman, Kim et al. 2012). 
Signal transduction inhibitors alone and in combination have shown improvements in response 
rates and OS compared to chemotherapy. A combination of dabrafenib, a BRAF inhibitor, and 
trametinib, a MEK inhibitor, led to an objective response rate (ORR) of 76% with a 
progression-free survival (PFS) of 9.4 months (Flaherty, Infante et al. 2012). Signal transduction 
inhibitors are promising but have the potential of selecting resistant tumor clones which will 
likely limit their ultimate effectiveness. Immunotherapy has the potential to overcome limitations 
of chemotherapy and possibly signal transduction inhibitors by disinhibiting the tumor immune 
response to all tumor clones. 
Two monoclonal antibodies to programmed death receptor-1 (PD-1), pembrolizumab and 
nivolumab, have been approved by United States Food and Drug Administration (FDA) for 


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treatment of metastatic melanoma (Bristol-Myers Squibb Company 2014, Merck & Co. 2015). 
Pembrolizumab is approved for the treatment of patients with unresectable or metastatic 
melanoma, for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors 
express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test and who 
have disease progression on or after platinum-containing chemotherapy, and for patients with 
recurrent or metastatic HNSCC with disease progression on or after platinum-containing 
chemotherapy. In a randomized open-label study, 834 patients with ipilimumab-naive metastatic 
melanoma were randomized to 1 of 2 doses of pembrolizumab or to ipilimumab (Merck & Co. 
2015). Pembrolizumab at 10 mg/kg either every 3 weeks (Q3W) or every 2 weeks (Q2W) 
demonstrated a statistically significant improvement in both OS and PFS compared to 
ipilimumab. OS hazard ratios were 0.69 (Q3W), 0.63 (Q2W), both compared to ipilimumab. 
Median PFS was 4.1 months (Q3W), 5.5 months (Q2W), and 2.8 months (ipilimumab). ORR 
was 33% (Q3W), 34% (Q2W) and 12% (ipilimumab). In a second trial of 540 patients with 
metastatic melanoma who had failed prior ipilimumab treatment, patients were randomized to 
pembrolizumab 2 mg/kg or 10 mg/kg given Q3W or to the investigator’s choice of 
chemotherapy. Both cohorts of pembrolizumab demonstrated a statistically significant 
improvement in PFS but no statistical difference in the interim OS analysis when compared to 
the control arm. Median PFS was 2.9 months in both pembrolizumab arms compared to 
2.7 months in the chemotherapy control arm (hazard ratio 0.57 [2 mg/kg] and 0.50 [10 mg/kg] 
compared to control). ORR was 21%, 25%, and 4% for the 2 mg/kg, 10 mg/kg, and control arm, 
respectively. Nivolumab was studied as a single agent compared to dacarbazine in a randomized 
double-blind study of 418 patients with BRAF V600 wild-type unresectable or metastatic 
melanoma (Bristol-Myers Squibb Company 2014). Nivolumab demonstrated a statistically 
significant improvement in both median OS (not reached versus 10.8 months, hazard ratio [HR] 
= 0.42, P < 0.0001) and PFS (5.1 vs 2.2 months, HR = 0.43, P < 0.0001). The ORR was 34% for 
nivolumab versus 9% for dacarbazine. In a second randomized double-blind trial of 945 patients 
with previously untreated, unresectable or metastatic melanoma, patients were randomized to 
nivolumab plus ipilimumab, nivolumab alone, or ipilimumab alone. Nivolumab, as a single agent 
or in combination with ipilimumab, demonstrated a statistically significant improvement in PFS 
compared to ipilimumab alone. Median PFS was 11.5 months (combination), 6.9 months 
(nivolumab alone), and 2.9 months (ipilimumab alone). Compared to ipilimumab alone, PFS 
HRs were 0.42 for the drug combination (P < 0.0001) and 0.57 for nivolumab alone 
(P < 0.0001). ORR was 50% (combination), 40% (nivolumab alone), and 14% (ipilimumab 
alone). 
There remains an unmet need to improve disease control and OS for patients with metastatic 
melanoma, both frontline and following progression from ipilimumab, or 1 of the approved 
anti-programmed death receptor-1/ligand 1 (anti-PD-1/L1) agents. 


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2.1.2 
Head and Neck Squamous Cell Carcinoma 
Head and neck cancer is the sixth most common cancer worldwide, with the predominant 
histology involving head and neck squamous cell carcinoma (HNSCC) (Vermorken and 
Specenier 2010). In the US, HNSCC accounts for 3% of cancers diagnosed annually and 2% of 
cancer-related deaths. The 2016 estimates for number of new cases and anticipated deaths in the 
US are approximately 62,000 and 13,000, respectively (American Cancer Society 2016). The 
majority of patients with HNSCC initially present with advanced stage disease (stage III-IV), 
requiring site-specific multimodal therapy (Vermorken and Specenier 2010). For patients who 
develop recurrent or metastatic disease that is not amenable to curative intent treatment, 
cancer-related morbidity is high and survival is dismal (Hoffman 2016). Historically, the most 
active standard cytotoxic regimens have been platinum-based and associated with response rates 
of up to 30%, with a median OS expectancy of 6 to 9 months. At present, targeted therapy added 
to cytotoxic chemotherapy results in median survival of approximately 8 months, underscoring 
the lack of durable efficacy among the most active regimens for patients with recurrent or 
metastatic HNSCC, and the urgent need to develop novel therapeutic options which prolong 
survival while optimizing quality of life (Vermorken and Specenier 2010). Nivolumab was 
compared to chemotherapy in 240 patients with recurrent or metastatic HNSCC that progressed 
within 6 months of platinum-based chemotherapy. Nivolumab demonstrated a statistically 
significant survival advantage (7.5 months versus 5.1 months, HR=0.70; 95% CI, 0.51- 0.96; 
P = 0.10). The ORR was 11.7% for nivolumab versus 7.4% for chemotherapy, and the 
radiographic PFS was 2.0 months for nivolumab versus 2.4 months for chemotherapy (Hoffman 
2016). Single agent pembrolizumab was reported to have an 18.2% ORR in a Phase 1b study of 
132 patients with advanced squamous cell carcinoma of the head and neck (Seiwert, Haddad et 
al. 2015).  
There is a large unmet need to improve upon clinical results with anti-PD-1/L1 single agent 
activity in HNSCC. 
2.2 
Oligodeoxynucleotides With CpG Motifs in Cancer Immunotherapy 
Bacterial deoxyribonucleic acid (DNA) has long been recognized as having potent stimulatory 
effects on the immune system, including stimulating rejection of transplantable tumors in mice 
(Yamamoto, Kuramoto et al. 1988). This activity is mediated preferentially by specific DNA 
motifs containing a cytosine phosphoguanosine (CpG) dinucleotide and can be replicated by 
short synthetic oligodeoxynucleotides (ODN) (Kuramoto, Yano et al. 1992, Tokunaga, Yano et 
al. 1992, Roman, Martin-Orozco et al. 1997). CpG-ODNs stimulate specific immune cell types 
by activation of the innate recognition receptor, Toll-like receptor 9 (TLR9) (Krieg 2006), and 
have no activity in mice with a homozygous deletion of the TLR9 gene (Campbell, Cho et al. 
2009). 


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Based on studies with cultured human peripheral blood mononuclear cells (PBMCs), CpG-ODNs 
can stimulate interferon (IFN)-alpha (IFN-α) and interleukin-12 production as well as functional 
maturation of plasmacytoid dendritic cells (pDCs) (Duramad, Fearon et al. 2005) and can induce 
proliferation and immunoglobulin production in human B-cells (Krieg, Yi et al. 1995). Signaling 
by CpG-ODNs through TLR9 requires active uptake of the ODN as TLR9 is present only in 
specific intracellular compartments (Krieg 2002). TLR9 signaling occurs in 2 distinct 
intracellular structures, early and late endosomes (Honda, Ohba et al. 2005, Guiducci, Ott et al. 
2006), leading to different outcomes. In pDCs, TLR9 signaling in the early endosome leads to 
induction of type I IFNs, especially IFN-α, whereas signaling in late endosomes results in 
differentiation of pDCs to potent antigen-presenting cells. Differences in sequence and structure 
lead to different localization to these 2 intracellular compartments, allowing selection of 
CpG-ODNs that stimulate low or high levels of type I IFNs (termed CpG-B and CpG-C class 
ODN, respectively). SD-101 belongs to the CpG-C class of CpG-ODN and was optimized to 
stimulate very high levels of IFN-α as well as inducing maturation of pDCs to antigen-presenting 
cells. Results from a Phase 1 trial in healthy normal volunteers (DV3-HNV-01) demonstrated 
that subcutaneous administration of SD-101 generates a response characterized by a 
dose-dependent upregulation of type I IFN regulated genes detectable in PBMCs. 
In a number of different animal models, intratumoral injection of CpG-ODNs has proven 
significantly more effective for tumor killing and generation of anti-tumor immunity than 
systemic administration (Kawarada, Ganss et al. 2001, Lou, Liu et al. 2011). The rationale is that 
intratumoral delivery of CpG enhances the antigen presenting property of infiltrating dendritic 
cells promoting cross-presentation of tumor associated antigens and increased natural killer (NK) 
cell cytotoxic activity against the tumor (Sparwasser, Vabulas et al. 2000, Bauer, Redecke et al. 
2001, Marabelle, Kohrt et al. 2014). The net result is activation of both innate and adaptive 
anti-tumor responses (Figure 2-1). Dynavax has demonstrated in mouse tumor models that 
SD-101 given intratumorally as a single agent is able to promote an IFN response, infiltration of 
T cells, and durable tumor control. 
Please refer to the Investigator’s Brochure for additional information on nonclinical studies. 
 
 


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Figure 2-1: 
SD-101 Cellular Mechanism of Action 
 
Source: Dynavax internal presentation. 
IFN = interferon; MHC = major histocompatibility complex; MyD = Myeloid differentiation; NK = natural killer; 
pDCs = plasmacytoid dendritic cells; TLR = Toll-like receptor. 
Both innate and adaptive immune responses are increased by intratumoral injection of SD-101. SD-101 induces pDCs to secrete 
high levels of IFN-α, a potent immunomodulatory cytokine able to boost NK-cell cytotoxic activity and induce recruitment of T 
cells. In addition SD-101 induces pDC maturation and the ability to cross-present tumor associated antigens, promoting a CD8+ 
T-cell response. 
Clinical studies combining radiation therapy which causes tumor cell death and intratumoral 
CpG-ODN administration have shown efficacy in patients with indolent B-cell lymphomas 
(Brody, Ai et al. 2010) and cutaneous T-cell lymphoma (Kim, Gratzinger et al. 2012). 
Regression of non-injected tumor sites in a subset of patients provided clear evidence for 
generation of systemic anti-tumor immunity in each of these studies. These 2 studies, as well as 
other published trials of CpG-ODN treatment in cancer patients, were done with CpG-ODNs 
belonging to the CpG-B class, which induces significantly lower levels of type I IFNs in humans 
than does SD-101, a CpG-C class ODN. 


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2.3 
PD-1 Blockade With Anti-PD-1 Antibody 
The PD-1/ PD-L1 pathway has been shown to be an important pathway inhibiting cytotoxic 
activity of tumor-infiltrating T cells. PD-L1 (also known as B7-H1) is the counter-receptor of 
PD-1 (Sznol and Chen 2013). The PD-1 receptor is predominantly expressed on activated T- and 
B- lymphocytes and downregulates T-cell activation that occurs with recognition by the T-cell 
receptor of tumor antigens expressed in the context of the major histocompatibility complex 
(MHC) on tumor cells. High PD-1 expression on antigen-specific T cells, as a consequence of 
chronic antigenic stimulation in the tumor microenvironment, is thought to be a marker of T-cell 
exhaustion. PD-L1 expression has been found on tumor cells in a variety of tumors and on 
myeloid cells infiltrating the tumor and it is a mechanism by which tumors and infiltrating cells 
can directly engage PD-1 on T cells to evade an effective anti-tumor immune response (Sznol 
and Chen 2013). 
Blockade of PD-1/PD-L1 pathway with antibodies against PD-1 or PD-L1 restore the function of 
tumor-infiltrating CD8+ and CD4+ T cells in mouse tumor studies (Figure 2-2:) (Sznol and Chen 
2013). These data supported clinical development of human antibodies blocking either PD-1 or 
PD-L1. Two of these agents, pembrolizumab and nivolumab, monoclonal antibodies directed 
against PD-1, were recently approved for treatment of metastatic melanoma (Webster 2014). 


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Figure 2-2: 
Blocking PD-1/PD-L1 Pathway Mechanism of Action 
 
Anti-PD-1 = anti-programmed death receptor-1; B7-H1 = B7 – homolog 1; MHC = major histocompatibility complex; 
PD-1 = programmed death receptor-1; PD-L1 = programmed death-ligand 1; TCR = T-cell receptor. 
A: Ligation of T-cell PD-1 by tumor PD-L1 (B7-H1 in the figure) results in the downregulation of T-cell effector functions that 
destroy tumor cells. 
B: Blockade of this pathway by anti-PD-1 antibodies prevents this downregulation, and allows T cells to maintain their 
anti-tumor functionality and ability to mediate tumor cell death. 
2.4 
Combined Anti-PD-1 Therapy and Intratumoral CpG-ODN Treatment of 
Melanoma 
Although anti-PD-1 therapy has shown high rates of durable response in metastatic melanoma 
patients, only a subset of patients are currently benefiting from monotherapy as many fail to 
respond or eventually relapse after an initial response (Bristol-Myers Squibb Company 2014, 
Merck & Co. 2015). 
The identification and characterization of factors in the tumor microenvironment at baseline that 
predict response to anti-PD-1 therapy are currently a priority for the cancer immunotherapy field 
(Ribas and Tumeh 2014). Recent new studies have found that response to anti-PD-1 therapy is 
contingent on the presence of infiltrating T cells in the tumor and patients with poor T-cell 
infiltration at baseline fail to respond to treatment (Tumeh, Harview et al. 2014). This finding is 
consistent with retrospective studies in selected tumor types, including melanoma, demonstrating 
a strong association between T-cell content in the tumor and OS (Angell and Galon 2013). In 


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addition, the degree of T-cell infiltration in melanoma is associated with the presence of a type I 
IFN signature, suggesting that in absence of type I IFN (Bald, Landsberg et al. 2014), the tumor 
is unable to sustain an immune rich environment which is necessary for the response to 
anti-PD-1/L1 targeting agents. Therefore, there is a strong rationale for combination therapies 
that increase type I IFN in the tumor microenvironment and promote T-cell infiltration. 
Intratumoral injection of SD-101 is expected to augment the response to anti-PD-1 antibodies by 
inducing type I IFN and promoting T-cell infiltration and activation at the tumor sites (see the 
Investigator’s Brochure). This hypothesis is supported by the nonclinical data in mouse models 
of carcinoma (CT26) in which tumors that do not respond to anti-PD-1 therapy fail to upregulate 
IFN genes and have very low amounts of infiltrating T cells (data on file) consistent with 
findings in humans as discussed above (Tumeh, Harview et al. 2014). In this CT26 model of 
transplantable colon carcinoma with PD-1 blockade, this lack of a permissive environment was 
shown to be modified by addition of intratumoral SD-101 which leads to a conspicuous 
infiltration of activated T cells that correlates to tumor rejection. In this model the combination 
of anti-PD-1 antibody and SD-101 has been shown to be far superior in inducing tumor rejection 
than the single agents alone (see the Investigator’s Brochure). In addition, initiating dosing with 
an anti-PD-1 for 7 days prior to SD-101 led to a more consistent and durable tumor response 
than when the anti-PD-1 and SD-101 were initially dosed on the same day (data on file). 
2.5 
SD-101 Alone and in Combination With Anti-PD-1 in Head and Neck Squamous 
Cell Carcinoma Preclinical Models 
Active research for anti-PD-1/L1 therapy and combinations with other immunologic agents are 
ongoing in clinical studies in multiple tumor types including HNSCC. The preclinical rationale 
for combining SD-101 and pembrolizumab is based on data with a mouse HNSCC tumor model. 
Murine (human papillomavirus [HPV]-positive murine tonsil epithelial cells) MEER or 
HPV-negative murine HNSCC cells (SCC-7) bearing mice were intratumorally treated with 
SD-101 alone or in combination with anti-PD-1 mAb. When SD-101 was used as a single agent 
injected intratumorally, it significantly suppressed the growth of tumors at the injected site in 
both models. In addition, SD-101 suppressed tumor growth at the distant (non-injected) site in 
the HPV+ MEER model (Figure 2-3 A). In the HPV− SCC-7 model, combining SD-101 therapy 
with anti-PD-1 treatment significantly enhanced the suppression by SD-101 single agent 
treatment at the distal tumor and improved survival (Figure 2-3 B). These anti-tumor effects of 
SD-101 were accompanied by an increase in IL-12 and type 1 IFN. In summary, SD-101 alone is 
effective at reducing tumor growth in both HPV+ and HPV− murine HNSCC models and 
SD-101 further enhances the efficacy of PD-1 blockade (data on file). 
 


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Figure 2-3: 
Intratumoral SD-101 Reduced Tumor Growth in Murine Models of HPV-Positive (A) and Negative (B) Head 
and Neck Squamous Cell Carcinoma 
 
 
ANOVA = analysis of variance; aPD-1 = anti- programmed death receptor-1; HNSCC = head and neck squamous cell carcinoma; HPV = human papillomavirus;  
PD-1 = programmed death receptor-1; SCC-7 = squamous cell carcinoma-7. 
(A) HPV-positive murine tonsil epithelial cells (MEER cells) were subcutaneously implanted in C57BL/6 mice (both flanks). The tumor bearing mice were treated with SD-101 (50 µg per 
site, Days 12, 15, 18, and 22), or in combination with anti-PD-1 monoclonal Ab (aPD-1, 250 µg, Days 11, 14, 17, and 21). 
(B) HPV-negative murine HNSCC cells (SCC-7) were subcutaneously implanted in C3H mice (both flanks). The tumor bearing mice were treated with SD-101 (50 µg, Days 7, 11, 14, 18, 
and 21) or in combination with anti-PD-1 monoclonal Ab (aPD-1, 250 µg, Days 4, 6, 10, 13, 17, and 20). Tumor growth and survival of the mice were monitored. Significance of survival 
was analyzed by two-way ANOVA. 
*P < 0.05 (tumor volumes) and P < 0.0125 (survival) versus vehicle treated mice. 


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2.6 
Clinical Experience With SD-101  
In the phase 1, single-blind, dose-escalation trial of systemic SD-101 in 20 healthy normal male 
volunteers, aged 18 years and over (DV3-HNV-01), adverse events (AEs) included flu-like 
symptoms such as headache, chills, fatigue, and pyrexia, as well as injection-site reactions such 
as erythema, induration and pain. Dose-limiting toxicities (DLTs) of severe headache, 
injection-site induration, and neck pain were observed in 1 subject given 5.0 mg of SD-101, 
resulting in a halt in Dose Escalation and accrual. Transient lymphopenia was the most common 
laboratory abnormality observed. There was no evidence of complement activation, coagulation 
abnormalities, or auto-antibody development. 
In the phase 1 single-blind, dose-escalation trial of systemic SD-101 in 28 men and women, aged 
18 to 55 years, with chronic hepatitis C virus (HCV) infection, SD-101 was administered alone 
or in combination with ribavirin (DV3-HCV-01). Including doses up to 5.0 mg of SD-101, the 
majority of AEs were injection-site reactions (erythema, swelling, pain, and pruritus), 
influenza-like illness, pyrexia, and myalgia. Most AEs were mild or moderate in reported 
severity. One subject in the 0.1 mg SD-101/ribavirin group experienced a serious adverse event 
(SAE) of hyperthyroidism that the investigator considered probably related to SD-101 and 
unrelated to ribavirin. No deaths occurred during the trial. 
A phase 1/2 trial of SD-101 in combination with low-dose radiation therapy for untreated 
low-grade B-cell lymphoma is completed (DV3-LYM-01). A total of 13 patients were dosed in 
Phase 1 Dose Escalation (4 cohorts comprising 3 patients at each of SD-101 intratumoral doses 
of 1.0 mg, 2.0 mg, and 4.0 mg, and 4 patients at the 8.0 mg dose). A total of 16 patients were 
dosed in Dose Expansion (2 cohorts comprising of 7 patients at the 1.0 mg and 9 patients at the 
8.0 mg dose levels). SD-101 was well tolerated. Treatment emergent adverse events consisted 
mainly of Grade 1 to 2 flu like symptoms or local site reactions, with a trend toward more 
frequent Grade 3 events at the highest tested dose of 8 mg. Intratumoral SD-101 in combination 
with low-dose radiation resulted in regression of both treated and untreated sites of disease 
(systemic or abscopal responses) in subjects with previously untreated indolent B-cell 
lymphoma.  
A phase 1 clinical trial of SD-101 in lymphoma patients who had relapsed after allogeneic 
marrow cell transplantation (IND #111985) was conducted. In this trial, 3 patients received 
3 weekly intratumoral doses of SD-101 0.3 mg, and 3 patients received 3 weekly intratumoral 
doses of SD-101 1.0 mg. Several patients have shown objective abscopal tumor responses. There 
were no treatment-related severe AEs, and study treatment was generally well tolerated, as noted 
by the investigator. One unrelated SAE of Klebsiella bacteremia was reported in a patient 
55 days after the first SD-101 injection (1.0 mg) and 41 days after the third and final injection 
which resolved. The study is closed. 


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CONFIDENTIAL AND PROPRIETARY 
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A Phase 1/2 investigator-sponsored trial (Principal Investigator: Dr. Ronald Levy of Stanford 
University Medical Center) of SD-101 in combination with local radiation therapy for low-grade 
B-cell lymphoma patients was conducted and 7 patients were enrolled and treated, and the study 
is now closed. One SAE of death was reported in a patient who had progressive disease and was 
subsequently treated with gemcitabine, dexamethasone, carboplatin, and obinutuzumab. The 
SAE was assessed by the investigator as related to the subsequent cytotoxic chemotherapy and 
not to study treatment.  
In this Phase 1b/2 DV3-MEL-01 (SYNERGY-001) study, Phase 1 Dose Escalation is designed 
to identify an optimal dose of SD-101 (RP2D) given in combination with pembrolizumab to be 
evaluated in Phase 2. The selected RP2D going into the Phase 2 Dose Expansion was based on 
an evaluation of the early available data from Phase 1 Dose Escalation Cohorts (1.0 mg, 2.0 mg, 
4.0 mg, and 8.0 mg) where SD-101 was injected into a single target lesion. Data review included 
an evaluation of SD-101 target engagement assessed by IFN activity and effect on immune cells, 
clinical safety data, and preliminary efficacy data for patients who were anti-PD-1 treatment 
naïve (n = 9) or experienced with progressive disease (n = 13). Observations included: 
1) SD-101 engaged its target, TLR9, as demonstrated by the dose dependent induction of 
IFN-responsive genes (pharmacodynamic) systemically and in the tumor 
microenvironment. 
2) Nanostring data showed that SD-101 was able to generate an increase in immune cell 
types in the tumor microenvironment. These increases were generally not 
dose-dependent. 
3) Objective responses were observed at SD-101 dose range of 1.0 mg – 8.0 mg in 
anti-PD-1/L1 inhibitor naïve patients, with tumor shrinkage at the injected and 
non-injected lesions. 
4) A single patient responded and durable stable disease was seen at the 8.0 mg dose in 
anti-PD-1/L1 inhibitor experienced patients. 
5) There were no DLTs. 
6) SD-101 administered intratumorally in combination with IV pembrolizumab 
demonstrated no worsening of the expected toxicities of each of the individual 
monotherapies. The most common (≥ 20%) treatment-related AEs were transient 
low-grade fatigue, myalgia, headache, chills and injection site reactions. Grade ≥ 3 
treatment-related AEs were observed in 59.1% patients (most common: myalgia 13.6% 
and injection site pain 13.6%). Immune- related AEs occurred in 2 patients (2/22 or 9%). 


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SD-101 
 
Protocol Amendment #8 
 
CONFIDENTIAL AND PROPRIETARY 
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One had a Grade 2 pneumonitis on Day 23 resulting in drug withdrawal and the other had 
hypophysitis (85 days after last treatment). 
Based on preliminary review of the data, the efficacy of 2.0 mg per lesion was higher than 
8.0 mg in one lesion in patients who are naïve to anti-PD-1/L1 and the RP2D was updated to 
2.0 mg in 1 to 4 lesions and/or regions. The study with the new dosing of 2 mg per injection is 
ongoing also in patients who are resistant/refractory to anti-PD1/PD-L1 therapy. 
A summary of the clinical studies conducted to date with SD-101 is provided in the 
Investigator’s Brochure. 
2.7 
About 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/approved labeling for detailed background information on 
pembrolizumab.  
2.8 
Trial Rationale and Doses to be Evaluated 
This open-label, multicenter, dose-ranging and expansion trial is designed to evaluate the safety 
and preliminary efficacy of intratumoral SD-101 in combination with pembrolizumab for the 
treatment of metastatic melanoma and HNSCC. The hypothesis to be tested in the clinical 
development of SD-101 is that SD-101, by virtue of its potency and its ability to induce high 
levels of IFNs, will have meaningful efficacy in generating anti-tumor immune responses when 
combined with an anti-PD-1 antibody. IFNs have multiple effects on both tumor cells and 
tumor-infiltrating leukocytes. These IFNs can directly inhibit the proliferation of tumor cells and 
increase MHC class I expression, enhancing antigen recognition. Additionally IFNs have potent 
effects on tumor-infiltrating leukocytes, including enhancing the antigen presenting function of 
dendritic cells, increasing the effect or function of T cells, and activating cytotoxic activity of 
NK cells (Hervas-Stubbs, Perez-Gracia et al. 2011). 
The rationale for treating metastatic melanoma and HNSCC with combination anti-PD-1/L1 
therapy plus SD-101 is based on the unmet need to improve upon single anti-PD-1/L1 activity in 


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Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #8 
 
CONFIDENTIAL AND PROPRIETARY 
Page 51 of 163 
these patient populations and nonclinical data (Sections 2.4 and 2.5) which suggest improved 
anti-tumor activity with the combination compared to anti-PD-1/L1 alone. 
The study will be performed in 2 phases. The population to be studied in Phase 1 (Dose 
Escalation) will be patients with metastatic melanoma. The populations to be studied in Phase 2 
(Dose Expansion) will be patients with metastatic melanoma and patients with recurrent or 
metastatic HNSCC. In phase 1 of the study, doses of 1.0 mg, 2.0 mg, 4.0 mg, and 8.0 mg of 
SD-101 each in a single lesion will be tested in a modified, staggered, 3 + 3 trial design, to 
identify an optimal dose of SD-101 given in combination with pembrolizumab to be used in 
Phase 2. This optimal dose from Phase 1 is referred to in the protocol as the recommended 
Phase 2 dose (RP2D) of SD-101. Phase 2 of the study is designed to evaluate the safety and 
efficacy of SD-101 plus pembrolizumab in both metastatic melanoma and HNSCC patients. 
Tumor response will be evaluated separately for injected and non-injected lesions as well as all 
combined lesions in order to assess both a local and systemic response to study treatment. 
The SD-101 doses selected are based on the mechanism of action, results of nonclinical and 
previous clinical studies conducted with SD-101 (DV3-HNV-01, DV3-HCV-01), and an ongoing 
trial of SD-101 in low-grade lymphoma (DV3-LYM-01). Based on data from a trial in healthy 
normal male volunteers (DV3-HNV-01), elevation of IFN-α inducible genes was seen after a 
single 0.1 mg subcutaneous dose and increased with doses up to 5 mg. AEs were limited to 
flu-like symptoms and administration-site pain and induration. For further information, see the 
Investigator’s Brochure.  
The starting dose of SD-101 (2.0 mg intratumorally) was chosen based on safety data from the 
DV3-LYM-01 study and in consideration that the safety profile of SD-101 given together with 
pembrolizumab is unknown. A lower dose of SD-101 1.0 mg was added in Amendment 4 of this 
protocol to determine optimal dosing and not because of a safety concern. With Amendment 5, 
8.0 mg was selected as the RP2D and another RP2D of 2.0 mg was selected for testing in 
Amendment 6. The rationale for modifying the SD-101 dose to 2.0 mg/lesion is based on 
preliminary internal data which suggest that overall objective response could potentially double 
when dosing at 2.0 mg as compared with 8.0 mg per lesion. Furthermore, increasing the number 
of tumor lesions for injection may enhance priming of neoantigen-specific anti-tumor T-cells to 
address potential tumor heterogeneity at different tumor locations. Selection of a 2.0 mg per 
injection permits injection in up to 4 lesions/regions to reach a maximum of 8.0 mg dose per 
subject, the highest total dose cleared based on Phase 1b. 
Based on the preliminary results for PD-1/PD-L1 naive patients in the ongoing Phase 1b/2 
DV3-MEL-01 (SYNERGY-001) study, the number of patients who are resistant/refractory to 
anti-PD1/PD-L1 therapy was expanded in Amendment 8 to further evaluate 2.0 mg-dosing of 
SD-101. 


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Protocol Amendment #8 
 
CONFIDENTIAL AND PROPRIETARY 
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The dose of pembrolizumab chosen for this study (200 mg Q3W) is the dose currently 
recommended in both monotherapy and combination studies with pembrolizumab.  
3.0 
TRIAL OBJECTIVES 
NOTE: As of Amendment 9, Phase 1 of the trial is complete. For Phase 2, the trial will stop 
collecting efficacy endpoints and exploratory objectives will not be pursued. 
3.1 
Phase 1 (Dose Escalation: Metastatic Melanoma) 
3.1.1 
Primary Objectives 
• To assess the safety and tolerability of escalating intratumoral doses of SD-101 in 
combination with intravenous pembrolizumab in patients with metastatic melanoma 
• To evaluate the expression of IFN-inducible genes in whole blood 24 hours after intratumoral 
injection of SD-101 given with pembrolizumab in patients with metastatic melanoma as a 
pharmacodynamic marker of SD-101 activity 
• To determine an RP2D of SD-101 in combination with pembrolizumab to be evaluated in 
Phase 2 
3.1.2 
Exploratory Objectives 
• To assess the preliminary response both locally and systemically including: 
• Treatment response of the injected Lesion A (local response) 
• Treatment response of the non-injected lesion(s) (systemic response) 
• Treatment response of all lesions 
• Time to response 
• To assess changes in tumor biomarkers 
3.2 
Phase 2 (Dose Expansion: Metastatic Melanoma or Recurrent or Metastatic Head 
and Neck Squamous Cell Carcinoma) 
3.2.1 
Primary Objectives 
• To assess the tumor response both locally and systemically including: 
• Treatment response of the injected lesion(s) (local response) 
• Treatment response of the non-injected lesion(s) (systemic response) 
• Treatment response of all lesions 


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SD-101 
 
Protocol Amendment #8 
 
CONFIDENTIAL AND PROPRIETARY 
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3.2.2 
Secondary Objectives  
• To assess the safety and tolerability of SD-101 in combination with pembrolizumab 
• To assess the time frame of tumor responses: 
• Time to response 
• Duration of response 
• To assess PFS 
3.2.3 
Exploratory Objectives 
• To assess changes in tumor biomarkers 
• To identify and assess changes in potential tumor neoantigens in patients with recurrent or 
metastatic HNSCC 
• To evaluate the expression of IFN inducible genes in whole blood 24 hours after intratumoral 
injection of SD-101 given with pembrolizumab in patients with recurrent or metastatic 
HNSCC as a pharmacodynamic marker of SD-101 activity 
4.0 
INVESTIGATIONAL PLAN 
4.1 
Trial Design 
NOTE: As of Amendment 9, Phase 1 of the trial is complete. Phase 2 of the trial has been 
modified to continue dosing per protocol; however, efficacy and exploratory endpoints will 
no longer be collected.  
This is a phase 1b/2, open-label, multicenter trial designed to evaluate the safety, tolerability, 
biologic activity, and preliminary efficacy of intratumoral SD-101 injections in combination with 
intravenous pembrolizumab in patients with metastatic melanoma or recurrent or metastatic 
HNSCC. 
This study will be conducted in 2 phases. Phase 1 evaluates SD-101 given in combination with 
pembrolizumab in melanoma populations (anti-PD-1/L1 naïve and anti-PD-1/L1 experienced 
with progressive disease) in up to 4 Dose Escalation cohorts to identify an RP2D to be evaluated 
in Phase 2. Phase 2 includes up to 4 Dose Expansion cohorts in patients with melanoma 
(anti-PD-1/L1 naïve and anti-PD-1/L1 experienced with progressive disease) and up to 4 Dose 
Expansion cohorts of patients with HNSCC (anti-PD-1/L1 naïve and anti-PD-1/L1 experienced 
with progressive disease). Two RP2Ds were selected to be evaluated in the Dose Expansion 
phase. 


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Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #8 
 
CONFIDENTIAL AND PROPRIETARY 
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The trial population includes a total of approximately 284 men and women with at least 1 site of 
disease that qualifies as a target lesion per RECIST v1.1 and is accessible for intratumoral 
injection. 
Phase 1 Dose Escalation Cohorts 1-4 will include up to 24 patients with metastatic melanoma 
who are anti-PD-1 naïve or experienced. 
Phase 2 Dose Expansion will include approximately 160 patients with metastatic melanoma and 
approximately 100 patients with recurrent or metastatic HNSCC: 
1) Expansion Cohort 1 of approximately 60 melanoma patients who are anti-PD-1/L1 naïve 
2) Expansion Cohort 2 of approximately 25 melanoma patients who have disease progression 
on anti-PD-1/L1 therapy  
3) Expansion Cohort 3 of approximately 25 HNSCC patients who are anti-PD-1 naïve 
4) Expansion Cohort 4 of approximately 25 HNSCC anti-PD-1/L1 who have disease 
progression on anti-PD-1/L1 therapy  
5) Expansion Cohort 5 of approximately 25 melanoma patients who are anti-PD-1/L1 naïve 
6) Expansion Cohort 6 of approximately 25 HNSCC patients who are anti-PD-1/L1 naïve 
7) Expansion Cohort 7 of approximately 25 HNSCC patients who are refractory or resistant to 
anti-PD-1/L1 therapy 
8) Expansion Cohort 8 of approximately 50 melanoma patients who are refractory or resistant to 
anti-PD-1/L1 therapy 
Figure 4-1 presents the study design for Phase 1 and Phase 2 at Amendment 9. 
 


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Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 55 of 163 
Figure 4-1: 
DV3-MEL-01 Study Design Schema at Amendment 9 – Phase 1 and Phase 2   
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 56 of 163 
 
Figure 4-1 Footnotes 
Anti-PD-1/L1 = anti-programmed death receptor-1/ligand 1; HNSCC = head and neck squamous cell carcinoma; RP2D = recommended Phase 2 dose. 
a 
1.0 mg of SD-101 was added at Amendment 4 
b 
At Protocol Amendment 5, enrollment in Dose Escalation Cohorts 1-4 was CLOSED. Based on available data (including efficacy, safety, and pharmacodynamics 
biomarkers), the sponsor selected 8.0 mg in a single injectable lesion if 1 lesion is selected or 2.0 mg per lesion if 2 to 4 lesions are selected for injection as the RP2D 
to be evaluated in the Dose Expansion phase. 
c 
At Protocol Amendment 6 and based on available data (including efficacy, safety, and pharmacodynamics biomarkers), the sponsor selected a second Phase 2 dose of 
2.0 mg per lesion in 1 to 4 injectable lesions to be evaluated in the Dose Expansion phase. Expansion Cohorts 1, 2, 3, and 4 in which patients were treated with 
8.0 mg in a single injectable lesion were CLOSED to further enrollment. Cohort 5 (melanoma anti-PD-1/L1 –naïve), Cohort 6 (HNSCC anti-PD-1/L1 –naïve), and 
Cohort 7 (HNSCC anti-PD-1/L1 –refractory or resistant) were ADDED with patients receiving 2.0 mg per lesion in 1 to 4 injectable lesion(s). 
d 
At Protocol Amendment 7 and based on available data (including efficacy, safety, and pharmacodynamics biomarkers), Cohort 8 (melanoma anti-PD-1/L1–refractory 
or resistant) was ADDED with patients receiving 2.0 mg per injection in 1 to 4 injectable lesions/regions. 
e 
For Protocol Amendment 9 and based on available data from the ongoing trial (including efficacy, safety, and pharmacodynamics biomarkers), Cohorts 5 and 6 were 
CLOSED. Additionally, Cohort 8 (melanoma anti-PD-1/L1–refractory or resistant) was expanded to approximately 50 patients. 
Note: For Protocol Amendment 9, enrollment is closed for all cohorts. Enrolled patients should continue to receive their assigned trial treatments as per the protocol. 
 
 


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Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 57 of 163 
The status of cohorts for this DV3-MEL-01 protocol at Amendment 9 is in Table 4-1. 
Table 4-1: 
Status of Cohorts for DV3-MEL-01 Protocol at Amendment 9 
Cohort 
Anti-PD-1 /L1 
Treatment Status 
Orig 
A 
1 
A 
2 
A 
3 
A 
4 
A 5 
A 6 
A 7 
A 8 
 
 
 
A9 
Ph 1 Mel – 
1 
Naïve or 
experienced 
X 
X 
X 
X 
X 
Closed 
Closed 
Closed 
Closed 
Complete 
Ph 1 Mel – 
2 
Naïve or 
experienced 
X 
X 
X 
X 
X 
Closed 
Closed 
Closed 
Closed 
Complete 
Ph 1 Mel – 
3 
Naïve or 
experienced 
X 
X 
X 
X 
X 
Closed 
Closed 
Closed 
Closed 
Complete 
Ph 1 Mel – 
4 
Naïve or 
experienced 
- 
- 
- 
- 
X 
Closed 
Closed 
Closed 
Closed 
Complete 
 
 
 
 
 
 
 
 
 
 
 
 
Ph 2 Mel – 
1 
Naive 
- 
- 
X 
X 
X 
X 
Closed 
Closed 
Closed 
Closed 
Ph 2 Mel – 
2 
Experienced 
- 
- 
X 
X 
X 
X 
Closed 
Closed 
Closed 
Closed 
Ph 2 Mel – 
5 
Naive 
- 
- 
- 
- 
- 
- 
X 
X 
Closed 
Closed 
Ph 2 Mel – 
8 
Refractory or 
resistant 
- 
- 
- 
- 
- 
- 
- 
X 
X 
Closed 
 
 
 
 
 
 
 
 
 
 
 
 
Ph 2 
HNSCC – 
3  
Naive 
- 
- 
- 
- 
X 
X 
Closed 
Closed 
Closed 
Closed 
Ph 2 
HNSCC – 
4  
Experienced 
- 
- 
- 
- 
X 
X 
Closed 
Closed 
Closed 
Closed 
Ph 2 
HNSCC – 
6  
Naive 
- 
- 
- 
- 
- 
- 
X 
X 
Closed 
Closed 
Ph 2 
HNSCC – 
7  
Refractory or 
resistant 
- 
- 
- 
- 
- 
- 
X 
X 
X 
Closed 
A = Amendment; Closed = Closed to enrollment; Complete = last patient last visit (LPLV) has been reached for all 
patients; HNSCC = head and neck squamous cell carcinoma; Mel = melanoma; Orig = original; Ph = phase; X = 
Open for enrollment. 


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Protocol DV3-MEL-01 (SYNERGY-001) 
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
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4.1.1 
Phase 1 Dose Escalation: Melanoma (COMPLETE) 
The Phase 1 will consist of up to 4 Dose Escalation cohorts to evaluate the safety and tolerability 
of SD-101 given in combination with pembrolizumab in melanoma populations (anti-PD-1/L1 
naïve and anti-PD-1/L1 experienced with progressive disease) to identify an RP2D to be 
evaluated in Phase 2.  
Phase 1 employs a modified 3 + 3 study design, evaluating escalating or intermediate dose levels 
of SD-101 (given with a fixed dose of pembrolizumab) in patients with metastatic melanoma. 
Cohorts of 3 to 6 patients will be enrolled at each dose level, and each patient will participate in 
only 1 cohort. Patients at each dose level will be treated and observed for dose-limiting toxicities 
(DLTs) through the DLT assessment period (Study Day 1-29). Once an RP2D is declared, an 
additional 6 patients may be enrolled to assess safety at this dose.  
Patients in Escalation Cohorts 1-4 will be administered 2.0 mg, 4.0 mg, 8.0 mg, and 1.0 mg, 
respectively, of SD-101 in combination with 200 mg pembrolizumab Q3W per the Schedule of 
Trial Events. 
The melanoma Dose Escalation cohorts, patient populations, and treatment assignments are 
outlined in Table 4-2.  
Table 4-2: 
Phase 1 Melanoma Dose Escalation Cohorts (COMPLETE)  
Cohort Anti-PD-1/L1 Experience 
SD-101 Dose 
n 
Dosing Schemaa 
1 
Naïve or experienced 
2.0 mg per lesion in 1 injectable lesion  
(Lesion A) 
3 - 6 
A 
2 
Naïve or experienced 
4.0 mg per lesion in 1 injectable lesion 
(Lesion A) 
3 - 6 
A 
3 
Naïve or experienced 
8.0 mg per lesion in 1 injectable lesion 
(Lesion A) 
3 - 6 
A 
4 
Naïve or experienced 
1.0 mg per lesion in 1 injectable lesion  
(Lesion A) 
3 - 6 
Ab 
Anti-PD-1/L1 = anti-programmed death receptor-1/ligand 1.  
a 
Dosing Schema: 
A: SD-101 and pembrolizumab dosing both start on Day 1 and patients receive 1 course of SD-101 (4 weekly doses and 
then every 3 weeks on schedule with pembrolizumab for 7 additional doses). 
b 
1.0 mg was added at Protocol Amendment 4. 
 
4.1.1.1 
Dosing Schedule (COMPLETE) 
Phase 1 portion of this trial is a Dose Escalation of SD-101 with a fixed dose of pembrolizumab 
as depicted in Figure 4-2. SD-101 will be administered intratumorally as 4 weekly doses 


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Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
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followed by 1 dose Q3W for 7 additional doses. Pembrolizumab 200 mg will be administered 
intravenously Q3W starting on Day 1 for up to 35 treatments (approximately 2 years) or until 
disease progression. SD-101 will be administered before pembrolizumab on days when both 
drugs are scheduled to be used. 
Figure 4-2: 
Trial Flow Diagram for Phase 1 Dose Escalation Cohorts 1 to 4 
(COMPLETE) 
 
4.1.1.2 
DLT Assessment (COMPLETE) 
Cohorts of 3 to 6 patients will be enrolled at each dose level, and each patient will participate in 
only 1 cohort. Patients at each dose level will be treated and observed for DLT through the DLT 
assessment period (Study Day 1-29). In addition to use of a modified 3 + 3 Dose Escalation 
design to assess a maximum tolerated dose (MTD), Phase 1 implements a staggered enrollment 
for a cohort. Patients enrolled under staggered enrollment in Phase 1 are referred to as sentinel 
patients in the protocol. The starting dose of SD-101 will be 2.0 mg administered intratumorally 
and will be given to 1 sentinel patient. If the sentinel patient does not experience a DLT within 
Screening
EOS
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
Day:
-28
1
8
15
22
29
43
64
85 106 127 148 169 190 … Q21Days…
715
Week:
-4
0
1
2
3
4
6
9
12
15
18
21
24
27 … Q3Weeks…
102
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
DLT = dose limiting toxicity; EOS = end of study; Q = every; × = times.
Note:  SD-101 is administered intratumorally. SD-101 is administered prior to pembrolizumab on the days when patients receive 
both treatments.
Trial Treatment
Extended Pembrolizumab 
Treatment
SD-101
Dose Q1 week × 4 followed by dose Q3 weeks × 7
 (11 doses)
EOS visit 28 
days after 
last dose
DLT Assessment Period
Pembrolizumab
Dose Q3 weeks × 2 years (up to 35 doses)


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72 hours, the second patient in the cohort may be dosed. If no DLT is experienced in the second 
patient after 72 hours, the third patient (and up to 3 additional patients) may be dosed. If a DLT 
is experienced in the first sentinel patient within 72 hours of injection, a second sentinel patient 
may be dosed with SD-101 following a safety review by the Safety Review Team (comprised of 
the Dynavax Medical Monitor, Phase 1 coordinating investigator, and other key safety Dynavax 
personnel as described in the Cohort Safety Review Plan) and an evaluation of safe to proceed. If 
no DLT is observed after 72 hours in the second sentinel patient, the third and subsequent 
patients in the cohort may be enrolled. 
If there is no DLT observed (Section 9.1) in the group of 3 or more patients, the next cohort will 
be enrolled, and escalation will proceed to the next highest dose with a sentinel patient receiving 
SD-101 at least 72 hours prior to dosing of subsequent patients. 
If a DLT is observed in 1 patient in the first 3 patients enrolled in a cohort, enrollment will 
proceed and the cohort size will be increased up to 6 patients. If only 1 DLT is observed in 
6 patients in a cohort, escalation will proceed, and the next cohort may begin enrollment. 
A minimum of 3 patients will be enrolled in each Cohort. Dose escalation will proceed if no 
DLT is observed in all patients enrolled. If 1 DLT is observed in any cohort after 3 patients have 
been enrolled, the cohort size will be increased to 6 patients. The maximum allowed DLTs per 
cohort to allow subsequent Dose Escalation is 1 DLT observed in 6 patients. The sponsor may 
also choose to enroll up to 6 patients initially into a cohort. Dose escalation will proceed if no 
more than 1 DLT is observed in 6 patients. 
If only 1 DLT is observed in 6 patients in a cohort, escalation will proceed and the next cohort 
may begin enrollment. 
If ≥ 2 of 6 patients experience a DLT in any cohort, Dose Escalation will cease and the previous 
lower dose of SD-101 may be designated the MTD. However, the sponsor may also decide to 
investigate an additional lower or intermediate dose cohort(s) than have already been tested. 
Patients will be enrolled and evaluated as described above for previous Dose Escalation cohorts 
except that staggered enrollment with a sentinel patient will not be required. Three to 6 patients 
will be enrolled at the intermediate or lower dose and DLT assessments performed, with 
expansion to 6 patients as required and applicable. A maximum of 0 DLTs in the first 3 patients 
or 1 DLT in the first 6 patients will define this dose as the MTD. 
The planned dose cohorts for SD-101 are 2.0 mg, 4.0 mg, and 8.0 mg. Dose Escalation will 
continue until an MTD is determined or a maximum planned dose (ie, a total body dose of 
8.0 mg) is reached. In addition, a 1.0 mg dose cohort, added in Amendment 4 of this protocol, 
will not require staggered enrollment with a sentinel patient as long as any higher dose cohort 


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Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
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has completed the DLT assessment period and met protocol criteria for Dose Escalation as 
described in this section. Decisions to escalate the dose of SD-101 to the next highest level will 
be based on review of safety data from the time of the first injection (Day 1) through Day 29 (the 
DLT assessment period). If 1 DLT in 6 patients or 2 Grade 2 AEs considered drug-related 
(except for malaise, headache, myalgia, fatigue, or chills) occur in 3 patients in a dose cohort, the 
Dose Escalation increment for the next dosing cohort will be decreased from 100% to 50%. 
Intra-patient Dose Escalation is not permitted. 
The RP2D of SD-101 given in combination with pembrolizumab will be chosen based on all 
available data including efficacy, safety, and pharmacodynamic biomarkers (eg, IFN-inducible 
gene signature and tumor-infiltrating lymphocytes). The RP2D will not exceed the MTD. 
Disease response and study treatment management for Dose Escalation will be assessed by the 
investigator based on RECIST v1.1 and immune-related Response Evaluation Criteria In Solid 
Tumors (irRECIST) (ie, scans obtained at least 4 weeks later that qualify as PD per RECIST v1.1 
[Appendix 6]). This assessment of disease response and progression is consistent with current 
pembrolizumab studies and is implemented due to observed pseudoprogression as well as late 
responses with immunotherapy. The protocol also allows patients who are clinically stable and 
have unconfirmed PD to continue on pembrolizumab and SD-101 per investigator decision. All 
patients who develop confirmed progressive disease must discontinue all study treatment unless 
requested by an investigator and approved by a Dynavax Medical Monitor. Patients who 
discontinue pembrolizumab must discontinue SD-101. Pembrolizumab may be continued as a 
single agent if SD-101 is discontinued per investigator decision as described in Section 9.2.  
4.1.2 
Phase 2 Dose Expansion – Cohorts (CLOSED) 
NOTE: As of Amendment 9, enrollment in Phase 2 of the trial is closed. Enrolled patients 
should continue receiving their assigned treatment per protocol. 
4.1.2.1 
Melanoma Cohorts 
Melanoma Dose Expansion cohorts in Phase 2 will be treated with 8.0 mg or 2.0 mg of SD-101 
from Phase 1 in combination with 200 mg pembrolizumab Q3W.  
For metastatic melanoma, planned enrollment is approximately 60 patients in Expansion 
Cohort 1 and approximately 25 each in Expansion Cohort 2 and Cohort 5, and approximately 50 
in Cohort 8. Patients in Cohort 2 will have had disease progression on anti-PD-1/L1 therapy, 
those in Cohort 8 will have had refractory or resistant response to anti-PD-1/L1 therapy, and 
patients in Cohorts 1 and 5 will be naïve to anti-PD-1/L1 therapy.  


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The melanoma expansion cohorts, patient populations, and treatment assignments are outlined in 
Table 4-3. 
Table 4-3: 
Phase 2 Melanoma Dose Expansion Cohorts (CLOSED) 
Cohort 
Anti-PD-1/L1 
Experience 
SD-101 Dose 
n 
Dosing 
Schemaa 
1 
Naïve 
8.0 mg in a single injectable lesion if 1 lesion is 
selected (Lesion A) or 2.0 mg per lesion if 2 to 
4 lesions are selected for injection (Lesion A, Lesion 
B, Lesion C, Lesion D) 
Approximately 60 
B 
2 
Experiencedb 
8.0 mg in a single injectable lesion 
(Lesion A) 
Approximately 25 
A 
5 
Naïve 
2.0 mg per lesion in 1 to 4 injectable lesions (Lesion A, 
Lesion B, Lesion C, Lesion D) 
Approximately 25 
A1 
8 
Refractory or 
resistantc 
2.0 mg in 1 ml per injection in 1 to 4 separate lesions 
for lesions measuring up to 5 cm in the longest 
diameter; or for lesions larger than 5 cm, 2.0 mg in 1 
ml per injection in 1 to 4 separate regions where the 
injections are ≥ 5 cm apart (maximum total dose is 
8.0 mg) 
Approximately 50 
A1 
Anti-PD-1/L1 = anti-programmed death receptor-1/ligand 1. 
a 
Dosing Schema: 
A: SD-101 and pembrolizumab dosing both start on Day 1 and patients receive 2 courses of SD-101 (each course, separated 
by 9 weeks, is 4 weekly doses and then every 3 weeks on schedule with pembrolizumab for 7 additional doses) 
B: SD-101 dosing starts on Day 22 at the second dose of pembrolizumab and patients receive 2 courses of SD-101 (each 
course, separated by 9 weeks, is 4 weekly doses and then every 3 weeks on schedule with pembrolizumab for 7 additional 
doses) 
A1: SD-101 and pembrolizumab dosing both start on Day 1 and patients receive 1 course of SD-101 (4 weekly then every 
3 weeks on schedule with pembrolizumab up to Week 51) 
b 
Received prior treatment regimen containing an anti-PD-1/L1 drug. 
c 
Received at least 2 doses of an anti-PD-1/L1 therapy and experienced PD within 3 months after last dose of anti-PD-1/L1 
therapy. Anti-PD-1/L1 refractory or resistant patients must have documented PD per RECIST v.1.1, which has been 
confirmed by a second scan at least 4 weeks from the date of the first documented PD, in the absence of rapid clinical 
progression. 
 
4.1.2.2 
HNSCC Cohorts  
HNSCC Dose Expansion cohorts in Phase 2 will be treated with the selected RP2D (8.0 mg or 
2.0 mg of SD-101) from Phase 1 in combination with 200 mg pembrolizumab Q3W.  
In Phase 2 HNSCC, approximately 25 anti-PD-1/L1 naïve patients in each of Expansion 
Cohorts 3 and 6, and approximately 25 patients who have disease progression on anti-PD-1/L1 
therapy in each of Expansion Cohorts 4 and 7 will be enrolled.  


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The HNSCC Dose Expansion cohorts, patient populations, and treatment assignments are 
outlined in Table 4-4. 
Table 4-4: 
Phase 2 HNSCC Dose Expansion (CLOSED) 
Cohort 
Anti-PD-1/L1 
Experience 
SD-101 Dose 
n 
Dosing 
Schemaa 
3 
Naïve 
8.0 mg in a single injectable lesion 
(Lesion A)b 
Approximately 25 
B 
4 
Experiencedc 
8.0 mg in a single injectable lesion 
(Lesion A)b 
Approximately 25 
A 
6 
Naïve 
2.0 mg per lesion in 1 to 4 injectable lesions 
(Lesion A, Lesion B, Lesion C, Lesion D) 
Approximately 25 
A1 
7 
Refractory or 
resistantd 
2.0 mg per lesion in 1 to 4 injectable lesions 
(Lesion A, Lesion B, Lesion C, Lesion D) 
Approximately 25 
A1 
Anti-PD-1/L1 = anti-programmed death receptor-1/ligand 1. 
a 
Dosing Schema: 
A: SD-101 and pembrolizumab dosing both start on Day 1 and patients receive 2 courses of SD-101 (each course, separated 
by 9 weeks, is 4 weekly doses and then every 3 weeks on schedule with pembrolizumab for 7 additional doses) 
B: SD-101 dosing starts on Day 22 at the second dose of pembrolizumab and patients receive 2 courses of SD-101 (each 
course, separated by 9 weeks, is 4 weekly doses and then every 3 weeks on schedule with pembrolizumab for 7 additional 
doses) 
A1: SD-101 and pembrolizumab dosing both start on Day 1 and patients receive 1 course of SD-101 (4 weekly then every 
3 weeks on schedule with pembrolizumab up to Week 51) 
b 
Patients will receive 8.0 mg per lesion in 1 lesion with the option of injecting into up to 4 regions within the lesion in 
approximate equally divided volumes of an 8.0 mg dose. 
c 
Received prior treatment regimen containing an anti-PD-1/L1 drug. 
d 
Received at least 2 doses of an anti-PD-1/L1 therapy, where the last dose of anti-PD-1/L1 therapy was within 6 months of 
study enrollment (Day 1) and have either refractory response (PD occurred within 3 months duration of the start of 
treatment on anti-PD-1/L1 therapy) OR resistant response (PD occurred beyond 3 months duration of treatment on 
anti-PD-1/L1 therapy and within 6 months after the last dose of treatment on anti-PD-1/L1 therapy). Anti-PD-1/L1 
refractory or resistant patients must have documented PD per RECIST v.1.1, which has been confirmed by a second scan at 
least 4 weeks from the date of the first documented PD, in the absence of rapid clinical progression. 
 
4.1.3 
Phase 2 Dose Expansion – Dosing Schedule 
As presented in the Trial Flow Diagrams for the Dose Expansion Cohorts 1 to 4, patients with 
metastatic melanoma or HNSCC will receive 2 courses of the SD-101 dose regimen, with 
9 weeks off between the 2 courses. In Cohorts 1 and 3 (Figure 4-3), patients will have a lead-in 
dose of pembrolizumab at Day 1 and start the treatment course on Day 22; whereas, in Cohorts 
2 and 4 (Figure 4-4), SD-101 and pembrolizumab treatments will both start on Day 1. Metastatic 
melanoma or HNSCC patients in Cohorts 5, 6, 7, and 8 (Figure 4-5) will receive 1 course of 
SD-101 and dosing with SD-101 and pembrolizumab both start on Day 1. Pembrolizumab 
200 mg will be administered intravenously Q3W until disease progression or up to 2 years. 
SD-101 will be administered before pembrolizumab on days when both drugs are scheduled to 
be used. 


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Figure 4-3: 
Trial Flow Diagram for Dose Expansion Cohorts 1 and 3 (CLOSED)  
 
Screening
EOS
↓↓
↓
↓↓↓↓↓↓↓↓↓↓
↓
↓↓↓↓↓↓↓
↓
↓
↓
Day:
-28
1
22
29
36
43
64
85
106
127
148
169
190
211
232
253
260
267
274
295
316
337
358
379
400
421
442
… Q21Days…
715
Week:
-4
0 3 4 5 6
9 12 15 18 21 24 27 30 33 36 37 38 39
42 45 48 51 54 57 60 63… Q3Weeks… 102
↑↑↑↑
↑↑↑↑↑↑↑
↑↑↑↑
↑↑↑↑↑↑↑
EOS = end of study; Q = every; × = times.
Note:  SD-101 is administered intratumorally. SD-101 is administered prior to pembrolizumab on the days when patients receive both treatments.
Pembrolizumab
Dose Q3 weeks × 2 years (up to 35 doses)
EOS visit 28 
days after 
last dose
SD-101
Dose Q1 week × 4 followed by dose Q3 weeks × 7, then 9 weeks off, and then Dose 
Q1 week × 4 followed by dose Q3 weeks × 7 (22 doses)
Trial Treatment
Extended 
Pembrolizumab 
Treatment


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Figure 4-4: 
Trial Flow Diagram for Dose Expansion Cohorts 2 and 4 (CLOSED) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening
EOS
↓
↓
↓↓↓↓↓↓↓↓↓↓
↓
↓↓↓↓↓↓↓↓
↓
↓
Day:
-28
1
8
15
22
43
64
85
106
127
148
169
190
211
232
239
246
253
274
295
316
337
358
379
400
421
… Q21Days…
715
Week:
-4
0 1 2 3
6 9 12 15 18 21 24 27 30 33 34 35 36
39 42 45 48 51 54 57 60… Q3Weeks…102
↑↑↑↑
↑↑↑↑↑↑↑
↑↑↑↑
↑↑↑↑↑↑↑
Trial Treatment
Extended 
Pembrolizumab 
Treatment
Pembrolizumab
Dose Q3 weeks × 2 years (up to 35 doses)
SD-101
Dose Q1 week × 4 followed by dose Q3 weeks × 7, then 9 weeks off, and then 
Dose Q1 week × 4 followed by dose Q3 weeks × 7 (22 doses)
EOS = end of study; Q = every; × = times.
Note:  SD-101 is administered intratumorally. SD-101 is administered prior to pembrolizumab on the days when patients receive both treatments.
EOS visit 28 
days after last 
dose


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Figure 4-5: 
Trial Flow Diagram for Dose Expansion Cohorts 5, 6, 7, and 8 
(CLOSED) 
 
 
 
 
4.1.4 
Phase 1 and Phase 2 – Assessments 
NOTE: As of Amendment 9, Phase 1 of the trial is complete and enrollment in Phase 2 is 
closed. Phase 2 of the trial has been modified to continue dosing per protocol. The trial will 
stop collecting all efficacy endpoints. Assessments of disease response should be made per 
Investigator based on local standard of care and assessment guidelines. This section has 
been modified accordingly. 
All patients will undergo safety assessments, pharmacodynamic assessments, tumor response 
assessments, and tumor biopsies performed at specified trial visits, as indicated in the Schedule 
of Trial Events (Appendix 1 through Appendix 4). 
Once informed consent is obtained, disease assessments prior to treatment will include: 
• Complete physical examination including assessment of superficial lesions with 
photographic documentation and measurement of these lesions 
Screening
EOS
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
Day:
-28
1
8
15
22
43
64
85
106
127
148
169
190
211
232
253
274
295
316
337
358
379
715
Week:
-4
0
1
2
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
102
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
SD-101 (Intra-tumoral)
Dose Q1 week × 4, followed by dose Q3 weeks × 16 (up to 20 doses)
EOS = end of study; Q = every; × = times.
Note:  SD-101 is administered intratumorally. SD-101 is administered prior to pembrolizumab on the days when patients receive both 
treatments.
EOS visit 28 
days after 
last dose
Trial Treatment
Extended 
Pembrolizumab 
Treatment
… Q21Days…
… Q3Weeks…
Pembrolizumab (Intravenous)
Dose Q3 weeks × 2 years (up to 35 doses)


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• Radiographic imaging including computed tomography (CT) or magnetic resonance imaging 
(MRI) scans of the chest, abdomen, pelvis, brain, and other areas (Appendix 7), as clinically 
indicated. CT imaging is preferred. In addition, screening imaging for HNSCC patients 
requires imaging of the neck. The screening radiographic imaging will serve as baseline and 
must be obtained within 4 weeks of study enrollment, ie, receiving the first trial treatment. 
• Laboratory assessments 
• Baseline confirmation of PD-L1 expression from a biopsy of the target lesion (Lesion A) that 
will be injected with SD-101 in Phase 2 Expansion patients. A baseline biopsy should be 
collected within 28 days prior to the initiation of study treatment. Archival tissue of the target 
lesion within 3 months of screening is acceptable.  
• Copy of pathology report confirming diagnosis 
Disease assessment will include physical examination, photographic documentation and 
measurement of superficial lesions, and radiographic imaging (Appendix 7) with CT or MRI 
(with preference for CT) scans. 
Repeat tumor biopsies will be conducted for all Cohorts. Biopsies of the target lesion (Lesion A) 
which has been injected with SD-101 are required at the time points as outlined in the Schedule 
of Trial Events (Appendix 1 through Appendix 4). At each biopsy collection time point, 2 tissue 
biopsy samples will be collected per the study laboratory manual. Lesion A should be of a 
sufficient size such that the intratumoral biopsy does not compromise the investigator’s ability to 
assess the lesion size changes per Response Evaluation Criteria in Solid Tumors (RECIST) over 
time. Biopsies from Lesion A are required. Additional biopsies from other injected lesions are 
optional, but strongly encouraged. Of note, 1 to 3 additional biopsies may be collected from 
other injected lesions if a cohort allows for injecting up to 4 lesions. Separate and additional 
biopsies from a non-injected lesion are also optional but strongly encouraged. If Lesion A or 
other biopsied lesions have regressed, further biopsies are not required. If an injected lesion has 
completely regressed, and there is no other replacement lesion (Section 6.2.2.2), SD-101 will be 
injected peritumorally for up to the next 3 doses of SD-101. Further details on tumor biopsies are 
in Section 10.1.2. 
In Phase 1, response will be assessed by evaluating Lesion A, all sites of disease outside 
Lesion A, and all lesions combined. In Phase 2, response will be assessed by evaluating all 
lesions injected with SD-101, lesion(s) not injected with SD-101, and all lesions combined. 
Disease response and study treatment management for Dose Expansion will be assessed by the 
investigator based on RECIST v1.1 and irRECIST (ie, scans obtained at least 4 weeks later that 
qualify as PD per RECIST v1.1 [Appendix 6]). This assessment of disease response and 
progression is consistent with current pembrolizumab studies and was implemented due to 


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observed pseudoprogression as well as late responses with immunotherapy. The protocol also 
allows patients who are clinically stable and have unconfirmed PD to continue pembrolizumab 
and SD-101 per investigator decision and Dynavax Medical Monitor approval. All patients who 
develop confirmed disease progression per local assessment guidelines should be discontinued 
from the study. Pembrolizumab may be continued as a single agent if SD-101 is discontinued per 
investigator decision as described in Section 9.2. Patients who discontinue pembrolizumab must 
discontinue SD-101. 
4.2 
Duration of Trial 
The total duration of patient participation in this trial is up to approximately 110 weeks. This 
includes a Screening period beginning up to 28 days prior to the first trial treatment, and a trial 
completion visit approximately 28 days after the last dose of trial treatment.  
4.3 
Trial Endpoints 
NOTE: As of Amendment 9, Phase 1 of the trial is complete. Phase 2 of the trial has been 
modified to continue dosing per protocol; however, efficacy and exploratory endpoints will 
no longer be collected. The collection of safety endpoints has been simplified. This section 
has been modified accordingly. 
4.3.1 
Phase 1 – Dose Escalation  
4.3.1.1 
Primary Endpoints  
• Incidence of DLTs 
• Incidence of injection-site reactions, AEs, and SAEs 
• Changes in the expression of IFN-inducible genes in whole blood 
4.3.1.2 
Exploratory Endpoints  
• ORR per RECIST v1.1 
• Disease control rate (DCR) per RECIST v1.1 
• Time to response per RECIST v1.1  
• Changes in tumor-infiltrating lymphocytes, PD-L1 expression, and other gene expression in 
tumor biopsies 
4.3.2 
Phase 2 – Dose Expansion 
The primary radiographic endpoints of the study will be based on RECIST v1.1 and exploratory 
radiographic endpoints will be based on irRECIST. All imaging endpoints will be based on 


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investigator evaluation. A central imaging laboratory for study image collection and radiographic 
endpoint determination will be used per sponsor decision. 
4.3.2.1 
Primary Endpoints – No longer collected as of Amendment 9 
• ORR per RECIST v1.1  
4.3.2.2 
Secondary Endpoints  
• Incidence of injection-site reactions, AEs, and SAEs 
The following Secondary Endpoints (Phase 2) will not be collected as of Amendment 9: 
• Time to response using RECIST v1.1 
• Duration of response per RECIST v1.1 
• Radiographic PFS per RECIST v1.1 
4.3.2.3 
Exploratory Endpoints – No longer collected as of Amendment 9 
• Radiographic primary and secondary endpoints evaluated using irRECIST (Appendix 6, 
Immune-related RECIST) 
• Changes in correlative biomarkers including tumor-infiltrating lymphocytes and PD-L1 
expression at baseline and after SD-101 treatment 
• Changes in potential tumor neoantigens in patients with recurrent or metastatic HNSCC 
• Changes in the expression of IFN-inducible genes in whole blood in patients with metastatic 
head and neck squamous cell carcinoma 
4.4 
Randomization 
None of the patients in this trial will be randomized. 
4.5 
Blinding 
Blinding will not be performed as this is an open-label trial. 
4.6 
Appropriateness of Measurements 
The measures of safety in the trial are routine clinical and laboratory procedures. AEs will be 
assessed using the Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
(National Cancer Institute 2010) (Table 11-1). The measurement of injection-site reactions is 
based on the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials (Center for Biologics Evaluation and Research 2007) 


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(Appendix 5). The primary measure of response of lesions in this trial is based on standard 
RECIST v1.1 guidelines (Appendix 6). 
4.7 
Trial Termination 
The End-of-Study (EOS) date is defined as the date of the last visit of the last participant. 
However, the sponsor reserves the right to terminate the trial at any time. Reasons for 
discontinuation include but are not limited to: 
• Inability to enroll sufficient patients into the trial 
• Good clinical practices (GCP) compliance issues that compromise the validity of the trial 
Procedures for withdrawal of individual patients can be found in Section 5.3. 
5.0 
SELECTION OF PATIENTS 
As of Amendment 9, enrollment is closed and this section is no longer applicable. 
The trial population in Phase 1 Escalation Cohort 1-4 will include men and women with 
metastatic melanoma with at least 1 site of disease that qualifies as a target lesion per RECIST 
v1.1 and is accessible for intratumoral injection. Patients must meet the inclusion and exclusion 
criteria as described in detail in Sections 5.1 and 5.2 to be enrolled (defined as receiving the first 
trial treatment [ie, pembrolizumab or SD-101]) in the trial. An estimated 24 patients will be 
enrolled in Phase 1. 
The trial population in Phase 2 metastatic melanoma will include approximately 160 men and 
women with metastatic melanoma with at least 2 target lesions per RECIST v1.1 and at least 1 of 
the qualifying lesions must be accessible for intratumoral injection; the target lesion could be the 
injectable lesion.  
The trial population in Phase 2 HNSCC will include approximately 100 men and women with 
recurrent or metastatic HNSCC with at least 1 target lesions per RECIST v1.1, and which must 
be accessible for intratumoral injection. Phase 2 expansion cohorts are described in Sections 
4.1.1.1 and 4.1.2.2.  
A number of measures will be taken to ensure the safety of patients participating in this trial. 
These measures will be addressed through inclusion/exclusion criteria and routine safety 
monitoring. 


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5.1 
Inclusion Criteria  
A patient must meet all the following criteria to be eligible for enrollment (defined as receiving 
the first trial treatment [ie, pembrolizumab or SD-101]) in the trial: 
Phase 1 and Phase 2 
1) Willing and able to provide written informed consent for the trial 
2) Aged 18 years and older 
3) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 
4) Patient must have adequate organ function as indicated by the following laboratory values: 
Hematological 
• Absolute neutrophil count (ANC) ≥ 1,500 /mcL 
• Platelet count ≥ 100,000 /mcL 
• Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L 
Renal 
• Serum creatinine ≤ 1.5 × upper limit of normal (ULN) OR 
• Measured or calculated creatinine clearance (GFR can also be used in place of creatinine 
or CrCl) ≥ 60 mL/min for subject with creatinine levels > 1.5 × institutional ULN 
Hepatic 
• Serum total bilirubin: 
• ≤ 1.5 × ULN OR 
• < 3 × ULN for persons with Gilbert’s syndrome OR 
• Direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 × ULN 
• Aspartate transaminase (AST) and alanine transaminase (ALT) (also known as serum 
glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase) 
• ≤ 2.5 × ULN OR 
• ≤ 5 × ULN for patients with liver metastases 


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Coagulation 
• International normalized ratio or prothrombin time (PT) ≤ 1.5 × ULN unless patient is 
receiving anticoagulant therapy, and as long as PT or partial thromboplastin time (PTT) is 
within therapeutic range of intended use of anticoagulants  
• Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless patient is receiving 
anticoagulant therapy, and as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants 
5) Have provided 2 tissue biopsy samples taken of the target lesion (Lesion A) as a single 
biopsy split into 2 samples or 2 separate biopsies that meet the minimal sample size 
requirement per the study laboratory manual. One sample is for determining PD-L1 
expression level by immunohistochemistry and can be an archival sample of the anticipated 
target lesion that has been collected within 3 months of screening. The other sample is for 
RNA expression profiling and must be a fresh biopsy.  
6) Life expectancy of at least 6 months 
7) Female patients of childbearing potential, as defined in Section 5.2.1, must have a negative 
urine or serum pregnancy test within 72 hours prior to taking the first dose of trial treatment. 
If the urine test is positive or cannot be confirmed as negative then a serum test is required 
which must be negative for the patient to enroll. Women of childbearing potential (WOCBP) 
must be willing to use 2 medically acceptable methods of contraceptive from Day 1 through 
120 days after the last dose of trial treatment. The 2 medically acceptable birth control 
methods can be either 2 barrier methods or a barrier method plus a hormonal method to 
prevent pregnancy. 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, subcutaneous, intrauterine, or intramuscular agents). 
Male patients of reproductive potential, as described in Section 5.2.1, must agree to use an 
adequate method of contraception from Day 1 through 120 days after the last dose of trial 
treatment. 
Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
patient. 


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Inclusion Criteria (Phase 1 only: Melanoma) 
A patient must meet the following to be eligible for Phase 1: 
8) Histologically or cytologically confirmed unresectable or metastatic (stage IV) melanoma 
9) For Phase 1 Escalation Cohorts 1-4, must have at least 1 lesion that qualifies as a target 
lesion per RECIST v1.1 except for the minimum measurement of 10 mm in diameter for 
superficial lesions, is easily accessible (palpable or can be visualized by ultrasound), and is 
amenable to multiple intratumoral injections. If superficial, the target lesion must be 
documented photographically.  
Inclusion Criteria (Phase 2 only: Melanoma) 
A patient must meet the following to be eligible for Phase 2 (as applicable to the expansion 
cohorts): 
10) Histologically or cytologically confirmed recurrent or unresectable or metastatic (stage IV) 
melanoma 
11) Must have at least 2 lesions that qualify as a target lesion per RECIST v1.1, and 1 of the 
qualifying lesions must be easily accessible (palpable or can be visualized by ultrasound) and 
amenable to multiple intratumoral injections. The target lesion should be of sufficient size 
such that the required tumor biopsies do not significantly affect tumor assessment per 
RECIST v1.1. If superficial, the target lesion must measure at least 10 mm in diameter, be 
measured by calipers, and be documented photographically. Tumor lesions situated in a 
previously irradiated area, or in an area subjected to other loco-regional therapy, are usually 
not considered measurable unless there has been demonstrated progression in the lesion. 
Approval from the Medical Monitor is required to inject a previously radiated lesion. 
12) Expansion Cohort 2: Must have documented PD per RECIST v1.1 on a prior treatment 
regimen containing an anti-PD-1/L1 drug (see Appendix 6 for definition of PD per RECIST 
v1.1) 
13) Expansion Cohort 8: Must have all of the following:  
a) Received at least 2 doses of an anti-PD-1/L1 therapy 
b) PD occurred within 3 months after last dose of anti-PD-1/L1 therapy 
c) Documented PD per RECIST v.1.1, which has been confirmed by a second assessment at 
least 4 weeks from the date of the first documented PD, in the absence of rapid clinical 
progression 


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Inclusion Criteria (Phase 2 only: HNSCC) 
A patient must meet the following to be eligible for Phase 2 (as applicable to the expansion 
cohorts): 
14) Histologically or cytologically confirmed recurrent or metastatic HNSCC that could not be 
treated with curative intent. 
15) Must have at least 1 lesion that qualifies as a target lesion per RECIST v1.1, and which must 
be easily accessible (palpable or can be visualized by ultrasound) and amenable to multiple 
intratumoral injections. The target lesion should be of sufficient size such that the required 
tumor biopsies do not significantly affect tumor assessment per RECIST v1.1. Tumor lesions 
situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, 
are usually not considered measurable unless there has been demonstrated progression in the 
lesion. Approval from the Medical Monitor is required to inject a previously radiated lesion. 
16) Expansion Cohort 4: Must have documented confirmed PD per RECIST v1.1 on a prior 
treatment regimen containing an anti-PD-1/L1 drug (see Appendix 6 for definition of PD per 
RECIST v1.1) 
17) Expansion Cohort 7: Must have all of the following:  
a) Received at least 2 doses of an anti-PD-1/L1 therapy, where the last dose of anti-PD-1/L1 
therapy was within 6 months of study enrollment (Day 1) 
b) Refractory response, ie, PD occurred within 3 months duration of the start of treatment on 
anti-PD-1/L1 therapy; OR resistant response, ie, PD occurred beyond 3 months duration 
of treatment on anti-PD-1/L1 therapy and within 6 months after the last dose of treatment 
on anti-PD-1/L1 therapy 
c) Documented PD per RECIST v.1.1, which has been confirmed by a second assessment at 
least 4 weeks from the date of the first documented PD, in the absence of rapid clinical 
progression 
5.2 
Exclusion Criteria  
A patient with any 1 of the following criteria is not eligible for enrollment in the trial:  
Phase 1 and Phase 2 
1) Received systemic chemotherapy or biological cancer therapy (except anti-PD-1/L1 therapy) 
within 3 weeks prior to study enrollment 
2) Received prior radiotherapy within 2 weeks of start of study therapy. A shorter washout 
period may be permitted after approval by the Medical Monitor. 


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3) Received small molecule inhibitor targeted therapy, such as tyrosine kinase inhibitors, within 
2 weeks prior to study enrollment 
4) Has not recovered to CTCAE Grade 1 or better from the AEs due to cancer therapeutics prior 
to study enrollment 
NOTE: Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia or Grade 2 AEs that 
qualify as Grade 2 due to replacement hormonal or steroid therapy are exceptions to this 
criterion and may qualify for the study with approval by a Dynavax Medical Monitor.  
If a patient received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to enrollment. 
5) Received a transfusion of blood products (including platelets or red blood cells) or 
colony-stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) 
within 4 weeks prior to study enrollment 
6) Is expected to require any other form of anti-cancer therapy while in the trial 
7) Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy (including immune modulators or systemic corticosteroids) 
within 7 days prior to study enrollment 
8) Positive for active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection 
as determined by laboratory tests for HBsAg, anti-HBc, and anti-HBs; anti-HCV; and 
anti-HIV -1/2, respectively 
9) History of or current uveal or mucosal ocular melanoma 
10) Active infection including cytomegalovirus 
11) Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial through 120 days after the last dose of trial treatment 
12) Active autoimmune disease requiring systemic treatment in the past 2 years or a disease that 
requires immunosuppressive medication including systemic lupus erythematosus, rheumatoid 
arthritis, multiple sclerosis, Sjogren’s syndrome, or autoimmune thrombocytopenia. 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. 
13) Current pneumonitis or history of (non-infectious) pneumonitis that required steroids 
14) An immune-related AE from a previous immunotherapeutic agent that has not resolved to 
Grade 1 or less prior to study enrollment. The exception is a Grade 2 AE which qualifies as 
Grade 2 due to replacement steroid therapy which may be allowed with approval by a 
Dynavax Medical Monitor. 
15) Known active central nervous system metastases or carcinomatous meningitis 


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NOTE: Patients with previously treated brain metastases may participate provided they are 
stable (without evidence of progression by imaging [using the identical imaging modality for 
each assessment, either MRI or CT scan] for at least 4 weeks prior to the first dose of trial 
treatment and with any neurologic symptoms returned to baseline), have no evidence of new 
or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial 
treatment. This exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability. 
16) Use of any investigational agent within the last 28 days prior to study enrollment 
17) Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu 
vaccines that do not contain live virus are permitted. 
18) Any other significant medical or psychiatric condition, laboratory abnormality, or difficulty 
complying with protocol requirements that may increase the risk associated with trial 
participation or trial drug administration that may interfere with the interpretation of trial 
results and, in the judgment of the investigator, would make the patient inappropriate for this 
trial 
19) History of sensitivity to any component of SD-101 or hypersensitivity reaction to treatment 
with a monoclonal antibody and/or any of its excipients 
20) Any known additional malignancy that is progressing or requires active treatment. 
Exceptions are cutaneous melanoma or HNSCC under study per protocol, or basal cell 
carcinoma of the skin, squamous cell carcinoma of the skin or in situ cervical cancer that has 
undergone potentially curative therapy. 
Exclusion Criteria (Phase 2, Melanoma Expansion Cohorts 1 and 5 only) 
21) Melanoma considered resectable with curative intent 
22) Prior therapy with an anti-PD-1/L1 agent 
23) Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients 
Exclusion Criteria (Phase 2, Melanoma Expansion Cohorts 2 and 8 only) 
24) Melanoma considered resectable with curative intent 
25) Any prior combination therapy involving agents given by intratumoral injection that target 
the innate immune pathway or system such as oncolytic viral or microbial therapy (eg, 
T-VEC [talimogene laherparepvec]), toll-like receptors (TLR) agonists, STING or RIG-1 and 
an anti-PD-1/L1 inhibitor 


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Exclusion Criteria (Phase 2, HNSCC Expansion Cohorts 3 and 6 only) 
26) HNSCC considered resectable with curative intent 
27) Prior therapy with an anti-PD-1/L1 agent 
28) Require anticoagulation therapy 
Exclusion Criteria (Phase 2, HNSCC Expansion Cohorts 4 and 7 only) 
29) HNSCC considered resectable with curative intent 
30) Any prior combination therapy involving agents given by intratumoral injection that target 
the innate immune pathway or system such as oncolytic viral or microbial therapy (eg, 
T-VEC), TLR agonists, STING or RIG-1 and an anti-PD-1/L1 inhibitor. 
31) Require treatment on anticoagulation therapy 
5.2.1 
Contraception 
WOCBP include any female who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or is not postmenopausal. All female patients are considered to be WOCBP 
except if they have been postmenopausal for at least 2 years or surgically sterile for at least 
1 year. 
Postmenopause is defined as: 
• Women on hormone replacement therapy 
• Amenorrhea ≥ 12 consecutive months without another cause and a documented serum 
follicle stimulating hormone (FSH) level >35 mIU/mL 
• Women with irregular menstrual periods and a documented FSH level > 35 mIU/mL 
FSH level testing is not required for women > 62 years old with amenorrhea for > 1 year.  
NOTE:  
• Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, 
skin patches, or implanted or injectable products), or mechanical products such as an 
intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent 
pregnancy, or where their partner is sterile (eg, vasectomy) should be considered to be of 
childbearing potential. 


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• For this trial, male patients will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
• Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
patient. 
5.3 
Removal of Patients From the Trial 
Patients may choose to withdraw from the trial at any time. The reason for withdrawal will be 
recorded on the case report form (CRF). 
Patients may also be discontinued from the trial by the investigator for any of the following 
reasons: 
• Patient does not receive the first dose of SD-101 
• Pembrolizumab is discontinued because of toxicity 
• Patient begins new cancer treatment for melanoma or HNSCC (as applicable) 
• Noncompliance with trial procedures as determined by the investigator or sponsor 
• At the discretion of the investigator if it is felt to no longer be in the best interest of the 
patient to remain in the trial 
• If patient becomes pregnant and/or starts breastfeeding 
• The sponsor decides to terminate the trial 
The investigator or designee should discuss with the Dynavax Medical Monitor prior to 
withdrawing a patient from the trial before trial completion. When a patient discontinues the 
trial, they should undergo an EOS/Safety Follow-up Visit 28 days after the last dose of trial 
treatment as described in Section 10.8. Required procedures are listed in Appendix 1 through 
Appendix 4. Additional information about stopping treatment or terminating the trial may be 
found in Sections 7.6, 9.1 and 9.2. 
6.0 
TRIAL TREATMENT AND SUPPLIES 
The identities and instructions for administration, storage, and handling of SD-101 and 
pembrolizumab are described below. Both SD-101 and pembrolizumab are considered as, and 
referred to as, trial drug(s) or trial treatment in this protocol. 


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6.1 
Trial Treatments 
6.1.1 
Pembrolizumab 
Pembrolizumab [Keytruda® (US)], a humanized monoclonal antibody against the PD-1 protein, 
has been developed by Merck & Co for the treatment of cancer. 
Pembrolizumab is supplied as a sterile, preservative-free, clear to slightly opalescent, colorless to 
slightly yellow solution that requires dilution for intravenous infusion. Each vial contains 100 mg 
of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab 
and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and water 
for injection, USP. 
Further details regarding formulation of pembrolizumab are provided in the current approved 
product labels and Investigator’s Brochure for pembrolizumab.  
A fixed dose of 200 mg of pembrolizumab will be administered via intravenous infusion Q3W 
for up to 35 treatments (approximately 2 years).  
6.1.2 
SD-101  
SD-101 is a clear to slightly opalescent, colorless to pale yellow solution, free of visible particles 
and will be supplied by Dynavax in single-use vials. Dilution with sterile 0.9%, preservative-free 
sodium chloride for injection to the appropriate concentration for dosing will be required for all 
doses; instructions for dilution are provided in the Pharmacy Manual. The dose cohorts for 
SD-101 are 1.0 mg, 2.0 mg, 4.0 mg, and 8.0 mg. 
6.2 
Instructions for Administration 
6.2.1 
 Pembrolizumab 
Pembrolizumab will be administered using a 30-minute intravenous 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 (ie, infusion time is 30 minutes -5/+10 minutes). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of infusion solution. 
Designated site personnel will be responsible for preparing and administering pembrolizumab 
and will be required to record limited information during each infusion (eg, infusion date/time, 
lot number and expiry date for product administered, total dose/volume administered). See 
Pharmacy Manual for further details. 


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Pembrolizumab will be administered after SD-101 on days when both drugs are scheduled to be 
used. 
6.2.2 
SD-101 
SD-101 will be administered before pembrolizumab on days when both drugs are scheduled to 
be used. Designated trial-site personnel will be responsible for preparing and administering the 
trial injection with SD-101. At minimum, syringes will be labeled with the protocol number, 
patient initials, and patient number. 
Prior to injection, the site should be thoroughly cleansed and then wiped with alcohol. 
Ultrasound may be used to assist injection. Notation in the source documents should specify 
location and size (in 2 dimensions) in as much detail as possible. Injection should be made as 
close to the center of the tumor as possible. All of the drug should be injected.  
Note: Intratumoral injections are not allowed if a tumor is fully encasing or in close proximity to 
major blood vessel(s). In this situation another tumor site must be accessible for intratumoral 
injections. 
Table 6-1 summarizes the dosage and administration of SD-101 for Phase 1 and Phase 2 cohorts.  


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Table 6-1: 
Dosage and Dose Administration for Phase 1 and Phase 2 Cohorts 
Cohort 
Anti-PD-1/L1 
Experience 
SD-101 Dose 
Maximum 
Total Per-
patient SD-101 
Dose 
Phase 1 Melanoma Dose Escalation Cohorts 
 
1 
Naïve or experienced 2.0 mg per lesion in 1 injectable lesion (Lesion A) 
2.0 mg 
2 
Naïve or experienced 4.0 mg per lesion in 1 injectable lesion (Lesion A) 
4.0 mg 
3 
Naïve or experienced 8.0 mg per lesion in 1 injectable lesion (Lesion A) 
8.0 mg 
4 
Naïve or experienced 1.0 mg per lesion in 1 injectable lesion (Lesion A) 
1.0 mg 
Phase 2 Melanoma Dose Expansion Cohorts 
 
1 
Naïve 
8.0 mg in a single injectable lesion if 1 lesion is selected 
(Lesion A) or 2.0 mg per lesion if 2 to 4 lesions are selected for 
injection (Lesion A, Lesion B, Lesion C, Lesion D) 
8.0 mg 
2 
Experienced 
8.0 mg in a single injectable lesion (Lesion A) 
8.0 mg 
5 
Naïve 
2.0 mg per lesion in 1 to 4 injectable lesions (Lesion A, Lesion 
B, Lesion C, Lesion D) 
8.0 mg 
8 
Refractory or resistant 
2.0 mg in 1 ml per injection in 1 to 4 separate lesions for 
lesions measuring up to 5 cm in the longest diameter; or for 
lesions larger than 5 cm, 2.0 mg in 1 ml per injection in 1 to 
4 separate regions where the injections are ≥ 5 cm apart 
(maximum total dose is 8.0 mg) 
8.0 mg 
Phase 2 HNSCC Dose Expansion 
 
3 
Naïve 
8.0 mg per lesion in 1 lesion with the option of injecting into 
up to 4 regions within the lesion in approximate equally 
divided volumes of an 8.0 mg dose 
8.0 mg 
4 
Experienced 
8.0 mg per lesion in 1 lesion with the option of injecting into 
up to 4 regions within the lesion in approximate equally 
divided volumes of an 8.0 mg dose 
8.0 mg 
6 
Naïve 
2.0 mg per lesion in 1 to 4 injectable lesions (Lesion A, Lesion 
B, Lesion C, Lesion D) 
8.0 mg 
7 
Refractory or resistant 2.0 mg per lesion in 1 to 4 injectable lesions (Lesion A, Lesion 
B, Lesion C, Lesion D) 
8.0 mg 
Please refer to the Pharmacy Manual for additional details on dose administration. 
 


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6.2.2.1 
Phase 1 Metastatic Melanoma - COMPLETE 
In Phase 1 Escalation Cohorts 1-4, SD-101 is injected intratumorally into a target lesion (Lesion 
A), the same site used throughout the trial. If at any point during treatment, the lesion for 
injection has completely regressed the remaining SD 101 injections will be given peritumorally 
by injection into the site of Lesion A. 
6.2.2.2 
Phase 2 Metastatic Melanoma - CLOSED 
Lesion A must be selected and must meet the requirement of being amenable to multiple 
intratumoral injections of SD-101, and a target lesion as defined per RECIST v1.1. Biopsy and 
intratumoral injection of Lesion A may be performed on different days but must be completed 
within the window period allowed per protocol.  
The same site(s) will be used throughout the trial unless a lesion has completely regressed. If a 
selected lesion regresses and/or becomes inaccessible for injection, a replacement lesion, which 
could be either a target, non-target, or new lesion per RECIST v1.1, may be chosen for injection 
and will be injected at subsequent dosing time points. Injection into a new lesion may occur only 
after consultation with the Dynavax MM. 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Approval from the Medical Monitor is required to inject a previously 
radiated lesion. 
If at any point during treatment, the lesion for injection has completely regressed and there is no 
other replacement lesion, SD-101 will be injected peritumorally for up to the next 3 doses of 
SD-101.  
Please refer to the Pharmacy Manual for details. 
6.2.2.3 
Phase 2 HNSCC - CLOSED 
Lesion A must be selected and must meet the requirement of being amenable to multiple 
intratumoral injections of SD-­101, and a target lesion as defined per RECIST v1.1. Biopsy and 
intratumoral injection of Lesion A may be performed on different days but must be completed 
within the window period allowed per protocol.  
If a selected lesion has regressed to where injection can no longer be made to any region within 
the same lesion, a replacement lesion, which could be either a target, non-target, or new lesion 
per RECIST v1.1, may be chosen for injection and will be injected in a similar manner at 


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subsequent dosing points. Injection into a new lesion may occur only after consultation with the 
Dynavax MM. 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Approval from the Medical Monitor is required to inject a previously 
radiated lesion. 
If at any point during treatment, the lesion for injection has completely regressed and there is no 
other replacement lesion, SD-101 will be injected peritumorally for up to the next 3 doses of 
SD-101.  
Please refer to the Pharmacy Manual for details. 
6.3 
Labeling 
6.3.1 
Pembrolizumab 
During the course of the study, labeled pembrolizumab for clinical study use (MK-3475) will be 
provided.  
At a minimum, pembrolizumab (MK-3475) will be labeled with the following information: 
product name, product lot number, contents, volume, concentration, sponsor name, and a 
statement indicating that the drug is for investigational use only. Additionally, at a minimum, the 
intravenous bag will be labeled with the protocol number, patient initials, and patient number. 
6.3.2 
SD-101 
At a minimum, SD-101 will be labeled with the following information: product name, product 
lot number, contents, volume, concentration, sponsor name, and a statement indicating that the 
drug is for investigational use only. 
6.4 
Storage and Handling Instructions 
The clinical supplies storage area at the site must be monitored closely by the designated site 
staff for temperature consistency and documentation of temperature monitoring must be 
maintained. Temperature excursions outside of the recommended storage range may impact 
product quality and must be reported to Dynavax or its designee per the detailed instructions in 
the Pharmacy Manual. 


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6.4.1 
Pembrolizumab 
Pembrolizumab vials of solution for injection (MK-3475) must be stored at refrigerated 
conditions (2°C to 8°C) and protected from light. 
Note: Vials should be stored in the labeled box in which they are received to ensure the drug is 
protected from light. 
A detailed description of the storage and handling instructions for pembrolizumab (MK-3475) is 
provided in the Pharmacy Manual. 
6.4.2 
SD-101 
SD-101 contains no preservatives and must be stored under refrigerated conditions (2°C to 8°C). 
SD-101 is not to be frozen. Vials of SD-101 are for single use only. 
A detailed description of the storage and handling instructions for SD-101 is provided in the 
Pharmacy Manual. 
6.5 
Control and Accountability of Investigational Medicinal Product 
All investigational medicinal products must be received by a trained designated person at the 
trial site, handled and stored safely and properly, and kept in a secured location with limited 
access. 
The investigator (or responsible designee) must maintain current and accurate records of the 
receipt (documentation from shipments of trial treatments received), administration 
(patient-by-patient and overall accounting), and return of trial treatments to a Dynavax-specified 
facility for destruction. All trial treatments must be stored in a location with access restricted to 
authorized personnel only. 
A trial monitor will be responsible for monitoring the drug accountability at the site. The monitor 
should be contacted with any questions concerning administration of trial treatments. 
Records of trial treatments accountability, storage, and handling must be made available to the 
trial monitor for the purposes of trial treatments accountability. Any discrepancy and/or 
deficiency must be recorded with an explanation. 
The investigator must retain all expired, damaged, and unused trial treatment vials until 
accountability has been confirmed by the trial monitor. Any exceptions to this policy must be 
specifically granted by Dynavax. 


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At the end of the trial, or upon request by Dynavax, all unused trial treatments must be returned 
to a Dynavax-specified facility for adequate disposition. 
Refer to the Pharmacy Manual for detailed instructions on trial treatments. 
Trial treatments may not be used for any purpose other than that described in the protocol. 
6.6 
Treatment Compliance 
All trial injections and infusions will be administered by designated personnel only. 
7.0 
TREATMENT OF PATIENTS 
7.1 
Treatments Administered 
All patients will receive 200 mg of pembrolizumab administered intravenously Q3W (± 3 days) 
for up to 35 treatments (approximately 2 years) or until disease progression. All patients must 
have an ANC count of ≥ 1500 cells/mcL at screening and on the day of dosing in order to receive 
SD-101. ANC labs should be drawn on the day of dosing; however, if this is not possible, ANC 
labs can be drawn the day before dosing of SD-101. If ANC count ˂ 1500 cells/mcL or 
Grade ≥ 3 neutropenia develops while on study, then patients must have an ANC count of 
≥ 1500 cells/mcL on the day of dosing in order to receive SD-101. 
Concurrently, they will receive the following regimens of SD-101: 
• Phase 1 Escalation Cohorts 1-4: 4 weekly doses of SD-101 starting from Day 1 followed by 
1 dose Q3W for 7 additional doses; up to 11 total doses (Figure 4-3). Both SD-101 and 
pembrolizumab start on the same study day. 
• Phase 2 Expansion Cohorts 1-4: 2 courses of SD-101, each consisting of 4 weekly doses of 
SD-101 followed by 1 dose Q3W for 7 additional doses, with 9 weeks off between the 
courses, for up to 22 total doses (Figure 4-4 and Figure 4-5). Cohorts 1 and 3 patients will 
receive a single dose of pembrolizumab before commencing the first treatment course with 
SD-101, and patients in Cohorts 2 and 4 will start both SD-101 and pembrolizumab on the 
same study day. 
• Phase 2 Expansion Cohorts 5-8: 4 weekly doses of SD-101 starting from Day 1 followed by 
1 dose Q3W for 16 additional doses; up to 20 total doses. Both SD-101 and pembrolizumab 
start on the same study day. 
For the Phase 1 Dose Escalation, SD-101 doses are 1.0 mg, 2.0 mg, 4.0 mg, and 8.0 mg. Patients 
will be assigned to the current dose being evaluated per sponsor decision at the time they are 
enrolled in the trial.  


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Intra-patient Dose Escalation or dose reduction is not permitted. 
7.2 
Treatment Period 
All patients will receive 200 mg of pembrolizumab Q3W for up to 2 years from Day 1. 
In Phase 1 Dose Escalation, patients in Escalation Cohorts 1-4 will receive SD-101 from Day 1 
through Day 169 (Figure 4-2).  
In Phase 2 Dose Expansion, patients naïve to anti-PD-1/L1 in Cohorts 1 and 3 will receive 
SD-101 from Day 22 through Day 421 (Figure 4-3) and patients experienced with anti-PD-1/L1 
in Cohorts 2 and 4 will receive SD-101 from Day 1 through Day 400 (Figure 4-4). Patients in 
Cohorts 5, 6, 7, and 8 will receive SD-101 from Day 1 through Day 358 (Figure 4-5). 
Pembrolizumab will be continued until completion of planned dosing (up to 2 years) or required 
discontinuation as described in Section 7.6. SD-101 will be continued until completion of 
planned dosing, confirmed disease progression, or required discontinuation as described in 
Section 9.2 (whichever occurs sooner). 
Details of the dosing for Phase 1 and Phase 2 are provided in the Schedule of Trial Events 
(Appendix 1 through Appendix 4). 
SD-101 will be administered before pembrolizumab on days when both drugs are scheduled to 
be used.  
Note: If pembrolizumab treatment is temporarily withheld, treatment of SD-101 and 
pembrolizumab will start on the same day once pembrolizumab is resumed. Delayed dosing of 
SD-101 would be preferred over completely skipping a dose as long as the interval between 
SD-101 dosing is not less than 5 days with subsequent return of SD-101 dosing to per protocol 
schedule of events. See Section 7.6 for details regarding delayed or skipped doses. 
The protocol may be discontinued by Dynavax Technologies Corporation at any time 
(Section 4.7). 
7.3 
Treatment Precaution 
IFN-α has been shown to inhibit cytochrome P450 (CYP) enzyme 1A2 (Brennan 2012). Since 
SD-101 induces IFN-α, SD-101 may inhibit metabolism of drugs by CYP 1A2. CYP 1A2 
substrates with narrow therapeutic ranges should be used with caution. The following drugs 
should be used with caution through 7 days after each subsequent dose of SD-101: caffeine, 


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theophylline, warfarin, tricyclic antidepressants, clozapine, fluvoxamine, ciprofloxacin, 
propranolol, and verapamil. 
7.4 
Prohibited Treatments or Therapies 
Patients may receive other medications that the investigator deems to be medically necessary, 
with the exception of the medications listed below, which are prohibited during the trial. Patients 
who in the assessment by the investigator require the use of any of the following treatments for 
clinical management should be removed from the trial (see Section 5.3): 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
• Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on an exceptional case by case basis after consultation with Sponsor. The 
patient must have clear measurable disease outside the radiated field. Administration of 
palliative radiation therapy will be considered clinical progression for the purposes of 
determining PFS. 
• Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial. Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed. 
However, intranasal influenza vaccines (eg, Flu - Mist®) are live attenuated vaccines, and are 
not allowed. 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE that 
is suspected to have an immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Dynavax Medical Monitor. 
• Note: Inhaled steroids are allowed for management of asthma. 
• Surgery, unless approved by the Dynavax Medical Monitor  
Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  


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All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. 
The Exclusion Criteria (Section 5.0) describe other medications and therapies that are prohibited 
in this trial. 
7.5 
Permitted Therapy 
Topical or inhaled or intranasal corticosteroids (with minimal systemic absorption) and 
non-absorbed intra-articular steroid injections are permitted to treat AEs and may be continued 
with permission of the Dynavax Medical Monitor. Systemic corticosteroids required for the 
control of infusion reactions or immune-related AEs must be tapered and be at 
non-immunosuppressive doses (≤ 10 mg per day of prednisone or equivalent) before the next 
administration of SD-101 or pembrolizumab. A brief (< 24 hours) course of steroids for 
prophylaxis against contrast dye allergy is permitted for patients undergoing tumor assessments 
per institutional standard. Guidelines for steroid use to treat immunologic AEs are listed in 
Section 7.7. 
Acetaminophen (maximum 3 g per day), ibuprofen, and/or ondansetron may be used 
post-SD-101 treatment to treat flu-like symptoms and pre-dose as prophylaxis. Pre- and 
post-SD-101 treatment prophylaxis with these agents is allowed but not encouraged for the first 
SD-101 dose for a patient in Phase 1 unless recommended per the Dynavax Medical Monitor. 
The sponsor may make further recommendations with regards to prophylaxis treatments for 
potential flu-like symptoms as the study is ongoing. See Section 9.3 for additional details. 
Efforts should be made to keep all other concurrent medications at stable doses during the trial 
and to refrain from starting any new medications, unless clinically indicated. Therapy to prevent 
or treat local and/or systemic reactions following administration of either trial drug may include 
analgesics, antipyretics, and antihistamines. 
7.6 
Dose Modification, Dose Delays, and Missed Doses 
NOTE: As of Amendment 9, irRECIST for the determination of disease progression is no 
longer applicable and this section has been revised accordingly. 
 Only a limited number of patients have been treated with SD-101, and to date, the most common 
toxicities include transient Grade 1 to 2 flu-like symptoms. In mice, SD-101 has been injected 
intratumorally concurrently with a neutralizing anti-mouse PD-1 antibody. In multiple 
experiments using high doses of SD-101 (approximately 2 mg/kg), no evidence of acute 
morbidity or mortality in mice was observed that could be due to the interaction of the 2 agents. 


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To protect patient safety, patients will be closely monitored for any additional or synergistic 
toxicities observed with the combination. 
Withhold SD-101 for any Grade ≥ 3 injection-site reaction or drug-related AE that is not a DLT 
(see Section 9.1). SD-101 treatment may be resumed once the AE has resolved to Grade 0 or 1 
with standard treatment. SD-101 must also be held for an ANC count of < 1500 cells/mcL. 
Patients will be treated at the dose in their assigned Cohort and individual dose adjustment 
(reduction or increase) of SD-101 or pembrolizumab will not be permitted. 
Delayed dosing of SD-101 would be preferred over completely skipping a dose as long as the 
interval between SD-101 dosing is not less than 5 days with subsequent return of SD-101 dosing 
to per protocol schedule of events. If the 5-day interval cannot be adhered to, then the injection 
must be skipped to allow a minimum of 5-day interval window between the off-scheduled 
injection and next injection on schedule. After a delayed or skipped dose, dosing will return to 
the original interval as described under Schedule of Trial Events. 
For Phase 1, if ≥ 2 doses are missed during the DLT assessment period for any reason or if 
≥ 4 doses are missed due to AEs following the DLT period, then SD-101 should be permanently 
discontinued. For Phase 2, if ≥ 4 doses are missed due to AEs, then SD-101 should be 
permanently discontinued. 
If SD-101 dosing is delayed for more than 3 days, then the hematology and chemistry laboratory 
collections listed in the Schedule of Trial Events (Appendix 1 through Appendix 4) or the 
planned day of dosing that were missed should be done prior to dosing on that day (eg, if Day 22 
dosing is delayed and SD-101 is dosed on Day 26, then all the Day 22 labs should be repeated 
pre-dose on Day 26). 
SD-101 should be withheld if a patient requires greater than 10 mg per day of prednisone or 
equivalent to treat an AE (Section 9.3.2). SD-101 may be resumed when the corticosteroid is 
discontinued and pembrolizumab is resumed.  
If an HNSCC subject develops an AE which requires anticoagulation therapy, the Investigator in 
consultation with the Medical Monitor will determine whether SD-101 injection should be 
continued or interrupted. 
SD-101 should be permanently discontinued for any of the following: 
• SD-101 dosing is delayed for more than 6 weeks 
• DLT that occurs during the DLT assessment period in Phase 1 (Section 9.1) 


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• Clinically significant immune-related event 
• Pembrolizumab is permanently discontinued 
SD-101 will be permanently discontinued for any of the following adverse reactions (ARs): 
• Severe or life-threatening ARs, including any of the following: 
• Any Grade 4 (life-threatening) AR 
• Grade 3 or 4 pneumonitis 
• Grade 4 diarrhea/colitis 
• Grade 4 hyperthyroidism 
• Grade 3 AST or ALT of > 5 × ULN or Grade 3 total serum bilirubin > 3 × ULN  
• AST or ALT increases by greater than or equal to 50% relative to baseline and lasts 
for at least 1 week in patients with liver metastasis who begin treatment with a 
baseline Grade 2 AST or ALT of > 3 and ≤ 5 × ULN 
• Grade 3 or 4 nephritis 
• Any severe or Grade 3 AR that recurs 
• Inability to reduce corticosteroid dose (used for treatment of AEs) to 10 mg or less of 
prednisone or equivalent per day within 12 weeks of starting corticosteroids 
• Observation of any other toxicities that in the opinion of the investigators suggests that 
there may be a significant increase in either the incidence or severity of any events seen 
with either single agent. In this case, the sponsor and investigators will review all safety 
data. 
Pembrolizumab must be withheld for drug-related toxicities and severe or life-threatening AEs as 
listed in Table 7-1. If a patient`s AE prevents pembrolizumab dosing then SD-101 injection 
should be held if the AE also could at least be possibly related to SD-101. Delayed dosing of 
SD-101 would be preferred over completely skipping a dose as long as the interval between 
SD-101 dosing is not less than 5 days with subsequent return of SD-101 dosing to per protocol 
schedule of events. See Section 7.7 for use of corticosteroids. 
Grade 2 - 3 fatigue does not require the withholding of pembrolizumab or SD-101 treatment. 
It is at the discretion of the investigator whether to continue a patient on study treatment until 
repeat imaging is obtained. If repeat imaging confirms PD, patients will be discontinued from the 
study. 


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Two dosing delays of pembrolizumab due to toxicity will be permitted. In the event of a third 
occurrence of a toxicity which would require dosing delay, pembrolizumab will be discontinued 
permanently.  
If a subject resumes pembrolizumab treatment after a dose interruption, the interval between 
pembrolizumab dosing should not be less than 3 weeks (± 3 days) with subsequent return of 
pembrolizumab dosing to per protocol schedule of events. 
Dosing interruptions for SD-101 or pembrolizumab are permitted in the case of medical/surgical 
events. For Phase 2, dosing interruptions for logistical reasons not related to study therapy (eg, 
elective surgery, unrelated medical events, patient vacation, and/or holidays) are permitted. 
Patients should be placed back on trial treatment within 3 weeks of the scheduled interruption, 
unless otherwise discussed with the Dynavax Medical Monitor.  
The reason for any interruption in treatment should be documented in the patient's study record. 
7.7 
Dose Modification and Toxicity Management for Immune-Related Adverse Events 
Associated With Pembrolizumab 
Adverse events 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 one 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 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, or 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 7-1.  
 
 


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Table 7-1: 
Dose Modification and Toxicity Management Guidelines for 
Immune-related Adverse Events Associated with Pembrolizumab 
General instructions: 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to 
taper over at least 4 weeks. 
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.  
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 
(CTCAE v4.0) 
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 
 
 
 
 


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Table 7-1: 
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab (Cont’d) 
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 
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 (ie, 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation 
(ie, 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 
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. 


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Table 7-1: 
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab (Cont’d) 
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 
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 
discontinue  
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 
discontinue 
Hypothyroidism Grade 2-4 
Continue  
Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyroinine) 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 
(prednisone 1-2 mg/kg 
or equivalent) followed 
by taper. 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
 
Grade 3 or 4 
Permanently 
discontinue 


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Table 7-1: 
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab (Cont’d) 
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 
All other 
immune-related 
AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
Based on type and 
severity of AE 
administer 
corticosteroids 
(prednisone 1-2 mg/kg 
or equivalent) followed 
by taper. 
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-Barré 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
Withholding or permanently discontinuing pembrolizumab is at the discretion of the investigator or treating 
physician.  
NOTE: For participants with Grade 3 or 4 immune-related endocrinopathy where withholding 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).  
AE = adverse event; ALT = alanine transaminase; AR = adverse reaction; AST = aspartate transaminase; CTCAE = Common 
Terminology Criteria for Adverse Events; irAE = immune-related AE; IV = intravenous; T1DM = type 1 diabetes mellitus. 
 
 


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7.8 
 
Replacement of Patients 
NOTE: As of Amendment 9, enrollment is closed and this section is no longer applicable. 
Patients who complete screening but are not treated or patients who do not complete at least 
3 injections of SD-101 during the DLT assessment period for reasons other than drug-related 
toxicity will be replaced. Patients who withdraw from the trial during the DLT assessment 
interval prior to Day 29 for reasons other than a drug-related toxicity may be replaced. 
Patients who received < 90% of pembrolizumab during the DLT assessment period (eg, because 
the infusion had to be discontinued due to an infusion reaction) and did not experience a DLT 
will not be taken into account in the assessment of the overall DLT rate for the particular dose 
level cohort and will be replaced. 
Phase 2 patients who do not receive the following may be replaced at the decision of the 
Dynavax Medical Monitor: 
• At least 1 dose of SD-101 and pembrolizumab 
• Baseline and at least 1 post-baseline imaging 
• Baseline and at least 1 post-baseline tumor biopsy 
8.0 
ASSESSMENT OF RESPONSE 
NOTE: As of Amendment 9, efficacy and exploratory endpoints will no longer be collected. 
The collection of safety endpoints has been simplified. Assessments of disease response to 
treatment should be made per Investigator based on local standard of care. 
Response assessments will be performed at specified time points as listed in the Schedule of 
Trial Events (Appendix 1 through Appendix 4). 
8.1 
Interferon-inducible Genes 
NOTE: As of Amendment 9, this section is no longer applicable. 
IFN-inducible gene expression will be measured in Phase 1 to indirectly determine the induction 
of IFN-α by different doses of SD-101. In addition to DLT assessment, the levels of 
IFN-inducible gene expression may be used to determine the optimal RP2D of SD-101 for 
further evaluation of combination therapy in oncology trials. The rationale for utilizing 
IFN-inducible gene expression as a factor in choosing an optimal dose of SD-101 is to ensure 
that an appropriately active dose of SD-101 will be used since preclinical data have suggested 
that high doses of CpGs may paradoxically lower CpG stimulated immune response due to a 


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compensatory mechanism of the immune system. Induction of IFN-α responsive genes is 
considered a surrogate for the activity of SD-101 since engagement of TLR9, the target of 
SD-101, indirectly resulting in an upregulation of these genes. Specifically, fold increases in 
IFN-inducible genes will be analyzed per individual gene and as a combination of genes on a 
cohort basis to provide assurances that an appropriately active dose of SD-101 will be used. 
IFN-inducible gene expression may also be measured in up to 12 patients in each of the Phase 2 
Expansion HNSCC cohorts to understand HNSCC tumor responses. 
8.2 
Response Evaluation and Criteria 
NOTE: As of Amendment 9, Section 8.2 and its subsections (8.2.1, 8.2.1.1, and 8.2.1.2) are 
no longer applicable. All disease response assessments, including the timing, type, and 
evaluation of imaging, are to be performed and assessed per the Investigator based on local 
standard of care; the data will not be collected and no longer need to be recorded in the 
CRF. Confirmation of progression by repeat imaging is not mandatory. Decisions on 
treatment discontinuation should be made per Investigator based on local standard of care 
and in accordance with the stopping rules outlined in Section 9.2. The text in these sections 
is retained as a reference only to aid Investigators in making treatment decisions and is not 
mandatory. 
All baseline efficacy evaluations will be performed at Screening. Baseline radiographic and 
superficial measurement (as applicable for superficial lesions) must be performed no more than 
4 weeks prior to study enrollment. The same imaging method used at baseline should be used 
throughout the study unless a change is required due to AEs (eg, new radiographic contrast 
allergy) per local radiology guidelines. 
Evaluation of superficial lesions requires both photographic and manual (caliper) measurement 
at all time points that radiographic imaging is required per Schedule of Trial Events (Appendix 1 
through Appendix 4). Although radiographic imaging collected at the scheduled time points is 
preferred, it is allowed to be obtained the day prior to study treatment.  
Response to treatment and disease progression will be evaluated by the investigator and recorded 
on the CRF every 9 weeks after the first trial injection until Day 379 and then every 12 weeks 
thereafter for the remainder of the trial. All treatment response and disease progression require 
confirmation of response (complete response [CR] or partial response [PR]) using RECIST v1.1 
and irRECIST, which is the study-specific irRECIST that requires confirmation of disease 
progression with an additional scan obtained at least 4 weeks later that also meets the criteria of 
PD per RECIST v1.1 (Appendix 6, Immune-related RECIST). Patients with suspected disease 
progression should continue to follow trial procedures until they have confirmed disease 


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progression. It is at the discretion of the investigator whether to continue a patient on study 
treatment until repeat imaging is obtained (per irRECIST patient management). This clinical 
judgment decision by the investigator should be based on the patient’s overall clinical stability 
defined as the following: 
1) Absence of symptoms and signs indicating clinically significant progression of disease, 
including worsening of laboratory values 
2) No decline in ECOG PS 
3) Absence of rapid progression of disease 
4) Absence of progressive tumor at critical anatomical sites (eg, cord compression) requiring 
urgent alternative medical intervention 
If repeat imaging confirms PD due to any of the scenarios listed in Appendix 6, Immune-related 
RECIST, patients will be discontinued from study therapy. If repeat imaging does not confirm 
PD by irRECIST and the patient continues to be clinically stable, treatment may continue and 
follow the regular radiographic imaging schedule. If a patient requires another anti-cancer 
therapy, radiographic imaging and measurement of superficial lesions will be discontinued. 
Please refer to Section 10.8 for EOS visit and procedures regarding discontinuation from the 
trial. 
8.2.1 
Response Criteria  
8.2.1.1 
RECIST v1.1 and Immune-related RECIST  
NOTE: As of Amendment 9, this section is no longer applicable. All disease response 
assessments are to be performed and assessed per the Investigator based on local standard 
of care; the data will not be collected and no longer need to be recorded in the CRF. The 
analysis of ORR and DCR may be performed based on data collected prior to 
Amendment 9. 
Response of lesions and disease status will be assessed using standard RECIST 1.1 for the 
primary evaluation of response and the study specific modified RECIST referred to as irRECIST 
for an exploratory evaluation. The primary difference between RECIST v1.1 and irRECIST is 
the requirement for confirmation of PD with additional imaging at least 4 weeks later that also 
qualifies as PD per RECIST v1.1. Details are listed in Appendix 6, Immune-related RECIST. 
Throughout the trial, each respective investigator will determine and manage disease status 
(progression or response) of patients per RECIST v1.1 and irRECIST at the specified imaging 
time points (Appendix 1 through Appendix 4) or more frequently as clinically indicated. 


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RECIST v1.1 was adapted to account for the unique tumor response characteristics seen with 
treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may produce 
anti-tumor effects by potentiating endogenous cancer-specific immune responses. The response 
patterns seen with such an approach may extend beyond the typical time course of responses 
seen with cytotoxic agents, and can manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. Standard RECIST may not provide an accurate 
response assessment of immunotherapeutic agents such as pembrolizumab. Therefore, 
RECIST v1.1 will be used with the following adaptations (see Appendix 6, Immune-related 
RECIST): 
• Determination of PD requires a confirmation of PD by imaging ≥ 4 weeks later. In order to 
confirm PD, both the initial lesion assessment and lesion assessment on the confirmatory 
scan must meet PD criteria (≥ 20% increase in sum of diameters [SOD]). 
• Continued treatment while awaiting radiologic confirmation of progression is encouraged if 
the patient is clinically stable. 
Patients that are deemed clinically unstable are not required to have repeat imaging for the 
confirmation of PD. 
In Phase 2, ORR and DCR will be evaluated, which will comprise all lesions as well as for 
injected and non-injected lesions independently. The ORR will include patients with CR or PR. 
The DCR will include patients with CR, PR, or stable disease. The ORR and DCR will be 
determined using both RECIST v1.1 and irRECIST. Details of analyses will be provided in a 
separate study statistical analysis plan. 
8.2.1.2 
Radiographic Assessment 
NOTE: As of Amendment 9, this section is no longer applicable. All disease response 
assessments, including the timing, type, and evaluation of imaging, are to be performed and 
assessed per the Investigator based on local standard of care; the data will not be collected 
and no longer need to be recorded in the CRF. Decisions on treatment discontinuation 
should be made per Investigator based on local standard of care and in accordance with 
the stopping rules outlined in Section 9.2. 
Disease assessment will include CT (preferred) or MRI scan of chest, abdomen and pelvis, brain, 
and other areas as clinically indicated (Appendix 7). Screening imaging for all patients requires 
imaging of the brain, chest, abdomen, pelvis, and other areas as clinically indicated. In addition, 
screening imaging for HNSCC patients requires imaging of the neck. Post-baseline imaging for 
melanoma patients includes chest, abdomen, pelvis, and other areas as clinically indicated. 
Post-baseline imaging for HNSCC patients includes chest, abdomen, pelvis, neck, and other 


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areas as clinically indicated. The same imaging techniques used at baseline MUST be used at all 
subsequent time points to permit accurate and comparable measurement of lesions. Post-baseline 
radiographic assessment must image all anatomic areas in which there are malignant 
disease/metastases demonstrated on screening imaging. 
Patients are required to have their baseline radiographic evaluations within 4 weeks of study 
enrollment and will have their first post-baseline radiographic assessment in the trial on 
Day 64 (± 3 days), unless there is clinical indication warranting earlier imaging, and will have 
follow-up assessments every 9 weeks (± 3 days) until Day 379 then every 12 weeks (± 3 days) 
thereafter until the end of the trial. Although radiographic imaging collected at the scheduled 
time points is preferred, it is allowed to be obtained the day prior to study treatment.  
Trial treatment will be discontinued for a patient if the patient shows confirmed disease 
progression (unless requested by an investigator with written approval by a Dynavax Medical 
Monitor) as described in Section 9.2. 
Radiographic imaging will be continued until start of a new anti-cancer treatment or the end of 
the trial.  
8.3 
Biomarker Analysis 
NOTE: As of Amendment 9, this section is no longer applicable. 
Biopsies of Lesion A and 1 or more other accessible lesions will be analyzed for changes in 
correlative biomarkers (changes over time relative to baseline) including tumor-infiltrating 
lymphocytes and PD-L1 expression.  
9.0 
MANAGEMENT OF TRIAL TREATMENT TOXICITIES 
NOTE: As of Amendment 9, Phase 1 of the trial is complete. Phase 2 of the trial has been 
modified to continue dosing per protocol. The collection of safety endpoints has been 
simplified. Decisions on treatment discontinuation should be made per Investigator based 
on local standard of care. This section has been updated accordingly. 
Safety will be evaluated through the careful monitoring of all clinical and laboratory AEs. Safety 
assessments may include vital signs, weight, physical examinations, ECOG PS, 
electrocardiograms (ECGs) and laboratory safety tests (eg, complete blood count [CBC], serum 
chemistry, PTT or aPTT, urinalysis, thyroid function). See Section 10.3.6 for additional details 
of laboratory testing. Special attention will be given to immune-related adverse effects (eg, gut, 
skin, liver, endocrine organs). 


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All AEs will be graded and recorded throughout the trial according to National Cancer Institute 
(NCI) CTCAE, Version 4.03. The severity of the local post-injection reactions, including those 
that become AEs because they persist more than 7 days, will be graded using the Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials (Appendix 5). Characterization of toxicities will include time to onset, severity, 
and duration. Safety endpoints will include all types of drug-related AEs and SAEs regardless of 
causality. 
Phase 1 will be reviewed by a Safety Review Team comprised of the Dynavax Medical Monitor, 
Phase 1 coordinating investigator, and other key safety Dynavax personnel as described in the 
Cohort Safety Review Plan. Before Dose Escalation at each dose level of SD-101 and at any 
other time during Phase 1 or Phase 2 that warrants additional review due to emerging safety data, 
the investigators will discuss and review the safety data with the Dynavax Medical Monitor. 
9.1 
Dose-limiting Toxicity Definitions and Stopping Rules (COMPLETE) 
Standard safety monitoring will be employed for DLT assessment and dose-escalation decisions. 
All AEs will be considered in DLT assessment unless an event is clearly unrelated to trial 
treatment.  
Before Dose Escalation at each dose level of SD-101 and at any other time that safety data 
warrant review, the investigators will participate in a teleconference with the Dynavax Medical 
Monitor to review all safety data. Additionally, at all times during the course of the study, an 
increased frequency of Grade 3 immune-related AEs to 2 times that which would be anticipated 
with pembrolizumab alone will require a halt in accrual and a review of all safety data by the 
sponsor and investigators. 
All AEs, including DLTs, are to be reported according to instructions in the Study Reference 
Manual and graded using NCI CTCAE, Version 4.03 (National Cancer Institute 2010). If a 
patient experiences a DLT, he or she will be treated according to clinical practice and will be 
monitored for resolution of the toxicity. 
The safety profiles of SD-101 (see Investigator’s Brochure) and pembrolizumab (Merck & Co. 
2015) as monotherapies have been previously described. The safety profile of the combination of 
the drugs is unknown. Toxicity of the combination of SD-101 and pembrolizumab may likely 
manifest as there might be an increase in the frequency, severity, or duration of known toxicity 
such as flu-like illness due to SD-101 or immune-related AEs due to pembrolizumab. The 
outcome of a DLT considered related to SD-101 will be discontinuation of SD-101. Toxicity due 
to pembrolizumab will lead to dose interruption and/or discontinuation as described in Section 
7.6 and be managed according to Section 7.7. DLTs considered related to the combination of the 


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2 drugs will be reviewed and assessed in a teleconference with the Dynavax Medical Monitor 
and the investigators. 
For Dose Escalation purposes, a DLT will be defined as any of the following AEs occurring 
from the time of the first injection (Day 1) through Study Day 29 of any of the following: 
Non-hematologic adverse event 
• Grade ≥ 3 non-hematologic AE related to SD-101 (eg, post-injection reaction or 
influenza-like illness) that does not resolve to Grade ≤ 1 with standard treatment by the time 
of the next treatment, with the exclusion of fatigue 
• Grade 3 non-hematologic AE (not laboratory, specifically nausea, vomiting, and diarrhea) 
lasting > 3 days despite optimal supportive care, with the following exceptions: 
• Grade 3 fatigue will NOT be classified as a DLT, regardless of duration. 
• A Grade 3 non-hematologic laboratory AE will only be considered a DLT if it is 
clinically significant, such as: 
• Medical intervention is required to treat the patient 
• The abnormality leads to hospitalization 
• The abnormality persists for > 1 week 
• Grade 4 or 5 non-hematologic AE (not laboratory) 
Hematologic toxicity 
• Grade 4 or 5 hematologic AE 
• Any Grade 3 hematologic laboratory AE, with the exception of lymphopenia, which lasts 
> 7 days 
• Febrile neutropenia Grade 3 or Grade 4: 
• Grade 3 is defined as ANC < 1000/mL with a single temperature of > 38.3°C (101°F) or 
a sustained temperature of ≥ 38°C (100.4°F) for more than 1 hour. 
• Grade 4 is defined as ANC < 1000/mL with a single temperature of > 38.3°C (101°F) or 
a sustained temperature of ≥ 38°C (100.4°F) for more than 1 hour, with life-threatening 
consequences and urgent intervention indicated. 
Prolonged delay (> 3 weeks) of SD-101 or pembrolizumab dosing due to treatment-related 
toxicity qualifies as a DLT. 


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If a patient experiences a DLT, they should not receive further injections of SD-101. If SD-101 is 
discontinued, a patient may continue to receive pembrolizumab alone with approval by the 
Dynavax Medical Monitor until required discontinuation per Section 9.2. 
After a patient is discontinued from trial treatment and if progressive disease has been 
confirmed, a mandatory EOS visit should be performed approximately 28 days after the last 
administration of trial treatment (See Section 10.8 for details). 
9.1.1 
Staggered Dosing for Phase 1 (COMPLETE) 
For Dose Escalation cohorts in Phase 1, SD-101 and pembrolizumab will be administered first to 
a sentinel patient. In the 2.0 mg cohort, if after 72 hours no DLT has occurred, the second patient 
may be treated. If after 72 hours no DLT has occurred, the third patient may be treated. In the 
4.0 mg, and 8.0 mg cohorts, a sentinel patient will be treated. If after 72 hours no DLT has 
occurred, the dose will be considered as tolerated in the sentinel patient and the remaining 
2 patients will receive SD-101 and pembrolizumab. Lower or intermediate dose cohorts will not 
require staggered enrollment with a sentinel patient and may be enrolled concurrently with the 
higher dose cohorts.  
If DLT occurs in the first sentinel patient within 72 hours, dosing will not continue with the 
remainder of the cohort until review of the sentinel patient safety data by the investigators and 
medical monitors. Dosing of a second sentinel patient with SD-101 and pembrolizumab may be 
considered if agreed upon by the investigators and sponsor. If no DLT is observed for the second 
cohort patient within 72 hours, then the remaining patients in the cohort may be enrolled and 
treated. If the second sentinel patient in the dose cohort experiences DLT within 72 hours and 
DLT is confirmed in safety review, then 2 DLTs will have been observed and the dose will be 
considered not tolerated. No further patients will be enrolled or dosed at that dose level. 
9.1.2 
Safety Review and Dose Escalation (COMPLETE) 
Prior to proceeding with Dose Escalation, the safety data during the DLT Assessment Period will 
be evaluated for the entire dose cohort. The cohort safety data will be reviewed at that time for 
DLTs and declared as either tolerated or not tolerated, based on the number of patients 
experiencing DLTs as follows: 
• 0 - 1 patients with DLT: dose tolerated  
• 2 or more patients with DLT: dose not tolerated 


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If no more than 1 DLT is observed in all patients in the current cohort, Dose Escalation will 
proceed and the sentinel patient in the next cohort will receive the assigned dose. The same 
process will be followed sequentially for all dose cohorts. 
If a dose is declared not tolerated, additional patients may be enrolled in a lower or intermediate 
dose cohort following discussions between the investigators and the sponsor to determine the 
MTD. Once the proposed RP2D has been declared, an additional 6 patients may be enrolled and 
evaluated at this dose for safety. If 6 patients have not been dosed and cleared of DLT at the 
proposed RP2D or a higher dose level, additional patient(s) will be enrolled and undergo DLT 
evaluation to meet this 6-patient minimum prior to declaration of an RP2D and enrollment of 
Phase 2 patients. Sites will be notified in real time when the MTD has been defined or when 
study stopping rules have been applied to prevent unnecessary patient exposure. 
The outcome of each safety review will be documented and disseminated via e-mail to all 
participating clinical sites upon the completion of each meeting. Official documentation 
submitted to clinical sites will note whether any DLTs or significant safety data trends were 
observed. It will also include instructions to all personnel with respect to decisions regarding 
expansion of enrollment within a particular cohort, Dose Escalation or halting of further 
enrollment or dosing in the study. 
9.2 
Reasons for Stopping a Patient From Receiving Additional Treatment  
NOTE: As of Amendment 9, the use of irRECIST for determination of disease progression 
is no longer applicable and this section has been revised accordingly. It is at the discretion 
of the investigator as per local standard of care and assessment guidelines whether to 
repeat imaging for confirmation and whether to continue a patient on study treatment until 
repeat imaging is obtained. 
Patients will be discontinued from either trial treatment by the investigator for any of the 
following reasons: 
• Noncompliance with trial procedures as determined by the investigator or sponsor 
• Pregnancy in patient and/or initiation of breast feeding (see Section 10.3.7) 
• Use of or need for prohibited medications (as described in Section 7.4) 
• Confirmed PD per local standard of care and local assessment guidelines  
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable AEs 
• Adverse drug reaction that requires study drug discontinuation per protocol (see Section 7.6) 


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• Need for > 2 dose delays due to toxicity as per the dose modification guidelines described in 
Section 7.6 
• If in the opinion of the investigator, a change or discontinuation of therapy would be in the 
best interest of the patient 
• Patient has completed 35 doses and/or 2 years (Study Day 715) of pembrolizumab therapy 
The investigator or designee must notify Dynavax when a patient has been discontinued from 
treatment. If SD-101 is discontinued prior to completion of planned study dosing, a patient may 
continue on pembrolizumab alone per investigator decision and approval of the Dynavax 
Medical Monitor.  
In patients who have initial evidence of radiographic PD, it is at the discretion of the investigator 
whether to repeat imaging for confirmation and whether to continue a patient on study treatment 
until repeat imaging is obtained. This clinical judgment decision should be based on the patient’s 
overall clinical condition, including ECOG PS, clinical symptoms, and laboratory data. Patients 
may receive pembrolizumab and SD-101 treatment while waiting for confirmation of PD if they 
are clinically stable as defined by the following criteria: 
• Absence of signs and symptoms indicating disease progression 
• No decline in ECOG PS 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (eg, cord compression) requiring 
urgent alternative medical intervention 
Patients who discontinue pembrolizumab must discontinue SD-101. If pembrolizumab treatment 
is temporarily withheld, treatment of SD-101 and pembrolizumab will start on the same day once 
pembrolizumab is resumed. Pembrolizumab may be continued as a single agent if SD-101 is 
discontinued per investigator decision. Delayed dosing of SD-101 would be preferred over 
completely skipping a dose as long as the interval between SD-101 dosing is not less than 5 days 
with subsequent return of SD-101 dosing to per protocol schedule of events. See Section 7.6 for 
details regarding delayed or skipped doses. 
Note: Written informed consent must be obtained from a subject prior to receiving 
study treatment after disease progression has been confirmed. 


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9.3 
Management of Patient Safety 
NOTE: As of Amendment 9, Phase 1 of the trial is complete. Phase 2 of the trial has been 
modified to simplify collection of safety endpoints. This section has been updated 
accordingly. 
If a patient experiences any flu-like symptoms during the 24 to 48 hour period following SD-101 
injection, then the patient may take acetaminophen, maximum 3 g per day, ibuprofen (at labeled 
dosing), or ondansetron as needed for 24 to 48 hours post-injection. If symptoms are severe and 
unresponsive to standard therapy, codeine may also be used. For subsequent injections of 
SD-101, acetaminophen, ibuprofen, or ondansetron may be taken prophylactically before and 
after SD-101 injection. For prophylaxis, recommended dosing of acetaminophen and/or 
ibuprofen is 2 hours before and 6 hours after dosing with continuation for 24 to 48 hours. Doses 
and frequencies of acetaminophen, ibuprofen, ondansetron, and codeine should be per the 
product label. 
9.3.1 
Management of Injection-site Reactions  
Injection-site reactions should be managed conservatively, as they are expected to spontaneously 
subside. Local pruritus can be treated with diphenhydramine and pain can be treated with oral 
medications as described in the previous section. If significant symptoms of pain and induration 
persist for more than 12 hours, applications of an ice pack locally for 30 minutes every 2 hours, 
as needed, may be instituted. Use of ice pack prior to 12 hours after the onset of symptoms is 
discouraged as it may interfere with the action of the drug. The site is not to be injected if local 
pain, tenderness, or swelling persists from a previous injection or other cause has not resolved to 
Grade 0 or 1 for local site reactions (see Appendix 5). The injection may be delayed until the 
symptoms have resolved or the injection may be skipped (see Section 7.6). 
An unscheduled visit (UNS) (Section 10.9) should be performed if there is suspected disease 
progression or patient safety concerns. All supportive therapies will be recorded in the patient’s 
CRF. All patients are required to have an EOS visit (Section 10.8) 28 days after discontinuation 
of all study treatments. 
9.3.2 
Management of Infusion Reactions 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. 
Table 9-1 shows treatment guidelines for patients who experience an infusion reaction associated 
with administration of pembrolizumab. 


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Table 9-1: 
Infusion Reaction 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 patient is deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2: 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (eg, antihistamines, 
nonsteroidal anti-inflammatory 
drugs [NSAIDS], narcotics, IV 
fluids); prophylactic medications 
indicated for ≤ 24 hr 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is 
not limited to: 
• 
Intravenous fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
Increase monitoring of vital signs as medically indicated 
until the patient 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 (eg, from 100 mL/hr to 50 mL/hr). Otherwise 
dosing will be held until symptoms resolve and the patient 
should be premedicated for the next scheduled dose. 
Patients who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further trial treatment administration. 
Patient may be 
premedicated 
1.5 hr (± 30 minutes) 
prior to infusion of 
pembrolizumab with: 
Diphenhydramine 50 
mg orally (or 
equivalent dose of 
antihistamine). 
Acetaminophen 500-
1000 mg orally (or 
equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (eg, renal 
impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is 
not limited to: 
• 
Intravenous fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids 
• 
Epinephrine 
Increase monitoring of vital signs as medically indicated 
until the patient is deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Patient is permanently discontinued from further trial 
treatment administration. 
No subsequent dosing 
Source: From Merck guidance (on file with sponsor) 
IV = Intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; 
NSAIDS = nonsteroidal anti-inflammatory drugs. 
Note: Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration. 


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10.0 
TRIAL PROCEDURES 
NOTE: As of Amendment 9, trial procedures have been simplified. This section has been 
updated accordingly.  
All tests and evaluations required at specified time points are listed in the Schedule of Trial 
Events (Appendix 1 through Appendix 4). The results of these tests and evaluations must be 
entered in the patient’s source document and also recorded on the patient's CRF. All other tests 
and evaluations, including disease assessment and safety monitoring, are to be performed at the 
discretion of the investigator per local standard of care; these data will not be collected or 
recorded on the patient’s CRF. Adverse events should be reported through safety reporting as 
described in Sections 10.3.9 and 10.3.10. 
10.1 
Informed Consent and Screening Log 
The investigator or designee must review the informed consent form (ICF) with each prospective 
patient to be certain that the prospective patient understands the procedures and risks of the trial. 
Prospective patients who wish to participate in the trial must provide written informed consent 
by signing the ICF before undergoing any screening procedures. Patients may undergo trial 
screening tests prior to giving written informed consent provided that these tests are considered 
part of standard care. 
The information from the consent form should be translated and communicated to the patient in 
language understandable to the patient. 
A copy of the signed and dated consent form should be given to the patient before participation 
in the trial. The initial ICF and any subsequent revised written ICF, and written information must 
receive the Institutional Review Board (IRB) approval/favorable opinion in advance of use. The 
patient or his/her legally acceptable representative should be informed in a timely manner if new 
information becomes available that may be relevant to the patient’s willingness to continue 
participation in the trial. The communication of this information should be documented. 
The investigator or designee will maintain a log of all patients who sign the ICF. At a minimum, 
the log will include a patient identifier, the dates of informed consent and screening procedures, 
the outcome of the screening, and the reason the patient did not enroll in the trial. 
Additional requirements for informed consent are presented in Section 14.3. 


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10.1.1 
Eligibility 
After written consent is obtained, screening procedures must be carried out per the Schedule of 
Trial Events (Appendix 1 through Appendix 4). A patient must meet all of the inclusion criteria 
and none of the exclusion criteria to be eligible to participate in the trial. A copy of the pathology 
report confirming diagnosis of metastatic melanoma or recurrent or metastatic HNSCC must be 
obtained prior to enrollment. Assignment of patient number and dose is described in the Study 
Reference Manual. 
10.1.2 
Tumor Biopsy 
Tumor biopsies from Lesion A (the target lesion to be injected) are required at Screening within 
28 days prior to the first dose of SD-101. Two samples are required. The 2 samples can be taken 
as a single biopsy split into 2 samples or 2 separate biopsies and must meet the minimal sample 
size requirement per the study laboratory manual (ie, a minimum of 4 to 6 mm specimen, 
obtained via punch, core needle [14 gauge or smaller gauge needle], or surgical excision). One 
sample is for determining the expression level of PD-L1, and the other sample is for RNA 
expression profiling. The PD-L1 expression could be from an archival tissue sample of the target 
lesion if collected within 3 months of screening. A fresh biopsy needs to be obtained for the 
RNA profiling. 
Subsequent tumor biopsies, which are taken after the start of study treatment, are obtained at 
time points specified per the schedule of trial events (Appendix 1 through Appendix 4) and are 
collected pre-injection on treatment days or within the visit window. Two samples are required 
for these subsequent biopsies. A single biopsy can be split into 2 samples or 2 separate biopsies 
can be collected. Biopsies are required to meet the minimal sample size as indicated in the study 
laboratory manual. One sample will be used for immunohistochemistry and the second sample 
will be used for RNA expression profiling to identify and assess changes in immune cells and 
gene expression responses in the tumor microenvironment. Lesion A should be of a sufficient 
size such that the intratumoral biopsy does not compromise the investigator’s ability to assess the 
lesion size changes per RECIST over time. If Lesion A is completely regressed, subsequent 
replacement lesion(s) do(es) not need to be biopsied. For Lesion A, biopsies would not be done 
in cases where it is judged by the investigator and in consultation with the Dynavax Medical 
Monitor to be not appropriate or feasible for either medical or technical reasons. 
Written patient consent is required for biopsies. Tumor biopsies may be obtained via punch, core 
needle, or surgical excision. Biopsies should be limited to readily accessible tumor lesions (eg, 
skin; peripheral lymph nodes). If a core biopsy is performed, a tissue cylinder should be obtained 
that has proper size for histological examination and biomarker analysis (eg, 
immunohistochemistry of PD-L1, PD-L2, and other immunological markers; ribonucleic acid 


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[RNA] signature profiling), mutational load (HNSCC only), and formation of neoantigens 
(HNSCC only). (Details of tumor biopsy procedures including tumor biopsy processing and 
shipping procedures are provided in the study laboratory manual.)  
Tumor biopsies should be collected prior to injection of SD-101. When collecting biopsies, local 
anesthetics may be used with the exception of topical anti-inflammatories or topical steroids. 
Local anesthetics should be given such that subsequent SD-101administration will not result in 
dilution of the study drug (ie, avoid needle tracking between procedures and administer local 
anesthetic not directly in the tumor or away from the targeted site of intratumoral injection of 
SD-101). 
A biopsy from a non-injected lesion and an injected lesion other than Lesion A at the same 
baseline and treatment time points as required for Lesion A is optional but highly desired. In 
addition, a biopsy of Lesion A, an injected lesion other than Lesion A, and a non-injected lesion 
at disease progression is optional but highly desirable. Collections are to be done pre-injection 
and may occur pre-injection on treatment days or within the visit window prior to treatment.  
Exceptions for not performing biopsies are when there is a potential safety risk to the patient as 
determined by the Investigator in consultation with the Dynavax Medical Monitor. 
10.2 
Trial Visits 
Procedures should be performed as close to the scheduled time as possible. The window for 
weekly study visits is ± 1 day and ± 3 days for every 3 week visits. The window for 24-hour 
visits is ±3 hours. Windows for protocol specified imaging is ± 3 days. The visit schedule during 
the SD-101 dosing varies for the Phase 1 and Phase 2 Cohorts. After completion of SD-101 
dosing (Trial Treatment Period), the visit schedule follows pembrolizumab dosing (Extended 
Pembrolizumab Treatment) with study visits Q3W until EOS. 
A detailed outline of all scheduled trial procedures is provided in the Schedule of Trial Events 
(Appendix 1 through Appendix 4). Procedures should be performed at the trial center where the 
patient is being treated. Patients who fail screening may be rescreened per approval by the 
sponsor. 
The exact time at which a procedure is performed must be recorded in the patient’s trial records 
or appropriate worksheet (if applicable). Any nonscheduled procedures required for urgent 
evaluation of safety concerns take precedence over all routine scheduled procedures. 
Blood collections for safety evaluation assume priority over other procedures. Whenever 
possible, blood samples should be obtained by fresh peripheral venipuncture. If a patient does 
not have peripheral access, the sample may be collected from a central catheter immediately after 


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an initial withdrawal of at least 10 mL of blood; or preferably, after a series of other blood 
sample collections from the central catheter. 
The patient will be assessed for AEs per the Schedule of Trial Events (Appendix 1 through 
Appendix 4).  
During Extended Pembrolizumab Treatment, sites will administer pembrolizumab Q3W and 
follow standard of care laboratory and assessment practices. Sites are required to report SAEs 
that occur during the Extended Pembrolizumab Treatment as described in Section 10.3.10 but are 
not required to document in the eCRF laboratory, imaging, or other patient assessments 
performed to monitor safety or to assess disease response or treatment during the Extended 
Pembrolizumab Treatment period. 
If pembrolizumab treatment is temporarily withheld, treatment of SD-101 and pembrolizumab 
will start on the same day once pembrolizumab is resumed. Delayed dosing of SD-101 would be 
preferred over completely skipping a dose as long as the interval between SD-101 dosing is not 
less than 5 days with subsequent return of SD-101 dosing to per protocol schedule of events (see 
Section 7.6 for details regarding delayed or skipped doses). If both study drugs are on hold, the 
study visit(s) during the hold period may be skipped, with the exception that radiographic 
imaging must be performed according to schedule. 
10.3 
Safety Assessments 
The safety assessments are listed below. The Schedule of Trial Events is provided in Appendix 1 
through Appendix 4. 
10.3.1 
Medical and Medication History 
Medical history includes clinically significant diseases, surgeries, cancer history, and all 
medications (eg, prescription drugs, over-the-counter drugs, herbal/homeopathic remedies, 
nutritional supplements) used by the patient within 28 days prior to the Screening Visit. Baseline 
melanoma and HNSCC disease status, histology, stage, and molecular profiling of genetic 
alterations or mutations (if available) will be recorded. Prior treatment includes treatment for the 
primary diagnosis, including prior systemic, radiation treatment and surgical treatment. Results 
from any prior genetic screening tests and any immunohistochemical (IHC) tests, such as for 
PD-L1, will be recorded. The date of last prior cancer treatment and the response to that 
treatment must be documented. Radiographic studies performed prior to trial entry may be 
collected for review by the investigator.  
 


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10.3.2 
ECOG Performance Status Assessment 
An assessment of PS will be performed using the ECOG PS scale of 0 to 5 (Appendix 8). 
10.3.3 
Vital Signs 
Vital signs will be recorded and will include measurements of heart rate, respiratory rate, systolic 
and diastolic blood pressure, and pulse oximetry. Vital signs taken at injection visits will include 
oral temperature. 
10.3.4 
Physical Examinations 
The investigator or qualified designee will conduct physical examinations. A complete physical 
examination will be conducted at Screening and EOS/Safety Follow-up Visit, and a targeted 
physical examination (based on interval history and/or AEs) including assessment of superficial 
lesions will be conducted at other visits per the Schedule of Trial Events (Appendix 1 through 
Appendix 4). 
10.3.5 
Electrocardiogram 
An ECG (12-lead with standard parameters of heart rate, shape, size and duration of P wave, P-R 
interval, QRS, QT interval, QTc interval, and T wave configuration) will be performed at 
Screening, after treatment on Day 15 and 29, and EOS for Phase 1 and at Screening for Phase 2. 
Additional ECGs should be obtained to evaluate AEs as applicable per standard of care. 
10.3.6 
Safety Laboratory Assessments 
Laboratory assessments are listed below and will be performed according to the Schedule of 
Trial Events (Appendix 1 through Appendix 4). Sample collections prior to injection and 
infusion on treatment days are preferred; however, these samples are allowed to be obtained the 
day prior to dosing. Routine laboratory tests (serum chemistry, hematology) for screening, 
including pregnancy testing may be obtained per standard of care and used for screening 
laboratory and determination of study eligibility as long as obtained within 28 days of first dose 
of pembrolizumab. Laboratories obtained within 7 days of Day 1 visit, with the exception of a 
CBC with ANC, do not need to be repeated on Day 1.  
• Hepatitis and HIV testing at Screening Visit: serum hepatitis B, hepatitis C, and HIV testing 
per institutional standard of care as determined by laboratory tests for HBsAg, anti-HBc, and 
anti-HBs; anti-HCV; and anti-HIV -1/2, respectively 


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• Chemistry: sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, 
glucose, calcium, AST, ALT, LDH, bilirubin, alkaline phosphatase, and C-reactive protein 
(CRP) 
• Hematology: hemoglobin, hematocrit, white blood cell count with differential, and platelet 
count 
• Thyroid function tests: free T3, free T4, and thyroid stimulating hormone (TSH) 
• Coagulation: PT and aPTT 
• Reserve serum aliquot specimens will be collected and stored frozen for possible future 
testing. 
• Urinalysis with microscopy 
Additional details for specific tests are provided in the Laboratory Manual. 
10.3.7 
Pregnancy 
10.3.7.1 
Pregnancy Testing 
All WOCBP (as defined in Section 5.2.1) who are being considered for participation in the trial 
will be tested for pregnancy with a serum or urine β-hCG test within 72 hours prior to taking the 
first dose of trial treatment. If the urine test is positive or cannot be confirmed as negative, then a 
serum test is required which must be negative for the patient to enroll. Additional pregnancy 
testing should be scheduled per local regulations where applicable. 
10.3.8 
Injection-site Reaction Assessments  
Assessments of injection-site reactions will be collected for a minimum of 90 minutes following 
each of the first 4 initial weekly SD-101 injections in Phase 1 as outlined in the Schedule of Trial 
Events (Appendix 1 through Appendix 4) at the clinical site and as reported by the patient on the 
Diary Card for 7 days in Phase 1.  
With Protocol Amendment 6, Diary Cards are discontinued in Phase 2; however, injection site 
reactions listed on the Toxicity Grading scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical trials (Appendix 5) that persist for more than 7 days will 
be recorded as AEs (Section 11.1). 
Prior to the first 4 initial weekly injections of SD-101 in Phase 1 (Appendix 1), patients will 
receive a new Diary Card with instructions to measure and record local injection-site reactions 
and solicited AEs that occur post SD-101 injection. The completed Diary Cards will be reviewed 
with the patients at their next study visit.  


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For the first 4 weekly injections of SD-101 in the first course in Phase 1, Dynavax will capture 
all injection-site reactions that occur, even if the diameter of the largest dimension does not meet 
a Grade 1 on the severity scale (Appendix 5). As such, any reaction smaller than this size cannot 
be graded, but will still be recorded in the clinical database and the severity will be marked as 
not applicable (N/A). 
All data documented by the patient on Diary Cards will be collected, reviewed by the trial 
nurse/coordinator with the patient, and recorded on the appropriate CRF.  
Injection-site reactions need to be recorded also on the AE eCRF for the following: 
1) The duration of the injection-site reaction exceeds 7 days 
2) The verbatim term for the injection-site reaction is different than the terms listed for the diary 
and provided for recording on the injection-site reaction eCRF 
3) The injection-site reaction qualifies as an SAE. 
10.3.9 
Adverse Events 
All AEs, as defined in Section 11.2, will be evaluated from immediately after the first trial 
treatment on Day 1 through 28 days after last dose of trial treatment. 
10.3.10 
Serious Adverse Events 
All SAEs, as defined in Section 11.3.1, will be evaluated from the time the consent is signed 
through 90 days following cessation of trial treatment or EOS (whichever is later), or 28 days 
following cessation of trial treatment if the patient initiates new anti-cancer therapy. Any SAE 
must be reported to Dynavax or its designee within 24 hours of the knowledge of the event. 
An SAE, whether assessed as related or not related to study treatment, will be followed until 
considered stable, resolved, or until EOS, or the patient initiates new anti-cancer therapy 
(whichever is earlier). 
10.3.11 
Concomitant Medications 
Any prescription medication, over-the-counter drug or natural/herbal preparations, including 
vitamins and dietary supplements, and transfusions, including those for the treatment of any AEs, 
taken by the patient from Screening through 28 days after permanent discontinuation of all study 
treatment must be recorded in EDC. 


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10.4 
Disease Assessments 
 NOTE: As of Amendment 9, all disease response assessments, including the timing and 
type of imaging, are to be performed per the Investigator based on local standard of care; 
the data will not be collected and no longer need to be recorded in the CRF. This section 
has been updated accordingly. 
Disease assessment will consist of: 1) clinical assessment of superficial lesions, and 
2) radiographic imaging (See Section 8.2.1.2). Such assessments will be performed at baseline 
no more than 28 days prior to the first dose of trial treatment and at the discretion of the 
investigator as per local standard of care thereafter (Appendix 1 through Appendix 4). 
10.4.1 
Confirmation of Progressive Disease (Based on irRECIST) 
NOTE: As of Amendment 9, irRECIST is no longer applicable and this section has been 
deleted accordingly. All imaging will be performed as per local standard of care guidelines. 
It is at the discretion of the investigator whether to repeat imaging for confirmation and 
whether to continue a patient on study treatment. 
Determination of PD is per local standard of care and local assessment guidelines. 
10.5 
Pharmacodynamic Assessments 
NOTE: As of Amendment 9, this section is no longer applicable. 
• 
Phase 1: Blood will be collected for assessing IFN-inducible gene expression. Collections 
are to be done pre-injection on treatment Days 1 and 8 (Appendix 1). On Day 9, the sample is to 
be collected 24 hours after the Day 8 injection. 
• 
Phase 2: Blood will be collected for possible future testing of RNA gene expression. 
Collections are to be done at Screening and pre-injection on study days as specified in 
Appendix 2 and Appendix 4. 
For both phases of the study, an extra aliquot of serum will be collected and stored frozen for 
possible future testing at time points outlined in Appendix 1 through Appendix 4. 
10.6 
Immunogenicity Assessments 
NOTE: As of Amendment 9, this section is no longer applicable. 
To determine if antibodies to SD-101 are generated following administration of SD-101, blood 
will be collected as outlined in Appendix 1 through Appendix 4. 


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10.7 
Exploratory Assessments 
NOTE: As of Amendment 9, Sections 10.7.1, 10.7.2, and 10.7.3 are no longer applicable. 
10.7.1 
Expression Profiling 
Exploratory assessments for PD-L1 expression by immunohistochemistry, and RNA expression 
profiling to determine the infiltration of lymphocytes and other immune-related responses may 
be assessed and correlated with clinical response. 
10.7.2 
Neoantigen and DNA Mutational Analyses 
Studies of genetic mutations, polymorphisms, and rearrangements are increasingly important in 
understanding and ultimately predicting responses to cancer therapies targeting the anti-tumor 
immune response. For recurrent or metastatic HNSCC, sequence analysis of selected samples of 
tumor and blood may be conducted as an exploratory assessment. 
In addition to understanding the anti-tumor responses, the sequence analysis can identify 
mutations that, when expressed by a tumor, are potentially immunogenic (ie, neoantigens) and 
can inform additional targeting therapeutic strategies for future clinical studies. Confirmation of 
the identification of neoantigens will be done using PBMCs, which will be stimulated with 
peptides corresponding to the identified neoantigens and analyzed for activation through 
secretion of cytokines by ELISpot. Sequencing may be conducted for biopsies collected in the 
HNSCC trial. PBMCs for confirmation of the identification of neoantigens may be obtained at 
sites that are able to isolate and freeze viable PBMCs at the time of biopsy collection in the 
HNSCC portion of the trial. Collection time points are indicated in the Schedule of Trial Events 
located in Appendix 2 and Appendix 4. The Laboratory Manual will provide details on the 
procedure for sample collection. 
10.7.3 
Human Papillomavirus Status 
For HNSCC patients only, HPV status (positive + or negative) at Screening will be determined 
from either archival test results or new testing as described in the Schedule of Trial events 
Appendix 2 through Appendix 4. 
10.8 
End-of-Study/Safety Follow-up Visit 
NOTE: As of Amendment 9, trial procedures have been simplified. This section has been 
updated accordingly.  


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The EOS /Safety Follow-up Visit is required after permanent discontinuation of trial treatments 
(both SD-101 and pembrolizumab), regardless of the reason for discontinuation [to be completed 
28 (± 3) days after last dose of trial treatment]. 
10.9 
Unscheduled Visit for Safety or Disease Progression 
NOTE: As of Amendment 9, all disease assessments will be performed as per local 
standard of care guidelines. Confirmation of disease progression by repeat imaging is not 
mandatory.  
A UNS should be performed if there is suspected disease progression or patient safety concerns. 
Procedures for the visit are at the discretion of the investigator according to local standard of care 
guidelines. 
If the patient has permanent discontinuation of trial treatments (both SD-101 and 
pembrolizumab), an EOS Visit (Section 10.8) should be scheduled 28 days after the date of last 
trial treatment administration. 
10.10 Duration of Follow-up 
NOTE: As of Amendment 9, follow-up procedures have been simplified. This section has 
been updated accordingly. 
All patients must be followed for at least 28 days after their last dose of trial treatment (Section 
11.0). Patients who discontinue trial treatment without documented disease progression should 
be assessed per local standard of care guidelines until the EOS/Study Follow-up visit is 
complete. 
11.0 
 INVESTIGATOR’S RESPONSIBILITIES 
This trial will be conducted in accordance with the protocol, the International Council for 
Harmonisation (ICH) E6(R2) GCP guidelines and applicable US Code of Federal Regulations 
(CFR) and local regulatory requirements. Investigators are responsible for monitoring the safety 
of patients throughout the course of the trial and for providing appropriate medical care. The 
investigator will perform all tasks directly or is responsible for overseeing and training qualified 
site personnel as delegated to perform trial tasks. In addition, investigators are responsible for 
alerting Dynavax to any event that seems unusual and for reporting all AEs, event of clinical 
interests (ECIs), SAEs, pregnancies, and deaths in the appropriate CRFs. 


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11.1 
Injection-site Reactions 
Local injection-site reactions will be assessed and documented per Section 10.3.8. Local 
injection-site reactions are considered AEs if they persist longer than 7 days and need to be 
recorded and reported per protocol Section 11.2. The severity of the injection-site reactions will 
be graded using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (Appendix 5). 
The severity of all injection-site reactions that are not listed on the Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
(Appendix 5) will be assessed and confirmed by the investigator and will be graded using the 
adapted NCI CTCAE Version 4.03 grading scale (Table 11-1). 
Further information is provided in the Study Reference Manual. 
11.2 
Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug, whether or not 
considered drug-related. An AE can therefore be any unfavorable and unintended sign (including 
a clinically significant abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the trial treatment. 
Medical conditions present at Screening (ie, before informed consent is obtained) or present 
before the first trial treatment (Day 1) are not AEs and are not recorded on the AE CRF. These 
medical conditions should be adequately documented on the Medical History CRFs. Any 
increase in severity or frequency of a medical condition documented as medical history after the 
first trial treatment will be recorded as an AE and will be captured on the AE CRF. 
Progression of the cancer under study is not considered an AE or SAE and should not be 
reported as an AE or SAE. 
An uncomplicated pregnancy is not an AE or SAE and should not be reported as an AE/SAE. 
Patients should be followed as described in Section 11.5. 
The reporting period for all non-serious AEs begins at the time of the first trial treatment (Day 1) 
through 28 days after last dose of trial treatment. Patients who are withdrawn due to an AE 
should have an AE assessment completed 28 days or more after their last trial treatment. All AEs 
will be captured on the AE CRF. 


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AEs should be documented in terms of a single medical diagnosis. When this is not possible, the 
AE should be documented in terms of signs and/or symptoms observed by the investigator or 
reported by the patient at each trial visit. 
The investigator will follow all related AEs observed during the trial until the AEs are 
considered resolved or until 28 days after last dose of trial treatment or the patient begins new 
anti-cancer therapy, whichever is earlier. Dynavax or the Dynavax designee may request 
additional follow-up on specific unresolved events. 
11.2.1 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as ECIs and must be reported to 
the sponsor. 
ECIs must be reported following the reporting period for AEs (the initiation of study treatment 
through 28 days after permanent discontinuation of trial treatment) or, if they qualify as an SAE, 
following the reporting period for SAEs (through 90 days following cessation of trial treatment 
or EOS (whichever is later), or 28 days following cessation of trial treatment if the patient 
initiates new anti-cancer therapy). Any ECIs (as defined in this section) or follow up to an ECI 
that occurs in any patient must be reported to Dynavax or its designee within 24 hours of 
investigator awareness of the event (regardless of whether the investigator assesses the event 
as probably or possibly related to study drug). Reporting must be made by electronic media and 
on the Safety Report Form (regardless of whether the investigator assessed the event as serious 
or not serious) per SAE reporting procedures. Electronic reporting procedures can be found in 
the electronic data capture (EDC) data entry guidelines. Safety reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent). 
ECIs for this trial include: 
1) An overdose of SD-101 or pembrolizumab, as defined in Section 11.2.2. 
OR 
2) An elevated AST or ALT lab value that is greater than or equal to 3 X the ULN and an 
elevated total bilirubin lab value that is greater than or equal to 2 X the ULN and, at the same 
time, an alkaline phosphatase lab value that is less than 2 X the ULN, as determined by way 
of protocol-specified laboratory testing or UNS 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 follow up of these criteria can 
be found in the Investigator Trial File Binder (or equivalent). 


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11.2.2 
Overdoses 
An overdose of SD-101 is defined as more than twice the protocol-specified dose.  
An overdose of pembrolizumab is defined as ≥1000 mg (≥ 5 x the prescribed dose).  
An overdose of SD-101 or pembrolizumab, regardless of the presence of an associated AE or 
SAE, is considered an ECI and must be documented and reported according to the ECI 
requirements described in Section 11.2.1. 
Additionally, an AE or SAE associated with an overdose of SD-101 or pembrolizumab must be 
documented and reported according to the respective requirements for AEs or SAEs.  
11.2.3 
New Cancer (Not the Cancer Being Investigated Under the Study) 
Any new non-serious or serious cancer (not the cancer being investigated under the study), 
whether or not the new cancer is related to the trial treatment (SD-101 and/or pembrolizumab), 
must be reported to Dynavax or its designee within 24 hours of investigator awareness of 
the event per SAE reporting procedures.  
The occurrence of any non-serious new cancer will follow the reporting period for AEs 
(Section 11.2) and the occurrence of any serious new cancer will follow the reporting period for 
SAEs (Section 11.3).  
11.2.4 
Definition of Adverse Reaction 
An AR is defined as any AE caused by the use of a pharmaceutical product. ARs are a subset of 
all suspected AEs for which there is reason to conclude that the pharmaceutical product caused 
the event. 
11.2.5 
Definition of Suspected Adverse Reaction 
Suspected adverse reaction (SAR) means any AE for which there is a reasonable possibility that 
the trial treatment caused the AE. Reasonable possibility means there is evidence to suggest a 
causal relationship between the trial treatment and AE. An SAR implies a lesser degree of 
certainty about causality than AR, which means an AE caused by a trial treatment. 
11.2.6 
Definition of Unexpected Adverse Event or Unexpected Suspected Adverse 
Reactions 
An AE or SAR is considered unexpected if it is not listed in the Investigator’s Brochure or is not 
listed at the specificity or severity that has been previously observed. 


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11.3 
Serious Adverse Events 
11.3.1 
Definition of Serious Adverse Events 
An AE is considered an SAE if it meets any of the following criteria: 
• Results in death; 
• Is life-threatening; 
Note: An AE or SAR is considered life-threatening if, in the view of either the investigator or 
sponsor, its occurrence places the patient at immediate risk of death. It does not include an 
AE or SAR that, had it occurred in a more severe form, might have caused death; 
• Requires inpatient hospitalization or prolongs existing hospitalization; 
• Results in persistent or significant disability or incapacity; 
That is, the event severely or permanently disrupts the patient's ability to perform normal life 
functions or daily activities. 
• Results in a congenital anomaly or birth defect; 
• Is medically significant (Important Medical Event); 
Medical and scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient. Examples 
of such events are allergic bronchospasm requiring treatment in an emergency room, serious 
blood dyscrasias, or seizures/convulsions that do not result in hospitalization. The 
development of drug dependence or drug abuse would also be examples of important medical 
events. 


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11.3.2 
Serious Adverse Event Reporting Requirements 
Any SAE that occurs from the time the consent is signed through 90 days following cessation of 
trial treatment or EOS (whichever is later), or 28 days following cessation of trial treatment if the 
patient initiates new anti-cancer therapy, whether or not the SAE is related to the trial treatment 
(SD-101 and/or pembrolizumab), must be reported to Dynavax or its designee within 
24 hours of investigator awareness of the event. The contact information for reporting SAEs is 
provided in the Study Reference Manual. General SAE reporting instructions are as follows: 
• Submit SAE documents according to instructions in the Study Reference Manual. 
• Record all SAEs on the AE CRF. 
• For SAEs, record the primary event on the AE CRF; describe events occurring secondary to 
that primary event on the SAE form in the narrative description of the case. 
• Death is an outcome, not an event. Record the event that resulted in the death as the fatal 
event on the AE CRF. 
• For hospitalizations for surgical or diagnostic procedures, record the illness leading to the 
surgical or diagnostic procedure as the SAE, not the procedure itself. Capture the procedure 
in the narrative as part of the action taken in response to the illness. 
• Elective hospitalizations will not be considered SAEs and do not need to be reported. 
Complications that prolong elective hospitalizations should be recorded as SAEs. Emergency 
room visits of less than 24 hours do not meet the criterion of hospitalization for SAE 
reporting purposes. 
The SAE report should contain, at a minimum, the following information: 
• Patient identifiers (ie, patient number) 
• Suspected medicinal product 
• AE term (must be listed as serious) 
• Contact information for person reporting event 
The relationship of the SAE to trial treatment will be assessed by the investigator 
(Section 11.4.2). Follow-up information should be actively sought and submitted as it becomes 
available. 
The investigator will assess relationship to trial treatment. In addition, the sponsor will assess 
relationship to trial treatment and determine expectedness to SD-101 based on the current 
SD-101 Investigator's Brochure and to pembrolizumab based on the pembrolizumab 
Investigator’s Brochure. The sponsor will report all SD-101 suspected and unexpected serious 


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adverse reactions (SUSARs) to regulatory authorities as expedited reports in accordance with 
applicable regulatory requirements (eg, 21 CFR 312.32[c] in the US). All other SAEs will be 
reported as part of regulatory safety updates, as required, such as in annual reports. Merck will 
be responsible for pembrolizumab global reporting requirements. 
11.4 
Adverse Event Severity and Relationship to Trial Treatment 
11.4.1 
Severity Grading of Adverse Events 
The severity of predefined AEs and other health changes will be assessed and confirmed by the 
investigator and will be graded using the NCI CTCAE Version 4.03 grading scale by system 
organ class (National Cancer Institute 2010). If the appropriate grading or description cannot be 
applied, then the investigator may elect to use the adapted NCI CTCAE, Version 4.03 (Table 11-
1) to assess the AE. 
Table 11-1: 
National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE, Version 4.03) 
AE Severity 
Definition 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated;  
limiting age-appropriate instrumental ADLa 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE 
Source: Adapted from NCI CTCAE, Version 4.03 (National Cancer Institute 2010) 
ADL = Activities of Daily Living; AE = adverse event; CTCAE = common terminology criteria for adverse events;  
NCI = National Cancer Institute. 
a 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
b 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
NOTE: For all AEs and SAEs, if there is a change in the severity after onset of either an AE 
or SAE, the AE or SAE should be reported as a single entry with the maximum severity 
grading captured. 
 


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11.4.2 
Relationship of Adverse Events to Trial Treatment 
The investigator will determine the relationship of the AE to trial treatment using the definitions 
provided in Table 11-2. 
Table 11-2: 
Definitions for Relationship of Adverse Events to Trial Treatment 
Relationship to 
Trial Treatment 
Definition 
Not Related 
Another cause of the event is most plausible; or clinically plausible temporal sequence is 
inconsistent with the onset of the event and the trial treatment administration; or a causal 
relationship is considered biologically implausible. 
Possibly Related 
An event that follows a reasonable temporal sequence from administration of the trial 
treatment or a known or expected response pattern to the suspected drug, but that could 
readily have been produced by a number of other factors. 
Probably Related 
An event that follows a reasonable temporal sequence from administration of the trial 
treatment, and there is a biologically plausible mechanism for trial treatment causing or 
contributing to the AE, and the event could not be reasonably explained by the known 
characteristics of the patient’s clinical state. In addition, the relationship may be confirmed by 
improvement on stopping the trial treatment and reappearance of the event on repeated 
exposure. 
AE = adverse event. 
The investigator will follow all related AEs observed during the trial until the AEs are 
considered resolved or until trial termination. 
The investigator will follow all SAEs, whether assessed as possibly, or probably related, or not 
related to study treatment, until the SAEs are considered stable, resolved, or until EOS, or the 
patient begins new anti-cancer therapy (whichever is earlier).  
The sponsor may request additional follow-up on specific unresolved AEs. 
11.5 
Reporting and Documentation of Pregnancy 
Any patient who becomes pregnant during the trial will be discontinued from all trial treatments 
and followed for pregnancy outcome. Any pregnancy in a partner of a male trial participant must 
be reported to Dynavax or its designee. Follow-up information should be actively sought by the 
investigator and submitted to Dynavax or designee as soon as it becomes available. The 
investigator will complete the pregnancy reporting form and all other relevant CRFs. 
Uncomplicated pregnancies are not considered an AE/SAE. A complicated pregnancy or a 
pregnancy with an adverse outcome may meet criteria for an AE or SAE and would then also be 
reported according to the appropriate requirements.  


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A patient who becomes pregnant will be instructed to report the pregnancy to the trial site as 
soon as possible. A report of the pregnancy will be completed by the investigator or designee and 
will document details of the pregnancy, outcome of pregnancy, and details of delivery. The 
patient should be followed by the investigator through the remainder of the pregnancy for safety 
assessments.  
Pregnancies and breastfeedings that occur from Day 1 through 120 days after the last dose of 
trial treatment or 28 days following cessation of trial treatment if the patient initiates new 
anti-cancer therapy (whichever is earlier) must be reported by the investigator. The sponsor or 
designee must be notified as soon as possible once the trial site learns of a pregnancy or 
breastfeeding. Pregnancy report forms provided by the sponsor or designee must be completed 
and submitted to Dynavax or designee. The contact information for reporting pregnancy is 
provided in the Study Reference Manual. 
12.0 
STATISTICAL METHODS 
NOTE: As of Amendment 9, Phase 1 of the trial is complete. All analyses related to data 
collected in Phase 1 will be performed as detailed in this section. As of Amendment 9, the 
trial will stop collecting efficacy and exploratory data, and the collection of safety data has 
been simplified. Thus, after trial completion, only selected analyses related to data collected 
in Phase 2 of the trial will be performed, and exploratory objectives will not be pursued.  
This section outlines the statistical analysis strategy and procedures for the trial. If, after the trial 
has begun, changes are made to primary or exploratory objectives and/or hypotheses, or to the 
statistical methods related to those objectives and/or hypotheses, then those changes, along with 
an explanation as to when and why they occurred, will be listed in the Clinical Study Report 
(CSR) for the trial. Post hoc exploratory analyses will be clearly identified in the CSR. No 
imputations will be made for missing data. Additional details of the statistical analyses to be 
performed will be provided in the trial Statistical Analysis Plan. 
12.1 
General 
This trial is designed to allow preliminary assessments of safety, biological activity, and 
biomarkers. No pre-specified hypothesis testing will be performed. All analyses of 
demographics, safety, biological activity, and biomarkers will be descriptive. 
Injection-site reactions, AEs, SAEs, and abnormal laboratory values will be summarized by the 
proportion of patients who experience them.  
ORR will be presented as the proportion of patients who achieved CR or PR. The DCR will be 
presented as the proportion of patients who achieved CR, PR, or stable disease.  


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In general, categorical data will be summarized as counts and percentages (or proportions) and 
continuous data will be summarized with descriptive statistics such as mean, standard deviation, 
median, minimum and maximum. 
Final analyses will be carried out after the last participant has completed their last trial visit, the 
trial database has been authorized by Dynavax as complete and final, and major protocol 
deviations have been identified. Patient data will be reviewed for major protocol deviations by 
the Medical Monitor prior to database lock. A listing of patients with major protocol deviations 
will be provided, sorted by treatment and describing their deviations. Efficacy and safety data 
from each cohort may be analyzed and reported separately from other cohorts. In addition, safety 
data will be summarized overall and for each separate tumor indication. 
12.2 
Sample Size Considerations 
The Phase 1 trial is designed to allow preliminary assessments of safety, biological activity, and 
biomarkers in approximately 24 patients. Phase 2 of this trial is designed to allow preliminary 
assessments of efficacy, safety, and changes in biomarkers in approximately 210 patients. All 
analyses will be descriptive. 
The Phase 1 trial sample size is based on a modified 3 + 3 dose-escalation trial design. 
For the Phase 2 expansion cohorts, the sample sizes were determined based on power analysis of 
hypothesis tests and/or confidence intervals, although the efficacy analyses will be descriptive.  
In Expansion Cohort 1, approximately 60 anti PD 1/L1 naïve patients with metastatic melanoma 
will be enrolled. The null hypothesis that the response rate is < 35% will be tested against a 
1-sided alternative at a significance level of 0.05. The design will provide greater than 
90% power if the true response rate is > 55%. There will be no adjustments for multiplicity. 
An exploratory sub-group analysis will be performed for those Expansion Cohort 1 subjects with 
PD-L1 negative tumors (ie, < 1% positivity) at baseline. It was estimated that this subgroup will 
have approximately 30 subjects. The analysis will have 80% power to reject the null hypothesis 
that the response rate is <15% with a one-sided test at a significance level of 0.05 when the true 
response rate is 35%. There will be no adjustments for multiplicity. 
In Expansion Cohort 2, approximately 25 metastatic melanoma patients who have disease 
progression on anti-PD-1/L1 therapy will be enrolled. The null hypothesis that the true response 
rate is 10% will be tested against a 1-sided alternative and will be rejected if 6 or more responses 
are observed. This design yields a type I error rate of 0.05 and 80% power when the true 
response rate is 30%. There will be no adjustments for multiplicity. 


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In Expansion Cohort 5, approximately 25 anti-PD-1/L1 naïve melanoma patients will be 
enrolled. This will allow preliminary estimate of the response rate associated with the dose and 
dosing schedule chosen for Expansion Cohort 5. If 14 or more responses are observed, the 
95% exact confidence interval will yield a lower bound of no less than 37%. 
In Expansion Cohort 3, approximately 25 anti-PD-1/L1 naïve HNSCC patients will be enrolled. 
The null hypothesis that the response rate is < 20% will be tested against a 1-sided alternative at 
a significance level of 0.05. The design will provide greater than 80% power if the true response 
rate is > 40%. There will be no adjustments for multiplicity. 
In Expansion Cohort 4, approximately 25 HNSCC patients who have disease progression on 
anti-PD-1/L1 therapy will be enrolled. The null hypothesis that the true response rate is 5% will 
be tested against a 1-sided alternative and will be rejected if 4 or more responses are observed. 
This design yields a type I error rate of 0.05 and 80% power when the true response rate is 21%. 
There will be no adjustments for multiplicity. 
In Expansion Cohort 6, approximately 25 anti-PD-1/L1 naïve HNSCC patients will be enrolled. 
This will allow preliminary estimate of the response rate associated with the dose and dosing 
schedule chosen for Expansion Cohort 6. If 9 or more responses are observed, the 95% exact 
confidence interval will yield a lower bound of no less than 20%. 
In Expansion Cohort 7, approximately 25 patients who are refractory or resistant to anti-PD-1/L1 
therapy will be enrolled. This will allow preliminary estimate of the response rate associated 
with the dose and dosing schedule chosen for Expansion Cohort 7. If 4 or more responses are 
observed, the 95% exact confidence interval will yield a lower bound of no less than 5%. 
In Expansion Cohort 8, approximately 50 metastatic melanoma patients who are refractory or 
resistant to anti-PD-1/L1 therapy will be enrolled. If 13 or more responses are observed, the 
95% exact confidence interval will yield a lower bound of no less than 15.0%. 
12.3 
Analysis Endpoints 
12.3.1 
Safety Endpoints 
The primary safety endpoint in Phase 1 of the trial is incidence of DLTs. Other safety measures 
evaluated in all parts of the trial are injection-site reactions, all other AEs, laboratory safety 
assessments, and vital signs. 
12.3.2 
Efficacy Endpoints 
Response of lesions and disease status will be assessed using standard RECIST v1.1 for the 
primary evaluation of response and a study specific modified RECIST referred to as irRECIST 


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for an exploratory evaluation (Appendix 6). Throughout the trial, each respective investigator 
will determine and manage disease status (progression or response) of patients per RECIST v1.1 
and irRECIST at the specified imaging time points (Appendix 1 through Appendix 4) or more 
frequently as clinically indicated. 
Endpoints will include ORR, DCR, time to response, and duration of response for Lesion A and 
lesions not injected with SD-101 independently and combined. 
12.3.3 
Exploratory Biomarker Endpoints 
The primary candidate biomarker to be investigated is PD-L1 expression levels in tumor tissue at 
baseline, which will be assessed by immunohistochemistry. Other candidate biomarkers which 
may be investigated include tumor-infiltrating lymphocytes, expression of PD-L2 and PD-1, 
RNA signature profiles, and quantitative RNA expression of candidate genes of interest, 
including PD-L1. 
12.4 
Trial Analysis Populations 
The safety population will include all enrolled patients who receive at least 1 dose of both 
pembrolizumab and SD-101. The primary analysis population for the study will include the 
safety population with separate analyses for Phase 1 Dose Escalation and each Phase 2 Dose 
Expansion cohort. The efficacy population will comprise all patients who receive at least 1 dose 
of both pembrolizumab and SD-101 and who have baseline and at least 1 post-baseline imaging 
assessment. The ITT population will include all enrolled subjects regardless of having a 
post-baseline radiographic assessment. Additional subpopulations for an exploratory and 
retrospective analysis may include PD-L1 status (positive or negative [ie, < 1% positivity]) and 
specific prior anti-PD-1/PD-L1 therapy. Further details of statistical considerations will be 
provided in a separate Statistical Analysis Plan. 
12.5 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be listed by patient and summarized using the 
all-treated population. Descriptive summary statistics (sample size, mean, median, SD, and 
range, when appropriate) will be provided for the continuous variables such as age, weight, and 
height. Count and percentage will be reported for categorical variables such as sex, race, and 
ethnicity. 
12.6 
Pharmacodynamic Analyses 
IFN-α inducible genes will be assayed by quantitative polymerase chain reaction of mRNA 
isolated from blood from before administration of the first and second doses of SD-101 and 


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approximately 24 hours after administration of the second dose of SD-101. The fold increase in 
gene expression after administration of the second dose of SD-101 relative to administration 
before the first and second doses will be analyzed as a surrogate for the activity of SD-101. The 
core group of genes measured will be ISG-54, Mx-B, IFN-α, TNF-α, IP-10, IRF-7, GBP-1, 
MCP-1, and MCP-2. Other genes may be tested to elucidate anti-tumor immune responses and 
the patterns seen in the core genes. The fold increases will be analyzed per individual gene and 
as the geometric mean of their combination or a subset of the same. 
12.7 
 Safety Analyses 
All safety data will be analyzed descriptively and will be based on the all-treated population. The 
most important safety parameters will be presented for all sites combined. Summary statistics 
will be used to describe the incidence of all injection-site reactions, AEs, SAEs, deaths, and 
laboratory values. DLTs occurring in Phase 1 will be summarized by dose level received and 
presented in both tables and listings. 
12.8 
Response Analyses 
ORR, DCR, time to response, and duration of response, comprising the response of lesions 
injected with SD-101 and all non-injected lesions and the ORR and DCR of lesions injected with 
SD-101 and non-injected lesions respectively, will be analyzed descriptively. The ORR will be 
defined as the proportion of patients who achieve a best objective response of either CR or PR 
(see Appendix 6). 
The time to response will be defined as the time from the first dose of SD-101 until the onset of 
CR or PR. Time to response will be summarized descriptively for patients who achieved CR or 
PR in the trial. 
The duration of response is defined as the period of time from the date of initial confirmed PR or 
CR until the date of PD or death, whichever is earlier. 
12.9 
Source Documents 
The investigator must maintain detailed records of all trial participants who are enrolled in the 
trial or who undergo screening. Source documents include, but are not limited to, patient medical 
records and investigator’s patient trial files, as well as all test results. 


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The following minimum information should be entered into the enrolled patient’s source 
documents: 
• The date the patient entered the trial and the patient number 
• The trial protocol number and the name Dynavax Technologies 
• The date that informed consent was signed 
• Evidence that the patient meets trial eligibility requirements (eg, medical history, trial 
procedures, evaluations) 
• The dates of all trial-related patient visits 
• Evidence that trial-required procedures and/or evaluations were completed 
• Use of any concurrent medications 
• Documentation of trial treatment accountability 
• Occurrence and status of any AEs 
• The date the patient exited the trial, and a notation as to whether the patient completed the 
trial or was discontinued early, including the reason for discontinuation 
• Any deviations from the protocol 
12.10 Direct Access to Source Data/Documents 
Qualified individuals designated by Dynavax or its representative will monitor all aspects of the 
trial at regular intervals throughout the trial and following trial completion. This monitoring is 
for the purpose of verifying adherence to the protocol including appropriate storage of trial 
treatments, completeness and exactness of the data being entered onto the CRFs, and compliance 
with FDA or other regulatory agency regulations. The investigator and investigator’s institution 
agree to allow these monitors access to all trial records, CRFs, and corresponding portions of the 
patient’s clinical trial files; to allow access to the clinical supplies, dispensing, and storage areas; 
and if requested, to assist the monitors. The investigator further agrees to permit direct access to 
source data/documents for trial-related monitoring, audits, IRB/Independent Ethics Committee 
(IEC) review, and regulatory inspection(s). 
In certain circumstances, a secondary audit may be conducted by members of Dynavax’s Quality 
Assurance group or by Dynavax’s designated representative. The investigator will be notified if 
this is to take place and advised as to the nature of the audit. 


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13.0 
DATA QUALITY ASSURANCE 
The trial sites will be monitored by Dynavax or its designee according to GCP and standard 
operating procedures. Prior to initiation of the trial, representatives from Dynavax or its designee 
will review with the site personnel information about the investigational product, proper storage 
of trial treatments, protocol requirements, and monitoring requirements. During and after the 
trial, periodic site visits will be made to monitor for compliance, including verification of the 
accuracy and completeness of data recorded on the CRFs, source documents, and trial treatments 
accountability records. 
14.0 
ETHICS 
14.1 
Institutional Review Board/Independent Ethics Committee 
The protocol and informed consent documents must be reviewed and approved by an 
appropriately composed IRB/IEC. The trial will not be initiated at a site until appropriate written 
IRB/IEC approval of the protocol, ICF, and all recruiting materials (if applicable) is obtained by 
the investigator. Copies should be reviewed and approved by Dynavax prior to submission to the 
IRB/IEC. The investigator will submit periodic reports on the progress of the trial as required by 
the IRB/IEC, in accordance with applicable governmental regulations, and in agreement with the 
policy established by Dynavax. In addition, the investigator will inform the IRB/IEC of any 
protocol amendments and administrative changes, and will obtain appropriate written IRB/IEC 
approval of all protocol amendments. 
14.2 
Ethical Conduct of the Trial 
This trial will be conducted in accordance with ICH E6(R2) GCP guidelines and applicable local 
legal and regulatory requirements. 
The trial will be submitted to required clinical trial registries such as www.clinicaltrials.gov. 
14.3 
Informed Consent 
The investigator is responsible for obtaining informed consent from each patient participating in 
the trial in compliance with US CFR Title 21, Part 50, Title 45 Part 46, and ICH and IRB 
guidelines. Prior to initiation of the trial at the site, the ICF must be reviewed and accepted by 
Dynavax and approved by the governing IRB. The investigator or authorized designee will 
discuss the purpose and pertinent details of the trial with each patient, and the patient must 
understand, sign, and date the appropriate IRB-approved ICF before undergoing any 
trial-specific procedures. The ICF must be personally signed and dated by the patient and by the 
person who conducted the informed consent discussion. Additional signature requirements may 
exist. The original signed and dated ICF will be retained with the patient’s trial records, and a 


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copy of the signed ICF will be given to the patient. The investigator or designee will maintain a 
log of all patients who sign the ICF. At a minimum, the log will include a patient identifier, the 
dates of informed consent and screening procedures, the outcome of the screening, and the 
reason the patient did not enroll in the trial, if applicable. 
14.4 
Patient Confidentiality 
The investigator is responsible for maintaining the privacy and confidentiality of the patient’s 
medical or health information collected during the trial. The investigator is also responsible for 
ensuring that all use, review and disclosure of patient’s medical or health information is in 
accordance with Health Insurance Portability and Accountability Act (HIPAA) regulations and 
the ICF approved by the IRB and signed by the patient. Specifically, all data collected about a 
patient during the trial will be identified only by a number and the patient’s initials.  
15.0 
DATA HANDLING AND RECORD KEEPING 
15.1 
Case Report Forms 
Electronic case report forms (eCRF) will be used at the clinical trial site to collect trial data for 
enrolled patients. Screening failure patients will not be captured on eCRFs. When data are 
available, authorized clinical trial site personnel will carefully and accurately record the data on 
the eCRF. Sites must ensure that all source documents are maintained according to ICH/GCP 
guidance and support the data that are entered onto the eCRFs. 
The eCRF data will be captured in a system validated according to procedures that comply with 
the 21 CFR Part 11 and the ICH E6(R2) GCP guidelines, Section 5.5. The eCRFs will be 
reviewed and signed by the principal investigator or someone clinically qualified and identified 
on the delegation log as someone that can sign-off on the eCRF. 
15.2 
Data Handling 
The sponsor will designate a Contract Research Organization (CRO) to perform data 
management. The CRO will write a data management plan outlining the data management 
systems, procedures, and agreements between the CRO and sponsor. The plan will be reviewed 
and signed by a representative of the sponsor’s data management department. 
Outside the EDC system, when appropriate, the CRO will receive FDA 21 CRF 11 compliant 
external lab data transfers from a validated laboratory information management system. After 
database lock, the investigator will receive a copy of the patient data for archiving at the trial 
site. 


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Validation checks will be conducted to capture data errors, and data clarification queries will be 
generated at the time of data monitoring. Validation checks and queries will be issued to the 
investigational site for resolution, and the database will be updated to reflect query resolutions as 
appropriate. 
Data verification against the source documents at the site will be performed by the sponsor or its 
designee prior to locking of the trial database. Following the completion of source data 
verification, a thorough review of data will be completed manually by the clinical data managers 
to ensure data consistency and to identify and request correction of any remaining data errors. 
All queries will be resolved or closed with written documentation providing reasons for 
irresolvable queries. Additional manual validation checks will be performed as needed. 
15.3 
Coding of Adverse Events, Drugs, and Diseases 
AEs and medical histories will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Prior and concomitant medications will be coded according to the World Health 
Organization Drug Dictionary. 
15.4 
Record Retention 
The investigator must retain all records relating to the conduct of this trial (including patient’s 
trial records, receipt and disposition of all investigational materials, patient exclusion logs, 
signed consent forms, CRFs, all correspondence, and other supporting documentation) for at 
least 2 years after a marketing application for the drug is approved; or if an application is not 
filed or not approved for the drug, for at least 2 years after clinical development for the drug has 
been formally discontinued and the appropriate regulatory or health authorities have been 
notified. However, in certain instances, documents may need to be retained for a longer period if 
required by regulatory requirements or by an agreement with Dynavax. 
The investigator may withdraw from the responsibility of retaining records only after transferring 
custody of the records to another individual who will accept responsibility for them. A written 
notice of transfer must be provided to Dynavax prior to or no later than 10 days after transfer. 
The investigator must allow representatives of the FDA, the governing IRB, or other regulatory 
agencies to inspect all trial records. If informed of such an inspection, the investigator will notify 
Dynavax immediately. 
The investigator must obtain written approval from Dynavax prior to the destruction of any 
records relating to the conduct of this trial. 


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16.0 
USE OF INFORMATION AND PUBLICATION 
It is understood by the investigator that the information generated in this trial is the property of 
Dynavax. It is understood that the investigator is obliged to provide Dynavax with complete test 
results, all trial data, and access to all trial records. 
All efforts should be made for abstracts and publications to be jointly authored by investigators 
and Dynavax. Dynavax will be furnished with a copy of any proposed publication. Dynavax’s 
comments shall be given without undue delay, and not later than within 60 days. 
Results from the investigation shall not be made available to any third party by the investigators 
or any of their staff. 
It is understood by the investigator that the information generated in this trial may be used by 
Dynavax in connection with the development of the product and therefore may be disclosed to 
government agencies in various countries. 
Dynavax recognizes the importance of communicating medical trial data, and therefore 
encourages their publication in reputable scientific journals and at seminars or conferences. 
Any results of medical investigations with Dynavax’s products and all publications, lectures, 
presentations, and manuscripts based thereon shall be exchanged and discussed by the 
investigators and Dynavax’s representatives prior to submission for publication or presentation. 
Due regard shall be given to Dynavax's legitimate interests, eg, manuscript authorship, obtaining 
optimal patent protection, coordinating and maintaining the proprietary nature of submissions to 
health authorities, coordinating with other ongoing studies in the same field, and protecting 
confidential data and information. 
Dynavax will be furnished with a copy of any proposed publication and allowed to make 
comments. In cases of publications or presentations of material arising from multicenter clinical 
investigations, Dynavax is to serve as coordinator and referee. Individual investigators who are 
part of a multicenter investigation may not publish or present data that are considered common to 
a multicenter investigation without the consent and the prior review of Dynavax. In case of 
disagreement among the investigators participating in a multicenter investigation, Dynavax will 
be the final arbiter. If Dynavax’s comments are not accepted, the senior author of the manuscript 
and Dynavax’s representatives shall promptly meet and endeavor to agree mutually on the final 
wording and disposition of the publication. The above procedure also applies to information on 
prematurely discontinued and other incomplete studies. 
Results from investigations shall not be made available to any third party by the investigating 
team outside the publication procedure as outlined previously. Dynavax will not quote from 


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publications by investigators in its scientific information or promotional material without full 
acknowledgment of the source (ie, author and reference). 


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17.0 
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SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 140 of 163 
APPENDIX 1: 
SCHEDULE OF TRIAL EVENTS (PHASE 1 DOSE ESCALATION COHORTS 1-4) - COMPLETE 
Screening Through Day 29 
Trial Period: 
Screening 
Trial Treatment 
(± 1 day for weekly visits) 
Day: 
- 28 to -1a 
1 
8 
9b 
15 
22 
29 
 
 
DLT Assessment Periodc 
Study Procedures 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
Demographics/Medical history/Prior medicationsg 
X 
X 
 
 
 
 
 
Vital signsh 
X 
X 
X 
 
X 
X 
X 
Physical examinationi 
X 
X 
X 
 
X 
X 
X 
ECOG Performance Status 
X 
 
 
 
 
 
X 
12-Lead ECGj 
X 
 
 
 
X 
 
X 
Review AEsk  
 
X 
X 
 
X 
X 
X 
Review SAEs  
X 
X 
X 
 
X 
X 
X 
Concomitant medicationsl  
X 
X 
X 
 
X 
X 
X 
HIV and hepatitis testingm 
X 
 
 
 
 
 
 
Serum chemistry and CRPn 
X 
X 
X 
 
X 
X 
X 
Hematologyo 
X 
X 
X 
 
X 
X 
X 
Coagulationp  
X 
X 
X 
 
X 
X 
X 
Thyroid function testsq 
X 
 
 
 
 
 
X 
Urinalysis with microscopy 
 
X 
X 
 
X 
X 
X 
Pregnancy testingr 
X 
 
 
 
 
 
 
Blood for IFN-alpha inducible gene expression (pharmacodynamic)s 
 
X 
X 
X 
 
 
 
SD-101anti-drug antibodiest 
X 
 
 
 
 
 
 
Reserve serum aliquotu  
 
X 
X 
X 
X 
X 
X 
 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01(SYNERGY-001)  
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 141 of 163 
APPENDIX 1: 
SCHEDULE OF TRIAL EVENTS (PHASE 1 DOSE ESCALATION COHORTS 1-4) - COMPLETE (CONT’D) 
Screening Through Day 29 (Cont’d) 
Trial Period: 
Screening 
Trial Treatment 
(± 1 day for weekly visits) 
Day: 
- 28 to -1a 
1 
8 
9b 
15 
22 
29 
 
 
DLT Assessment Periodc 
Efficacy Measurement 
 
 
 
 
 
 
 
Clinical assessment of superficial lesionsy 
X 
 
 
 
 
 
 
Radiographic imagingz 
X 
 
 
 
 
 
 
Drug Administration and Observation 
 
 
 
 
 
 
 
Pembrolizumab therapyaa  
 
X 
 
 
 
X 
 
Diary card issuance and/or reviewbb 
 
X 
X 
 
X 
X 
 
SD-101 intratumoral injection aa 
 
X 
X 
 
X 
X 
 
SD-101 Post-treatment observation (minimum 90 minutes)cc 
 
X 
X 
 
X 
X 
 
Injection-site reaction assessmentk 
 
X 
X 
 
X 
X 
 
Tumor Biopsies 
 
 
 
 
 
 
 
Tumor biopsies (consent required)dd 
X 
 
 
 
 
 
X 
 
 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01(SYNERGY-001)  
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 142 of 163 
APPENDIX 1: 
SCHEDULE OF TRIAL EVENTS (PHASE 1 DOSE ESCALATION COHORTS 1-4) - COMPLETE (CONT’D) 
Day 43 Through End of Study  
Trial Period: 
 
Trial Treatment 
(± 3 days for every 3 week visits) 
Extended Pembrolizumab 
Treatmentd 
(Note: pembrolizumab is 
administered every 3 weeks, but 
study visits are every 3 months ± 3 
days) 
EOS / Safety FUe 
(± 3 days) 
UNSf 
Day: 
43 
64 
85 
106 
127 
148 
169 
190 
211 
232 
253 
274 
295 
316 
337 
358 
379 
421 
463 
505 
547 
589 
631 
673 
715 
28 days after 
last dose  
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Physical examinationi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
12-Lead ECGj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Review AEsk  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Review SAEs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Concomitant medicationsl  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Serum chemistry and CRPn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Hematologyo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Coagulationp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Thyroid function testsq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Urinalysis with microscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
SD-101 anti-drug 
antibodiest 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Reserve serum aliquotu 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01(SYNERGY-001)  
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 143 of 163 
APPENDIX 1: 
SCHEDULE OF TRIAL EVENTS (PHASE 1 DOSE ESCALATION COHORTS 1-4) - COMPLETE (CONT’D) 
Day 43 Through End of Study (Cont’d) 
Trial Period: 
 
Trial Treatment 
(± 3 days for every 3 week visits) 
Extended Pembrolizumab 
Treatmentd 
(Note: pembrolizumab is 
administered every 3 weeks, but 
study visits are every 3 months ± 3 
days) 
EOS / Safety FUe 
(± 3 days) 
UNSf 
Day: 
43 
64 
85 
106 
127 
148 
169 
190 
211 
232 
253 
274 
295 
316 
337 
358 
379 
421 
463 
505 
547 
589 
631 
673 
715
28 days after 
last dose  
Efficacy Measurements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment of 
superficial lesionsy 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X  
X 
Radiographic imagingz 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X  
X 
Drug Administration and 
Observation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab therapyaa  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
Diary card issuance and/or 
review bb 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SD-101 intratumoral 
injectionaa 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SD-101 Post-treatment 
observation (minimum 30 
minutes)cc  
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection-site reaction 
assessmentk 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsies (consent 
required)dd 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01(SYNERGY-001)  
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 144 of 163 
APPENDIX 2: 
SCHEDULE OF TRIAL EVENTS (PHASE 2 EXPANSION COHORTS 1 AND 3 – ANTI-PD-1/L1 NAÏVE) – 
CLOSED 
NOTE: As of Amendment 9, Phase 2 of the trial has been modified to continue dosing per protocol; however, efficacy and exploratory 
endpoints will no longer be collected, and the collection of safety endpoints has been simplified. The final study visit will be the 
EOS/Safety Follow-up. All other procedures to monitor disease progression and safety should be performed at the investigator’s 
discretion according to local standard of care; these data do not need to be collected on the CRF. This Schedule of Trial Events has 
been amended and assessments that are no longer required have been deleted.  
Screening Through Day 421 
Trial Period: 
Screening 
Trial Treatment 
(every week ± 1 day) 
(every 3 weeks ± 3 days) 
(every week 
± 1 day) 
(every 3 weeks ± 3 days) 
Day: 
- 28 
to -1a 
1 
22 
29 
30b,ee 
36 
43 
50 
64 
85 
106 
127 
148 
169 
190 
211 
232 
253 
260 
267 
274 
295 
316 
337 
358 
379 
400 
421 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical history/Prior 
medicationsg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
Physical examinationi 
X 
ECOG Performance Status 
X 
12-Lead ECGj 
X 
Review AEsk  
 
X 
X 
X 
X 
X X  
X X X X X X X X 
X 
X X X 
X X X X X X X X 
Review SAEs   
X 
X 
X 
X 
X 
X X  
X X X X X X X X 
X 
X X X 
X X X X X X X X 
Concomitant Medicationsl  
X 
X 
X 
X 
X 
X 
X 
 X X X X X X X X 
X 
X X X 
X X X X X X X X 
HIV, HPV status, and hepatitis testingm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01(SYNERGY-001)  
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 145 of 163 
APPENDIX 2: 
SCHEDULE OF TRIAL EVENTS (PHASE 2 EXPANSION COHORTS 1 AND 3 – ANTI-PD-1/L1 NAÏVE) – 
CLOSED (CONT’D) 
Screening Through Day 421 (Cont’d) 
Trial Period: 
Screening 
Trial Treatment 
(every week ± 1 day) 
(every 3 weeks ± 3 days) 
(every week 
± 1 day) 
(every 3 weeks ± 3 days) 
Day: 
- 28 
to -1a 
1 
22 
29 
30b,ee 
36 
43 
50 
64 
85 
106 
127 
148 
169 
190 
211 
232 
253 
260 
267 
274 
295 
316 
337 
358 
379 
400 
421 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry and CRPn  
 
X 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
 
Hematologyo 
X 
Coagulationp 
X 
Thyroid function testsq 
X 
Urinalysis with microscopy 
 
Pregnancy testingr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Measurements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment of superficial lesionsy 
X 
 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
 
Radiographic imagingz 
X 
Drug Administration and Observation 
 
 
                          
Pembrolizumab therapyaa 
 
X 
X 
 
 
 
X 
 
X X X X X X X X X X 
 
 
X X X X X X X X 
SD-101 intratumoral injectionaa 
 
 
X 
X 
 
X 
X 
 
X X X X X X X 
 
 
X X X 
X X X X X X X X 
SD-101 post-treatment observationcc 
 
 
X 
X 
 
X 
X 
 
X X X X X X X 
 
 
X X X 
X X X X X X X X 
Injection-site reaction assessmentk 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsies (consent required)dd 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01(SYNERGY-001)  
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 146 of 163 
APPENDIX 2: 
SCHEDULE OF TRIAL EVENTS (PHASE 2 EXPANSION COHORTS 1 AND 3 – ANTI-PD-1/L1 NAÏVE) – 
CLOSED (CONT’D) 
Day 442 Through End of Study 
Trial Period: 
Extended Pembrolizumab Treatmentd 
(Note: pembrolizumab is administered every 3 weeks ± 3 days) 
EOS/ Safety F/Ue  
(± 3 days ) 
UNSf 
Day: 442 463 484 505 526 547 568 589 610 631 652 673 694 715 
28 days after last dose 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
 
As of Amendment 9, per local standard of care at the discretion of the 
investigator. 
 
X 
X 
Physical examinationi 
X 
X 
ECOG Performance Status 
X 
X 
Review AEsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review SAEs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medicationsl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry and CRPn 
 
 
As of Amendment 9, per local standard of care at the discretion of the 
investigator. 
 
X 
X 
Hematologyo 
X 
X 
Thyroid function testsq 
X 
X 
Urinalysis with microscopy 
X 
X 
Efficacy Measurements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment of superficial lesionsy 
 
As of Amendment 9, per local standard of care at the discretion of the 
investigator. 
 
Radiographic imagingz 
 
Drug Administration and Observation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab therapyaa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01(SYNERGY-001)  
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 147 of 163 
APPENDIX 3: 
SCHEDULE OF TRIAL EVENTS (PHASE 2 EXPANSION COHORTS 2 AND 4 – ANTI-PD-1/L1 
EXPERIENCED) – CLOSED 
NOTE: As of Amendment 9, Phase 2 of the trial has been modified to continue dosing per protocol; however, efficacy and exploratory 
endpoints will no longer be collected, and the collection of safety endpoints has been simplified. The final study visit will be the 
EOS/Safety Follow-up. All other procedures to monitor disease progression and safety should be performed at the investigator’s 
discretion according to local standard of care; these data do not need to be collected on the CRF. This Schedule of Trial Events has 
been amended and assessments that are no longer required have been deleted.  
Screening Through Day 400 
Trial Period: 
Screening 
Trial Treatment 
(every week ± 1 day) 
(every 3 weeks ± 3 days) 
(every week 
± 1 day) 
(every 3 weeks ± 3 days) 
Day: 
- 28 
to -
1a 
1 
8 
9b, 
ee
15 
22 
29 
43 
64 
85 
106 
127 
148 
169 
190 
211 
232 
239 
246 
253 
274 
295 
316 
337 
358 
379 
400 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical history/Prior medicationsg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
 
Physical examinationi 
X 
ECOG Performance Status 
X 
12-Lead ECGj 
X 
Review AEs  
 
X 
X 
X 
X 
X 
 
X X X X X X X X X 
X 
X 
X 
X 
X X X X X X X 
Review SAEs  
X 
X 
X 
X 
X 
X 
 
X X X X X X X X X 
X 
X 
X 
X 
X X X X X X X 
 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01(SYNERGY-001)  
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 148 of 163 
APPENDIX 3: 
SCHEDULE OF TRIAL EVENTS (PHASE 2 EXPANSION COHORTS 2 AND 4 – ANTI-PD-1/L1 
EXPERIENCED) – CLOSED (CONT’D) 
Screening Through Day 400 (Cont’d) 
Trial Period: 
Screenin
g 
Trial Treatment 
(every week ± 1 day) 
(every 3 weeks ± 3 days) 
(every week 
± 1 day) 
(every 3 weeks ± 3 days) 
Day: 
- 28 
to -
1a 
1 
8 
9b, 
ee
15 
22 
29 
43 
64 
85 
106 
127 
148 
169 
190 
211 
232 
239 
246 
253 
274 
295 
316 
337 
358 
379 
400 
Concomitant medicationsl  
X 
X 
X 
X 
X 
X 
 
X X X X X X X X X X 
X 
X 
X X X X X X X X 
HIV, HPV status, and hepatitis testingm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry and CRPn 
X 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
 
Hematologyo 
X 
Coagulationp 
X 
Thyroid function testsq 
X 
Urinalysis with microscopy 
 
Pregnancy testingr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Measurements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment of superficial lesionsy 
X 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
 
Radiographic imagingz 
X 
Drug Administration and Observation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab therapyaa 
 
X 
 
 
 
X 
 
X X X X X X X X X X 
 
 
X X X X X X X X 
SD-101 intratumoral injectionaa 
 
X 
X 
 
X 
X 
 
X X X X X X X 
 
 
X 
X 
X 
X X X X X X X X 
SD-101 post-treatment observationcc 
 
X 
X 
 
X 
X 
 
X X X X X X X 
 
 
X 
X 
X 
X X X X X X X X 
Injection-site reaction assessmentk 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsies (consent required)dd 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01(SYNERGY-001)  
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 149 of 163 
APPENDIX 3: 
SCHEDULE OF TRIAL EVENTS (PHASE 2 EXPANSION COHORTS 2 AND 4 – ANTI-PD-1/L1 
EXPERIENCED) – CLOSED (CONT’D) 
Day 421 Through End of Study 
Trial Period: 
Extended Pembrolizumab Treatmentd 
(Note: pembrolizumab is administered every 3 weeks ± 3 days) 
EOS/ Safety 
F/Ue (± 3 days ) 
UNSf 
Day: 421 442 463 484 505 526 547 568 589 610 631 652 673 694 715 28 days after last 
dose 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
 
X 
X 
Physical examinationi 
X 
X 
ECOG Performance Status 
X 
X 
12-Lead ECGj 
 
 
Review AEsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review SAEs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationsl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry and CRPn 
 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
 
X 
X 
Hematologyo 
X 
X 
Thyroid function testsq 
X 
X 
Urinalysis with microscopy 
X 
X 
Efficacy Measurements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment of superficial lesionsy 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
 
 
X 
Radiographic imagingz 
 
X 
Drug Administration and Observation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab therapyaa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01(SYNERGY-001)  
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 150 of 163 
APPENDIX 4: 
SCHEDULE OF TRIAL EVENTS (PHASE 2 EXPANSION COHORTS 5 AND 6 [ANTI-PD-1/L1 NAÏVE] 
AND COHORTS 7 AND 8 [ANTI-PD-1/L1 REFRACTORY OR RESISTANT]) - CLOSED 
NOTE: As of Amendment 9, Phase 2 of the trial has been modified to continue dosing per protocol; however, efficacy and exploratory 
endpoints will no longer be collected, and the collection of safety endpoints has been simplified. The final study visit will be the 
EOS/Safety Follow-up. All other procedures to monitor disease progression and safety should be performed at the investigator’s 
discretion according to local standard of care; these data do not need to be collected on the CRF. This Schedule of Trial Events has 
been amended and assessments that are no longer required have been deleted.  
Screening Through Day 358 
Trial Period: 
Screening 
Trial Treatment 
(every week ± 1 day) 
(every 3 weeks ± 3 days) 
(every 3 weeks ± 3 days) 
Day: 
- 28 to 
-1a 
1 
8 
9b, ee 
15 
22 
29 
43 
64 
85 
106 
127 
148 
169 
190 
211 
232 
253 
274 
295 
316 
337 
358 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical history/Prior medicationsg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
 
Physical examinationi 
X 
ECOG Performance Status 
X 
12-Lead ECGj 
X 
Review AEsk  
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review SAEs  
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationsl  
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV, HPV status, and hepatitis testingm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Dynavax Technologies Corporation 
 
Protocol DV3-MEL-01(SYNERGY-001)  
SD-101 
 
Protocol Amendment #9 
 
CONFIDENTIAL AND PROPRIETARY 
Page 151 of 163 
APPENDIX 4: 
SCHEDULE OF TRIAL EVENTS (PHASE 2 EXPANSION COHORTS 5 AND 6 [ANTI-PD-1/L1 NAÏVE] 
AND COHORTS 7 AND 8 [ANTI-PD-1/L1 REFRACTORY OR RESISTANT]) (CLOSED) (CONT’D) 
Screening Through Day 358 (Cont’d) 
Trial Period: 
Screening 
Trial Treatment 
(every week ± 1 day) 
(every 3 weeks ± 3 days) 
(every 3 weeks ± 3 days) 
Day: 
- 28 to -
1a 
1 
8 
9b, ee 
15 
22 
29 
43 
64 
85 
106 
127 
148 
169 
190 
211 
232 
253 
274 
295 
316 
337 
358 
Serum chemistry and CRPn 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyo 
X 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
 
Coagulationp 
X 
Thyroid function testsq 
X 
Urinalysis with microscopy 
 
Pregnancy testingr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Measurements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment of superficial lesionsy 
X 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
 
Radiographic imagingz 
X 
Drug Administration and Observation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab therapyaa 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SD-101 intratumoral injectionaa 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SD-101 post-treatment observationcc 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection-site reaction assessmentk 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsies (consent required)dd 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 


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Protocol DV3-MEL-01(SYNERGY-001)  
SD-101 
 
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CONFIDENTIAL AND PROPRIETARY 
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APPENDIX 4: 
SCHEDULE OF TRIAL EVENTS (PHASE 2 EXPANSION COHORTS 5 AND 6 [ANTI-PD-1/L1 NAÏVE] 
AND COHORTS 7 AND 8 [ANTI-PD-1/L1 REFRACTORY OR RESISTANT]) (CLOSED) (CONT’D) 
Day 379 Through End of Study 
Trial Period: 
Extended Pembrolizumab Treatmentd 
(Note: pembrolizumab is administered every 3 weeks ± 3 days) 
EOS/ Safety 
F/Ue (± 3 days ) UNSf 
Day: 379 400 421 442 463 484 505 526 547 568 589 610 631 652 673 694 715 28 days after last 
dose 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
 
X 
X 
Physical examinationi 
X 
X 
ECOG Performance Status 
X 
X 
Review AEsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review SAEs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationsl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry and CRPn 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
 
X 
X 
Hematologyo 
X 
X 
Thyroid function testsq 
X 
X 
Urinalysis with microscopy 
X 
X 
Efficacy Measurements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment of superficial lesionsy 
As of Amendment 9, per local standard of care at the discretion of the investigator. 
 
 
X 
Radiographic imagingz 
 
X 
Drug Administration and Observation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab therapyaa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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APPENDIX 1-4 FOOTNOTES 
AE = adverse event; ALT = alanine transaminase; ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; AST = aspartate transaminase; BUN = blood urea 
nitrogen; CBC = complete blood count; Cr = creatinine; CRP = C-reactive protein; CT = computed tomography; D = Day; DLT = dose-limiting toxicity; ECG = electrocardiogram; ECOG = 
Eastern Cooperative Oncology Group; eCRF = electronic case report form; EOS = End-of-Study; F/U = follow-up; Hgb = hemoglobin; HIV = human immunodeficiency virus; IFN = 
interferon; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; PD = 
progressive disease; PD-1 = programmed death receptor-1; PD-L1 = programmed death-ligand 1; PT = prothrombin time; Q3W = every 3 weeks; RECIST = Response Evaluation Criteria In 
Solid Tumors; RNA = ribonucleic acid; SAE = serious adverse event; TSH = thyroid stimulating hormone; UNS = unscheduled visit/Safety Follow-up Visit; WBC = white blood cell; 
WOCBP = women of childbearing potential. 
Screeninga 
Routine laboratory tests (serum chemistry, hematology) for screening should be performed within 28 days prior to enrollment or can be obtained from a 
standard of care visit within 28 days of first dose of pembrolizumab. Laboratories obtained within 7 days of Day 1 visit, with the exception of a CBC with 
ANC, do not need to be repeated on Day 1. 
24-hour postdose visitb 
The window for 24-hour postdose visit is ±3 hours. 
DLT Assessment Periodc 
DLT assessment period is Study Day 1 through Study Day 29. 
Extended 
Pembrolizumab 
Treatmentd 
During Extended Pembrolizumab Treatment, pembrolizumab will be administered Q3W with standard of care procedures performed by the site. Data 
related to dosing, concomitant medications, AEs, and SAEs must be entered in the CRF. 
EOS / Safety FUe 
After a patient is discontinued from both trial treatments, a mandatory EOS/Safety Follow-up visit will be performed 28 (± 3) days after the last 
administration of trial treatment, regardless of the reason for permanent discontinuation. 
UNSf 
A UNS should be performed if there is suspected disease progression or patient safety concerns. Procedures for the visit are at the discretion of the 
investigator according to local standard of care guidelines. All disease assessments will be performed as per local standard of care guidelines. 
Confirmation of disease progression by repeat imaging is not mandatory. 
Demographics/Medical 
history/Prior 
medicationsg 
Medical history includes clinically significant diseases, surgeries, cancer history, response to cancer treatment, and all medications (eg, prescription 
drugs, over the counter drugs, herbal/homeopathic remedies, nutritional supplements) used by the patient within 28 days prior to the Screening Visit. 
Baseline melanoma and HNSCC disease status, histology, stage and molecular profiling of genetic alterations or mutations (if available) will be 
recorded. Prior treatment includes treatment for the primary diagnosis, including prior systemic, radiation treatment and surgical treatment. Results of 
any prior genetic screening tests and any immunohistochemical (IHC) tests, such as for PD-L1, will also be recorded. The date of last prior cancer 
treatment must be documented. Radiographic studies performed prior to trial entry may be collected for review by the investigator. 
Vital signsh 
Includes oral temperature (only at trial injection visits), heart rate, respiratory rate, systolic and diastolic blood pressure, and pulse oximetry. 
Physical examinationi 
The investigator or qualified designee will conduct physical examinations. A complete physical examination is conducted at Screening and EOS, and 
a targeted physical examination (based on interval history and/or AEs) including assessment of superficial lesions is conducted at all other visits per 
the Schedule of Trial Events. 
12-Lead ECGj 
Electrocardiogram (12-lead ECG) should be performed at Screening, after treatment on Days 15 and 29, and at EOS in Phase 1, and collected at 
Screening only in Phase 2. 
 


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APPENDIX 1-4 FOOTNOTES (CONT’D) 
Review AEsk 
In Phase 1, assessments of injection-site reactions will be collected for a minimum of 90 minutes through the first 4 weekly injections and for 30 
minutes following the remaining injections of SD-101 at the clinical site. Injection-site reactions will be graded based on the Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (Appendix 5). In Phase 2, injection-site reactions that 
persist for more than 7 days will be recorded as AEs. All other AEs and laboratory safety measurements will be graded per NCI CTCAE Version 4.03. 
All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness. AEs will be collected through 28 days after the last dose of trial 
treatment.  
Concomitant medicationsl 
All concomitant medications taken by the patient from Screening through the EOS visit will be reported. 
HIV and hepatitis testingm 
Serum hepatitis B, hepatitis C, and HIV testing as determined by laboratory tests for HBsAg, anti-HBc, and anti-HBs; anti-HCV; and anti-HIV -1/2, 
respectively. For HNSCC patients only, HPV status (positive + or negative) at Screening will be determined from either archival test results or new 
testing. 
Serum chemistry and CRPn 
Per local standard of care at the discretion of the investigator. 
Hematologyo 
Per local standard of care at the discretion of the investigator. 
Coagulationp 
Per local standard of care at the discretion of the investigator. 
Thyroid function testsq 
Per local standard of care at the discretion of the investigator. 
Pregnancy testingr 
For WOCBP, serum or urine pregnancy test must be negative within 72 hours prior to the first trial treatment. If the urine test is positive or cannot be 
confirmed as negative then a serum test is required which must be negative for the patient to enroll. Dipstick can be used. Additional pregnancy testing 
should be scheduled per local regulations where applicable. All female patients are considered to be WOCBP except if they have been postmenopausal 
for at least 2 years or surgically sterile for at least 1 year. 
Blood for IFN-alpha inducible 
gene expression 
(pharmacodynamic)s 
Phase 1 Dose Escalation Cohorts 1-4 only: IFN-inducible gene expression measured at pre-dose on Day 1 (baseline), at Day 8 prior to injection, and 
at Day 9 which is 24 hours after injection. 
 
 
 


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CONFIDENTIAL AND PROPRIETARY 
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APPENDIX 1-4 FOOTNOTES (CONT’D) 
Diary card issuance and/or 
reviewbb 
Prior to each of the first 4 initial weekly doses of SD-101 in Phase 1, patients will receive a new Diary Card with instructions to measure and record 
local injection- site reactions and solicited AEs that occur post SD-101 injection. Note that injection-site reactions are not required to be recorded 
separately on the AE eCRF unless the duration is greater than 7 days. The completed Diary Cards will be reviewed with the patients at their next study 
visit. 
SD-101 Post-treatment 
observation (minimum 90 
minutes)cc 
Patients will remain in clinic for 90 minutes after each of the first 4 weekly SD-101 injections in their first course and for 30 minutes after subsequent 
injections. 
Tumor biopsies (consent 
required)dd 
Tumor biopsy of Lesion A will be performed within 28 days prior to the first dose of SD-101. Two samples are required at each time point. See 
specific guidance for samples in Section 10.1.2. Lesion A should be of a sufficient size such that the intratumoral biopsy does not compromise the 
investigator’s ability to assess the lesion size changes per RECIST over time. Biopsies may be obtained via punch, core needle, or surgical excision. 
Biopsies should be limited to readily accessible tumor lesions (eg, skin; peripheral lymph nodes). (See specific guidance for minimum needle gauge in 
the Study Reference Manual). Collections are to be done pre- injection on treatment days and may occur pre-injection on treatment days or within the 
visit window prior to treatment. Repeat samples may be required if adequate tissue is not provided. Details of tumor biopsy procedures including 
processing and shipping are provided in the study laboratory manual. Biopsies will be collected on: 
• 
Phase 1 Dose Escalation Cohorts 1-4 only: Screening, Days 29, 85 and 169 visits. 
• 
Phase 2 Dose Expansion Cohorts 1 and 3 only: Screening, Days 50, 106, and Day 190 visits. 
• 
Phase 2 Dose Expansion Cohorts 2 and 4 to 8 only: Screening, Days 29, 85, and Day 169 visits. 
Day 9 and Day 30 visitsee 
These visits are for HNSCC patients in Phase 2 Dose Expansion: Cohort 3 on Day 30, and Cohorts 4, 6 and 7 only on Day 9. 
 
 
 
 


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CONFIDENTIAL AND PROPRIETARY 
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APPENDIX 5: 
TOXICITY GRADING SCALE FOR HEALTHY ADULT AND 
ADOLESCENT VOLUNTEERS ENROLLED IN PREVENTIVE 
VACCINE CLINICAL TRIALS 
Local Reaction to 
Injectable Product 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours or 
interferes with 
activity 
Any use of narcotic 
pain reliever or 
prevents daily activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/Rednessa 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative dermatitis 
Induration/Swellingb 2.5 – 5 cm and does 
not interfere with 
activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or prevents 
daily activity 
Necrosis 
Source: (Center for Biologics Evaluation and Research 2007). 
a  
In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable. 
b 
Induration/swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
 
 


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CONFIDENTIAL AND PROPRIETARY 
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APPENDIX 6: 
RECIST V1.1 AND IMMUNE-RELATED RECIST RESPONSE 
DEFINITION 
NOTE: As of Amendment 9, this Appendix is for information only. Use of the guidelines 
outlined within is at the discretion of the investigator and is not mandatory. All disease 
response assessments, including the timing, type, and evaluation of imaging, are to be 
performed and assessed at the investigator’s discretion per local standard of care. 
Confirmation of progression by repeat imaging is not mandatory. Decisions on treatment 
discontinuation should be made per investigator based on local standard of care. All 
imaging will be performed as per local standard of care guidelines.  
Assessments will use RECIST v1.1 guidelines (Eisenhauer, Therasse et al. 2009), which are 
included in the Study Reference Manual, and study specific modification of the RECIST v1.1 
guidelines referred to as irRECIST. 
RECIST v1.1  
Baseline selection of lesions 
All lesions are measured by long axis and short axis (perpendicular to the long axis). At baseline, 
all tumor lesions are identified as either target lesions or non-target lesions and will be evaluated 
at baseline and every post-baseline imaging time point. 
Target lesions: Minimal size of 1.0 cm by long axis unless a lymph node which must be a 
minimal size of 1.5 cm by short axis. Superficial lesions must measure at least 10 mm in long 
diameter and be measurable by calipers to qualify as target lesions. Maximum target lesions are 
5 with a maximum of 2 lesions per organ representative of all involved organs. 
Non-target lesions: Radiographically visible but do not meet size qualification of target lesions. 
Lymph nodes must measure at least 1.0 cm by short diameter to qualify as non-target lesions (if 
smaller considered non-pathologic). Excess target lesions (> 5 overall or 2 per organ) are 
followed as non-target lesions. 
Baseline measurement of lesions 
At baseline, the sum of the long diameters of all target lesions (5 lesions total with maximum of 
2 lesions per organ representative of all involved organs), is calculated. The sum is referred to as 
the SOD for the baseline time point. All other lesions should be identified as non-target lesions 
and be recorded at baseline. 


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Post-baseline radiographic response assessment 
At each post-baseline imaging time point, the long axis diameter of all target lesions is measured 
and recorded. A response of the target lesions is assessed by determination of the overall SOD of 
the lesions (SOD for that imaging time point). A response for each baseline non-target lesion is 
determined and recorded. The presence of any new lesions is recorded (of note a lymph node 
must measure at least 1.0 cm by short axis diameter to qualify as a pathologic lesion). 
Target lesion response 
Complete response (CR): disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial response (PR): At least a 30% decrease in the SOD of target lesions, taking as reference 
the baseline SOD. 
Progressive disease (PD): At least 20% increase in the SOD of target lesions, taking as reference 
the smallest prior SOD in the trial (this includes the baseline sum if that is the smallest in the 
trial). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of least 5 mm. 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest SOD while in the trial. 
Non-target lesion response assessment  
Complete response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of 1 or more non–target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.  
Progressive disease (PD): Unequivocal progression of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
New lesion assessment 
At each post-baseline imaging time point, an evaluation of the presence of new lesions (yes/no) 
is made. The lesions are recorded as new lesions and not target or non-target lesions. 
Lymph nodes must be a new lesion and measure at least 10 mm by short diameter to qualify as a 
new lesion overall response assessment. 


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A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion. 
Overall response assessment 
Overall response assessment is based on target lesion response, non-target lesion response and 
new lesions and is listed in Table 1 below. 
Table 1: Overall Response Definitions Using RECIST v1.1 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Source: (Eisenhauer, Therasse et al. 2009) 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease. 
Immune-related RECIST 
irRECIST is a modification of RECIST v1.1 which requires confirmation of initial PD per 
RECIST v1.1 with an additional scan obtained at least 4 weeks later that also meets the criteria 
of PD progression per RECIST v1.1. In determining whether or not PD is confirmed per 
irRECIST, the investigator should consider all target and non-target lesions as well as any 
incremental new lesion(s). 
The following are scenarios where PD is confirmed at repeat imaging if ANY of the following 
occurs by irRECIST: 
• Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to nadir 
• Non-target disease resulting in initial PD is qualitatively worse 
• New lesion resulting in initial PD is qualitatively worse 


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CONFIDENTIAL AND PROPRIETARY 
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• Additional new lesion(s) since last evaluation 
• Additional new non-target progression since last evaluation 
The following are scenarios where PD is not confirmed at repeat imaging if ALL of the 
following occur by irRECIST: 
• Tumor burden is < 20 % or < 5 mm absolute increase compared to nadir 
• Non-target disease resulting in initial PD is stable or qualitatively improved 
• New lesion resulting in initial PD is stable or qualitatively improved 
• No incremental new lesion(s) since last evaluation 
• No incremental new non-target progression since last evaluation 
The rationale of the modification is to address observed pseudoprogression as well as late 
responses that are expected with immunotherapy. Guidance for continued imaging and treatment 
following an initial determination of PD per RECIST v1.1 is provided in the protocol in 
Section 10.4.1. 
 
 


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APPENDIX 7: 
IMAGING MODALITIES 
NOTE: As of Amendment 9, all post-baseline imaging is to be performed according to local 
standard of care. The modality, anatomic areas, and timing of imaging is at the discretion 
of the investigator. This section has been updated accordingly. 
Contrast enhanced CT (preferred) or enhanced MRI are the preferred imaging modalities to be 
used. Chest x-rays performed during the Screening phase (and repeated at any time during the 
trial if clinically indicated) may be used as supportive data, as an accessory to the chest CT 
scans. 
All imaging data are to be collected on film or in digital format. 
CT/MRI of the Chest/Abdomen/Pelvis 
CT/MRI imaging of the chest, abdomen, and pelvis is required at Screening, regardless of the 
location of known metastases. For HNSCC, imaging of the neck is also required. In addition, 
CT/MRI scans must be obtained of anatomic regions not covered by the chest, abdomen and 
pelvic scans, in patients where there is clinical suspicion of malignant disease/metastases. Such 
additional CT/MRIs will be required at Screening only when malignant disease/metastases is 
known/suspected.  
Brain MRI/CT 
Brain scans (MRI or CT) are required at Screening. Brain scans should be conducted during the 
course of the trial if the Screening scan was positive as clinically indicated. 
Non-radiographic Assessments/Digital Photography 
These should be made at the sites and recorded in the source documents at the time points 
indicated in Appendix 1 through Appendix 4. Visible skin lesions should be measured clinically 
and documented digitally using standardized photographic images, including a ruler for scale as 
part of the image. Superficial lesions not well captured by imaging scans should be documented 
using standardized photographic images, including a ruler for scale as part of the image to track 
the lesion size. 
Image Acquisition Guidelines 
Similar methods of tumor assessment and similar techniques must be used to characterize each 
identified and reported lesion at baseline. Image acquisition guidelines should be consistent with 
the American College of Radiology imaging guidelines and local imaging guidelines. All 


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CONFIDENTIAL AND PROPRIETARY 
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measurable and non-measurable lesions should be assessed at Screening and at any tumor 
assessment time points indicated as mandatory in Appendix 1 through Appendix 4. Additional 
assessments may be performed, as clinically indicated, if there is a suspicion of progression or 
for confirmation of response. The investigator will base response to treatment on local 
assessment guidelines. Imaging-based evaluation is preferred to physical examination. Helical 
(spiral) CT scans of chest, abdomen and pelvis are preferred. If not available, conventional (non-
helical, non-spiral CT) should be used. 
Intravenous contrast should be used for all CT scans. Oral contrast should be used for CT 
abdomen and pelvis. If intravenous contrast is contraindicated, CT may be performed without 
contrast. If oral contrast is indicated, milk or other suitable substitution per local imaging 
standards may be used. CT scan of the chest is preferred compared to MRI of the chest. 
However, for patients who cannot receive intravenous contrast, MRI may be used as an 
alternative imaging modality. Intravenous imaging agent (gadolinium or acceptable alternative 
per local institutional standards) should be used for all MRI scans. Patients who develop contrast 
allergy after trial enrollment may be followed by MRI for subsequent tumor measurements or 
have non-contrast CT scans per approval by a Dynavax Medical Monitor and per institutional 
standard practice. Sections should be contiguous, similarly sized and consistent from 
visit-to-visit. Section thickness must be based on institutional standards (eg, from 5 to 8 mm; 10 
mm cuts are not recommended). Chest x-ray, ultrasound, and positron emission tomography 
scans are not acceptable methods to measure baseline disease status for the purposes of this trial. 
 
 


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CONFIDENTIAL AND PROPRIETARY 
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APPENDIX 8: 
ECOG PERFORMANCE STATUS INDEX 
The ECOG Performance Status is credited to the Eastern Cooperative Oncology Group, Robert 
Comis MD, Group Chair. 
Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light housework, 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. 
Source: (Oken, Creech et al. 1982). 
Available at: http://www.ecog.org/general/perf_stat.html. Accessed 21 February 2015. 
 

SAP_001.pdf: 
Protocol Title: 
A Phase 1b/2, Open-label, Multicenter, Dose-escalation and Expansion Trial of Intratumoral 
SD-101 in Combination With Pembrolizumab in Patients With Metastatic Melanoma or 
Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma 
Protocol No.: 
DV3-MEL-01 (SYNERGY-001) 
Document Name: 
Statistical Analysis Plan v1.0 dated 04 November 2019 
NCT No.: 
NCT02521870 
 


Dynavax Technologies Corporation 
STATISTICAL ANALYSIS PLAN 
Study Title: 
A Phase 1b/2, Open-label, Multicenter, Dose 
escalation and Expansion Trial of Intratumoral SD 
101 in Combination with Pembrolizumab in 
Patients with Metastatic Melanoma or Recurrent or 
Metastatic Head and Neck Squamous Cell 
Carcinoma 
Protocol Identifier: 
DV3-MEL-01 
Phase 
Phase 1b/2 
Investigational Product: 
SD-101 
Indication: 
Metastatic Melanoma 
Sponsor: 
 
Dynavax Technologies Corporation  
2100 Powell Street Suite 900 
Emeryville, CA 94608 
United States of America 
Reference Numbers: 
United States IND No. 125878 
 
 
 
 
 
 
Original Version: 
Version 1: 04 November 2019 
Based on Protocol Version: 
Amendment # 8: 08 February 2018 
 
 
 
 
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Dynavax Technologies 
  
 
DV3-MEL-01 
  
04 November 2019  
CONFIDENTIAL AND PROPRIETARY 
 
Page 2 of 30 
 
 
FINAL STATISTICAL ANALYSIS PLAN APPROVAL  
 
Prepared by: 
____________________________ 
 
_________________ 
Fang Xie            
 Date 
Consulting Biostatistician 
Clinical Development  
Dynavax Technologies Corporation 
 
 
 
Reviewed by: 
____________________________ 
 
_________________ 
Fang Xie            
 Date 
For Head of Biometrics 
Clinical Development  
Dynavax Technologies Corporation 
 
 
Approved by: 
____________________________ 
 
_________________ 
 
Robert Janssen, MD 
 
 
 
Date 
 
Senior Vice President Clinical Development  
and Medical and Regulatory Affairs 
and Chief Medical Officer  
 
Dynavax Technologies Corporation 
 
 
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Dynavax Technologies 
  
 
DV3-MEL-01 
  
04 November 2019  
CONFIDENTIAL AND PROPRIETARY 
 
Page 3 of 30 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND TERMS ..............................................................................5 
1.0 
INTRODUCTION..............................................................................................................7 
2.0 
STUDY OVERVIEW ........................................................................................................7 
2.1 
Phase 1 .....................................................................................................................9 
2.2 
Phase 2 .....................................................................................................................9 
3.0 
STUDY OBJECTIVES ....................................................................................................10 
3.1 
Phase 1 (Dose Escalation: Metastatic Melanoma) .................................................10 
3.1.1 
Primary Objectives ................................................................................10 
3.1.2 
Exploratory Objectives..........................................................................10 
3.2 
Phase 2 (Dose Expansion: Metastatic Melanoma or Recurrent or 
Metastatic Head and Neck Squamous Cell Carcinoma) ........................................10 
3.2.1 
Primary Objectives ................................................................................10 
3.2.2 
Secondary Objectives ............................................................................10 
3.2.3 
Exploratory Objectives..........................................................................10 
4.0 
ANALYSIS VARIABLES ...............................................................................................11 
5.0 
SAMPLE SIZE CONSIDERATIONS ...........................................................................12 
6.0 
ANALYSIS POPULATIONS .........................................................................................13 
6.1 
Enrolled Population ...............................................................................................13 
6.2 
Safety Population ...................................................................................................13 
6.3 
Efficacy Population ................................................................................................13 
6.4 
Pharmacodynamic Population ...............................................................................14 
7.0 
DEFINITIONS, COMPUTATIONS, AND CONVENTIONS ....................................14 
7.1 
Definitions and Computations ...............................................................................14 
7.2 
Conventions ...........................................................................................................15 
7.3 
Rules for Missing Data ..........................................................................................15 
8.0 
TIMING OF ANALYSES ...............................................................................................17 
9.0 
STATISTICAL METHODS ...........................................................................................17 
9.1 
Patient Disposition .................................................................................................17 
9.2 
Protocol Deviations ................................................................................................17 
9.3 
Demographics and Baseline Characteristics ..........................................................17 
9.4 
Prior and Concomitant Medications ......................................................................18 
9.5 
Medical History .....................................................................................................18 
9.6 
Efficacy Analyses ..................................................................................................18 
9.6.1 
Objective Response Rate.......................................................................19 
9.6.2 
Best Overall Response ..........................................................................19 
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9.6.3 
Disease Control Rate .............................................................................19 
9.6.4 
Time to Objective Response .................................................................19 
9.6.5 
Duration of Response ............................................................................19 
9.6.6 
Progression-Free Survival .....................................................................19 
9.7 
Safety Analyses ......................................................................................................19 
9.7.1 
Dose Limiting Toxicities.......................................................................20 
9.7.2 
Injection Related Reactions...................................................................21 
9.7.3 
Adverse Events......................................................................................21 
9.7.4 
Laboratory Assessments........................................................................22 
9.7.5 
Vital Signs .............................................................................................22 
9.7.6 
Physical Examinations ..........................................................................22 
9.7.7 
Electrocardiograms ...............................................................................22 
9.8 
Pharmacodynamic Analyses ..................................................................................22 
9.9 
Other Analyses .......................................................................................................22 
9.10 
Interim Analysis .....................................................................................................22 
9.11 
Reporting Output ...................................................................................................22 
10.0 
REVISION HISTORY ....................................................................................................23 
11.0 
REFERENCES .................................................................................................................23 
12.0 
LIST OF TABLES ...........................................................................................................24 
13.0 
LIST OF FIGURES .........................................................................................................25 
14.0 
LIST OF PATIENT DATA LISTINGS .........................................................................26 
APPENDIX 1 
RECIST V1.1 .......................................................................................27 
ANNEX 1 
PLAN FOR PHARMACODYMAMIC ANALYSIS ........................................30 
 
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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation or Term 
Definition 
AE 
adverse event 
anti-PD-1/L1 
anti-programmed death receptor-1/ligand 1 
ATC 
anatomical therapeutic chemical 
BORR 
best objective response rate 
CR 
complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EOS 
End-of-Study (visit) 
IFN 
interferon 
ITT 
Intent-To-Treat 
HNSCC 
head and neck squamous cell carcinom 
irRECIST 
immune-related Response Evaluation Criteria In Solid Tumors 
MHC 
major histocompatibility complex 
NK 
natural killer 
ORR 
objective response rate 
PD 
progressive disease 
PD-1 
programmed death receptor-1 
PD-L1 
programmed death-ligand 1 
PFS 
progression free survival 
PR 
partial response 
PT 
preferred term 
Q3W 
every 3 weeks 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
recommended Phase 2 dose  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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Abbreviation or Term 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
 
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1.0 
INTRODUCTION 
This statistical analysis plan contains definitions of analysis populations and endpoints, 
outlines the timing of statistical analyses, and provides a comprehensive description of 
statistical analyses to be implemented to assess the safety, tolerability, biologic activity, and 
preliminary efficacy of SD-101 in combination with pembrolizumab as described in Protocol 
DV3-MEL-01 (Amendment 8: 08 February 2018): “A Phase 1b/2, Open-label, Multicenter, 
Dose escalation and Expansion Trial of Intratumoral SD-101 in Combination With 
Pembrolizumab in Patients With Metastatic Melanoma or Recurrent or Metastatic Head and 
Neck Squamous Cell Carcinoma (HNSCC)”. 
Due to strategic changes, only some of the objectives will be evaluated. Those objectives not 
evaluated will be italicized and annotated as “(not implemented)”, where applicable, 
throughout this SAP; statistical methods for these objectives are also not described. The main 
text of this SAP covers only assessment of the objectives by data contained in the clinical 
database. Pharmacodynamic assessment will be described in an annex to this SAP. 
Pharmacodynamic objectives will also be annotated.  
Groupings of patients to be used in the analyses are also changed from what were described 
in the protocol, based on the knowledge accumulated through the conduct of the trial.  
2.0 
STUDY OVERVIEW 
This open-label, multicenter, dose-ranging and expansion trial is designed to evaluate the 
safety and preliminary efficacy of intratumoral SD-101 in combination with pembrolizumab 
for the treatment of metastatic melanoma and HNSCC. The hypothesis to be tested in the 
clinical development of SD-101 is that SD-101, by virtue of its potency and its ability to 
induce high levels of interferons (IFNs), will have meaningful efficacy in generating anti-
tumor immune responses when combined with an anti-PD-1 antibody. IFNs have multiple 
effects on both tumor cells and tumor-infiltrating leukocytes. These IFNs can directly inhibit 
the proliferation of tumor cells and increase MHC class I expression, enhancing antigen 
recognition. Additionally, IFNs have potent effects on tumor-infiltrating leukocytes, 
including enhancing the antigen presenting function of dendritic cells, increasing the effect or 
function of T cells, and activating cytotoxic activity of NK cells. 
The rationale for treating metastatic melanoma and HNSCC with combination anti-PD-1/L1 
therapy plus SD-101 is based on the unmet need to improve upon single anti-PD-1/L1 
activity in these patient populations and nonclinical data (Protocol Sections 2.4 and 2.5) 
which suggest improved anti-tumor activity with the combination compared to anti-PD-1/L1 
alone. 
The study will be performed in 2 phases. The population to be studied in Phase 1 (Dose 
Escalation) will be patients with metastatic melanoma. The populations to be studied in 
Phase 2 (Dose Expansion) will be patients with metastatic melanoma and patients with 
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recurrent or metastatic HNSCC. In phase 1 of the study, doses of 1.0 mg, 2.0 mg, 4.0 mg, and 
8.0 mg of SD-101 each in a single lesion will be tested in a modified, staggered, 3 + 3 trial 
design, to identify an optimal dose of SD-101 given in combination with pembrolizumab to 
be used in Phase 2 (see Protocol section 9.1 for DLT definitions and stopping rules). This 
optimal dose from Phase 1 is referred to in the protocol as the recommended Phase 2 dose 
(RP2D) of SD-101. Phase 2 of the study is designed to evaluate the safety and efficacy of 
SD-101 plus pembrolizumab in both metastatic melanoma and HNSCC patients. Tumor 
response will be evaluated separately for injected and non-injected lesions as well as all 
combined lesions in order to assess both a local and systemic response to study treatment. 
The trial population includes a total of approximately 284 men and women with at least 1 site 
of disease that qualifies as a target lesion per RECIST v1.1 and is accessible for intratumoral 
injection. 
Phase 1 Dose Escalation Cohorts 1-4 will include up to 24 patients with metastatic melanoma 
who are anti-PD-1 naïve or experienced. 
Phase 2 Dose Expansion will include approximately 160 patients with metastatic melanoma 
and approximately 100 patients with recurrent or metastatic HNSCC: 
1) Expansion Cohort 1 of approximately 60 melanoma patients who are anti-PD-1/L1 naïve 
2) Expansion Cohort 2 of approximately 25 melanoma patients who have disease progression 
on anti-PD-1/L1 therapy 
3) Expansion Cohort 3 of approximately 25 HNSCC patients who are anti-PD-1/L1 naïve 
4) Expansion Cohort 4 of approximately 25 HNSCC patients who have disease progression 
on anti-PD-1/L1 therapy 
5) Expansion Cohort 5 of approximately 25 melanoma patients who are anti-PD-1/L1 naïve 
6) Expansion Cohort 6 of approximately 25 HNSCC patients who are anti-PD-1/L1 naïve 
7) Expansion Cohort 7 of approximately 25 HNSCC patients who are refractory or resistant 
to anti-PD-1/L1 therapy 
8) Expansion Cohort 8 of approximately 50 melanoma patients who are refractory or 
resistant to anti-PD-1/L1 therapy. 
Some of these study groups will be rearranged for final analysis as analysis groups based on 
tumor indications, anti-PD-1/L1 experience, and dose of SD-101. 
Phase 1 results will be presented for each of the 4 dose groups. 
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Results for Phase 2 objectives, using combined Phases 1 and 2 data, will be presented by 
2mg/lesion and 8mg/lesion doses for 
x MEL/NAIVE: metastatic melanoma patients who are anti-PD-1/L1 naïve, including 
x subjects in Phase 1 2mg and 8mg groups 
x subjects in Phase 2 Cohort 1 (both 2mg/lesion and 8mg single lesion) and Cohort 5 
(2mg/lesion) 
x MEL/EXP: metastatic melanoma patients who are anti-PD-1/L1 experienced, including 
x subjects in Phase 1 2mg and 8mg groups 
x subjects in Phase 2 Cohort 2 (both 2mg/lesion and 8mg/lesion) and Cohort 8 
(2mg/lesion) 
x HNSCC/NAIVE: HNSCC patients who are anti-PD-1/L1 naïve, including 
x subjects in Phase 2 Cohort 3 (both 2mg/lesion and 8mg/lesion) and Cohort 6 
(2mg/lesion) 
x HNSCC/EXP: HNSCC patients who are anti-PD-1/L1 experienced, including 
x subjects in Phase 2 Cohort 4 (both 2mg/lesion and 8mg/lesion) and Cohort 7 
(2mg/lesion) 
2.1 
Phase 1 
Patients in Escalation Cohorts 1-4 will be administered 1.0 mg, 2.0 mg, 4.0 mg, and 8.0 mg, 
respectively, of SD-101 in combination with 200 mg pembrolizumab Q3W per the Schedule 
of Trial Events (see Protocol Section 4.1.1 for dosing schema). 
2.2 
Phase 2 
Melanoma Dose Expansion cohorts in Phase 2 will be treated with 8.0 mg or 2.0 mg of SD-
101 from Phase 1 in combination with 200 mg pembrolizumab Q3W (see Protocol Section 
4.1.2 for dosing schema). 
HNSCC Dose Expansion cohorts in Phase 2 will be treated with the selected RP2D (8.0 mg 
or 2.0 mg of SD-101) from Phase 1 in combination with 200 mg pembrolizumab Q3W (see 
Protocol Section 4.1.2 for dosing schema). 
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3.0 
STUDY OBJECTIVES 
3.1 
Phase 1 (Dose Escalation: Metastatic Melanoma) 
3.1.1 
Primary Objectives 
x To assess the safety and tolerability of escalating intratumoral doses of SD-101 in 
combination with intravenous pembrolizumab in patients with metastatic melanoma 
x To evaluate the expression of IFN-inducible genes in whole blood 24 hours after 
intratumoral injection of SD-101 given with pembrolizumab in patients with metastatic 
melanoma as a pharmacodynamic marker of SD-101 activity (pharmacodynamic)  
x To determine a RP2D of SD-101 in combination with pembrolizumab to be evaluated in 
Phase 2 
3.1.2 
Exploratory Objectives  
x To assess the preliminary response both locally and systemically including:  
x Treatment response of the injected Lesion A (local response) (not implemented) 
x Treatment response of the non-injected lesion(s) (systemic response) (not 
implemented) 
x Treatment response of all lesions  
x Time to response (not implemented) 
x To assess changes in tumor biomarkers (pharmacodynamic) 
3.2 
Phase 2 (Dose Expansion: Metastatic Melanoma or Recurrent or Metastatic 
Head and Neck Squamous Cell Carcinoma) 
3.2.1 
Primary Objectives  
x To assess the tumor response both locally and systemically including:  
x Treatment response of the injected lesion(s) (local response)  
x Treatment response of the non-injected lesion(s) (systemic response)  
x Treatment response of all lesions  
3.2.2 
Secondary Objectives  
x To assess the safety and tolerability of SD-101 in combination with pembrolizumab  
x To assess the time frame of tumor responses:  
x Time to response  
x Duration of response 
x To assess PFS  
3.2.3 
Exploratory Objectives 
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x To identify and assess changes in potential tumor neoantigens in patients with recurrent 
or metastatic HNSCC (pharmacodynamic) 
x To evaluate the expression of IFN inducible genes in whole blood 24 hours after 
intratumoral injection of SD-101 given with pembrolizumab in patients with recurrent or 
metastatic HNSCC as a pharmacodynamic marker of SD-101 activity (pharmacodynamic) 
4.0 
ANALYSIS VARIABLES 
Phase 1 – Dose Escalation  
Primary Endpoints  
x Incidence of DLTs  
x Incidence of injection-site reactions, AEs, and SAEs  
x Changes in the expression of IFN-inducible genes in whole blood (pharmacodynamic) 
Exploratory Endpoints  
x ORR per RECIST v1.1  
x Changes in tumor-infiltrating lymphocytes, PD-L1 expression, and other gene expression 
in tumor biopsies (pharmacodynamic) 
Phase 2 – Dose Expansion  
The primary radiographic endpoints of the study will be based on RECIST v1.1 and 
exploratory radiographic endpoints will be based on irRECIST (not implemented). All 
imaging endpoints for the overall response assessment will be based on investigator 
evaluation. A central imaging laboratory for study image collection and radiographic 
endpoint determination will be used per sponsor decision.  
Primary Endpoints  
x ORR per RECIST v1.1  
Secondary Endpoints  
x Incidence of injection-site reactions, AEs, and SAEs  
x Time to response using RECIST v1.1  
x Duration of response per RECIST v1.1 
x PFS per RECIST v1.1  
Exploratory Endpoints  
x Changes in correlative biomarkers including tumor-infiltrating lymphocytes and PD-L1 
expression at baseline and after SD-101 treatment (pharmacodynamic)  
x Changes in potential tumor neoantigens in patients with recurrent or metastatic HNSCC 
(pharmacodynamic) 
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x Changes in the expression of IFN-inducible genes in whole blood in patients with 
metastatic HNSCC (pharmacodynamic) 
5.0 
SAMPLE SIZE CONSIDERATIONS 
The Phase 1 trial is designed to allow preliminary assessments of safety, biological activity, 
and biomarkers in approximately 24 patients. Phase 2 of this trial is designed to allow 
preliminary assessments of efficacy, safety, and changes in biomarkers in approximately 210 
patients. All analyses will be descriptive. 
The Phase 1 trial sample size is based on a modified 3 + 3 dose-escalation trial design. 
For the Phase 2 expansion cohorts, the sample sizes were determined based on power 
analysis of hypothesis tests and/or confidence intervals, although the efficacy analyses will 
be descriptive. 
In Expansion Cohort 1, approximately 60 anti-PD-1/L1 naïve patients with metastatic 
melanoma will be enrolled. The null hypothesis that the response rate is < 35% will be tested 
against a 1-sided alternative at a significance level of 0.05. The design will provide greater 
than 90% power if the true response rate is > 55%. There will be no adjustments for 
multiplicity. 
An exploratory sub-group analysis will be performed for those Expansion Cohort 1 subjects 
with PD-L1 negative tumors (ie, < 1% positivity) at baseline. It was estimated that this 
subgroup will have approximately 30 subjects. The analysis will have 80% power to reject 
the null hypothesis that the response rate is <15% with a one-sided test at a significance level 
of 0.05 when the true response rate is 35%. There will be no adjustments for multiplicity. 
In Expansion Cohort 5, approximately 25 anti-PD-1/L1 naïve melanoma patients will be 
enrolled. This will allow preliminary estimate of the response rate associated with the dose 
and dosing schedule chosen for Expansion Cohort 5. If 14 or more responses are observed, 
the 95% exact confidence interval will yield a lower bound of no less than 37%. 
In Expansion Cohort 2, approximately 25 metastatic melanoma patients who have disease 
progression on anti-PD-1/L1 therapy will be enrolled. The null hypothesis that the true 
response rate is 10% will be tested against a 1-sided alternative and will be rejected if 6 or 
more responses are observed. This design yields a type I error rate of 0.05 and 80% power 
when the true response rate is 30%. There will be no adjustments for multiplicity. 
In Expansion Cohort 8, approximately 50 metastatic melanoma patients who are refractory or 
resistant to anti-PD-1/L1 therapy will be enrolled. If 13 or more responses are observed, the 
95% exact confidence interval will yield a lower bound of no less than 15.0%. 
In Expansion Cohort 3, approximately 25 anti-PD-1/L1 naïve HNSCC patients will be 
enrolled. The null hypothesis that the response rate is < 20% will be tested against a 1-sided 
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alternative at a significance level of 0.05. The design will provide greater than 80% power if 
the true response rate is > 40%. There will be no adjustments for multiplicity. 
In Expansion Cohort 6, approximately 25 anti-PD-1/L1 naïve HNSCC patients will be 
enrolled. This will allow a preliminary estimate of the response rate associated with the dose 
and dosing schedule chosen for Expansion Cohort 6. If 9 or more responses are observed, the 
95% exact confidence interval will yield a lower bound of no less than 20%. 
In Expansion Cohort 4, approximately 25 HNSCC patients who have disease progression on 
anti-PD-1/L1 therapy will be enrolled. The null hypothesis that the true response rate is 5% 
will be tested against a 1-sided alternative and will be rejected if 4 or more responses are 
observed. This design yields a type I error rate of 0.05 and 80% power when the true 
response rate is 21%. There will be no adjustments for multiplicity. 
In Expansion Cohort 7, approximately 25 HNSCC patients who are refractory or resistant to 
anti-PD-1/L1 therapy will be enrolled. This will allow a preliminary estimate of the response 
rate associated with the dose and dosing schedule chosen for Expansion Cohort 7. If 4 or 
more responses are observed, the 95% exact confidence interval will yield a lower bound of 
no less than 5%. 
Although changes to the groupings for the final analysis will be made, there is no impact to 
the sample size calculation, as all analyses will be descriptive. At some places in above 
sample size calculation one-sided significance level of 0.05 was referenced, to standardize 
the analyses, two-sided significance level of 0.05 is used throughout. Power and 95% exact 
confidence interval descriptions are still applicable if the underlying conditions in various 
analysis groups hold. 
6.0 
ANALYSIS POPULATIONS 
6.1 
Enrolled Population 
The enrolled population is defined as all patients who enrolled in the study.  
6.2 
Safety Population 
The safety population will include all enrolled patients who receive at least 1 dose of SD-101 
(Protocol section 12.4). The primary analysis population for the study will include the safety 
population with separate analyses for Phase 1 Dose Escalation and each Phase 2 Dose 
Expansion analysis group. 
6.3 
Efficacy Population 
The evaluable population will comprise all patients who receive at least 1 dose of both 
pembrolizumab and SD-101 and who have baseline and at least 1 post-baseline imaging 
assessment. The ITT population will include all enrolled subjects regardless of having a post-
baseline radiographic assessment. Additional subpopulations for an exploratory and 
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retrospective analysis may include baseline PD-L1 status (positive or negative [ie, < 1% 
positivity]) and specific prior anti-PD-1/PD-L1 therapy (Protocol section 12.4).  
Prior anti-PD-1/PD-L1 therapy subpopulations are reflected in the study groups. Analyses 
will be performed according to the dose groups in Phase 1 and study groups in Phase 2 for 
evaluable and ITT population. 
6.4 
Pharmacodynamic Population 
The pharmacodynamic population will include all enrolled patients who receive at least 1 
dose of SD-101 and who have screening and at least 1 post-baseline assessment of INF-alpha 
inducible gene expression. 
7.0 
DEFINITIONS, COMPUTATIONS, AND CONVENTIONS 
7.1 
Definitions and Computations 
Study Day 
Study day will be calculated in reference to the date of first dose (Day 1). For assessments 
conducted on or after the first dose date, study day is calculated as (assessment date – first 
dose date + 1). For assessments conducted before the first dose date, study day is calculated 
as (assessment date – first dose date). There will be no Day 0.  
Date of First Dose and Date of Last Dose of Study Drug 
The date of the first dose of study drug is defined as the date a patient receives the first dose 
of the study drug. The date of the last dose of study drug is the date a patient receives the last 
dose of the study drug. 
Treatment-Emergent Period 
Treatment-emergent periods are updated from what were described in the protocol (sections 
10.3.9 and 10.3.10) to cover the maximum possible reporting periods. 
Treatment-emergent period for AEs is defined the date and time of the first dose of study 
drug administration through 90 days after last dose of study drug administration. 
Treatment-emergent period for SAEs is defined as the date and time of the first dose of study 
drug administration through EOS. 
Baseline Value and Post-baseline Value 
Unless otherwise specified, the baseline value is defined as the last measurement before the 
first dose (date and time) of study drug. Post-baseline value is defined as a measurement 
taken after the first dose of study drug. Change from baseline is defined as (post-baseline 
value – baseline value). Both date and time of study drug administration and measurement 
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will be considered when calculating baseline value. If time is not available, then date only 
will be used.  
7.2 
Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses: 
x 1 year = 365.25 days. Year is calculated as (days/365.25) rounded up to 1 significant 
digit. 
x 1 month = 30.4375 days. Month is calculated as (days/30.4375) rounded up to 
1 significant digit. 
x Age will be calculated by the following SAS code: age = floor(yrdif(birth_date, 
consent_date, 'AGE')) 
x 1 pound = 0.454 kg 
x 1 inch = 2.54 cm 
x Missing safety data will not be imputed unless otherwise specified. 
x For laboratory results collected as < or > a numeric value, 0.0000000001 will be 
subtracted or added, respectively, to the value. 
x For safety analyses, percentages will be calculated based on the number of patients in the 
analysis population. 
x For by-visit observed data analyses, percentages will be calculated based on the number 
of patients with nonmissing data as the denominator unless otherwise specified. 
x For other continuous endpoints, the summary statistics will include mean, standard 
deviation, median, and range (minimum and maximum). 
x For categorical endpoints, the summary statistics will include counts and percentages. 
x AEs and medical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 17 or higher. 
x Prior therapies and concomitant medications will be coded using the World Health 
Organization (WHO) Drug Dictionary version 201506. 
7.3 
Rules for Missing Data 
Missing data will not be imputed, except for missing date information for AEs and 
concomitant medications. The imputed dates will be used to determine the treatment-
emergent period. For AEs with a partial date, available date parts (year, month, and day) of 
the partial date will be compared with the corresponding date components of the start date 
and end date of the treatment-emergent period to determine if the event is treatment 
emergent. When in doubt, the AE will be considered treatment emergent by default. 
The following rules will be applied to impute partial dates for AEs: 
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x If start date of an AE is completely or partially missing, impute as follows: 
x If both month and day are missing and year = year of first dose date, then set to first 
dose date. 
x If both month and day are missing and year ≠ year of first dose date, then set to 
January 1. 
x If day is missing and month and year = month and year of first dose date, then set to 
first dose date. 
x If day is missing and month and year ≠ month and year of first dose date, then set to 
first of the month. 
x If start date is completely missing and AE end date is on or after the first dose date, 
set to first dose date.  
x If start date is completely missing and AE end date is prior to the first dose date, do 
not impute an AE start date. 
x If end date of an AE is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31. 
x If only day is missing, then set to last day of the month. 
x If end date is completely missing, do not impute. 
When the start date or end date of a medication is partially missing, the date will be imputed 
to determine whether the medication is prior or concomitant (or both). The following rules 
will be applied to impute partial dates for medications: 
x If start date of a medication is partially missing, impute as follows: 
x If both month and day are missing, then set to January 1. 
x If only day is missing, then set to the first of the month. 
x If end date of a medication is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31. 
x If only day is missing, then set to last day of the month. 
x If start date or end date of a medication is completely missing, do not impute. 
Listings will show the original date information without imputation, but derived parameters 
(TEAE indicator and duration of AE) will be flagged to indicate the type of imputation 
performed. 
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8.0 
TIMING OF ANALYSES 
Final analyses will be carried out after the last participant has completed their last trial visit, 
the trial database has been authorized by Dynavax as complete and final, and major protocol 
deviations have been identified. No interim analysis is planned for this study. 
9.0 
STATISTICAL METHODS 
This trial is designed to allow preliminary assessments of safety, biological activity, and 
biomarkers. No pre-specified hypothesis testing will be performed. All analyses of 
demographics, safety, biological activity, and biomarkers will be descriptive.  
Efficacy and safety data will be analyzed and reported separately by Phase 1 dose group or 
Phase 2 analysis group.  
Descriptive statistics, including the number of patients (n), mean, standard deviation (SD), 
median, minimum, and maximum, will be used to summarize continuous variables. 
Categorical variables will be summarized by number (n) and percentage (or proportions) of 
patients in each category. All data processing, summarization, and analyses will be 
performed using SAS Version 9.3 or higher. Specifications for tables, graphs, and data 
listings will be provided in the tables, figures, listings (TFL) specifications document.  
9.1 
Patient Disposition 
Patient disposition will be summarized for all enrolled patients by dose or analysis group 
including patients in the safety, evaluable and ITT populations and patients discontinuing the 
study along with the reasons for discontinuation (as documented on the case report form 
study exit status).  
A listing of patients discontinuing the study after enrollment will be produced.  
9.2 
Protocol Deviations 
Patient data will be reviewed for major protocol deviations by the Medical Monitor prior to 
database lock. A listing of patients with major protocol deviations will be provided, sorted by 
treatment and describing their deviations. Any exclusions from analysis populations due to 
protocol deviations will be highlighted. 
9.3 
Demographics and Baseline Characteristics 
Summary statistics for age, weight, height, body mass index at baseline, sex, race, and 
ethnicity will be presented by dose or analysis group for the safety, evaluable and ITT 
populations.  
Listings will be provided for these parameters for all patients.  
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9.4 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Dictionary (version 201506). Prior medications are drugs and therapies used 
before the first dose date. Medications or therapies are considered concomitant if exposure 
occurs after the first dose date. The number and percentage of patients with concomitant 
medications will be presented alphabetically by anatomical therapeutic chemical (ATC) class 
and by decreasing order of frequency of preferred terms within each ATC class for the safety 
population. Patients taking the same medication multiple times will be counted once per 
medication.  
All medications recorded on the case report form will be listed. 
9.5 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA V17.0 or higher).  All medical history data will be provided in a listing.  
9.6 
Efficacy Analyses 
Response of lesions and disease status will be assessed using standard RECIST v1.1 for the 
primary evaluation of response and a study specific modified RECIST v1.1 referred to as 
immune related-RECIST v1.1 (irRECIST v1.1) for an exploratory evaluation (not 
implemented). Therefore, RECIST v1.1 will be used with the following adaptations 
(Appendix 1): 
x Determination of progressive disease (PD) requires a confirmation of PD by imaging ≥ 4 
weeks later. In order to confirm PD, both the initial lesion assessment and lesion 
assessment on the confirmatory scan must meet PD criteria (≥ 20% increase in sum of 
diameters). 
x Continued treatment while awaiting radiologic confirmation of progression is encouraged 
if the patient is stable. 
Patients that are deemed clinically unstable are not required to have repeat imaging for the 
confirmation of PD. 
Objective response rate (ORR) and disease control rate (DCR) will be evaluated for injected 
and non-injected lesions as well as for all target lesions. The ORR will include patients with 
complete response (CR) or partial response (PR). The DCR will include patients with CR, 
PR, or stable disease.  The ORR and DCR will be determined by Investigator using RECIST 
v1.1.  
Unless otherwise specified, all efficacy analyses will be performed by: 
x Lesion type – injected, non-injected lesions, all target lesions 
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x Evaluation criteria – RECIST v1.1 
x Study Phase – Phase 1 by dose groups, Phase 2 by analysis groups 
9.6.1 
Objective Response Rate  
The ORR is the proportion of patients who achieve a response of either CR or PR. ORR will 
be summarized and 95% Clopper Pearson confidence interval will be reported for each dose 
or analysis group. 
9.6.2 
Best Overall Response  
The best overall response rate (BORR) is the proportion of patients who achieve a best 
response recorded at any post-baseline assessment. BORR will be summarized and 95% 
Clopper Pearson confidence interval will be reported for each dose or analysis group. 
9.6.3 
Disease Control Rate  
The disease control rate (DCR) is the proportion of patient who had CR, PR, or stable 
disease.  DCR will be summarized and 95% Clopper Pearson confidence interval will be 
reported for each dose or analysis group. 
9.6.4 
Time to Objective Response 
The time to response (TOR) will be defined as the time from the first dose of SD-101 until 
the onset of CR or PR. TOR will be summarized descriptively for patients who achieved CR 
or PR. 
9.6.5 
Duration of Response 
The duration of response is defined as the period of time from the date of initial confirmed 
PR or CR until the date of PD or death, whichever is earlier. For those patients who achieved 
response, duration of response will be summarized descriptively. Kaplan-Meier estimate of 
median duration and 95% confidence interval will be provided. 
9.6.6 
Progression-Free Survival 
The progressive-free survival (PFS) is defined as the period of time from baseline to 
confirmed PD or death. Administration of palliative radiation therapy will be considered 
clinical progression for the purposes of determining PFS. The proportion of patients who had 
PFS at the end of the study will be summarized and PFS will be analyzed by Kaplan-Meier 
method; 95% confidence interval for the median will be provided. Overall survival (OS) is 
defined as the period of time from baseline to death, and analysis of OS will also be provided 
similarly as PFS. 
9.7 
Safety Analyses 
Injection related reactions, AEs, SAEs, and abnormal laboratory values will be summarized 
by the proportion of patients who experience them.  
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All patients in the safety population will be used in the safety analyses. Safety analyses will 
be summarized by dose or analysis group. 
The treatment-emergent period is defined in Section 7.1.  
9.7.1 
Dose Limiting Toxicities 
For Dose Escalation purposes, a DLT will be defined as any of the following AEs occurring 
from the time of the first injection (Day 1) through Study Day 29 of any of the following:  
Non-hematologic adverse event 
• Grade ≥ 3 non-hematologic AE related to SD-101 (eg, post-injection reaction or influenza-
like illness) that does not resolve to Grade ≤ 1 with standard treatment by the time of the next 
treatment, with the exclusion of fatigue 
• Grade 3 non-hematologic AE (not laboratory, specifically nausea, vomiting, and diarrhea) 
lasting > 3 days despite optimal supportive care, with the following exceptions: 
• Grade 3 fatigue will NOT be classified as a DLT, regardless of duration. 
• A Grade 3 non-hematologic laboratory AE will only be considered a DLT if it is 
clinically significant, such as: 
• Medical intervention is required to treat the patient 
• The abnormality leads to hospitalization 
• The abnormality persists for > 1 week 
• Grade 4 or 5 non-hematologic AE (not laboratory) 
Hematologic toxicity 
• Grade 4 or 5 hematologic AE 
• Any Grade 3 hematologic laboratory AE, with the exception of lymphopenia, which lasts > 
7 days 
• Febrile neutropenia Grade 3 or Grade 4: 
• Grade 3 is defined as ANC < 1000/mL with a single temperature of > 38.3°C 
(101°F) or a sustained temperature of ≥ 38°C (100.4°F) for more than 1 hour. 
• Grade 4 is defined as ANC < 1000/mL with a single temperature of > 38.3°C 
(101°F) or a sustained temperature of ≥ 38°C (100.4°F) for more than 1 hour, with 
life-threatening consequences and urgent intervention indicated. 
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Prolonged delay (> 3 weeks) of SD-101 or pembrolizumab dosing due to treatment-related 
toxicity qualifies as a DLT. 
Incidence of DLTs will be tabulated by dose groups in Phase 1, and bar chart of incidence 
rates of DLTs by dose groups will be generated, if DLTs were observed. 
9.7.2 
Injection Related Reactions 
Incidence of injection-site reactions from the diary card will be tabulated by maximum 
severity and injection and by analysis group. 
Injection related general body symptoms, defined as those symptoms, as determined by the 
Medical Monitor, with onset with 7 days of and related to the study injection, will be 
tabulated by maximum severity and injection and by analysis group. 
9.7.3 
Adverse Events 
All AEs will be coded to preferred term and system organ class using MedDRA 17.0 or 
higher. An AE that started or increased in severity during the treatment-emergent period 
(refer to Section 7.1) will be considered a TEAEs. Severity of TEAEs will be graded 
according to the National Cancer Institute Cancer Therapy and Evaluation Program Common 
Terminology Criteria for Adverse Events (CTCAE). A study drug-related TEAE is defined 
as any TEAE with at least a possible relationship to the study drug as assessed by the 
investigator or that is missing the assessment of causal relationship whose relationship to the 
study drug could not be ruled out.  
Patients with multiple occurrences of events for a given preferred term, system organ class, 
or overall will only be counted once at the worst severity and strongest relationship to study 
drug for each preferred term, system organ class, and overall, respectively. AEs that are 
continuous but change in grade, relationship, or seriousness will be counted as 1 event. 
TEAEs of unknown severity will be categorized separately. A TEAE of unknown 
relationship will be considered to be probably related to study drug.  
Tabular summaries including numbers and percentages of the following adverse events will 
be provided: 
x 
Overview of TEAEs;  
x 
TEAEs by SOC and PT; 
x 
TEAEs by SOC, PT, and severity; 
x 
TEAEs by SOC, PT, and relationship to study drug; 
x 
TEAEs leading to study drug discontinuation; 
x 
Serious TEAEs by SOC, PT, and severity; 
x 
Serious TEAEs by SOC, PT, and relationship to study drug; 
x 
Immune Related TEAEs by SOC and PT; 
x 
TEAEs leading to death by SOC and PT. 
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Listings will be provided for all TEAEs.  
9.7.4 
Laboratory Assessments 
Laboratory test results for neutrophils, lymphocytes, and platelets and their change from 
baseline will be summarized by tumor type and scheduled visit. 
Laboratory data listings will not be produced as clinically significant abnormal laboratory 
findings are included in AE data. 
Anti-dsDNA antibodies (not implemented) and anti-SD-101 antibodies results will be 
provided as part of the Annex 1 analysis. 
9.7.5 
Vital Signs 
Vital sign data will be provided in a data listing.  
9.7.6 
Physical Examinations 
Individual physical examination data with abnormal findings flagged will be provided in data 
lists. 
9.7.7 
Electrocardiograms 
ECG data with abnormal findings flagged will be provided in a data listing.  
9.8 
Pharmacodynamic Analyses 
Plan for pharmacodynamic analyses is included in Annex 1 of this SAP. 
9.9 
Other Analyses 
No other analyses are planned.  
9.10 
Interim Analysis 
No interim analysis is planned for this protocol. Safety will be monitored on a regular basis.   
9.11 
Reporting Output 
All outputs will be produced using SAS® version 9.3 or later. The REPORT procedure will 
be used to produce all tables and listings whenever possible. The SGPLOT procedure will be 
used to produce all figures whenever possible. All statistical appendices (supportive SAS 
output) will be output directly from the appropriate SAS procedure. 
Post-text tables, listings, and statistical appendices will be produced as RTF files using 
output delivery system (ODS) and Times New Roman or a similar font size 8 or larger. Data 
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will be presented in RTF tables with data in individual cells. Figures will be produced as 
RTF files using ODS and simplex font. For all outputs, the page numbering will be applied to 
ensure that when the RTF files are combined, the page numbering remains fixed. 
All tables, listings and statistical appendices will be produced to landscape orientation and 
will be incorporated into a Word 2010 or later document (margins: top 1.5”, left, right and 
bottom 1”) using 8pt font or larger. 
Dose and analysis groups for tables and figures will be as follows: 
x 
for Phase 1: Dose Escalation Phase objectives 
x 
1 mg, 2 mg, 4 mg, 8 mg 
x 
for Phase 2: Expansion Phase objectives 
x 
MEL/Naive (metastatic melanoma patients anti-PD-1/L1 therapy naïve) 
x 
2mg, 8mg 
x 
MEL/Experienced (metastatic melanoma patients progressed on anti-PD-1/L1 
therapy) 
x 
2mg, 8mg 
x 
HNSCC/Naive (HNSCC patients anti-PD-1/L1 therapy naïve) 
x 
2mg, 8mg 
x 
HNSCC/Experienced (HNSCC patients progressed on anti-PD-1/L1 therapy) 
x 
2mg, 8mg 
10.0 
REVISION HISTORY 
Version Date 
Author 
Comments/Rationale for Revision 
1.0 
04NOV2019 
Fang Xie 
New Document 
 
11.0 
REFERENCES 
 
 
 
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ents anti-P
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HISTORY
ISTORY
Autho
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$
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12.0 
LIST OF TABLES  
List of tables will be provided in a separate Table of Contents of Tables, Figures and Listings 
document. 
 
 
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13.0 
LIST OF FIGURES 
List of figures will be provided in a separate Table of Contents of Tables, Figures and 
Listings document. 
 
 
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14.0 
LIST OF PATIENT DATA LISTINGS 
List of listings will be provided in a separate Table of Contents of Tables, Figures and 
Listings document. 
 
 
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APPENDIX 1 
RECIST V1.1 
Response Definition 
Assessments will use RECIST 1.1 guidelines, which are included in the Study Reference 
Manual, and study specific modification of the RECIST 1.1 guidelines referred to as immune 
related RECIST 1.1 (irRECIST 1.1). 
RECIST 1.1  
Baseline selection of lesions 
All lesions are measured by long axis and short axis (perpendicular to the long axis). At 
baseline, all tumor lesions are identified as either target lesions or non-target lesions and will 
be evaluated at baseline and every post baseline imaging timepoint. 
Target lesions:  Minimal size of 1.0 cm by long axis unless a lymph node which must be a 
minimal size of 1.5 cm by short axis. Superficial lesions must measure at least 10 mm in long 
diameter and be measurable by calipers to qualify as target lesions. Maximum target lesions 
are 5 with a maximum of 2 lesions per organ representative of all involved organs. 
Non-target lesions:  Radiographically visible but do not meet size qualification of target 
lesions. Lymph nodes must measure at least 1.0 cm by short diameter to qualify as non-target 
lesions (if smaller considered non-pathologic). Excess target lesions ( > 5 overall or 2 per 
organ) are followed as non-target lesions. 
Baseline measurement of lesions 
At baseline, the sum of the long diameters of all target lesions (5 lesions total with maximum 
of 2 lesions per organ representative of all involved organs), is calculated. The sum is 
referred to as the sum of diameters (SOD) for the baseline timepoint. All other lesions should 
be identified as non-target lesions and be recorded at baseline. 
Postbaseline radiographic response assessment 
At each post baseline imaging timepoint, the long axis diameter of all target lesions are 
measured and recorded. A response of the target lesions is assessed by determination of the 
overall SOD of the lesions (SOD for that imaging timepoint). A response for each baseline 
non-target lesion is determined and recorded. The presence of any new lesions are recorded 
(of note a lymph node must measure at least 1.0 cm by short axis diameter to qualify as a 
pathologic lesion). 
Target lesion response 
Complete response (CR):  disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
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Partial response (PR):  At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters. 
Progressive disease (PD):  At least 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest prior sum of diameters in the trial (this includes the baseline 
sum if that is the smallest in the trial). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of least 5 mm. 
Stable disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while in the trial. 
Non-target lesion response assessment  
Complete response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD:  Persistence of 1 or more non–target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.  
Progressive disease (PD):  Unequivocal progression of existing non-target lesions. (Note:  the 
appearance of 1 or more new lesions is also considered progression). 
New lesion assessment 
At each post baseline imaging timepoint, an evaluation of the presence of new lesions 
(yes/no) is made. The lesions are recorded as new lesions and not target or non-target lesions. 
Lymph nodes must be a new lesion and measure at least 10 cm by short diameter to qualify 
as a new lesion overall response assessment. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion. 
Overall response assessment 
Overall response assessment is based on target lesion response, non-target lesion response 
and new lesions and is listed in Figure 1 below. 
Figure 1:  Overall Response Definitions Using RECIST 1.1 
Target Lesions  
Non-target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
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PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease. 
 
 
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ANNEX 1 
PLAN FOR PHARMACODYMAMIC ANALYSIS 
Biomarker, anti-SD101 antibodies and pharmacodynamic analysis report including the 
methods will be provided as part of the final clinical study report. 
 
 
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Dynavax Technologies Corporation 
STATISTICAL ANALYSIS PLAN 
Study Title: 
A Phase 1b/2, Open-label, Multicenter, Dose 
escalation and Expansion Trial of Intratumoral SD 
101 in Combination with Pembrolizumab in 
Patients with Metastatic Melanoma or Recurrent or 
Metastatic Head and Neck Squamous Cell 
Carcinoma 
Protocol Identifier: 
DV3-MEL-01 
Phase 
Phase 1b/2 
Investigational Product: 
SD-101 
Indication: 
Metastatic Melanoma 
Sponsor: 
 
Dynavax Technologies Corporation  
2100 Powell Street Suite 900 
Emeryville, CA 94608 
United States of America 
Reference Numbers: 
United States IND No. 125878 
 
 
 
 
 
 
Original Version: 
Version 1: 04 November 2019 
Based on Protocol Version: 
Amendment # 8: 08 February 2018 
 
 
 
 
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anoma
noma
echnologies Corpo
ogies Co
well Street Suite 90
Street Suit
yville, CA 94608
, CA 9460
ted States of Amer
States of
United States IND
ed State
Versio
Versio
Version:
ersion:
Am
Am
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FINAL STATISTICAL ANALYSIS PLAN APPROVAL  
 
Prepared by: 
____________________________ 
 
_________________ 
Fang Xie            
 Date 
Consulting Biostatistician 
Clinical Development  
Dynavax Technologies Corporation 
 
 
 
Reviewed by: 
____________________________ 
 
_________________ 
Fang Xie            
 Date 
For Head of Biometrics 
Clinical Development  
Dynavax Technologies Corporation 
 
 
Approved by: 
____________________________ 
 
_________________ 
 
Robert Janssen, MD 
 
 
 
Date 
 
Senior Vice President Clinical Development  
and Medical and Regulatory Affairs 
and Chief Medical Officer  
 
Dynavax Technologies Corporation 
 
 
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______________
________
rt Janssen
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, MD
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or Vice President
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Medical an R
Chief Medic
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND TERMS ..............................................................................5 
1.0 
INTRODUCTION..............................................................................................................7 
2.0 
STUDY OVERVIEW ........................................................................................................7 
2.1 
Phase 1 .....................................................................................................................9 
2.2 
Phase 2 .....................................................................................................................9 
3.0 
STUDY OBJECTIVES ....................................................................................................10 
3.1 
Phase 1 (Dose Escalation: Metastatic Melanoma) .................................................10 
3.1.1 
Primary Objectives ................................................................................10 
3.1.2 
Exploratory Objectives..........................................................................10 
3.2 
Phase 2 (Dose Expansion: Metastatic Melanoma or Recurrent or 
Metastatic Head and Neck Squamous Cell Carcinoma) ........................................10 
3.2.1 
Primary Objectives ................................................................................10 
3.2.2 
Secondary Objectives ............................................................................10 
3.2.3 
Exploratory Objectives..........................................................................10 
4.0 
ANALYSIS VARIABLES ...............................................................................................11 
5.0 
SAMPLE SIZE CONSIDERATIONS ...........................................................................12 
6.0 
ANALYSIS POPULATIONS .........................................................................................13 
6.1 
Enrolled Population ...............................................................................................13 
6.2 
Safety Population ...................................................................................................13 
6.3 
Efficacy Population ................................................................................................13 
6.4 
Pharmacodynamic Population ...............................................................................14 
7.0 
DEFINITIONS, COMPUTATIONS, AND CONVENTIONS ....................................14 
7.1 
Definitions and Computations ...............................................................................14 
7.2 
Conventions ...........................................................................................................15 
7.3 
Rules for Missing Data ..........................................................................................15 
8.0 
TIMING OF ANALYSES ...............................................................................................17 
9.0 
STATISTICAL METHODS ...........................................................................................17 
9.1 
Patient Disposition .................................................................................................17 
9.2 
Protocol Deviations ................................................................................................17 
9.3 
Demographics and Baseline Characteristics ..........................................................17 
9.4 
Prior and Concomitant Medications ......................................................................18 
9.5 
Medical History .....................................................................................................18 
9.6 
Efficacy Analyses ..................................................................................................18 
9.6.1 
Objective Response Rate.......................................................................19 
9.6.2 
Best Overall Response ..........................................................................19 
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9.6.3 
Disease Control Rate .............................................................................19 
9.6.4 
Time to Objective Response .................................................................19 
9.6.5 
Duration of Response ............................................................................19 
9.6.6 
Progression-Free Survival .....................................................................19 
9.7 
Safety Analyses ......................................................................................................19 
9.7.1 
Dose Limiting Toxicities.......................................................................20 
9.7.2 
Injection Related Reactions...................................................................21 
9.7.3 
Adverse Events......................................................................................21 
9.7.4 
Laboratory Assessments........................................................................22 
9.7.5 
Vital Signs .............................................................................................22 
9.7.6 
Physical Examinations ..........................................................................22 
9.7.7 
Electrocardiograms ...............................................................................22 
9.8 
Pharmacodynamic Analyses ..................................................................................22 
9.9 
Other Analyses .......................................................................................................22 
9.10 
Interim Analysis .....................................................................................................22 
9.11 
Reporting Output ...................................................................................................22 
10.0 
REVISION HISTORY ....................................................................................................23 
11.0 
REFERENCES .................................................................................................................23 
12.0 
LIST OF TABLES ...........................................................................................................24 
13.0 
LIST OF FIGURES .........................................................................................................25 
14.0 
LIST OF PATIENT DATA LISTINGS .........................................................................26 
APPENDIX 1 
RECIST V1.1 .......................................................................................27 
ANNEX 1 
PLAN FOR PHARMACODYMAMIC ANALYSIS ........................................30 
 
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RECIST V1.1
CIST V
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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation or Term 
Definition 
AE 
adverse event 
anti-PD-1/L1 
anti-programmed death receptor-1/ligand 1 
ATC 
anatomical therapeutic chemical 
BORR 
best objective response rate 
CR 
complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EOS 
End-of-Study (visit) 
IFN 
interferon 
ITT 
Intent-To-Treat 
HNSCC 
head and neck squamous cell carcinom 
irRECIST 
immune-related Response Evaluation Criteria In Solid Tumors 
MHC 
major histocompatibility complex 
NK 
natural killer 
ORR 
objective response rate 
PD 
progressive disease 
PD-1 
programmed death receptor-1 
PD-L1 
programmed death-ligand 1 
PFS 
progression free survival 
PR 
partial response 
PT 
preferred term 
Q3W 
every 3 weeks 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
recommended Phase 2 dose  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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Abbreviation or Term 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
 
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1.0 
INTRODUCTION 
This statistical analysis plan contains definitions of analysis populations and endpoints, 
outlines the timing of statistical analyses, and provides a comprehensive description of 
statistical analyses to be implemented to assess the safety, tolerability, biologic activity, and 
preliminary efficacy of SD-101 in combination with pembrolizumab as described in Protocol 
DV3-MEL-01 (Amendment 8: 08 February 2018): “A Phase 1b/2, Open-label, Multicenter, 
Dose escalation and Expansion Trial of Intratumoral SD-101 in Combination With 
Pembrolizumab in Patients With Metastatic Melanoma or Recurrent or Metastatic Head and 
Neck Squamous Cell Carcinoma (HNSCC)”. 
Due to strategic changes, only some of the objectives will be evaluated. Those objectives not 
evaluated will be italicized and annotated as “(not implemented)”, where applicable, 
throughout this SAP; statistical methods for these objectives are also not described. The main 
text of this SAP covers only assessment of the objectives by data contained in the clinical 
database. Pharmacodynamic assessment will be described in an annex to this SAP. 
Pharmacodynamic objectives will also be annotated.  
Groupings of patients to be used in the analyses are also changed from what were described 
in the protocol, based on the knowledge accumulated through the conduct of the trial.  
2.0 
STUDY OVERVIEW 
This open-label, multicenter, dose-ranging and expansion trial is designed to evaluate the 
safety and preliminary efficacy of intratumoral SD-101 in combination with pembrolizumab 
for the treatment of metastatic melanoma and HNSCC. The hypothesis to be tested in the 
clinical development of SD-101 is that SD-101, by virtue of its potency and its ability to 
induce high levels of interferons (IFNs), will have meaningful efficacy in generating anti-
tumor immune responses when combined with an anti-PD-1 antibody. IFNs have multiple 
effects on both tumor cells and tumor-infiltrating leukocytes. These IFNs can directly inhibit 
the proliferation of tumor cells and increase MHC class I expression, enhancing antigen 
recognition. Additionally, IFNs have potent effects on tumor-infiltrating leukocytes, 
including enhancing the antigen presenting function of dendritic cells, increasing the effect or 
function of T cells, and activating cytotoxic activity of NK cells. 
The rationale for treating metastatic melanoma and HNSCC with combination anti-PD-1/L1 
therapy plus SD-101 is based on the unmet need to improve upon single anti-PD-1/L1 
activity in these patient populations and nonclinical data (Protocol Sections 2.4 and 2.5) 
which suggest improved anti-tumor activity with the combination compared to anti-PD-1/L1 
alone. 
The study will be performed in 2 phases. The population to be studied in Phase 1 (Dose 
Escalation) will be patients with metastatic melanoma. The populations to be studied in 
Phase 2 (Dose Expansion) will be patients with metastatic melanoma and patients with 
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recurrent or metastatic HNSCC. In phase 1 of the study, doses of 1.0 mg, 2.0 mg, 4.0 mg, and 
8.0 mg of SD-101 each in a single lesion will be tested in a modified, staggered, 3 + 3 trial 
design, to identify an optimal dose of SD-101 given in combination with pembrolizumab to 
be used in Phase 2 (see Protocol section 9.1 for DLT definitions and stopping rules). This 
optimal dose from Phase 1 is referred to in the protocol as the recommended Phase 2 dose 
(RP2D) of SD-101. Phase 2 of the study is designed to evaluate the safety and efficacy of 
SD-101 plus pembrolizumab in both metastatic melanoma and HNSCC patients. Tumor 
response will be evaluated separately for injected and non-injected lesions as well as all 
combined lesions in order to assess both a local and systemic response to study treatment. 
The trial population includes a total of approximately 284 men and women with at least 1 site 
of disease that qualifies as a target lesion per RECIST v1.1 and is accessible for intratumoral 
injection. 
Phase 1 Dose Escalation Cohorts 1-4 will include up to 24 patients with metastatic melanoma 
who are anti-PD-1 naïve or experienced. 
Phase 2 Dose Expansion will include approximately 160 patients with metastatic melanoma 
and approximately 100 patients with recurrent or metastatic HNSCC: 
1) Expansion Cohort 1 of approximately 60 melanoma patients who are anti-PD-1/L1 naïve 
2) Expansion Cohort 2 of approximately 25 melanoma patients who have disease progression 
on anti-PD-1/L1 therapy 
3) Expansion Cohort 3 of approximately 25 HNSCC patients who are anti-PD-1/L1 naïve 
4) Expansion Cohort 4 of approximately 25 HNSCC patients who have disease progression 
on anti-PD-1/L1 therapy 
5) Expansion Cohort 5 of approximately 25 melanoma patients who are anti-PD-1/L1 naïve 
6) Expansion Cohort 6 of approximately 25 HNSCC patients who are anti-PD-1/L1 naïve 
7) Expansion Cohort 7 of approximately 25 HNSCC patients who are refractory or resistant 
to anti-PD-1/L1 therapy 
8) Expansion Cohort 8 of approximately 50 melanoma patients who are refractory or 
resistant to anti-PD-1/L1 therapy. 
Some of these study groups will be rearranged for final analysis as analysis groups based on 
tumor indications, anti-PD-1/L1 experience, and dose of SD-101. 
Phase 1 results will be presented for each of the 4 dose groups. 
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Results for Phase 2 objectives, using combined Phases 1 and 2 data, will be presented by 
2mg/lesion and 8mg/lesion doses for 
x MEL/NAIVE: metastatic melanoma patients who are anti-PD-1/L1 naïve, including 
x subjects in Phase 1 2mg and 8mg groups 
x subjects in Phase 2 Cohort 1 (both 2mg/lesion and 8mg single lesion) and Cohort 5 
(2mg/lesion) 
x MEL/EXP: metastatic melanoma patients who are anti-PD-1/L1 experienced, including 
x subjects in Phase 1 2mg and 8mg groups 
x subjects in Phase 2 Cohort 2 (both 2mg/lesion and 8mg/lesion) and Cohort 8 
(2mg/lesion) 
x HNSCC/NAIVE: HNSCC patients who are anti-PD-1/L1 naïve, including 
x subjects in Phase 2 Cohort 3 (both 2mg/lesion and 8mg/lesion) and Cohort 6 
(2mg/lesion) 
x HNSCC/EXP: HNSCC patients who are anti-PD-1/L1 experienced, including 
x subjects in Phase 2 Cohort 4 (both 2mg/lesion and 8mg/lesion) and Cohort 7 
(2mg/lesion) 
2.1 
Phase 1 
Patients in Escalation Cohorts 1-4 will be administered 1.0 mg, 2.0 mg, 4.0 mg, and 8.0 mg, 
respectively, of SD-101 in combination with 200 mg pembrolizumab Q3W per the Schedule 
of Trial Events (see Protocol Section 4.1.1 for dosing schema). 
2.2 
Phase 2 
Melanoma Dose Expansion cohorts in Phase 2 will be treated with 8.0 mg or 2.0 mg of SD-
101 from Phase 1 in combination with 200 mg pembrolizumab Q3W (see Protocol Section 
4.1.2 for dosing schema). 
HNSCC Dose Expansion cohorts in Phase 2 will be treated with the selected RP2D (8.0 mg 
or 2.0 mg of SD-101) from Phase 1 in combination with 200 mg pembrolizumab Q3W (see 
Protocol Section 4.1.2 for dosing schema). 
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3.0 
STUDY OBJECTIVES 
3.1 
Phase 1 (Dose Escalation: Metastatic Melanoma) 
3.1.1 
Primary Objectives 
x To assess the safety and tolerability of escalating intratumoral doses of SD-101 in 
combination with intravenous pembrolizumab in patients with metastatic melanoma 
x To evaluate the expression of IFN-inducible genes in whole blood 24 hours after 
intratumoral injection of SD-101 given with pembrolizumab in patients with metastatic 
melanoma as a pharmacodynamic marker of SD-101 activity (pharmacodynamic)  
x To determine a RP2D of SD-101 in combination with pembrolizumab to be evaluated in 
Phase 2 
3.1.2 
Exploratory Objectives  
x To assess the preliminary response both locally and systemically including:  
x Treatment response of the injected Lesion A (local response) (not implemented) 
x Treatment response of the non-injected lesion(s) (systemic response) (not 
implemented) 
x Treatment response of all lesions  
x Time to response (not implemented) 
x To assess changes in tumor biomarkers (pharmacodynamic) 
3.2 
Phase 2 (Dose Expansion: Metastatic Melanoma or Recurrent or Metastatic 
Head and Neck Squamous Cell Carcinoma) 
3.2.1 
Primary Objectives  
x To assess the tumor response both locally and systemically including:  
x Treatment response of the injected lesion(s) (local response)  
x Treatment response of the non-injected lesion(s) (systemic response)  
x Treatment response of all lesions  
3.2.2 
Secondary Objectives  
x To assess the safety and tolerability of SD-101 in combination with pembrolizumab  
x To assess the time frame of tumor responses:  
x Time to response  
x Duration of response 
x To assess PFS  
3.2.3 
Exploratory Objectives 
x To assess changes in tumor biomarkers 
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x To identify and assess changes in potential tumor neoantigens in patients with recurrent 
or metastatic HNSCC (pharmacodynamic) 
x To evaluate the expression of IFN inducible genes in whole blood 24 hours after 
intratumoral injection of SD-101 given with pembrolizumab in patients with recurrent or 
metastatic HNSCC as a pharmacodynamic marker of SD-101 activity (pharmacodynamic) 
4.0 
ANALYSIS VARIABLES 
Phase 1 – Dose Escalation  
Primary Endpoints  
x Incidence of DLTs  
x Incidence of injection-site reactions, AEs, and SAEs  
x Changes in the expression of IFN-inducible genes in whole blood (pharmacodynamic) 
Exploratory Endpoints  
x ORR per RECIST v1.1  
x Changes in tumor-infiltrating lymphocytes, PD-L1 expression, and other gene expression 
in tumor biopsies (pharmacodynamic) 
Phase 2 – Dose Expansion  
The primary radiographic endpoints of the study will be based on RECIST v1.1 and 
exploratory radiographic endpoints will be based on irRECIST (not implemented). All 
imaging endpoints for the overall response assessment will be based on investigator 
evaluation. A central imaging laboratory for study image collection and radiographic 
endpoint determination will be used per sponsor decision.  
Primary Endpoints  
x ORR per RECIST v1.1  
Secondary Endpoints  
x Incidence of injection-site reactions, AEs, and SAEs  
x Time to response using RECIST v1.1  
x Duration of response per RECIST v1.1 
x PFS per RECIST v1.1  
Exploratory Endpoints  
x Changes in correlative biomarkers including tumor-infiltrating lymphocytes and PD-L1 
expression at baseline and after SD-101 treatment (pharmacodynamic)  
x Changes in potential tumor neoantigens in patients with recurrent or metastatic HNSCC 
(pharmacodynamic) 
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x Changes in the expression of IFN-inducible genes in whole blood in patients with 
metastatic HNSCC (pharmacodynamic) 
5.0 
SAMPLE SIZE CONSIDERATIONS 
The Phase 1 trial is designed to allow preliminary assessments of safety, biological activity, 
and biomarkers in approximately 24 patients. Phase 2 of this trial is designed to allow 
preliminary assessments of efficacy, safety, and changes in biomarkers in approximately 210 
patients. All analyses will be descriptive. 
The Phase 1 trial sample size is based on a modified 3 + 3 dose-escalation trial design. 
For the Phase 2 expansion cohorts, the sample sizes were determined based on power 
analysis of hypothesis tests and/or confidence intervals, although the efficacy analyses will 
be descriptive. 
In Expansion Cohort 1, approximately 60 anti-PD-1/L1 naïve patients with metastatic 
melanoma will be enrolled. The null hypothesis that the response rate is < 35% will be tested 
against a 1-sided alternative at a significance level of 0.05. The design will provide greater 
than 90% power if the true response rate is > 55%. There will be no adjustments for 
multiplicity. 
An exploratory sub-group analysis will be performed for those Expansion Cohort 1 subjects 
with PD-L1 negative tumors (ie, < 1% positivity) at baseline. It was estimated that this 
subgroup will have approximately 30 subjects. The analysis will have 80% power to reject 
the null hypothesis that the response rate is <15% with a one-sided test at a significance level 
of 0.05 when the true response rate is 35%. There will be no adjustments for multiplicity. 
In Expansion Cohort 5, approximately 25 anti-PD-1/L1 naïve melanoma patients will be 
enrolled. This will allow preliminary estimate of the response rate associated with the dose 
and dosing schedule chosen for Expansion Cohort 5. If 14 or more responses are observed, 
the 95% exact confidence interval will yield a lower bound of no less than 37%. 
In Expansion Cohort 2, approximately 25 metastatic melanoma patients who have disease 
progression on anti-PD-1/L1 therapy will be enrolled. The null hypothesis that the true 
response rate is 10% will be tested against a 1-sided alternative and will be rejected if 6 or 
more responses are observed. This design yields a type I error rate of 0.05 and 80% power 
when the true response rate is 30%. There will be no adjustments for multiplicity. 
In Expansion Cohort 8, approximately 50 metastatic melanoma patients who are refractory or 
resistant to anti-PD-1/L1 therapy will be enrolled. If 13 or more responses are observed, the 
95% exact confidence interval will yield a lower bound of no less than 15.0%. 
In Expansion Cohort 3, approximately 25 anti-PD-1/L1 naïve HNSCC patients will be 
enrolled. The null hypothesis that the response rate is < 20% will be tested against a 1-sided 
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alternative at a significance level of 0.05. The design will provide greater than 80% power if 
the true response rate is > 40%. There will be no adjustments for multiplicity. 
In Expansion Cohort 6, approximately 25 anti-PD-1/L1 naïve HNSCC patients will be 
enrolled. This will allow a preliminary estimate of the response rate associated with the dose 
and dosing schedule chosen for Expansion Cohort 6. If 9 or more responses are observed, the 
95% exact confidence interval will yield a lower bound of no less than 20%. 
In Expansion Cohort 4, approximately 25 HNSCC patients who have disease progression on 
anti-PD-1/L1 therapy will be enrolled. The null hypothesis that the true response rate is 5% 
will be tested against a 1-sided alternative and will be rejected if 4 or more responses are 
observed. This design yields a type I error rate of 0.05 and 80% power when the true 
response rate is 21%. There will be no adjustments for multiplicity. 
In Expansion Cohort 7, approximately 25 HNSCC patients who are refractory or resistant to 
anti-PD-1/L1 therapy will be enrolled. This will allow a preliminary estimate of the response 
rate associated with the dose and dosing schedule chosen for Expansion Cohort 7. If 4 or 
more responses are observed, the 95% exact confidence interval will yield a lower bound of 
no less than 5%. 
Although changes to the groupings for the final analysis will be made, there is no impact to 
the sample size calculation, as all analyses will be descriptive. At some places in above 
sample size calculation one-sided significance level of 0.05 was referenced, to standardize 
the analyses, two-sided significance level of 0.05 is used throughout. Power and 95% exact 
confidence interval descriptions are still applicable if the underlying conditions in various 
analysis groups hold. 
6.0 
ANALYSIS POPULATIONS 
6.1 
Enrolled Population 
The enrolled population is defined as all patients who enrolled in the study.  
6.2 
Safety Population 
The safety population will include all enrolled patients who receive at least 1 dose of SD-101 
(Protocol section 12.4). The primary analysis population for the study will include the safety 
population with separate analyses for Phase 1 Dose Escalation and each Phase 2 Dose 
Expansion analysis group. 
6.3 
Efficacy Population 
The evaluable population will comprise all patients who receive at least 1 dose of both 
pembrolizumab and SD-101 and who have baseline and at least 1 post-baseline imaging 
assessment. The ITT population will include all enrolled subjects regardless of having a post-
baseline radiographic assessment. Additional subpopulations for an exploratory and 
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retrospective analysis may include baseline PD-L1 status (positive or negative [ie, < 1% 
positivity]) and specific prior anti-PD-1/PD-L1 therapy (Protocol section 12.4).  
Prior anti-PD-1/PD-L1 therapy subpopulations are reflected in the study groups. Analyses 
will be performed according to the dose groups in Phase 1 and study groups in Phase 2 for 
evaluable and ITT population. 
6.4 
Pharmacodynamic Population 
The pharmacodynamic population will include all enrolled patients who receive at least 1 
dose of SD-101 and who have screening and at least 1 post-baseline assessment of INF-alpha 
inducible gene expression. 
7.0 
DEFINITIONS, COMPUTATIONS, AND CONVENTIONS 
7.1 
Definitions and Computations 
Study Day 
Study day will be calculated in reference to the date of first dose (Day 1). For assessments 
conducted on or after the first dose date, study day is calculated as (assessment date – first 
dose date + 1). For assessments conducted before the first dose date, study day is calculated 
as (assessment date – first dose date). There will be no Day 0.  
Date of First Dose and Date of Last Dose of Study Drug 
The date of the first dose of study drug is defined as the date a patient receives the first dose 
of the study drug. The date of the last dose of study drug is the date a patient receives the last 
dose of the study drug. 
Treatment-Emergent Period 
Treatment-emergent periods are updated from what were described in the protocol (sections 
10.3.9 and 10.3.10) to cover the maximum possible reporting periods. 
Treatment-emergent period for AEs is defined the date and time of the first dose of study 
drug administration through 90 days after last dose of study drug administration. 
Treatment-emergent period for SAEs is defined as the date and time of the first dose of study 
drug administration through EOS. 
Baseline Value and Post-baseline Value 
Unless otherwise specified, the baseline value is defined as the last measurement before the 
first dose (date and time) of study drug. Post-baseline value is defined as a measurement 
taken after the first dose of study drug. Change from baseline is defined as (post-baseline 
value – baseline value). Both date and time of study drug administration and measurement 
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will be considered when calculating baseline value. If time is not available, then date only 
will be used.  
7.2 
Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses: 
x 1 year = 365.25 days. Year is calculated as (days/365.25) rounded up to 1 significant 
digit. 
x 1 month = 30.4375 days. Month is calculated as (days/30.4375) rounded up to 
1 significant digit. 
x Age will be calculated by the following SAS code: age = floor(yrdif(birth_date, 
consent_date, 'AGE')) 
x 1 pound = 0.454 kg 
x 1 inch = 2.54 cm 
x Missing safety data will not be imputed unless otherwise specified. 
x For laboratory results collected as < or > a numeric value, 0.0000000001 will be 
subtracted or added, respectively, to the value. 
x For safety analyses, percentages will be calculated based on the number of patients in the 
analysis population. 
x For by-visit observed data analyses, percentages will be calculated based on the number 
of patients with nonmissing data as the denominator unless otherwise specified. 
x For other continuous endpoints, the summary statistics will include mean, standard 
deviation, median, and range (minimum and maximum). 
x For categorical endpoints, the summary statistics will include counts and percentages. 
x AEs and medical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 17 or higher. 
x Prior therapies and concomitant medications will be coded using the World Health 
Organization (WHO) Drug Dictionary version 201506. 
7.3 
Rules for Missing Data 
Missing data will not be imputed, except for missing date information for AEs and 
concomitant medications. The imputed dates will be used to determine the treatment-
emergent period. For AEs with a partial date, available date parts (year, month, and day) of 
the partial date will be compared with the corresponding date components of the start date 
and end date of the treatment-emergent period to determine if the event is treatment 
emergent. When in doubt, the AE will be considered treatment emergent by default. 
The following rules will be applied to impute partial dates for AEs: 
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x If start date of an AE is completely or partially missing, impute as follows: 
x If both month and day are missing and year = year of first dose date, then set to first 
dose date. 
x If both month and day are missing and year ≠ year of first dose date, then set to 
January 1. 
x If day is missing and month and year = month and year of first dose date, then set to 
first dose date. 
x If day is missing and month and year ≠ month and year of first dose date, then set to 
first of the month. 
x If start date is completely missing and AE end date is on or after the first dose date, 
set to first dose date.  
x If start date is completely missing and AE end date is prior to the first dose date, do 
not impute an AE start date. 
x If end date of an AE is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31. 
x If only day is missing, then set to last day of the month. 
x If end date is completely missing, do not impute. 
When the start date or end date of a medication is partially missing, the date will be imputed 
to determine whether the medication is prior or concomitant (or both). The following rules 
will be applied to impute partial dates for medications: 
x If start date of a medication is partially missing, impute as follows: 
x If both month and day are missing, then set to January 1. 
x If only day is missing, then set to the first of the month. 
x If end date of a medication is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31. 
x If only day is missing, then set to last day of the month. 
x If start date or end date of a medication is completely missing, do not impute. 
Listings will show the original date information without imputation, but derived parameters 
(TEAE indicator and duration of AE) will be flagged to indicate the type of imputation 
performed. 
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8.0 
TIMING OF ANALYSES 
Final analyses will be carried out after the last participant has completed their last trial visit, 
the trial database has been authorized by Dynavax as complete and final, and major protocol 
deviations have been identified. No interim analysis is planned for this study. 
9.0 
STATISTICAL METHODS 
This trial is designed to allow preliminary assessments of safety, biological activity, and 
biomarkers. No pre-specified hypothesis testing will be performed. All analyses of 
demographics, safety, biological activity, and biomarkers will be descriptive.  
Efficacy and safety data will be analyzed and reported separately by Phase 1 dose group or 
Phase 2 analysis group.  
Descriptive statistics, including the number of patients (n), mean, standard deviation (SD), 
median, minimum, and maximum, will be used to summarize continuous variables. 
Categorical variables will be summarized by number (n) and percentage (or proportions) of 
patients in each category. All data processing, summarization, and analyses will be 
performed using SAS Version 9.3 or higher. Specifications for tables, graphs, and data 
listings will be provided in the tables, figures, listings (TFL) specifications document.  
9.1 
Patient Disposition 
Patient disposition will be summarized for all enrolled patients by dose or analysis group 
including patients in the safety, evaluable and ITT populations and patients discontinuing the 
study along with the reasons for discontinuation (as documented on the case report form 
study exit status).  
A listing of patients discontinuing the study after enrollment will be produced.  
9.2 
Protocol Deviations 
Patient data will be reviewed for major protocol deviations by the Medical Monitor prior to 
database lock. A listing of patients with major protocol deviations will be provided, sorted by 
treatment and describing their deviations. Any exclusions from analysis populations due to 
protocol deviations will be highlighted. 
9.3 
Demographics and Baseline Characteristics 
Summary statistics for age, weight, height, body mass index at baseline, sex, race, and 
ethnicity will be presented by dose or analysis group for the safety, evaluable and ITT 
populations.  
Listings will be provided for these parameters for all patients.  
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9.4 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Dictionary (version 201506). Prior medications are drugs and therapies used 
before the first dose date. Medications or therapies are considered concomitant if exposure 
occurs after the first dose date. The number and percentage of patients with concomitant 
medications will be presented alphabetically by anatomical therapeutic chemical (ATC) class 
and by decreasing order of frequency of preferred terms within each ATC class for the safety 
population. Patients taking the same medication multiple times will be counted once per 
medication.  
All medications recorded on the case report form will be listed. 
9.5 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA V17.0 or higher).  All medical history data will be provided in a listing.  
9.6 
Efficacy Analyses 
Response of lesions and disease status will be assessed using standard RECIST v1.1 for the 
primary evaluation of response and a study specific modified RECIST v1.1 referred to as 
immune related-RECIST v1.1 (irRECIST v1.1) for an exploratory evaluation (not 
implemented). Therefore, RECIST v1.1 will be used with the following adaptations 
(Appendix 1): 
x Determination of progressive disease (PD) requires a confirmation of PD by imaging ≥ 4 
weeks later. In order to confirm PD, both the initial lesion assessment and lesion 
assessment on the confirmatory scan must meet PD criteria (≥ 20% increase in sum of 
diameters). 
x Continued treatment while awaiting radiologic confirmation of progression is encouraged 
if the patient is stable. 
Patients that are deemed clinically unstable are not required to have repeat imaging for the 
confirmation of PD. 
Objective response rate (ORR) and disease control rate (DCR) will be evaluated for injected 
and non-injected lesions as well as for all target lesions. The ORR will include patients with 
complete response (CR) or partial response (PR). The DCR will include patients with CR, 
PR, or stable disease.  The ORR and DCR will be determined by Investigator using RECIST 
v1.1.  
Unless otherwise specified, all efficacy analyses will be performed by: 
x Lesion type – injected, non-injected lesions, all target lesions 
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x Evaluation criteria – RECIST v1.1 
x Study Phase – Phase 1 by dose groups, Phase 2 by analysis groups 
9.6.1 
Objective Response Rate  
The ORR is the proportion of patients who achieve a response of either CR or PR. ORR will 
be summarized and 95% Clopper Pearson confidence interval will be reported for each dose 
or analysis group. 
9.6.2 
Best Overall Response  
The best overall response rate (BORR) is the proportion of patients who achieve a best 
response recorded at any post-baseline assessment. BORR will be summarized and 95% 
Clopper Pearson confidence interval will be reported for each dose or analysis group. 
9.6.3 
Disease Control Rate  
The disease control rate (DCR) is the proportion of patient who had CR, PR, or stable 
disease.  DCR will be summarized and 95% Clopper Pearson confidence interval will be 
reported for each dose or analysis group. 
9.6.4 
Time to Objective Response 
The time to response (TOR) will be defined as the time from the first dose of SD-101 until 
the onset of CR or PR. TOR will be summarized descriptively for patients who achieved CR 
or PR. 
9.6.5 
Duration of Response 
The duration of response is defined as the period of time from the date of initial confirmed 
PR or CR until the date of PD or death, whichever is earlier. For those patients who achieved 
response, duration of response will be summarized descriptively. Kaplan-Meier estimate of 
median duration and 95% confidence interval will be provided. 
9.6.6 
Progression-Free Survival 
The progressive-free survival (PFS) is defined as the period of time from baseline to 
confirmed PD or death. Administration of palliative radiation therapy will be considered 
clinical progression for the purposes of determining PFS. The proportion of patients who had 
PFS at the end of the study will be summarized and PFS will be analyzed by Kaplan-Meier 
method; 95% confidence interval for the median will be provided. Overall survival (OS) is 
defined as the period of time from baseline to death, and analysis of OS will also be provided 
similarly as PFS. 
9.7 
Safety Analyses 
Injection related reactions, AEs, SAEs, and abnormal laboratory values will be summarized 
by the proportion of patients who experience them.  
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All patients in the safety population will be used in the safety analyses. Safety analyses will 
be summarized by dose or analysis group. 
The treatment-emergent period is defined in Section 7.1.  
9.7.1 
Dose Limiting Toxicities 
For Dose Escalation purposes, a DLT will be defined as any of the following AEs occurring 
from the time of the first injection (Day 1) through Study Day 29 of any of the following:  
Non-hematologic adverse event 
• Grade ≥ 3 non-hematologic AE related to SD-101 (eg, post-injection reaction or influenza-
like illness) that does not resolve to Grade ≤ 1 with standard treatment by the time of the next 
treatment, with the exclusion of fatigue 
• Grade 3 non-hematologic AE (not laboratory, specifically nausea, vomiting, and diarrhea) 
lasting > 3 days despite optimal supportive care, with the following exceptions: 
• Grade 3 fatigue will NOT be classified as a DLT, regardless of duration. 
• A Grade 3 non-hematologic laboratory AE will only be considered a DLT if it is 
clinically significant, such as: 
• Medical intervention is required to treat the patient 
• The abnormality leads to hospitalization 
• The abnormality persists for > 1 week 
• Grade 4 or 5 non-hematologic AE (not laboratory) 
Hematologic toxicity 
• Grade 4 or 5 hematologic AE 
• Any Grade 3 hematologic laboratory AE, with the exception of lymphopenia, which lasts > 
7 days 
• Febrile neutropenia Grade 3 or Grade 4: 
• Grade 3 is defined as ANC < 1000/mL with a single temperature of > 38.3°C 
(101°F) or a sustained temperature of ≥ 38°C (100.4°F) for more than 1 hour. 
• Grade 4 is defined as ANC < 1000/mL with a single temperature of > 38.3°C 
(101°F) or a sustained temperature of ≥ 38°C (100.4°F) for more than 1 hour, with 
life-threatening consequences and urgent intervention indicated. 
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Prolonged delay (> 3 weeks) of SD-101 or pembrolizumab dosing due to treatment-related 
toxicity qualifies as a DLT. 
Incidence of DLTs will be tabulated by dose groups in Phase 1, and bar chart of incidence 
rates of DLTs by dose groups will be generated, if DLTs were observed. 
9.7.2 
Injection Related Reactions 
Incidence of injection-site reactions from the diary card will be tabulated by maximum 
severity and injection and by analysis group. 
Injection related general body symptoms, defined as those symptoms, as determined by the 
Medical Monitor, with onset with 7 days of and related to the study injection, will be 
tabulated by maximum severity and injection and by analysis group. 
9.7.3 
Adverse Events 
All AEs will be coded to preferred term and system organ class using MedDRA 17.0 or 
higher. An AE that started or increased in severity during the treatment-emergent period 
(refer to Section 7.1) will be considered a TEAEs. Severity of TEAEs will be graded 
according to the National Cancer Institute Cancer Therapy and Evaluation Program Common 
Terminology Criteria for Adverse Events (CTCAE). A study drug-related TEAE is defined 
as any TEAE with at least a possible relationship to the study drug as assessed by the 
investigator or that is missing the assessment of causal relationship whose relationship to the 
study drug could not be ruled out.  
Patients with multiple occurrences of events for a given preferred term, system organ class, 
or overall will only be counted once at the worst severity and strongest relationship to study 
drug for each preferred term, system organ class, and overall, respectively. AEs that are 
continuous but change in grade, relationship, or seriousness will be counted as 1 event. 
TEAEs of unknown severity will be categorized separately. A TEAE of unknown 
relationship will be considered to be probably related to study drug.  
Tabular summaries including numbers and percentages of the following adverse events will 
be provided: 
x 
Overview of TEAEs;  
x 
TEAEs by SOC and PT; 
x 
TEAEs by SOC, PT, and severity; 
x 
TEAEs by SOC, PT, and relationship to study drug; 
x 
TEAEs leading to study drug discontinuation; 
x 
Serious TEAEs by SOC, PT, and severity; 
x 
Serious TEAEs by SOC, PT, and relationship to study drug; 
x 
Immune Related TEAEs by SOC and PT; 
x 
TEAEs leading to death by SOC and PT. 
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Listings will be provided for all TEAEs.  
9.7.4 
Laboratory Assessments 
Laboratory test results for neutrophils, lymphocytes, and platelets and their change from 
baseline will be summarized by tumor type and scheduled visit. 
Laboratory data listings will not be produced as clinically significant abnormal laboratory 
findings are included in AE data. 
Anti-dsDNA antibodies (not implemented) and anti-SD-101 antibodies results will be 
provided as part of the Annex 1 analysis. 
9.7.5 
Vital Signs 
Vital sign data will be provided in a data listing.  
9.7.6 
Physical Examinations 
Individual physical examination data with abnormal findings flagged will be provided in data 
lists. 
9.7.7 
Electrocardiograms 
ECG data with abnormal findings flagged will be provided in a data listing.  
9.8 
Pharmacodynamic Analyses 
Plan for pharmacodynamic analyses is included in Annex 1 of this SAP. 
9.9 
Other Analyses 
No other analyses are planned.  
9.10 
Interim Analysis 
No interim analysis is planned for this protocol. Safety will be monitored on a regular basis.   
9.11 
Reporting Output 
All outputs will be produced using SAS® version 9.3 or later. The REPORT procedure will 
be used to produce all tables and listings whenever possible. The SGPLOT procedure will be 
used to produce all figures whenever possible. All statistical appendices (supportive SAS 
output) will be output directly from the appropriate SAS procedure. 
Post-text tables, listings, and statistical appendices will be produced as RTF files using 
output delivery system (ODS) and Times New Roman or a similar font size 8 or larger. Data 
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will be presented in RTF tables with data in individual cells. Figures will be produced as 
RTF files using ODS and simplex font. For all outputs, the page numbering will be applied to 
ensure that when the RTF files are combined, the page numbering remains fixed. 
All tables, listings and statistical appendices will be produced to landscape orientation and 
will be incorporated into a Word 2010 or later document (margins: top 1.5”, left, right and 
bottom 1”) using 8pt font or larger. 
Dose and analysis groups for tables and figures will be as follows: 
x 
for Phase 1: Dose Escalation Phase objectives 
x 
1 mg, 2 mg, 4 mg, 8 mg 
x 
for Phase 2: Expansion Phase objectives 
x 
MEL/Naive (metastatic melanoma patients anti-PD-1/L1 therapy naïve) 
x 
2mg, 8mg 
x 
MEL/Experienced (metastatic melanoma patients progressed on anti-PD-1/L1 
therapy) 
x 
2mg, 8mg 
x 
HNSCC/Naive (HNSCC patients anti-PD-1/L1 therapy naïve) 
x 
2mg, 8mg 
x 
HNSCC/Experienced (HNSCC patients progressed on anti-PD-1/L1 therapy) 
x 
2mg, 8mg 
10.0 
REVISION HISTORY 
Version Date 
Author 
Comments/Rationale for Revision 
1.0 
04NOV2019 
Fang Xie 
New Document 
 
11.0 
REFERENCES 
 
 
 
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ents anti-P
tic melanoma patie
elanoma p
NSCC patients ant
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(HN
, 8mg
HISTORY
ISTORY
Autho
A
$
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12.0 
LIST OF TABLES  
List of tables will be provided in a separate Table of Contents of Tables, Figures and Listings 
document. 
 
 
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13.0 
LIST OF FIGURES 
List of figures will be provided in a separate Table of Contents of Tables, Figures and 
Listings document. 
 
 
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14.0 
LIST OF PATIENT DATA LISTINGS 
List of listings will be provided in a separate Table of Contents of Tables, Figures and 
Listings document. 
 
 
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APPENDIX 1 
RECIST V1.1 
Response Definition 
Assessments will use RECIST 1.1 guidelines, which are included in the Study Reference 
Manual, and study specific modification of the RECIST 1.1 guidelines referred to as immune 
related RECIST 1.1 (irRECIST 1.1). 
RECIST 1.1  
Baseline selection of lesions 
All lesions are measured by long axis and short axis (perpendicular to the long axis). At 
baseline, all tumor lesions are identified as either target lesions or non-target lesions and will 
be evaluated at baseline and every post baseline imaging timepoint. 
Target lesions:  Minimal size of 1.0 cm by long axis unless a lymph node which must be a 
minimal size of 1.5 cm by short axis. Superficial lesions must measure at least 10 mm in long 
diameter and be measurable by calipers to qualify as target lesions. Maximum target lesions 
are 5 with a maximum of 2 lesions per organ representative of all involved organs. 
Non-target lesions:  Radiographically visible but do not meet size qualification of target 
lesions. Lymph nodes must measure at least 1.0 cm by short diameter to qualify as non-target 
lesions (if smaller considered non-pathologic). Excess target lesions ( > 5 overall or 2 per 
organ) are followed as non-target lesions. 
Baseline measurement of lesions 
At baseline, the sum of the long diameters of all target lesions (5 lesions total with maximum 
of 2 lesions per organ representative of all involved organs), is calculated. The sum is 
referred to as the sum of diameters (SOD) for the baseline timepoint. All other lesions should 
be identified as non-target lesions and be recorded at baseline. 
Postbaseline radiographic response assessment 
At each post baseline imaging timepoint, the long axis diameter of all target lesions are 
measured and recorded. A response of the target lesions is assessed by determination of the 
overall SOD of the lesions (SOD for that imaging timepoint). A response for each baseline 
non-target lesion is determined and recorded. The presence of any new lesions are recorded 
(of note a lymph node must measure at least 1.0 cm by short axis diameter to qualify as a 
pathologic lesion). 
Target lesion response 
Complete response (CR):  disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
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Partial response (PR):  At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters. 
Progressive disease (PD):  At least 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest prior sum of diameters in the trial (this includes the baseline 
sum if that is the smallest in the trial). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of least 5 mm. 
Stable disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while in the trial. 
Non-target lesion response assessment  
Complete response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD:  Persistence of 1 or more non–target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.  
Progressive disease (PD):  Unequivocal progression of existing non-target lesions. (Note:  the 
appearance of 1 or more new lesions is also considered progression). 
New lesion assessment 
At each post baseline imaging timepoint, an evaluation of the presence of new lesions 
(yes/no) is made. The lesions are recorded as new lesions and not target or non-target lesions. 
Lymph nodes must be a new lesion and measure at least 10 cm by short diameter to qualify 
as a new lesion overall response assessment. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion. 
Overall response assessment 
Overall response assessment is based on target lesion response, non-target lesion response 
and new lesions and is listed in Figure 1 below. 
Figure 1:  Overall Response Definitions Using RECIST 1.1 
Target Lesions  
Non-target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
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PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease. 
 
 
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ANNEX 1 
PLAN FOR PHARMACODYMAMIC ANALYSIS 
Biomarker, anti-SD101 antibodies and pharmacodynamic analysis report including the 
methods will be provided as part of the final clinical study report. 
 
 
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