Clinical trial NCT03937141
Conditions: Metastatic Head and Neck Cancer Recurrent Head and Neck Cancer
Sponsor: Chinook Therapeutics, Inc. (formerly Aduro)
Start date: 2019-08-26; Completion date: 2021-06-10
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
ADU-CL-20 is an open-label, multicenter Phase 2 clinical trial to evaluate the efficacy and safety of intratumoral ADU-S100 (also referred to as MIW815) administered with pembrolizumab in the first-line setting. The population will consist of adults with PD-L1 positive recurrent or metastatic HNSCC.

Detailed description:

Arms: arm 1: All eligible subjects will receive intravenous (IV) infusions of pembrolizumab and intratumoral injections of ADU-S100.
Interventions: intervention 1: ADU-S100
Intervention descriptions: intervention 1: intratumoral

Protocol documents:
Prot_000.pdf: 
CLINICAL TRIAL PROTOCOL 
A Phase 2 Efficacy and Safety Trial of ADU-S100 and Pembrolizumab 
in Adults with Head and Neck Cancer 
Protocol Number: 
ADU-CL-20 
Amendment 4 Date: 
19 January 2021 
Investigational Product: 
ADU-S100 (MIW815; a synthetic cyclic dinucleotide 
agonist of human stimulator of interferon genes 
[STING]) 
IND Number: 
122605 
Trial Registration: 
NCT03937141 
Sponsor: 
Chinook Therapeutics, Inc. (f/k/a Aduro Biotech, Inc.) 
740 Heinz Avenue 
Berkeley, CA 94710 USA 
Telephone: +1 510-848-4400 
Medical Monitor: 
Michael Kurman, MD  
Precision for Medicine, Oncology and Rare Disease  
Telephone: +1 201-236-9730 
Email: Michael.kurman@precisionformedicine.com 
ADUCL202@precisionformedicine.com   
Confidentiality Statement 
The information in this document is the confidential information of Chinook Therapeutics, Inc. (Aduro 
Biotech, Inc.) Disclosure of this document is subject to an agreement between you or your institution and 
Chinook Therapeutics, Inc. When using this document: 
- Limit disclosure to the Institutional Review Board or Independent Ethics Committee and study 
personnel directly involved with conducting this protocol. 
- Inform the recipient of the confidential nature of this document and limit its use to the conduct of 
the study. 
- Direct any questions to Chinook Therapeutics, Inc. 


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DOCUMENT HISTORY 
Protocol Version 
Date 
Original Protocol 
08 January 2019 
Amendment 1 
14 April 2019 
Amendment 2 
27 November 2019 
Amendment 3 
07 April 2020 
Amendment 4 
19 January 2021 


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2 
SYNOPSIS 
TITLE: A Phase 2 Efficacy and Safety Trial of ADU-S100 and Pembrolizumab in Adults with 
Head and Neck Cancer 
PROTOCOL NUMBER: ADU-CL-20 
INVESTIGATIONAL PRODUCT: ADU-S100 (MIW815; a synthetic cyclic dinucleotide 
agonist of human stimulator of interferon genes [STING]) 
PHASE: 2 
INVESTIGATIONAL SITES: Multicenter clinical trial conducted at approximately 25 sites in 
North America 
INDICATION: Treatment of adults with recurrent or metastatic head and neck squamous cell 
cancer (HNSCC) 
NUMBER OF SUBJECTS: Up to 20 subjects 
OBJECTIVES AND ENDPOINTS: 
OBJECTIVES 
ENDPOINTS 
Primary 
• Evaluate the clinical efficacy of ADU-
S100 administered in combination with 
pembrolizumab    
• Objective response rate (ORR; complete response [CR] and 
partial response [PR]) per Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1 
Secondary 
• Characterize safety and tolerability  
• Occurrence and severity of treatment-emergent adverse events 
• Changes from baseline in safety assessments 
• Further evaluate clinical activity 
 
 
 
 
[removed by amendment] 
• Overall survival  
• ORR per modified RECIST v1.1 for immune-based 
therapeutics (iRECIST) 
• Progression-free survival, duration of response, disease 
control, and duration of disease control per RECIST v1.1 and 
iRECIST 
• Characterize the pharmacokinetics (PK) of 
ADU-S100 administered by intratumoral 
injection following a single dose and 
multiple doses 
• Plasma concentration-time profiles and if feasible, derived 
noncompartmental PK parameters (including Cmax, AUC) 
Exploratory [removed by amendment] 
• Assess pharmacodynamic, 
immunomodulatory, and potential 
prognostic and/or predictive biomarkers 
• Pharmacogenetic analysis  
• Changes from baseline in selected protein, cellular, and 
genomic expression parameters from blood and tissue 
samples; prognostic and/or predictive value 
• Exploration of individual subject DNA sequence variations 
(e.g. single nucleotide polymorphisms [SNPs]) and 
relationship with safety, tolerability, and clinical benefit 


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DESIGN: 
ADU-CL-20 is an open-label, multicenter Phase 2 clinical trial to evaluate the efficacy and safety 
of intratumoral ADU-S100 (also referred to as MIW815) administered with standard of care 
treatment (i.e. pembrolizumab) in the first-line setting. The population will consist of adults with 
PD-L1 positive recurrent or metastatic HNSCC. Up to twenty (20) evaluable subjects will be 
enrolled.   
The trial design consists of a Screening Period, Treatment Period, and an End of Treatment 
(EOT) Visit as depicted in the diagram below. All eligible subjects will receive intravenous (IV) 
infusions of pembrolizumab (200 mg; per approved product labeling) and intratumoral injections 
of ADU-S100 (800 mcg/lesion; up to 2 lesions). During the Treatment Period ADU-S100 and 
pembrolizumab will be administered in 21-day dosing cycles; tumor responses will initially be 
evaluated at 9-week intervals. If the injected lesion(s) shows signs of significant regression (i.e. 
shrinkage) such that repeat administration of ADU-S100 is no longer possible in any lesion, the 
subject will be scheduled to complete the EOT visit and may continue treatment with 
pembrolizumab as monotherapy/standard of care outside the context of the ADU-CL-20 clinical 
trial. Subjects who do not complete at least one response evaluation, unless they discontinue due 
to toxicity, will not be considered evaluable. An EOT visit will be conducted to assess subsequent 
anti-cancer therapy and complete safety reporting requirements. A schedule of visits and 
procedures is provided in Table 2-1. 
ADU-CL-20 Design 
DURATION OF SUBJECT PARTICIPATION: 
Following a Screening Period (up to 28 days), eligible subjects will be enrolled and receive ADU-
S100 and pembrolizumab in continuous, 21-day cycles during the Treatment Period until criteria 


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for treatment discontinuation are met, or up to 35 cycles. At the end of the Treatment Period, 
subjects will complete an EOT visit. 
POPULATION: 
Inclusion Criteria 
Individuals eligible to participate must meet the following criteria: 
1. Male or female aged ≥18 years  
2. Histological or cytological confirmation of recurrent or metastatic HNSCC 
3. Measurable disease as defined by RECIST v1.1 
4. [Criterion removed in Amendment 3]  
5. PD-L1 positive (defined as combined positive score [CPS] ≥1 using the Dako PD-L1 22C3 
pharmDx companion diagnostic assay) 
6. At least one lesion that is: 
• Superficial (e.g. cutaneous, subcutaneous) and/or nodal 
• Measures ≥10 millimeters (mm; post-biopsy) and <100 mm in longest diameter; nodal 
lesions must be ≥15 mm (post-biopsy) at short axis 
• Accessible for repeat intratumoral injection: Tumors encasing or abutting major vascular 
structures (such as the carotid artery) or tumors in locations at high risk for adverse effects 
(e.g. pneumothorax, brain lesions) are not considered appropriate for intratumoral 
injection. An irradiated mass cannot be used for intratumoral injection unless radiotherapy 
was completed at least 28 days prior to first dose of study drug and/or the lesion 
demonstrates evidence of growth (metabolically active by positive positron emission 
tomography or an unambiguous increase in size). 
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
8. Adequate organ and marrow function at Screening, as defined by the following laboratory 
parameters: 
Hematologic 
Renal 
Hepatic 
White blood cell count ≥2000/µL 
Absolute neutrophil count ≥1000/µL 
Platelets ≥75,000/µL 
Hemoglobin ≥9 g/dL 1 
Albumin ≥3.0 g/dL 
aPTT and/or INR ≤1.5 × ULN 2 
Creatinine ≤1.5 × ULN or GFR 
≥ 30 mL/min/1.73m2 by CKD-EPI equation: 
 
GFR = 141 x min (SCr /k, 1)α x max (SCr /k, 
1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 
[if black]  
 
Note: SCr is standardized serum creatinine in 
mg/dL, k is 0.7 for females and 0.9 for males, 
a is -0.329 for females and -0.411 for males, 
min indicates the minimum of SCr /k or 1, and 
max indicates the maximum of SCr /k or 1. 
AST/ALT ≤2.5 × ULN; 
or  
≤5 × ULN for subjects 
with liver metastases  
Bilirubin ≤1.5 × ULN; 
or  
≤3 × ULN if due to 
Gilbert’s disease 
ALT = alanine aminotransferase; aPTT= activated partial thromboplastin time; AST = aspartate aminotransferase; 
INR= International normalized ratio of prothrombin time; ULN = institutional upper limit of normal 
1 Transfusions are allowed; hemoglobin must be ≥9 g/dL for at least 7 days after transfusion and prior to dosing 
2 If receiving anticoagulant therapy, values should be within therapeutic range of intended use 
 


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9. Women of childbearing potential (WOCBP) and fertile males with WOCBP partners must use 
highly effective contraception (CTFG 2014) throughout the trial and for the latter of: 4 
months following the final dose of pembrolizumab or 30 days after the last dose of ADU-
S100 
10. Provide written informed consent and is willing and able to comply with all study procedures. 
 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate: 
1. Diagnosis of recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma 
of unknown primary histology; or salivary gland or non-squamous histologies (e.g. mucosal 
melanoma) 
2. Disease amenable to local therapy with curative intent (surgery or radiation therapy with or 
without chemotherapy) 
3. Prior systemic anti-cancer therapy (use of chemotherapeutic agents, targeted small molecules, 
immunotherapy, or monoclonal antibodies) for the treatment of recurrent or metastatic 
HNSCC  
[Prior chemotherapy and/or or radiotherapy in the adjuvant or neoadjuvant setting is 
acceptable provided at least 28 days have elapsed since last dose, and/or the irradiated lesion 
demonstrates evidence of growth or active tumor).] 
[Prior use of anti-PD-1 (or other drugs targeting immune checkpoint pathways) in the 
adjuvant or neoadjuvant setting is acceptable provided the total treatment period was ≤3 
months in duration; the last dose was ≥6 months before the first dose of study drug; and anti-
PD-1 treatment was not discontinued due to treatment-related toxicity.] 
4. Symptomatic or untreated leptomeningeal disease 
5. Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that 
require local CNS-directed therapy (such as radiation or surgery) or increasing doses of 
corticosteroids within the 2 weeks prior to first dose of study drug. Any symptomatic brain 
metastases should be neurologically stable (for 4 weeks post treatment and prior to study 
entry) with no corticosteroids administered for at least 2 weeks before first dose of study drug. 
Definitively treated CNS disease following gamma knife/stereotactic radiosurgery with no 
corticosteroids administered for at least 1 week before first dose of study drug should not be 
excluded. 
6. Radiotherapy within 2 weeks of the first dose of study drug, except for palliative radiotherapy 
to a limited field, such as for the treatment of bone pain or a focally painful tumor mass  
7. Participation in an interventional, investigational trial where an intervention was received 
within 4 weeks of the first dose of study drug 
8. Prior severe hypersensitivity (≥ Grade 3) to pembrolizumab or any study drug excipients (e.g. 
L-histidine, sucrose or polysorbate 80) 
9. History of or current drug-induced interstitial lung disease or pneumonitis Grade ≥2  


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10. Impaired cardiac function or clinically significant cardiac disease, including any of the 
following: 
• Symptomatic congestive heart failure requiring treatment 
• Clinically significant cardiac arrhythmia 
• Uncontrolled hypertension 
• Corrected QT interval (QTcF) >480 msec at Screening (average of triplicate ECGs) or 
congenital long QT syndrome 
• Acute myocardial infarction or unstable angina pectoris < 3 months prior to the first dose 
of study drug 
• New York Heart Association Functional Class III or higher (i.e. marked limitation of 
physical activity due to symptoms, or unable to carry on any physical activity without 
discomfort) 
11. Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (>10 mg/day 
prednisone or equivalent) or any immunosuppressive therapy within 7 days prior to the first 
dose of study drug. Topical (<class III), inhaled, nasal and ophthalmic steroids are allowed 
except in the anatomic location of injected and non-injected lesions. 
12. Receipt of any live vaccines within 4 weeks prior to first dose of study drug 
13. Use of hematopoietic colony-stimulating growth factors [e.g. granulocyte colony-stimulating 
factor (G-CSF), GM-CSF, macrophage colony-stimulating factor (M-CSF)], thrombopoietin 
mimetics or erythroid stimulating agents ≤2 weeks prior to first dose of study drug. Erythroid 
stimulating agents may be maintained if initiated more than 4 weeks prior to the first dose of 
study drug and the dose is stable. 
14. Received a diagnosis of, and/or tests positive at Screening for human immunodeficiency virus 
(HIV) 
15. Active Epstein-Barr virus (EBV), hepatitis B virus (HBV), or hepatitis C virus (HCV) 
infection 
16. Active infection (viral, bacterial, or fungal) requiring systemic therapy 
17. Prior history of or active malignant disease other than that being treated in this study. 
Exceptions: malignancies that were treated curatively and have not recurred within the past 2 
years; completely resected basal cell carcinoma and squamous cell carcinoma of the skin; and 
completely resected carcinoma in situ of any type. 
18. Active, known, or suspected autoimmune disease or a documented history of autoimmune 
disease, except vitiligo or resolved childhood asthma/atopy. 
Individuals with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone 
replacement, psoriasis not requiring systemic treatment, history of Hashimoto’s thyroiditis on 
stable dose of thyroid hormone replacement therapy, adrenal insufficiency only requiring 
physiologic steroid replacement, or conditions not expected to recur should not be excluded. 
19. Major surgery within 2 weeks of the first dose of study drug 


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20. If WOCBP, pregnant or breastfeeding; negative pregnancy status must be confirmed by serum 
pregnancy (human chorionic gonadotropin) test at Screening 
21. Intercurrent illness that is either life-threatening or of clinical significance such that it might 
limit compliance with study requirements, or in the Investigator’s assessment would place the 
subject at an unacceptable risk for participation. 
DOSAGE AND ROUTE OF ADMINISTRATION: 
Investigational Product (ADU-S100): 800 mcg/lesion (up to 1600 mcg maximum total dose in 2 
lesions) administered in a volume of 1.0 mL per lesion by intratumoral injection (injection of 
visceral lesions per Investigator discretion) on Days 1 and 8 of a 21-day cycle 
Standard of Care (pembrolizumab): 200 mg administered by IV infusion on Day 1 of a 21-day 
cycle per approved product label 
STATISTICAL ANALYSES: 
Descriptive summaries for categorical variables will include counts and percentages. Descriptive 
summaries for continuous variables will include means, medians, standard deviations and 
minimum and maximum values. Graphical summaries of the data may be presented. All data will 
be listed for all subjects. Further details of the analysis, including the handling of missing data, 
transformations, other data handling procedures, and analytical methodology will be provided in 
the Statistical Analysis Plan. Exploratory analyses of the data will be conducted as deemed 
appropriate. 
Efficacy Analyses 
Tumor response will be determined by the Investigator’s assessment. All efficacy endpoints will 
be defined and analyzed according to RECIST v1.1 (primary evaluation); and iRECIST 
(secondary evaluation). Occurrence of objective response (complete and partial response), 
duration of response, occurrence of disease control (complete response, partial response, and 
stable disease), and duration of disease control will be summarized. Estimates of progression-free 
survival and overall survival will be assessed using the Kaplan-Meier method. Because of 
truncated enrollment by amendment, some analyses may not be performed if limited data are 
available. 
Safety Analyses 
AEs will be coded according to Medical Dictionary for Regulatory Activities (MedDRA) and 
assessed for severity using the NCI-CTCAE v. 5.0. AEs will be summarized by system organ 
class and preferred term and presented in decreasing order of frequency. Changes from baseline 
for safety laboratory parameters; clinically significant changes from baseline in vital signs and 
electrocardiogram parameters; and shifts from baseline to most extreme ECOG value will be 
presented. 
 


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Pharmacodynamic and Exploratory Analyses 
Pharmacodynamics, pharmacokinetics, biomarkers, and all available data related to research 
laboratory samples, tumor biopsies, and immune response data may be described in separate 
analysis documents. By amendment, no further samples will be obtained for analysis. 
SAMPLE SIZE DETERMINATION: 
The original sample size was based on a Simon’s 2-stage minimax design (Simon 1989) to test 
the null hypothesis that the objective response rate (ORR; complete response [CR] and partial 
response [PR]) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1) is less than or 
equal to 0.19 versus the alternative hypothesis that ORR is greater than or equal to 0.38, with a 
Type 1 error rate of 0.05 and power of 80%. Because of truncated enrollment, the total sample 
size will be limited to approximately 20 evaluable subjects as planned for the first stage. 


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Table 2-1 Schedule of Events 
Study Period 
Screening 
Treatment Period 
EOT 2, 3 
Cycle 1 
Cycle 2 and Beyond 
Cycle Day (21-day cycles)1
-28 to -1 
1 
2 
8 
1 
8 
30 d post last dose 
Visit Window (days) 
- 
- 
- 
±1 
±1 (±3 Cycles 3-7; 
±5 Cycles 8+) 
±1 (±3 Cycles 3-7; 
±5 Cycles 8+) 
+7 
Informed consent 
X 
Demographics, Medical history, Height 4 
X 
Inclusion/Exclusion criteria 
X 
SAFETY & EFFICACY EVALUATIONS 
Tumor imaging & response assessment 5 
X 
Cycle 4 Day 1 (-7 days), Q9W (-14 days) × 27 wks, then Q12W thereafter 5 
Vital status (survival), Current cancer therapy 
X 
ECOG performance status 
X 
X 
X 
X 
Vital signs 6 
X 
X 
X 
X 
X 
X 
Physical examination, Weight 7 
X 
X 
X 
X 
Electrocardiogram 8 
X 
X 
X 
Cycles 2-3  
X 
Adverse events 9
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
LABORATORY ASSESSSMENTS (obtain prior to dosing unless otherwise indicated) 
Virology, Serology 10 
X 
Urinalysis, Coagulation panel 10 
X 
As clinically indicated 
Hematology, Chemistry 10 
X 
X 10 
X 
X 10 
X 
Thyroid function 10, 11 
X 
X 11
odd cycles 11 
X 
Pregnancy (WOCBP) 10 
Serum 
Serum 
X 
X 
Plasma cytokines (safety) 12 
X 
As clinically indicated for CRS initial diagnosis & follow up monitoring 
STUDY DRUG ADMINISTRATION 
Pembrolizumab (IV infusion) 13 
X 
X 
ADU-S100 (intratumoral injection)14 
X 14
X 
X 
X 
FOOTNOTES FOR TABLE 2-1 (See Sections 9 and 10 for additional information) 
1 Cycle length is 21 days. If a dose of either study drug is delayed, shift scheduled assessments accordingly. 
2 EOT Visit occurs 30 days (+7 days) after the last dose of study drug (ADU-S100 or standard of care [pembrolizumab]) or prior to commencing new anti-cancer 
therapy. 
3 Safety Follow-up to complete required Safety Reporting Periods (Table 10-1), as indicated. Concomitant medications will only be collected if associated with the 
management of an ongoing AE or SAE, or if a new anti-cancer treatment. Following EOT, subject may be contacted by phone to complete SAE reporting period as 
applicable. 


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4 Demographics, Medical History, Height: includes date of birth, age, gender, ethnicity, and race. Medical history includes all active conditions and any condition 
considered to be clinically significant by the Investigator. Disease-specific details include date of diagnosis, primary tumor histology, prior surgery(ies), radiation 
therapy, chemo- and biological therapies, and stage of cancer. Obtain standing height. 
5 Tumor imaging: See Section 10.2.1. Collect scans electronically; perform response assessments per RECIST 1.1 and iRECIST. Tumor assessments should be fixed 
according to calendar, regardless of treatment delays. After 27 weeks, the imaging frequency for all subjects will be performed at a Q12W (-14 days) frequency until 
confirmed disease progression, withdrawal, or study end. Perform at EOT if more than 6 weeks have passed since last evaluation.  
6 Vital Signs: Blood pressure, pulse, respiratory rate, and temperature. Cycles 1 and 2: scheduled time points relative to the start of the pembrolizumab infusion (Day 1) = 
pre-dose, end of infusion (+30 minutes); scheduled time points relative to the start of the ADU-S100 injection (Days 1, 8) = pre-dose, 3 hour (±30 minutes) and 6 
hours (±30 minutes) post-dose. On all other dosing days, perform vital sign assessment prior to the start of each study drug or more frequently as clinically indicated. 
7 Physical Examination: Complete physical examinations at Screening and EOT; all other indicated visits are symptom-directed physical examinations. Weight at each 
indicated visit. Assessment may be done up to 3 days prior to visit. 
8 Electrocardiogram: Collect 12-lead ECGs as specified in Table 2-2. Perform routine 12-lead ECG with subject in recumbent or semi-recumbent position after 5 minutes 
rest. Additional ECGs may also be performed throughout the study if clinically indicated. Perform ECGs prior to study drug administration unless otherwise indicated. 
Procedures should be performed in the following order: ECG, vital signs, blood draw. 
9 Adverse events: Collect from date of informed consent according to safety-reporting periods specified in Table 10-1 and reporting procedures in Section 11. 
10 Virology, Serology, Urinalysis, Coagulation panel, Hematology, Chemistry, Thyroid function, Pregnancy Tests (WOCBP only):  See Sections 10.4.1 and 10.4.2 for 
specific analytes. Collect samples as outlined in the Laboratory Manual; testing performed at local laboratory unless otherwise indicated. Collect Screening blood 
samples after other requisite tests for eligibility have been completed. Samples indicated on dosing days must be pre-dose and Cycle 1-3 samples may be obtained up 
to 3 days before dosing. For WOCBP, perform serum pregnancy test (hCG) at Screening and within 24 hours prior to first dose of study drug (unless Screening 
assessment performed within 72 hours of Cycle 1 Day 1); perform urine pregnancy test at all other indicated visits. 
11 Thyroid function: Repeat on Cycle 1 Day 1 only if Screening result was abnormal (Section 10.4.2). Required during odd-numbered cycles only; additional tests may 
be performed if clinically indicated. 
12 Plasma cytokines (safety): See Section 10.4.2.2 for specific analytes. Collect at Screening and as clinically indicated. If CRS is suspected, blood (plasma) sample 
should be collected within 5 hours (or as soon as possible) after occurrence of the event, and 1 week after occurrence of the event. Ship all samples to central 
laboratory(ies) as outlined in the Laboratory Manual. 
13 Pembrolizumab: administer 200 mg by IV infusion on Day 1 of each 21-day cycle as specified in Section 9.3. 
14 ADU-S100: administer by intratumoral injection on Days 1 and 8 of each 21-day cycle as specified in Section 9.4. Confirm biopsy area has healed prior to initiating 
dosing. 
ABBREVIATIONS FOR TABLE 2-1  
CRS = cytokine release syndrome; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = End of treatment; hCG = human chorionic 
gonadotropin; iRECIST = modified RECIST1.1 for immune-based therapeutics; IV = intravenous; RECIST = Response Evaluation Criteria in Solid Tumors (v 1.1); 
WOCBP = women of childbearing potential 


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Table 2-2 
12-lead ECG Collection Timepoints 
Triplicate ECGs should be completed at each timepoint, and the mean QTcF values should be 
calculated. 
Cycle 
Day 
Time 
Screening 
Anytime during the screening period 
1 
1 
Pre-dose and within 30 minutes after start of ADU-S100 
injection 
1 
8 
Pre-dose and within 30 minutes after start of ADU-S100 
injection 
2 
1 
Pre-dose 
3 
1 
Pre-dose 
EOT 
EOT 
Unscheduled 
Anytime if clinically indicated 
ABBREVIATIONS FOR TABLE 2-2  
ECG = electrocardiogram; EOT = end of treatment 


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3 
TABLE OF CONTENTS 
1 
TITLE PAGE……………………………………………………………………………...1 
2 
SYNOPSIS .......................................................................................................................... 3 
3 
TABLE OF CONTENTS .................................................................................................. 13 
3.1 
LIST OF TABLES ...................................................................................................... 17 
3.2 
LIST OF FIGURES .................................................................................................... 17 
4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................... 18 
5 
INTRODUCTION ............................................................................................................ 21 
5.1 
Cancer Immunotherapy Targeting STING ................................................................. 21 
5.2 
ADU-S100 .................................................................................................................. 21 
5.2.1 Summary of Nonclinical Studies with ADU-S100 ............................................... 22 
5.2.2 Summary of Clinical Studies with ADU-S100 ..................................................... 23 
5.3 
Scientific Rationale for the Use of ADU-S100 with Pembrolizumab ........................ 24 
5.3.1 Dose Selection Rationale ...................................................................................... 25 
5.4 
Potential Risks, Benefits and Mitigation Strategy ...................................................... 26 
5.4.1 Safety Review Team ............................................................................................. 27 
6 
OBJECTIVES AND ENDPOINTS .................................................................................. 29 
7 
INVESTIGATIONAL PLAN ........................................................................................... 30 
7.1 
Study Design ............................................................................................................... 30 
7.2 
Duration of Subject Participation................................................................................ 31 
7.2.1 End of Study ......................................................................................................... 31 
7.2.2 Stopping Rules ...................................................................................................... 31 
7.3 
Discussion of Study Design ........................................................................................ 31 
8 
STUDY POPULATION ................................................................................................... 33 
8.1 
Inclusion Criteria ........................................................................................................ 33 
8.2 
Exclusion Criteria ....................................................................................................... 34 
8.3 
Subject Completion, Treatment Discontinuation, or Removal from Study ................ 36 
8.3.1 Subject Completion ............................................................................................... 36 
8.3.2 Discontinuation from Study Treatment ................................................................ 36 
8.3.3 Subject Discontinuation/Withdrawal from the Study ........................................... 37 
9 
STUDY DRUGS AND ADDITIONAL MEDICATIONS ............................................... 38 


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9.1 
Method of Subject Assignment ................................................................................... 38 
9.2 
Blinding....................................................................................................................... 38 
9.3 
Standard of Care: Pembrolizumab .............................................................................. 38 
9.3.1 Pembrolizumab Pre-Medications .......................................................................... 38 
9.3.2 Pembrolizumab Infusion ....................................................................................... 38 
9.3.3 Supportive Care .................................................................................................... 38 
9.3.4 Criteria for Continued Pembrolizumab Dosing .................................................... 39 
9.4 
Investigational Product: ADU-S100 ........................................................................... 39 
9.4.1 ADU-S100 Pre-Medications ................................................................................. 39 
9.4.2 ADU-S100 Administration ................................................................................... 40 
9.5 
Dose Interruptions and Dose Modification for Treatment-related Toxicities ............ 41 
9.5.1 General Toxicity and Dose Modification Guidelines ........................................... 42 
9.5.2 Management of Immune-related Adverse Events ................................................. 44 
9.5.3 Guidelines for Pembrolizumab Infusion-related Reactions .................................. 44 
9.5.4 Guidelines for ADU-S100 Injection Site Reactions ............................................. 44 
9.5.5 Cytokine Release Syndrome ................................................................................. 44 
9.6 
Concomitant Medications ........................................................................................... 45 
9.6.1 Prohibited Medications ......................................................................................... 45 
9.7 
Treatment Compliance ................................................................................................ 46 
10 
STUDY ASSESSMENTS AND PROCEDURES ............................................................ 47 
10.1 
General Assessments .................................................................................................. 47 
10.1.1 Informed Consent.................................................................................................. 47 
10.1.2 Demographics, Medical History, and Height ....................................................... 47 
10.1.3 Eligibility .............................................................................................................. 48 
10.2 
Efficacy Measures ....................................................................................................... 48 
10.2.1 Tumor Imaging and Response Assessments ......................................................... 48 
10.2.2 Photography of Injected Lesions .......................................................................... 49 
10.2.3 Subsequent Anti-Cancer Therapy Follow-Up ...................................................... 49 
10.3 
Safety Assessments ..................................................................................................... 49 
10.3.1 Eastern Cooperative Oncology Group Scale of Performance Status .................... 49 
10.3.2 Vital Signs ............................................................................................................. 50 


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10.3.3 Physical Examination and Weight ........................................................................ 50 
10.3.4 Electrocardiogram ................................................................................................. 50 
10.3.5 Adverse Events ..................................................................................................... 51 
10.3.6 Prior and Concomitant Medications ..................................................................... 52 
10.3.7 Clinical Laboratory Evaluation for Safety ............................................................ 53 
10.4 
Laboratory Assessments ............................................................................................. 53 
10.4.1 Screening-specific Laboratory Assessments ......................................................... 53 
10.4.2 Safety Laboratory Assessments ............................................................................ 53 
10.4.3 Drug Concentration Measurements ...................................................................... 55 
10.4.4 Biomarker Assessments ........................................................................................ 55 
10.5 
Appropriateness of Measures ...................................................................................... 55 
11 
ADVERSE EVENT REPORTING................................................................................... 57 
11.1 
Adverse Events ........................................................................................................... 57 
11.1.1 Disease-Related Events ......................................................................................... 58 
11.1.2 Assessment of Adverse Events by the Investigator .............................................. 58 
11.1.3 Adverse Event Follow-up ..................................................................................... 60 
11.2 
Serious Adverse Events .............................................................................................. 60 
11.3 
Serious Adverse Event Reporting ............................................................................... 61 
11.3.1 Initial Reports ........................................................................................................ 61 
11.3.2 Safety Reporting Contact Information .................................................................. 61 
11.3.3 Expedited Reporting Requirements ...................................................................... 61 
11.3.4 Follow-Up Reports................................................................................................ 61 
11.4 
Drug-induced Liver Injury .......................................................................................... 62 
11.5 
Pregnancy Reporting ................................................................................................... 62 
12 
STATISTICAL ANALYSIS ............................................................................................ 63 
12.1 
Sample Size Determination ......................................................................................... 63 
12.2 
General Considerations ............................................................................................... 63 
12.3 
Analysis Sets ............................................................................................................... 63 
12.4 
Subject Information .................................................................................................... 64 
12.5 
Efficacy Variables and Analyses ................................................................................ 64 
12.5.1 Primary Efficacy Endpoint ................................................................................... 64 


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12.5.2 Secondary Efficacy Endpoints .............................................................................. 64 
12.6 
Safety Analyses ........................................................................................................... 65 
12.7 
Pharmacodynamic, Pharmacokinetic and Research Analyses .................................... 65 
12.8 
Timing of Analyses ..................................................................................................... 65 
12.9 
Interim Analysis .......................................................................................................... 65 
12.10 Data Monitoring Committee ....................................................................................... 65 
13 
DATA MANAGEMENT AND RECORD KEEPING..................................................... 66 
13.1 
Data Handling ............................................................................................................. 66 
13.2 
Data Entry ................................................................................................................... 66 
13.3 
Data Validation ........................................................................................................... 66 
13.4 
Record Keeping .......................................................................................................... 66 
14 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ............................. 67 
14.1 
Ethical Conduct of the Study ...................................................................................... 67 
14.2 
Investigator Requirements .......................................................................................... 67 
14.2.1 Disposition and Accountability of Investigational Products ................................ 67 
14.3 
Institutional Review Board/Ethics Committee ........................................................... 68 
14.4 
Informed Consent........................................................................................................ 68 
14.5 
Study Monitoring Requirements ................................................................................. 68 
14.6 
Disclosure of Data ....................................................................................................... 69 
14.7 
Retention of Records ................................................................................................... 69 
14.8 
Publication Policy ....................................................................................................... 69 
14.9 
Financial Disclosure .................................................................................................... 70 
14.10 Insurance and Indemnity ............................................................................................. 70 
15 
REFERENCES ................................................................................................................. 71 
Appendix A: Management and Dose Modifications of Immune-Mediated Adverse Reactions .. 73 
Appendix B: RECIST v1.1 CRITERIA ........................................................................................ 78 
Appendix C: iRECIST CRITERIA ............................................................................................... 81 
Appendix D: COVID-19 GUIDANCE ......................................................................................... 84 
SIGNATURE PAGE .................................................................................................................... 86 
INVESTIGATOR AGREEMENT................................................................................................ 87 
 
 


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3.1 
LIST OF TABLES 
Table 2-1 
Schedule of Events .................................................................................................. 10 
Table 2-2 
12-lead ECG Collection Timepoints ....................................................................... 12 
Table 5-1 
Proposed ADU-S100 Dose Levels .......................................................................... 26 
Table 5-2 
Key Safety Considerations and Mitigation Strategy ............................................... 27 
Table 9-1 
Continued Dosing Requirements 1 .......................................................................... 39 
Table 9-2 
Toxicities Requiring Dose Modification or Treatment Discontinuation................. 43 
Table 10-1 
Safety Reporting Periods ......................................................................................... 52 
 
3.2 
LIST OF FIGURES 
Figure 7-1 
ADU-CL-20 Study Design ...................................................................................... 30 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ADU-S100 
synthetic cyclic dinucleotide agonist of human stimulator of 
interferon genes (also referred to as MIW815) 
AE 
adverse event 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
CDNs 
cyclic dinucleotides 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentration 
CPS 
combined positive score 
CR 
complete response 
CRA 
clinical research associate 
CRS 
cytokine release syndrome 
CNS 
central nervous system 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DOR 
duration of response 
EAS 
evaluable analysis set 
EBV 
Epstein-Barr virus 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
End of Treatment 
EU 
European Union 
FDA 
United States Food and Drug Administration 
FFPE 
formalin-fixed, paraffin embedded 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GFR 
glomerular filtration rate 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HIV 
human immunodeficiency virus 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
hERG 
human Ether-à-go-go-related gene 


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Abbreviation 
Definition 
HNSCC 
head and neck squamous cell cancer 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IFN 
interferon 
IL-x 
IP 
interleukin-type 
investigational product 
INR 
international normalized ratio of prothrombin time 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
iRECIST 
modified RECIST1.1 for immune-based therapeutics 
IV 
intravenous(ly) 
MABEL 
minimum anticipated biologic effect level 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
ORR 
objective response rate 
OS 
overall survival 
PD 
pharmacodynamic(s) 
PD-1/L1 
programmed death receptor-1/ligand-1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
prothrombin time 
QTcF 
QT interval (Fridericia correction formula) 
QxW 
once every x weeks 
RECIST 
response evaluation criteria in solid tumors 
SAE 
serious adverse event 
SAP 
SoD 
statistical analysis plan 
Sum of diameters 
SCr 
Serum creatinine 
SRT 
safety review team 
STING 
stimulator of interferon genes 
T1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time of maximum concentration 
TME 
tumor microenvironment 
ULN 
upper limit of normal 
WOCBP 
women of child-bearing potential 
 


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Definition of Terms: 
In this protocol, the Investigational Product (IP) ADU-S100 and Standard of Care 
pembrolizumab are both considered ‘study drug’. Throughout the protocol the term ‘study drug’ 
is interchangeable between ADU-S100 and pembrolizumab. When referring to only one study 
drug, the protocol will specify ADU-S100 to indicate the IP or specify pembrolizumab to 
indicate the Standard of Care. 


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5 
INTRODUCTION 
The purpose of this clinical trial is to evaluate the efficacy and safety of ADU-S100 (also 
referred to as MIW815) when administered in combination with pembrolizumab to adults with 
head and neck squamous cell cancer (HNSCC) with lesions amenable to intratumoral injection; 
and in whom programmed death receptor-1/ligand (PD-1/L1) inhibitor therapy is the current 
standard of care. 
A summary of the background and scientific rationale, nonclinical and clinical studies, starting 
dose selection, and risk/mitigation strategy are presented within this section. For the most 
comprehensive nonclinical and clinical information refer to the latest version of the Investigator's 
Brochure (IB) for ADU-S100 and the approved product labeling for pembrolizumab 
(KEYTRUDA 2020). 
5.1 
Cancer Immunotherapy Targeting STING 
Spontaneous T cell infiltration of tumor lesions in humans is correlated with a type I interferon 
(IFN) transcriptional profile in the tumor microenvironment (TME) and infiltration of 
lymphocytes, indicative of ongoing innate immune recognition within the tumor. Stimulator of 
interferon genes (STING) is an essential receptor of the innate immune response (Ishikawa, and 
Barber 2008). STING senses cytosolic double-stranded DNA through a signaling intermediate or 
by directly binding cyclic dinucleotides (CDNs) which serve as danger signals originating from 
pathogens or the host.  
Stimulation of the STING pathway by CDNs has been shown to induce type I IFN, cytokines, 
and chemokines which together activate innate immune effector cells such as dendritic cells, 
macrophages and natural killer cells. Dendritic cell production of type I IFN in the TME leads to 
activation and expansion of a tumor antigen-specific CD8+ T cell response resulting in the 
inhibition of tumor growth in both treated and untreated lesions. 
The proposed therapeutic approach is based on the finding that the responsiveness of tumors to 
immunotherapy depends, at least in part, on the immunophenotype of the TME (Woo et al. 2015; 
Gajewski, Woo, et al. 2013; Gajewski et al. 2012; Gajewski, Schreiber, et al. 2013). Substantial 
evidence indicates the presence of tumor infiltrating lymphocytes is correlated with favorable 
prognosis in diverse malignancies (Galon et al. 2012). The presence of tumor infiltrating 
lymphocytes in the TME also predicts a positive clinical outcome in response to several 
immunotherapy strategies (Postow et al. 2012; Wolchok et al. 2013). One newly explored 
approach to potentially establish, re-establish, or enhance active immune surveillance conditions 
within the TME is to inject immune modulators directly into the tumor for the purposes of 
devascularizing injected lesions and initiating an adaptive tumor-specific immune response. 
5.2 
ADU-S100 
ADU-S100 (MIW815; disodium dithio-(RP, RP)-[cyclic [A(2',5')pA(3',5')p]]), is a synthetic 
CDN composed of two adenosine monophosphate (AMP) analogues cyclized via a 2',5' 


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(noncanonical) and a 3',5' (canonical) phosphodiester bond. ADU-S100 is in clinical 
development for the potential use as a monotherapy or with other anti-cancer therapies for the 
treatment of advanced/metastatic solid tumors and lymphomas. ADU-S100 is intended for direct 
administration to the tumor site via intratumoral injection. 
In nonclinical studies, ADU-S100 has demonstrated significantly higher activity than natural 
STING ligands produced by bacteria or human cells. ADU-S100 acts as an agonist of STING in 
tumor-resident cells including dendritic cells, endothelial cells and other cell populations in the 
TME. Direct activation of STING via intratumoral injection of ADU-S100 is hypothesized to 
overcome active tolerance mechanisms through stimulation of resident leukocyte populations. 
This results in the local production of type I and type II interferons, TNF and other cytokines and 
chemokines, and stimulates tumor-specific CD8+ T cell immunity, leading to clearance of 
treated lesions, and control of distal uninjected lesion growth. 
5.2.1 
Summary of Nonclinical Studies with ADU-S100 
In vitro studies with ADU-S100 demonstrated ADU-S100 broadly activated STING across a 
diverse human population.  
ADU-S100 was evaluated in multiple murine tumor models. Results from preclinical studies 
demonstrated a potent anti-tumor immune response and significant tumor regression. In murine 
syngeneic tumor models, intratumoral injection with ADU-S100 inhibited the treated tumor and 
stimulated an effective systemic CD8+ T cell immune response that controlled the growth of 
distal, untreated lesions, and conferred protection against tumor challenge. When ADU-S100 
was administered intratumorally to mice expressing defective STING, anti-tumor efficacy was 
completely lost. When ADU-S100 was given as a subcutaneous injection, no tumor regression 
was observed. These results suggest direct activation of tumor-resident antigen presenting cells 
through the STING pathway is important for cross-presentation of tumor-specific CD8+ T cells 
and tumor destruction. 
In pharmacology studies, cytokine concentrations increased in the plasma or serum of mice, 
rabbits, and monkeys. Changes were similar in magnitude following intratumoral or SC injection 
of ADU-S100 in the mouse but were not present in mice lacking a functional STING gene 
(Tmem173). Thus, changes in cytokine levels were an indication of target engagement.  
In a series of pharmacokinetic-pharmacodynamic (PK-PD) studies to define the relationship 
between the dose of ADU-S100, exposure, and pharmacodynamic (PD) effect on serum 
cytokines, the minimum anticipated biologic effect level (MABEL) for cytokine changes in the 
mouse, rabbit, and monkey was determined to be 0.03, 0.01, and 0.03 mg/kg, respectively. There 
were minimal differences across species in exposure or the sensitivity towards production of a 
cytokine response. 
Evaluation of cardiac safety in an in vitro assay for human Ether-à-go-go-related gene (hERG) 
activity and in conscious telemetry-instrumented rabbits indicated ADU-S100 has a low risk of 
inducing delayed ventricular repolarization, prolongation of the QTc interval, and unstable 


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arrhythmias. There were no ADU-S100-related adverse findings in neurobehavioral assessments 
incorporated in the Good Laboratory Practices (GLP) 4-week repeat-dose toxicity study in mice. 
The CD-1 mouse and New Zealand white rabbit were established as relevant toxicity species 
based on pharmacology data and were used for repeat-dose GLP toxicology studies. Based on 
results of GLP studies in mouse and rabbit, bone marrow (including hematopoietic parameters), 
liver, reproductive organs, and skin (injection site) were defined as potential targets of dose-
dependent toxicity related to the administration of ADU-S100. Consequently, particular caution 
should be provided in monitoring for signs of hematopoietic toxicity, liver toxicity, and injection 
site toxicity. Generally, most adverse findings observed during nonclinical studies were 
reversible. Overall, nonclinical studies support use of ADU-S100 in humans at the proposed dose 
levels. A complete summary of nonclinical information on ADU-S100 is provided in the IB. 
5.2.2 
Summary of Clinical Studies with ADU-S100 
ADU-CL-20 is ongoing; as of 17 Dec 2020, treatment related SAEs of Grade 3 laryngeal edema, 
Grade 3 hypophysitis, Grade 3 cytokine release syndrome (CRS) and Grade 3 neck edema have 
been reported in 3 of 16 patients treated.   
The ADU-S100 clinical development program also includes two additional studies in adults with 
advanced/metastatic solid tumors or lymphomas. A Phase 1, open label, multicenter study 
examines the safety and efficacy of ADU-S100 (referred to as MIW815) with or without 
ipilimumab (CMIW815X2101/ADU-CL-07; NCT02675439); and a Phase 1b, open label, 
multicenter study examines the safety and efficacy of ADU-S100 (referred to as MIW815) 
administered with the investigational anti-PD-1 checkpoint inhibitor, PDR001 
(CMIW815X2102J; NCT03172936). In these trials, ADU-S100 is administered by intratumoral 
injection on Days 1, 8 and 15 or on Day 1 only of every 28-day cycle.  
Available safety data as of the 09 October 2019 clinical cutoff date and PK data as of the 10 
January 2019 data cutoff date are summarized below. Consult the IB for additional current 
information. 
CMIW815X2101/ADU-CL-07 
A total of 47 subjects have been treated with ADU-S100 at doses ranging from 50 to 6400 mcg 
and evaluated for dose-limiting toxicity (DLT) in the first in human study. Following 
intratumoral dose administration, ADU-S100 exhibits rapid absorption in the plasma, with Cmax 
achieved right after injection in most subjects. ADU-S100 showed fast clearance in plasma, with 
mean apparent clearance (CL/F) ranging from 55.9 to 275 L/h and mean elimination t1/2 of 
approximately 10 to 23 minutes across the dose range of 50 to 6400 mcg. Inter-subject exposure 
variability was high and exposure of ADU-S100 generally increased with doses increasing from 
50 to 6400 mcg. 
One DLT has been reported at 6400 µg (injection site ulcer). TEAEs, all grades, suspected to be 
related to study drug, were reported in 36 subjects (76.6%) overall. To date, the most frequently 


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reported AEs (>10% of subjects) include pyrexia (8 subjects, 17.0%), chills and injection site 
pain (7 subjects, 14.9%) and headache (6 subjects, 12.8%). Five subjects experienced Grade 3 
events including injection site reaction and lipase increased (2 subjects, 4.3%), injection site 
ulcer, amylase increased, tumor pain and dyspnea (1 subject, 2.1%). One subject experienced a 
Grade 4 event, respiratory failure (2.1%). No clinically relevant changes of vital and ECG-
parameters were observed. 
CMIW815X2102J 
A total of 102 subjects have been treated with ADU-S100 plus a PD-1 inhibitor, PDR001, at 
ADU-S100 doses ranging from 50 to 3200 mcg and on 2 different dosing schedules. Per 28-day 
cycle, subjects were dosed with PDR001 IV on Day 1, and with ADU-S100 intratumorally on 
Days 1, 8, and 15 (Group A) or on Day 1 (Group B) per 28-day cycle. 
One DLT (injection site reaction) was reported at ADU-S100 3200 mcg dose level in 
combination with PDR001. TEAEs, all grades, suspected to be related to study drugs, were 
reported in 65 subjects (63.7%) overall - 41 subjects in Group A (65.1%) and 24 subjects 
(61.5%) in Group B. To date, the most frequently reported AEs (≥ 10% of subjects) include 
pyrexia (20 subjects, 19.6%) injection site pain (18 subjects, 17.6%) and diarrhea (11 subjects, 
10.8%). Of the 65 subjects who experienced AEs suspected to be related to study drugs, 9 
subjects (8.8%) had Grade 3 events including alanine aminotransferase increased, aspartate 
aminotransferase increased and diarrhea (2 subjects, 2.0%), neutropenia, hyperthyroidism, 
pyrexia, fatigue, asthenia, lipase increased, lipase, dyspnea, immune-mediated pneumonitis and 
rash maculo-papular (1 subject, 1.0%). Three subjects (2.9%) reported at least one Grade 4 event 
including amylase increased, lipase increased, hyponatremia, and partial seizures (1 subject, 
1.0%). 
Additional details on clinical experience with ADU-S100 are provided in the IB. 
5.3 
Scientific Rationale for the Use of ADU-S100 with Pembrolizumab  
In preclinical models, STING-mediated induction of innate immunity leads to the cross-priming 
of tumor antigen-specific CD8+ T cells. Treatment of tumor-bearing mice with intratumoral 
injection of STING agonist ADU-S100 resulted in local and distal tumor shrinkage, improved 
survival, and induction of immunological memory. When ADU-S100 was administered with an 
anti-PD-1 antibody, survival and local tumor shrinkage were significantly enhanced suggesting 
the anti-tumor activity of PD-1 blockade may be complemented by concomitant STING 
activation. Recent data also suggest that acquired resistance to checkpoint blockade 
immunotherapy in patients with melanoma was associated with defects in the pathways involved 
in interferon receptor signaling that may be partially overcome by activation of the STING 
pathway (Zaretsky et al. 2016). 
Immunotherapeutic approaches for a variety of advanced malignancies include use of the PD-1 
blocking antibody, pembrolizumab, administered both as monotherapy and with other agents. 


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Pembrolizumab is approved for the treatment of adults with recurrent or metastatic HNSCC with 
disease progression on or after platinum-containing chemotherapy (KEYTRUDA 2020). 
KEYNOTE-048 was a randomized, active-controlled, open-label study in adults with metastatic 
or recurrent HNSCC in the first-line setting. Interim analyses demonstrated pembrolizumab 
(administered as monotherapy or with platinum/5-fluorouracil) significantly improved OS 
relative to cetuximab/platinum/5-fluorouracil in populations with tumor and/or surrounding cells 
with high levels of PD-L1 expression (combined positive score [CPS] ≥20; median 14.9 vs 10.7 
months; p = 0.0007) and in populations with lower degrees of PD-L1 expression (CPS ≥1; 
median 12.3 vs 10.3 months; p = 0.0086) (Burtness et al. 2018; Rischin et al. 2019). There were 
no statistically significant differences in progression-free survival (PFS). In this trial, 
pembrolizumab showed a lower objective response rate (ORR) than cetuximab/platinum/5-
fluorouracil although responses were more durable (CPS ≥1, patients treated with 
pembrolizumab had an ORR of 19.1% and median duration of response 20.9 months; patients 
treated with cetuximab/platinum/5-fluorouracil had an ORR of 34.9% and median duration of 
response 4.5 months). The data support pembrolizumab monotherapy as a new first-line standard 
of care for patients with recurrent or metastatic HNSCC (Burtness et al. 2018; Rischin et al. 
2019). 
Immune checkpoint inhibitors such as pembrolizumab have demonstrated significant 
improvements in duration of response and long-term survival compared to traditional 
chemotherapy or other standards of care. However, a significant percentage of patients are either 
nonresponsive to these immunotherapies, most likely due to innate immunosuppressive 
mechanisms within the TME, or experience disease relapse following an acquired means of 
immune escape (Chen et al. 2016). This highlights the need for new, additional therapies with 
novel mechanisms to fill these treatment gaps. 
This clinical trial is designed to evaluate the efficacy and safety of ADU-S100 administered with 
the checkpoint inhibitor, pembrolizumab, in HNSCC with lesions amenable to intratumoral 
injection, and for which PD-1/L1 inhibitor therapy is standard of care. 
5.3.1 
Dose Selection Rationale 
Pembrolizumab will be dosed consistent with the product label (KEYTRUDA 2020) and clinical 
trial experience in the first-line HNSCC setting (KEYNOTE-048) (Burtness et al. 2018; Rischin 
et al. 2019) at 200 mg every 3 weeks.  
The ADU-S100 doses and dosing schedule selected for this study are primarily based on 
nonclinical data and available clinical data from two clinical trials with ADU-S100. In the Phase 
1 trial (CMIW815X2101/ADU-CL-07), ADU-S100 administered at doses up to 3200 mcg has 
been well-tolerated. Initial results from the Phase 1b trial (CMIW815X2102J) where ADU-S100 
is administered with an investigational anti-PD1 (i.e. PDR001) provide preliminary clinical 
activity and additional safety and tolerability data to support the dose levels of ADU-S100 
planned for investigation with pembrolizumab in this trial (Section 5.2.2).  


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In the Phase 1 study, clinical responses (partial response [PR]) have been observed in subjects 
with Merkel cell carcinoma (1 subject) and parotid gland (1 subject) at ADU-S100 dose levels of 
100 mcg and 800 mcg, respectively (Meric-Bernstam et al. 2018). Changes in biomarkers, 
including increases in CD8+ TILs, upregulation of genes involved in the anti-tumor immune 
response and systemic cytokines have also been observed at the 800 mcg ADU-S100 dose level 
(Meric-Bernstam et al. 2018), providing rationale for further evaluation of ADU-S100 at the 
800 mcg dose level. 
It is expected that intratumoral administration of ADU-S100 activates cells locally in the tumor 
environment and draining lymph node to contribute to therapeutic benefit. Administering a 
consistent dose per lesion provides the same opportunity for response for each injected lesion. 
The total dose administered will vary by subject depending on the number of accessible target 
lesions, but will not exceed a maximum total dose of 1600 mcg (i.e. no more than 2 concurrently 
injected lesions). Lower doses of ADU-S100 would be anticipated to provide limited therapeutic 
benefit; dose reductions below 200 mcg/lesion will not be allowed. 
Thus, adequate safety factors exist to support the proposed dose levels of ADU-S100 
administered with pembrolizumab in this study; the maximum dose administered will not exceed 
a total dose of 1600 mcg (i.e. 800 mcg/lesion in up to 2 lesions; Table 5-1). The maximum dose 
takes into consideration the proposed mechanism of action of ADU-S100 and prior clinical 
experience in adults with advanced cancers. The dosing schedule is predicated on available 
nonclinical and clinical PK-PD data and aligned with the approved pembrolizumab regimen. 
Table 5-1 Proposed ADU-S100 Dose Levels 
ADU-S100 Dose 
ADU-S100 Total Dose Level 1 
800 mcg/lesion 
Up to 1600 mcg (maximum dose) 
1 A maximum of 2 lesions may be injected. ADU-S100 total dose level assumes maximum number of lesions (2) 
injected; total dose will vary by subject depending on number of accessible target lesions but will not exceed 
1600 mcg.  
5.4 
Potential Risks, Benefits and Mitigation Strategy 
ADU-S100 is in clinical development for potential use as a monotherapy and in combination 
with other anti-cancer therapies. Available nonclinical and clinical data indicate ADU-S100 has 
the potential to exhibit clinical activity in the treatment of HNSCC and other advanced cancers. 
To date no unexpected safety issues that would preclude use in this study population have been 
identified.  
Although the risk of significant systemic activation of the immune system, including 
autoimmune disease or CRS, is considered low with intratumoral drug delivery, the risk cannot 
be excluded. Clinical signs and symptoms of cytokine activation include fever and chills. 
Approximately 150 subjects have been treated with ADU-S100. As of 28 January 2020), pyrexia 
was reported in 12 subjects (25.5%) and 26 subjects (25.5%) in the single agent and combination 
studies, respectively. Chills were reported in 8 subjects (17%) and 9 subjects (8.8%) in the single 


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agent and combination studies, respectively. No grade 3 or grade 4 fever or chills were reported. 
In addition, Grade 3 CRS was reported as a SAE in 1 patient receiving ADU-S100 in 
combination with pembrolizumab enrolled in the ADU-CL-20 study. 
Based on clinical trial results (KEYNOTE-048), pembrolizumab is now considered first-line 
standard of care and will be administered in this trial at a dose level and regimen aligned with 
KEYNOTE-048 and the approved prescribing information. Treatment with pembrolizumab has 
been associated with severe and life-threatening immune-mediated adverse reactions in some 
patients, requiring close monitoring during and after discontinuation of pembrolizumab 
(KEYTRUDA 2020). The safety mitigation plan (Table 5-2) is based on general risks associated 
with the route of administration, clinical experience, and the proposed mode of action of ADU-
S100/pembrolizumab. 
Since this is the first study to investigate administration of ADU-S100 with pembrolizumab, 
there may be unexpected toxicities. All available data will be reviewed as needed by a Safety 
Review Team (SRT; Section 5.4.1). The risk to subjects in this trial may be mitigated by 
compliance with the eligibility criteria and study procedures, close clinical monitoring, and by 
applying dose modification/dose delay criteria when necessary.  
Table 5-2 Key Safety Considerations and Mitigation Strategy  
Safety 
Consideration 
Basis for 
Potential Risk 
Mitigation Strategy 
Immune-related 
adverse events 
Mechanism of 
action 
• Symptom management and dose modification guidelines based on 
historical data and current standards of care (e.g. pembrolizumab 
prescribing information) provided in protocol 
• Extended safety monitoring and continued dosing eligibility based 
on warnings and precautions noted in pembrolizumab prescribing 
information 
Infusion-related 
reaction 
Route of 
administration 
Symptom management and dose modification guidelines based on 
pembrolizumab prescribing information 
ADU-S100 related 
adverse events 
Mechanism of 
action 
Dose modification guidelines based on available data and general 
practices in the development of immunomodulatory drugs provided in 
protocol  
Injection site 
reactions 
Route of 
administration 
Symptom management and dose modification guidelines provided in 
the protocol and IB 
Cytokine release 
syndrome 
Mechanism of 
action 
• Symptom management guidelines provided in protocol and IB 
• Laboratory assessment of cytokine panel for safety incorporated in 
Schedule of Events 
Embryo-fetal toxicity 
Mechanism of 
action 
Trial eligibility includes contraception requirements for WOCBP and 
male subjects with WOCBP partners; pregnant or breast-feeding 
WOCBP are excluded 
IB=Investigator Brochure; WOCBP=women of child-bearing potential 
5.4.1 
Safety Review Team 
Subject safety will be monitored throughout the trial by an SRT established by the Sponsor. This 
committee will monitor treatment-emergent safety data (or other available data as warranted) on 
an ongoing basis for the purpose of ensuring the continued safety of subjects enrolled in this 
study. 


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The SRT consists of investigators who enrolled subjects in the study, the Medical Monitor, and 
Sponsor representatives. The SRT will meet on an ad hoc basis to review available data; 
documentation of meeting outcomes will be maintained by the Sponsor. The SRT may also 
recommend a pause or discontinuation in enrollment or recommend discontinuation of the study 
if an unfavorable change in subject risk/benefit assessment is observed. 


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6 
OBJECTIVES AND ENDPOINTS 
The study has been designed with an appropriate study population, sufficient size, and duration 
to meet the study objectives and associated endpoints: 
OBJECTIVES 
ENDPOINTS 
Primary 
• Evaluate the clinical efficacy of ADU-
S100 administered in combination with 
pembrolizumab    
• Objective response rate (ORR; complete response [CR] and 
partial response [PR]) per Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1 
Secondary 
• Characterize safety and tolerability  
• Occurrence and severity of treatment-emergent adverse events 
• Changes from baseline in safety assessments 
• Further evaluate clinical activity 
 
 
 
[removed by amendment] 
• Characterize the pharmacokinetics (PK) of 
ADU-S100 administered by intratumoral 
injection following a single dose and 
multiple doses 
• Overall survival  
• ORR per modified RECIST v1.1 for immune-based 
therapeutics (iRECIST) 
• Progression-free survival, duration of response, disease 
control, and duration of disease control per RECIST v1.1 and 
iRECIST 
• Plasma concentration-time profiles and if feasible derived 
noncompartmental PK parameters (including Cmax, AUC) 
Exploratory [removed by amendment] 
• Assess pharmacodynamic, 
immunomodulatory, and potential 
prognostic and/or predictive biomarkers 
• Pharmacogenetic analysis  
• Changes from baseline in selected protein, cellular, and 
genomic expression parameters from blood and tissue 
samples; prognostic and/or predictive value 
• Exploration of individual subject DNA sequence variations 
(e.g. single nucleotide polymorphisms [SNPs]) and 
relationship with safety, tolerability, and clinical benefit 
 
 


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7 
INVESTIGATIONAL PLAN 
7.1 
Study Design  
ADU-CL-20 is an open-label, multicenter Phase 2 clinical trial to evaluate the efficacy and 
safety of intratumoral ADU-S100 (also referred to as MIW815) administered with standard of 
care treatment (i.e. pembrolizumab) in the first-line setting. The population will consist of adults 
with PD-L1 positive recurrent or metastatic HNSCC. Up to twenty (20) evaluable subjects will 
initially be enrolled.   
The trial design consists of a Screening Period, Treatment Period, and an End of Treatment 
(EOT) visit as depicted in Figure 7-1. All eligible subjects will receive intravenous (IV) 
infusions of pembrolizumab (200 mg; per approved product label) and intratumoral injections of 
ADU-S100 (800 mcg/lesion). During the Treatment Period, study medications will be 
administered in 21-day dosing cycles; tumor responses will be evaluated at 9-week intervals. If 
the injected lesion(s) shows signs of significant regression (i.e. shrinkage) such that repeat 
administration of ADU-S100 is no longer possible in any lesion, the subject will be scheduled to 
complete the EOT visit and may continue treatment with pembrolizumab as 
monotherapy/standard of care outside the context of the ADU-CL-20 clinical trial. Subjects who 
do not complete at least one response evaluation, unless they discontinued due to toxicity, will 
not be considered evaluable. An EOT visit will be conducted to assess subsequent anti-cancer 
therapy, and complete safety reporting requirements. A schedule of visits and procedures is 
provided in Table 2-1. 
Figure 7-1 
ADU-CL-20 Study Design 
 


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7.2 
Duration of Subject Participation 
Following a Screening Period (up to 28 days), eligible subjects will be enrolled and receive 
ADU-S100 and pembrolizumab in continuous, 21-day cycles during the Treatment Period until 
criteria for treatment discontinuation are met (Section 8.3) or up to 35 cycles. At the end of the 
Treatment Period, subjects will complete an EOT visit and complete requisite safety reporting 
periods (Table 10-1). 
7.2.1 
End of Study 
The end of the study is defined as the date when all subjects have completed the final protocol-
specified assessment and/or discontinued study participation (withdrawal of consent or lost to 
follow-up). 
The Sponsor may terminate the study at any time for any reason. Should the study be terminated, 
subjects will be contacted to complete the End of Treatment (EOT) visit and protocol-defined 
safety follow-up procedures. 
7.2.2 
Stopping Rules 
Subjects will be monitored throughout the study for toxicities; provisions are in place for dose 
modification and oversight by the SRT. If the SRT considers the safety profile and/or biological 
activity of ADU-S100/pembrolizumab inadequate (at one or both dose levels), enrollment may 
be stopped, or the study may be terminated at any time. 
The following additional safety rules apply to further mitigate potential risk to subjects: 
• Grade 5 toxicity (death) in any subject within 28 days of receipt of study drug(s) unless 
clearly related to an alternative cause other than study drug 
• Unacceptable toxicity leading to treatment discontinuation (per Section 8.3.2) occurring 
in >33% of subjects  
Should these events occur the SRT will evaluate available data within 72 hours of notification of 
the event(s) and recommend whether to stop the study, suspend dosing and/or enrollment, or 
determine whether additional dose adjustments are warranted. 
7.3 
Discussion of Study Design 
This trial is a Phase 2 open-label study intended to provide information regarding the efficacy, 
safety, and biological activity of ADU-S100 when administered with pembrolizumab. The dose 
of ADU-S100 selected for evaluation is based on available clinical data from other studies of 
ADU-S100 administered as monotherapy or with another checkpoint inhibitor. As of 28 January 
2020, ADU-S100 has been administered to approximately 150 subjects with advanced cancers; 
no DLTs have been observed at dose levels proposed in this trial.  


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Given the life-threatening nature of the disease and the availability of pembrolizumab as an 
approved treatment option in this study population, a placebo-controlled trial is not appropriate 
in this setting or at this stage of clinical development. Since all subjects will receive the same 
study drugs (ADU-S100 and pembrolizumab) blinding is unnecessary; study drugs will be 
provided open-label.  
The trial is the first to investigate injection of multiple lesions (where available). The study was 
also initially designed to characterize the plasma concentrations of ADU-S100 following a single 
dose and repeat dosing. Abscopal effect (i.e. treatment effect at a site outside the injected lesion) 
may also be assessed by biomarker analysis using tumor tissue from distal/non-injected lesion or 
tumor imaging should a distal lesion not be amenable to biopsy. 
The data obtained in this study will inform further clinical development decisions and provide 
necessary data for the design and conduct of future trials. 


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8 
STUDY POPULATION 
The population for this study will consist of adults with metastatic HNSCC where 
pembrolizumab is indicated as standard of care first line treatment.  
Individuals with intercurrent illnesses, inadequate organ function, various conditions impacting 
immune function, or other mitigating factors as detailed in the exclusion criteria will not be 
enrolled as these factors may interfere with the proposed mode of action of ADU-S100 and 
pembrolizumab, introduce undue safety risks, or confound interpretation of study results.  
8.1 
Inclusion Criteria 
Individuals eligible to participate in this study must meet the following criteria: 
1. Male or female aged ≥18 years  
2. Histological or cytological confirmation of recurrent or metastatic HNSCC 
3. Measurable disease as defined by RECIST v1.1  
4. [Criterion removed in Amendment 3] 
5. PD-L1 positive (defined as combined positive score [CPS] ≥1 using the Dako PD-L1 22C3 
pharmDx companion diagnostic assay) 
6. At least one lesion that is: 
• Superficial (e.g. cutaneous, subcutaneous) and/or nodal 
• Measures ≥10 millimeters (mm; post-biopsy) and <100 mm in longest diameter; nodal 
lesions must be ≥15 mm (post-biopsy) at short axis 
• Accessible for repeat intratumoral injection: Tumors encasing or abutting major vascular 
structures (such as the carotid artery) or tumors in locations at high risk for adverse 
effects (e.g. pneumothorax, brain lesions) are not considered appropriate for intratumoral 
injection. An irradiated mass cannot be used for intratumoral injection unless 
radiotherapy was completed at least 28 days prior to first dose of study drug and/or the 
lesion demonstrates evidence of growth (metabolically active via positive positron 
emission tomography or an unambiguous increase in size). 
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 


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8. Adequate organ and marrow function at Screening, as defined by the following laboratory 
parameters: 
Hematologic 
Renal 
Hepatic 
White blood cell count ≥2000/µL 
Absolute neutrophil count ≥1000/µL 
Platelets ≥75,000/µL 
Hemoglobin  ≥9 g/dL 1 
Albumin ≥3.0 g/dL 
aPTT and/or INR ≤1.5 × ULN 2 
Creatinine ≤1.5 × ULN or GFR 
≥ 30 mL/min/1.73m2 by CKD-EPI 
equation:  
 
GFR = 141 x min(SCr /k, 1)α x max(SCr 
/k, 1)-1.209 x 0.993Age x 1.018 [if female] x 
1.159 [if black]  
 
Note: SCr is standardized serum 
creatinine in mg/dL, k is 0.7 for females 
and 0.9 for males, a is -0.329 for females 
and -0.411 for males, min indicates the 
minimum of SCr /k or 1, and max 
indicates the maximum of SCr /k or 1 
AST/ALT ≤2.5 × ULN; 
or  
≤5 × ULN for subjects 
with liver metastases  
Bilirubin ≤1.5 × ULN; 
or  
≤3 × ULN if due to 
Gilbert’s disease 
ALT = alanine aminotransferase; aPTT= activated partial thromboplastin time; AST = aspartate 
aminotransferase; INR= International normalized ratio of prothrombin time; ULN = institutional upper limit 
of normal 
1 Transfusions are allowed; hemoglobin must be ≥9 g/dL for at least 7 days after transfusion and prior to 
dosing 
2 If receiving anticoagulant therapy, values should be within therapeutic range of intended use 
9. Women of childbearing potential (WOCBP) and fertile males with WOCBP partners must 
use highly effective contraception (CTFG 2014) throughout the trial and for the latter of: 4 
months following the final dose of pembrolizumab or 30 days after the last dose of ADU-
S100 
10. Provide written informed consent and is willing and able to comply with all study 
procedures. 
8.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study: 
1. Diagnosis of recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma 
of unknown primary histology; or salivary gland or non-squamous histologies (e.g. mucosal 
melanoma) 
2. Disease amenable to local therapy with curative intent (surgery or radiation therapy with or 
without chemotherapy) 
3. Prior systemic anti-cancer therapy (use of chemotherapeutic agents, targeted small 
molecules, immunotherapy, or monoclonal antibodies) for the treatment of recurrent or 
metastatic HNSCC  
[Prior chemotherapy and/or or radiotherapy in the adjuvant or neoadjuvant setting is 
acceptable provided at least 28 days have elapsed since last dose, and/or the irradiated lesion 
demonstrates evidence of growth or active tumor).] 


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[Prior use of anti-PD-1 (or other drugs targeting immune checkpoint pathways) in the 
adjuvant or neoadjuvant setting is acceptable provided the total treatment period was ≤3 
months in duration; the last dose was ≥6 months before the first dose of study drug; and anti-
PD-1 treatment was not discontinued due to treatment-related toxicity.] 
4. Symptomatic or untreated leptomeningeal disease 
5. Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that 
require local CNS-directed therapy (such as radiation or surgery) or increasing doses of 
corticosteroids within the 2 weeks prior to first dose of study drug. Any symptomatic brain 
metastases should be neurologically stable (for 4 weeks post treatment and prior to study 
entry) with no corticosteroids administered for at least 2 weeks before first dose of study 
drug. Definitively treated CNS disease following gamma knife/stereotactic radiosurgery with 
no corticosteroids administered for at least 1 week before first dose of study drug should not 
be excluded. 
6. Radiotherapy within 2 weeks of the first dose of study drug, except for palliative 
radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful 
tumor mass  
7. Participation in an interventional, investigational trial where an intervention was received 
within 4 weeks of the first dose of study drug 
8. Prior severe hypersensitivity (≥ Grade 3) to pembrolizumab or any study drug excipients 
(e.g. L-histidine, sucrose or polysorbate 80) 
9. History of or current drug-induced interstitial lung disease or pneumonitis Grade ≥2  
10. Impaired cardiac function or clinically significant cardiac disease, including any of the 
following: 
• Symptomatic congestive heart failure requiring treatment 
• Clinically significant cardiac arrhythmia 
• Uncontrolled hypertension 
• Corrected QT interval (QTcF) >480 msec at Screening (average of triplicate ECGs) or 
congenital long QT syndrome 
• Acute myocardial infarction or unstable angina pectoris < 3 months prior to the first dose 
of study drug 
• New York Heart Association Functional Class III or higher (i.e. marked limitation of 
physical activity due to symptoms, or unable to carry on any physical activity without 
discomfort) 
11. Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (>10 mg/day 
prednisone or equivalent) or any immunosuppressive therapy within 7 days prior to the first 
dose of study drug. Topical (<class III), inhaled, nasal and ophthalmic steroids are allowed 
except in the anatomic location of injected and non-injected lesions. 
12. Receipt of any live vaccines within 4 weeks prior to first dose of study drug 
13. Use of hematopoietic colony-stimulating growth factors [e.g. granulocyte colony-stimulating 
factor (G-CSF), GM-CSF, macrophage colony-stimulating factor (M-CSF)], thrombopoietin 


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mimetics or erythroid stimulating agents ≤2 weeks prior to first dose of study drug. Erythroid 
stimulating agents may be maintained if initiated more than 4 weeks prior to the first dose of 
study drug and the dose is stable 
14. Received a diagnosis of, and/or tests positive at Screening for human immunodeficiency 
virus (HIV) 
15. Active Epstein-Barr virus (EBV), hepatitis B virus (HBV), or hepatitis C virus (HCV) 
infection 
16. Active infection (viral, bacterial, or fungal) requiring systemic therapy 
17. Prior history of or active malignant disease other than that being treated in this study. 
Exceptions: malignancies that were treated curatively and have not recurred within the past 2 
years; completely resected basal cell carcinoma and squamous cell carcinoma of the skin; 
and completely resected carcinoma in situ of any type. 
18. Active, known, or suspected autoimmune disease or a documented history of autoimmune 
disease, except vitiligo or resolved childhood asthma/atopy. 
Individuals with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone 
replacement, psoriasis not requiring systemic treatment, history of Hashimoto’s thyroiditis on 
stable dose of thyroid hormone replacement therapy, adrenal insufficiency only requiring 
physiologic steroid replacement, or conditions not expected to recur should not be excluded. 
19. Major surgery within 2 weeks of the first dose of study drug 
20. If WOCBP, pregnant or breastfeeding; negative pregnancy status must be confirmed by 
serum pregnancy (human chorionic gonadotropin) test at Screening 
21. Intercurrent illness that is either life-threatening or of clinical significance such that it might 
limit compliance with study requirements, or in the Investigator’s assessment would place 
the subject at an unacceptable risk for participation. 
8.3 
Subject Completion, Treatment Discontinuation, or Removal from Study 
8.3.1 
Subject Completion 
Subject completion is defined as completion of scheduled visits and assessments up to and 
including the last protocol-specified visit; or when the subject has experienced a clinical 
endpoint (e.g. death, unacceptable toxicity, confirmed disease progression) that precludes further 
continuation in the study. 
8.3.2 
Discontinuation from Study Treatment 
A subject should be discontinued from treatment for any of the following reasons: 
• Withdrawal of consent or subject requests study treatment discontinuation for any reason 
• Occurrence of any medical condition or circumstance that exposes the subject to 
substantial risk and/or does not allow the subject to adhere to the requirements of the 
protocol 
• Confirmed disease progression (Section 10.2.1.1) 


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• Any unacceptable toxicity, SAE, clinically significant AEs, severe laboratory 
abnormality, intercurrent illness, or other medical condition which indicates to the 
Investigator that continued participation is not in the best interest of the subject 
• Subject experiences any Grade 4 adverse event, with the exception of those listed in 
Table 9-2 
• Pregnancy 
• Subject failure to comply with protocol requirements or study-related procedures. 
[Dosing compliance issues should be reviewed on a case-by-case basis with Medical 
Monitor.] 
• Termination of the study by the Sponsor or regulatory authority 
Subjects who experience unacceptable toxicity directly attributable to pembrolizumab may 
continue on study and receive ADU-S100 as single agent study treatment with approval by the 
Medical Monitor. 
If a subject's study treatment (ADU-S100 and/or pembrolizumab) is discontinued, this will not 
result in automatic withdrawal of the subject from the study. The Investigator will provide a 
reason for treatment discontinuation. Subjects who discontinue treatment will be encouraged to 
complete EOT and follow-up assessments. 
8.3.3 
Subject Discontinuation/Withdrawal from the Study 
A subject will be withdrawn from the study for any of the following reasons: 
• Death 
• Lost to follow-up 
• Withdrawal of consent 
• Termination of the study by the Sponsor or regulatory authority 
Subjects who do not complete at least one response evaluation, prior to their withdrawal from the 
study, unless they discontinued due to toxicity, will not be considered evaluable for the primary 
efficacy endpoint.   
If a subject is lost to follow-up, reasonable efforts must be made by the study site personnel to 
contact the subject and determine the reason for discontinuation/withdrawal. The measures taken 
to follow up must be documented. 
When a subject withdraws for other reasons before completing the study, the Investigator will 
provide a reason for withdrawal in the electronic case report form (eCRF). 


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9 
STUDY DRUGS AND ADDITIONAL MEDICATIONS 
All subjects will receive the investigational product, ADU-S100, and standard of care, 
pembrolizumab (per approved label language). Information regarding study drug administration 
is provided in the sections below. 
9.1 
Method of Subject Assignment 
All subjects will be sequentially assigned a unique identification number during Screening. The 
study is designed as a single-arm study; all subjects will receive ADU-S100 and pembrolizumab 
as indicated. 
9.2 
Blinding 
All study treatments will be administered open-label; no study participants or site personnel will 
be blinded to study treatment. 
9.3 
Standard of Care: Pembrolizumab 
Pembrolizumab is an IgG4 kappa immunoglobulin with an approximate molecular weight of 146 
kDa. Pembrolizumab for injection is supplied in single-dose vials as a sterile, preservative-free, 
white to off-white lyophilized powder; each vial is reconstituted and diluted for IV infusion.  
Pembrolizumab is indicated for the treatment of HNSCC as a single agent for the first-line 
treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors 
express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test. 
Additional information on the product presentation, formulation, storage, preparation and 
administration of pembrolizumab may be found in the package insert (KEYTRUDA 2020). 
On dosing days where both pembrolizumab and ADU-S100 are indicated, administer the 
pembrolizumab infusion first, followed by intratumoral injection of ADU-S100. 
9.3.1 
Pembrolizumab Pre-Medications 
Use of pre-medications (e.g. anti-pyretic or anti-emetic) for infusions should be based on 
Investigator discretion, institutional guidelines, and the subject’s tolerance of prior infusions. 
9.3.2 
Pembrolizumab Infusion 
Prepare, store, and administer pembrolizumab per package insert. The dose of pembrolizumab is 
200 mg Q3W by IV infusion over approximately 30 minutes. Record the start and stop times for 
each infusion. 
9.3.3 
Supportive Care  
Supportive care according to local standards may be used as needed. Record all medications for 
supportive care as concomitant medications.  


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9.3.4 
Criteria for Continued Pembrolizumab Dosing  
Immune-mediated reactions have been associated with pembrolizumab (KEYTRUDA 2020) and 
can result in severe and life-threatening events. Subjects will be assessed prior to each dose of 
pembrolizumab per criteria in Table 9-1; symptom-directed examinations according to local 
standards of care and laboratory tests may be performed up to 3 days before dosing. 
Table 9-1 Continued Dosing Requirements 1 
Clinical Assessment 
Organ Function 
Assess for clinically meaningful signs and 
symptoms of: 
• Colitis 
• Skin adverse reactions 
• Pneumonitis 
• Hypophysitis 
Monitor for clinically significant, treatment-emergent changes in: 
• Liver function 
• Thyroid function 
• Hyperglycemia 
• Renal function 
1Adapted from KEYTRUDA Warnings and Precautions (KEYTRUDA 2020); the most recent label should also be 
consulted for any updates to Warnings and Precautions. 
Subjects who do not meet dosing eligibility requirements will be monitored; guidelines for dose 
interruption (Section 9.5) and dose modification (Appendix A) should be followed where 
appropriate. 
9.4 
Investigational Product: ADU-S100 
ADU-S100 is supplied as a sterile solution for injection. ADU-S100 is a clear to slightly 
opalescent, colorless to pale yellow solution of 1 mg/mL. ADU-S100 is supplied in a single-use, 
2 mL, Type 1 clear glass vial with a butyl stopper and a flip-off overseal. 
The investigational product was manufactured, packaged, and labeled according to Good 
Manufacturing Practice (GMP) regulations. Section 14.2.1 provides guidance for disposition and 
accountability of investigational products. Additional information on physical and chemical 
properties of ADU-S100 may be found in the IB.  
Details for storage, preparation, and administration of ADU-S100 are provided in the Pharmacy 
Manual. The following sections provide general guidance on ADU-S100 administration, dosing 
modifications, and management of study-drug associated toxicities. 
9.4.1 
ADU-S100 Pre-Medications 
Use of pre-medications (e.g. local anesthetic and/or acetaminophen) for intratumoral injections 
will be based on Investigator discretion, institutional guidelines, and the subject’s tolerance of 
prior injections. Local anesthetic should not be injected directly into the target lesion. 


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9.4.2 
ADU-S100 Administration 
9.4.2.1 
Identification of Lesions for Intratumoral Injection 
At the Screening Visit (or prior to first dose of ADU-S100), the Investigator will document all 
potential lesions available for intratumoral injection, and identify the lesions selected for 
intratumoral injection.  
• Up to 2 cutaneous, subcutaneous, or nodal lesions may be designated for intratumoral 
injection. Per eligibility criteria, one subcutaneous/cutaneous lesion must measure ≥10 mm 
(post-biopsy, if applicable), or ≥15 mm if nodal; and <100 mm in longest diameter. The 
second injectable lesion may be smaller than the specified size if no other injectable lesion 
of the specified size can be identified. Selection of injectable lesions should be from 
different regions of the body (if possible) to provide greatest coverage and target multiple 
draining lymph nodes. Should any initial lesion recede following treatment such that they 
are no longer visible, or injection is no longer feasible, other lesions may be selected for 
injection (Section 9.4.2.3). These lesions may also be smaller than the specified size, if no 
other injectable lesions of the specified size can be identified. 
• Tumors encasing or abutting major vascular structures (such as the carotid artery) or 
tumors in locations at high risk for adverse effects (e.g. pneumothorax, brain lesions) are 
not considered appropriate for intratumoral injection. 
• An irradiated mass cannot be used for intratumoral injection unless radiotherapy has 
occurred at least 3 months prior to first dose of study drug and/or the lesion demonstrates 
evidence of growth or active tumor (e.g. positive PET scan or increase in size). 
• All injected lesions must be deemed measurable and followed per RECIST 1.1 (see 
Appendix B) 
The priority is to identify and inject ADU-S100 in up to 2 lesions. If a subject has >2 lesions, or 
if a lesion is not amenable to repeat intratumoral injection, but is accessible and amenable to 
biopsy, one lesion (or visceral tumor) may be designated a “non-injected” lesion.  
9.4.2.2 
Intratumoral Injection of Lesions 
The intratumoral injection of ADU-S100 should only be performed by trained personnel. On 
dosing days where pembrolizumab is also administered, ADU-S100 should be administered 
following completion of the pembrolizumab infusion provided the subject is considered 
clinically stable. 
All lesions designated for ADU-S100 administration should be injected on Days 1 and 8 of each 
dosing cycle (i.e. do not rotate/alternate sites for injection, all designated lesions will be injected 
on every dosing day unless repeat administration is no-longer possible, See Section 9.4.2.3). 
Confirm biopsy area has healed prior to initiating dosing.  


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ADU-S100 will be diluted as described in the Pharmacy Manual to achieve the assigned dose 
level prior to administration. An injection volume of 1.0 mL ADU-S100 dosing solution should 
be administered per lesion. 
Local anesthetic may be used per institutional guidelines but should not be injected directly into 
the lesion. Injection of ADU-S100 should be conducted per institutional guidelines using sterile 
technique. Ultrasound-guided injection may be utilized per institutional guidelines. The best 
attempt should be made to distribute the entire volume of ADU-S100 throughout the lesion; 
multiple passes may be used. Record the start and stop times for each administration. 
9.4.2.3 
Regression of Injected Lesions 
If a lesion shows signs of significant regression (i.e. shrinkage) that precludes the ability to re-
inject the lesion, other accessible lesions may be injected after documented discussion between 
the Investigator and the Medical Monitor.  
If the injected lesion(s) shows signs of significant regression such that only scar tissue is 
remaining, a PET scan should be performed to identify whether any tumor tissue remains. If no 
tumor tissue remains, administration of ADU-S100 at the lesion may be discontinued.  
After all lesions that meet requirements in Section 9.4.2.1 have been successfully treated, 
additional smaller lesions may be injected with ADU-S100 following consultation with the 
Medical Monitor. 
If the injected lesion(s) shows signs of significant regression (i.e. shrinkage) such that repeat 
administration of ADU-S100 is no longer possible in any lesion, the subject will be scheduled to 
complete the EOT visit and may continue treatment with pembrolizumab as 
monotherapy/standard of care outside the context of the ADU-CL-20 clinical trial. Previously 
resolved injected lesions that recur can be re-injected as long as the subject has not met criteria 
for treatment discontinuation (Section 8.3.2). 
9.5 
Dose Interruptions and Dose Modification for Treatment-related Toxicities 
Dose interruptions are recommended for subjects who do not tolerate the protocol-specified 
dosing schedule. In the case of acute reaction to pembrolizumab infusion, the scheduled dose of 
ADU-S100 may be delayed (or withheld) following consultation with the Medical Monitor.  
Following the first 4 cycles of study treatment, dosing interruptions are also permitted in the case 
of medical / surgical events, palliative radiation, or logistical reasons not related to study therapy 
(e.g. elective surgery, unrelated medical events, vacation, and/or holidays), after discussion with 
the Medical Monitor. Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Medical Monitor. The reason for 
interruption should be documented in the subject’s study record. 


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Pembrolizumab: No dose reductions of pembrolizumab are recommended. Subjects who 
experience unacceptable toxicity directly attributable to pembrolizumab may continue on study 
and receive ADU-S100 as single agent study treatment with approval by the Medical Monitor.  
ADU-S100: For subjects who experience systemic TEAEs with a suspected relationship to ADU-
S100, the dose level of ADU-S100 may be reduced following sufficient resolution of the event 
(Section 9.5.1) and after consultation with the Medical Monitor.  
General guidelines for ADU-S100 dose reduction: 
• Reduce dose to 400 mcg/lesion 
• If tolerability issues persist, the dose level may be further reduced to 200 mcg/lesion 
• If tolerability issues persist at 200 mcg/lesion; discontinue ADU-S100 treatment 
The following sections provide guidance for management of general and specific toxicities 
which may be associated with administration of pembrolizumab or ADU-S100. 
9.5.1 
General Toxicity and Dose Modification Guidelines 
Occurrence of any of the TEAEs outlined in Table 9-2 requires dose modification and/or 
treatment discontinuation. No dose reductions of pembrolizumab are recommended. If 
discontinuation of pembrolizumab is warranted, a subject may continue on ADU-S100 
monotherapy following consultation with the Medical Monitor (Section 9.5.2). If ADU-S100 is 
discontinued due to a Grade 4 injection site reaction, monotherapy with pembrolizumab should 
continue and the subject will complete the EOT visit and safety monitoring periods. 
ADU-S100 dose reductions may be allowed following consultation with the Medical Monitor 
(Section 9.5.3). 


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Table 9-2 
Toxicities Requiring Dose Modification or Treatment Discontinuation 
Any Grade 4 AEs will lead to permanent treatment discontinuation with the exception of: 
• 
Neutropenia lasting ≤ 5 days that is not associated with fever or other clinical symptoms 
• 
Lymphopenia or leukopenia 
• 
Electrolyte abnormalities not associated with clinical sequelae or deemed not clinically 
significant and are corrected with appropriate management or supplementation within 72 
hours of onset 
Drug Induced Liver Injury (DILI) will lead to permanent study treatment discontinuation as 
indicated by serum chemistry values consistent with Hy’s Law criteria (all 3 of the following must 
co-exist): 
• 
ALT or AST ≥3× institutional upper limit of normal (ULN) 
• 
Total bilirubin ≥2× ULN 
• 
Alkaline phosphatase <2× ULN 
Grade 4 injection site reaction will lead to discontinuation of ADU-S100 
Grade 3 or higher infusion-related reaction will lead to discontinuation of pembrolizumab 
Any Grade 3 AEs may lead to dose modification or delay of either ADU-S100 or pembrolizumab 
after consultation with the medical monitor with the exception of: 
• 
Serum lipase and/or serum amylase (asymptomatic) CTCAE Grade 3 < 7 consecutive days 
• 
Nausea and vomiting that resolves within 2 days after starting optimal anti-emetic therapy 
• 
Thrombocytopenia without significant bleeding 
• 
Anemia that resolves within 7 days in the absence of transfusion 
• 
Diarrhea that resolves within 2 days after starting optimal anti-diarrhea treatment 
• 
Hypertension that resolves within 7 days after starting treatment 
• 
Infection or fever in the absence of neutropenia that resolves within < 5 days 
• 
Rash or photosensitivity that resolves within 7 days after starting treatment 
• 
Fatigue that resolves within 7 days 
Grade 2 or 3 clinically significant injection site reactions will lead to delay and/or dose 
modification of ADU-S100 (See Section 9.5.4) 
Grade 2 clinically significant immune-related toxicities, including a single event or multiple 
occurrences of the same event per investigator discretion may lead to discontinuation of 
pembrolizumab 
Eye pain or reduction of visual acuity that does not respond to topical therapy and does not improve 
to Grade 1 severity within 2 weeks of the initiation of topical therapy OR requires systemic 
treatment may lead to discontinuation of pembrolizumab 
Any immune related AE that meets criteria for discontinuation (Appendix A) 
The following general dose modification guidelines should be followed for AEs outlined in 
Table 9-2 or other suspected study drug-related events: 
• If a subject experiences an AE outlined in Table 9-2 or other unacceptable toxicity, 
consult the Medical Monitor prior to resuming treatment 
• Generally if a dose is interrupted or withheld for AE, treatment may be resumed 
following resolution of the AE to Grade 1 or baseline 
o If the Investigator considers it in the subject’s best interest to resume treatment before 
the AE has resolved to Grade 1, the Medical Monitor should first be consulted. 


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• If dose interruptions persist > 6 weeks (from the expected day of dosing), the subject will 
be discontinued from the study treatment unless there is evidence of clinical benefit and 
the Investigator deems it is in the subject’s best interest to remain on study. In such cases, 
the Medical Monitor must be consulted. 
• ADU-S100 only: If a subject requires more than 2 dose interruptions for the same 
toxicity, ADU-S100 should be discontinued. 
9.5.2 
Management of Immune-related Adverse Events  
AEs with suspected immunologic etiology, which may be severe or fatal, can occur in any organ 
system or tissue in subjects receiving immunotherapy. These immune-related AEs (irAEs) may 
occur after the first dose or several months after the treatment discontinuation. Suspected irAEs 
should be adequately evaluated to confirm etiology or exclude other causes; additional 
procedures or tests may be included as part of the evaluation.  
Guidelines for dose modification and toxicity management for irAEs are provided in Appendix 
A; additional recommendations are provided in the American Society of Clinical Oncology 
clinical practice guideline for the management of irAE (Brahmer et al. 2018).  
Consult the current prescribing information for any updates to dose modification language for 
irAE or infusion reactions. 
9.5.3 
Guidelines for Pembrolizumab Infusion-related Reactions 
Per approved product label (KEYTRUDA 2020) the following guidelines are recommended for 
infusion-related reactions associated with pembrolizumab: 
• Grades 1 or 2: Interrupt or slow the rate of infusion 
• Grades 3 or 4: Discontinue pembrolizumab permanently 
9.5.4 
Guidelines for ADU-S100 Injection Site Reactions 
The following guidelines are recommended for injection site reactions related to ADU-S100: 
• Grade 1: Continue study treatment 
• Grade 2: Delay study treatment until resolved to ≤ Grade 1 
• Grade 3: Delay study treatment until resolved to ≤ Grade 1; resume treatment after 
consultation with the Medical Monitor 
• Grade 4: Permanently discontinue ADU-S100 treatment. 
9.5.5 
Cytokine Release Syndrome 
CRS is caused by a release of inflammatory cytokines such as IL-6, IL-1b, IFN-γ, and TNF-α. 
This type of reaction is sometimes observed in cancer immunotherapy and typically presents 
with symptoms including fever, nausea, chills, rash, flushing, rigors, hypotension, tachycardia, 
headache, throat tightness, and dyspnea. Capillary leak with fluid retention can be worsened by 


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hydration commonly given to treat hypotension. CRS may also be associated with pulmonary 
infiltrates, pulmonary edema, arrhythmias, and cardiac arrest. Note that symptoms of CRS vary 
greatly and may be difficult to distinguish from other conditions. 
If CRS is suspected, all subjects should be managed per local institutional practice based upon 
clinical signs and symptoms, and response to interventions. Patient management in an intensive 
care unit may be required and the timing is dependent upon local institutional practice. 
Tocilizumab may be administered in cases of moderate to severe CRS if any of the following are 
present: 
• Hemodynamic instability despite IV fluid challenges and moderate stable vasopressor 
support 
• Worsening respiratory distress, including pulmonary infiltrates, increasing oxygen 
requirement including high-flow O2, and/or need for mechanical ventilation 
• Any other signs or symptoms of rapid deterioration despite medical management 
Supportive care measures should be undertaken immediately as per institutional guidelines to 
include frequent vital signs, IV fluids, oxygen, steroids, and vasopressors as clinically indicated. 
If CRS is suspected, cytokines IL-6, IL-1, IFN-γ, and TNF-α and serum C-reactive protein 
(CRP) and ferritin will be analyzed at central laboratories to determine if cytokine elevation and 
biochemical abnormalities associated with CRS are observed. Refer to laboratory manual for 
further information.  
9.6 
Concomitant Medications 
Subjects may receive concomitant medications and procedures as required or deemed necessary 
for supportive care, unless specifically restricted or prohibited in this study (Section 9.6.1).  
During the course of the study, subjects should continue the use of prescribed medications 
identified during the screening procedures, consistent with study inclusion and exclusion criteria. 
• Anticoagulation therapy is permitted. Ongoing anticoagulant therapy should be 
temporarily discontinued to allow tumor biopsies according to institutional guidelines. 
• Coronavirus (COVID-19) vaccines are encouraged provided the vaccine is not a live 
vaccine (i.e. RNA vaccines are allowed); the vaccine should not be administered on the 
same day as study drug administration 
9.6.1 
Prohibited Medications 
A subject may be discontinued from study drug for use of prohibited medications or procedures. 
Approval must be obtained from the Medical Monitor for a subject to continue dosing if a 
prohibited medication is administered during study treatment. The following therapies are not 
permitted or are restricted during the study: 


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• Non-study chemotherapy, small molecule, immunotherapy, or other therapeutic 
monoclonal antibodies or biologics (approved or investigational) intended to treat the 
disease under study. 
• Additionally, no other immunosuppressive medication may be administered while on 
study treatment unless given for the management of immune toxicity. 
• Radiation therapy (non-palliative)  
NOTE: limited field palliative radiotherapy to non-target lesion(s) may be allowed as 
concomitant therapy after documented discussion with Medical Monitor 
• Any other investigational product or device 
• Systemic corticosteroids > 10 mg/day of prednisone or equivalent (unless used for 
treatment of study drug-related toxicity) except if given as a pre-medication or for 
contrast dye allergy 
• Live vaccines (including, but not limited to 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. Intranasal influenza 
vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not allowed. 
There are no prohibited therapies or procedures once the subject has completed the EOT visit. 
9.7 
Treatment Compliance 
Study drug will be administered by a qualified health care professional at an approved study site. 
The date, time, volume, location, and route of each dose of study drug administered to each 
subject must be recorded in the appropriate source document. 


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10 
STUDY ASSESSMENTS AND PROCEDURES 
Screening assessments will be conducted to confirm eligibility and to obtain baseline (pre-
treatment) measurements. Screening must be completed within 28 days prior to Cycle 1 Day 1. 
An enrollment form will confirm subject eligibility; baseline biopsies should not be performed 
until enrollment is confirmed.  
Subjects will be requested to complete multiple clinic visits during all dosing cycles. An EOT 
Visit should occur 30 (+7) days after the last dose of ADU-S100 and/or pembrolizumab. All 
EOT Visit assessments should be completed prior to commencing any new anti-cancer therapy. 
Subjects who discontinue ADU-S100 and pembrolizumab early for reasons other than 
progressive disease will complete the EOT. 
The EOT visit will be conducted to satisfy protocol-specified safety reporting periods (Table 10-
1) and collect data on any subsequent cancer-related therapies. 
All study visits (and visit windows), assessments, and procedures will be performed as indicated 
in the Schedule of Events (Table 2-1). On days when ADU-S100 or pembrolizumab is 
administered, assessments should be performed prior to dosing unless otherwise specified. 
Further details of study procedures and assessments can be found in the Study Reference and 
Laboratory Manuals. 
10.1 
General Assessments 
10.1.1 
Informed Consent 
Before any screening assessments are conducted, an individual must be given a complete 
explanation of the purpose and requirements of the study; an informed consent form (ICF) and 
an authorization for use and disclosure of protected health information must be signed. An 
original signed consent form will be retained in the subject’s source documentation at the site; a 
copy will be provided to the subject.  
Assessments conducted as standard of care prior to signing informed consent may be considered 
toward eligibility requirements if performed within the 28-day Screening Period. 
10.1.2 
Demographics, Medical History, and Height 
Demographic data and a complete medical history will be collected at Screening by the 
Investigator or qualified designee. Demographic information (as allowed by local regulations) 
will include date of birth, age, gender, ethnicity, and race. Medical history should include all 
active conditions and any past condition considered to be clinically significant by the 
Investigator.  
Details regarding the disease for which the subject has enrolled in this study (e.g. date of 
diagnosis, primary tumor histology, prior surgery(ies), radiation therapy, other prior treatment 
regimens, and current stage of cancer) will be recorded. 


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Height (without shoes) will be obtained at Screening with a stadiometer.  
10.1.3 
Eligibility  
Potential subjects will be evaluated for entry into the study according to the stated inclusion and 
exclusion criteria (Sections 8.1 and 8.2). Individuals deemed ineligible for study enrollment do 
not need to complete all screening procedures. The reason for ineligible status will be 
documented. Tests with results that fail eligibility requirements may be repeated once during the 
Screening Period if the Investigator believes the results to be in error. Additionally, a subject 
who fails screening may repeat the screening process one time if the Investigator believes there 
has been a change in eligibility status (e.g. after recovery from an infection). 
For subjects who meet all inclusion/exclusion criteria, an enrollment form will be completed and 
sent to Sponsor or designee for review and approval. No protocol eligibility waivers will be 
granted. The first dose of pembrolizumab and ADU-S100 will not be administered until the 
Investigator receives approval of the enrollment form. 
10.2 
Efficacy Measures 
The assessments to derive efficacy variables are described below and will be conducted 
according to the Schedule of Events in Table 2-1. Efficacy variables and associated analyses are 
described in Sections 6 and 12.5. 
10.2.1 
Tumor Imaging and Response Assessments 
Radiographic tumor evaluation should include baseline computed tomography (CT) scans with 
contrast of the chest, abdomen, head and neck. Magnetic resonance imaging (MRI) is the 
preferred imaging method for brain metastasis should be conducted if there are known or 
suspected CNS metastases. MRI is also the preferred imaging method for bone metastasis. In 
either case, if CT is performed instead of MRI, ambiguous results may be confirmed by MRI. An 
MRI scan may also be conducted for known or suspected bone metastases. Collect scans 
electronically. All injected lesions identified at baseline will be considered measurable lesions 
and measurements will be recorded per RECIST v1.1 (see Appendix B).  Additional lesions that 
are injected following successful treatment of initial injected lesions do not have to be 
measurable lesions. 
If CT scan is contraindicated (e.g. allergy to contrast dye), MRI should be performed. However, 
if lesion being followed cannot be imaged but can be assessed by clinical examination, 
measurements taken by usage of calipers will be acceptable. Tumor imaging will be performed 
using the same assessment technique throughout the study as indicated.  
For each scan, tumor measurements and assessment should be obtained using RECIST v1.1 
(Eisenhauer et al. 2009), see Appendix B; response assessment will be determined by the local 
Investigator. The Investigator/local radiology review will also use iRECIST (Seymour et al. 
2017) to assess tumor response and progression and make treatment decisions (see Appendix C).  


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10.2.1.1 
Confirmation of Disease Progression 
If disease progression is observed, another scan should be performed at 4-9 weeks later to 
confirm disease progression per iRECIST prior to treatment discontinuation (see Appendix C). 
While awaiting confirmation of disease progression subjects may continue to receive 
pembrolizumab and/or ADU-S100 provided the treatment discontinuation criteria in 
Section 8.3.2 do not apply.  
Subjects who have confirmed disease progression but have evidence of clinical benefit per the 
Investigator’s assessment may be considered for continued treatment after documented 
discussion with the Medical Monitor. Following that discussion, the subject should be informed 
by the Investigator of the option to continue study treatment or consider other therapeutic options 
with proven benefit, if those exist. 
In cases of clinical deterioration or suspicion of disease progression, follow-up imaging 
assessment should be performed promptly rather than waiting for the next scheduled assessment. 
Subjects with evidence of further disease progression and who are no longer deriving clinical 
benefit will be discontinued from treatment; the subject should complete the EOT Visit and enter 
the Follow-Up Period.  
Subjects who do not complete at least one response evaluation prior to their withdrawal from the 
study, unless they discontinued due to toxicity, will not be considered evaluable for the primary 
efficacy endpoint.   
10.2.2 
Photography of Injected Lesions 
[Removed by Amendment 4] 
10.2.3 
Subsequent Anti-Cancer Therapy Follow-Up 
At the EOT visit, any subsequent cancer-related therapy will be assessed until completion of the 
required safety reporting periods, death of the subject, withdrawal of consent, loss to follow-up, 
or close of study by the Sponsor.  
 All deaths must be reported on the eCRF. 
10.3 
Safety Assessments 
Safety will be assessed by collection of data on ECOG performance status, vital signs, weight, 
physical examination, electrocardiogram (ECG) parameters, TEAEs, concomitant medications, 
and routine clinical laboratory assessments. Clinically significant changes from pre-treatment 
values in safety assessments should be reported as AEs. Safety assessments described below will 
be conducted according to the Schedule of Events (Table 2-1). 
10.3.1 
Eastern Cooperative Oncology Group Scale of Performance Status 
The ECOG Scale of Performance Status is recognized as a standard tool to measure disease 
impact on daily living activities (Oken et al. 1982). The ECOG scale will be used by site 


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personnel to determine eligibility and characterize a subject’s level of functioning (self-care, 
daily activity, and basic physical ability) as indicated in Table 2-1. 
10.3.2 
Vital Signs 
Vital signs, including blood pressure, pulse rate, respiratory rate, and temperature will be 
obtained at each indicated visit (prior to dosing, as applicable). Serial time points following 
ADU-S100 administration support monitoring for CRS during Cycle 1. Collect vital signs prior 
to dosing and as indicated in Table 2-1. Additional measurements should be obtained if clinically 
indicated.  
10.3.3 
Physical Examination and Weight 
Comprehensive Physical Examination 
Comprehensive physical examinations will be conducted at Screening and EOT. Comprehensive 
physical examinations must be performed by a medically qualified individual such as a licensed 
Physician, Physician's Assistant, or an advanced Registered Nurse Practitioner, as local law 
permits.  
The comprehensive physical examination will include the following organ or body system 
assessments: skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular system; 
abdomen (liver and spleen); extremities; lymph nodes; and a brief neurological examination. 
Symptom-directed Physical Examination 
Symptom-directed physical examinations may be conducted at all other visits as indicated (up to 
3 days prior to dosing). The Investigator or medically licensed designee will perform a symptom-
directed evaluation as clinically indicated, including assessment(s) of the body systems or organs 
based on a subject’s symptoms, AEs, or other findings.  
Weight 
Weight (kilograms) will be obtained at each indicated visit (prior to dosing, if applicable). 
10.3.4 
Electrocardiogram 
At screening and during the study (Table 2-2), triplicate ECG assessments will be performed 
with local 12-lead ECG equipment according to standard procedures to determine the corrected 
QT interval calculated by Fridericia formula (QTcF). At screening, the average value of the 
triplicate will be utilized for enrollment into the study.  
The triplicates should be performed no less than 3 minutes apart, and within approximately 30 
minutes of the initial ECG to determine the mean QTcF interval. All 12-lead ECGs should be 
performed after the subject has rested in a recumbent or semi-recumbent position for ≥5 minutes. 
Additional ECGs may also be performed throughout the study if clinically indicated. Perform the 
ECGs prior to study drug administration for all pre-dose assessments, as outlined in Table 2-2. If 


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blood sampling or vital sign measurement is scheduled for the same visit as an ECG recording, 
the procedures should be performed in the following order: ECG, vital signs, blood draw. 
ECG parameters to be evaluated include heart rate, PR interval, QT interval, QRS duration, and 
QTcF (Fridericia's correction):  
QTcF = QT/ (RR)0.33 
The ECG will be interpreted by the Investigator as normal, not clinically significant abnormal, or 
clinically significant abnormal. If the mean QTcF is prolonged (i.e. >500 msec, or CTCAE 
Grade 3) or if the mean change from baseline (value obtained at screening) is ≥60 msec, the 
ECGs should be reevaluated by a qualified person. Abnormalities in the ECG that lead to a 
change in subject management (e.g. dose reduction, interruption, treatment discontinuation, 
requirement for additional medication or monitoring) or results in clinical signs and symptoms 
that are considered clinically significant will be deemed AEs or SAEs if serious criteria are met 
(see Section 10.3.5). 
10.3.5 
Adverse Events 
After signing informed consent, and prior to the first study drug administration, any medical 
occurrence considered related to screening procedures (e.g. tumor biopsy, venipuncture) will be 
captured as an AE; all other medical events will be captured in the subject’s medical history 
(Section 10.1.2). 
Safety reporting periods for this study are defined in Table 10-1. The determination, evaluation, 
reporting, and follow-up of AEs will be performed as outlined in Section 11 (irrespective of 
timing of withdrawal of consent of a subject). 


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Table 10-1 
Safety Reporting Periods 
Event Type 
Reporting Period 
Additional Requirements 
Adverse Events/Serious 
Adverse Events (Screening) 
Date of informed consent and prior to 
first dose of pembrolizumab 
Report as AE/SAE only if related to 
study procedures during Screening 
Adverse Events (treatment-
emergent) 
First dose of pembrolizumab through 
30 days following last dose of ADU-
S100 or pembrolizumab 
Report new AEs outside of window if 
assessed as related to study drug(s) 
Serious Adverse Events 
(treatment-emergent) 
First dose of pembrolizumab through 
30 days following last dose of ADU-
S100 or 90 days following last dose of 
pembrolizumab (if the subject initiates 
new anticancer therapy following 
cessation of pembrolizumab treatment, 
SAEs will be collected up to 30 days 
following cessation of pembrolizumab 
treatment.) 
Report new SAEs outside of window if 
assessed as related to study drug(s) 
Contact the subject by phone to 
complete the SAE reporting periods as 
applicable. 
Drug-induced liver injury 
(treatment-emergent) 
First dose of pembrolizumab through 
30 days following last dose of ADU-
S100 or pembrolizumab 
Report outside of window if assessed as 
related to study drug(s) 
Pregnancy of subject or 
partner 
Date of informed consent through 120 
days following last dose of 
pembrolizumab (if the subject initiates 
new anticancer therapy following 
cessation of pembrolizumab treatment, 
pregnancy information will be 
collected up to 30 days following 
cessation of pembrolizumab 
treatment.), or 30 days following last 
dose of ADU-S100 
Follow pregnancy reporting and follow-
up procedures per Section 11.5 
10.3.6 
Prior and Concomitant Medications 
Medications used within 28 days prior to the first dose of ADU-S100 will be recorded as prior 
medications.  
Concomitant medications include pre-medications and all prescription, over the counter 
medications, herbal remedies and dietary supplements administered from Cycle 1 Day 1 until the 
EOT visit. The generic name, dosage, duration, and reason for the concomitant medication 
should be documented. If a subject is using biotin supplements (found in multivitamins, biotin 
supplements, and supplements for hair, skin, and nail growth), also note for laboratory 
assessments (Section 10.4.2). Changes in the use of concomitant medications will be captured at 
each study visit. 
Following the EOT visit, concomitant medications will only be collected if associated with the 
management of an ongoing AE or SAE, or if a new anti-cancer treatment. 


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10.3.7 
Clinical Laboratory Evaluation for Safety 
Routine hematology, serum chemistry, coagulations, urinalysis, and thyroid function testing will 
be performed throughout the study as a safety measure (Section 10.4.2). The Medical Monitor 
may, depending on study criteria, be consulted before enrollment about a potential subject with 
abnormal laboratory values that are not considered clinically significant by the Investigator.  
The clinical significance of laboratory parameter findings will be determined by the Investigator 
throughout the study. More frequent clinical laboratory tests may be performed if indicated by 
the overall clinical condition of the subject or by abnormalities that warrant more frequent 
monitoring.  
Additional safety laboratory assessments include baseline cytokine levels and additional cytokine 
monitoring associated with CRS when clinically indicated. 
10.4 
Laboratory Assessments 
Laboratory assessments on blood, urine, and tumor tissue samples may be used to characterize 
the study population, assess safety, and characterize PD throughout the study per the Schedule of 
Events (Table 2-1). If indicated, collect Screening blood samples after requisite tests for 
eligibility have been completed. Samples indicated on dosing days must be pre-dose and may be 
obtained up to 3 days before Day 1 of each dosing cycle, unless otherwise indicated. 
10.4.1 
Screening-specific Laboratory Assessments 
Blood and urine samples will be obtained at screening to confirm eligibility for each subject. 
These initial laboratory assessments will be conducted at the institution’s local laboratory:   
Virology/Serology Screen: HIV antibody, HBV surface antigen, HCV antibody, HCV 
viral load (if indicated), EBV (EBNA, VCA IgG, VCA IgM, EBV PCR as clinically 
indicated) 
Urinalysis (dipstick or automated analysis): bilirubin, blood, glucose, ketones, 
leukocytes, nitrite, pH, protein, and specific gravity  
• If dipstick result is abnormal, microscopy will be used to measure sediment (red 
blood cells, white blood cells, epithelial cells, crystals, casts, bacteria) 
• Additional urinalysis may be performed throughout the study if clinically indicated 
10.4.2 
Safety Laboratory Assessments 
Routine hematology, serum chemistry, and thyroid function testing will be conducted to assess 
eligibility and as a measure of safety throughout the study per protocol requirements. All clinical 
laboratory evaluations will be performed by the institution’s local laboratory. Communicate to 
the laboratory if the subject is taking biotin (Section 10.3.6). Laboratory assessments for 
continued dosing of pembrolizumab must be confirmed prior to dosing (Section 9.3.4); testing 
may be completed up to 3 days prior to study drug administration for each cycle. Fasting is not 


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required; however fasting blood glucose should be performed if clinically indicated 
(Section 9.3.4).  
The following parameters will be evaluated:  
Hematology:  complete blood count (hematocrit, hemoglobin, platelets, red blood cells, 
white blood cells with differential [absolute counts: basophils, eosinophils, lymphocytes, 
monocytes, neutrophils]) 
Serum chemistry: albumin, alkaline phosphatase, ALT, AST, bicarbonate, calcium, 
chloride, lactate dehydrogenase, sodium, potassium, creatinine, glucose, magnesium, 
phosphate (inorganic phosphorus), bilirubin (total, direct), blood urea nitrogen, uric acid, 
total protein 
Coagulation panel: prothrombin time, international normalized ratio of prothrombin 
time, activated partial thromboplastin time 
Thyroid function: thyroid stimulating hormone (TSH), free tri-iodothyronine (FT3), free 
thyroxine (FT4) 
10.4.2.1 
Pregnancy Testing and Contraception Requirements 
The effects of ADU-S100 on a fetus in utero or on the composition of sperm are unknown. 
Based on its mechanism of action and data from animal studies, pembrolizumab can cause fetal 
harm when administered to a pregnant woman. Therefore WOCBP and fertile males must 
consent to use highly effective contraception per (CTFG 2014) while receiving study drug and 
for 4 months after the last dose of pembrolizumab (and/or 30 days after the last dose of ADU-
S100, whichever occurs later).  
A WOCBP is defined as any female who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal. 
Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 years in 
the absence of other biological or physiological causes.  
For study eligibility, WOCBP must have a negative serum pregnancy test (hCG) at Screening 
and within 24 hours prior to first dose of study drug (unless Screening assessment completed 
within 72 hours of Cycle 1 Day 1 visit). A urine pregnancy test may be performed at all other 
indicated visits. In case of delayed menstrual period (>1 month), confirm absence of pregnancy 
prior to next dose of study drug or next study visit, whichever occurs first. If a urine pregnancy 
test is positive, the results should be confirmed with a serum pregnancy test. Pregnancy of a 
subject or partner must be reported and followed (Section 11.4). 
10.4.2.2 
Laboratory Assessments for Cytokine Release Syndrome 
Blood (plasma) samples will be collected at Screening and as clinically indicated (Section 9.5.5) 
for assessment of IFN-γ, IL-6, IL-1, TNF-α, C-reactive protein, and ferritin. If CRS is suspected, 
a blood (plasma) sample should be collected within 5 hours (or as soon as possible) after 


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occurrence of the event, and 1 week after occurrence of the event. Samples will be shipped to the 
central laboratories for analysis. 
10.4.3 
Drug Concentration Measurements  
[Sample acquisition removed by Amendment 4] 
10.4.4 
Biomarker Assessments  
[Sample acquisition removed by Amendment 4] 
Evaluations that may be performed in this study include but are not limited to:  
• Measurement of systemic cytokines to assess PD 
• Determine relationship of STING genotype to response 
• Assess gene expression changes in the TME and the periphery  
• Determine phenotype and function of immune cells 
• Assessment of TME markers associated with immune infiltrate in injected and distal 
lesions 
10.4.4.1 
Pharmacogenetic Sample 
[Sample acquisition removed by Amendment 4] 
10.4.4.2 
Tumor Tissue (Biopsy) 
[Sample acquisition removed by Amendment 4] 
10.4.4.3 
Pharmacodynamics, Biomarkers, and Indicators of Biological Activity 
[Sample acquisition removed by Amendment 4] 
Additional analytical assessments and methodologies may be used to understand the mechanism 
of action ADU-S100 and pembrolizumab, or to understand factors associated with response or 
cancer progression. These tests may be performed at the Sponsor’s discretion and may include: 
additional phenotyping and cellular function analysis in the periphery; and gene expression 
changes in the tumor or periphery. 
10.5 
Appropriateness of Measures 
Clinical indicators of efficacy will be evaluated using RECIST v1.1 criteria for tumor response 
assessments, which are widely accepted as uniform response criteria for HNSCC. Since 
immunotherapeutic agents may produce antitumor effects by potentiating endogenous cancer-
specific immune responses, tumor response will also be evaluated using iRECIST. These 
response patterns may extend beyond the typical time course of responses seen with cytotoxic 


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agents and can manifest a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions.  
Assessments of progression-free and overall survival are also planned; PFS and OS are objective, 
direct measures of benefit, although interpretation may not only be limited by the size of the data 
set but also confounded by subsequent anti-cancer therapies and non-cancer deaths.  
The safety parameters to be evaluated in this study include standard assessments such as 
recording of medical history, AEs and SAEs, physical examination, vital signs, ECGs, serum 
chemistry and hematology, urinalysis, concomitant medications, and other routine clinical and 
laboratory procedures.  
The criteria for dose modification or treatment discontinuation are based on available clinical 
and nonclinical data for ADU-S100 combined with clinical experience and label language for 
pembrolizumab, and general practices in the development of immunotherapeutic agents. Since 
the safety profile of ADU-S100 has not been fully characterized and pembrolizumab is 
associated with serious risks, additional safety precautions (i.e. dosing eligibility and extended 
safety-reporting period) have been included to monitor subject safety. 
As may occur with any immunotherapeutic agent, ADU-S100 may elicit an immune response 
resulting in CRS. Subjects will therefore be monitored at baseline and as clinically indicated for 
cytokine levels as added safety measure (Section 9.5.5). 
Pre-treatment and on-treatment blood samples and tumor biopsies will provide an initial 
investigation into the mechanism of action of ADU-S100 when administered with 
pembrolizumab. Characterization of a broad panel of biomarkers may be predictive of response 
to therapy and may also give insight into appropriate endpoints in additional clinical studies.  


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11 
ADVERSE EVENT REPORTING 
AEs, SAEs, and pregnancy occurring during the protocol-specified timeframes defined in 
Section 10.3.5 will be assessed and reported following guidelines provided in the following 
sections. 
11.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An AE can therefore be any unfavorable and/or 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational medicinal product, whether or not related to the 
investigational medicinal product.  
Subjects should be instructed to report any AE that they experience to the Investigator. At each 
indicated visit, Investigators will assess for AEs. AEs will be monitored and documented on the 
AE eCRF.  
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE on the eCRF. Additionally, 
the condition that led to a medical or surgical procedure (e.g. surgery, endoscopy, tooth 
extraction, or transfusion) should be recorded as the AE term, not the procedure.  
For existing medical conditions reported as part of the medical history, clinically significant 
changes in signs or symptoms, or change in severity or seriousness should be reported as an AE.  
Clinically significant abnormal laboratory or other examination (e.g. ECG) findings that are 
detected during the study or are present at Screening and significantly worsen during the study 
should be reported as AEs. The Investigator will exercise his or her medical and scientific 
judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is 
clinically significant. Any abnormal test that is determined to be an error does not require 
reporting as an AE.  
Examples of AEs include the following:  
• Exacerbation of a chronic or intermittent preexisting condition, including an increase in 
frequency or intensity of the condition  
• Signs, symptoms, or the clinical sequelae of a suspected interaction with another medical 
product 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational agent or a concurrent medication.  


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Examples of AEs do not include the following:  
• Medical or surgical procedures (e.g. endoscopy, appendectomy); instead, the medical 
condition that led to the procedure is the AE term 
• Situations that are unwanted but in which an untoward medical occurrence did not occur 
(e.g. admissions for respite care)  
• Anticipated day-to-day fluctuations of a pre-existing disease or condition (present or 
detected before enrollment) that does not worsen overall  
11.1.1 
Disease-Related Events  
The term "disease progression" should be recorded as an AE only if there are no other 
identifiable AEs associated with the disease progression at the time of reporting. For events 
associated with disease progression, the relevant signs and symptoms should be reported using a 
diagnosis whenever possible rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate AE. 
If the events resulting from disease progression meet the criteria for an SAE (e.g. resulted in 
hospitalization, a life-threatening event, or death), the specific event(s) should be reported as an 
SAE(s).  
11.1.2 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each AE and the potential relationship 
between the AE and the study drug(s). 
11.1.2.1 
Assessment of Severity  
The severity of all AEs should be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE v. 5.0; 
http://ctep.cancer.gov/reporting/ctc.html). For AEs not listed in the CTCAE, the following 
grading system should be used:  
• Mild (CTCAE Grade 1): Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
• Moderate (CTCAE Grade 2): Moderate; minimal, local or noninvasive intervention 
indicated; limiting instrumental activities of daily living 
• Severe (CTCAE Grade 3): Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living 
• Life-threatening (CTCAE Grade 4): Life-threatening consequences; urgent intervention 
indicated  
• Death (CTCAE Grade 5): Death related to AE  


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11.1.2.2 
Assessment of Attribution 
The Investigator is obligated to estimate the relationship between the study drug(s) and the 
occurrence of each AE or SAE. The relationship (synonym: causality) is based on the 
Investigator’s clinical judgment regarding the likelihood that study drug caused the AE and may 
include consideration of some or all of the following factors:  
• Alternative possible causes of the AE, including the subject’s underlying disease or co-
morbid conditions, other drugs, or other host and environmental factors  
• The temporal sequence between the exposure to study drug and the AE  
• Whether the clinical or laboratory manifestations of the AE are consistent with known 
actions or toxicity of the study drug  
• Whether the AE resolved or improved with decreasing the dose or stopping the study 
drug (i.e. dechallenge); or recurred or worsened with re-exposure to the drug (i.e. 
rechallenge).  
The Investigator should consult the IB in the determination of the assessment. The Investigator 
should consider all possible etiologies for the AE and render a causality assessment based on the 
most likely contributing factor to the AE.  
There may be situations when an SAE has occurred and the Investigator has minimal information 
to include in the initial report. However, the Investigator must assess causality for every event 
before the transmission of the SAE. The Investigator may change his or her opinion of the 
causality in light of follow-up information, amending the SAE report.  
The assessment of the relationship between the AE and the study drug will be determined using 
one of the following attribution categories: 
RELATIONSHIP 
DESCRIPTION 
Unrelated to investigational 
agent/intervention 
The AE is clearly NOT related to the intervention 
The AE is doubtfully related to the intervention 
Related to investigational 
agent/intervention 
The AE may be related to the intervention 
The AE is likely related to the intervention 
The AE is clearly related to the intervention 
 
AEs listed as related are considered to have a suspected “reasonable causal relationship” to the 
investigational agent/intervention (ICH E2A). Per the ICH E2A and FDA guidelines, the 
expression "reasonable causal relationship" is meant to convey in general that there are facts 
(evidence) or arguments to suggest a causal relationship. 
Additional guidelines in describing relationship:  
• Related AEs follow a reasonable temporal sequence from the study drug administration 
and cannot be excluded as possibly or probably being caused by the study drug (e.g. 


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existence of similar reports attributed to the suspected drug and/or its analogues; 
reactions attributable to the pharmacologic effect of the drug) and can be excluded as 
possibly being caused by other factors such as underlying disease, complications, 
concomitant drugs, or concurrent treatment. The AE can be fully explained by the 
administration of study drug.  
• Not Related: AE does not follow a reasonable temporal sequence from the study drug 
administration and can be reasonably explained by other factors, including underlying 
disease, complications, concomitant drugs, or concurrent treatment. Another factor is 
clearly the cause of the AE.  
• For AEs occurring prior to initiation of study drug administration, the Investigator will 
assess relationship between the event and the protocol-required study procedures.  
11.1.3 
Adverse Event Follow-up 
Follow-up is required for all subjects with AEs until the event has been resolved or the condition 
has stabilized. Clinically significant abnormal laboratory values occurring during the clinical trial 
or at the EOT Visits should be followed until repeat tests return to normal, stabilize, or are no 
longer clinically significant. 
11.2 
Serious Adverse Events 
An AE or adverse reaction is considered serious if, in the view of either the Investigator or 
Sponsor, it results in any of the following outcomes:  
• Death  
• A life-threatening AE 
o NOTE: An AE or adverse reaction is considered “life-threatening” if, in view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk 
of death. It does not include an event that, had it occurred in a more severe form, 
might have caused death.  
• Requires hospitalization or prolongation of existing hospitalization 
o NOTE: Any hospital admission with at least one overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission will 
not be recorded as an SAE under this criterion, nor will hospitalization for a 
procedure scheduled or planned before signing of informed consent. However, 
unexpected complications and/or prolongation of hospitalization that occur during 
elective surgery should be recorded as AEs and assessed for seriousness. Admission 
to the hospital for social or situational reasons (i.e. no place to stay, live too far away 
to come for hospital visits) or for observation post-study drug administration will not 
be considered a SAE.  
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
• A congenital anomaly/birth defect  


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• An important medical event. 
o NOTE: Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, they may jeopardize the subject and/or may require medical or 
surgical intervention to prevent one of the outcomes listed above. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalizations, or the development of drug dependency.  
11.3 
Serious Adverse Event Reporting 
11.3.1 
Initial Reports 
An SAE report will be completed for each observed or reported SAE as thoroughly as possible 
including all available details about the event and the signature of the Investigator. If the 
Investigator does not have all information about an SAE, the Investigator will not wait to receive 
additional information before notifying the Sponsor of the event. The report will be updated 
when additional information is received. 
SAE information will be reported to the Sponsor or designee within 24 hours of awareness of the 
initial or any follow-up information. 
11.3.2 
Safety Reporting Contact Information 
SAE and pregnancy reporting contact information may be found in the Study Reference Manual. 
Sites should contact the Medical Monitor for any safety concerns or questions. 
11.3.3 
Expedited Reporting Requirements 
The Sponsor (or designee) will report all SAEs that are unexpected and considered related to the 
administration of the study drug to the appropriate health and regulatory authorities and 
Investigators in the form of an expedited safety report within 15 calendar days after receiving 
information on the SAE. The Investigators will notify their reviewing IRB/EC and other 
committee(s) as required by institutional policies.  
The Sponsor will also report to the appropriate health and regulatory authorities by facsimile, 
email, or phone within 7 days of receiving the information, any unexpected life-threatening or 
fatal SAEs that are considered related to the study drug. 
11.3.4 
Follow-Up Reports 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
subject dies.  


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Within 24 hours of receipt of follow-up information, the Investigator must update the SAE report 
and submit any supporting documentation (e.g. subject discharge summary or autopsy reports) 
via facsimile or email to the Sponsor or designee. 
11.4 
Drug-induced Liver Injury 
The potential for drug-induced liver injury will be monitored using assessments of liver function 
via serum chemistry at regular intervals. Laboratory values consistent with Hy’s Law criteria will 
be used to indicate the potential for drug-induced liver injury (i.e. all 3 of the following must 
coexist): 
1) ALT or AST ≥ 3 × ULN 
2) Total bilirubin ≥ 2 × ULN 
3) ALP < 2 × ULN 
Should the laboratory parameters suggesting drug-induced liver injury be observed, other 
potential causative factors may be investigated (e.g. viral hepatitis A, HBV, or HCV; preexisting 
or acute liver disease; or another drug capable of causing the observed injury).  
11.5 
Pregnancy Reporting 
If the subject or partner of a subject participating in the study becomes pregnant the Investigator 
should report the pregnancy and any follow-up information to the Sponsor or its designee within 
24 hours of awareness of the information.  
A subject becoming pregnant while on study drug will immediately be withdrawn from the study 
treatment and EOT and follow-up visit study procedures will be performed as appropriate. The 
Investigator should counsel the subject, discussing any risks of continuing the pregnancy and any 
possible effects on the fetus. If the subject gives permission for her treating physician to be 
informed, the Investigator is to notify the physician that she was participating in a clinical trial at 
the time she became pregnant and provide details of the treatment that the subject received.  
Monitoring of the subject or partner and pregnancy should occur until the conclusion of the 
pregnancy or final outcome. Therapeutic, accidental, or spontaneous abortion should be reported 
as an SAE. Similarly, maternal and/or newborn complications, any congenital anomaly or birth 
defect in a child born to a subject exposed to the study drug should be reported as an SAE.  
Report the outcome, including any premature termination. Follow live births for a minimum of 
12 months. Any relevant information received by the Investigator after these time periods will be 
forwarded to the sponsor.  
The pregnancy reporting form along with completion instructions are provided in the Study 
Reference Manual. 


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12 
STATISTICAL ANALYSIS 
The completeness of the data affects the integrity and accuracy of the final study analysis. 
Therefore, efforts will be made to ensure complete, accurate and timely data collection, and to 
avoid missing data. The procedures for handling missing, unused, or spurious data, along with 
the detailed method for analysis of each variable, transformations, and exploratory analyses will 
be presented in the Statistical Analysis Plan (SAP). 
Collection and Sponsor analysis of PK, PD, and other exploratory assessments was discontinued 
(Protocol Amendment 4); analysis of available PK/PD data and other exploratory laboratory 
assessments (obtained prior to Amendment 4) will be described separately. The information 
below is intended as a guide to planned analyses. 
12.1 
Sample Size Determination 
The original sample size was based on a Simon’s 2-stage minimax design (Simon 1989) test the 
null hypothesis that the objective response rate (ORR; complete response [CR] and partial 
response [PR]) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1) is less than or 
equal to 0.19 versus the alternative hypothesis that ORR is greater than or equal to 0.38, with a 
Type 1 error rate of 0.05 and power of 80%.   
Because of truncated enrollment, the total sample size will be limited to approximately 20 
evaluable subjects as planned for the first stage.   
Subjects who do not complete a response assessment will not be considered evaluable. 
The ORR criteria are based on the pembrolizumab first in human study in a similar patient 
population with similar prior treatment where the response rate was approximately 19% 
(Burtness et al. 2018; Rischin et al. 2019). 
12.2 
General Considerations 
Descriptive statistics will be provided for selected demographic, safety, and clinical activity data. 
Descriptive summaries on continuous data will include number of subjects, means, medians, 
standard deviations, minimum and maximum values. Categorical data will be summarized using 
frequency counts and percentages. Descriptive summaries of time to event data from Kaplan 
Meier estimates will include the number of events, number censored, medians, quartiles and 95% 
CIs. Graphical summaries of the data may be presented. All data will be listed for all subjects. 
Because of truncated enrollment by amendment, some analyses may not be performed if limited 
data are available. 
12.3 
Analysis Sets 
The following analysis sets will be used for this study: 
Evaluable Analysis Set (EAS): All subjects who received any amount of study drug and 
have at least one evaluable response assessment or were discontinued due to toxicity. The 


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EAS will be used for analysis of the primary efficacy endpoint and clinical activity. 
Safety population, defined as all subjects who receive any amount of study drug. All 
safety analyses will be based on this population.  
12.4 
Subject Information 
Subject disposition summaries will include the number of enrolled subjects, the number of 
subjects receiving any study drug, the number of subjects completing the study, the number of 
subjects withdrawing prematurely, and the reasons for treatment and study discontinuation.  
Demographics, baseline disease characteristics, prior disease related therapies, and concomitant 
medications will be summarized using descriptive statistics. 
12.5 
Efficacy Variables and Analyses 
Clinical response to ADU-S100/pembrolizumab will be determined by Investigator assessment. 
All efficacy endpoints will be defined and analyzed according to RECIST v1.1 (Eisenhauer et al. 
2009) (primary evaluation) and iRECIST (Seymour et al. 2017) (secondary evaluation).  
The following efficacy endpoints will be derived and summarized descriptively.  
12.5.1 
Primary Efficacy Endpoint 
Objective Response Rate defined as occurrence of complete response (CR) and partial response 
(PR). 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 will be used for the primary 
efficacy endpoint. 
12.5.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints are defined as: 
Overall Survival (OS) is defined as the time from first dose of study drug until date of death due 
to any cause. Subjects without documentation of death at the time of analysis will be censored as 
of the date the subject was last known to be alive.  
Progression-free survival (PFS) is defined as the time from first dose of study drug to first 
documentation of disease progression or death due to any cause. Subjects who do not experience 
progressive disease and are alive will be censored at the time of last evaluable tumor assessment. 
Duration of response (DOR) is defined as the time from the first tumor assessment that supports 
the subject’s objective disease response to the time of disease progression or death due to any 
cause.  
Disease control rate (DCR) is defined as subjects with CR, PR, or stable disease (SD).  
Duration of disease control (DODC) is defined as the time from the first tumor assessment that 
supports the subject’s disease control (CR, PR, SD) to the time of disease progression or death 
due to any cause.  


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ORR per iRECIST 
RECIST v1.1 and iRECIST will be used for all secondary efficacy endpoints, as applicable. 
Estimates of PFS and OS will be assessed using Kaplan-Meier methodology. 
12.6 
Safety Analyses 
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) and 
assessed for severity by the Investigator using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v. 5.0. TEAEs will be summarized by 
system organ class and preferred term and presented in decreasing order of frequency. Incidences 
of TEAEs and serious TEAEs will be summarized overall and with respect to CTCAE grade and 
relationship to study drug. TEAEs leading to study drug discontinuation, dose 
reduction/interruption, and with an outcome of death will also be summarized. Incidences of 
SAEs will be summarized overall and with respect to relationship to study drug. 
Changes from baseline for safety laboratory parameters; clinically significant changes from 
baseline in vital signs and electrocardiogram parameters; and shifts from baseline to most 
extreme ECOG value will be presented. 
12.7 
Pharmacodynamic, Pharmacokinetic and Research Analyses 
Available PK analyses and PD, biomarkers, and immune response data related to research 
laboratory samples may be described in a separate analysis document outside the context of this 
protocol and the associated SAP. Per amendment, no further samples will be obtained for 
analysis. 
12.8 
Timing of Analyses 
Analyses will be conducted after all subjects have discontinued study drug, and/or have 
documented disease progression, withdrawn from the study; or when the study is terminated by 
the Sponsor. 
Available data will be reviewed periodically by the SRT. 
12.9 
Interim Analysis 
No formal interim analyses are planned during this study.  
12.10 
Data Monitoring Committee 
There will be no independent Data Monitoring Committee for this study. Safety data and other 
relevant data will be reviewed by the SRT comprised of participating Investigators in the study, 
the Medical Monitor, and Sponsor representatives. 


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13 
DATA MANAGEMENT AND RECORD KEEPING 
13.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the clinical research associate (CRA) 
during monitoring visits. The CRA will verify data recorded in the electronic data capture (EDC) 
system with source documents. All corrections or changes made to any study data must be 
appropriately tracked in an audit trail in the EDC system. An eCRF will be considered complete 
when all missing, incorrect, and/or inconsistent data has been accounted for and electronically 
signed by the Investigator or assignee.  
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
13.2 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure username and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations (21 
CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
13.3 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the data, will be applied to the data in order to ensure accurate, 
consistent, and reliable data. Data identified as erroneous, or data that are missing, will be 
referred to the site for resolution through data queries.  
The eCRFs must be reviewed and electronically signed by the Investigator in order to be 
considered complete. 
13.4 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study drugs, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data 
are contained in source documents (original records or certified copies). These records will be 
retained in a secure file for the period as set forth in the Clinical Study Agreement. Prior to 
transfer or destruction of these records, the Sponsor must be notified in writing and be given the 
opportunity to further store such records. 


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14 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
14.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that have their origin in the Declaration of 
Helsinki, and that the clinical study data are credible. 
14.2 
Investigator Requirements 
Each Investigator must provide the Sponsor and/or its designee completed and signed 
documentation as required by national competent authorities or regulatory agencies. 
Investigators may only initiate the study upon authorization by appropriate regulatory authorities 
and the Sponsor. 
14.2.1 
Disposition and Accountability of Investigational Products 
The Investigator is responsible for the control of investigational products under study. An 
investigational product dispensing log must be kept current and should contain the following 
information:  
• The identification number for each subject who is administered the investigational 
product  
• The date(s) and quantity of the investigational product administered to the subject  
• Documentation of proper disposal of used investigational product vials or unused vials 
subjected to temperature excursion  
• Documentation of proper disposal (or return, at Sponsor’s request) of unused 
investigational product vials.  
The Investigator is responsible for investigational product accountability during on-site 
monitoring visits. All records and used/unused supplies of the investigational product must be 
available for inspection at every monitoring visit.  
The study sites, per institutional guidelines, will destroy used investigational product vials after 
formulation for administration. The formulation of investigational product for administration and 
the destruction of each used vial will be documented in the investigational product accountability 
log. Unused investigational product will be destroyed at the study site, if possible, after final 
investigational product accountability and notification by Sponsor, unless otherwise directed by 
Sponsor. 


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14.3 
Institutional Review Board/Ethics Committee 
The IRB/EC will review all appropriate study documentation in order to safeguard the rights, 
safety, and well-being of subjects. The study will only be conducted at sites where IRB/EC 
approval has been obtained. The protocol, IB, ICF, advertisements (if applicable), written 
information given to the subjects, safety updates, annual progress reports, and any revisions to 
these documents will be provided to the IRB/EC by the Investigator.  
Federal regulations and International Council on Harmonisation (ICH) require that approval be 
obtained from an IRB/EC prior to participation of subjects in research studies. Prior to study 
onset, the protocol, any protocol amendments, ICFs, advertisements to be used for subject 
recruitment, and any other written information regarding this study to be provided to a subject or 
subject’s legal guardian must be approved by the IRB/EC.  
No study drug will be released to the site for dosing until written IRB/EC authorization has been 
received by the Sponsor. 
14.4 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by 
the Sponsor or designee and the IRB/EC prior to its use and must be in compliance with all ICH 
GCP, local regulatory requirements, and legal requirements.  
The Investigator must ensure each study subject is fully informed about the nature and objectives 
of the study and possible risks associated with participation and must ensure the subject has been 
informed of his/her rights to privacy. The Investigator will obtain written informed consent from 
each subject before any study-specific activity is performed and will document consent was 
obtained prior to enrollment in the study in the source documentation. The original signed copy 
of the ICF must be maintained by the Investigator and is subject to inspection by a representative 
of the Sponsor, auditors, the IRB/EC, and/or regulatory agencies. A copy of the signed ICF will 
be given to the subject. 
14.5 
Study Monitoring Requirements 
To ensure the study is conducted in accordance with the protocol, ICH, GCP and applicable 
government regulations, the study monitor will aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. 
Before the enrollment of any subject in this study, the Sponsor or their designee will review with 
the Investigator and site personnel the following documents: protocol, IB, eCRFs and procedures 
for their completion, informed consent process, study drug management, and the procedure for 
reporting SAEs.  
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. 
During monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data are 


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entered by the site, the monitor will review the data for safety information, completeness, 
accuracy, and logical consistency. Computer programs that identify data inconsistencies may be 
used to help monitor the clinical study. If necessary, requests for clarification or correction will 
be sent to Investigators. The Investigator and his/her staff will be expected to cooperate with the 
monitor and provide any missing information, whenever possible.  
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the site by signature and date on the study-specific monitoring log. 
14.6 
Disclosure of Data 
Data generated by this study must be available for inspection by health and regulatory authorities 
(such as FDA, Health Canada, European Medicines Authority, and others), the Sponsor or 
designee, and the IRB/EC as appropriate. Subjects or their legal representatives may request their 
medical information be given to their personal physician or other appropriate medical personnel 
responsible for their welfare.  
Subject medical information obtained during the study is confidential and disclosure to third 
parties other than those noted above is prohibited. 
14.7 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating subjects (sufficient information to 
link records, e.g. eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE 
forms, source documents, and detailed records of treatment disposition. The records should be 
retained by the Investigator according to specifications in the ICH guidelines, local regulations, 
or as specified in the Clinical Study Agreement, whichever is longer. The Investigator must 
obtain written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met.  
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor 
should be prospectively notified. The study records must be transferred to an acceptable 
designee, such as another Investigator, another institution, or to the Sponsor. 
14.8 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication 
rights until mutual agreement on the content, format, interpretation of data in the manuscript, and 
journal selected for publication are achieved. 


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14.9 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR §54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a 
period of 1 year after the completion of the study. 
14.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out subject liability 
insurance for all subjects who have given their consent to the clinical study. This cover is 
designed for the event that a fatality, physical injury, or damage to health occurs during the 
clinical study’s execution. 


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15 
REFERENCES 
Brahmer, J. R., C. Lacchetti, B. J. Schneider, et al. 2018. Management of immune-related 
adverse events in patients treated with immune checkpoint inhibitor therapy: American 
Society of Clinical Oncology Clinical Practice Guideline, J Clin Oncol, 36: 1714-68. 
Burtness, B., K. J. Harrington, R. Greil, et al. 2018. KEYNOTE-048: Phase 3 study of first-line 
pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma 
(R/M HNSCC), Ann Oncol, 29 (Suppl 8): Abstract LBA8_PR. 1. 
Chen, P. L., W. Roh, A. Reuben, et al. 2016. Analysis of immune signatures in longitudinal 
tumor samples yields insight into biomarkers of response and mechanisms of resistance 
to immune checkpoint blockade, Cancer Discov, 6: 827-37. 
CTFG. 2014. Recommendations related to contraception and pregnancy testing in clinical trials, 
Clinical Trial Facilitation Group, Accessed 16 June 2016. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
Eisenhauer, E. A., P. Therasse, J. Bogaerts, et al. 2009. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1), Eur J Cancer, 45: 228-47. 
Gajewski, T. F., M. B. Fuertes, and S. R. Woo. 2012. Innate immune sensing of cancer: clues 
from an identified role for type I IFNs, Cancer Immunol Immunother, 61: 1343-7. 
Gajewski, T. F., H. Schreiber, and Y. X. Fu. 2013. Innate and adaptive immune cells in the 
tumor microenvironment, Nat Immunol, 14: 1014-22. 
Gajewski, T. F., S. R. Woo, Y. Zha, et al. 2013. Cancer immunotherapy strategies based on 
overcoming barriers within the tumor microenvironment, Curr Opin Immunol, 25: 268-
76. 
Galon, J., F. Pages, F. M. Marincola, et al. 2012. The immune score as a new possible approach 
for the classification of cancer, J Transl Med, 10: 1. 
Ishikawa, H., and G. N. Barber. 2008. STING is an endoplasmic reticulum adaptor that 
facilitates innate immune signalling, Nature, 455: 674-8. 
KEYTRUDA. 2020. Keytruda (Pembrolizumab package insert, Merck & Co., Accessed 07 APR 
2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s067lbl.pdf. 
Meric-Bernstam, F., T. L. Werner, F. S. Hodi, et al. 2018. "Phase I dose-finding study of 
MIW815 (ADU-S100), an intratumoral STING agonist, in patients with advanced solid 
tumors or lymphomas." In Society for Immunotherapy of Cancer's (SITC) 33rd Annual 
Meeting. Washington, D.C. 
Oken, M. M., R. H. Creech, D. C. Tormey, et al. 1982. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group, Am J Clin Oncol, 5: 649-55. 
Postow, M. A. 2015. Managing immune checkpoint-blocking antibody side effects, Am Soc Clin 
Oncol Educ Book: 76-83. 
Postow, M. A., M. K. Callahan, C. A. Barker, et al. 2012. Immunologic correlates of the 
abscopal effect in a patient with melanoma, N Engl J Med, 366: 925-31. 


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Rischin, D., K. J. Harrington, R. Greil, et al. 2019. Protocol-specified final analysis of the phase 
3 KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy for 
recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), J Clin 
Oncol, 37, no. 15_suppl(May 20, 2019)6000-6000. 
Seymour, L., J. Bogaerts, A. Perrone, et al. 2017. iRECIST: guidelines for response criteria for 
use in trials testing immunotherapeutics, Lancet Oncol, 18: e143-e52. 
Wolchok, J. D., H. Kluger, M. K. Callahan, et al. 2013. Nivolumab plus ipilimumab in advanced 
melanoma, N Engl J Med, 369: 122-33. 
Woo, S. R., L. Corrales, and T. F. Gajewski. 2015. The STING pathway and the T cell-inflamed 
tumor microenvironment, Trends Immunol, 36: 250-6. 
Zaretsky, J. M., A. Garcia-Diaz, D. S. Shin, et al. 2016. Mutations associated with acquired 
resistance to PD-1 blockade in melanoma, N Engl J Med. 
 
 
 


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Appendix A: Management and Dose Modifications of Immune-Mediated Adverse 
Reactions 
These general guidelines for management of toxicities (Postow 2015) constitute guidance to 
the Investigator and are not intended to substitute for institutional standard of care practice. 
Additional recommendations are provided in the American Society of Clinical Oncology clinical 
practice guideline for the management of irAE (Brahmer et al. 2018). A general principle is that 
differential diagnoses should be diligently evaluated according to standard medical practice. 
Non-inflammatory etiologies should be considered and appropriately treated. 
 
irAE 
SEVERITY 
per CTCAE v 
5.0 
DOSE 
MODIFICAT-
ION OR 
TREATMENT 
DELAY 
MANAGEMENT 
FOLLOW UP 
Pneumonitis 
Grade 1 
Consider delay 
of IO therapy 
• Monitor for symptoms 
every 2-3 days 
• Consider Pulmonary and 
ID consults 
• Re-image at least every 3 
weeks 
• If worsen, treat as Grade 
2 or 3-4 
Grade 2 
Withhold a 
• Pulmonary and ID 
consults.  
• Monitor symptoms daily, 
consider hospitalization 
• 1.0mg/kg/day methyl 
prednisolone IV or oral 
equivalent 
• Consider bronchoscopy, 
lung biopsy 
• Re-image every 1-3 days 
• If improves, taper 
steroids over at least 1 
month and then resume 
IO therapy and consider 
prophylactic antibiotics 
• If does not improve after 
2 weeks or worsen: Treat 
as Grade 3 or 4 
Grades 3 or 4 or 
recurrent Grade 
2 
Permanently 
discontinue 
• Hospitalize 
• Pulmonary and ID 
consults  
• 2-4 mg/kg/day methyl 
prednisolone IV or oral 
equivalent 
• Add prophylactic 
antibiotics for 
opportunistic infections 
• Consider bronchoscopy, 
lung biopsy 
• If improves to baseline, 
taper steroids over at 
least 6 weeks 
• If does not improve after 
48 hrs or worsen: Add 
additional 
immunosuppression (e.g. 
infliximab, 
cyclophosphamide, IVIG 
or mycophenolate 
mofetil) 
Diarrhea/ 
Colitis 
Grade 1 
 
Consider delay 
of IO therapy 
Symptomatic treatment 
• Close monitoring for 
worsening symptoms 
• Educate subject to report 
worsening symptoms 
immediately 
• If worsen, treat as Grade 
2 or Grade 3/4 


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irAE 
SEVERITY 
per CTCAE v 
5.0 
DOSE 
MODIFICAT-
ION OR 
TREATMENT 
DELAY 
MANAGEMENT 
FOLLOW UP 
 
Grade 2  
Withhold a 
Symptomatic treatment 
• If improves to Grade 1, 
resume IO therapy 
• If persists >5-7 days or 
recur: 0.5-1.0 mg/kg/day 
methylprednisolone or 
oral equivalent 
• When symptoms 
improve to Grade 1, 
taper steroids over at 
least 1 month, consider 
prophylactic antibiotics 
for opportunistic 
infections and resume IO 
therapy per protocol 
• If worsens or persists >3-
5 days with oral steroids: 
treat as Grade 3 
 
Grade 4 
Permanently 
discontinue 
• -2.0 mg/kd/day 
methylprednisolone IV 
or IV equivalent 
• Add prophylactic 
antibiotics for 
opportunistic infections 
• Consider lower 
endoscopy 
• If improves, continue 
steroids until Grade 1, 
then taper over at least 1 
month 
• If persists >3-5 days or 
recurs after 
improvement, add 
inflizimab 5 mg/kg (if no 
contraindication). Note: 
infliximab should not be 
used in cases of 
perforation or sepsis 
Liver Test 
Elevation  
Grade 1 
Continue IO 
therapy 
 
• Continue LFT 
monitoring per protocol 
• If worsen, treat as Grade 
2 or Grade 3/4  
Grade 2 
Withhold a 
Increase frequency of 
monitoring to every 3 days 
• If returns to baseline, 
resume monitoring, 
resume IO therapy per 
protocol 
• If elevations persist >5-7 
days or worsen, 0.5-1.0 
mg/kg/day 
methylprednisolone or 
oral equivalent and when 
LFT returns to grade 1 or 
baseline, taper steroids 
over at least 1 month, 
consider prophylactic 
antibiotics for 
opportunistic infections 
and resume IO therapy 


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irAE 
SEVERITY 
per CTCAE v 
5.0 
DOSE 
MODIFICAT-
ION OR 
TREATMENT 
DELAY 
MANAGEMENT 
FOLLOW UP 
Grade 3-4 
Permanently 
discontinue 
• Increase frequency of 
monitoring to every 1-2 
days 
• 1.0-2.0 mg/kg/day 
methylprednisolone or 
IV equivalent 
• Add prophylactic 
antibiotics for 
opportunistic infections 
• Consult 
gastroenterologist 
• If returns to grade 2, 
taper steroids over 1 
month 
• If does not improve in 
>3-5 days, worsens or 
rebounds, add 
mycophenolate mofetil 
1g BID. If no response 
within an additional 3-5 
days, consider other 
immunosuppressants per 
local guidelines 
Endocrino-
pathies 
Asymptomatic 
TSH elevation 
Continue IO 
therapy 
If TSH <0.5 X LLN or TSH >2 X ULN, or consistently 
out of range in 2 subsequent measurements: include fT4 
at subsequent cycles as indicated; consider endocrinology 
consult 
Symptomatic 
endocrinopathy 
Withhold a 
Evaluate endocrine 
function 
Consider pituitary scan 
• If symptomatic with 
abnormal lab/pituitary 
scan, 1-2 mg mg/kg/day 
methylprednisolone or 
PO equivalent and 
initiate appropriate 
hormone therapy 
• If no abnormal lab/ 
pituitary MRI scan but 
symptoms persist, repeat 
labs in 1-3 weeks/ MRI 
in 1 month 
If improves (with or 
without hormone 
replacement), taper 
steroids over 1 month and 
consider prophylactic 
antibiotics for 
opportunistic infections. IO 
therapy should resume. 
Subjects with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid 
component. 
Suspicion of 
adrenal crisis 
(e.g. severe 
dehydration, 
hypotension, 
shock out of 
proportion to 
current illness 
Withhold until 
clinically stable 
or discontinue 
• Rule out sepsis 
• Stress dose of IV steroids with mineralocorticoid 
activity 
• IV fluids 
• Consult endocrinologist 
• If adrenal crisis ruled out, then treat as for symptomatic 
endocrinopathy 
Creatinine 
Elevation 
Grade 1  
Continue IO 
therapy 
Monitor creatinine weekly 
• If returns to baseline, 
resume routine creatinine 
monitoring per protocol 
• If worsen, treat as Grade 
2 or 3/4 


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irAE 
SEVERITY 
per CTCAE v 
5.0 
DOSE 
MODIFICAT-
ION OR 
TREATMENT 
DELAY 
MANAGEMENT 
FOLLOW UP 
 
Grade 2-3 
Withhold a 
• Monitor creatinine every 
2-3 days 
• 0.5-1.0 mg/kg/day 
methylprednisolone or 
oral equivalent 
• Consider renal biopsy 
 
• If returns to Grade 1, 
taper steroids over at 
least 1 month, consider 
prophylactic antibiotics 
for opportunistic 
infections, and resume 
IO therapy and routine 
creatinine monitoring per 
protocol 
• If elevation persist > 7 
days or worsen, treat as 
Grade 4 
 
Grade 4 
Permanently 
discontinue 
• Monitor creatinine daily 
• 1.0-2.0 mg/kg/day 
methylprednisolone or 
IV equivalent 
• Consult nephrologist 
• Consider renal biopsy 
• If returns to Grade 1, 
taper steroids over at 
least 1 month, and add 
prophylactic antibiotics 
for opportunistic 
infections 
Skin 
Grade 1-2 
(covering ≥ 
30% BSA) 
Continue IO 
therapy 
Symptomatic therapy (e.g. 
antihistamines, topical 
steroids) 
• If persists >1-2 weeks or 
recurs, consider skin 
biopsy, delay IO therapy, 
consider 0.5-1.0 
mg/kg/day 
methylprednisolone or 
oral equivalent. Once 
improving, taper steroids 
over at least 1 month, 
consider prophylactic 
antibiotics for 
opportunistic infections, 
and resume IO therapy 
• If worsens, treat as Grade 
3-4 
 
Grade 3 
(covering > 
30% BSA) or 
suspected 
Stevens-
Johnson 
syndrome (SJS) 
or toxic 
epidermal 
necrolysis 
(TEN) 
Withhold a 
• Consider skin biopsy 
• Dermatology consult 
• 1.0-2.0 mg/kg/day 
methylprednisolone or 
IV equivalent 
 
 
If improves to Grade 1, 
taper steroids over at least 
1 month and add 
prophylactic antibiotics for 
opportunistic infections. 
Resume IO therapy. 
 
Grade 4 
(covering > 
30% BSA) or 
confirmed SJS 
or TEN 
Permanently 
discontinue 
• Consider skin biopsy 
• Dermatology consult 
• 1.0-2.0 mg/kg/day 
methylprednisolone or 
IV equivalent 
If improves to Grade 1, 
taper steroids over at least 
1 month and add 
prophylactic antibiotics for 
opportunistic infections 


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irAE 
SEVERITY 
per CTCAE v 
5.0 
DOSE 
MODIFICAT-
ION OR 
TREATMENT 
DELAY 
MANAGEMENT 
FOLLOW UP 
Other 
Grades 2 or 3 
based on 
severity and 
type of adverse 
reaction 
Withhold a 
 
 
Grade 3 based 
on the severity 
and type of 
reaction or 
Grade 4 
Permanently 
discontinue 
 
 
Recurrent 
immune-
mediated 
reactions 
Recurrent 
Grade 2 
pneumonitis  
Recurrent 
Grades 3 or 4 
Permanently 
discontinue 
 
 
Inability to 
taper 
corticosteroid 
Requirement 
for ≥10 mg/day 
prednisone or 
equivalent for 
more than 12 
weeks after last 
dose of 
pembrolizumab 
Permanently 
discontinue 
 
 
Persistent 
immune-
mediated 
reaction 
(excluding 
endocrino-
pathy) 
Grades 2 or 3 
adverse 
reactions lasting 
12 weeks or 
longer after last 
dose of 
pembrolizumab 
Permanently 
discontinue 
 
 
Infusion-
related 
reactions 
See Section 9.5.3 
 
 
* Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 5.0 
(NCI-CTCAE v5.0). 
a Resume treatment when adverse reaction improves to Grade 0 or 1 after corticosteroid taper 
 
 


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Appendix B: RECIST V1.1 CRITERIA 
Adapted from (Eisenhauer et al. 2009).  
Imaging Methods: The same method of assessment and same technique should be used at 
baseline and all follow up assessments. CT is the preferred method of tumor evaluation for this 
study. If lesion being followed cannot be imaged but can be assessed by clinical examination, 
measurements taken by usage of calipers will be acceptable. MRI is the preferred method for 
brain and bone lesions. If CT is performed instead of MRI, ambiguous results may be confirmed 
by MRI. MRI is also indicated if CT scan is contraindicated (e.g. allergy to contrast dye). Chest 
x-rays, positron emission tomography (PET), ultrasound and bone scans will not be used for 
response assessments in this study.  
Lesion Definitions: 
1) Measurable lesions: Those lesions (except lymph node lesions) that can be accurately 
measured and longest diameter to be recorded as ≥10 mm with CT scan (if CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion is twice the slice 
thickness). 
Pathological lymph nodes will be considered measurable if they are ≥15mm in the short axis 
as measured by CT scan (CT scan thickness is recommended to be no greater than 5mm). 
At least 1 injectable lesion will be considered a measurable lesion and measurements will be 
recorded per RECIST v1.1. 
Cystic lesions thought to represent cystic metastasis can be measurable lesions, if they meet 
measurable lesion criteria. Simple cysts should not be considered measurable lesions.  
If CT scan is contraindicated, MRI should be performed. The minimal size for measurability 
is the same as for CT, i.e. 10 mm for non-nodal lesions (if scans have slice thickness greater 
than 5mm, the minimum size for a measurable lesion is twice the slice thickness), or ≥15mm 
for nodal lesions.  
2) Non-measurable lesions: All other lesions, including small lesions that are <10mm (or for 
pathological lymph node lesions, short axis that is <15mm and ≥10mm) are considered non-
measurable lesions. Lymph nodes that have a short axis that is <10mm are considered non-
pathological are not recorded or followed.  
Bone disease is considered non-measurable, with the exception of soft tissue components that 
can be evaluated with CT or MRI and meet the definition of measurable (see above). Bone 
scans, PET scans or plain films are not considered appropriate for the evaluation of bone 
lesions.  
A previously irradiated lesion, or a lesion that is in an area that has been subjected to loco-
regional therapy, is considered non-measurable unless it has progressed since last treatment. 
Simple cysts should not be considered non-measurable lesions. 
Tumor Assessments: Baseline assessments should be conducted at screening, within 28 days 
prior to C1D1. Tumor assessments should be fixed according to calendar, regardless of treatment 


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delays. At each evaluation, progression status is based upon the timepoint status of target, non-
target and new lesions.  
1) Target lesions: Measurable lesions, up to a maximum of 5 total lesions (up to 2 lesions per 
organ) representing all involved organs should be identified as target lesions at baseline. 
They should be selected based on size and accuracy for repeated measurements.  
At each assessment, the sum of diameters (SoD; longest diameter for non-nodal lesions, and 
short axis for nodal lesions) will be calculated and recorded in source documents. If 2 lesions 
coalesce, the measurement of the coalesced mass is used. If a target lesion splits, the sum of 
the parts is used. If a target lesion is considered to have disappeared, 0 mm should be 
recorded. If a target lesion becomes too small to measure, a default value of 5 mm should be 
recorded.  
The baseline SoD should be used as a comparison for any objective tumor regression. The 
lowest SoD (nadir) should be used as reference for evaluating progression. 
Response Criteria for target lesions 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all non-nodal target lesions. In addition, any pathological 
lymph nodes assigned as target lesions must have a reduction in short axis to < 
10 mm1 
Partial Response (PR): 
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded 
at or after baseline. In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm2. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD 
Unknown (UNK) 
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline. 
1 SOD for CR may not be zero when nodal lesions are part of target lesions 
2 Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all 
nodal lesions are <10 mm in size. In this case, the target lesion response is CR 
2) Non-target lesions: All non-measurable lesions are non-target lesions. Measurement of these 
lesions are not required; instead, the presence, absence or unequivocal progression of each 
are to be recorded. Following CR, non-target and new lymph node lesions are to be measured 
to determine if they have become pathological in size.  
3) New lesions: these are to be recorded separately in the eCRF. Finding of new lesions should 
not be attributed to differences in scanning technique, change in imaging modality or 
findings thought to represent something other than tumor. A lesion identified in an anatomic 
location that was not scanned at baseline is considered a new lesion.  
If a new lesion is equivocal, continue assessment until etiology can be clarified. If at the next 
assessment the new lesion is confirmed, the date of progression should be recorded as the 
date the new lesion was first noted.  


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Evaluation of Overall Response: 
Target Lesion 
Non-target lesion 
New Lesion 
Objective Status 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Indeterminate or missing 
No 
PR 
PR 
Non-CR/ Non-PD, Indeterminate 
or missing 
No 
PR 
SD 
Non-CR/ Non-PD, Indeterminate 
or missing 
No 
SD 
Indeterminate 
or 
missing 
Non-PD 
No 
Indeterminate 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR=complete response; PR=partial response; SD=stable disease; PD= progression; non-CR/non-PD=criteria for 
neither CR nor PD have been met.  
 
All noted regressions should be confirmed at next tumor assessment.  
 


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Appendix C: IRECIST CRITERIA 
Increasing experience indicates that traditional response criteria may not be sufficient to fully 
characterize activity in this new era of immunotherapeutic agents. For example, agents such as 
anti-CTLA-4 and anti-PD1 and anti-PD-L1 exert anti-tumor activity by augmenting activation 
and proliferation of T-cells, thus leading to tumor infiltration by T cells and tumor regression 
rather than direct cytotoxic effects. In early trials of immune-based therapeutics in melanoma, 
investigators described unique response patterns, termed pseudo-progression, whereby subjects 
met the criteria based on traditional response criteria such as RECIST were noted to have late but 
deep and durable responses.   
 
On the basis of these observations, a number of immune related criteria were developed and 
substantial variability in their usage across clinical studies were noted. This led to the 
development of iRECIST (immune RECIST) criteria by the RECIST working group in 2017 
(Seymour et al. 2017).  
 
iRECIST is based on RECIST criteria. There are no changes compared to RECIST to the 
recommendations regarding the method of measurement. All responses per iRECIST have a 
prefix of “i” (i.e. immune)—e.g. “immune” complete response (iCR) or partial response (iPR), 
and unconfirmed progressive disease (iUPD) or confirmed progressive disease (iCPD) to 
differentiate them from responses assigned using RECIST 1.1. Similar nomenclature is used for 
stable disease (iSD).  
 
The major concept is resetting the bar once progression is identified per RECIST v1.1. This 
initial progression is identified as iUPD per iRECIST. Note that treatment past RECIST 1.1 PD 
should only be considered if: 
  
1) Subject clinically stable 
2) There is no worsening of ECOG status 
3) No clinically relevant increase in disease related symptoms 
4) No requirement for intensified management of disease related symptoms (analgesics, 
radiation, palliative care) 
 
Any new lesions identified at iUPD will be assessed and subcategorized into those that qualify as 
target lesions (new lesion, target; maximum of 5 target lesions and maximum of 2 per organ 
should be identified) or non-target lesions (new lesion, non-target) and will be recorded 
separately from the original target and non-target lesions.  
 
Progression must be confirmed on the next scan that is completed 4 to 9 weeks following initial 
iUPD; if confirmed, this will be categorized as iCPD (for immune confirmed progression). As 
such, should an iCR, iPR or iSD follow the initial iUPD, the next progression that follows will 
also be categorized as iUPD. However, if the next assessment following iUPD is not done or not 
evaluable, then if the following assessment is progression, then it should be labeled as iCPD. 
 
Progression is only confirmed (i.e. iCPD) if the next scan following iUPD indicates a ≥5mm 
increase in target lesions, any size increase in non-target lesions, a ≥5mm increase in new lesion 
target lesions, any size increase in new lesions non-target lesions, or the appearance of another 


Chinook Therapeutics, Inc. Clinical Trial Protocol ADU-CL-20 
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Protocol Amendment 4, 19-JAN-2021 
82 
new lesion. If progression is not confirmed, and there is no subsequent iSD, iPR or iCR, the 
reasons for a lack of confirmation must be recorded. The reasons should include: 
 
1. Not stable 
2. Worsening of ECOG status 
3. Clinical increase in disease related symptoms 
4. Treatments stopped and subject not reassessed/ imaging not performed 
5. Subject has died 
6. iCPD never occurred 
 
In this case, for statistical purposes, the progression event date should be the iUPD date.  
 
Assignment of Timepoint Response Using iRECIST 
 
Timepoint response 
with no previous 
iUPD in any 
category 
Timepoint response with previous iUPD in 
any category* 
Target lesions: iCR; non-target lesions: 
iCR; 
new lesions: no 
iCR 
iCR 
Target lesions: iCR; non-target lesions: 
non-iCR/non-iUPD; new lesions: no 
iPR 
iPR 
Target lesions: iPR; non-target lesions: 
non-iCR/non-iUPD; new lesions: no 
iPR 
iPR 
Target lesions: iSD; non-target lesions: 
non-iCR/non-iUPD; new lesions: no 
iSD 
iSD 
Target lesions: iUPD with no change, 
or with a 
decrease from last timepoint; non-target 
lesions: iUPD with no change, or 
decrease from last timepoint; new 
lesions: yes 
Not applicable 
New lesions confirm iCPD if new lesions 
were previously identified and they have 
increased in size (≥5 mm in sum of measures 
for new lesion target or any increase for new 
lesion non-target) or number; if no change is 
seen in new lesions (size or number) from last 
timepoint, assignment remains iUPD 
Target lesions: iSD, iPR, iCR; non-
target lesions: iUPD; new lesions: no 
iUPD 
Remains iUPD unless iCPD is confirmed on 
the basis of a further increase in the size of 
non-target disease (does not need to meet 
RECIST 1.1 criteria for unequivocal 
progression) 
Target lesions: iUPD; non-target 
lesions: 
non-iCR/non-iUPD, or iCR; new 
lesions: no 
iUPD 
Remains iUPD unless iCPD is confirmed on 
the basis of a further increase in sum of 
measures ≥5 mm; otherwise, assignment 
remains iUPD 
Target lesions: iUPD; non-target 
lesions: iUPD; new lesions: no 
iUPD 
Remains iUPD unless iCPD is confirmed 
based on a further increase in previously 
identified target lesion iUPD in sum of 
measures ≥5 mm or non-target lesion iUPD 
(previous assessment need not have shown 
unequivocal progression) 
Target lesions: iUPD; non-target 
lesions: iUPD; new lesions: yes 
iUPD 
Remains iUPD unless iCPD is confirmed on 
the basis of a further increase in previously 
identified target lesion iUPD sum of measures 
≥5 mm, previously identified non-target lesion 


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Protocol Amendment 4, 19-JAN-2021 
83 
 
Timepoint response 
with no previous 
iUPD in any 
category 
Timepoint response with previous iUPD in 
any category* 
iUPD (does not need to be unequivocal), or an 
increase 
in the size or number of new lesions 
previously identified 
Target lesions: non-iUPD or 
progression; 
non-target lesions: non-iUPD or 
progression; new lesions: yes 
iUPD 
Remains iUPD unless iCPD is confirmed on 
the basis of an increase in the size or number 
of new lesions previously identified 
*Previously identified in assessment immediately before this timepoint. “i” indicates immune responses assigned 
using iRECIST. iCR=complete response; iPR=partial response; iSD=stable disease; iUPD=unconfirmed 
progression; non-iCR/non-iUPD=criteria for neither CR nor PD have been met; iCPD=confirmed progression; 
RECIST=Response Evaluation Criteria in Solid Tumors. 
 
 
 


Chinook Therapeutics, Inc. Clinical Trial Protocol ADU-CL-20 
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Protocol Amendment 4, 19-JAN-2021 
84 
Appendix D: COVID-19 GUIDANCE  
All provisions outlined should be viewed as temporary and will be applicable only for the duration of the 
pandemic. If any provisions are modified due to the coronavirus (COVID-19) pandemic, please clearly 
document the planned deviation was due to COVID-19 and document the effective date of the interim 
measure in the subject’s medical records. 
In general, the subject and Investigator should together make the best and safest decision for the subject. 
Due to the requirement for certain individuals to self-isolate, and the issuance of shelter in place policies 
in a number of metropolitan areas, we recommend all sites contact each subject by telephone or email 
prior to the scheduled visit to determine if an in-person visit is feasible.  
COVID-19 Screening 
Incorporation of the following screening questions to identify potential COVID-19 exposure during the 
telephone or email contact prior to the scheduled visits are recommended: 
• 
Have you traveled anywhere in the past 14 days? 
• 
Have you had any of the following symptoms in the past 14 days without confirmation as 
something other than COVID-19 (such as a positive flu test, chronic medical condition, etc.)?  
· Fever greater than 100.4°F (38oC) 
· Cough 
· Difficulty breathing 
· Sore throat 
• 
In the last 14 days, have you lived with, visited, cared for, or been in a room for a prolonged 
period of time with someone who is under investigation or has been confirmed for COVID-19? 
Should a subject respond yes to any of the above questions, it is recommended site personnel identify a 
resource to direct the subject to. Scheduled visits should be rescheduled if possible; if this is not possible, 
the visit should be marked as “not done” and reasons should be noted in study files. 
For Subjects who are Unable to Travel to Site 
If the subject is unable to travel to the trial site due to COVID-19 infection, self-quarantines, or travel 
restrictions, we recommend the following procedures be completed by phone, email or telehealth: 
• 
Concomitant medications 
• 
Adverse events  
• 
If available, physical exams may be conducted using telehealth methods 
Sites should also determine if home visits can be conducted with visiting nurses or home health aides. If 
available, safety evaluations (labs, vital signs and ECG [if available]) should be completed. If available, 
treatment with pembrolizumab may continue; however, treatment with ADU-S100 outside of a clinical 
setting is not recommended. 
Limited Site Staff 
The Sponsor also recognizes that site staff may also be limited during this pandemic. Though we ask that 
the sites be as compliant with the protocol as possible, we recognize that this might not be feasible at this 


Chinook Therapeutics, Inc. Clinical Trial Protocol ADU-CL-20 
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Protocol Amendment 4, 19-JAN-2021 
85 
time. In this case, priority should be given to the following protocol specific procedures (from the highest 
to the lowest priority): 
1. Administration of pembrolizumab and ADU-S100 
2. Concomitant medications, adverse events  
3. Safety labs 
4. Vital signs, physical examination 
5. ECG 
6. Tumor imaging 
If tumor imaging is not feasible, for example due to shortage of staff, and if the Principal Investigator or 
designee considers the subjects clinically stable and it’s in the subject’s best interest, treatment should 
continue. Images should be taken at the next available opportunity. Reasons for imaging delay should be 
documented in source documents and the sponsor (or its representatives) should be notified. 
If shipping capabilities are no-longer available, sites should hold samples till shipping capabilities are 
restored. Please refer to the Central Laboratory Manual for appropriate storage conditions Reduced Visits 
for Subject Safety 
If it is determined that frequent visits to the site is not safe for the subject, visits whereby treatment 
(pembrolizumab and/ or ADU-S100) is administered should be prioritized.  
 


Chinook Therapeutics, Inc. Clinical Trial Protocol ADU-CL-20 
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Protocol Amendment 4, 19-JAN-2021 
86 
SIGNATURE PAGE 
TITLE: A Phase 2 Efficacy and Safety Trial of ADU-S100 and Pembrolizumab in Adults 
with Head and Neck Cancer 
I, the undersigned, have read study protocol ADU-CL-20 Amendment 4 and agree it contains all 
necessary information required to conduct the study. 
 
Signature 
 
 
 
 
 
 
 
Date 
 
 
 
Jackie Walling, MBChB PhD 
Sponsor Responsible Medical Officer 
Chinook Therapeutics, Inc. (f/k/a Aduro Biotech, Inc.) 
 
 
 
 
19-Jan-2021 | 3:13 PM PST


Chinook Therapeutics, Inc. Clinical Trial Protocol ADU-CL-20 
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Protocol Amendment 4, 19-JAN-2021 
87 
INVESTIGATOR AGREEMENT 
TITLE: A Phase 2 Efficacy and Safety Trial of ADU-S100 and Pembrolizumab in Adults 
with Head and Neck Cancer 
By signing below I agree that: 
I have read the protocol and agree it contains all necessary details for carrying out the study as 
described. I will conduct this study in accordance with the design and specific provisions of this 
protocol and will make a reasonable effort to complete the study within the time designated. I 
will provide copies of this protocol and access to all information furnished by the Sponsor to 
study personnel under my supervision. I will discuss this material with them to ensure they are 
fully informed about the study product and study procedures. I will let them know this 
information is confidential and proprietary to the Sponsor and may not be further disclosed to 
third parties. I understand that the study may be terminated or enrollment suspended at any time 
by the Sponsor, with or without cause. I have the right to suspend enrollment of subjects at my 
study site if necessary to protect the best interests of the study subjects. 
I agree to conduct this study in full accordance with United States Food and Drug Administration 
Regulations, Institutional Review Board/Ethics Committee Regulations, and International 
Council on Harmonisation (ICH) Guidelines for Good Clinical Practices. 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
  
 
 

SAP_001.pdf: 
 
Aduro Biotech, Inc. 
Statistical Analysis Plan
ADU-CL-20 
 
Version 1.0; 09 October 2020
 
Form BS-003-A                                               Precision for Medicine            
v01.1 
SAP Template                                                          Confidential 
Page 1 of 38 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Aduro Biotech, Inc. 
ADU-CL-20 
 
 
 
 
Protocol Title: 
A Phase 2 Efficacy and Safety Trial of ADU-S100 and 
Pembrolizumab in Adults with Head and Neck Cancer 
Protocol Version 
and Date: 
Amendment 3; 07 April 2020 
Sponsor: 
Aduro Biotech, Inc. 
740 Heinz Avenue 
Berkeley, CA 94710 USA 
Prepared By: 
John Morcos 
Precision for Medicine 
6005 Hidden Valley Road, Suite 170 
Carlsbad, CA 92011 
Document Version 
and Date: 
Version 1.0; 09 October 2020 
 


 
Aduro Biotech, Inc. 
Statistical Analysis Plan
ADU-CL-20 
 
Version 1.0; 09 October 2020
 
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1 STATISTICAL ANALYSIS PLAN APPROVAL 
Sponsor: 
Aduro Biotech, Inc. 
Clinical Protocol Number: ADU-CL-20 
Protocol Title: 
A Phase 2 Efficacy and Safety Trial of ADU-S100 and 
Pembrolizumab in Adults with Head and Neck Cancer 
Document File Name: 
Aduro_ADU-CL-20_SAP_v1.0_09Oct2020.pdf 
Document Version and 
Effective Date: 
Version 1.0; 09 October 2020 
Approved By: 
 
 
  
Candy Bermingham, PhD 
Sr. Director Clinical Science 
Aduro Biotech, Inc. 
 
Date 
 
 
 
 
 
 
 
  
Aparna Anderson 
Chief Scientific Officer, Statistics Collaborative, Inc. 
Biostatistics Consultant to Aduro Biotech, Inc. 
 
Date 
2020-10-09
2020-10-09


 
Aduro Biotech, Inc. 
Statistical Analysis Plan
ADU-CL-20 
 
Version 1.0; 09 October 2020
 
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Page 3 of 38 
 
  
John Morcos 
Biostatistician I 
Precision for Medicine 
 
Date 
 
 
 
 
 
 
 
 
  
Laura Holland 
Biostatistician II 
Precision for Medicine 
 
Date 
2020-10-09
2020-10-09


 
Aduro Biotech, Inc. 
Statistical Analysis Plan
ADU-CL-20 
 
Version 1.0; 09 October 2020
 
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Page 4 of 38 
2 TABLE OF CONTENTS 
 
1 
Statistical Analysis Plan Approval ......................................................................... 2 
2 
Table of Contents .................................................................................................... 4 
3 
List of Abbreviations .............................................................................................. 7 
4 
Introduction ............................................................................................................ 9 
5 
Study Objectives ..................................................................................................... 9 
5.1 
Primary Study Objective ................................................................................... 9 
5.2 
Secondary Study Objectives .............................................................................. 9 
5.3 
Exploratory Study Objectives ........................................................................... 9 
6 
Investigational Plan .............................................................................................. 10 
6.1 
Overall Study Design ....................................................................................... 10 
6.2 
Determination of Sample Size.......................................................................... 11 
6.3 
Schedule of Assessments .................................................................................. 12 
6.4 
Treatments ....................................................................................................... 12 
6.4.1 
Treatments Administered .......................................................................... 12 
6.4.2 
Method of Assigning Subjects to Treatment Groups ................................ 13 
6.5 
Efficacy and Safety Variables .......................................................................... 13 
6.5.1 
Efficacy Variables ...................................................................................... 13 
6.5.2 
Description of Safety Variables ................................................................. 14 
6.5.3 
Description of Pharmacokinetic Variables ................................................ 19 
6.5.4 
Biomarker Assessments ............................................................................. 20 
6.6 
Data Quality Assurance ................................................................................... 20 
7 
Statistical Methods ............................................................................................... 21 
7.1 
General Methodology ....................................................................................... 21 
7.1.1 
Reporting Conventions .............................................................................. 21 
7.1.2 
Summarization by Visit.............................................................................. 22 
7.1.3 
Data Handling Rules .................................................................................. 22 
7.1.4 
Standard Calculations ................................................................................ 22 
7.2 
Analysis Populations ........................................................................................ 23 
7.3 
Study Subjects .................................................................................................. 23 
7.3.1 
Disposition of Subjects ............................................................................... 23 
7.3.2 
Protocol Deviations .................................................................................... 23 
7.4 
Efficacy Evaluation .......................................................................................... 24 
7.4.1 
Datasets Analyzed ...................................................................................... 24 
7.4.2 
Demographic and Other Baseline Characteristics .................................... 24 
7.4.3 
Measurements of Treatment Compliance ................................................. 24 
7.4.4 
Primary Efficacy Endpoint Analysis Methods .......................................... 25 
7.4.5 
Secondary Endpoint Analysis Methods ..................................................... 26 
7.4.6 
Statistical/Analytical Issues ........................................................................ 27 
7.4.7 
Plasma Concentrations .............................................................................. 30 
7.4.8 
Pharmacokinetic Analysis .......................................................................... 30 
7.4.9 
Biomarker Analysis .................................................................................... 30 


 
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Statistical Analysis Plan
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7.5 
Safety Evaluation ............................................................................................. 30 
7.5.1 
Extent of Exposure ..................................................................................... 30 
7.5.2 
Adverse Events ........................................................................................... 31 
7.5.3 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ........................................................................................... 32 
7.5.4 
Clinical Laboratory Evaluation ................................................................. 32 
7.5.5 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety .......................................................................................................... 33 
7.5.6 
Exploratory Safety Endpoint Analysis Methods ....................................... 35 
7.6 
Changes in the Conduct of the Study or Planned Analyses ............................ 35 
8 
Reference List ....................................................................................................... 36 
Appendix A: Schedule of Events ................................................................................. 37 
 
 
 


 
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Statistical Analysis Plan
ADU-CL-20 
 
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TABLE OF TABLES 
Table 1 
List of Abbreviations .............................................................................. 7 
Table 2 
ADU-S100 PK Sampling Schedule ....................................................... 19 
Table 3 
Censoring Rules for OS, PFS, DOR, and DODC ................................ 27 
Table 4 
Scenarios of Assignments of Best Overall Response using iRECIST . 28 
 
TABLE OF FIGURES 
Figure 1 
ADU-CL-20 Study Design .................................................................... 11 


Aduro Biotech, Inc. 
Statistical Analysis Plan
ADU-CL-20 
 
Version 1.0; 09 October 2020
 
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    Page 7 of 38 
 
 
3 LIST OF ABBREVIATIONS  
Table 1 
List of Abbreviations  
Abbreviation 
Definition  
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under curve 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CI 
confidence interval 
CR 
complete response 
CRS 
cytokine release syndrome 
CSR 
clinical study report 
CV 
coefficient of variation 
DCR 
disease control rate 
DNA 
deoxyribonucleic acid 
DODC 
duration of disease control 
DOR 
duration of response 
EAS 
evaluable analysis set 
EBV 
Epstein-Barr virus 
EBNA 
Epstein-Barr nuclear antigen 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EOT 
end of treatment 
FT3 
free tri-iodothyronine 
FT4 
free thyroxine 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HNSCC 
head and neck squamous cell cancer 
HPV 
human papillomavirus 
iBOR 
immune best overall response 
ICH 
International Council for Harmonisation 
iCR 
immune complete response 
iCPD 
immune confirmed progressive disease 


Aduro Biotech, Inc. 
Statistical Analysis Plan
ADU-CL-20 
 
Version 1.0; 09 October 2020
 
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    Page 8 of 38 
 
 
Abbreviation 
Definition  
IFN 
interferon 
Ig 
immunoglobulin 
IL 
interleukin 
IP 
investigational product 
iPR 
immune partial response 
iRECIST 
modified RECIST v1.1 for immune-based therapeutics 
iSD 
immune stable disease 
iUPD 
immune unconfirmed progressive disease 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NE 
not evaluable 
ORR 
objective response rate 
OS 
overall survival 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PCR 
polymerase chain reaction 
PR 
partial response 
Q1 
25th percentile 
Q3 
75th percentile 
RECIST 
Response Evaluation Criteria in Solid Tumors v1.1 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOD 
sum of diameters 
SD 
stable disease 
SI 
Système International 
SNP 
single nucleotide polymorphisms 
TEAE 
treatment-emergent adverse event 
TNF 
tumor necrosis factor 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
VCA 
viral capsid antigen 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
 
 
 


Aduro Biotech, Inc. 
Statistical Analysis Plan
ADU-CL-20 
 
Version 1.0; 09 October 2020
 
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4 INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide comprehensive and 
detailed descriptions of the methods and presentation of data analyses proposed for 
Aduro Biotech, Inc. Protocol ADU-CL-20 (A Phase 2 Efficacy and Safety Trial of ADU-
S100 and Pembrolizumab in Adults with Head and Neck Cancer). Descriptions of 
planned analyses are provided in order to avoid post hoc decisions that may affect the 
interpretation of the statistical analysis. The statistical methods applied in the design and 
planned analyses of this study are consistent with the International Council for 
Harmonisation (ICH) guideline Statistical Principles for Clinical Trials (E9) (1998).  
This SAP will be finalized prior to data analysis and before database lock; a separate 
document with templates for tables, listings, and figures will include the planned displays 
for the clinical study report (CSR). Any changes between the statistical methods provided 
in the clinical study protocol and this SAP will be explained herein; any changes or 
deviations from this SAP relative to the final analysis will be fully documented in the 
CSR. Minor changes or deviations from the templates for tables, figures, and listings will 
not be documented in the CSR. 
In this SAP, the Investigational Product (IP) ADU-S100 and Standard of Care 
pembrolizumab are both considered “study drug.” Throughout the SAP the term “study 
drug” is interchangeable between ADU-S100 and pembrolizumab. When referring to 
only one study drug, the SAP will specify ADU-S100 to indicate the IP or specify 
pembrolizumab to indicate the Standard of Care. 
5 STUDY OBJECTIVES 
5.1 
Primary Study Objective 
The primary objective of this study is to evaluate the clinical efficacy of ADU-S100 
administered in combination with pembrolizumab.  
5.2 
Secondary Study Objectives 
The secondary objectives of this study are to: 
 Characterize safety and tolerability 
 Further evaluate clinical activity 
 Characterize the pharmacokinetics (PK) of ADU-S100 administered by 
intratumoral injection following a single dose and multiple doses 
5.3 
Exploratory Study Objectives 
The exploratory objectives of this study are to: 


Aduro Biotech, Inc. 
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 Assess pharmacodynamics, immunomodulatory, and potential prognostic and/or 
predictive biomarkers 
 Perform pharmacogenetic analysis 
6 INVESTIGATIONAL PLAN 
6.1 
Overall Study Design 
The ADU-CL-20 study is an open-label, multicenter Phase 2 clinical trial to evaluate the 
efficacy and safety of intratumoral ADU-S100 (also referred to as MIW815) 
administered with standard of care treatment (ie, pembrolizumab) in the first-line setting. 
The multicenter clinical trial will be conducted at approximately 25 sites in North 
America. Twenty evaluable subjects will initially be enrolled. If the total number 
responding is greater than or equal to 4, then an additional 14 evaluable subjects will be 
enrolled in the second stage for a total of 34 evaluable subjects. 
The population for this study will consist of adults with metastatic head and neck 
squamous cell cancer (HNSCC) where pembrolizumab is indicated as the standard of 
care first line treatment. Individuals with intercurrent illnesses, inadequate organ 
function, various conditions impacting immune function, or other mitigating factors as 
detailed in the exclusion criteria will not be enrolled as these factors may interfere with 
the proposed mode of action of ADU-S100 and pembrolizumab, introduce undue safety 
risks, or confound interpretation of study results. 
The trial design consists of a Screening Period, Treatment Period, and a Follow-up Period 
as depicted in Figure 1. Screening assessments will be conducted to confirm eligibility 
and to obtain baseline (pre-treatment) measurements. Screening must be completed 
within 28 days prior to the first dose of either study drug. An enrollment form will 
confirm subject eligibility; baseline biopsies will not be performed until enrollment is 
confirmed. All eligible subjects will receive intravenous (IV) infusions of pembrolizumab 
(200 mg) and intratumoral injections of ADU-S100 (800 mcg/lesion; up to 2 lesions). 
During the Treatment Period, study medications will be administered in 21-day dosing 
cycles until criteria for treatment discontinuation are met, or up to 35 cycles. Tumor 
responses will be evaluated at 9-week intervals. The Follow-up Period is designed to 
assess vital status, subsequent anti-cancer therapy, and complete safety reporting 
requirements. 


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ADU-CL-20 
 
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Figure 1 
ADU-CL-20 Study Design 
 
Subjects will be requested to complete multiple clinic visits during all dosing cycles. An 
end of treatment (EOT) visit will occur 30 (+7) days after the last dose of study drug. All 
EOT visit assessments will be completed prior to commencing any new anti-cancer 
therapy.  
After completion of the EOT visit, follow-up visits will be conducted at 8-week intervals 
to satisfy protocol-specified safety reporting periods, and collect data on any subsequent 
cancer-related therapies as well as vital status. Follow-up visits may be conducted at the 
site or via telephone call, as appropriate.  
Subjects who discontinue study drug early for reasons other than progressive disease will 
complete the EOT visit and will be asked to continue tumor response assessments. 
Follow-up visits will also be conducted at 8-week intervals for these subjects. 
All study visits (and visit windows), assessments, and procedures will be performed as 
indicated in Appendix A: Schedule of Events. On days when the study drug is 
administered, assessments will be performed prior to dosing unless otherwise specified.  
6.2 
Determination of Sample Size 
The study will include up to 34 evaluable subjects to assess the clinical efficacy of ADU-
S100 administered in combination with pembrolizumab in adults with head and neck 
cancer. Power calculations based on a Simon’s 2-stage minimax design test the null 
hypothesis that the objective response rate (ORR) is less than or equal to 0.19 versus the 


Aduro Biotech, Inc. 
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alternative hypothesis that the ORR is greater than or equal to 0.38 with a Type 1 error 
rate of 0.05 and power of 80%. A sample size of 20 evaluable subjects will be enrolled in 
the first stage. If the total number responding is greater than or equal to 4, an additional 
14 evaluable subjects will be enrolled in the second stage for a total of 34 evaluable 
subjects.  For the second stage, if the total number responding is less than or equal to 10, 
the effectiveness of treatment based on ORR will be rejected. 
If treatment is actually not effective and ORR ≤ 0.38, then the expected sample size is 
25.3 evaluable subjects with a 0.456 probability of early termination and a 0.044 
probability of incorrectly concluding the treatment is effective (the target for this Type 1 
error rate was 0.05 or less). If the treatment is actually effective, there is a 0.200 
probability of incorrectly concluding it is not effective (the target for this Type 2 error 
rate was 0.200 or less). 
Subjects who do not complete a response assessment will not be considered evaluable 
and will be replaced. 
The ORR criteria are based on the pembrolizumab first-in-human study in a similar 
patient population with similar prior treatment where the response rate was 
approximately 19% (Burtness et al. 2018; Rischin et al. 2019). 
6.3 
Schedule of Assessments 
For the complete schedule of assessments, refer to Appendix A: Schedule of Events. 
6.4 
Treatments 
6.4.1 
Treatments Administered 
 ADU-S100 (MIW815; disodium dithio-(RP, RP)-[cyclic [A(2',5')pA(3',5')p]]), is 
a synthetic CDN composed of two adenosine monophosphate (AMP) analogues 
cyclized via a 2',5' (noncanonical) and a 3',5' (canonical) phosphodiester bond. 
All lesions designated for ADU-S100 administration will be injected on Days 1 
and 8 of each dosing cycle (ie, do not rotate/alternate sites for injection; all 
designed lesions will be injected on every dosing day). 
 Pembrolizumab is an immunoglobulin G4 (IgG4) kappa immunoglobin with an 
approximate molecular weight of 146 kDa.  
On dosing days where both pembrolizumab and ADU-S100 are indicated, the 
pembrolizumab infusion will be administered first, followed by an intratumoral 
injection of ADU-S100. 


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6.4.2 
Method of Assigning Subjects to Treatment Groups 
All subjects will be sequentially assigned a unique identification number during 
Screening. The study is designed as a single-arm study; all subjects will receive ADU-
S100 and pembrolizumab as indicated. 
6.5 
Efficacy and Safety Variables 
6.5.1 
Efficacy Variables 
6.5.1.1 
Primary Efficacy Variable 
The primary efficacy endpoint is the objective response rate (ORR) defined as the 
proportion of subjects in whom a complete response (CR) or a partial response (PR) is 
observed. The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 will be used 
to evaluate the primary efficacy endpoint. All responses will be confirmed at the 
subsequent tumor assessment. 
6.5.1.2 
Secondary Efficacy Variables 
Secondary efficacy endpoints include the following: 
 Overall Survival (OS): defined as the time from first dose of either study drug 
until date of death due to any cause. Subjects without documentation of death at 
the time of analysis will be censored as of the date the subject was last known to 
be alive. 
 Progression-Free Survival (PFS): defined as the time from first dose of either 
study drug to first documentation of disease progression or death due to any 
cause. Subjects who do not experience progressive disease and are alive at the 
time of analysis will be censored at the time of last evaluable tumor assessment. 
Subjects who receive anti-cancer therapy prior to documented disease progression 
will be censored on the date of last evaluable tumor assessment on or prior to the 
start date of the anti-cancer therapy. Subjects with no on-treatment tumor 
assessments will be censored on the date of treatment start. 
 Duration of Response (DOR): defined as the time from the first tumor assessment 
that supports the subject’s objective disease response to the time of disease 
progression or death due to any cause. Subjects who have ongoing response at the 
time of analysis will be censored at the time of last evaluable tumor assessment. 
Subjects who receive anti-cancer therapy prior to documented disease progression 
will be censored on the date of last evaluable tumor assessment on or prior to the 
start date of the anti-cancer therapy. Subjects with no on-treatment tumor 
assessments will be censored on the date of treatment start. 
 Disease Control Rate (DCR): defined as the proportion of subjects with CR, PR, 
or stable disease (SD). 


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 Duration of Disease Control (DODC): defined as the time from the first tumor 
assessment that supports the subject’s disease control (CR, PR, SD) to the time of 
disease progression or death due to any cause; if the subject has a best response of 
SD, then DODC is calculated from date of baseline tumor assessment to the time 
of disease progression or death due to any cause. For subjects who have ongoing 
disease control at the time of analysis, their DODC will be censored at the time of 
last evaluable tumor assessment. Subjects who receive anti-cancer therapy prior to 
documented disease progression will be censored on the date of last evaluable 
tumor assessment on or prior to the start date of the anti-cancer therapy. Subjects 
with no on-treatment tumor assessments will be censored on the date of treatment 
start. 
 ORR per modified RECIST v1.1 for immune-based therapeutics (iRECIST), 
where all noted disease progression will be confirmed at the subsequent tumor 
assessment 
 Occurrence and severity of treatment-emergent adverse events 
 Changes from baseline in safety assessments 
 Plasma concentration-time profiles and derived noncompartmental PK parameters 
(including Cmax, area under curve [AUC]) 
Progression-free survival, DOR, DCR, and DODC will be determined per RECIST v1.1 
and iRECIST. Section 7.4.6.2 contains a full table of the censoring rules that will be used 
in these analyses. Section 7.4.6.3 contains additional information regarding response 
assessment per iRECIST. Section 7.4.6.8 contains additional information regarding 
subgroup analysis. 
6.5.2 
Description of Safety Variables 
Safety will be assessed by collection of data on treatment-emergent adverse events 
(TEAEs), Eastern Cooperative Oncology Group (ECOG) performance status, vital signs, 
weight, physical examination, electrocardiogram (ECG) parameters, concomitant 
medications, and routine clinical laboratory assessments. Clinically significant changes 
from pre-treatment values in safety assessments will be reported as adverse events (AEs). 
Safety assessments described below will be conducted according to Appendix A: 
Schedule of Events. 
6.5.2.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug-related. An AE can therefore be any 
unfavorable and/or unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational medicinal 
product, whether or not related to the investigational medicinal product. 


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See Section 11.1.2 of the study Protocol for further details regarding the definition of 
AEs. 
6.5.2.2 
Serious Adverse Events 
An AE or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes:   
 Death  
 A life-threatening AE  
 Requires hospitalization or prolongation of existing hospitalization  
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions   
 A congenital anomaly/birth defect  
 An important medical event 
See Section 11.2 and 11.3 of the study Protocol for further details regarding serious 
adverse events (SAEs) and reporting. 
6.5.2.3 
Eastern Cooperative Oncology Group (ECOG) Scale of Performance 
Status 
The ECOG Scale of Performance Status is recognized as a standard tool to measure 
disease impact on daily living activities (Oken et al. 1982). The ECOG scale will be used 
by site personnel to determine eligibility and characterize a subject’s level of functioning 
(self-care, daily activity, and basic physical ability) as indicated in Appendix A: Schedule 
of Events. 
The ECOG performance status will be classified according to the following categories: 
 0; Fully active, able to carry on all pre-disease performance without restriction 
 1; Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work 
 2; Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
 3; Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
 4; Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 


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 5; Dead 
6.5.2.4 
Vital Signs 
Vital signs, including blood pressure, pulse rate, respiratory rate, and temperature will be 
obtained at each indicated visit (prior to dosing, as applicable). Serial time points 
following ADU-S100 administration support monitoring for cytokine release syndrome 
(CRS) during Cycle 1. Vital signs will be collected prior to dosing and as indicated in 
Appendix A: Schedule of Events. Additional measurements will be obtained if clinically 
indicated. 
6.5.2.5 
Comprehensive Physical Examination 
Comprehensive physical examinations will be conducted at Screening and EOT. The 
comprehensive physical examination will include the following organ or body system 
assessments: skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular 
system; abdomen (liver and spleen); extremities; lymph nodes; and a brief neurological 
examination.  
6.5.2.6 
Symptom-directed Physical Examination  
Symptom-directed physical examinations may be conducted at all other visits as 
indicated (up to 3 days prior to dosing). The Investigator or medically licensed designee 
will perform a symptom-directed evaluation as clinically indicated, including 
assessment(s) of the body systems or organs based on a subject’s symptoms, AEs, or 
other findings.   
6.5.2.7 
Weight  
Weight (kg) will be obtained at each indicated visit (prior to dosing, if applicable). 
6.5.2.8 
Electrocardiogram (ECG) 
At screening and during the study, triplicate ECG assessments will be performed with 
local 12-lead ECG equipment according to standard procedures to determine the 
corrected QT interval calculated by Fridericia’s formula (QTcF). At screening, the 
average value of the triplicate will be utilized for enrollment into the study. 
The triplicates will be performed no less than 3 minutes apart and within approximately 
30 minutes of the initial ECG to determine the mean QTcF interval. All 12-lead ECGs 
should be performed after the subject has rested in a recumbent or semi-recumbent 
position for ≥ 5 minutes. Additional ECGs may also be performed throughout the study if 
clinically indicated. The ECGS will be performed prior to study drug administration for 
all pre-dose assessments. If blood sampling or vital sign measurement is scheduled for 
the same visit as an ECG recording, the procedures will be performed in the following 
order: ECG, vital signs, blood draw. 


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ECG parameters to be evaluated include heart rate, PR interval, QT interval, QRS 
duration, and QTcF. 
The ECG will be interpreted by the Investigator as normal, not clinically significant 
abnormal, or clinically significant abnormal. If the mean QTcF is prolonged (ie, > 500 
msec, or CTCAE Grade 3) or if the mean change from baseline is ≥ 60 msec, the ECGs 
will be reevaluated by a qualified person. 
6.5.2.9 
Prior and Concomitant Medications 
Medications used within 28 days prior to the first dose of ADU-S100 will be recorded as 
prior medications.   
Concomitant medications include pre-medications and all prescription, over the counter 
medications, herbal remedies and dietary supplements administered from Cycle 1 Day 1 
until the EOT visit. The generic name, dosage, duration, and reason for the concomitant 
medication will be documented. If a subject is using biotin supplements (found in 
multivitamins, biotin supplements, and supplements for hair, skin, and nail growth), these 
will also be noted for laboratory assessments. Changes in the use of concomitant 
medications will be captured at each study visit.  
Following the EOT visit, concomitant medications will only be collected if associated 
with the management of an ongoing AE or SAE, or if a new anti-cancer treatment. 
6.5.2.10 
Screening-Specific Laboratory Assessments 
Blood and urine samples will be obtained at screening to confirm eligibility for each 
subject. These initial laboratory assessments will be conducted at the institution’s local 
laboratory:    
 Virology/Serology Screen: human immunodeficiency virus (HIV) antibody, 
hepatitis B (HBV) surface antigen, hepatitis C (HCV) antibody, HCV viral load 
(if indicated), Epstein-Barr virus (EBV) (Epstein-Barr nuclear antigen [EBNA], 
viral capsid antigen [VCA] immunoglobulin G [IgG], VCA immunoglobulin M 
[IgM], EBV polymerase chain reaction [PCR] as clinically indicated)  
 Urinalysis (dipstick or automated analysis): bilirubin, blood, glucose, ketones, 
leukocytes, nitrite, pH, protein, and specific gravity 
o If dipstick result is abnormal, microscopy will be used to measure 
sediment (red blood cells, white blood cells, epithelial cells, crystals, casts, 
bacteria)  
o Additional urinalysis may be performed throughout the study if clinically 
indicated 


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6.5.2.11 
Safety Laboratory Assessments 
Routine hematology, serum chemistry, coagulation panel, and thyroid function testing 
will be conducted to assess eligibility and as a measure of safety throughout the study per 
protocol requirements. All clinical laboratory evaluations will be performed by the 
institution’s local laboratory. Laboratory assessments for continued dosing of 
pembrolizumab must be confirmed prior to dosing; testing may be completed up to 3 
days prior to study drug administration for each cycle. Fasting is not required; however 
fasting blood glucose will be performed if clinically indicated.  
The following parameters will be evaluated:   
 Hematology: complete blood count (hematocrit, hemoglobin, platelets, red blood 
cells, white blood cells with differential [absolute counts: basophils, eosinophils, 
lymphocytes, monocytes, neutrophils])  
 Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), bicarbonate, calcium, chloride, lactate 
dehydrogenase, sodium, potassium, creatinine, glucose, magnesium, phosphate 
(inorganic phosphorus), bilirubin (total, direct), blood urea nitrogen, uric acid, 
total protein  
 Coagulation panel: prothrombin time, international normalized ratio of 
prothrombin time, activated partial thromboplastin time  
 Thyroid function: thyroid stimulating hormone (TSH), free tri-iodothyronine 
(FT3), free thyroxine (FT4) 
6.5.2.12 
Drug-induced Liver Injury 
The potential for drug-induced liver injury will be monitored using assessments of liver 
function via serum chemistry at regular intervals. Laboratory values consistent with Hy’s 
Law criteria will be used to indicate the potential for drug-induced liver injury (ie, all 3 of 
the following must coexist):  
1) ALT or AST ≥ 3 × upper limit of normal (ULN)  
2) Total bilirubin ≥ 2 × ULN  
3) ALP < 2 × ULN  
Should the laboratory parameters suggesting drug-induced liver injury be observed, other 
potential causative factors may be investigated (eg, viral hepatitis A, HBV, or HCV; 
preexisting or acute liver disease; or another drug capable of causing the observed 
injury). 


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6.5.2.13 
Laboratory Assessments for Cytokine Release Syndrome 
Blood (plasma) samples will be collected at Screening and as clinically indicated for 
assessment of interferon gamma (IFN-γ), interleukin 6 (IL-6), IL-1, tumor necrosis factor 
alpha (TNF-α), C-reactive protein, and ferritin. If CRS is suspected, a blood (plasma) 
sample will be collected within 5 hours (or as soon as possible) after occurrence of the 
event, and 1 week after occurrence of the event. 
6.5.2.14 
Pregnancy Testing and Contraception Requirements 
For study eligibility, women of childbearing potential must have a negative serum 
pregnancy test at Screening and within 24 hours prior to first dose of study drug. A urine 
pregnancy test may be performed at all other indicated visits. In case of delayed 
menstrual period (> 1 month), absence of pregnancy will be confirmed prior to next dose 
of study drug or next study visit, whichever occurs first. If a urine pregnancy test is 
positive, the results will be confirmed with a serum pregnancy test. Pregnancy of a 
subject or partner will be reported and followed. 
6.5.2.15 
Exploratory Safety Variables 
Exploratory safety endpoints include the following: 
 Changes from baseline in selected protein, cellular, and genomic expression 
parameters from blood and tissue samples; prognostic and/or predictive value 
 Exploration of individual subject deoxyribonucleic acid (DNA) sequence 
variations (eg, single nucleotide polymorphisms [SNPs]) and relationship with 
safety, tolerability, and clinical benefit  
6.5.3 
Description of Pharmacokinetic Variables 
Blood samples will be obtained at time points specified in Table 2 to characterize the 
plasma concentrations of ADU-S100 when administered with pembrolizumab after a 
single dose (Cycle 1 Day 1) and after repeat dosing (Cycle 1 Day 8 and Cycle 2 Day 1).  
Table 2 
ADU-S100 PK Sampling Schedule 
CYCLE 
DAY 
SCHEDULED TIME (Sampling Window) 1 
Cycle 1 
1 
Pre-dose (within 60 min prior to ADU-S100 dosing) 
Post-dose: 1 h (±15 min), and 2 h (±15 min) 
8 
Pre-dose (within 60 min prior to ADU-S100 dosing) 
Post-dose: 1 h (±15 min), and 2 h (±15 min) 
Cycle 2 
1 
Pre-dose (within 60 min prior to ADU-S100 dosing) 
Post-dose: 1 h (±15 min), and 2 h (±15 min) 
1 Post-dose is defined as time from completion of first ADU-S100 intratumoral injection. 


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The time points specified in Table 2 are applicable to subjects who consented under 
Protocol Amendment 3 or beyond. Subjects who consented under Protocol Amendment 1 
will have the following post-dose sampling time points: 2 min (±2 min), 15 min (±2 min), 
30 min (±5 min), 1 h (±5 min), and 2 h (±10 min). Subjects who consented under 
Protocol Amendment 2 will have the following post-dose sampling time points: 
approximately 2 min, approximately 15 min, 30 min (±5 min), 1 h (±5 min), and 2 h (±10 
min). 
When feasible, the following PK parameters will be estimated by non-compartmental 
methods using actual elapsed time from dosing: 
 AUC0-last: Area under the concentration-time curve 
<insert unit as concentration unit * hours>(h*ng/mL) from time zero (pre-dose) 
to the last measureable concentration, calculated by the linear trapezoidal rule; 
 Cmax: Maximum concentration <insert unit>(ng/mL), obtained directly from the 
observed concentration versus time data; 
For calculations using the linear trapezoidal rule, the following formula will be used: 
𝐴𝑈𝐶= 1
2 (𝐶1 + 𝐶2)(𝑡2 −𝑡1) 
6.5.4 
Biomarker Assessments 
Whole blood, plasma, and tumor tissue will be collected from all enrolled subjects (where 
not prohibited by local regulations or policies). The results may help to inform dose 
selection, monitor baseline and post-treatment immune responses; and possibly further 
characterize the mechanism of action and/or determine potential prognostic and/or 
predictive biomarkers. 
6.6 
Data Quality Assurance 
Report summaries will be generated using validated Base SAS software, version 9.4 or 
higher, on a PC or server-based platform. Additional validated software may be used to 
generate analyses, as needed.  
All SAS programs that create outputs or supporting analysis datasets will be validated by 
a second statistical programmer or biostatistician. At a minimum, validation of programs 
will consist of a review of the program log, review of output or dataset format and 
structure, and independent confirmatory programming to verify output results or dataset 
content. Additionally, all outputs will undergo a review by a senior level team member 
before finalization. 
The content of the source data will be reviewed on an ongoing basis by project statistical 
programmers and statisticians. Data will be checked for missing values, invalid records, 
and extreme outliers through defensive programming applications, analysis-based edit 


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checks, and other programmatic testing procedures. All findings will be forwarded to the 
project data manager for appropriate action and resolution.  
7 STATISTICAL METHODS 
7.1 
General Methodology 
Data will be analyzed by Precision for Medicine biostatistics personnel unless otherwise 
noted. Statistical analyses will be reported with tables, figures, and listings, presented in 
rich text format, and using recommended ICH numbering. Output specifications for all 
tables, figures, and listings will be in conformance with guidelines specified by the ICH 
in Appendix 7 of the Electronic Common Technical Document Specification (Apr 2003).  
7.1.1 
Reporting Conventions 
In general, all data collected and any derived data will be presented in subject data 
listings, for all enrolled subjects. Listings will be ordered by subject number and 
assessment or event date.  
In general, continuous variables will be summarized to indicate the study population 
sample size (N), number of subjects with available data (n), mean, standard deviation, 
median, 25th (Q1) and 75th (Q3) quartiles, minimum, and maximum values. Categorical 
variables will be summarized by the population size (N), number of subjects with 
available data (n), number of subjects in each category, and the percentage of subjects in 
each category. Unless otherwise noted, the denominator to determine the percentage of 
subjects in each category will be based on the number of subjects with available data. 
Select ordinal data may be summarized using both descriptive statistics and counts and 
percentages of subjects in each category, as appropriate. 
Non-zero percentages will be rounded to one decimal place. Rounding conventions for 
presentation of summary statistics will be based on the precision of the variable of 
summarization, as it is collected in its rawest form (ie, on the electronic Case Report 
Form [eCRF] or as provided within an external file) and are outlined as follows: 
 The mean and median will be rounded to one more decimal place than the 
precision of the variable of summarization; 
 Measures of variability (eg, standard deviation) will be rounded to two more 
decimal places than the precision of the variable of summarization; and 
 Minimum and maximum values will be presented using the same precision as the 
variable of summarization. 
Other statistics (eg, confidence intervals) will be presented using the same general rules 
outlined above, or assessed for the most appropriate presentation based on the underlying 
data. 


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7.1.2 
Summarization by Visit 
Data summarized by study visit will be based on the nominal, scheduled visit label as 
reported on the eCRF. Data will also be summarized separately for the last visit 
completed on study.  
Data collected at unscheduled visits will not be included in by-visit summaries, but will 
be considered when endpoint derivations potentially include multiple visits (eg, 
determination of baseline value, determination of worst post-baseline value, etc.). All 
data will be included in subject listings. 
7.1.3 
Data Handling Rules 
Unless otherwise noted, values reported as greater than or less than some quantifiable 
limit (eg, “< 1.0”) will be summarized with the sign suppressed in summary tables and 
figures, using the numeric value reported. Data will display on subject listings to include 
the sign. 
7.1.4 
Standard Calculations 
Where appropriate, the calculated study day of each assessment or event will be 
presented with the assessment or event date on subject data listings, where study day will 
be determined as: 
 The assessment/event date minus the date of study drug dosing, if the 
assessment/event date is prior to the date of study drug dosing; and 
 The assessment/event date minus the date of study drug dosing, plus one, if the 
assessment/event date is on or after the date of study drug dosing. 
Other variables requiring calculations will be derived using the following formulas: 
 Days: A duration between two dates expressed in days will be calculated using 
the following conventions: 
o Later date – earlier date + 1, if the earlier date is on or after the date of 
study drug dosing; or 
o Later date – earlier date, if the earlier date is prior to the date of study drug 
dosing. 
 Months: A duration expressed in months will be calculated by dividing the 
duration in days by (365.25 / 12); 
 Years: A duration expressed in years will be calculated by dividing the duration 
in days by 365.25; 


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 Change from Baseline: Baseline is defined as the last available measurement 
taken prior to the first dose of either study drug. Change from baseline will be 
calculated as the post-baseline value minus the baseline value; 
 Percentage Change from Baseline: Percentage change from baseline will be 
calculated as the change from baseline divided by the baseline value, multiplied 
by 100. 
7.2 
Analysis Populations 
The analysis populations are defined as follows:  
 All Treated Population: Includes all subjects who received any amount of either 
study drug. 
 Evaluable Analysis Set (EAS): Includes all subjects who received any amount of 
either study drug and additionally who either have at least one evaluable response 
assessment or who discontinued the study for a reason of toxicity, clinical 
progression, or death. 
 Modified All Treated Population: The protocol inclusion criteria require eligible 
subjects to be PD-L1 positive (defined as combined positive score [CPS] ≥1). If 
any subject with baseline CPS<1 were to be enrolled (a protocol deviation), then a 
Modified All Treated Population is defined as the All Treated Population 
excluding subjects with baseline CPS<1. 
 
Though subjects with baseline CPS<1 are not expected on study, if this were to occur, the 
Modified All Treated Population would be used for Efficacy summary analysis, rather 
than the All Treated Population. Otherwise, the All Treated Population will be used for 
both Efficacy and Safety analyses. Sensitivity analysis of efficacy on the EAS population 
will be presented only if there is a considerable difference between the EAS and the All 
Treated Population. 
7.3 
Study Subjects 
7.3.1 
Disposition of Subjects 
Subject disposition will be summarized for all enrolled subjects. Summaries will include 
the number and percentage of subjects in each analysis population, receiving each study 
drug and both study drugs, study completion, primary reason for early discontinuation of 
treatment, and primary reason for early discontinuation from study.  
7.3.2 
Protocol Deviations 
Important protocol deviations will be summarized over all subjects combined for the All 
Treated Population and will be listed for all subjects. Important protocol deviations are 


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protocol deviations captured on-study that are deemed by the Sponsor to potentially 
impact the efficacy or safety conclusions of the study.  
All important protocol deviations will be determined and appropriately categorized prior 
to database lock. Important deviations are collected as “major”. The number and 
percentage of subjects with any important protocol deviations as well as the number and 
percentage of subjects with deviations within each category will presented. Protocol 
deviations related to the coronavirus (COVID-19) pandemic will be summarized and 
listed separately. 
7.4 
Efficacy Evaluation 
7.4.1 
Datasets Analyzed 
All efficacy summaries will be based on the All Treated Population, as described in 
Section 7.2. A data listing of subjects excluded from the efficacy analysis, to include the 
reason for exclusion, will be presented. 
7.4.2 
Demographic and Other Baseline Characteristics 
Demographic variables including age, sex, ethnicity and race will be summarized for the 
All Treated Population. Age will be summarized using descriptive statistics. Sex, 
ethnicity, and race will be summarized with the number and percentage of subjects in 
each parameter category. 
Baseline characteristics include medical history, cancer history, prior cancer treatment, 
height, weight, body mass index (BMI), smoking history, and ECOG performance status 
Disease characteristics include disease stage at study entry, type of staging, site of 
primary tumor, HPV status, PD-L1 status, time from diagnosis of HNSCC, number of 
tumors, and sum of target lesion diameters. Height, weight, BMI, time from diagnosis of 
HNSCC, number of tumors, and sum of target lesion diameters at baseline will be 
summarized using descriptive statistics; frequency counts and percentages to summarize 
prior cancer treatment, smoking history, ECOG performance, disease stage, type of 
staging, site of primary tumor, HPV status, and PD-L1 status  at baseline will be 
presented. Frequency counts and percentages to summarize subjects reporting medical 
history by body system will also be presented. 
7.4.3 
Measurements of Treatment Compliance 
Treatment compliance will be summarized for the All Treated Population. The numbers 
of delays of each study drug will be presented. For Pembrolizumab, which is 
administered as an infusion, the drug administration could be interrupted or discontinued. 
For ADU-S100, which is administered as an injection, the drug administration could be 
paused or stopped. The number and percentage of subjects with delays of each study drug 
will also be presented. 


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7.4.4 
Primary Efficacy Endpoint Analysis Methods 
The primary efficacy endpoint is ORR as defined in Section 6.4.1.1 and will be 
summarized for the All Treated Population.  
Summaries of ORR will include the number and percentage of subjects with an objective 
response and the corresponding two-sided 95% confidence interval (CI) based on the 
exact binomial method (Clopper-Pearson). Waterfall plots will be provided showing the 
best overall tumor response. A swimmer plot of disease status for RECIST and iRECIST 
will be provided. Also, a spider plot of percent change in tumor size relative to baseline 
will be provided.  
Tumor diameters recorded on the Target and New Lesions CRF pages will be utilized for 
analysis summaries. Diameters recorded on the Dose Administration CRF page or the 
Injected Lesion Photo CRF page will not be utilized for analysis.  
7.4.4.1 
Supplemental Analysis for Primary Efficacy Endpoint 
Of exploratory interest are potential differences in tumor shrinkage in injected target 
lesions and non-injected target lesions within the same subject. A waterfall plot showing 
the maximal percentage change from baseline for sum of diameters (SOD) for injected 
target lesions and for SOD for non-injected target lesions will be provided dependent on 
collection of measurement data for both types of target lesions. Tumor measurements 
recorded on Target Lesion and New Lesion pages will be utilized for analysis. 
Measurements on the Dose Administration page will not be utilized here. 
The protocol specifies that if an injected lesion shows signs of significant regression (i.e. 
shrinkage) that precludes the ability to re-inject the lesion, other accessible lesions may 
be injected. As such, a non-injected target lesion may become an injected target lesion at 
a subsequent timepoint. As stated in Goldmacher et al 2020, “... it is not meaningful to 
report maximal shrinkage of injected lesions compared with the chronologic baseline. ... 
measuring the maximal effect on only the lesions initially chosen for injection may miss 
critical information.”  
Under these considerations, data for the injected target and non-injected target lesions 
will be analyzed on an exploratory basis using the following definitions adapted from 
Goldmacher et al 2020: 
A. For injected target lesions, the baseline for each individual lesion will be defined 
as the measurement obtained prior to first injection of that lesion. Specifically, 
o For target lesions injected at C1D1, the baseline will be defined as the 
measurement obtained prior to C1D1. 
o As the protocol allows for injection of other accessible lesions if a lesion 
shows signs of significant regression (i.e. shrinkage) that precludes the 
ability to re-inject the lesion, the baseline measurement for these newly 
injected lesions will be the preceding measurement obtained prior to the 


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lesion’s initial injection. The baseline for these lesions will not be the 
measurement prior to C1D1.  
o As this analysis will consider any new lesion target lesions (per iRECIST), 
if these new target lesions are injected, the baseline measurement for these 
lesions will be the preceding measurement obtained prior to the lesion’s 
initial injection. The baseline for these lesions will not be the measurement 
prior to C1D1.  
o Baseline SOD is defined as the sum of the individual lesion diameters at 
baseline. If a lesion becomes injected after C1D1, the baseline injected 
SOD will incorporate data from different timepoints.  
o Best response SOD also can incorporate data from different timepoints, 
regardless of if a lesion was injected after C1D1. However, only 
measurements which occur after initial injection can be considered for best 
response. 
B. For non-injected target lesions 
o As long as the non-injected target lesions remain non-injected, the non-
injected target SOD is compared with measurements obtained prior to 
C1D1. If any non-injected target lesion must be injected (eg, because 
disappearance of other injected target lesions or because of inaccessibility 
of other lesions), the maximal non-injected response has been achieved 
and any subsequent non-injected response is considered nonevaluable. 
A lesion’s injection status will be determined based on the ADU-S100 Administration 
page of the CRF which collects “Was this lesion injected at this visit?”. If a lesion is 
reported as “Yes” at a specific time point, then the lesion is considered injected from that 
timepoint onwards. Prior to that injection timepoint, it will be considered non-injected. 
Once a lesion is injected, it will be considered an injected target lesion for all subsequent 
timepoints, even if it is not injected at a later timepoint. 
 
7.4.5 
Secondary Endpoint Analysis Methods  
The calculation of ORR and accompanying CI will be repeated for the EAS. The 
secondary efficacy endpoints described in Section 6.4.1.2 will be summarized for the All 
Treated Population.  
Overall survival and PFS will be analyzed with standard survival methods (Kaplan-Meier 
estimates) to include the number of subjects who are alive at data cut-off, number of 
subjects censored, percentiles (including 95% CIs determined by the Brookmeyer and 
Crowley method) and range. Kaplan-Meier summaries, including graphs of survival 
curves, will be generated for all subjects receiving study drug.  


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Progression-free survival at 6, 12, and 24 months (including 95% CIs determined by 
Greenwood’s formula), DOR, and DODC will be analyzed with the same statistical 
methodologies as applied to OS. 
DCR will be calculated along with accompanying CIs, similar to ORR. 
Censoring rules for the analysis of each endpoint are described in Section 7.4.6.2. 
Subgroup analysis is described in Section 7.4.6.8. 
7.4.6 
Statistical/Analytical Issues 
7.4.6.1 
Adjustments for Covariates 
There are no planned applications of covariate adjustments; all statistical results are 
descriptive in nature. 
7.4.6.2 
Handling of Dropouts or Missing Data 
Censoring rules for the analysis of each secondary endpoint are summarized in Table 3 
shown on the next page. 
 
Table 3 
Censoring Rules for OS, PFS, DOR, and DODC 
No other missing data will be imputed. 
7.4.6.3 
iRECIST Response Assessment 
iRECIST is based on RECIST criteria. There are no changes compared to RECIST to the 
recommendations regarding the method of measurement. All responses per iRECIST have a 
prefix of “i” (ie, immune)—eg, “immune” complete response (iCR) or partial response (iPR), 
Endpoint 
Situation 
Date of Censoring 
OS 
No documentation of death 
Date that the subject was last 
known to be alive 
PFS, DODC 
No progression and no death 
Date of last evaluable tumor 
assessment 
PFS, DODC 
Anti-cancer therapy prior to 
documented disease progression 
Date of last evaluable tumor 
assessment on or prior to the 
start date of the anti-cancer 
therapy 
PFS, DODC, DOR No on-treatment tumor 
assessment 
Date of treatment start 
DODC 
Ongoing disease control at time 
of analysis 
Date of last evaluable tumor 
assessment 
DOR 
Ongoing response 
Date of last evaluable tumor 
assessment 


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and unconfirmed progressive disease (iUPD) or confirmed progressive disease (iCPD) to 
differentiate them from responses assigned using RECIST 1.1. Similar nomenclature is used 
for stable disease (iSD).  
The iRECIST response assessment allows for the occurrence of pseudoprogression where 
a subject may appear to worsen before a delayed response occurs. Thus, instances of 
iRECIST progressive disease require confirmation. That is, if iUPD is not confirmed as 
iCPD, then the response effectively resets with the next iRECIST evaluation. In the event 
that no further response assessment follows the iUPD assessment (eg, subject was not 
judged to be clinically stable or subject refusal, protocol noncompliance, or death) or if 
all subsequent timepoint responses are iUPD, then date of iUPD can be used for analysis. 
Several examples of assignments of best overall response using iRECIST, are presented 
in Table 4, adapted from the RECIST working group guidelines (Seymour et al. 2017). 
Table 4 
Scenarios of Assignments of Best Overall Response using iRECIST  
 
Timepoint 
Response 1 
Timepoint 
Response 2 
Timepoint 
Response 3 
Timepoint 
Response 4 
Timepoint 
Response 5 
iBOR 
Ex. 1 
iCR 
iCR, iUPD, 
or NE 
iCR, iUPD, 
or NE 
iUPD 
iCPD 
iCR 
Ex. 2 
iUPD 
iPR, iSD, or 
NE 
iCR 
iCR, iUPD, 
or NE 
iCR, iPR, 
iSD, iUPD, 
iCPD, or 
NE 
iCR 
Ex. 3 
iUPD 
iPR 
iPR, iSD, 
iUPD, or 
NE 
iPR, iSD, 
iUPD, NE, 
or iCPD 
iPR, iSD, 
iUPD, NE, 
or iCPD 
iPR 
Ex. 4 
iUPD 
iSD or NE 
iPR 
iPR, iSD, 
iUPD, or 
NE 
iPR, iSD, 
iUPD, 
iCPD, NE 
iPR 
Ex. 5 
iUPD 
iSD 
iSD, iUPD, 
or NE 
iSD, iUPD, 
iCPD, or 
NE 
iSD, iUPD, 
iCPD, NE 
iSD 
Ex. 6 
iUPD 
iCPD 
Any 
Any 
Any 
iCPD 
Ex. 7 
iUPD 
iUPD (no 
iCPD) 
iCPD 
Any 
Any 
iCPD 
Ex. 8 
iUPD 
NE 
NE 
NE 
NE 
iUPD 


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Abbreviations for Table 4: iBOR = immune best overall response; iCPD = immune 
confirmed progressive disease; iCR = immune complete response; iPR = immune partial 
response; iSD = immune stable disease; iUPD = immune unconfirmed progressive 
disease; NE = not evaluable 
7.4.6.4 
Interim Analyses and Data Monitoring 
There are no interim analyses planned, nor is there a plan to establish a data monitoring 
committee for this study. 
7.4.6.5 
Multicenter Studies 
This is a multicenter study, with approximately 25 sites expected to participate. Efficacy 
data collected from all study sites will be pooled for data analysis. The effect of study site 
on the efficacy analysis results may be explored post-hoc, as needed. 
7.4.6.6 
Multiple Comparisons/Multiplicity 
There will be no adjustments for multiple comparisons in the efficacy analysis for this 
study. Results are descriptive in nature and there will be no formal comparisons made. 
7.4.6.7 
Active-Control Studies Intended to Show Equivalence 
This study does not include an active-control product and is not intended to demonstrate 
equivalence between any two drug products. 
7.4.6.8 
Examination of Subgroups 
Subgroup analysis provides further exploratory information. Subgroups may have small 
samples sizes insufficient for statistical inference, and statistical information such as CIs 
would be informational only. The ORR, OS, and PFS will be summarized by various 
subgroups of interest including combined positive score (1% ≤ PD-L1 expression < 20% 
and ≥ 20% PD-L1 expression) and human papillomavirus (HPV) status.  
Waterfall plots will be provided showing the best overall tumor response by primary 
tumor location and by disease status. A swimmer plot will be provided by primary tumor 
location and by disease status. 
A forest plot showing the ORR of subgroups will be created for subgroups of interest 
provided that sufficient data are collected within the subgroups. Subgroups of interest 
could include the following characteristics: combined positive score ( 1 ≤ PD-L1 
expression < 20 and ≥ 20% PD-L1 expression), HPV status, age (< 65 years old and ≥ 65 
years old), gender, race, ECOG performance status at baseline, disease stage at baseline, 
tobacco use, prior surgery, prior radiotherapy, site of primary tumor (larynx, oral cavity, 
oropharynx, hypopharynx, and all other [nasal cavity, paranasal sinuses, other]), and 
subsequent therapy. 


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7.4.7 
Plasma Concentrations 
Plasma concentration values will be summarized for the All Treated Population by 
sampling time point using descriptive statistics, to include the geometric mean and 
geometric CV (%). The geometric CV is calculated as 100*sqrt[exp(σ2)-1], where σ2 is 
the variance of the log-transformed data. Each subject’s plasma concentrations will be 
plotted over time. For the purposes of plotting the data, plasma concentrations below the 
limit of quantification (BLQ) that are imbedded between two measurable concentrations 
will be set to missing; however, BLQ values occurring prior to the first measurable 
concentration or after the last measurable concentration will be set to zero. For 
summaries of plasma concentrations, BLQ values will be set to missing. The number and 
percentage of subjects with BLQ values will be summarized by time point and treatment 
group. 
7.4.8 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be analyzed based on the All Treated Population. For 
each subject, the PK parameters described in Section 6.5.3 will be determined by a non-
compartmental approach when feasible. For the purpose of the non-compartmental PK 
analysis, all plasma concentration BLQ values occurring prior to the first measurable 
concentration will be set to zero. BLQ values occurring after the first measurable plasma 
concentration will be set to missing. 
PK parameters will be summarized for the All Treated Population using descriptive 
statistics that includes the CV. Summaries of Cmax and AUC will also include point 
estimates for the geometric mean and geometric CV. The geometric mean is calculated 
by computing the mean of the log-transformed concentration values and then presented in 
the original scale by calculating the anti-log of the mean result. The geometric CV is 
calculated as 100*sqrt[exp(σ2)-1], where σ2 is the variance of the log-transformed data. 
Listings of calculated PK parameters will be provided.  
7.4.9 
Biomarker Analysis 
Biomarker analysis is outside the scope of this SAP. 
7.5 
Safety Evaluation 
Safety analysis will be carried out for the All Treated Population, to include all subjects 
who receive at least one dose of either study drug. Subjects who do not complete the 
study, for whatever reason, will have all available data up until the time of termination 
included in the analysis. For safety analysis presented by study visit, the baseline value 
will be defined as the last value reported prior to first administration of either study drug. 
7.5.1 
Extent of Exposure 
Extent of exposure to study treatment will be summarized for the All Treated Population. 
The duration of exposure will be presented in days and calculated as the date of last dose 
of study drug minus the date of first dose of study drug, plus one. The dose intensity will 


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be calculated as the total dose administered divided by the duration of exposure. Duration 
of exposure, total dose received (mg for Pembrolizumab; mcg for ADU-S100), and dose 
intensity will be summarized using descriptive statistics. The number of injected lesions 
per subject will be summarized. 
7.5.2 
Adverse Events 
Treatment-emergent adverse events are defined as those AEs with onset after the first 
dose of either study drug or existing events that worsened after the first dose during the 
study. Treatment-emergent AEs will be summarized for all subjects combined. Events 
reported with a partial onset date (eg, month and year are reported but the day is missing) 
will be considered to be treatment-emergent if it cannot be confirmed that the event onset 
was prior to the first dose of either study drug based on the available date entries. 
Verbatim terms on case report forms will be mapped to preferred terms and system organ 
classes using the Medical Dictionary for Regulatory Activities (MedDRA, version 23.0). 
Adverse events will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE). 
Summaries that are displayed by system organ class and preferred terms will be ordered 
by descending incidence of system organ class and preferred term within each system 
organ class. Summaries displayed by preferred term only will be ordered by descending 
incidence of preferred term. Summaries of the following types will be presented: 
 Overall summary of number of unique TEAEs and treatment-emergent SAEs and 
subject incidence of TEAEs meeting various criteria; 
 Subject incidence of TEAEs by MedDRA system organ class and preferred term; 
 Subject incidence of the most frequently-occurring TEAEs (ie, TEAEs occurring 
in ≥ 10% of the All Treated Population) by MedDRA preferred term; 
 Subject incidence of TEAEs by NCI-CTCAE grade, MedDRA system organ 
class, and preferred term; 
 Subject incidence of TEAEs related to each study drug and both study drugs by 
NCI-CTCAE grade, MedDRA system organ class, and preferred term; 
 Subject incidence of TEAEs by relationship to each study drug, MedDRA system 
organ class, and preferred term;  
 Subject incidence of the most frequently-occurring TEAEs related to each study 
drug and both study drugs (ie, related TEAEs occurring in ≥ 10% of the All 
Treated Population) by MedDRA preferred term; 
 Subject incidence of TEAEs with NCI-CTCAE grade ≥ 3 and related to each 
study drug and both study drugs by MedDRA system organ class and preferred 
term;  


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 Subject incidence of treatment-emergent SAEs by MedDRA system organ class 
and preferred term; 
 Subject incidence of treatment-emergent SAEs by NCI-CTCAE grade, MedDRA 
system organ class, and preferred term; 
 Subject incidence of treatment-emergent SAEs related to each study drug and 
both study drugs by NCI-CTCAE grade, MedDRA system organ class, and 
preferred term; and 
 Subject incidence of TEAEs leading to withdrawal, delay, reduction, or 
interruption of each study drug and both study drugs by MedDRA system organ 
class and preferred term. 
At each level of summarization (eg, any AE, system organ class, and preferred term), 
subjects experiencing more than one TEAE will be counted only once. In the summary of 
TEAEs by severity grade, subjects will be counted once at the highest severity reported at 
each level of summarization; in the summary of TEAEs by relationship, subjects will be 
counted once at the closest relationship to study drug. 
Adverse event data will be presented in data listings by subject and event.  
7.5.3 
Deaths, Other Serious Adverse Events, and Other Significant Adverse 
Events 
All deaths during the study, including the post-treatment follow-up period, will be listed 
by subject, to include the primary cause of death. Serious AEs and other significant AEs, 
including those that led to withdrawal, delay, interruption, or reduction of each study 
drug, will be provided in separate subject data listings. 
7.5.4 
Clinical Laboratory Evaluation 
All descriptive summaries of laboratory results will be based on data collected on the 
eCRF and presented in Système International (SI) units, as suggested by the Center for 
Biologics Evaluation and Research and the Center for Drug Evaluation and Research 
Position on Use of SI Units for Lab Tests (Oct 2013). All data will be included in by-
subject data listings. Laboratory measurements identified as abnormal (ie, outside the 
normal range) will also be listed separately by subject, laboratory test, and unit. In 
addition, normal ranges provided by each site will be presented in a separate listing. 
Clinical laboratory measurements, including serum chemistry and hematology, will be 
summarized for all subjects combined. Descriptive statistics will be presented for 
observed values and changes from baseline at each visit where parameters were 
scheduled to be collected per the clinical study protocol.  
Where applicable, laboratory results will be classified as “low,” “normal,” or “high” with 
respect to the parameter-specific reference ranges (ie, below the lower limit of the normal 
range, within the normal range, or above the upper limit of the normal range). Three-by-


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three contingency tables will be presented for each laboratory parameter to summarize 
the shift from the baseline category to the worst post-baseline measurement, defined as 
the value numerically farthest outside of the normal range across all post-baseline visits 
through the end of the study. 
Summary results will include the count and percentage of subjects within each shift 
category. 
Where applicable, hematology, chemistry, and coagulation results for select parameters 
will be assigned a toxicity grade based on the NCI-CTCAE. If the quantitative criteria for 
grading are equivalent for two grades and the differentiation is described by clinical 
interventions, the clinical intervention component will not be considered and the highest 
NCI-CTCAE grade will be assigned. Similarly, death related to AE (ie, Grade 5) cannot 
be determined with available laboratory-based data collection and, thus, will not be 
summarized as a category. Laboratory parameters that include multiple sets of criteria for 
each direction (eg, separate criteria for potassium measures to assess hyperkalemia and 
hypokalemia) will be summarized separately to reflect each set of criteria. 
A five-by-five contingency table will be presented for lab tests where toxicity grading 
can be applied, to summarize the shift from the baseline grade to the worst post-baseline 
grade. Grades will be presented as none (Grade 0; ie, measurements did not meet any 
NCI-CTCAE criteria for Grades 1 through 4), mild (Grade 1), moderate (Grade 2), severe 
(Grade 3), or life-threatening (Grade 4). Summary results will include the count and 
percentage of subjects within each shift category.  
A separate table will be provided to assess the potential for drug-induced liver injury. 
Laboratory values consistent with Hy’s Law criteria will be presented. Summary results 
will include the count and percentage of subjects within each shift category. 
7.5.5 
Vital Signs, Physical Findings, and Other Observations Related to Safety 
7.5.5.1 
Vital Signs 
Vital sign parameter measurements will be summarized for all subjects combined. 
Descriptive statistics will be presented for observed values and changes from baseline at 
each visit where parameters were scheduled to be collected.  
7.5.5.2 
12-Lead Electrocardiogram 
Twelve-lead ECG interval parameters will be summarized for all subjects combined. 
Descriptive statistics will be presented for observed values and changes from baseline at 
each visit where parameters were scheduled to be collected. Measurements will be taken 
in triplicate, and the average measurement will be summarized. 
Twelve-lead ECG will be classified by the investigator as “normal,” “abnormal, not 
clinically significant,” or “abnormal, clinically significant.” Three-by-three contingency 
tables will be presented to summarize the shift from the baseline category to the worst 


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post-baseline value. Summary results will include the count and percentage of subjects 
within each shift category. 
Prolonged QTcF intervals will be summarized as QTcF measurements (msec) that are 
> 450, > 480, and > 500 at each visit where ECG is routinely collected per the clinical 
study protocol. Change from baseline categories will also be summarized for 
measurements that represent an average change > 30 or > 60 relative to the average 
baseline value. Summary results will include the percentage of subjects within each 
category. 
7.5.5.3 
Physical Examination 
Results of the physical examination will be presented in subject data listings by subject 
and study visit. 
7.5.5.4 
Eastern Cooperative Oncology Group (ECOG) Scale of Performance 
Status 
The ECOG performance status will be summarized for all subjects combined. Descriptive 
statistics will be presented for observed values and changes from baseline at each visit 
where status was scheduled to be collected. Five-by-five contingency tables will be 
presented to summarize the shift from the baseline category to the worst post-baseline 
value. Summary results will include the count and percentage of subjects within each 
shift category. 
7.5.5.5 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary 
Enhanced (WHODDE) Global B3, March 1, 2019. Medications entered on the eCRF will 
be mapped to Anatomic Therapeutic Chemical (ATC) drug class (level 4) and drug name.  
Prior and concomitant medications will be summarized separately and the study phase of 
each medication will be determined programmatically based on medication start and end 
dates. A prior medication is defined as any medication used within 28 days prior to the 
first dose of ADU-S100. A concomitant medication is defined as any medication 
administered from Cycle 1 Day 1 until the EOT visit. A medication may be defined as 
both prior and concomitant. If it cannot be determined whether a medication was received 
prior to the start of study drug dosing due to partial or missing medication start and/or 
end dates, it will be considered a prior medication. Likewise, if it cannot be determined 
whether a medication was received after the start of study drug dosing, it will be 
considered concomitant. 
For both prior and concomitant medications summaries, the number and percentage of 
subjects receiving any medication by ATC drug class and generic drug name will be 
summarized. Prior and concomitant medications will also be summarized over all 
subjects combined. Subjects reporting use of more than one medication at each level of 
summarization (any medication received, ATC class, and generic drug name) will be 
counted only once. ATC class terms will be displayed by descending order of incidence, 


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as will generic drug names within each ATC class. The study phase during which each 
medication was received (eg, prior, concomitant, or both) will be presented on the listing 
of prior and concomitant medications. 
7.5.6 
Exploratory Safety Endpoint Analysis Methods 
All exploratory endpoint laboratory data will be presented in by-subject data listings. 
7.6 
Changes in the Conduct of the Study or Planned Analyses 
Section 12.3 (“Analysis Sets”) of the protocol states the following: 
Evaluable Analysis Set (EAS): All subjects who received any amount of study drug and 
have at least one evaluable response assessment or were discontinued due to toxicity. The 
EAS will be used for analysis of the primary efficacy endpoint and clinical activity. 
 The EAS will also include subjects who died or discontinued due to clinical 
progression or toxicity.  
 The All Treated Population will be used for analysis of the primary efficacy 
endpoint and clinical activity. The All Treated Population is identical to the 
Safety Population that is described in the protocol. 
 For RECIST response SD in the calculation of DODC, duration of SD is 
calculated from date of baseline tumor assessment to the time of disease 
progression or death due to any cause. The protocol specifies to calculate this 
duration “from the first tumor assessment that supports the subject’s disease 
control” for all associated RECIST responses. This SAP further clarifies that the 
baseline tumor assessment can be taken as the date “supporting” the period of 
stable disease.  
 
 


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8 REFERENCE LIST 
Burtness, B., K. J. Harrington, R. Greil, D. Soulières, M. Tahara, G. de Castro, Jr., et al. 
2018. KEYNOTE-048: Phase 3 study of first-line pembrolizumab (P) for 
recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), Ann Oncol, 
29 (Suppl 8): Abstract LBA8_PR. 1. 
Goldmacher, G.V., A.D. Khilnani, R.H.I. Andtbacka, J.J. Luke, F.S. Hodi, et al. 2020. 
Response Criteria for Intratumoral Immunotherapy in Solid Tumors: itRECIST, Journal 
of Clinical Oncology, 1-11. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 1982. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group, Am J Clin 
Oncol, 5: 649-55. 
Rischin, D., K. J. Harrington, R. Greil, D. Soulieres, M. Tahara, G. de Castro, et al. 2019. 
Protocol-specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab 
(pembro) as first-line therapy for recurrent/metastatic head and neck squamous cell 
carcinoma (R/M HNSCC), J Clin Oncol, 37, no. 15_suppl(May 20, 2019)6000-6000. 
Seymour, L., J. Bogaerts, A. Perrone, R. Ford, L. H. Schwartz, S. Mandrekar, et al. 2017. 
iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics, 
Lancet Oncol, 18: e143-e52. 
 
 


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APPENDIX A: SCHEDULE OF EVENTS 
 
 
 


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