A Phase 1/1b Trial of MK-1966 in Combination With SD-101 in Subjects With Advanced Malignancies
Phase: PHASE1
Conditions: Neoplasms, Advanced
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02731742 
Document Date: 
9-Feb-2017
A Phase 1/1b Trial of MK-1966 in Combination with 
SD-101 in Subjects with Advanced Malignancies

Product:  MK-1966 
1
Protocol/Amendment No.: 001-03 
MK-1966-001-03 Final Protocol
9-Feb-2017
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
This protocol amendment is applicable only to US.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase 1/1b Trial of MK-1966 in Combination with SD-101 in Subjects with Advanced 
Malignancies
IND NUMBER:  126,897
EudraCT NUMBER:  N/A
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
2.1
Trial Diagram........................................................................................................ 15
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 15
Primary Objective(s) & Hypothesis(es) .............................................................. 15
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 16
3.2
Exploratory Objectives......................................................................................... 16
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 17
Background ........................................................................................................... 17
4.1
Pharmaceutical and Therapeutic Background .................................................... 17
4.1.1
MK-1966 Background ................................................................................. 17
4.1.1.1
SD-101 Background..................................................................................... 17
4.1.1.2
Pre-clinical and Clinical Trials ........................................................................... 18
4.1.2
MK-1966 Preclinical and Clinical Trials..................................................... 18
4.1.2.1
Ongoing Clinical Trials....................................................................................... 22
4.1.3
Ongoing Clinical Trials with Anti-IL-10 Monoclonal Antibody ................ 22
4.1.3.1
SD-101 Clinical Trials ................................................................................. 22
4.1.3.2
Information on Other Trial-Related Therapy...................................................... 23
4.1.4
Rationale................................................................................................................ 23
4.2
Rationale for the Trial and Selected Subject Population .................................... 23
4.2.1
Rationale for Dose Selection/Regimen............................................................... 23
4.2.2
Rationale for the Use of Comparator/Placebo ............................................. 24
4.2.2.1
Starting Dose for This Trial ......................................................................... 24
4.2.2.2
4.2.2.2.1
Rationale for MK-1966 Dose ............................................................... 24
4.2.2.2.2
Rationale for SD-101 Dose................................................................... 27
Maximum Dose/Exposure for This Trial..................................................... 27
4.2.2.3
Rationale for Dose Interval and Trial Design .............................................. 28
4.2.2.4
 
 
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Rationale for Endpoints ...................................................................................... 28
4.2.3
Safety Endpoints .......................................................................................... 28
4.2.3.1
Efficacy Endpoints....................................................................................... 28
4.2.3.2
Pharmacokinetic Endpoints ......................................................................... 29
4.2.3.3
Pharmacodynamic Endpoints....................................................................... 29
4.2.3.4
Cheson Criteria for Lymphomas.................................................................. 29
4.2.3.5
Immune-related RECIST (irRECIST) ......................................................... 30
4.2.3.6
4.2.3.6.1
Target Engagement (TE) ...................................................................... 32
4.2.3.6.2
Anti-Drug Antibody (ADA) Assay....................................................... 32
4.2.3.6.3
Cytokines of Systemic Immune Activation.......................................... 33
4.2.3.6.4
Exploratory RNA Profiling and IHC Markers...................................... 33
4.2.3.6.5
Exploratory Objective on the Longitudinal Change of Tumor Size ..... 33
Planned Exploratory Biomarker Research................................................... 33
4.2.3.7
Future Biomedical Research........................................................................ 33
4.2.3.8
Benefit/Risk ........................................................................................................... 34
4.3
5.0
METHODOLOGY ................................................................................................... 34
Entry Criteria........................................................................................................ 34
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 34
5.1.1
Subject Inclusion Criteria.................................................................................... 34
5.1.2
Subject Exclusion Criteria .................................................................................. 37
5.1.3
Trial Treatment(s) ................................................................................................ 38
5.2
Dose Selection/Modification .............................................................................. 39
5.2.1
Dose Selection (Preparation) ....................................................................... 39
5.2.1.1
Dose Escalation............................................................................................ 39
5.2.1.2
5.2.1.2.1
3+3 Dose Escalation ............................................................................. 39
5.2.1.2.2
Dose Confirmation/Expansion.............................................................. 40
Definition of Dose Limiting Toxicity ................................................................. 42
5.2.2
Guidelines for Dose Modifications..................................................................... 42
5.2.3
Dose Modification ....................................................................................... 42
5.2.3.1
Replacement of Subjects in DLT Evaluation Period .......................................... 45
5.2.4
Timing of Dose Administration .......................................................................... 45
5.2.5
Trial Blinding/Masking....................................................................................... 46
5.2.6
 
 
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Randomization or Treatment Allocation............................................................ 46
5.3
Stratification.......................................................................................................... 46
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 46
5.5
Acceptable Concomitant Medication.................................................................. 46
5.5.1
Prohibited Concomitant Medications.................................................................. 46
5.5.2
Treatment Precaution........................................................................................... 47
5.6
Rescue Medications & Supportive Care............................................................. 47
5.7
Supportive Care Guidelines ................................................................................ 47
5.7.1
Diet/Activity/Other Considerations..................................................................... 51
5.8
Diet...................................................................................................................... 51
5.8.1
Contraception...................................................................................................... 51
5.8.2
Use in Pregnancy ................................................................................................ 53
5.8.3
Use in Nursing Women....................................................................................... 53
5.8.4
Subject Withdrawal/Discontinuation Criteria................................................... 53
5.9
Subject Replacement Strategy............................................................................. 54
5.10
Beginning and End of the Trial ........................................................................... 54
5.11
Clinical Criteria for Early Trial Termination ................................................... 54
5.12
6.0
TRIAL FLOW CHART ........................................................................................... 55
7.0
TRIAL PROCEDURES ........................................................................................... 59
Trial Procedures ................................................................................................... 59
7.1
Administrative Procedures.................................................................................. 59
7.1.1
Informed Consent......................................................................................... 59
7.1.1.1
7.1.1.1.1
General Informed Consent.................................................................... 59
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 60
Inclusion/Exclusion Criteria ........................................................................ 60
7.1.1.2
Subject Identification Card .......................................................................... 60
7.1.1.3
Medical History ........................................................................................... 60
7.1.1.4
Prior and Concomitant Medications Review ............................................... 60
7.1.1.5
7.1.1.5.1
Prior Medications.................................................................................. 60
7.1.1.5.2
Concomitant Medications..................................................................... 60
Disease Details and Treatments................................................................... 61
7.1.1.6
 
 
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7.1.1.6.1
Disease Details...................................................................................... 61
7.1.1.6.2
Prior Oncology Treatment History ....................................................... 61
Assignment of Screening Number............................................................... 61
7.1.1.7
Assignment of Treatment/Randomization Number ..................................... 61
7.1.1.8
Trial Compliance (Study Drug Administration) .......................................... 61
7.1.1.9
7.1.1.9.1
MK-1966............................................................................................... 61
7.1.1.9.2
SD-101.................................................................................................. 62
Clinical Procedures/Assessments........................................................................ 62
7.1.2
Adverse Event (AE) Monitoring.................................................................. 62
7.1.2.1
Full Physical Examination ........................................................................... 63
7.1.2.2
7.1.2.2.1
Directed Physical Exam........................................................................ 63
Vital Signs and Weight ................................................................................ 63
7.1.2.3
Electrocardiogram (ECG) ............................................................................ 63
7.1.2.4
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 63
7.1.2.5
Disease Assessments.................................................................................... 63
7.1.2.6
7.1.2.6.1
Solid Tumors......................................................................................... 63
7.1.2.6.2
B Cell Lymphoma................................................................................. 64
Unilateral Bone Marrow Biopsy and Aspirate................................. 64
7.1.2.6.2.1
7.1.2.6.3
Solid Tumors and B Cell Lymphoma................................................... 64
Imaging ............................................................................................ 64
7.1.2.6.3.1
Tumor Tissue Collection and Correlative Studies Blood Sampling 65
7.1.2.6.3.2
Laboratory Procedures/Assessments .................................................................. 65
7.1.3
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 66
7.1.3.1
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 67
7.1.3.2
7.1.3.2.1
Blood Collection (Serum) for MK-1966 .............................................. 67
7.1.3.2.2
Blood Collection for Anti- MK-1966 Antibodies (ADA) .................... 67
Planned Genetic Analysis Sample Collection.............................................. 67
7.1.3.3
Future Biomedical Research Sample Collection ......................................... 67
7.1.3.4
Other Procedures................................................................................................. 67
7.1.4
Withdrawal/Discontinuation........................................................................ 67
7.1.4.1
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 68
Blinding/Unblinding .................................................................................... 68
7.1.4.2
 
 
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Calibration of Critical Equipment................................................................ 68
7.1.4.3
Visit Requirements.............................................................................................. 68
7.1.5
Screening...................................................................................................... 68
7.1.5.1
Treatment Period.......................................................................................... 69
7.1.5.2
7.1.5.2.1
Safety Follow-up Visit.......................................................................... 69
Assessing and Recording Adverse Events .......................................................... 69
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 70
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 71
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 71
7.2.3
Serious Adverse Events ............................................................................... 71
7.2.3.1
Events of Clinical Interest............................................................................ 72
7.2.3.2
Evaluating Adverse Events ................................................................................. 73
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 76
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 76
Statistical Analysis Plan Summary ..................................................................... 76
8.1
Study has no interim analyses..................................................................................... 76
8.2
Responsibility for Analyses/In-House Blinding ................................................. 77
8.3
Hypotheses/Estimation ......................................................................................... 77
8.4
Analysis Endpoints ............................................................................................... 77
8.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints..................................... 77
8.4.2
Safety Endpoints ................................................................................................. 77
8.4.3
Derivations of Efficacy/Immunogenicity/Pharmacokinetics Endpoints............. 77
8.4.4
Derivations of Safety Endpoints ......................................................................... 77
8.5
Analysis Populations............................................................................................. 78
8.5.1
Safety Analysis Populations ............................................................................... 78
8.5.2
Pharmacokinetic Analysis Populations............................................................... 78
8.5.3
Efficacy Analysis Populations ............................................................................ 78
8.6
Statistical Methods................................................................................................ 78
8.6.1
Statistical Methods for Efficacy Analyses .......................................................... 78
8.6.2
Statistical Methods for Safety Analyses ............................................................. 78
8.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 79
 
 
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8.6.3.1
Demographic and Baseline Characteristics ................................................. 79
8.6.3.2
Pharmacokinetics and Pharmacodynamics Modeling Analysis .................. 79
8.6.3.3
Interim Analyses .......................................................................................... 79
8.6.3.4
Multiplicity .................................................................................................. 79
8.6.3.5
Sample Size and Power Calculations........................................................... 79
8.6.4
Precision of the DLT rate at RPTD..................................................................... 80
8.7
Subgroup Analyses and Effect of Baseline Factors ........................................... 81
8.8
Compliance (Medication Adherence).................................................................. 81
8.9
Extent of Exposure................................................................................................ 81
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 81
Investigational Product ........................................................................................ 81
9.1
Packaging and Labeling Information ................................................................. 82
9.2
Clinical Supplies Disclosure................................................................................. 82
9.3
Storage and Handling Requirements.................................................................. 82
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 82
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 83
Confidentiality....................................................................................................... 83
10.1
Confidentiality of Data ....................................................................................... 83
10.1.1
Confidentiality of Subject Records ..................................................................... 83
10.1.2
Confidentiality of Investigator Information........................................................ 83
10.1.3
Confidentiality of IRB/IEC Information............................................................. 84
10.1.4
Compliance with Financial Disclosure Requirements....................................... 84
10.2
Compliance with Law, Audit and Debarment ................................................... 84
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 86
10.4
Quality Management System............................................................................... 86
10.5
Data Management................................................................................................. 86
10.6
Publications ........................................................................................................... 87
10.7
11.0
LIST OF REFERENCES......................................................................................... 89
12.0
APPENDICES........................................................................................................... 91
Merck Code of Conduct for Clinical Trials........................................................ 91
12.1
 
 
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Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 93
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff ...................................................................................... 97
ECOG Performance Status................................................................................ 108
12.4
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 109
12.5
List of Abbreviations and Definitions of Terms............................................... 110
12.6
13.0
SIGNATURES......................................................................................................... 112
Sponsor's Representative ................................................................................... 112
13.1
Investigator.......................................................................................................... 112
13.2
 
 
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LIST OF TABLES
    
Table 1
Historical Monkey and Human PK Parameters for MK-7089. Estimated 
Scaling Factor was Used for MK-1966 Exposure Predictions in Human
24
Table 2
Estimated Steady-State Exposure and Target Engagement Following 
Administration of MK-1966 (IV Q3W)
24
Table 3
Response Criteria for Non-Hodgkin’s Lymphoma
30
Table 4
Adequate Organ Function Laboratory Values
36
Table 5
Trial Treatment for MK-1966 and SD-101
38
Table 6
Dose Confirmation Rules
41
Table 7
MK-1966 and SD-101 Dose Modification Guidelines for Drug-Related 
Adverse Events
43
Table 8
Infusion Reaction Treatment Guidelines
50
Table 9
Imaging by Anatomical Coverage
64
Table 10
Laboratory Tests
66
Table 11
Evaluating Adverse Events
74
Table 12
Precision of the Estimated DLT rates at RPTD
81
Table 13
Product Descriptions
82
 
 
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LIST OF FIGURES
          
Figure 1
Trial Design
15
Figure 2
Schematic Diagram Showing Mechanism of Action of TLR9 Agonism 
and Its Induction of Counter-regulatory Factors Including IL-10
18
Figure 3
Efficacy of SCH 708974 and SD-101 in HPV E6/E7TC-1 Syngeneic 
Mouse Bilateral Tumor Model
19
Figure 4
SD-101 Induces IL-10 in HPV E6/E7TC-1 Syngeneic Mouse Bilateral 
Tumor Model
20
Figure 5
SD-101 Induces IFN-α2a and IL-10 in Human PMBCs
20
Figure 6
SD-101 Induces mRNA Expression of IFN-α-inducible Genes, 
Cytokines, and Immune Activation Markers in Human Renal Cell 
Carcinoma Histoculture
21
Figure 7
Efficacy of SD-101 Alone (at 0.3 to 3 mg/kg) and in Combination With 
Surrogate Mouse Anti-IL-10 mAb SCH 708974 (1 and 10 mg/kg).
25
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
3.3 
4.2.3.6.3 
Exploratory Testing
Cytokine of Systemic Immune 
Activation
Cytokine 
testing 
updated 
to 
include: IL-10, IFN-γ, IL-12p70, 
IL-13, IL-1β, IL-2, IL-4, IL-6, IL-
8, TNF-α and IFN-α2a. 
Sections updated to agree with the 
cytokine testing in the Biomarker 
Plan.  
4.2.3.2
4.2.3.6
7.1.2.6.1
Efficacy Endpoints 
immune-related RECIST 
(irRECIST)
Solid Tumors
Updated/clarified 
that 
when 
feasible, 
study 
subjects 
can 
continue 
on 
treatment 
until 
progression is confirmed by the 
local site investigator/radiology 
assessment.
Updated/clarified discontinuing 
subjects with PD from study based 
on investigator feedback. 
4.2.3.6.1
Target Engagement 
Changed “validated” to “qualified 
”in the third sentence
A qualified total IL-10 assay is 
being used for supporting the 
Phase I clinical studies
5.1.2 (b and e)
Subject Inclusion
Removed “local surgical resection 
is permitted” was eliminated.   
Deleted based on investigator 
feedback. 
5.1.2 (Table 4)
Adequate Organ Function 
Laboratory Values
AST criterion and footnote c were 
added.  
AST criterion added for subjects 
with liver metastases and also 
added language to include 
adequate PT or partial 
thromboplastin time (PTT) range 
for subjects receiving 
anticoagulant therapy.  
5.2 (Table 5)
Trial Treatment 
MK-1966 will be administered at 
least 30 minutes after the SD-101 
injection added to footnote 2.
Added to ensure agreement with 
information in the Pharmacy and 
Procedures Manual(s). 
 
 
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5.6
Treatment Precaution
Added drugs that should be used 
with caution through 7 days after 
each subsequent dose of SD-101. 
Updated protocol based on 
documents received from 
Dynavax. 
5.9
Subject 
Withdrawal/Discontinuation
Removed/clarified language 
related to discontinuing subjects 
with confirmed disease 
progression.  
Revised based on site feedback.  
6
Trial Flow Chart Updated 
Simplified/clarified multiple 
footnotes.  
Added the following:
- Required 90 minute observation 
after SD-101 injection 
- MK-1966 will be administered at 
least 30 minutes after the SD-101 
injection.
- Free T4, Total T3 added to clarify 
TSH testing.  
- Lab and Procedure collection 
inconsistencies corrected.  
Revised/updated based on 
discrepancies/feedback from the 
sites.   
7.1.2.6.3.1
Imaging 
Added Table 9 (Imaging by 
Anatomical Coverage) that 
includes updated imaging 
requirements.   
Updated protocol to include 
Imaging by Anatomical Coverage 
Table from Imaging Manual.  
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
4.1.1.2
SD-101 Background 
Reference 0477BF changed to 
03QCKP.  
Corrected reference error. 
5.2.3 
5.7 
Guidelines for Dose Modification
Supportive Care Guidelines
Updated protocol with additional 
toxicities and Supportive Care 
Guidelines. 
Updated sections to agree with 
required 
Merck 
Oncology 
Protocol Language.  
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase 1/1b Trial of MK-1966 in Combination with SD-101 in 
Subjects with Advanced Malignancies
Sponsor Product Identifiers
MK-1966, SD-101
N/A
Trial Phase
Phase I/Ib
Clinical Indication
Part A- Treatment of subjects with B-cell lymphoma, melanoma, 
squamous cell cancer of head and neck, breast cancer with dermal 
metastasis
Part B- Treatment of subjects with melanoma
Part C- Treatment of subjects with squamous cell cancer of head and 
neck
Trial Type
Interventional
Type of control
None
Route of administration
MK-1966 given intravenously and SD-101 given intratumorally
Trial Blinding
Unblinded Open-label
Treatment Groups
Part A: Dose escalation of MK-1966 in combination with a fixed dose 
of SD-101 in subjects with B-cell lymphoma, melanoma, squamous 
cell cancer of head and neck, breast cancer with dermal metastasis.  
Part B: Confirmation/Expansion Cohort of maximum tolerated 
dose/maximum administered dose MTD (maximum tolerated dose) 
/MAD (maximum administered dose) of MK-1966 with fixed dose 
SD-101 in melanoma.  
Part C: Confirmation/Expansion Cohort of MTD/MAD of MK-
1966 with fixed dose SD-101 in squamous cell cancer of head and 
neck.
Number of trial subjects
Approximately 64 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 1.8
years from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject 
signs the Informed Consent Form (ICF) through the final contact.  
After a screening phase of up to 28 days, eligible subjects will be 
enrolled in Part A treatment with MK-1966 and SD-101 and will 
continue for up to 8 cycles (approximately 24 weeks) of treatment. 
Treatment in Parts B and C will be with the MTD or MAD of MK-
1966 determined in Part A. Subjects in Parts A, B and C may 
receive up to 8 cycles (approximately 24 weeks) of treatment or 
continue treatment until disease progression, unacceptable adverse 
event(s), intercurrent illness that prevents further administration of 
treatment, Investigator’s decision to withdraw the subject, subject 
withdraws consent, pregnancy of the subject, noncompliance with 
trial treatment or procedure requirements, or administrative reasons 
requiring cessation of treatment.  After the end of treatment (EOT), 
each subject will be followed for 30 days.  Serious adverse events 
(SAEs) will be collected for 30 days after EOT.
A list of abbreviations used in this document can be found in Section 12.6.
Randomization Ratio
N/A
 
 
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2.0 TRIAL DESIGN
Trial Design
2.1
This is a non-randomized, multi-site, open-label trial of MK-1966 in combination with SD-
101 in subjects with B-cell lymphoma, melanoma, squamous cell cancer of head and neck 
(SCCHN), breast cancer with dermal metastasis (see Section 5.1.2 for enrollment criteria).  
This trial will use an adaptive design based on the pre-specified criteria of dose limiting 
toxicity (DLT). For Dose Escalation (Part A) a 3+3 dose escalation design will be utilized 
(See Section 5.2.1.4). For Dose Confirmation (Parts B and C) the toxicity probability interval 
(TPI) design [1] will be utilized to refine the estimate of MTD.
In Part A, MK-1966 will be given in combination with SD-101 and will enroll subjects with 
one of the four potential malignancies described above.  Enrollment to each dose level in Part 
A will occur sequentially, with each successively higher dose level initiating if the preceding 
dose is deemed tolerable per the DLT criteria (see Section 5.2.2).  Subjects will continue at 
their enrolled dose for the duration of their participation.  The study will begin with a 3+3 
design to identify a preliminary MTD or MAD of the combination. During 3+3 dose 
escalation, an initial cohort of 3 subjects will be enrolled to a dose level. If none of the 3 
subjects experience a DLT, escalation to the next dose will occur. If one of the 3 subjects 
experiences a DLT, another 3 subjects will be enrolled at this dose level. If 1 DLT is 
observed among the 6 subjects, the dose escalation will continue. If ≥2/3 or ≥2/6 subjects at 
a dose level develop DLTs, dose escalation will be terminated, and the study will proceed to 
the dose confirmation stage at the previous dose level. At least 2 days of observation will 
occur between each of the first 3 subjects in the first 2 dose levels.  
In Parts B and C, dose confirmation will refine the estimate of the tolerability of the 
MTD/MAD, using a toxicity probability interval.  Enrollment to Parts B and C will occur in 
parallel with treatment allocation accomplished by non-random assignment to either part.  
Part B will enroll subjects with melanoma and Part C will enroll subjects with SCCHN (see 
Section 5.1.2 for enrollment criteria). 
Subjects will receive assessments at week 12 (or Day 84), week 24 and every 12 weeks that a 
subject remains in study. Subjects in Parts A, B and C may receive up to 8 cycles 
(approximately 24 weeks) of treatment or continue treatment until disease progression, 
unacceptable adverse event(s), intercurrent illness that prevents further administration of 
treatment, Investigator’s decision to withdraw the subject, subject withdraws consent, 
pregnancy of the subject, noncompliance with trial treatment or procedure requirements, or 
administrative reasons requiring cessation of treatment.
The final number of subjects enrolled in the dose escalation and confirmation parts of the 
study will depend on the DLT observations, in particular, at what dose the 3+3 design is 
triggered and what dose is identified as the ready for recommended phase 2 dose (RPTD). 
For example, in a scenario where dose escalation in Parts A continues to the highest dose 
with flat dose response so that all 4 doses (including the top one) are given to 6 subjects each 
in Part A (Refer to section 5.2.1.2) the sample size is 24 subjects. In Parts B and C the 
sample size for the dose confirmation/expansion phase will be a maximum of 20 subjects. In 
this scenario, the total sample size across Parts A, B and C is 64 subjects. The final number 
will depend on empirical safety data and observed DLTs.
 
 
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The trial will be conducted in conformance with Good Clinical Practices (GCP). Adverse 
Experiences (AEs) will be evaluated according to criteria outlined in the NCI Common 
Terminology Criteria for Adverse Experiences (CTCAE), version 4.  Approximately 64
subjects evaluable for safety, tolerability, and efficacy will be enrolled in the overall study.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
All the information collected from dose escalation phase of the study, Part A, will be 
reviewed to define the dose to be tested in Part B and C of the trial.   Details are described in 
Section 5.1- Inclusion and Exclusion Criteria and Section 8.0 - Statistical Analysis Plan.
Trial Diagram
2.2
The trial design is depicted in Figure 1. 
Figure 1
Trial Design
In Part A, combination study with dose escalation of MK-1966 and the recommended phase 
2 dose (RPTD) of SD-101 with a 3+3 design to identify a preliminary MTD or MAD. In Part 
B and C dose confirmation/expansion will refine the estimate of the tolerability of the MTD 
(or MAD), using a toxicity probability interval [1]
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1) Objective:  To determine the safety and tolerability of MK-1966 in combination with 
SD-101 and to establish a MTD or MAD in male/female subjects with advanced 
 
 
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malignancies (B-cell lymphoma, melanoma, squamous cell cancer of head and neck, 
breast cancer with dermal metastasis) of at least 18 years of age.
Secondary Objective(s) & Hypothesis(es)
3.2
1) Objective:  To characterize the PK profile of MK-1966 when given in combination 
with SD-101.
2) Objective:  To evaluate target engagement for MK-1966 as measured by modulation 
of circulating IL-10 concentrations.
Exploratory Objectives 
3.3
1) Objective: To evaluate the objective response rate (ORR), disease control rate 
(DCR), best overall response (BOR), best target lesion response, time to confirmed 
response, duration of response (DOR), progression-free survival (PFS) and overall 
survival (OS) of subjects with advanced tumors treated with the combination of MK-
1966 with SD-101 by Cheson criteria (for B Cell lymphoma) or irRECIST (for 
melanoma, squamous cell cancer of head and neck, breast cancer with dermal 
metastasis) as assessed by investigator review.
2) Objective: To investigate the relationship between candidate efficacy biomarkers 
and anti-tumor activity of MK-1966 in combination with SD-101. 
a.
Tumor microenvironment features including infiltrating lymphocytes (CD3+ 
total T cells and CD8+ T cells) and plasmacytoid dendritic cells.
b. IFNα and its associated gene expression profiles in pre and post treatment 
peripheral blood and tumor biopsies
c.
To correlate the clinical response to pre-treatment gene sequence expression
profiles.
3) Objective:  To investigate the relationship between anti-tumor activity of MK-1966 
in combination with SD-101 with potential patient selection biomarkers PD-L1 and 
TLR9 in pre-treatment tumor biopsies.
4) Objective: To evaluate the effect of MK-1966 in combination with SD-101 on 
immune activation biomarkers including IL-10, IFN-γ, IL-12p70, IL-13, IL-1β, IL-2, 
IL-4, IL-6, IL-8 TNF-α and IFN-α2a.
5) Objective: To evaluate development of circulating anti-MK-1966.
6) Objective: To explore the relationship between genomic variation and response to the 
treatment(s) administered. Variation across the human genome (germline and tumor) 
will be analyzed for association with clinical data collected in this study.
7) Objective: To evaluate the longitudinal change of tumor size.
 
 
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4.0 BACKGROUND & RATIONALE
Background
4.1
Detailed background information on MK-1966 and SD-101 is available in the MK-1966
Investigator’s Brochure (IB) and the SD-101 IB.  
Pharmaceutical and Therapeutic Background
4.1.1
MK-1966 Background
4.1.1.1
MK-1966 is a humanized IgG1/kappa neutralizing monoclonal antibody (mAb) that targets 
human interleukin (IL)-10.  Interleukin-10 is an anti-inflammatory cytokine that is expressed 
by cells of the innate and adaptive immune system, including dendritic cells (DCs), 
macrophages, mast cells, natural killer (NK) cells, eosinophils, neutrophils, CD4+ and CD8+ 
T cells, and B cells (reviewed in [2] and [3]).  Binding of dimeric IL-10 to heterodimeric IL-
10 receptor activates the Jak/STAT signaling pathway ([4],
[5],
[6],
and [7]).  
Immunosuppression mediated by IL-10 includes the inhibition of secretion of cytokines from 
activated macrophages, inhibition of production of CC and CXC chemokines, down-
regulation of MHC and costimulatory molecules on DCs, inhibition of a TH1 response, and 
induction of regulatory T cells (reviewed in [2]).  This known biology of IL-10 supports 
targeting disruption of the IL-10 pathway in combination with TLR9 agonism.
SD-101 Background
4.1.1.2
The toll-like receptor (TLR) family is a central mediator of innate immunity.  Recognition of 
both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular 
patterns (DAMPs) by these receptors triggers induction of cytokines and chemokines and 
activation of immature DCs that in turn induce activation of antigen-specific B and T cells 
(reviewed in Takeuchi, 2010 [8]).  Both pathogen-derived and synthetic TLR agonists have 
been investigated for treatment of cancer.  There are two FDA approved TLR agonists for the 
treatment of cancer: Bacillus Calmette-Guérin (BCG) and imiquimod.  BCG has been 
demonstrated to agonize TLR2 and TLR4 and is used for intravesical treatment of bladder 
carcinoma in situ and superficial bladder cancers.  Imiquimod is a TLR7 agonist and is used 
as a topical agent for viral warts and skin cancers (reviewed in [9]).  
In humans, TLR9 is expressed in pDCs and B cells [10] and [11].  Various synthetic CpG 
(cytidine-phosphodiester-guanine)-rich oligodeoxynucleotides (ODNs) that are potent TLR9 
agonists have been investigated in the clinic, including Pfizer’s CpG-7909 (PF-3512676), 
Idera’s IMO-2055 and IMO-2125, and Dynavax’s 1018 ISS and SD-101 (reviewed in [12]).  
It was demonstrated in Phase 1/2 clinical studies that intralesional administration of CpG-
7909 in combination with low-dose radiotherapy in patients with either low-grade B-cell 
lymphoma or mycosis fungoides resulted in regressions of the injected and non-injected
lesions ([13] and [14]).
There are three main classes of CpG ODNs: A, B, and C (reviewed in [12]).  CpG-7909, 
IMO-2055, and 1018-ISS are B-class, and IMO-2125 and SD-101 are C-class.  The A-class 
is a strong inducer of IFN-α from pDCs, and the B-class is a strong inducer of B-cell 
activation and pDC maturation.  The C-class embodies properties of both A- and B-classes.  
 
 
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However, different from the A- and B-classes, the C-class induces high levels of IL-12 from 
pDCs that have been costimulated through CD40 [15].  The immune activation profile for the 
CpG C-class potentially sets itself apart as a potent in situ vaccine.  In addition, the C-class, 
via induction of IFN-α, is a potent inducer of cytotoxic activity and interferon gamma (IFN-
γ) secretion by NK cells [16].
In addition to their immune stimulatory effects, TLR9 agonists induce an inhibitory feedback 
loop of suppressive factors, including IL-10.  The rationale to combine anti-IL-10 mAb with 
in situ vaccination of a TLR9 agonist is that an IL-10 blockade will abrogate IL-10-mediated
feedback inhibition of TLR9-mediated immune agonism and enable a robust systemic 
anti-tumor immune response (illustrated in Figure 2 from [12]).
Figure 2
Schematic Diagram Showing Mechanism of Action of TLR9 Agonism and Its 
Induction of Counter-regulatory Factors Including IL-10
Pre-clinical and Clinical Trials
4.1.2
MK-1966 Preclinical and Clinical Trials
4.1.2.1
MK-1966 does not cross-react with mouse IL-10; thus, a surrogate mouse anti-mouse IL-10 
mAb SCH 708974 was used in mouse studies.  
Anti-tumor efficacy of SCH 708974 in combination with SD-101 or mouse-specific CpG 
B-class ODN, CpG 1826 was assessed in the HPV E6/E7TC-1 syngeneic mouse bilateral 
tumor model; this tumor model is non-responsive to anti-PD-1 treatment.  SCH 708974 was 
administered intraperitoneally, and SD-101 and CpG 1826 were administered intratumorally.  
All test articles were administered every 4 days for a total of 4 doses (Figure 3).  
Compared to SD-101 alone (Group 2), administration of SD-101 in combination with 
SCH 708974 (Group 5) resulted in significantly reduced volumes of injected tumors on 
Day 12 (multiplicity-adjusted p 0.00255).  In 3 of 8 animals in Group 5, complete 
regression (CR) was observed.  In addition, 3 of 8 animals administered SD-101 in 
 
 
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combination with SCH 708974, CR of non-injected tumors was observed on Day 12.  
Complete regressions of non-injected tumors were not observed in any other group.
Administration of SCH 708974 in combination with CpG 1826 or SD-101 resulted in 
comparable number of CRs of injected tumors: 4 of 10 animals in Group 3 and 3 of 8 animals 
in Group 5.  However, administration of SCH 708974 in combination of CpG 1826 did not 
result in any CRs of non-injected tumors, suggesting greater abscopal effect with a CpG 
C-class ODN than CpG B-class ODN.
Figure 3
Efficacy of SCH 708974 and SD-101 in HPV E6/E7TC-1 Syngeneic Mouse 
Bilateral Tumor Model
Animals were assigned to groups based on tumor volume (TV) in the right flank (injected 
tumor) with mean TV of 58 mm3 on the day prior to treatment.  The TV in the right flank 
ranged from 39 to 87 mm3 and in the left flank (non-injected tumor) ranged from 0 to 
113 mm3.  SCH 708974 and SD-101 were administered intraperitoneally and intratumorally, 
respectively, every 4 days for a total of 4 doses.  In panel A, tumor growth curves for 
injected tumors are presented.  In panel B, tumor growth curves for non-injected tumors are 
presented.  Tumor volumes are presented as median with 68% confidence intervals.  
 
 
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Individual animal TV on Day 12 for injected and non-injected tumors are presented in panels 
C and D, respectively.  There were 10 animals per group.  
Concentrations of IL-10 in plasma from animals in the HPV E6/E7TC-1 mouse tumor 
model study were determined on Day 13 (Figure 4).  Median level of IL-10 in plasma in 
animals in control group (Group 1) was 124 pg/mL, and in animals administered SD-101 
(Group 2) was 1776 pg/mL.  Treatments that included SCH 708974 (Groups 3, 4, and 5) 
resulted in lower median levels of plasma IL-10 than that of control group (Group 1).
Figure 4
SD-101 Induces IL-10 in HPV E6/E7TC-1 Syngeneic Mouse Bilateral 
Tumor Model
Plasma was collected from animals in study described in Figure 2.  Concentrations of IL-10 
in the plasma were determined on Day 13.  Values are presented as median with 68% 
confidence intervals.  The minimum reportable concentration of IL-10 was 5 pg/mL.
In mice, TLR9 is expressed in monocytes, macrophages, myeloid DCs, activated T cells, B 
cells, and pDCs ([17], [18], and [19]).  Since the expression of TLR9 is broader in mice than 
in humans, immune modulation by SD-101 in human PBMCs and tumor samples were also 
assessed in preclinical studies.  
SD-101 induced IFN-α2a and IL-10 in human PBMCs (Figure 5).  The induction of IFN-α2a 
showed a “bell-shaped curve” dose-response, which was previously observed [20], likely 
because very high concentrations of a TLR9 stimulus triggers negative feedback. The data 
confirms that although TLR9 expression is limited to B cells and pDCs in humans, SD-101 is 
a potent inducer of IFN-α and IL-10 secretion in human PBMCs.
Figure 5
SD-101 Induces IFN-α2a and IL-10 in Human PMBCs
 
 
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Peripheral blood mononuclear cells were isolated from 2 healthy volunteers (panel A, Donor 
439 and panel B, Donor 975) and stimulated with SD-101 (0.0016, 0.008, 0.04, 0.2, 1, and 5 
M) or control ODN (7 M) for 48 hours.  Values are presented as mean ± standard 
deviation.
Induction of IFN-α-inducible genes, cytokines, and immune activation markers by SD-101 
was also evaluated in the human tumor histoculture.  This method allows assessment of the 
effect of the drug on cancer cells and pre-existing immune cells in the fresh tumor samples 
for up to 48 hours.  In these experiments, 5 samples of renal cell carcinoma (RCC), 3 samples 
of non-small cell lung cancer, and 1 sample each of bladder and colorectal cancer were 
evaluated.  Induction of immune genes by SD-101 was observed to varying extents among 
donors, but overall, treatment with SD-101 induced IFN-α-inducible genes (IFN-α2, MCP1, 
MCP2, OAS2, IP-10, GBP1, ISG-54, MxB, and TRAIL), cytokines (IFN-1, IL-10, IL-
12p35, IL-6, and TNF-α), and immune activation markers (CD80, CD86, CD40, and CD70, 
and OX40L).  Data from a RCC sample are presented in Figure 6.  The “bell shaped curve” 
dose response was also observed.
Figure 6
SD-101 Induces mRNA Expression of IFN-α-inducible Genes, Cytokines, and 
Immune Activation Markers in Human Renal Cell Carcinoma Histoculture
A sample of renal cell carcinoma was treated with SD-101 (0.1, 0.5, and 1 M) or control 
ODN (1 M) for 24 hours.  The sample was snap-frozen, and following RNA isolation, gene 
expression was analyzed using the Fluidigm RTqPCR platform.  The activity of SD-101 was 
assessed by the induction of an IFN-α-inducible gene set (panel A), cytokines (panel B), and 
immune cell activation markers (panel C).
 
 
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Ongoing Clinical Trials
4.1.3
Ongoing Clinical Trials with Anti-IL-10 Monoclonal Antibody
4.1.3.1
This is the first clinical trial of MK-1966. 
Previously, an anti-IL-10 antibody (MK-7089) was developed by Schering-Plough (merged 
with Merck 2009) which has the identical amino acid sequence and similar animal PK 
properties to MK-1966. As they were made in different Chinese Hamster Ovary cell lines 
they have some differences in glycosylation. MK-7089 was evaluated in a single-dose arm of 
a Phase 1 study evaluating the safety and tolerability of MK-7089 when administered 
intravenously in subjects with systemic lupus erythematosus (SLE). MK-7089 was safe when 
administered as a single dose up to the highest dose tested (10 mg/kg). Mild to moderate 
adverse events of oral ulcerations reported as aphthous stomatitis, stomatitis and oral 
ulceration were considered by the investigator to be related to the administration of MK-
7089. Adverse events of oral ulcers were treated with local care or topical agents as deemed 
appropriate by the investigators. Exposure to MK-7089 increased in a dose-related manner 
through the range of doses (0.3 to 10 mg/kg) evaluated. MK-7089 was slowly eliminated 
from plasma following doses ranging from 0.3 to 10 mg/kg. Development in SLE was 
terminated because of low probability of being an effective agent for SLE patients, not 
because of safety issues. It is expected that doses up to 10 mg/kg of MK-1966 will be 
tolerated.   
SD-101 Clinical Trials
4.1.3.2
In the phase 1, single-blind, dose-escalation study of SD-101 in 26 healthy normal male 
volunteers, aged 18 years and over (DV3-HNV-01), adverse events (AEs) included flu-like 
symptoms such as headache, chills, fatigue and pyrexia, as well as injection site reactions 
such as erythema, induration and pain. DLT’s of severe headache, injection site induration 
and neck pain were observed in 1 subject given 5.0 mg of SD-101, resulting in a halt in dose 
escalation and accrual. Transient lymphopenia was the most common laboratory abnormality 
observed. There was no evidence of complement activation, coagulation abnormalities or 
auto-antibody development.
In the phase 1, single-blind, dose escalation study of SD-101 in 28 men and women, aged 18 
to 55 years, with chronic hepatitis C virus (HCV) infection (DV3-HCV-01), SD-101 was 
administered alone or in combination with ribavirin. Including doses up to 5 mg of SD-101, 
the majority of AEs were injection site reactions (erythema, swelling, pain and pruritis), 
influenza-like illness, pyrexia and myalgia. Most AEs were mild or moderate in reported 
severity. One subject in the SD-101 0.1 mg/ribavirin group experienced a serious adverse 
event (SAE) of hyperthyroidism that was considered probably related to SD-101 and 
unrelated to ribavirin. No deaths occurred during the study.  
A phase 1/2 trial of SD-101 in combination with low-dose radiation therapy for untreated 
low-grade B-cell lymphoma is currently ongoing (DV3-LYM-01). Three patients have 
received 5 doses of 1.0 mg intratumoral SD-101 and 3 patients have received 5 doses of 
2.0 mg intratumoral SD-101 without DLTs. The most frequent AEs were transient flu-like 
illness in the 2.0 mg cohort.
 
 
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A phase 1, clinical trial of SD-101 in lymphoma patients who have relapsed after allogeneic 
marrow cell transplantation (NCT01745354) is ongoing. In this trial, patients are receiving 
low-dose radiation to one site of disease followed by intratumoral injection of SD-101 at 
doses of 0.3 mg, 1.0 mg, and 3.0 mg in successive cohorts. The first 2 dose cohorts have been 
completed and the 3.0 mg cohort is being enrolled. SD-101 has been well tolerated and no 
AEs related to SD-101 have been reported. Several patients have shown objective abscopal 
tumor responses.
A summary of the clinical studies conducted to date with SD-101 is provided in the 
Investigator’s Brochure.Information on Other Trial-Related Therapy
No comparators are proposed for this trial.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
MK-1966 is being developed to enhance the immune response in advanced tumors that have 
not fully responded or are expected to have inadequate response to other immune activation 
agents. The subjects selected for this study have tumors that are accessible to intratumoral 
injection and disease that has progressed after standard of care therapy/treatments and there 
is no available therapy likely to convey clinical benefit. The selected tumors are deemed 
good candidates to respond to immune activation therapy from recent clinical information. 
This trial is the First-In-Human (FIH) trial designed to assess the safety, tolerability, 
pharmacokinetics and pharmacodynamics of escalating doses of MK-1966 in combination 
with SD-101 in subjects with advanced tumors that have failed or have low likelihood of 
responding to monotherapy immune activators. The effect of the combination of MK-1966 
and SD-101 on tumor size will be explored.
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying Investigator Brochures (IBs) and Informed Consent 
documents. 
Rationale for Dose Selection/Regimen
4.2.2
Ongoing clinical studies with SD-101, as outlined in section 4.1.3.2 along with relevant 
nonclinical safety studies, will allow selection of the appropriate SD-101 dose for 
combination with MK-1966.  The FIH dose selection for MK-1966 in this combination 
therapy will be guided by data from MK-7089 (anti-IL-10 antibody single agent studies in 
SLE patients— {#P03722}), preclinical efficacy studies in tumor bearing mice, and PK/PD 
and safety studies in cynomolgus monkeys. Consequently doses above 700 mg of MK-1966 
will not be investigated. 
 
 
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Rationale for the Use of Comparator/Placebo
4.2.2.1
This study does not include comparator or placebo.
Starting Dose for This Trial
4.2.2.2
4.2.2.2.1 Rationale for MK-1966 Dose
Cynomolgus monkeys were used for predicting clinical PK of MK-1966 and demonstrating 
IL-10 target engagement. Human PK was predicted by scaling clearance (CL) and volume of 
distribution (Vss) parameters in cynomolgus monkeys. Scaling factors were calculated from 
monkey and human clinical studies conducted for MK-7089 (Table 1).
MK-1966 also showed dose-dependent increases of total IL-10 (a target-engagement 
biomarker) following multiple-dose administration of MK-1966 (study #14-M100-6618). A 
bimolecular interaction PK/PD model was used to characterize the relationship between MK-
1966 serum concentrations and total IL-10 concentrations, the latter being a surrogate 
measure of target engagement.
Table 1
Historical Monkey and Human PK Parameters for MK-7089. Estimated 
Scaling Factor was Used for MK-1966 Exposure Predictions in Human
CL (mL/day/kg)
Vss, (mL/Kg)
MK-7089
Observed Monkey (SN03248)
5.1
72.8
Observed Human (P03722)
2.1
93.9
Ratio
Monkey : Human
2.4
~1
MK-1966
Observed Monkey (14-M100-6618)
5.6
78
Predicted Human
2.4
78
To select doses of MK-1966 in man for the initial clinical study, percent of IL-10 suppression 
was predicted using: a) estimated clinical exposure of MK-1966 in man from early data and 
b) translation of antibody-antigen-binding interaction across species. A bimolecular 
interaction PK/PD model was used to account for species-specific differences related to 
binding affinity of MK-1966 to native IL-10, turnover rate, and baseline concentration of IL-
10.  Table 2 shows predicted IL-10 suppression, a measure of target engagement, at steady-
state following administration of MK-1966 (Q3W; dose range 0.1 to 30 mg/kg).
Table 2
Estimated Steady-State Exposure and Target Engagement Following 
Administration of MK-1966 (IV Q3W)
Dose, mg
AUC/,
µg/mL
Average % IL-10 
suppression
Cmax, 
ug/mL
% IL-10 suppression at 
Cmax
700
210
92
400
96
210
63
78
120
87
70
21
55
40
70
 
 
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Combination efficacy in mice with SD-101 and surrogate mouse anti-IL-10 mAb SCH 
708974
Efficacy of SD-101 alone (at 0.3 to 3 mg/kg) and in combination with SCH 708974 (1 and 10 
mg/kg) was evaluated in a preclinical study in tumor-bearing mice. Results from this study 
demonstrated up to a 25-fold increase in the apparent potency of SD-101 (Figure 7). Current 
results suggested no apparent potentiation of SD-101 PD effect (all doses) at 1 mg/kg dose of 
SCH 708974 under the experimental conditions employed (Figure 7).  
Figure 7
Efficacy of SD-101 Alone (at 0.3 to 3 mg/kg) and in Combination With 
Surrogate Mouse Anti-IL-10 mAb SCH 708974 (1 and 10 mg/kg). 
Combination of SD-101 with SCH 708974 Resulted in up to 25-fold Increases in the 
Apparent Potency of SD-101. There was Approximately 90 - 100% Inhibition of IL-10 with 
1 mg/kg SCH 708974 and 99 - 100% Inhibition of IL-10 with 10 mg/kg SCH 708974.
Nonclinical safety studies with MK-1966  
Current studies included a 4-week intravenous toxicity study with an 8-week treatment-free 
period in cynomolgus monkeys using doses of 25, 75, and 150 mg/kg/week, an intravenous 
cardiovascular and respiratory telemetry study in cynomolgus monkeys at 75 mg/kg/dose, 
and an in vitro tissue cross-reactivity study in normal human tissues. In the repeat-dose 
toxicity study, inflammation of the large intestine in both sexes in the 75 and 150 mg/kg 
groups was observed, with one early death in the 150 mg/kg males. Large intestinal 
inflammation fully resolved by the end of the treatment-free period and there were no clinical 
or postmortem effects in the 25 mg/kg animals, which was determined as the no-observable 
effect level (NOEL)/no-observable adverse effect level (NOAEL). The systemic exposure at 
the NOAEL corresponds to 2-fold predicted human exposure based on 10 mg/kg human dose 
every 2 weeks. Toxicokinetic measurements showed no sex-related differences in exposure, 
and systemic exposure increased with increasing dose and with repeated dosing. The mean 
half-life of MK-1966 in the cynomolgus was 12.7 days. Total IL-10, a marker of target 
engagement, showed increased serum concentration with systemic MK-1966 exposure. Anti-
MK-1966 antibodies were detected in the 75 and 150 mg/kg dose groups and were associated 
with increased elimination of serum MK-1966 and decreased total IL-10 concentration in 
some animals by the end of the study. In the single dose cardiovascular telemetry study, there 
was a lack of nocturnal decrease in blood pressure starting at 12 hours post-dose, a lack of 
 
 
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nocturnal decrease of heart rate starting at 30 hours post-dose, and increased body 
temperature from 30 hours post-dose through the end of the monitoring period at 72 hours 
post-dose. There were no ECG changes in the toxicity study, and no clinical signs of large 
intestinal inflammation in the telemetry study. In the tissue cross-reactivity study of MK-
1966, specific positive staining was limited to the placenta. An in vitro cytokine release assay 
in human blood showed no cytokine responses to MK-1966.
MK-1966 Safety 
Nonclinical safety studies in relevant pharmacological species reflected no significant 
toxicity following administration of weekly doses of MK-1966 at 25 mg/kg (NOAEL, 
section 4.2.2.1). Historical data also indicated absence of drug-related SAEs for MK-7089 
(the parental clone of MK-1966) in SLE patients following single bolus administration of 
doses up to 10 mg/kg (Study #P03722). Additionally, it is expected that following 
administration of MK-1966 at a 1mg/kg dose (every 3 weeks) serum antibody exposure 
(AUC) to fall approximately 20-fold lower than the observed NOAEL (25 mg/kg) in the 
nonclinical safety studies for MK-1966. Results from combination preclinical studies also 
reflected no apparent potentiation in SD-101 pharmacodynamic effects at the 1-mg/kg dose 
of Anti-IL-10 surrogate.
SD-101 Safety 
Following single agent intratumoral administration of SD-101 at fixed doses of 1, 2, 4, 8 mg 
in the ongoing clinical studies in cancer patients, no DLT up to 8 mg was observed thus far
however, at the 8 mg intra-tumoral dose of SD-101 the subjects developed a flu-like illness 
and fevers. It is expected, following intra-tumoral administration of SD-101 in the proposed 
clinical study, serum concentrations to fall below the limit of quantification of the assay 
(LLOQ=5 ng/ml).  The LLOQ of the assay for detection of SD-101 concentrations reflects 
approximately a 30- and 1000-fold safety window relative to the observed NOEL and 
NOAEL for SD-101 in previous nonclinical safety studies in cynomolgus monkeys, 
respectively (Dynavax report study #06-545). 
FIH Dose proposal 
A starting dose of 70 mg dose of MK-1966 is predicted to have partial target engagement 
with approximately 30-45% free IL-10 (Table 2) available for binding to IL-10R. From prior 
experience with MK-7089, treatment-related treatment emergent adverse event data at a 1 
mg/kg (70 mg for 70 kg individual) dose was considered relatively safe. Based on the 
integrated summary outlined above, a FIH dose of 70 mg for combination therapy with fixed 
dose of 1 mg SD-101 has been chosen for MK-1966. 
A fixed dosing regime is planned for this FIH trial. Recent publications show that both body 
weight adjusted dosing and fixed dosing approaches can lead to similar variability in human 
exposure depending on how clearance and volume of distribution are related to body weight.
([21] and [22]) In the absence of this information for MK-1966, a fixed dose approach has 
been chosen. An initial fixed dose is proposed as 70 mg, determined based on a 70 kg patient
receiving a dose of 1 mg/kg. The effect of body weight on the pharmacokinetics (PK) of 
MK-1966 and IL-10 target engagement will be evaluated to inform whether future studies 
will continue with a fixed dose regimen or switch to body weight based dosing.
 
 
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MK-1966 will be administered over approximately 30 to 60 minutes as an IV infusion 
depending on the concentration of drug product. Additional information regarding drug 
preparation and administration can be found in the Procedures Manual.
4.2.2.2.2 Rationale for SD-101 Dose
SD-101 being a TLR9 agonist is expected to induce high levels of IFN-α that may be 
responsible for anti-tumor effects. IFNs can directly inhibit the proliferation of tumor cells 
and increase major histocompatibility complex (MHC) class I expression, enhancing antigen 
recognition. Additionally IFNs have potent effects on tumor infiltrating leukocytes, including 
enhancing antigen presenting function of dendritic cells, increasing the effector function of 
T-cells, and activating cytotoxic activity of natural killer cells [23].
The 1 mg and subsequently the 4 mg fixed intratumoral dose of SD-101 is based on previous 
clinical studies conducted with subcutaneously dosing of SD-101 (DV3-HNV-01, DV3-
HCV-01), ongoing clinical study with intratumoral dosing (DV3-LYM-01), mechanism of 
action, and nonclinical studies with SD-101. The 1 mg dose of SD-101 was chosen as the 
starting dose as it demonstrated good safety and tolerability in the subjects with lymphoma 
and will allow a safety margin if co-administration with MK-1966 enhances its potential 
effects. If treatment with the 1 mg dose of SD-101 and the lowest dose of MK-1966 is 
tolerated the next cohort will receive a 4 mg dose of SD-101 with the lowest dose of MK-
1966. If treatment with 4 mg of SD-101 and the lowest dose of MK-1966 is not tolerated in 
cohort 2, further dosing with SD-101 will continue at the de-escalated dose of 1 mg.
Based on data from a study in healthy male volunteers (DV3-HNV-01), elevation of 
biomarkers was seen after a single 0.1 mg subcutaneous dose and increased with doses up to 
5 mg. From limited PK data after subcutaneous administration, maximum mean plasma 
levels were comparable at 3.0 mg (Cmax = 7 ng/mL; n = 6) and 5.0 mg (Cmax = 6 ng/mL; n= 
2) doses (DV3-HNV-01 CSR). SD-101 demonstrated a dose-dependent IFN-α-inducible 
gene and serum protein biomarker response. AEs were limited to flu-like symptoms and 
administration-site pain and induration. Data from DV3-HCV-01 suggest that SD-101 
appears to be generally safe and well tolerated with weekly subcutaneous doses of 0.1 mg, 
1.0 mg, 3.0 mg, and 5.0 mg (DV3-HCV-01 CSR). 
A summary of the clinical studies conducted to date with SD-101 is provided in the IB. For 
further information, see the IB.
Maximum Dose/Exposure for This Trial
4.2.2.3
Based on the current trial design and available safety data from the ongoing lymphoma trial 
(DV3-LYM-01), the maximum fixed intratumoral dose of SD-101 to be evaluated is 4 mg. 
Dose escalations will primarily depend on maximum feasible target engagement subject to 
safety evaluations. The maximum clinical dose with adequate safety margins is expected to 
be 700 mg for MK-1966, which is predicted to achieve >90% suppression of IL-10 in one 
dosing period (96% suppression of IL-10 at Cmax). Studies in the appropriate safety species 
(Cynomolgus monkeys) showed no adverse effects at doses where the Cmax and AUC values 
were 2.5-fold and 2-fold higher, respectively, relative to the highest human exposure 
expected at 700 mg.
 
 
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Rationale for Dose Interval and Trial Design
4.2.2.4
MK-1966 in combination with SD-101
MK-1966 is not expected to have anti-tumor activity as a stand-alone agent. Data from 
combination efficacy studies in mouse with SD-101 and a surrogate anti-IL-10 antibody 
suggest potentiation of tumor growth shrinkage compared to SD-101 alone. 
MK-1966 and SD-101 are expected to play complementary roles in stimulating and 
maintaining a robust innate immune response. SD-101 augments dendritic cell function and 
MK-1966 will maintain the immune activation seen with SD-101 by inhibiting IL-10 anti-
inflammatory effect and immune modulating effect.
The dose interval for MK-1966 is based on preclinical PK data in cynomolgus monkeys and 
from data collected in the FIH study with MK-7089. These studies have demonstrated a long 
half-life to justify every 3 week dosing. The dosing of SD-101 has been derived from the 
studies with this agent in normal healthy volunteers (NHV), subjects with hepatitis C and in 
subjects with low-grade B cell lymphoma. 
Rationale for Endpoints
4.2.3
Safety Endpoints
4.2.3.1
The primary safety endpoint of this trial is to characterize the safety and tolerability of MK-
1966 in combination with SD-101 in subjects with advanced tumors. The primary safety 
analysis will be based on subjects who experience toxicities as defined by CTCAE criteria. 
Safety will be assessed by quantifying the toxicities and grades experienced by subjects who 
have received MK-1966 in combination with SD-101, including serious adverse events 
(SAEs).
Safety will be assessed by reported adverse experiences using CTCAE, Version 4. The 
attribution to drug, time-of onset, duration of event, its resolution, and any concomitant 
medications administered will be recorded. AEs will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes.  
Efficacy Endpoints
4.2.3.2
An exploratory endpoint for this trial is to evaluate the anti-tumor activity of MK-1966 in 
combination with SD-101 in subjects with advanced solid malignancies. Tumor response will 
be accessed using Cheson criteria for B Cell lymphoma (see Section 4.2.3.5) or irRECIST 
(see Section 4.2.3.6).
Immunotherapeutic agents, such as MK-1966 and SD-101 may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses. The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with typical 
cytotoxic agents, and can manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. Standard response assessment criteria may not 
provide a comprehensive response assessment of immunotherapeutic agents such as MK-
1966 and SD-101. When feasible, study subjects can continue on treatment until progression 
is confirmed by the local site investigator/radiology assessment.  
 
 
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Pharmacokinetic Endpoints
4.2.3.3
A secondary objective of this trial is to characterize the PK profile of MK-1966 following 
administration with fixed dose SD-101. The serum concentration of the antibody will serve 
as the primary readout for the PK, and these data will be used to derive PK parameters for 
MK-1966 given in combination with SD-101. Furthermore, the results of these analyses will 
be used in conjunction with the pharmacodynamics, safety and anti-drug antibody endpoints 
to help assess future dosing strategies for MK-1966. MK-1966 concentrations in serum will 
be measured using a validated bioanalytical assay. The PK of SD-101 will not be determined 
in this study. 
Pharmacodynamic Endpoints
4.2.3.4
As a required first step in pharmacologic activity, target engagement is fundamental to 
dosing strategies.  To evaluate anti-IL-10 target engagement, total IL-10 concentration in the 
periphery (serum) will be monitored. IL-10 concentrations will be collected and reviewed as 
Part A progresses.  IL-10 concentration data may be required prior to the initiation of dose 
escalation during study. The induction of IFN-α and its associated downstream genes will be 
used to assess the activity of SD-101.  
Additional exploratory analyses will be performed to assess the effect of MK-1966 and SD-
101 on immune cells in tumor tissues and in the circulation and are discussed in following 
sections.
Cheson Criteria for Lymphomas
4.2.3.5
Response to treatment will be evaluated by the investigator at 12 weeks and 24 weeks after 
the first study injection.  Response to treatment will continue to be assessed every 12 weeks 
that a subject remains in the trial.  
Response of lesions will be assessed by CT or CT/PET and bone marrow biopsy using the 
Cheson criteria for lymphomas [24]. Response will be assessed on the basis of clinical, 
radiologic, and pathologic (ie, bone marrow) criteria: 
1. At a minimum, thoracic, abdominal, and pelvic CT scans will be performed even if 
those areas were not initially involved because of the unpredictable pattern of 
recurrence in NHL. CT/PET may be used if they are the standard tools for assessing 
disease status at a participating institution. 
2. Unilateral bone marrow biopsy and aspirates will be performed at Screening if not 
previously performed or if performed more than 90 days previously with negative 
results. The bone marrow biopsy will be performed to confirm a complete response 
(CR) if the subject was initially positive or if it is clinically indicated by new 
abnormalities in the peripheral blood counts or blood smear.
Response of lesions will be recorded on the CRF based on the definitions in Table 3 as 
appropriate. Suspected relapse or disease progression must be confirmed by physical exam, 
laboratory assessments, repeat bone marrow biopsy [24] and CT scan. If confirmed, 
 
 
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progressive disease should be reported to the sponsor within 7 days. Subjects with suspected 
relapse or disease progression should continue to follow study procedures until they need 
another therapy. If a subject requires another therapy, date of treatment and type of treatment 
will be recorded and they will then be removed from the trial. 
Tumor progression is defined as ≥ 50% increase from nadir in the sum of the products of the 
greatest diameters (SPD), as defined in the Cheson response criteria for NHL [24]. The 
response criteria should be recorded in the database. However, if the subject is evaluated by 
CT/PET scan then tumor response criteria should be evaluated using updated Cheson criteria 
[25] which includes CT and PET scans. 
Table 3
Response Criteria for Non-Hodgkin’s Lymphoma
Response 
Category
Physical 
Examination
Lymph Nodes
Lymph Node Masses
Bone Marrow
Complete 
Response
Normal
Normal
Normal
Normal
Complete 
Response/
Unconfirmed
Normal
Normal
Normal
Indeterminate
Normal
Normal
≥75% decrease
Normal or 
indeterminate
Partial 
Response
Normal
Normal
Normal
Positive
Normal
≥50% decrease
≥50% decrease
Irrelevant
Decrease in 
liver/spleen
≥50% decrease
≥50% decrease
Irrelevant
Relapse/ 
Progression
Enlarging liver/ 
spleen; new sites
New or increased
New or increased
Reappearance
Source [24]
Immune-related RECIST (irRECIST)
4.2.3.6
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment immunotherapeutic agents. Immunotherapeutic agents such as MK-1966 and 
SD-101 may produce antitumor effects by potentiating endogenous cancer-specific immune 
responses.  The response patterns seen with such an approach may extend beyond the typical 
time course of responses seen with cytotoxic agents, and can manifest a clinical response 
after an initial increase in tumor burden or even the appearance of new lesions.  Standard 
RECIST 1.1 may, thus, not provide an accurate response assessment of immunotherapeutic 
agents. With other immunotherapeutic agents, up to 7 % of evaluable patients experienced 
delayed or early tumor pseudoprogression.  Of note, patients who had progressive disease by 
RECIST 1.1 but not by immune related Response Criteria had longer OS than patients with 
progressive disease by both criteria.  These findings support the need to apply a modification 
 
 
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to RECIST 1.1 that takes into account the unique patterns of atypical response in 
immunotherapy and enable treatment beyond initial radiographic progression. 
Immune-related RECIST (irRECIST) is RECIST 1.1 adapted to account for the unique tumor 
response seen with immuno-therapeutics as described in [26]. The assessment of 
unidimensional target lesions and response categories per irRECIST are identical to RECIST 
1.1.  However, Merck has implemented an adaptation related to new lesions, non-target and 
tumor burden assessment in order to confirm radiographic progression. irRECIST will be 
used by local site investigators to assess tumor response and progression, and make treatment 
decisions.
Therefore, RECIST 1.1 will be used with the following adaptations:
In subjects who have initial evidence of radiological PD by RECIST 1.1, it is at the discretion 
of the PI whether to continue a subject on study treatment until repeat imaging is obtained 
(irRECIST subject management).  This clinical judgment decision by the site should be based 
on the subject’s overall clinical condition, including performance status, clinical symptoms, 
and laboratory data.  Subjects may receive study treatment and tumor assessment should be 
repeated ≥ 4 weeks later in order to confirm PD by irRECIST per site assessment.  Clinical 
stability is defined as the following: 
Absence of symptoms and signs indicating clinically significant progression of
disease, including worsening of laboratory values
No decline in ECOG performance status 
Absence of rapid progression of disease 
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention  
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the local site investigator should consider all target and non-target lesions as well as any 
incremental new lesion(s).
Scenarios where PD is confirmed at repeat imaging if ANY of the following occur by 
irRECIST:

Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to nadir

Non-target disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from study therapy (exception noted below and in Section 7.1.2.6.3).
 
 
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Scenarios where PD is not confirmed at repeat imaging if ALL of the following occur by 
irRECIST: 

Tumor burden is < 20 % or < 5 mm absolute increase compared to nadir

Non-target disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved 

No incremental new lesion(s) since last evaluation

No incremental new non-target progression since last evaluation
If repeat imaging does not confirm PD by irRECIST and the subject continues to be 
clinically stable, treatment may continue and follow the regular imaging schedule. 
When feasible, study subjects can continue on treatment until progression is confirmed by the 
local site investigator/radiology assessment This allowance to continue treatment despite 
initial radiologic progressive disease (PD) takes into account the observation that some 
subjects can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response.  Subjects that are deemed 
clinically unstable are not required to have repeat tumor imaging for confirmation of PD. 
Tumor flare includes any of the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesion(s)
Additional details about irRECIST are referenced in Imaging Manual.
4.2.3.6.1 Target Engagement (TE)
IL-10 target engagement will be assessed by measuring the total circulating IL-10, the 
combined total concentration of both free IL-10 and the IL-10 that is bound to MK-1966.  IL-
10 concentrations in serum will be measured using a qualified bioanalytical assay.  As the 
concentration of free IL-10 is expected to be quite low (pg/mL) and the clearance rate of IL-
10 bound to MK-1966 is expected to be slow, the target engagement assay is expected to 
measure primarily MK-1966 bound IL-10.
In previous studies with SD-101, the induction of IFN-associated genes in the peripheral 
blood was used to determine target engagement and used for dose selection.  IFN-
associated genes ISG-54, MX-b, IP-10 and MCP-1 were monitored and demonstrated to be 
upregulated greater than 3 fold (3 out of the 4 genes up-regulated at any time point).  Dose 
dependency was observed from 0 to 1.0 mg but from 1.0 to 5.0 mg no dose dependency was 
observed.  IFN-was not consistently upregulated with SD-101 administration.  
4.2.3.6.2 Anti-Drug Antibody (ADA) Assay
1) Screening ADA assay
ADA screening assay (including the Confirmatory test for specificity against the drug, 
and titer determination for confirmed positive samples) will be developed and validated 
 
 
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in human serum to support clinical studies.  A standard bridging ECL assay with the 
required sensitivity and drug tolerance using MSD platform will be used.  
The assay will be validated prior to FIH study start.
2) Neutralizing anti-drug antibody (NAb) assay
A non-cell-based NAb assay in human serum will be developed and validated for further 
characterization of confirmed ADA positive samples.  The assay will be used to support 
the early phases of the FIH study.  A cell based Nab assay will be developed and 
validated as well once an appropriate cell line is established to support the later phases 
of the FIH study.
4.2.3.6.3 Cytokines of Systemic Immune Activation
Due to immune stimulation by SD-101 and enhanced immune activation by the 
administration of SD-101, a panel of cytokine proteins will be monitored including IL-10, 
IFN-γ, IL-12p70, IL-13, IL-1β, IL-2, IL-4, IL-6, IL-8, TNF-α and IFN-α2a.
4.2.3.6.4 Exploratory RNA Profiling and IHC Markers
The relationship between anti-tumor activity of MK-1966 in combination with SD-101 will 
be investigated through evaluation of gene expression (including IFN-in blood and in pre 
and post biopsy tumor tissue.  Responses will also be correlated to pre-treatment gene 
expression data with a goal to identify potential patient selection biomarkers.  
Multiple immunohistochemistry (IHC) assays are planned and are currently in development 
to support exploratory biomarker research including CD3, CD8, pDC, TLR9 and PD-L1.
4.2.3.6.5 Exploratory Objective on the Longitudinal Change of Tumor Size  
The longitudinal measurement on tumor size will be investigated to collect information on 
the tumor response to the treatment. Several statistical modeling methods will be explored to 
analyze tumor size longitudinally based on imaging assessment.
Planned Exploratory Biomarker Research
4.2.3.7
Planned Genetic Analysis
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
Future Biomedical Research
4.2.3.8
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
 
 
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(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with advanced malignancies, of at least 18 years of age will be 
enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Have one of the following diagnoses
a.
A histologically- or cytologically-confirmed low grade B-cell lymphoma
which has progressed after standard of care therapy/treatments and there is no 
available therapy likely to convey clinical benefit.
b. Unresectable melanoma that in the opinion of the Investigator have progressed 
after anti-PD-1 therapy, and/or anti-PD-1 and
CTLA-4 combination 
treatments.  Subjects who have BRAF V600 mutant melanoma are required to 
have had a prior treatment regimen that included vemurafenib, dabrafenib, or 
other approved BRAF and/or MEK inhibitor.
c.
SCCHN that have progressed after standard of care therapy/treatments and 
there is no available therapy likely to convey clinical benefit. Subjects are 
 
 
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required to have been refractory to platinum (either cisplatin or carboplatin) 
and cetuximab.  Resistance is defined as tumor progression or recurrence 
within 6 months of platinum or cetuximab therapy in the adjuvant (e.g. with 
radiation after surgery), primary (e.g. with radiation), recurrent, or metastatic 
setting.  Subject must be resistant to both platinum and cetuximab.
d. Breast cancer with dermal metastasis, which has progressed after standard-of-
care therapy/treatments and there is no available therapy likely to convey 
clinical benefit.
e.
Part B will enroll subjects with unresectable melanoma that in the opinion of 
the Investigator have progressed after anti-PD-1 therapy, and/or anti-PD-1 and 
CTLA-4 combination treatments.  Subjects who have BRAF V600 mutant 
melanoma are required to have had a prior treatment regimen that included 
vemurafenib, dabrafenib, or other approved BRAF and/or MEK inhibitor.
f.
Part C will enroll SCCHN that have progressed after standard of care 
therapy/treatments and there is no available therapy likely to convey clinical
benefit. Subjects are required to have been refractory to platinum (either 
cisplatin or carboplatin) and cetuximab.  Resistance is defined as tumor 
progression or recurrence within 6 months of platinum or cetuximab therapy 
in the adjuvant (e.g. with radiation after surgery), primary (e.g. with 
radiation), recurrent, or metastatic setting.  Subject must be resistant to both 
platinum and cetuximab.  
2. Subjects with melanoma, squamous cell cancer of head and neck or breast cancer 
with dermal metastasis must have a tumor accessible to intralesional injection and 
have measurable disease by Cheson or irRECIST criteria.
3. Subjects with B Cell Lymphoma must have:
a.
Biopsy confirmed, low-grade B-cell lymphoma, including follicular (Grade 1, 
2, or 3A [27]), or marginal, or CLL/SLL with lymph node involvement that 
has progressed after standard of care therapy/treatments and there is no 
available therapy likely to convey clinical benefit. 
b. Measurable disease per Cheson criteria (1 lesion must measure at least 1.5 cm 
in any diameter or 1.0 cm in the shortest diameter if one of the diameters is 
not ≥ 1.5 cm), and be palpable and easily accessible in a low-risk site (eg, 
inguinal, axillary, cervical, subcutaneous) for intratumoral injection.
4. Be ≥18 years of age on day of signing informed consent.
5. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale (Appendix 12.4).
6. Have a life expectancy ≥6 months
7. Demonstrate adequate organ function as defined by the following table (Table 4). All 
screening labs should be performed within 7 days of treatment initiation.
 
 
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Table 4
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
>1,500/mcL
Platelets
>100,00/mcL
Hemoglobinb
>9 g/dL or > 5.6 mmol/L
Renal
Serum Creatinine or
Creatinine Clearance (CrCl) (measured or 
calculated) a or
Glomerular Filtration Rate (GFR) in place of 
CrCl
<1.5 X ULN 
or
> 60 mL/min for subject with creatinine levels > 1.5 X 
ULN
Hepatic
Total bilirubin (serum) 
<1.5 X ULN or
Direct bilirubin < ULN for subjects with total bilirubin  
levels > 1.5 X ULN
AST (SGOT) and ALT (SGPT)
<2.5 X ULN OR
≤ 5 × ULN for subjects with liver metastases
Coagulationc
International Normalized Ratio (INR) or  
Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT)
<1.5 X ULN 
<1.5 X ULN
a Creatinine clearance should be calculated per institutional standard
b Hemoglobin should be without transfusion within 4 weeks of Day 1.  
c If the subject is receiving anticoagulant therapy, the PT or partial thromboplastin time (PTT) should be within the 
therapeutic range of intended use of anticoagulants.
8. Have voluntarily agreed to participate by giving written informed consent. The 
subject may also provide consent for Future Biomedical Research.  However, the 
subject may participate in the main trial without participating in Future Biomedical 
Research
9. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test at Screening and again within 72 hours prior to receiving the first dose 
of study treatment.  If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.  The serum pregnancy test must be negative 
for the subject to be eligible.
10. Female subjects of childbearing potential (refer to Section 5.7.2) must be willing to 
use an adequate method of contraception as outlined in Section 5.7.2– Contraception,  
for the course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
11. Male subjects of childbearing potential (refer to Section 5.7.2) must agree to use an 
adequate method of contraception as outlined in Section 5.7.2– Contraception, 
starting with the first dose of study therapy through 120 days after the last dose of 
study therapy.
 
 
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Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
12. Submit archived or fresh tumor sample during screening period as specified in the 
Procedures Manual.  
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Has had chemotherapy, radiation, or biological cancer therapy within 4 weeks prior to 
the first dose of study therapy, or who has not recovered to CTCAE grade 1 or better 
from the adverse events due to cancer therapeutics administered more than 4 weeks 
earlier.
2. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 28 days of administration of MK-1966 or SD-101.
3. Is expected to require any other form of antineoplastic therapy while on study.  
4. Is on chronic systemic steroid therapy in excess of replacement doses, or on any other 
form of immunosuppressive medication.
5. Has a history of a malignancy, unless potentially curative treatment has been 
completed, with no evidence of malignancy for 5 years.
a.
Note: The time requirement for no evidence of disease for 5 years does not apply 
to the tumor for which a subject is enrolled in the study.  The time requirement 
does not apply to subjects who underwent successful definitive resection of basal 
cell carcinoma of the skin, superficial bladder cancer or in situ cervical cancer.
6. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
provided they are clinically stable for at least 4 weeks prior to study entry, have no 
evidence of new or enlarging brain metastases and are off steroids. 
7. Has had a severe hypersensitivity reaction to treatment with another monoclonal 
antibody.
8. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.
9. Has an active infection requiring therapy. 
10. Has active, current pneumonitis, or a history of (non-infectious) pneumonitis that 
required steroids.
11. Has had a prior stem cell or bone marrow transplant.
12. Is positive for Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C.
 
 
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13. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation 
for the full duration of the study, or is not in the best interest of the subject to 
participate, in the opinion of the treating Investigator.
14. Has known psychiatric disorder(s) that would interfere with cooperation with the 
requirements of the trial.
15. Is a regular user, as determined by investigator judgment, (including “recreational 
use”) of any illicit drugs or had a recent history (within the last year) of substance 
abuse (including alcohol), at the time of signing informed consent.
16. Has symptomatic ascites or pleural effusion. A subject who is clinically stable 
following treatment for these conditions (including therapeutic thoraco-
or 
paracentesis) is eligible.
17. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study. 
18. Has clinically significant heart disease that affect normal activities.
19. Has had major surgery (requiring at least a 3 day hospital stay) in the past 28 days.
20. Has received a live vaccine within 30 days prior to first dose.
Trial Treatment(s)
5.2
The treatment(s) to be used in this trial are outlined below in Table 5.  
Table 5
Trial Treatment for MK-1966 and SD-101
Treatment During Part A: Dose Finding
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment Period††
Use
MK-1966
70 mg
210 mg
700 mg
Day 1, then 
Q3W
Intravenous 
over 30 -120 
min
Day 1 then Q3W for 
7 additional doses
Experimental
SD-101
1 mg
4 mg†
Days 1, 8, 15, 
22 then Q3W
Intratumorally
Days 1, 8, 15, 22 then 
Q3W for 6 
additional doses
Experimental
Treatment During Part B and C: Expansion Cohort
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment Period††
Use
MK-1966
MTD/MAD
Every 3 weeks
Intravenous 
over 30 -120 
min
Day 1 then Q3W for 
7 additional doses
Experimental
SD-101
4 mg†
Days 1, 8, 15, 
22 then Q3W
Intratumorally
Days 1, 8, 15, 22 then 
Q3W for 6 additional 
doses
Experimental
† Note, if the 4 mg SD-101 and 70 mg MK-1966 combination (cohort 2) is not tolerated, then the dose of SD-101 for 
subsequent cohorts (3 & 4) in part A and expansion cohorts (Parts B and C) will be 1 mg.   
††When MK-1966 and SD-101 are scheduled at the same time:
1.
SD-101 will be administered first.
2.
MK-1966 will be administered at least 30 minutes after the SD-101 injection.  
 
 
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Trial treatment should begin on the day of treatment allocation/randomization or as close as 
possible to the date on which the subject is allocated/assigned.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1
Dose Selection (Preparation)
5.2.1.1
Details on dose calculation, preparation and administration of MK-1966 and SD-101 are 
provided in the Pharmacy Manual.
Dose Escalation
5.2.1.2
Enrollment to Arm A, (MK-1966 with SD-101) will begin at the 70 mg for MK-1966 and 1
mg for SD-101. The initial dose combination of SD-101 and MK-1966 will test the 
tolerability of administering both agents in subjects with advanced tumors. The following 
three dosing cohorts were chosen with administration of the higher fixed dose of SD-101 to 
increase immune activation combined with escalating doses of MK-1966. All dose levels in 
Part A will follow 3+3 design. Dose escalation of MK-1966 will continue to identify a 
preliminary MTD or MAD.
The dosing for each cohort is as follows:
1) 1 mg SD-101 intratumorally and 70 mg MK-1966 intravenously
2) 4 mg SD-101 intratumorally and 70 mg MK-1966 intravenously
3) 4 mg SD-101 intratumorally and 210 mg MK-1966 intravenously
4) 4 mg SD-101 intratumorally and 700 mg MK-1966 intravenously
Note, if the 4 mg SD-101 and 70 mg MK-1966 combination (cohort 2) is not tolerated, then 
SD-101 will be de-escalated to a 1 mg dose for subsequent cohorts (3 & 4). The study will 
include up to four dosing cohorts for SD-101 and MK-1966.
5.2.1.2.1 3+3 Dose Escalation
During 3+3 dose escalation, at least 2 days of observation will occur between each of the first 
3 subjects at each dose level.
Dose escalation will increase in increments of approximately 3 fold.  
The rules applied for the preliminary dose finding using the 3+3 design are as follows:
An initial cohort of 3 subjects is enrolled. 

If 0/3 subjects develops a DLT, escalation to the next dose will occur. 

If 1/3 subjects develops a DLT, another 3 subjects will be enrolled at this dose level. 
o
If 0 of the 3 new subjects develops a DLT (for a total of 1/6 subjects with a 
DLT at this dose level), escalation to the next dose level will occur. 
 
 
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o
If ≥1 of the 3 new subjects develops a DLT (for a total of ≥2/6 subjects with a 
DLT at this dose level), the dose escalation stage of the trial will be 
terminated.

If ≥2/3 subjects develop a DLT, the dose escalation stage of the trial will be 
terminated. If the dose directly below the current dose had been studied in at least 3 
subjects, the dose directly below the current dose will be considered the preliminary 
MTD, and the study will proceed to the confirmation/expansion stage. It is 
conceptually acceptable to de-escalate to an intermediate, not pre-defined and not 
previously-studied dose, if evaluation of toxicity at such a dose is desired in lieu of 
proceeding directly to the dose confirmation/expansion stage of the study. If this 
approach is taken, 3 new subjects should be enrolled at the new intermediate dose, 
and the aforementioned rules should be used to determine further enrollment at this 
dose level. 

If the highest candidate dose of MK-1966 is studied during dose escalation, and 0/3 
subjects or <2/6 subjects develop a DLT at that dose, then dose escalation will
terminate with this finding and this dose level will be taken to the 
confirmation/expansion stage. 
5.2.1.2.2 Dose Confirmation/Expansion
The objective of dose confirmation in Part B and C is to refine the estimate of the MTD 
based on TPI design [1] with target toxicity rate <30%.  Dose confirmation involves the 
expansion of at least 1 dose level studied in the dose escalation stage of the study. 
Dose confirmation will begin with expansion of the preliminary MTD/MAD identified in the 
dose escalation stage described in Section 5.2.1.2.1. The dose confirmation part will continue 
until 20 subjects are studied at the selected dose (combined from dose escalation and dose 
confirmation) with ≤7 of 20 subjects experiencing a DLT.  As subjects become evaluable for 
DLT assessment, the number of subjects who are evaluable for DLT versus the number of 
subjects who developed a DLT will be continuously assessed. De-escalation and escalation to 
eligible doses will occur during dose confirmation as shown in Table 6.  Escalation or 
reduction of dose for either agent will be to the next higher or lower dose on MK-1966 being 
examined in this study, while keeping SD-101 dose fixed.  However dose escalation will not 
exceed 700 mg of MK-1966 or 4 mg of SD-101.  Likewise a cohort dose will not be reduced 
below 70 mg of MK-1966 or 1 mg of SD-101.  
 
 
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Table 6
Dose Confirmation Rules
Number of subjects treated at current dose
Number 
of 
toxicities
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
0
S
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
S
S
S
E
E
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
S
S
S
E
E
E
E
E
E
3
DU
D
D
S
S
S
S
S
S
S
S
S
S
S
S
S
E
4
DU
DU
DU
D
D
D
S
S
S
S
S
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
D
S
S
S
S
S
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
D
D
S
S
S
S
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
D
D
D
S
S
S
8
DU
DU
DU
DU
DU
DU
DU
DU
DU
D
D
D
D
9
DU
DU
DU
DU
DU
DU
DU
DU
DU
DU
DU
D
10
DU
DU
DU
DU
DU
DU
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
DU
DU
DU
DU
DU
DU
12
DU
DU
DU
DU
DU
DU
DU
DU
DU
13
DU
DU
DU
DU
DU
DU
DU
DU
14
DU
DU
DU
DU
DU
DU
DU
15
DU
DU
DU
DU
DU
DU
16
DU
DU
DU
DU
DU
17
DU
DU
DU
DU
18
DU
DU
DU
19
DU
DU
20
DU
E = Escalate to the next higher dose
S = Stay at the current dose
D = De-escalate to the next lower dose
DU = The current dose is unacceptably toxic
Target toxicity rate = 30%
Non-informative prior is used: a=1; b=1; 
k1=1; k2=1.5; pow=1 per {Ji, 2007 #55124}.
Subjects may be enrolled continuously (i.e., without waiting for Cycle 1 completion of 
subjects who have received the first dose) unless a DLT is observed at the particular dose.  
Once a DLT is observed, the number of subjects who are enrolled at that dose but are not yet 
fully evaluable for DLT assessment may not exceed the number of remaining subjects who 
are at risk of developing a DLT before the dose would be considered unacceptably toxic 
(denoted as DU in Table 6).  For example, if 3/7 subjects have experienced a DLT at a given 
dose level, no more than an additional 2 subjects should be enrolled at this dose level until 
additional DLT data are available. This is because this dose level would be considered 
unacceptably toxic if all 2 of the additional subjects experience a DLT (i.e., 5/9 subjects with 
DLT in Table 6). To find out how many more subjects can be enrolled, one can count steps in 
diagonal direction (down and to the right) from the cell (7 subjects, 3 toxicities) to the first 
cell marked DU.
If enrollment expands to 20 subjects for a dose level, and ≤7 of the 20 subjects develop a 
DLT, then the dose confirmation will stop.  If enrollment expands to 20 subjects for a dose 
level and >7/20 subjects develop a DLT, then the next lower dose may be expanded to 
 
 
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further explore the dose-response relationship. Note that while 30% has been the target 
toxicity rate used to generate the guidelines in Table 6, the observed rate of subjects with 
DLT at the MTD may be slightly above or below 30%.
Definition of Dose Limiting Toxicity
5.2.2
DLT’s will be defined from toxicities observed during the first cycle of treatment (21 days) 
for each dose level. See Section 5.2.4 for rules on replacement of subjects in the DLT period. 
The occurrence of any of the following toxicities during Cycle 1, if assessed by the 
Investigator to be possibly, probably or definitely related to MK-1966 or SD-101 in Arm A, 
will be considered a DLT:
1. Grade 4 non-hematologic toxicity ( not laboratory)
2. Grade 4 hematologic toxicity lasting > 7 days, except thrombocytopenia
a.
Grade 4 thrombocytopenia of any duration
b. Grade 3 thrombocytopenia is a DLT if associated with bleeding:
3. Grade 3 non-hematologic toxicity (not laboratory) lasting > 3 days despite optimal 
supportive care.  Grade 3 nausea or vomiting will be considered a DLT if lasting 
more than 3 days despite optimal supportive care.
4. Any Grade 3 or Grade 4 non-hematologic laboratory abnormality, if

medical intervention is required, or

the abnormality leads to hospitalization, or

the abnormality persists for > 1 week
5. Febrile neutropenia Grade 3 or Grade 4
6. Any drug-related AE which caused subject to discontinue treatment during Cycle 1
7. Grade 5 toxicity
8. Delay in initiation of Cycle 2 for >2 weeks due to study drug-related toxicity
Guidelines for Dose Modifications 
5.2.3
Dose Modification
5.2.3.1
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) must be
used to grade the severity of adverse events.  If appropriate, the Investigator may attribute 
each toxicity event to MK-1966 or SD-101 alone or to the combination arm.
Part A
Subjects will continue at their enrolled dose for the duration of their participation.  Holding 
of one agent and not the other agent is appropriate if, in the opinion of the Investigator, the 
toxicity is clearly related to one of the study drugs. If, in the opinion of the Investigator, the 
toxicity is related to the combination of two agents, both drugs should be held.  
 
 
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Parts B and C
Dose modifications should be made according to Table 7.  If a dose reduction for toxicity 
occurs with any agent, the dose may not be re-escalated. Dose modifications are always 
based on the previous cycle.
Subjects may have 1 dose modification to MK-1966 or SD-101 throughout the course of the 
study.  If further toxicity occurs or the criteria for resuming treatment are not met, the subject 
must be discontinued from the agent. If a subject experiences several toxicities and there are 
conflicting recommendations, follow the most conservative dose adjustment recommended 
(dose reduction or holding as appropriate to the most severe toxicity).
Reduction or holding of one agent and not the other agents is appropriate if, in the opinion of 
the Investigator, the toxicity is clearly related to one of the study drugs. If, in the opinion of 
the Investigator, the toxicity is related to the combination of two agents, both drugs should be 
held or reduced according to recommended dose modifications.  
If in the opinion of the Investigator dose reduction is recommended, either agent can be 
reduced 1 dose level following consultation with the Sponsor.  Only 1 dose reduction (of 
either agent) is permitted for each subject.  If additional dose reduction is warranted, then 
the subject should be discontinued from the study.  Both MK-1966 and SD-101 may only 
be reduced to the next lowest dose being explored in this study (i.e., MK-1966 210 mg 
would be reduced to 70 mg).  Neither agent may be reduced below the lowest dose being 
tested in this protocol (MK-1966: 70 mg; SD-101: 1 mg).
Exceptional circumstances to following the dose modification tables below may be
considered after consultation with the Sponsor.
In all study Parts, both MK-1966 and SD-101 will be held for the adverse events described 
below in Table 7.
Table 7
MK-1966 and SD-101 Dose Modification Guidelines for Drug-Related 
Adverse Events
Toxicity
Hold 
Treatment 
For
Timing for Restarting 
Treatment
Treatment Discontinuation
Diarrhea/Colitis
Grade 2-3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 
weeks
Grade 4
Permanently discontinue
Permanently discontinue
AST, ALT, or 
Increased Bilirubin
Grade 2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks 
of last dose
Grade 3-4
Permanently discontinue
(see exception below)a
Permanently discontinue
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia
T1DM or
Grade 3-4
Hold SD-101 and MK-1966 for 
new onset Type 1 diabetes 
mellitus or Grade 3-4 
hyperglycemia associated with 
evidence of beta cell failure
Resume SD-101 and MK-1966 when 
patients are clinically and metabolically 
stable
 
 
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Toxicity
Hold 
Treatment 
For
Timing for Restarting 
Treatment
Treatment Discontinuation
Hypophysitis
Grade 2-4
Toxicity resolves to Grade 0-1. 
Therapy with SD-101 and MK-
1966 can be continued while 
endocrine replacement therapy 
is instituted
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 
weeks
Hyperthyroidism 
Grade 3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 
weeks
Grade 4
Permanently discontinue
Permanently discontinue
Hypothyroidism
Therapy with SD-101 and MK-
1966 can be continued while 
thyroid replacement therapy is 
instituted
Therapy with SD-101 and MK-1966 can 
be continued while thyroid replacement 
therapy is instituted
Infusion Reaction
Grade 2b
Toxicity resolves to Grade 0-1 Permanently discontinue if toxicity 
develops despite adequate premedication 
Grade 3-4
Permanently discontinue
Permanently discontinue
Injection Reaction 
≥ Grade 3 
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks 
of last dose
Pneumonitis
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 
weeks
3-4 (or 
recurrent 
Grade 2)
Permanently discontinue
Permanently discontinue
Renal Failure or 
Nephritis
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 
weeks
3-4
Permanently discontinue
Permanently discontinue
ANC
≤1500 
cells/mcL
≥ 1500 cells/mcL
ANC does not increase ≥ 1500 cells/mcL
within 12 weeks
 
 
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Toxicity
Hold 
Treatment 
For
Timing for Restarting 
Treatment
Treatment Discontinuation
All Other Drug-
Related Toxicityc
3 or Severe
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 
weeks
4
Permanently discontinue
Permanently discontinue
AE = adverse event; ALT = alanine transaminase; AR = adverse reaction; AST = aspartate transaminase; T1DM = type 1 
diabetes mellitus.
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for pneumonitis) drug-related AE that recurs or any life-
threatening event.
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% 
relative to baseline and lasts for at least 1 week then patients should be discontinued.
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate (e.g., from 
100 mL/hr to 50 mL/hr). Otherwise dosing will be held until symptoms resolve and the subject should be premedicated for the next 
scheduled dose. Refer to Table 8– Infusion Reaction Treatment Guidelines for further management details.
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. Permanently discontinue 
study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover toGrade 0-1 
within 12 weeks of the last dose.
Replacement of Subjects in DLT Evaluation Period
5.2.4
In order to determine safety, all subjects selected must meet the criteria for evaluability for 
Cycle 1. Subjects are considered non-evaluable and will be replaced if:

They are enrolled but not treated

They discontinue from the trial prior to completing all the safety evaluations for 
reasons other than treatment-related adverse events

They receive less than 90% of the total MK-1966 or SD-101 in Cycle 1 (e.g., because 
the infusion had to be discontinued due to an infusion reaction) and did not 
experience a DLT  
Non-evaluable subjects will not be counted toward the cohort total for DLT evaluation.
If a subject experiences a DLT in Cycle 1, trial treatment may be discontinued following 
discussion between the sponsor and Investigator. However, if the subject is deriving clinical 
benefit from the trial treatment, the subject may be allowed to continue after discussion 
between the sponsor and the Investigator.
Timing of Dose Administration
5.2.5
Minimal dosing interval between SD-101 dosing must be 5 days. Trial treatment may be 
administered up to 3 days before or 5 days after the scheduled Day 1 of each cycle, beginning 
in Cycle 3. Cycle 2 Day 1 may be administered up to 1 day after the scheduled day 1. In 
addition, dosing interruptions are permitted in the case of medical / surgical events or 
logistical reasons not related to study therapy (e.g., elective surgery, unrelated medical 
events, patient vacation, and/or holidays). Subjects should be placed back on study therapy 
 
 
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within 2 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor. 
The reason for interruption should be documented in the patient's study record.
Trial Blinding/Masking
5.2.6
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
5.3
In Parts A, B and C treatment allocation will manually occur by non-random assignment.  
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medication
5.5.1
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date will also be included on the CRF.
Palliative and supportive care is permitted during the course of the trial for underlying 
medical conditions and management of symptoms. Surgery or radiotherapy for tumor control 
is not permitted during the study; however, radiotherapy or procedures for symptom 
management is allowed.
All concomitant medications received within 30 days before the first dose of trial treatment 
through the Safety Follow-up Visit should be recorded.  After the Safety Follow-up Visit 
record all medications taken for SAEs as defined in Section 7.2.
Prohibited Concomitant Medications
5.5.2
Subjects are prohibited from receiving the following therapies during the Screening, and 
Treatment Phases of this trial:
 
 
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
Immunotherapy not specified in this protocol.

Antineoplastic systemic chemotherapy or biological therapy. Investigational agents 
not specified in this protocol.

Radiation therapy; radiotherapy for symptom management is allowed.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed. However, intranasal influenza vaccines (e.g. Flu - Mist®) 
are live attenuated vaccines, and are not allowed.
Glucocorticoids for any purpose other than to modulate symptoms from an adverse event.  
Glucocorticoids must be below 10 mg daily to restart SD-101 and/or MK-1966 dosing.
Chronic systemic replacement doses of steroids are allowed. Inhaled steroids for 
management of asthma are allowed.  
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.  
There are no prohibited therapies during the Follow-up visits.
Treatment Precaution
5.6
IFN-α has been shown to inhibit cytochrome P450 (CYP) enzyme 1A2 (Brennan 2012). 
Since SD 101 induces IFN-α, SD 101 may inhibit metabolism of drugs by CYP 1A2. CYP 
1A2 substrates with narrow therapeutic ranges should be used with caution. The following 
drugs should be used with caution through 7 days after each subsequent dose of SD-101:  
caffeine, theophylline, warfarin, tricyclic antidepressants, clozapine, fluvoxamine, 
ciprofloxacin, propranolol, and verapamil.
Rescue Medications & Supportive Care
5.7
Supportive Care Guidelines
5.7.1
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to MK-1966 or SD-101. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
 
 
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
Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).  
o
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis.
o
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with 
intravenous steroids followed by high dose oral steroids.  
o
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.

Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders.
o
Grade 2 hyperthyroidism events (and Grade 3-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism 

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours. 
o
When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks.
 
 
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
Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered.

Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
Table 8 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of MK-1966 or SD-101.
 
 
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Table 8
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for < =24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms resolve 
and the subject should be premedicated for the 
next scheduled dose.
Subjects who develop Grade 2 toxicity despite 
adequate 
premedication 
should 
be 
permanently discontinued from further trial 
treatment administration.
Subject may be premedicated 
1.5h (± 30-minutes) prior to 
infusion of MK-1966 with:
Diphenhydramine 50 mg po (or 
equivalent 
dose 
of 
antihistamine).
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as medically
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov

Management of Injection Site Reaction(s):
o
Subjects should receive full supportive care to treat injection site reactions.. 
Injection-site reactions are expected to spontaneously subside. Local reactions 
 
 
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are to be treated at the discretion of the treating physician. The site is not to be 
injected if local pain, tenderness, or swelling persists from a previous injection 
or other cause; the injection may be postponed until the symptoms have 
resolved. The injection may be skipped, following agreement with the 
Medical Monitor.

Pneumonitis: For Grade 2 events, treat with systemic corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids. 
Administer additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids
o
For Grade 3-4 events, treat with systemic corticosteroids
o
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.

Type 1 Diabetes Mellitus (if new onset, including diabetic ketoacidosis) or ≥ Grade 
3 hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (diabetic 
ketoacidosis)
o
Insulin replacement therapy is recommended for Type 1 diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.
o
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.
Diet/Activity/Other Considerations
5.8
Diet
5.8.1
Subjects should maintain a normal diet unless modifications are required to manage AEs 
such as diarrhea, nausea or vomiting.
Contraception
5.8.2
MK-1966 and SD-101 may have adverse effects on a fetus in utero.  Furthermore, it is not 
known if either drug has transient adverse effects on the composition of sperm.  Non-
pregnant, non-breast-feeding women may be enrolled if they are considered highly unlikely 
to conceive.  
Female subjects will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
 
 
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level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:  
(1) practice abstinence† from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):

intrauterine device (IUD)

vasectomy of a female subject’s male partner 

contraceptive rod implanted into the skin
Combination method (requires use of two of the following):

diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

cervical cap with spermicide (nulliparous women only)  

contraceptive sponge (nulliparous women only) 

male condom or female condom (cannot be used together)

hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
 
 
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‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
Subjects should be informed that taking the study medications may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study.
Use in Pregnancy
5.8.3
If a subject inadvertently becomes pregnant while on treatment with MK-1966 or SD-101, 
the subject will immediately be removed from the study.  The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the SPONSOR without delay 
and within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the SPONSOR.   
If a male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to the SPONSOR and followed as 
described above and in Section 7.2.2.
Use in Nursing Women
5.8.4
It is unknown whether MK-1966 or SD-101 is excreted in human milk.  Since many drugs 
are excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
5.9
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
In this trial, a subject may discontinue from treatment but continue to participate in the 
regularly scheduled activities, as long as the subject does not withdraw consent. Once a 
subject has discontinued treatment, even though he/she continues to be monitored in the trial, 
he/she may be allowed to begin treatment again if deemed medically appropriate.
A subject must be discontinued from the trial for any of the following reasons:
 
 
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●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

Confirmed disease progression per response assessment criteria (See Section 4.2.3)

Noncompliance with trial treatment or procedure requirements

Investigator’s decision to withdraw the subject

Clinical progression

Subject has a confirmed pregnancy test

Unacceptable adverse events 

Intercurrent illness that prevents further administration of treatment

Administrative reasons

Lost to follow-up
Subject Replacement Strategy
5.10
A subject who discontinues from the trial will not be replaced except as described in Section 
5.2.3 Replacement of Subjects During DLT Evaluation Period.
Beginning and End of the Trial
5.11
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.12
There are no pre-specified criteria for terminating the trial early.
 
 
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6.0 TRIAL FLOW CHART
Dose Escalation and Expansion Cohorts- MK-1966 + SD-101
Trial Period:
Screening 
Phase
Cycles 1
Cycle 2
Cycle 3
Cycle 4
(Day 1)
Cycle 5-
8
(Day 1)
End of 
Treatment 
Period
Post-
Treatment
Survival 
FU
Treatment Days:
Screening 
(Visit 1)
1
2
3
8
9
15
22
29
36
43
50
57
64
Safety 
Follow-up
At end of 
Cycle 8s or 
time of 
treatment 
discon
30 days
post end of 
Treatment 
Period
Every 12 
weeks
Scheduling Window 
(Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
Administrative 
Procedures
Informed Consent
X
Inclusion/Exclusion 
Criteria
X
Demographics and 
Medical History
X
Prior and Concomitant 
Medication Reviewo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical 
Procedures/Assessmentso
Review Adverse Events
Xp
X
X
X
X
X
X
X
X
X
X
X
X
Xp
12-Lead ECG (Local)
X
X
X
X
X
X
X
Full Physical Examination
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
Vital Signs, Weight, 
Heighta
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
X
Trial Treatment 
Administrationj
MK-1966
X
X
X
X
X
SD-101q,r
X
X
X
X
X
X
X
 
 
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Trial Period:
Screening 
Phase
Cycles 1
Cycle 2
Cycle 3
Cycle 4
(Day 1)
Cycle 5-
8
(Day 1)
End of 
Treatment 
Period
Post-
Treatment
Survival 
FU
Treatment Days:
Screening 
(Visit 1)
1
2
3
8
9
15
22
29
36
43
50
57
64
Safety 
Follow-up
At end of 
Cycle 8s or 
time of 
treatment 
discon
30 days
post end of 
Treatment 
Period
Every 12 
weeks
Scheduling Window 
(Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
Laboratory 
Procedures/Assessments:  
Analysis performed by 
LOCAL laboratory
Pregnancy Test – Serum 
or Urineb
X
X
X
X
X
X
X
X
PT/INR and aPTT
Xf
CBC with Differentialk
Xf
Xk
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry Panelk
Xf
Xk
X
X
X
X
X
X
X
X
X
X
X
X
HIV, Hepatitis B and Cl
X
Thyroid Function (TSH, 
Free T4, Total T3)k
Xf
X
X
X
X
X
Urinalysis
Xf
X
X
X
X
X
X
Laboratory 
Procedures/Assessments:  
Analysis performed by 
Sponsor or Central
laboratory
MK-1966 
Pharmacokineticsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IL-10d,h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Anti-MK-1966 Antibodies
X
X
X
X
X
X
X
Blood for RNA Analysesd
X
X
Xn
X
X
Blood for cytokines 
(plasma)d
X
X
X
X
Blood for Geneticsc,d
X
 
 
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Trial Period:
Screening 
Phase
Cycles 1
Cycle 2
Cycle 3
Cycle 4
(Day 1)
Cycle 5-
8
(Day 1)
End of 
Treatment 
Period
Post-
Treatment
Survival 
FU
Treatment Days:
Screening 
(Visit 1)
1
2
3
8
9
15
22
29
36
43
50
57
64
Safety 
Follow-up
At end of 
Cycle 8s or 
time of 
treatment 
discon
30 days
post end of 
Treatment 
Period
Every 12 
weeks
Scheduling Window 
(Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
Efficacy Measurements
irRESIST - melanoma, 
squamous cell cancer of 
head and neck, breast 
cancer with dermal 
metastasis e,
X
Xe
X
Cheson Criteria – B Cell 
Lymphomae, i
X
Xe
X
Tumor Tissue Collection
Archival and/or Newly 
Obtained Tissue 
Collectiond,o
X
Xt
Xt
Survival Status Telephone 
Contact 
Xm 
 
 
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a.
Height will be measured at Visit 1 only. 
b.
For women of reproductive potential, a urine pregnancy test will be performed within 72 hours of receiving the first dose of study medication. If urine pregnancy test cannot be 
confirmed as negative, a serum pregnancy test is required.
c.
Details for collection can be found in Section 7.1.3, Laboratory Procedures/Assessment. 
d.
If the subject signs the Future Biomedical Research consent, any leftover samples that would be ordinarily discarded at the end of the main study will be retained for Future Biomedical 
Research.  
e.
Tumor imaging (ie. CT scan, MRI, CT/PET, etc.) should be performed within 28 days of enrollment. Tumor imaging and response assessment(s) to be performed 12 weeks after first 
dose, than every 12 weeks until discontinuation or End of Treatment. Imaging assessments should be repeated every 12 weeks and follow calendar days and should not be adjusted for 
delays in Cycle starts or extensions of dosing frequencies.  The same imaging technique should be used on a subject throughout the trial.   Scans used for tumor measurements may be 
requested for central review. 
f.
Laboratory tests at Screening are to be performed within 7 days prior to the first dose of study treatment.
g.
MK-1966 Pharmacokinetics (PK) samples will be collected more frequently in Cycles 1-3.  On Days 1, 22 and 43 -collect predose, at the end of infusion and 2h after the start of the 
infusion (+10 minutes).  On Day1 of Cycles 4-8 collect PK samples predose.  Also collect PK Samples on Days 2, 3, 8, 15, 29, 36, 50, 57, at the treatment discontinuation, and Safety 
Follow-up visit (30 days post end of treatment). 
h.
Blood samples for IL-10 Pharmacodynamics (PD) will be drawn at Screening and at times that match PK sampling in footnote “i” above. 
i.
Unilateral bone marrow biopsy and aspirate will be performed at Screening if not previously performed or if performed more than 90 days previously with negative results. The bone 
marrow biopsy will be performed to confirm a CR if the subject was initially positive or if it is clinically indicated by new abnormalities in the peripheral blood counts or blood smear
(section 4.2.3.5)
j.
When SD-101 and MK-1966 are scheduled on the same day, SD-101 will be administered first.  MK-1966 will be administered at least 30 minutes after the SD-101 injection.  
k.
These samples may be performed up to 72 hours prior to dosing.   However, in Cycle 1 on Day 1, samples are to be drawn prior to dosing and should be used as the subject’s baseline 
(not screening) values.  
l.
Include HCV, RNA (qualitative) or Hepatitis C antibody, HBsAg, and HIV type 1 and type 2 (e.g., HIV-1/-2 antibody screening test and evaluation of HIV viral load as needed).
m.
Patients who discontinue from treatment or have completed post treatment follow up should be contacted every three months to monitor overall survival (for up to 2 years from last dose 
of study drug or until the sites are notified by the Sponsor that the survival follow up is no longer required).  
n.
The Day 9 visit must be 24 hours (+/- 4 hours) after the Day 8 visit.
o.
Sample(s) and/or procedures will be collected prior to dosing and when applicable as outlined in the Procedures Manual.
p.
Record all AEs occurring from signing of informed consent until 30 days after the last dose of MK-1966 and SD-101. Report all SAEs occurring up to 30 days after the last dose of 
treatment
q.
Dosing with MK-1966 and/or SD-101 will occur within the timeframes outlined in section 5.2.5. and/or the Procedures Manual.   
r.
After the SD-101 is injected, the injection site should be observed every 15 minutes for at least 90 minutes.
s.
End of Cycle 8 is defined as 21 days post Cycle 8, Day 1 or Day 168.  
t.
The Cycle 2 (or Day 22) and End of Treatment tumor samples are optional.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
Informed Consent
7.1.1.1
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
7.1.1.3
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
7.1.1.4
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered clinically significant by the Investigator. Details regarding the disease for 
which the subject has been enrolled in the trial will be recorded separately and should not be 
listed in medical history.  Smoking history will be obtained.
Prior and Concomitant Medications Review
7.1.1.5
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days before starting the trial. Prior anti-cancer treatment for the disease for which 
the subject has been enrolled in this trial will be recorded separately and should not be listed 
in prior medications.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial and through the 30-day Safety Follow-up visit. After the Safety visit, record 
all medications related to reportable SAEs.
If a subject initiates a new anti-cancer therapy within 30 days after the last dose of trial 
treatment, the 30 day Safety Follow-up visit must occur before the first new dose of the new 
therapy.
 
 
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Disease Details and Treatments
7.1.1.6
7.1.1.6.1 Disease Details
The Investigator or qualified designee will obtain prior and current details regarding disease 
status. 
7.1.1.6.2 Prior Oncology Treatment History
The Investigator or qualified designee will record all prior anti-cancer treatments including 
systemic treatments, radiation and surgeries radiations and surgeries regardless of time prior 
to first dose of trial treatment.
Assignment of Screening Number
7.1.1.7
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.
Assignment of Treatment/Randomization Number
7.1.1.8
All eligible subjects will be allocated, by non-random assignment, and will receive a 
randomization number.  The randomization number identifies the subject for all procedures 
occurring after treatment allocation.  While the subjects are being allocated to their treatment, 
and not ‘randomized’, this unique number is termed a randomization number throughout the 
protocol for operational purposes. Subjects will be manually assigned into Parts A, B and C.  
The appropriate site staff will forward each subject’s registration form as specified in the 
Procedures Manual.  
A single subject cannot be assigned more than 1 randomization number.
Trial Compliance (Study Drug Administration)
7.1.1.9
Interruptions from the protocol specified treatment(s) for 12 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management (see section 5.2.3).
7.1.1.9.1 MK-1966 
MK-1966 will be administered using intravenous infusion. The Pharmacy Manual contains 
specific instructions for the preparation and administration of the MK-1966 infusion solution.  
Designated site personnel will be responsible for preparing and administering MK-1966 and 
will be required to record limited information during each infusion (e.g., infusion date/time, 
 
 
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lot number and expiry date for product administered, total dose/volume administered). See 
Pharmacy Manual for further details. 
SD-101 will be administered before MK-1966 on days when both drugs are scheduled to be 
used.
7.1.1.9.2 SD-101
SD 101 will be administered by intratumoral injection into Lesion A in part A and up to 4 
lesions (Lesion A, Lesion B, Lesion C, Lesion D), the tumor site(s) selected to receive 
injections of trial treatment in parts B and C. In Parts B and C, if the patient has more than 1 
lesion, the investigator shall endeavor to choose the largest and most easily accessible tumor 
site as Lesion A. In Parts B and C, multiple lesions may be chosen (up to 4 [Lesions A, B, C, 
D]) and the dose will be equally divided (regardless of size of tumor) among the multiple 
lesions. In Parts A, B and C, if an injected lesion fully regresses, SD-101 at the dose that was 
previously administered into the lesion should continue to be injected.    
Ultrasound may be used to assess lesion(s). Notation in the source documents should specify 
location and size (in 2 dimensions) in as much detail as possible. 
Designated trial-site personnel will be responsible for preparing and administering the trial 
SD-101 injection.  At minimum, syringes will be labeled with the protocol number, patient 
initials, and patient number. 
Additional details related to SD 101 intratumoral injection(s) will be outlined in the 
Procedures and/or Pharmacy Manual(s).
Clinical Procedures/Assessments
7.1.2
Adverse Event (AE) Monitoring
7.1.2.1
The Investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated. Adverse events will be graded according to NCI CTCAE Version 4. Toxicities will 
be characterized in terms of seriousness, causality, toxicity grade and action taken with 
regard to trial treatment. 
This is a dose escalation trial to establish the MTD of MK-1966 in combination with SD-
101; therefore, each dose escalation will be based on the safety and tolerability experienced 
by subjects at each dose level. The safety and tolerability of each cohort for the DLT 
evaluation period will be reviewed prior to the start of the next cohort. The Sponsor and the 
Principal Investigators will review the safety and tolerability of each trial treatment, the 
appropriateness of dose escalation, when each cohort is completed and the next cohort is 
opened for enrollment. Frequency of these communications will depend on the enrollment of 
each cohort, as well as any potential new information regarding a safety concern in this trial 
or other relevant trials.
As a Phase 1 trial, there is no plan for an external safety reviewer. Data from individual 
subjects will be closely followed on an ongoing basis by the Principal Investigator and the 
Sponsor.
 
 
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Full Physical Examination 
7.1.2.2
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant findings from the screening exam should be recorded 
as medical history. 
A full physical exam should be repeated according to the frequency defined in the Study 
Flow Chart (Section 6.0). After the first dose of MK-1966, new clinically significant 
abnormal findings should be recorded as AEs.
7.1.2.2.1 Directed Physical Exam
For cycles that do not require a full physical examine per the Trial Flow Chart, the 
Investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to trial treatment administration. New clinically significant abnormal findings 
should be recorded as AEs. 
Vital Signs and Weight
7.1.2.3
The Investigator or qualified designee will take vital signs at screening, prior to the 
administration of trial treatment at each cycle, and at the 30 day safety follow up visit as 
specified in the Trial Flow Chart.  Vital signs should include temperature, pulse, respiratory 
rate, blood pressure and weight at the frequency defined in the Study Flow Chart (Section 
6.0).
Height will be obtained at Screening only.  
Electrocardiogram (ECG)
7.1.2.4
A standard 12-lead ECG will be performed using local standard procedure at Screening, with 
any clinically significant abnormal findings recorded as medical history. 
Additional timepoints for ECGs are according to the Trial Flow Chart (Section 6.0). 
Clinically significant abnormal findings seen on all ECGs performed after Screening should 
be recorded as AEs.
Eastern Cooperative Oncology Group (ECOG) Performance Status
7.1.2.5
The investigator or qualified designee will assess the ECOG performance status as the 
timepoints specified in the Trial Flow Chart (Section 6.0).
Disease Assessments 
7.1.2.6
7.1.2.6.1 Solid Tumors 
Response will be based on irRECIST version 1.1 by investigator assessment.
Immunotherapeutic agents, such as MK-1966 may produce antitumor effects by potentiating 
endogenous cancer-specific immune response. The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with typical cytotoxic 
agents, and can manifest a clinical response after an initial increase in tumor burden or even 
the appearance of new lesions. When feasible, study subjects can continue on treatment until 
 
 
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progression is confirmed by the local site investigator/radiology assessment (see Section
4.2.3.6).
7.1.2.6.2 B Cell Lymphoma
Response will be based on the Cheson criteria for lymphoma (see Section 4.2.3.5).  
Unilateral Bone Marrow Biopsy and Aspirate
7.1.2.6.2.1
Unilateral bone marrow biopsy and aspirate will be performed at Screening if not previously 
performed or if performed more than 90 days previously with negative results. The bone 
marrow biopsy will be performed to confirm a CR if they were initially positive or if it is 
clinically indicated by new abnormalities in the peripheral blood counts or blood smear.
7.1.2.6.3 Solid Tumors and B Cell Lymphoma
Imaging 
7.1.2.6.3.1
The process for image collection and transmission to the central vendor can be found in the
Site Imaging Manual.  Initial imaging (CT Scans, MRI, CT/PET, etc.) must be performed 
within 28 days prior to the first dose of treatment, and should be repeated at week 12 (or Day 
84), at week 24 and every 12 weeks until confirmed disease progression, the start of new 
anti-cancer therapy, withdrawal of consent, death or end of the study, whichever comes first.
Table 9 below outlines the imaging that should be performed for each tumor type.  The same 
imaging technique should be performed at each time point.
Table 9
Imaging by Anatomical Coverage
Organ coverage 
/Indication
B-Cell lymphoma
SCCHN
Melanoma
Breast Cancer
With dermal 
metastasis
Chest, Abdomen  
Mandatory
Mandatory
Mandatory
Mandatory
Pelvis
Mandatory
If clinically 
indicated
Mandatory
Mandatory
Soft Tissue Neck
If clinically 
indicated
Mandatory
If clinically 
indicated
If clinically 
indicated
Head 
If clinically 
indicated
If clinically 
indicated
If clinically 
indicated
If clinically 
indicated
Skin Photography
  NA
NA
If clinically 
indicated for 
cutaneous skin 
lesions
If clinically 
indicated for 
cutaneous skin 
lesions
Bone
If clinically 
indicated
If clinically 
indicated
If clinically 
indicated
If clinically 
indicated
 
 
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The process for image collection and transmission to the central vendor can be found in the
Site Imaging Manual.  Information for disease assessments may be submitted for central 
review.
Immunotherapeutic agents, such as MK-1966 and SD-101 may produce antitumor effects by 
potentiating endogenous cancer-specific immune response. The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with typical 
cytotoxic agents, and can manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. Therefore, the subject should not be 
discontinued from the trial until PD is confirmed.  
Tumor Tissue Collection and Correlative Studies Blood Sampling
7.1.2.6.3.2
Subjects may provide tumor sample(s) as specified in Procedures Manual. Sample collection, 
storage and shipment instructions for correlative study samples, archival tumor samples and 
newly obtained biopsy specimens will be provided in the Procedures Manual.  Archival 
samples are not required to be submitted within the screening period. 
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedure 
Manual.
 
 
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Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
7.1.3.1
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 10.
Table 10
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)a
Hemoglobin
Alkaline phosphatase
Glucose
Hepatitis HBsAg
Platelet count
Alanine aminotransferase (ALT) Protein
Hepatitis C (HCV RNA) or 
Hepatitis C antibody
WBC (total and 
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity 
HIV
RBC
Bicarbonate or carbon dioxide 
(CO2)b
Microscopic exam, if 
abnormal 
results 
are 
noted
blood 
for 
correlative 
studies
Absolute 
neutrophil count
Calcium
Urine pregnancy testa
Blood for genetics
Chloride
PT (INR)d
Creatinine
aPTT/PTT d
Glucose
TSH (TSH, Free T4, Total T3)
Lactate dehydrogenase (LDH)
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct 
Bilirubin, 
if 
total 
bilirubin is elevated above the 
upper limit of normal
Total protein
Blood Urea Nitrogen 
Ureac
Uric acid
a. Perform on women of childbearing potential only. Urine pregnancy test is preferred. If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.
b. If these tests are not done as part of standard of care in your region then these tests do not need to be performed.
c. Blood Urea Nitrogen is preferred; if not available urea may be tested.
d. Coagulation factors (PT/INR and aPTT/PTT) should be tested as part of the screening procedures for all subjects. Any 
subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout the trial.
Laboratory tests for Screening should be performed within 7 days prior to the first dose of 
MK-1966 and SD-101. After Cycle 1, pre-dose laboratory tests can be performed up to 72 
hours prior to dosing. Results must be reviewed by the investigator of qualified designee and 
found to be acceptable prior to each dose of study treatment
 
 
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Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2
7.1.3.2.1 Blood Collection (Serum) for MK-1966
Sample collection, storage and shipment instructions for PK samples will be provided in the
Procedure Manual.  
The time points for PK sampling are described in Section 6.0-Trial Flow Chart.
7.1.3.2.2 Blood Collection for Anti- MK-1966 Antibodies (ADA)
Sample collection, storage and shipment instructions for anti-MK-1966 antibodies (ADA) 
samples will be provided in the Procedures Manual. 
The timepoints for PK sampling are described in Section 6.0-Trial Flow Chart.
Planned Genetic Analysis Sample Collection
7.1.3.3
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual.  Sample(s) should be drawn for planned analysis 
of the association between genetic variants in DNA and drug response. If there is either a 
documented law or regulation prohibiting collection, or if the IRB/IEC does not approve the 
collection of the sample for these purposes, then this sample will not be collected at that site. 
If the sample is collected, leftover extracted DNA will be stored for future biomedical 
research if the subject signs the FBR consent. If the planned genetic analysis is not approved, 
but FBR is approved and consent is given, this sample will be collected for the purpose of 
FBR.   
Future Biomedical Research Sample Collection
7.1.3.4
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA for future research.

Leftover main study tumor stored for future research

Leftover RNA

Leftover Serum and Plasma
Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
Subjects who discontinue/withdraw from treatment prior to completion of the treatment/
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. .
 
 
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7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
7.1.4.2
This is an open label trial; there is no blinding for this trial.
Calibration of Critical Equipment
7.1.4.3
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
•
Laboratory equipment – as required for inclusion labs and trial assessments
•
Imaging equipment – as required for study objectives
•
ECG equipment- as required for trial assessments
•
Infusion syringe and/or pump – used to administer MK-1966 and SD-101
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
7.1.5.1
Approximately 28 days prior to randomization, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. 
 
 
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Screening procedures may be repeated after consultation with the Sponsor.
Written consent must be obtained prior to performing any protocol specific procedure. 
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following:
•
Screening laboratory tests are to be performed within 7 days prior to the first dose of trial 
treatment.
•
For women of reproductive potential, a urine pregnancy test will be performed within 72 
hours prior to first dose of trial treatment. If urine pregnancy results cannot be confirmed 
as negative, a serum pregnancy test, performed by the local study site laboratory, will be 
required.
•
Tumor imaging must be performed within 28 days prior to the first dose of trial
treatment.
Treatment Period
7.1.5.2
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
After a screening phase of up to 28 days, eligible subject(s) will be assigned a dose levels by 
the sponsor. MK-1966 and SD- 101 treatment will be administered as outlined in Section 5.2 
for 8 cycles (approximately 24 weeks) of study medication in Part A, B, C, or administrative 
reasons requiring cessation of treatment. After the end of treatment (EOT), each subject will 
be followed for 30 days.  Serious adverse events (SAEs) will be collected for 30 days after 
EOT.   
7.1.5.2.1 Safety Follow-up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new antineoplastic treatment, 
whichever comes first. Subjects with an AE of Grade >1 will be further followed until the 
resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, 
whichever occurs first. 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
 
 
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frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding (by > 50%) the 
prescribed dose for SD-101 and/or MK-1966.  No specific information is available on the 
treatment of overdose of MK-1966. In the event of overdose, MK-1966 should be 
discontinued and the subject should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
 
 
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reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies  must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
Serious Adverse Events
7.2.3.1
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
 
 
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Refer to Table 11 for additional details regarding each of the above criteria.
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
7.2.3.2
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
 
 
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than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
 
 
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Table 11 Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study.  Post hoc exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2 through 8.12.  
Study Design Overview
Phase 1/1b Trial MK-1966 in combination with SD-101 in Subjects 
With Advanced Malignancies. A 3+3 design in part A to identify 
preliminary MTD; TPI design for dose confirmation on two 
malignancies (melanoma and squamous cell cancer of head and neck), 
followed by approximately 24 weeks follow-up as an expansion 
cohort on both malignancies. 
Analysis Populations
Safety: All Subjects as Treated (ASaT)
PK and target engagement (secondary): Per-Protocol (PP)
Efficacy (exploratory):  Full Analysis Set (FAS)   
Primary Endpoint(s)
   Safety: DLT   
Key Secondary Endpoints
PK parameters of  MK-1966 in combination with SD-101
Target engagement for MK-1966
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
Serum concentrations of MK-1966 will be summarized by planned visit 
and time for each dose separately; PK parameters will be summarized 
by dose.
Target engagement will be summarized by planned visit and time for 
each dose separately.
Treatment Assignment
Subjects are allocated to increasing doses of  MK-1966 co-
administered with SD-101 without randomization; the study is open-
label
Statistical Methods for Key 
Safety Analyses
DLT and adverse experiences will be summarized as counts and 
frequencies for the dose level with at least three subjects. The estimate 
of the DLT rate among subjects treated with the RPTD and the 80% 
Bayesian probability interval for the estimate will be provided.
Interim Analyses
Study has no interim analyses
Multiplicity
   No multiplicity adjustment is planned in this Phase I/Ib study.
Sample Size and Power 
The sample size of the dose escalation (Part A), and dose 
confirmation/expansion (Parts B and C) depends on the observed DLT 
profiles of MK-1966 co-administered with SD-101.  The sample size 
of approximately 64 subjects will be used for study planning purposes. 
 
 
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8.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This trial is conducted as an open-label trial, i.e., subjects, investigators, and SPONSOR 
personnel will be aware of subject treatment assignments after each subject is enrolled and 
treatment is assigned. Allocation to treatment will not be randomized.
The database will be locked for analysis approximately 24 weeks after the enrollment of the 
last subject. 
8.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
8.4
Analysis Endpoints
Efficacy and safety endpoints are listed below, followed by the descriptions of the 
derivations of selected endpoints.
8.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Efficacy endpoints and their definitions are presented in Section 8.4.3.
8.4.2
Safety Endpoints
The primary safety endpoint is DLT.  Safety will be monitored by cumulative data reviews 
throughout the trial.  The toxicities and grades experienced by subjects who have received 
study treatment, including adverse events (AEs and serious adverse events (SAEs) will be 
summarized.  Other safety measures evaluated in all parts of the study include laboratory 
safety assessments, ECGs, vital signs, and physical examinations.
8.4.3
Derivations of Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Secondary PK endpoints and exploratory efficacy endpoints and their definitions are 
presented below. 
PK endpoints- serum concentrations of MK-1966 and derived PK parameters.
Target engagement endpoints – Total IL-10, free IL-10, to be used in descriptive analyses
Exploratory endpoints 
Exploratory endpoints are documented in a supplemental SAP (sSAP). Additional supportive 
analyses of these endpoints based on irRECIST or Cheson criteria and, if needed, central 
review might be conducted.   
8.4.4
Derivations of Safety Endpoints
Description of safety measures is provided in Section 7.
 
 
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8.5
Analysis Populations
8.5.1
Safety Analysis Populations
The All-Patients-as-Treated (APaT) population will be used for the analysis of safety data in 
this study. The APaT population consists of all subjects who received at least one dose of 
study treatment.  In case of treatment administration errors, subjects will be analyzed 
according to the treatment they actually received. For DLT evaluation, APaT subjects that 
were observed for safety for 21 days after the first dose of assigned treatment or experienced 
a DLT prior to 21 days after the first dose of assigned treatment will be used.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
8.5.2
Pharmacokinetic Analysis Populations
Per-Protocol (PP): The set of data generated by the subset of subjects who comply with the 
protocol sufficiently to ensure that these data will be likely to exhibit the effects of treatment, 
according to the underlying scientific model. Compliance covers such considerations as 
exposure to treatment, availability of measurements and absence of major protocol 
violations. Major protocol violators will be identified to the extent possible prior to 
unblinding by individuals responsible for data collection/compliance, and its analysis and 
interpretation. Any subjects or data values excluded from analysis will be identified, along 
with their reason for exclusion, in the CSR. At the end of the study, all subjects who are 
compliant with the study procedure as aforementioned and have available data from at least 
one treatment will be included. This population will be used for the PK and target 
engagement analyses.
8.5.3
Efficacy Analysis Populations
The full analysis set populations FAS are defined as all subjects with a baseline scan with 
measurable disease by investigator assessment who were administered MK-1966 and SD-101 
(FAS). These populations will be used for exploratory analyses of efficacy.
Analysis of response duration is based on all confirmed responders.
8.6
Statistical Methods
8.6.1
Statistical Methods for Efficacy Analyses
The statistical methods for efficacy analyses are documented in a supplemental SAP (sSAP).
8.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, ECG measurements and physical examinations.
DLTs will be listed.  DLTs and adverse experiences will be summarized as counts and 
frequencies for MK-1966 in combination with SD-101 dose level that had at least three 
subjects treated and listed for other dose levels. The estimate of the DLT rate among subjects 
treated with the RPTD and the 80% Bayesian probability interval with non-informative prior
for the estimate will be provided. Laboratory assessments, vital signs, and other safety 
endpoints will be summarized as appropriate.
 
 
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In addition, the broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, a drug related AE, a serious AE, an AE which is both drug-related and 
serious, and who discontinued due to an AE will be summarized for dose levels with at least 
3 subjects treated and listed for other doses. Percentages of subjects in these categories 
among subjects treated with RPTD and 80% confidence intervals for the estimated 
percentages calculated using the Clopper-Pearson method will be provided.
8.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3.1
Demographic and Baseline Characteristics
The number and percentage of subjects screened, allocated, the primary reasons for screening 
failure, and the primary reason for discontinuation will be displayed.  Demographic 
variables, baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized either by descriptive statistics or categorical tables 
for APaT population, the set of subjects treated with the RPTD dose for combination of MK-
1966 with SD-101.
8.6.3.2
Pharmacokinetics and Pharmacodynamics Modeling Analysis
Serum concentrations of MK-1966 will be summarized by planned visit and time for each 
dose separately; PK parameters will be summarized by dose. Descriptive statistics will be 
provided for each dose with at least 3 subjects; for other doses, the results will be listed.
Target engagement will be summarized by planned visit and time for each dose separately. 
Change from baseline in INF-alpha inducible gene expression will be estimated.
The data from the study will be used to quantitatively explore the relationships among 
pharmacokinetics, target engagement, exploratory biomarkers and tumor response 
measurements. A modeling analysis plan will be developed separately.
8.6.3.3
Interim Analyses
No interim analyses are planned for this study.
8.6.3.4
Multiplicity
There will be no multiplicity control in this study.
8.6.3.5
Sample Size and Power Calculations
Dose Escalation and Dose Confirmation/Expansion
The primary purpose of the dose escalation and dose confirmation/expansion parts of the trial 
is to investigate the safety and tolerability of MK-1966 co-administered with SD-101 in adult 
subjects with advanced malignancies (Parts A-C) and to establish RPTD for MK-1966 co-
administered with SD-101.  
The final number of subjects enrolled in the dose escalation and confirmation/expansion parts 
of the study will depend on the empirical safety (DLT) observations, in particular, at what 
dose is identified as the RPTD. Sample sizes for a few possible scenarios as well as the 
 
 
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estimated time required to enroll all subjects and the time required to determine the MTD are 
provided below.  The time required to estimate the MTD is the time from the first subject’s 
first dose to the end of the 3-week observation period following the first dose of the last 
subject enrolled in the dose confirmation/expansion part.  The study duration is derived as 
the time from the first subject’s first dose to the end of 6-month treatment period following 
the enrollment of the last subject.
The enrollment time was conservatively estimated assuming that during 3+3 parts and the 
dose confirmation/expansion a subject can be enrolled every week. The sample size for each 
malignancy is 20 subjects, for the purpose of efficacy assessment in exploratory objectives.
Scenario 1.  No DLTs during Parts A-C.   For MK-1966 with SD-101, in a scenario where  
no DLTs are encountered during the dose escalation and confirmation/expansion parts so that 
Part A continues to the highest dose in Table 5, the sample size to determine the MTD is 32
subjects (12 in Part A, 20 from Parts B and C). The total sample size is 52 subjects (12
subjects across 3 doses in Part A, 20 subjects on RPTD in Part B, and another 20 subjects on 
RPTD in Part C).  
It will take 52 weeks to enroll 52 subjects in Parts A-C. Thus, in this scenario the enrollment 
time across Parts A-C is 52 weeks and the time required to determine the MTD is 35 weeks 
for 32 subjects. The study duration then is approximately 52 weeks + 24 weeks or 1.8 years. 
If dose escalation stops at a dose below the highest dose, the study might require less than 52
subjects and the enrollment duration shorter than 52 weeks. 
Scenario 2: Flat DLT dose response.  Suppose dose escalation in Parts A continues to the 
highest dose with flat dose response so that all 4 doses (including the top one) are given to 6 
subjects each in Part A.  Also suppose that the top dose is confirmed as the RPTD dose 
without de-escalation in Parts B and C.  Thus, the sample size to determine the MTD is 44
subjects (24 in Part A, 20 in Parts B and C). The total sample size is 64 subjects (24 in Part 
A, 20 in Part B, and 20 in Part C). 
It will take 64 weeks to enroll 64 subjects in Parts A-C. Thus, in this scenario the enrollment 
time across Parts A-C is 64 weeks and the time required to determine the two MTDs is 47
weeks for 44 subjects. The study duration then is approximately 64 weeks + 24 weeks or 1.8
years. 
Any dose de-escalations and/or re-escalations in Parts B and/or C will increase the sample 
size in this example. 
8.6.4
Precision of the DLT rate at RPTD
Since the TPI approach will be used during the dose confirmation/expansion parts B and C, 
the estimated DLT rate, and its 80% Bayesian Probability Interval (PI) will be calculated 
from the posterior distribution of the DLT rate at RPTD using the model specified in the TPI 
approach. If 20 subjects are finally dosed at RPTD during the dose confirmation/expansion
stage, the estimated DLT rate and its 80% PI should be similar to one of the rows in Table 
12.  
 
 
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Table 12
Precision of the Estimated DLT rates at RPTD
Number of 
Subjects dosed at 
RPTD
Number of DLT 
Events
Estimated DLT 
Rate
Lower Bound of 
80% PI
Upper Bound of 
80% PI
20
2
0.10
0.036
0.206
20
3
0.15
0.069
0.267
20
4
0.20
0.105
0.325
20
5
0.25
0.144
0.381
20
6
0.30
0.185
0.435
20
7
0.35
0.228
0.487
Assume non-informative prior distribution of DLT.
8.7
Subgroup Analyses and Effect of Baseline Factors
No subgroup analyses will be performed.
8.8
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study.  Percent 
compliance with drug administration will be calculated for each subject for MK-1966 and 
SD-101 separately.
For MK-1966 and SD-101, percent compliance will be calculated as following: 
x 100.
For MK-1966, “Number of Doses that Should have been Taken” will be calculated as the 
minimum of the two numbers: 4 and (1 plus the number (integer) of 3-week intervals that fit
between the date of the first dose and the date of the last dose of MK-1966).
For SD-101, “Number of Doses that Should have been Taken” will be calculated as 1 plus 
the number (integer) of 3-week intervals that fit between the date of the first dose and the 
date of the last dose of SD-101.
8.9
Extent of Exposure
A subject’s extent of exposure to MK-1966 is defined as the total number of doses of MK-
1966 the subject received.  A subject’s extent of exposure to SD-101 is defined as the total 
number of doses of SD-101 the subject received.
Extent of Exposure will be summarized for MK-1966 in combination with SD-101 dose 
levels with at least 3 subjects enrolled and listed for other dose levels.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
 
 
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investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 13.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 13
Product Descriptions
Product Name & Potency
Dosage Form
MK-1966 50 mg/mL, 4 mL
Concentrate for solution for infusion 
SD-101 16 mg/mL, .75 mL
Injection
Other supplies not indicated in Table 13 may be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will be dosed using open label vials. No kitting is required.
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. MK-1966 and SD-101 (name, strength or potency) is included in 
the label text; random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
 
 
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discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
 
 
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investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
 
 
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The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
 
 
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conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
 
 
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electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
 
 
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contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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11.0 LIST OF REFERENCES
[1]
Ji Y, Li Y, Bekele BN. Dose-finding in phase l clinical trials based on toxicity 
probability intervals. Clin Trials 2007;4:235-44.
[2]
Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the 
interleukin-10 receptor. Annu Rev Immunol. 2001;19:683-765.
[3]
Saraiva M, O'Garra A. The regulation of IL-10 production by immune cells. Nat Rev 
Immunol. 2010 Mar;10(3):170-81.
[4]
Ho AS, Wei SH, Mui AL, Miyajima A, Moore KW. Functional regions of the mouse 
interleukin-10 receptor cytoplasmic domain. Mol Cell Biol. 1995 Sep;15(9):5043-53.
[5]
Finbloom DS, Winestock KD. IL-10 induces the tyrosine phosphorylation of tyk2 and 
Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T 
cells and monocytes. J Immunol. 1995 Aug 1;155(3):1079-90.
[6]
Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS, et al. Targeted 
disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the 
JAK-STAT signaling pathway. Cell. 1996 Feb 9;84(3):431-42.
[7]
Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Förster I, et al. Enhanced 
Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in 
macrophages and neutrophils. Immunity. 1999 Jan;10(1):39-49.
[8]
Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010 Mar 
19;140(6):805-20.
[9]
Vacchelli E, Galluzzi L, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, et al. 
Trial watch: FDA-approved Toll-like receptor agonists for cancer therapy. 
Oncoimmunology. 2012 Sep 1;1(6):894-907.
[10]
Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdörfer B, Giese T, et al. 
Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human 
peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J 
Immunol. 2002 May 1;168(9):4531-7.
[11]
Ketloy C, Engering A, Srichairatanakul U, Limsalakpetch A, Yongvanitchit K, 
Pichyangkul S, et al. Expression and function of Toll-like receptors on dendritic cells 
and other antigen presenting cells from non-human primates. Vet Immunol 
Immunopathol. 2008 Sep 15;125(1-2):18-30.
[12]
Krieg AM. Development of TLR9 agonists for cancer therapy. J Clin Invest 
2007;117(5):1184-94.
[13]
Kim YH, Gratzinger D, Harrison C, Brody JD, Czerwinski DK, Ai WZ, et al. In situ 
vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist 
combined with radiation: a phase 1/2 study. Blood. 2012 Jan 12;119(2):355-63.
[14]
Brody JD, Ai WZ, Czerwinski DK, Torchia JA, Levy M, Advani RH, et al. In situ 
vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II 
study. J Clin Oncol. 2010 Oct 1;28(28):4324-32.
 
 
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[15]
Duramad O, Fearon KL, Chan JH, Kanzler H, Marshall JD, Coffman RL, et al. IL-10 
regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory 
sequences. Blood. 2003 Dec 15;102(13):4487-92.
[16]
Marshall JD, Heeke DS, Abbate C, Yee P, Van Nest G. Induction of interferon-gamma 
from natural killer cells by immunostimulatory CpG DNA is mediated through 
plasmacytoid-dendritic-cell-produced interferon-alpha and tumour necrosis factor-
alpha. Immunology. 2006 Jan;117(1):38-46.
[17]
Martin-Orozco E, Kobayashi H, Van Uden J, Nguyen MD, Kornbluth RS, Raz E. 
Enhancement of antigen-presenting cell surface molecules involved in cognate 
interactions 
by 
immunostimulatory 
DNA 
sequences. 
Int 
Immunol. 
1999 
Jul;11(7):1111-8.
[18]
Gelman AE, Zhang J, Choi Y, Turka LA. Toll-like receptor ligands directly promote 
activated CD4+ T cell survival. J Immunol. 2004 May 15;172(10):6065-73.
[19]
Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. 
Nat Immunol. 2004 Oct;5(10):987-95.
[20]
Marshall JD, Fearon KL, Higgins D, Hessel EM, Kanzler H, Abbate C, et al. Superior 
activity of the type C class of ISS in vitro and in vivo across multiple species. DNA 
Cell Biol. 2005 Feb;24(2):63-72.
[21]
Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, et. al. A Guide to Rational 
Dosing of Monoclonal Antibodies.  Clin Pharmacokinet. 2012;51(2):119-135.
[22]
Wang DD, Zhang S, Zhao H, Men AY, Parivar K.  Fixed dosing versus body size-
based dosing of monoclonal antibodies in adult clinical trials.  J Clin Pharmacol. 
2009;49:1012-1024.
[23]
Hervas-Stubbs S, Perez-Gracia JL, Rouzaut A, Sanmamed MF, Le Bon A, Melero I. 
Direct effects of type I interferons on cells of the immune system. Clin Cancer Res. 
2011 May 1;17(9):2619-27.
[24]
Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, et al. Report of 
an international workshop to standardize response criteria for non-Hodgkin's 
lymphomas. J Clin Oncol 2010;17(4):1244-53.
[25]
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. 
Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-86.
[26]
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. 
Developing a common language for tumor response to immunotherapy: immune-
related response criteria using unidimensional measurements. Clin Cancer Res. 2013 
Jul 15;19(14):3936-43.
[27]
Swerdlow SH, Campo E, Harris NL, Jaffe, ES, Pileri SA, Stein H, editors. WHO 
classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: 
International Agency for Research on Cancer (IARC); c2008. Chapter 10, Mature B-
cell neoplasms: primary mediastinal (thymic) large B-cell lymphoma; p. 250-1.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.3 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
 
 
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mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
 
 
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through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).’]
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for
12.3
IRBs/IECs and Investigational Site Staff
 
 
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ECOG Performance Status
12.4
GRADE ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655
http://ecog-acrin.org/resources/ecog-performance-status
 
 
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
12.5
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.htm)
 
 
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List of Abbreviations and Definitions of Terms
12.6
Abbreviation or Term
Definition
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BCG
Bacillus Calmette-Guérin
BOR
best overall response 
CBC
complete blood count
CpG
Cytidine-phospho-guanosine
Cr
creatinine
CrCl
creatinine clearance 
CFR
Code of Federal Regulations
CR
complete response, complete remission
CRF
case report form
CRO
Contract Research Organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DAMPs
damage-associated molecular patterns
DCR
disease control rate
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG 
Eastern Cooperative Oncology Group 
EOT
end of treatment
eCRF
electronic case report form
EDC
electronic data capture
FDA
United States Food and Drug Administration
FIH
first in human 
FSH
follicle stimulating hormone 
GCP
good clinical practice
GFR
Glomerular Filtration Rate
HCV
hepatitis C virus
Hgb
hemoglobin
 
 
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Abbreviation or Term
Definition
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation
IL
human interleukin
IFN-γ
interferon gamma 
IRB/IEC
Institutional Review Board/Independent Ethics Committee
LDH
lactate dehydrogenase
mAB
monoclonal antibody 
MAD
maximum administered dose
MTD
maximum tolerated dose
NHV
normal healthy volunteers 
NOAEL
no-observable adverse effect level 
NOEL
no-observable effect level 
ODNs
oligodeoxynucleotides
ORR
objective response rate  
OS
overall survival 
PAMPs
pathogen-associated molecular patterns
PD
pharmacodynamics
PET
Positron Emission Tomography
PFS
progression-free survival 
PK
pharmacokinetics
PR
partial response, partial remission
RPTD
recommended phase 2 dose
RCC
renal cell  carcinoma 
SAE
serious adverse event 
SCCHN
squamous cell cancer of head and neck
SD
standard deviation
SLE 
systemic lupus erythematosus 
TPI
toxicity probability interval
TLR
toll-like receptor
TV
tumor volume 
 
 
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13.0
SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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