Clinical trial NCT03713320
Conditions: Cutaneous T-Cell Lymphoma/Mycosis Fungoides
Keywords: SOLAR Cutaneous T-cell Lymphoma CTCL Mycosis Fungoides Lymphoma Lymphoma, T-cell Lymphoma, T-cell, cutaneous Lymphoma, Non-Hodgkin Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Neoplasms MicroRNAs Vorinostat Histone Deacetylase Inhibitors
Sponsor: miRagen Therapeutics, Inc.
Start date: 2019-04-02; Completion date: 2020-12-01
Enrollment: 37 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of this clinical trial is to study the efficacy and safety of cobomarsen (also known as MRG-106) for the treatment of cutaneous T-cell lymphoma (CTCL), mycosis fungoides (MF) subtype. Cobomarsen is designed to inhibit the activity of a molecule called miR-155 that may be important to the growth and survival of MF cancer cells. The study will compare the effects of cobomarsen to vorinostat, a drug that has been approved for the treatment of CTCL in the United States and several other countries.

Participants in the clinical trial will be randomly assigned to receive either weekly doses of cobomarsen by injection into a vein or daily oral doses of vorinostat. Participants will continue on their assigned treatment as long as there is no evidence of progression of their cancer. The effects of treatment will be measured based on changes in skin lesion severity, as well as the length of time that the subject's disease remains stable or improved, without evidence of disease progression. The safety and tolerability of cobomarsen will be assessed based on the frequency and severity of observed side effects.

Participants assigned to receive vorinostat who experience progression of their disease during their participation in this study may have the option to be treated with cobomarsen in an open-label, crossover arm of the same study if they meet the entry criteria for that part of the study.

Detailed description:
Study Design:

Subjects will be randomly assigned in a 1:1 ratio to receive either cobomarsen or vorinostat. Approximately 126 subjects (63 per arm) are expected to be enrolled. Cobomarsen will be administered in the clinic by 2-hr intravenous infusion on Days 1, 3, 5 and 8, and weekly thereafter. Vorinostat will be dispensed to study subjects and taken as a daily oral dose according to the manufacturer's labeled dosing instructions. Treatment will continue until the subject becomes intolerant, develops clinically significant side effects, progresses, or the trial is terminated. An interim analysis will be conducted after approximately 40 subjects have been followed for a minimum of approximately 6 months. Enrollment will be suspended until the completion of the interim analysis.

Arms: arm 1: Cobomarsen will be administered by intravenous 2-hour infusion at a dose of 282 mg on Days 1, 3, 5, 8, and weekly thereafter arm 2: Vorinostat will be administered orally at a dose of 400 mg (four 100-mg capsules) once daily with food, at approximately the same time each day.
Interventions: intervention 1: Cobomarsen intervention 2: Vorinostat
Intervention descriptions: intervention 1: At least weekly doses of cobomarsen (282 mg) throughout study treatment period intervention 2: Daily doses of vorinostat throughout study treatment period

Protocol documents:
Prot_SAP_000.pdf: 
Proprietary and Confidential 
CLINICAL TRIAL PROTOCOL 
SOLAR: A Phase 2, Randomized, Open-label, Parallel-group, Active 
Comparator, Multi-center Study to Investigate the Efficacy and Safety of 
Cobomarsen (MRG-106) in Subjects with Cutaneous T-Cell Lymphoma 
(CTCL), Mycosis Fungoides (MF) Subtype  
Protocol Number:  MRG106-11-201 
EUDRACT NUMBER 2018-000727-13 
Version 4.0 
10 February 2020 
miRagen Therapeutics, Inc. 
6200 Lookout Road 
Boulder, CO 80301, USA 
CONFIDENTIALITY STATEMENT 
The information contained in this protocol is provided to you in confidence, for review by you, your 
staff, and any applicable regulatory authority or institutional review committee.  It is understood that 
this information may not be disclosed to any other party, in any form, without prior written 
authorization from miRagen Therapeutics, Inc. except to the extent necessary to obtain informed 
consent from the persons to whom the study treatment may be administered. 


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STATEMENT OF COMPLIANCE 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, and clinical research guidelines established by the United States 
Code of Federal Regulations (21 CFR Parts 50, 56, and 312), the European Clinical Trials 
Directive 2001/20/EC and implementing national regulations, the European Clinical Trials 
Regulation No. 536/2014 (upon implementation), and the International Conference on 
Harmonization (ICH) E6(R2) Guideline for Good Clinical Practice.   




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INVESTIGATOR AGREEMENT 
I confirm that I have read and understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the Sponsor, and agree to the following: 
•
To conduct this trial in accordance with the design and provisions of this protocol
•
To await IRB/IEC approval of the protocol and informed consent form before initiating
enrollment into the study
•
To ensure that the requirements for obtaining informed consent are met and to obtain
informed consent from subjects before their enrollment into the study
•
To provide sufficient and accurate financial disclosure and to update this information if
any relevant changes occur during the investigation and for one year following the
completion of the study
•
To collect and record data as required by this protocol into the case report form
•
To maintain the confidentiality of all information received or developed in connection
with this protocol
•
To conduct this trial in accordance with the International Conference on Harmonization
(ICH) Good Clinical Practice (GCP), the Declaration of Helsinki, and applicable
regulatory requirements
•
To permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s)
by providing direct access to source data/documents
•
To prepare annual, final and adverse event reports as required by this protocol and by
regulation under 21 CFR 312.64
•
To maintain study documentation for the period of time required as stipulated in the
protocol
•
To report all adverse events to miRagen Therapeutics, Inc. or Authorized Representative
within the timeframe specified
•
To report all serious adverse events immediately and not later than 24 hours after
becoming aware of the event as directed in the protocol
•
To comply with the provisions of the Clinical Trial Agreement to which I will be a
signatory, including but not limited to, the disclosure or publication of data collected
during this trial, as stipulated in that agreement.
Signature of Investigator 
Date 
Investigator Name (print or type) 
Site Number 


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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE .............................................................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
INVESTIGATOR AGREEMENT ...............................................................................................4 
TABLE OF CONTENTS ..............................................................................................................5 
LIST OF TABLES .......................................................................................................................11 
LIST OF FIGURES .....................................................................................................................11 
LIST OF ABBREVIATIONS .....................................................................................................12 
PROTOCOL SYNOPSIS ............................................................................................................15 
1 
KEY STUDY CONTACTS .................................................................................................29 
2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ........................29 
2.1 
Background Information ..................................................................................................29 
2.1.1 Cutaneous T-cell Lymphoma .....................................................................................29 
2.1.2 Human microRNA-155-5p ........................................................................................31 
2.1.3 Investigational Product: Cobomarsen ........................................................................32 
2.1.4 Active Control: Vorinostat .........................................................................................37 
2.2 
Scientific Rationale and Dose Selection ..........................................................................37 
2.3 
Potential Risks and Benefits ............................................................................................39 
2.3.1 Known Potential Risks of Cobomarsen .....................................................................39 
2.3.2 Known Potential Benefits of Cobomarsen .................................................................39 
3 
STUDY OBJECTIVES AND ENDPOINTS ......................................................................39 
3.1 
Objectives ........................................................................................................................39 
3.1.1 Primary Objective ......................................................................................................39 
3.1.2 Secondary Objectives .................................................................................................40 
3.2 
Endpoints .........................................................................................................................40 
3.2.1 Primary Endpoint .......................................................................................................40 
3.2.2 Secondary Endpoints .................................................................................................40 
4 
STUDY DESIGN ..................................................................................................................42 
4.1 
Randomized Period ..........................................................................................................42 
4.2 
Crossover Period ..............................................................................................................43 
4.3 
Treatments Administered .................................................................................................45 
4.3.1 Research Home Infusions ..........................................................................................46 


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5 
ENROLLMENT, DISCONTINUATION AND WITHDRAWAL OF STUDY 
SUBJECTS ...........................................................................................................................46 
5.1 
Randomized Period Entry Criteria ...................................................................................46 
5.1.1 Inclusion Criteria, Randomized Period ......................................................................46 
5.1.2 Exclusion Criteria, Randomized Period .....................................................................47 
5.2 
Crossover Period Entry Criteria .......................................................................................51 
5.2.1 Inclusion Criteria, Crossover Period ..........................................................................51 
5.2.2 Exclusion Criteria, Crossover Period .........................................................................52 
5.3 
Lifestyle Guidelines .........................................................................................................53 
5.3.1 Contraception Guidelines ...........................................................................................53 
5.3.2 Exercise Guidelines ...................................................................................................54 
5.4 
Subject Discontinuation or Withdrawal from Study ........................................................55 
5.4.1 Reasons for Subject Discontinuation or Withdrawal of Consent ..............................55 
5.4.2 Procedures for Subject Discontinuation or Withdrawal ............................................56 
6 
STUDY PRODUCTS ...........................................................................................................56 
6.1 
Study Product(s) Management .........................................................................................56 
6.1.1 Acquisition .................................................................................................................56 
6.1.2 Formulation, Appearance, Packaging, and Labeling .................................................56 
6.1.3 Storage and Stability ..................................................................................................57 
6.1.4 Accountability ............................................................................................................57 
6.2 
Dosage, Preparation and Administration of Study Products............................................57 
6.2.1 Dose and Regimen, Randomized Period....................................................................57 
6.2.2 Dose and Regimen, Crossover Period .......................................................................58 
6.2.3 Method of Assignment to Treatment .........................................................................58 
6.2.4 Dose Preparation and Administration ........................................................................58 
6.2.5 Assessment of Treatment Adherence .........................................................................58 
7 
STUDY PROCEDURES .....................................................................................................58 
7.1 
Clinical Assessments .......................................................................................................59 
7.1.1 Medical History .........................................................................................................59 
7.1.2 CTCL Staging ............................................................................................................59 
7.1.3 Prior MF Treatments ..................................................................................................59 
7.1.4 Vital Signs ..................................................................................................................60 


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7.1.5 Physical Examination .................................................................................................60 
7.1.6 ECOG Performance Status ........................................................................................60 
7.1.7 Prior and Concomitant Medications ..........................................................................61 
7.2 
Safety Assessments ..........................................................................................................65 
7.2.1 Adverse Events ..........................................................................................................65 
7.2.2 Clinical Laboratory Assessments ...............................................................................65 
7.2.3 Electrocardiograms ....................................................................................................68 
7.3 
Pharmacokinetic Sampling ..............................................................................................69 
7.4 
Pharmacodynamic and Anti-Drug Antibody Sampling ...................................................69 
7.4.1 Blood Sample Collection ...........................................................................................69 
7.5 
Efficacy Assessments .......................................................................................................70 
7.5.1 Response and Disease Progression Evaluations and mSWAT ..................................70 
7.6 
Screening Staging Assessments .......................................................................................72 
7.6.1 mSWAT Assessments ................................................................................................72 
7.6.2 Radiological Imaging (Lymph Nodes and Viscera Components) .............................72 
7.6.3 Flow Cytometry (Blood Component) ........................................................................72 
8 
STUDY SCHEDULE (RANDOMIZED PERIOD) ...........................................................73 
8.1 
Screening for the Randomized Period (Day -28 to Day -1) .............................................73 
8.2 
Randomized Period ..........................................................................................................75 
8.2.1 Day 1 (First Day of Study Treatment) .......................................................................75 
8.2.2 Day 2 ..........................................................................................................................76 
8.2.3 Day 3 (+ 1 Day) .........................................................................................................77 
8.2.4 Day 5 (± 1 Day) .........................................................................................................77 
8.2.5 Day 8 (± 1 Day) .........................................................................................................78 
8.2.6 Day 15 (± 1 Day) .......................................................................................................78 
8.2.7 Day 22 (± 2 Days) ......................................................................................................79 
8.2.8 Day 29 (± 3 Days) ......................................................................................................79 
8.2.9 Weekly Assessments Starting at Week 6 (± 3 Days) .................................................80 
8.2.10 Week 7 Visit (± 3 Days) (for Vorinostat Subjects only)............................................81 
8.2.11 Every-4-Week Assessments from Weeks 9 through 81, then Every-8-Week 
Assessments Thereafter (± 3 Days) ...........................................................................81 
8.3 
Post-treatment ..................................................................................................................82 


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8.4 
End of Treatment Visit .....................................................................................................83 
8.5 
Long-term Follow-up for Subjects Who Have Not Progressed at the Time of End of 
Treatment Visit ................................................................................................................83 
8.5.1 Every-4-Week Assessment through Week 81, then Every-8-Week Assessments 
Thereafter (± 3 Days) .................................................................................................84 
8.6 
Follow-up Visit 28 ± 5 days after the End of Treatment or Early Termination ..............84 
9 
CROSSOVER PERIOD ......................................................................................................85 
9.1 
Crossover Period Design ..................................................................................................85 
9.2 
Crossover Study Schedule ...............................................................................................85 
9.2.1 Crossover Screening Period (Day -28 to Day -1) ......................................................86 
9.2.2 Crossover Active Treatment ......................................................................................88 
9.2.3 End of Treatment Visit ...............................................................................................93 
9.3 
Long-term Follow-up for Subjects Who Have Not Progressed at the Time of End of 
Treatment Visit ................................................................................................................94 
9.3.1 Every-4-Week Assessment through Week 81, then Every-8-Week Assessments 
Thereafter (± 3 Days) .................................................................................................94 
9.3.2 Follow-up Visit 28 ± 5 days after the End of Treatment or Early Termination ........94 
10 ASSESSMENT OF SAFETY ..............................................................................................95 
10.1 Specification of Safety Parameters ..................................................................................95 
10.2 Dose Modifications Interruptions and Stopping Rules ....................................................95 
10.2.1 Cobomarsen Interruptions or Permanent Discontinuations .......................................96 
10.2.2 Vorinostat Dose Modifications, Interruptions, or Permanent Discontinuations ........97 
10.3 Definition of Adverse Events ...........................................................................................99 
10.3.1 Adverse Event ............................................................................................................99 
10.3.2 Suspected Adverse Reaction ......................................................................................99 
10.3.3 Life-Threatening Adverse Event or Life-Threatening Suspected Adverse Reaction 99 
10.3.4 Serious Adverse Event or Serious Suspected Adverse Reaction ...............................99 
10.3.5 Unexpected Adverse Event or Unexpected Suspected Adverse Reaction ...............100 
10.3.6 Adverse Events of Special Interest ..........................................................................100 
10.4 Adverse Event Classification .........................................................................................101 
10.4.1 Relationship to Study Treatments ............................................................................101 
10.4.2 Severity ....................................................................................................................101 
10.5 Collection and Reporting of Adverse Events .................................................................102 


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10.5.1 Reporting of Adverse Events ...................................................................................102 
10.5.2 Follow-up of Adverse Events ..................................................................................103 
10.6 Collection and Reporting of Serious Adverse Events ....................................................103 
10.6.1 Initial Serious Adverse Event Reports .....................................................................103 
10.6.2 Follow-up of Serious Adverse Events .....................................................................104 
10.7 Post-Trial Adverse Events .............................................................................................104 
10.8 Pregnancy Reporting and Follow-up .............................................................................104 
10.9 Study Termination .........................................................................................................105 
10.10 End of Study Definition .................................................................................................105 
10.11 Emergency Sponsor Contact ..........................................................................................105 
11 TRIAL-SPECIFIC COMMITTEES ................................................................................106 
11.1 Data Monitoring Committee ..........................................................................................106 
11.2 Steering Committee .......................................................................................................106 
12 STATISTICAL CONSIDERATIONS .............................................................................106 
12.1 Statistical and Analytical Plans ......................................................................................106 
12.2 Study Hypotheses ...........................................................................................................106 
12.3 Analysis Datasets ...........................................................................................................107 
12.3.1 Intent to Treat Analysis Set (ITT) ............................................................................107 
12.3.2 Safety Set .................................................................................................................107 
12.3.3 Per Protocol Set (PPS) .............................................................................................107 
12.3.4 Pharmacokinetic Analysis Set (PKAS) ....................................................................108 
12.4 Statistical Methods and Sample Size Justification .........................................................108 
12.4.1 General Approach ....................................................................................................108 
12.4.2 Analysis of Demographics and Other Baseline Characteristics...............................108 
12.4.3 Analysis of the Primary Efficacy Endpoint .............................................................108 
12.4.4 Analysis of the Secondary Endpoints ......................................................................108 
12.4.5 Safety Analyses ........................................................................................................109 
12.4.6 Pharmacokinetic Analysis ........................................................................................110 
12.4.7 Planned Interim Analyses ........................................................................................110 
12.5 Sample Size Determination ............................................................................................111 
12.5.1 Primary Endpoint Sample Size ................................................................................111 
12.5.2 Key Secondary Endpoint Sample Size.....................................................................112 


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12.6 Measures to Minimize Bias............................................................................................112 
12.6.1 Randomization Procedures ......................................................................................112 
12.6.2 Evaluation of Success of Blinding ...........................................................................112 
12.6.3 Breaking the Study Blind .........................................................................................112 
13 DATA HANDLING AND RECORD KEEPING ............................................................112 
13.1 Study Files and Subject Source Documents ..................................................................112 
13.2 Data Collection Methods ...............................................................................................113 
13.3 Retention of Records ......................................................................................................113 
13.4 Protocol Deviations ........................................................................................................114 
14 QUALITY CONTROL AND QUALITY ASSURANCE ...............................................115 
15 ETHICS/PROTECTION OF HUMAN SUBJECTS ......................................................115 
15.1 Ethical Conduct of the Study .........................................................................................116 
15.2 Institutional Review Board/Independent Ethics Committee Review ............................116 
15.3 Informed Consent Process .............................................................................................116 
15.4 Confidentiality of Information .......................................................................................117 
15.5 Future Use of Stored Specimens ....................................................................................117 
16 PUBLICATION POLICY .................................................................................................117 
17 REFERENCES ...................................................................................................................119 
18 LIST OF APPENDICES ...................................................................................................124 
 


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LIST OF TABLES 
Table 1: 
Key Study Contacts................................................................................................29 
Table 2: 
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale ...........60 
Table 3: 
Medications Known to be Highly Protein-Bound in Blood ..................................61 
Table 4: 
Medications Known to Prolong QT Interval and/or Cause Torsades de Pointes ..63 
Table 5: 
Summary of Clinical Laboratory Tests ..................................................................67 
Table 6: 
ORR4 Events Required to Demonstrate Superiority in Skin Objective Response 
for Interim Analysis (p < 0.01) ............................................................................111 
 
LIST OF FIGURES 
Figure 1. SOLAR Study Design Schematic ...................................................................................42 
 


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LIST OF ABBREVIATIONS 
Abs 
Absolute 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BIC 
B-cell Integration Cluster 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
°C 
Degree(s) Celsius 
CFR 
Code of Federal Regulations  
cGMP 
Current Good Manufacturing Practice 
CK 
Creatine kinase 
Cmax 
Maximum plasma concentration 
CMH 
Cochran-Mantel-Haenzel 
CR 
Complete response 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CRR 
Complete response rate 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCL 
Cutaneous T-cell lymphoma 
CYP 
Cytochrome P450 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form  
GLDH 
Glutamate dehydrogenase 
°F 
Degree(s) Fahrenheit 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate dehydrogenase 
Ha 
Alternative hypothesis 
HDAC 
Histone deacetylase 


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HEENT 
Head, eyes, ears, nose, and throat 
HIV 
Human immunodeficiency virus 
Ho 
Null hypothesis 
JAK 
Janus kinase 
IBM 
Ideal body mass 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IL 
Interleukin 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IUD 
Intrauterine device 
IWRS 
Interactive Web Response System 
LDH 
Lactate dehydrogenase 
LNA 
Locked nucleic acid 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
Mycosis fungoides 
miRNA 
Micro ribonucleic acid 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
mSWAT 
Modified Severity Weighted Assessment Tool 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NK 
Natural killer 
ORR1 
Objective response rate of at least 1 month duration  
ORR4 
Objective response rate of at least 4 months duration 
PD 
Pharmacodynamic(s) 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PKAS 
Pharmacokinetic Analysis Set 
PPS 
Per Protocol Set 
PR 
Partial response 
PT 
Prothrombin time 
Q4W 
Every 4 weeks 
Q8W 
Every 8 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 


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RBC 
Red blood cell(s) 
RNA 
Ribonucleic acid 
ROA 
Routes of administration 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Steering Committee 
SS 
Sézary syndrome 
t1/2 
Terminal half-life 
TEAE 
Treatment-emergent adverse event 
Th 
T helper 
Tmax 
Time to maximum plasma concentration 
Treg 
Regulatory T-cells 
TSEBT 
Total skin electron beam therapy 
TSH 
Thyroid-stimulating hormone 
TTP 
Time to progression 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell(s) 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
Women of childbearing potential 


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PROTOCOL SYNOPSIS 
Sponsor: 
miRagen Therapeutics, Inc.  
Protocol No.: 
MRG106-11-201 
Title: 
SOLAR:  A Phase 2, Randomized, Open-label, Parallel-group, 
Active Comparator, Multi-center Study to Investigate the 
Efficacy and Safety of Cobomarsen (MRG-106) in Subjects with 
Cutaneous T-Cell Lymphoma (CTCL), Mycosis Fungoides (MF) 
Subtype  
Phase: 
Phase 2  
Investigational Product 
and Comparators: 
Investigational Product: cobomarsen 
The Sponsor will provide cobomarsen (141 mg/mL) in single-
dose stoppered glass vials as a liquid formulation in isosmotic 
phosphate buffer, pH 7.4 ± 0.5.  Cobomarsen will be 
administered by 2-hour intravenous infusion at a dose of 282 mg. 
Active Comparator: vorinostat 
Vorinostat is available as 100 mg capsules.  A 400 mg (four 
100 mg capsules) dose of vorinostat will be administered orally, 
once daily with food, per approved label dosing instructions for 
MF. 
Subjects with abnormal ALT/AST (> ULN) or bilirubin 
(> 1.0 × ULN) at Screening will start vorinostat dosing at 
300 mg (three 100-mg capsules) once daily with food, at 
approximately the same time each day, per dosing 
guidelines. 
Population: 
Males/females, ≥ 18 years of age, with a diagnosis of cutaneous 
T-cell lymphoma (CTCL), mycosis fungoides (MF) subtype 
Number of Subjects 
Planned: 
The planned total enrollment is approximately 126 subjects.  
Subjects will be randomized in a 1:1 ratio to receive cobomarsen 
or vorinostat. 
Duration of 
Participation: 
Estimated up to 365 days or longer, including: 28-day Screening,  
active treatment, and follow-up for progression. 
Anticipated Study 
Duration: 
Up to 36 months 


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Clinical Sites: 
Approximately 25 centers globally 
Objectives: 
Primary: 
The primary objective of the study is to evaluate the efficacy of cobomarsen in subjects with 
MF. 
Secondary: 
• Investigate the safety and tolerability of cobomarsen in subjects with MF. 
• Characterize the population pharmacokinetics (PK) of cobomarsen in subjects with 
MF.  
• During the crossover portion of the study: 
o Evaluate the efficacy, safety and tolerability of cobomarsen in subjects with 
MF who have shown disease progression following treatment with vorinostat. 
Endpoints: 
Primary: 
Primary Efficacy Evaluation:  
• Proportion of subjects achieving an objective skin response (complete response [CR] 
or partial response [PR]) of at least 4 months duration (ORR4) using the Modified 
Severity Weighted Assessment Tool (mSWAT) scoring. 
Secondary: 
Efficacy measures: 
• Progression-free survival (PFS).  
• Complete response rate (CRR). 
• Time to progression (TTP). 
• Time to maximal effect in skin (mSWAT). 
• Proportion of subjects achieving ≥ 50% improvement in mSWAT of at least 28-days 
duration (ORR1). 
• Proportion of subjects achieving ≥ 50% improvement in mSWAT from baseline at 28 
days and at 4 months. 
• Time to ≥ 50% improvement in mSWAT. 
• Duration of response in skin (no progression after achieving ≥ 50% improvement in 
mSWAT). 
• Change in pruritus medication utilization from baseline and incidence of pruritus 
medication utilization.  


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• 
During the crossover portion of the study:  
o Proportion of subjects achieving an objective skin response (complete response 
[CR] or partial response [PR]) of at least 4 months duration (ORR4) using the 
mSWAT scoring (see Appendix F). 
o Progression-free survival (PFS).  
o Complete response rate (CRR). 
o Time to progression (TTP). 
o Time to maximal effect in skin (mSWAT). 
o Proportion of subjects achieving ≥ 50% improvement in mSWAT of at least 
28-days duration (ORR1). 
o Proportion of subjects achieving ≥ 50% improvement in mSWAT from 
baseline at 28 days and at 4 months. 
o Time to ≥ 50% improvement in mSWAT. 
o Duration of response in skin (no progression after achieving ≥ 50% 
improvement in mSWAT). 
o Change in pruritus medication utilization from baseline and incidence of 
pruritus medication utilization.  
Safety and Tolerability Evaluations: 
• Incidence and severity of clinically significant adverse events (AEs) (including grade 3 
and 4 AEs, treatment-related AEs, serious adverse events [SAEs], and AEs requiring 
discontinuation), physical examination findings, changes in electrocardiograms 
(ECGs), changes in laboratory parameters and changes in vital signs. 
• Characterization of anti-drug antibody generation. 
Pharmacokinetic Evaluation: 
• Population PK parameters.  
• During the crossover portion of the study: 
o Pharmacokinetic Cmax and trough concentration analysis 
Study Design: 
This is a Phase 2, randomized, open-label, parallel-group, active comparator, multi-center 
study to assess the efficacy and safety of cobomarsen compared to vorinostat in subjects with 
MF.  The randomization will be stratified based on subjects with at least one skin tumor at 
Screening vs. no skin tumors at Screening.  Subjects will also be stratified based on prognostic 
factors (age at diagnosis > 60 years and lactate dehydrogenase [LDH] level > the upper limit 
of normal [ULN] at diagnosis) (Scarisbrick et al., 2015).  Subjects will be stratified based on 
having 0-1 vs 2 of these prognostic factors. 


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This study will have 2 periods, a randomized period and a crossover period.  Subjects who are 
on the vorinostat arm in the randomized period and have confirmed skin disease progression 
may elect to participate in the crossover period of the study.  
Randomized Period  
Approximately 126 subjects are expected to be enrolled.  An interim analysis will be 
conducted after approximately 40 subjects have been followed for a minimum of 
approximately 6 months; enrollment will be suspended after approximately 40 subjects have 
been enrolled until the completion of the interim analysis.  
Methodology: 
Subjects will be randomized in a 1:1 ratio to receive cobomarsen or vorinostat.  Subjects will 
undergo Screening lasting up to 28 days from the time of informed consent, followed by active 
treatment, and then follow-up for response and disease progression. 
Subjects will remain on their assigned study treatment until one of the following occurs: 
1. Disease progression, defined as either: 
a. Confirmed progression in skin  
b. Clinical progression in other compartments, documented by assessments (flow 
cytometry and/or CT scan) completed per investigator discretion  
c. Partial or complete skin response followed by a confirmed loss of skin response 
as defined by an increase of mSWAT of greater than the sum of nadir plus 50% 
baseline score. 
Progressions based on mSWAT will be confirmed by repeated measurement 28 days 
(±3 days) after the first determination of progression.   
If confirmed, the date of progression will be based on the first determination of 
progression.  Subjects will continue the study treatment until disease progression is 
confirmed.   
2. Subject meets one of the other treatment discontinuation criteria described in the 
protocol. 
Study Treatment and Assessments: 
Subjects will be treated and monitored in the outpatient setting for the duration of the study.  
On Day 1, subjects will visit the clinic to undergo baseline assessments.  Upon confirmation of 
eligibility and completion of all predose assessments, subjects will receive the first dose of 
study treatment (i.e., initiation of the randomized period) according to their randomized 
treatment assignment (cobomarsen or vorinostat).  Subjects randomized to cobomarsen will 
remain in the clinic for PK sample collection and subjects in both groups will be monitored for 
safety for 4 hours postdose. 


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All subjects will return to the clinic on Day 2 for study assessments and on Days 3, 5, 8, 15, 
22, and 29 for safety and study assessments.  The cobomarsen group will continue to receive 
study treatment weekly and undergo study assessments.  Infusions may be administered at 
satellite locations on dosing days without efficacy assessments. 
After approximately 4 months of receiving the infusions and provided there are no safety 
concerns, subjects receiving cobomarsen may have the option of receiving their infusions at 
home using a research home health care service.   
The vorinostat group will return to the clinic at Day 29, then weekly through Week 8 and 
every 4 weeks thereafter for study assessments. 
The following study treatments will be administered according to randomized treatment 
assignment: 
• Cobomarsen will be administered by intravenous 2-hour infusion at a dose of 282 mg 
on Days 1, 3, 5, 8, and weekly thereafter; 
• A 400 mg (four 100 mg capsules) dose of vorinostat will be administered orally, once 
daily with food, at approximately the same time each day.  
o Subjects with abnormal ALT/AST (> ULN) or bilirubin (> 1.0 × ULN) at 
Screening will start vorinostat dosing at 300 mg (three 100-mg capsules) once 
daily with food, at approximately the same time each day, per dosing 
guidelines.  
Safety assessments will include monitoring the incidence and severity of AEs and SAEs, 
physical examination findings, vital signs, ECG monitoring, and clinical laboratory 
assessments. 
Samples will be collected for PK in the cobomarsen group on Days 1, 2, 3, 5, 8, 15, 29, and 
every 4 weeks from Weeks 9 through 81, every 8 weeks thereafter, and at follow-up/end of 
treatment visit. 
mSWAT evaluations will be completed on Day 1 and Day 29, every 4 weeks through Week 
81, then every 8 weeks thereafter, and at the End of Treatment and Follow-up Visits. Every 
effort will be made to perform a final disease assessment for subjects who withdraw from the 
study early. 
Crossover Period 
After completing the randomized period, subjects that have confirmed skin disease 
progression on the vorinostat arm can be assessed for eligibility for the crossover period.  
Eligible subjects may elect to enter this optional crossover period and must sign an informed 
consent form to proceed.   


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Potential subjects will need to complete the crossover screening activities and meet the entry 
criteria prior to enrollment into the crossover period of the study.   
Subjects in the randomized period of the study who withdrew consent without confirmation 
of skin disease progression are not eligible to enroll in the crossover period. In addition, 
subjects who received any subsequent systemic therapy for MF following confirmed disease 
progression in the randomized period are not eligible for the crossover period.  
Study procedures completed at the End of Treatment visit in the randomized period may be 
used for screening assessments in the crossover period, depending on the timing of the 
assessments. Subjects who initiate Screening in the crossover period > 28 days after 
completing the randomized period will need to complete all of the crossover Screening 
procedures.  
Subjects will undergo Screening lasting up to 28 days from the time of the first screening 
procedure, followed by active treatment and follow-up for response and disease progression. 
Subjects will remain on cobomarsen until one of the following occurs: 
1. Disease progression, defined as either (see Appendix F):
a.
Confirmed progression in skin
b. Clinical progression in other compartments, documented by assessments (flow
cytometry and/or CT scan) completed per investigator discretion
c.
Partial or complete skin response followed by a confirmed loss of skin response
as defined by an increase of mSWAT of greater than the sum of nadir plus 50%
baseline score.
Progressions based on mSWAT will be confirmed by repeated measurement 
28 days (±3 days) after the first determination of progression.   
If confirmed, the date of progression will be based on the first determination of 
progression.  Subjects will continue cobomarsen until disease progression is 
confirmed. 
2. Subject meets one of the other treatment discontinuation criteria (see Section 5.4.1).
Cobomarsen will be administered by intravenous 2-hour infusion at a dose of 282 mg on Days 
1, 3, 5, 8, and weekly thereafter. 
Safety assessments will include monitoring the incidence and severity of AEs and SAEs, 
physical examination findings, vital signs, ECG monitoring, and clinical laboratory 
assessments. 
Blood samples will be collected for PK on Days 1 and 29, every 4 weeks through Week 81, 
every 8 weeks thereafter, and at the End of Treatment and Follow-up visits.   


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mSWAT evaluations will be completed on Days 1 and 29, every 4 weeks through Week 81, 
every 8 weeks thereafter, and at the End of Treatment and Follow-up visits. 
Entry Criteria:  
Randomized Period 
Main Criteria for Inclusion: 
1. Must provide written informed consent (signed and dated) and any authorizations 
required by law and be able to comply with all study requirements. 
2. Males or females, ≥ 18 years of age at the time of informed consent. 
3. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. 
4. Biopsy-proven CTCL, MF subtype. 
5. Clinical stage IB, II or III, with staging based on Screening assessments and following 
staging parameters set in this protocol (see Appendix H). 
6. Minimum mSWAT score of 10 at Screening (see Appendix F, Table F1). 
7. Receipt of at least one prior therapy for CTCL (per National Comprehensive Cancer 
Network [NCCN] guidelines for generalized skin involvement; e.g., topical, 
phototherapy, total skin electron beam therapy [TSEBT], or systemic therapy [see 
Appendix G]).  
8. Meets the following criteria per the central laboratory at Screening: 
a. Calculated creatinine clearance ≥ 40 mL/min using 24-hour creatinine clearance 
OR modified Cockcroft-Gault equation (using ideal body mass [IBM] instead of 
mass); 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × 
ULN; bilirubin ≤ 1.5 × ULN (except subjects with Gilbert’s Syndrome who may 
have bilirubin ≤ 3.0 × ULN following discussion with the Sponsor). 
9. Females who had a menstrual cycle within 2 years of Screening must have a negative 
serum pregnancy test at Screening and a negative urine pregnancy test on their first 
dosing day. 
10. Subjects of childbearing potential must agree to use highly effective methods of 
contraception as defined in the protocol. 
Main Criteria for Exclusion: 
1. Previous enrollment in a cobomarsen study. 
2. Prior therapy with vorinostat or other HDAC inhibitors, or contraindication to an 
HDAC inhibitor. 


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3. Sézary syndrome or mycosis fungoides with B2 involvement, defined as a documented 
history of B2 and/or B2 staging at the Screening visit.  B2 means T-cell clone in 
peripheral blood + one of the following at Screening:  
a. ≥ 1000 Sézary cells by direct examination OR  
b. ≥ 1000/µL CD4+ CD26- OR  
c. ≥ 1000/µL CD4+ CD7-  
4. Current evidence of large cell transformation (LCT), defined as > 25% of the 
lymphocytes at least 4 × the size of normal lymphocytes.  Current evidence refers to 
LCT diagnosis from biopsy performed within 4 months prior to randomization.  
Subjects with a history of LCT but with a negative current biopsy (within 4 months) 
are eligible, provided there is no clinical indication for chemotherapy.  
5. Evidence of enlarged peripheral or central lymph node(s) > 1.5 cm in the long diameter 
or > 1.0 cm in the short diameter, by radiographical imaging at Screening.  A subject 
with one or more enlarged lymph node(s) may be allowed, provided that a 
representative lymph node has been confirmed (via biopsy or positron emission 
tomography [PET] scan) to be N0-N2 or SUV ≤ 5 within the 3 months prior to Day 1, 
and there has not been an appearance of new abnormal lymph nodes since the biopsy 
or PET scan.  Subjects with uncharacterized enlarged lymph nodes (i.e. not confirmed 
by biopsy or PET scan) will not be allowed. 
6. Any palpable peripheral node, regardless of size, that on physical examination is firm, 
irregular, clustered, or fixed, unless histologically confirmed to be non-malignant. 
7. Evidence of visceral involvement related to MF at Screening. 
8. Recent history of alcoholism (within the past 1 year). 
9. Known or suspected substance abuse within the past 1 year. 
10. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE, version 5.0), grade 0 or 1. 
11. Receipt of any of the following treatments: 
• Macrolide or tetracycline antibiotics within 28 days prior to Screening; 
• More than 3 short courses (≤ 7 days) of prednisone equivalent > 10 mg per day 
within 8 weeks prior to Screening; however, a stable regimen of systemic 
prednisone equivalent to ≤ 10 mg per day (or steroid equivalent) is permitted; 
• Total skin electron beam therapy or radiotherapy within 4 weeks prior to Screening; 
• Investigational small molecule drug within 5 half-lives prior to Screening; 
• Investigational biologic drug within 5 half-lives prior to Screening; 
• Phototherapy within 4 weeks prior to Screening; 


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• Antibody-directed or immunoglobulin-based immune therapy or other monoclonal 
antibody therapies within 8 weeks prior to Screening; 
• Previous chronic (more than 20 days total) high potency topical corticosteroid use 
within 4 weeks of Screening.  Stable doses of low to medium potency topical 
corticosteroids are allowed; 
• Previous chronic (more than 20 days total) use of topical MF treatments (not listed 
in the bullets above) within 4 weeks prior to Screening; 
• Previous systemic MF treatments (not listed in the bullets above) within 4 weeks 
prior to Screening; 
• Previous treatment with an oligonucleotide. 
• Patients on chronic prophylactic (for prevention, more than 20 days per month) 
nonsteroidal antipruritic medications within 4 weeks of screening are excluded.  
Patients on symptomatic (for current symptoms) stable nonsteroidal antipruritic 
medications (dose and frequency remain the same for at least 1 month prior to 
screening) for symptomatic pruritus are allowed.   
12. Positive test for blood (including trace) on urinalysis considered by the investigator to 
be consistent with undiagnosed clinically significant renal pathology requiring further 
investigation.  
13. An active or uncontrolled infection defined as subjects who require systemic 
antibacterial, antiviral, or antifungal therapy within the last 7 days prior to Screening. 
14. Clinically significant liver disease within 1 year prior to Screening. 
15. Positivity for human immunodeficiency virus (HIV), Hepatitis B surface antigen, or 
Hepatitis C at the time of Screening, per central laboratory.  Subjects who are positive 
for Hepatitis C but have HCV RNA below the limit of quantitation, may be enrolled. 
16. Clinically significant anemia (hemoglobin < 8 g/dL), neutropenia (absolute neutrophil 
count [ANC] < 1000/mm3) or thrombocytopenia (platelets < 50,000/mm3) at 
Screening. 
17. Bleeding diathesis or unstable coagulopathy within 2 years prior to Screening. 
18. Previous or concurrent malignancy with the following exceptions: 
• Adequately treated basal cell or squamous cell carcinoma of the skin (adequate 
wound healing is required prior to study entry), 
• In situ carcinoma of the cervix, treated curatively and without evidence of 
recurrence for at least 3 years prior to the study, 
• Or other solid tumor treated curatively, and without evidence of recurrence for at 
least 3 years prior to study entry. 
19. Presence on ECG of QT interval corrected for heart rate using Fridericia’s formula 
(QTcF) > 450 msec for males or > 470 msec for females or > 480 msec for subjects 


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with bundle branch block, based on a mean of the triplicate ECG measurements 
collected at Screening.   
20. History of long QT syndrome and/or a history of persistent hypokalemia.  
21. History of deep vein thrombosis and/or pulmonary embolism within 8 weeks of 
Screening. 
22. Unwillingness to comply with study procedures, including follow-up, as specified by 
this protocol, or inability to communicate or cooperate fully with the Investigator. 
23. Lactating or pregnant. 
24. Major surgery within 4 weeks of first dose of study treatment.  
25. Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure, as defined by the New York Heart 
Association Functional Classification; or a history of myocardial infarction, unstable 
angina, or acute coronary syndrome within 6 months prior to enrollment. 
26. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
27. Unable to understand the purpose and risks of the study and to provide a signed and 
dated informed consent form (ICF) and authorization to use protected health 
information (in accordance with national and local subject privacy regulations). 
28. Psychiatric illness, disability or social situation that would compromise the subject’s 
safety or ability to provide consent, or limit compliance with study requirements. 
29. Clinically significant abnormalities in medical history, physical examination, or 
laboratory values, which, in the opinion of the Investigator, would make the subject 
unsuitable for inclusion in the study.  
30. History of intolerance, or adverse or allergic reactions to oligonucleotide products 
and/or phosphate buffer solutions. 
Crossover Period  
Main Criteria for Inclusion: 
1. Must provide or has provided written informed consent for the crossover period 
(signed and dated), and any authorizations required by law and be able to comply with 
all study requirements. 
2. Must have participated in the comparator arm of the randomized period and completed 
the randomized period (confirmed disease progression in skin). Subjects who 
discontinued from the randomized period of SOLAR for any reason other than 
confirmed skin disease progression on the comparator arm are not eligible. 


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3. Meets the following criteria per the central laboratory at Screening:
a.
Calculated creatinine clearance ≥ 40 mL/min using 24-hour creatinine
clearance OR modified Cockcroft-Gault equation (using ideal body mass
[IBM] instead of mass).
b. AST and ALT ≤ 2.5 × the ULN; bilirubin ≤ 1.5 × ULN (except subjects with
Gilbert’s Syndrome who may have bilirubin ≤ 3.0 × ULN following discussion
with the Sponsor).
4. Females who had a menstrual cycle within 2 years of Screening must have a negative
serum pregnancy test at Screening and a negative urine pregnancy test on their first
dosing day.
5. Subjects of childbearing potential must agree to use highly effective methods of
contraception as defined in Section 5.3.1.
Main Criteria for Exclusion: 
1. Sézary syndrome or mycosis fungoides with B2 involvement, defined as a documented
history of B2 and/or B2 staging at the Screening visit. B2 means T-cell clone in
peripheral blood + one of the following at Screening:
a.
≥ 1000/µL Sézary cells by direct examination OR
b. ≥ 1000/µL CD4+ CD26- OR
c.
≥ 1000/µL CD4+ CD7-
2. Current evidence of large cell transformation (LCT), defined as >25% of the
lymphocytes at least 4 x the size of normal lymphocytes. Current evidence refers to
LCT diagnosis from biopsy performed within 4 months prior to dosing in the crossover
period.  Subjects with a history of LCT but with a negative current biopsy (within 4
months) are eligible, provided there is no clinical indication for chemotherapy.
3. History of visceral involvement related to MF at Screening.
4. Unresolved toxicities from prior vorinostat treatment, defined as having not resolved to
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE, version 5.0), grade 0 or 1.
5. Receipt of any of the following treatments:
•
Macrolide or tetracycline antibiotics within 28 days prior to Screening;
•
More than 3 short courses (≤ 7 days) of prednisone equivalent > 10 mg per day
within 8 weeks prior to Screening; however, a stable regimen of systemic
prednisone equivalent to ≤ 10 mg per day (or steroid equivalent) is permitted;
•
Any CTCL systemic therapy after completion of the randomization period and
prior to Day 1 for the crossover period.


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6. Positive test for blood (including trace) on urinalysis considered by the investigator to 
be consistent with undiagnosed clinically significant renal pathology requiring further 
investigation.   
7. An active or uncontrolled infection defined as subjects who require systemic 
antibacterial, antiviral, or antifungal therapy within the last 7 days prior to Screening. 
8. Clinically significant anemia (hemoglobin < 8 g/dL), neutropenia (absolute neutrophil 
count [ANC] < 1000/mm3) or thrombocytopenia (platelets < 50,000/mm3) at 
Screening. 
9. Presence on ECG of QT interval corrected for heart rate using Fridericia’s formula 
(QTcF) > 450 msec for males or > 470 msec for females or > 480 msec for subjects 
with bundle branch block, based on a mean of the triplicate ECG measurements 
collected at Screening. 
10. Unwillingness to comply with study procedures, including follow-up, as specified by 
this protocol, or inability to communicate or cooperate fully with the Investigator. 
11. Lactating or pregnant. 
12. Major surgery within 4 weeks of the first dose of study treatment. 
13. Unable to understand the purpose and risks of the study and to provide a signed and 
dated informed consent form (ICF) and authorization to use protected health 
information (in accordance with national and local subject privacy regulations). 
14. Clinically significant abnormalities in medical history, physical examination, or 
laboratory values that, in the opinion of the Investigator, would make the subject 
unsuitable for inclusion in the crossover period.  
15. History of intolerance, or adverse or allergic reactions to oligonucleotide products 
and/or phosphate buffer solutions. 
Statistical Methods: 
Details of statistical testing and data summaries will be described 
in the Statistical Analysis Plan, which will be finalized prior to 
database lock. 
The analysis of the primary efficacy endpoint is the proportion of 
subjects in the randomized period achieving an ORR4 in skin by 
mSWAT assessments.  The statistical test for the primary 
efficacy endpoint will be one-sided and will be split between the 
interim and final analysis and conducted using a total 0.025 
significance level.  Additional details of the primary efficacy 
endpoint in addition to the secondary efficacy endpoints will be 
detailed in the statistical analysis plan. 


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Safety analyses will include AEs, concomitant medications, 
laboratory data, physical examination, and ECG data. 
The following analysis populations will be defined: 
Intent to Treat Analysis Set (ITT) 
The ITT will include all randomized subjects who received at 
least one dose of study treatment (cobomarsen or vorinostat) and 
had at least one post-baseline assessment. 
Safety Set 
The Safety set will include all randomized subjects who received 
at least one dose of study treatment (cobomarsen or vorinostat). 
Per Protocol Set (PPS) 
The PPS will consist of all subjects randomized to the study, 
who received study treatment, and completed assessments 
necessary for the evaluation of the primary endpoint with no 
major protocol deviations that would affect endpoint analysis. 
Pharmacokinetic Analysis Set (PKAS) 
The PKAS will consist of subjects randomized to cobomarsen 
who received at least one dose of cobomarsen and had at least 
one post baseline PK sample taken and analyzed. 
Sample Size 
Justification:  
Total enrollment of approximately 126 subjects randomized 1:1 
provides greater than 80% power to detect a 25% difference 
(35% vs 10%) in the primary outcome, ORR4, between the 
investigational product and active comparator groups.  
Planned Interim 
Analysis: 
An interim analysis will be performed after approximately 
40 subjects are followed for a minimum of approximately 6 
months. 
Trial-specific 
Committees:  
Data Monitoring Committee 
The Data Monitoring Committee (DMC) will be responsible for 
reviewing safety data at regular intervals as well as to perform 
the interim analysis for futility.  A separate DMC Charter will be 
established that outlines DMC membership, precisely what data 
will be reviewed, along with the timing and frequency of the 
reviews.  DMC recommendation will be provided to the Sponsor 
in compliance with the DMC Charter.  


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Steering Committee  
The study Steering Committee (SC) will be appointed by the 
Sponsor prior to the initiation of the study.  The SC will include 
principal investigators from the study and Sponsor 
representatives.  The SC will be involved in the oversight of the 
study and will ensure transparent management of the study 
according to the protocol through recommending modifications 
as circumstances require.  Details on the role of the SC and 
working procedures will be defined in the SC Charter.   
Protocol Version and 
Date: 
Version 4.0, 10 February 2020 
 
 


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1 
KEY STUDY CONTACTS 
A contact information list for the Sponsor, Medical Monitor, Contract Research Organization 
(CRO), and selected service providers will be provided to each site.  General advice on protocol 
procedures should be obtained through the monitor assigned to each trial site.  Information on 
service providers is given in the study reference manual provided to each site. 
The following table lists contact information for investigator reports of serious adverse events 
(SAEs) and pregnancies occurring in study subjects. 
Table 1: 
Key Study Contacts 
Role 
Name and 
Affiliation 
Phone 
Email/Fax 
Serious 
Adverse Event 
and Pregnancy 
Reporting 
 
 
  
 
 
 
 
 
 
2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
Background Information 
2.1.1 
Cutaneous T-cell Lymphoma 
Cutaneous lymphomas of T-cell or B-cell origin comprise approximately 3.9% of all 
non-Hodgkin’s lymphomas.  Of these, approximately 53% are of T-cell origin (cutaneous T-cell 
lymphoma or CTCL).  The prevalence of the disease in the United States (US) is estimated at 
30,000 cases (Cutaneous Lymphoma Foundation 2014), although this estimate is acknowledged 
to be low due to the difficulty of diagnosis in the early stages of the disease.  The annual 
age-adjusted incidence of CTCL in the US is estimated at 6.4 to 9.6 cases per million people 
(Jawed et al. 2014a). 
CTCL presents in the skin with no evidence of extracutaneous disease at the time of diagnosis.  
Mycosis fungoides (MF) is the most prevalent subtype of CTCL, accounting for 50-70% of all 
primary cutaneous T-cell lymphomas.  The second most prevalent subtype is Sézary syndrome 
(SS), comprising 15% of CTCL cases.  MF is characterized by proliferation of atypical small- to 
medium-sized T lymphocytes with cerebriform nuclei that form patches, plaques, or nodular 
tumors in the epidermis.  MF typically affects older adults (median age of diagnosis: 55 to 


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60 years) and has an indolent clinical course where patches and plaques precede or are 
concurrent with the formation of tumors.  In some late tumor-stage cases, lymph node and 
visceral organ involvement are observed.  During tumor-stage MF, the dermal infiltrates become 
more diffuse and the epidermotropism of the atypical T-cells may be lost.  In contrast, SS is a 
more aggressive, leukemic form of CTCL, characterized by widespread redness and scaling of 
the skin (erythroderma), enlarged lymph nodes, and malignant cells in the peripheral circulation 
(Jawed et al. 2014a; Yamashita et al. 2012).  
The trigger for atypical T-cell epidermotropism is unclear.  Infectious agents such as the human 
T-cell lymphotropic virus type 1, Epstein-Barr virus, cytomegalovirus, and Staphylococcus 
aureus have been hypothesized as possible triggers, but a definitive link with any of these agents 
has not been established.  Chronic antigen stimulation, due to inflammation or trauma has also 
been hypothesized as a driver of CTCL pathogenesis (Burg et al. 2002; Tan et al. 1974), as have 
medications (Samimi et al. 2013).  Molecular analyses of tumor stage MF have revealed 
significant changes in gene expression compared to normal skin, inflamed skin and normal 
T-cells (van Kester et al. 2012), although the genetic or epigenetic origin of these differences in 
gene expression are unknown.  Advanced stage and erythrodermic MF patients can exhibit 
immunosuppression, as demonstrated histopathologically by loss of T-cell surface antigens in 
patients as the disease progresses (Jawed et al. 2014a; Jawed et al. 2014b).  Significant 
differences in the gene expression profiles of MF and SS cells have also been observed, 
consistent with a distinct pathogenesis for these variants of CTCL (Campbell et al. 2010; 
van Doorn et al. 2009). 
Currently there are no therapies that cure or prolong the survival of late-stage CTCL patients 
(Prince et al. 2009).  Treatments for CTCL patients at an early-stage of disease are palliative and 
non-aggressive with careful physician monitoring.  More advanced stage CTCL patients are 
typically treated with systemic drugs, such as retinoids (bexarotene) or histone deacetylase 
inhibitors (vorinostat or romidepsin), phototherapy or total skin electron beam irradiation.  
Patients with MF expressing the CD30 cell surface antigen may be eligible for treatment with 
brentuximab vedotin, an anti-CD30 monoclonal antibody-cytotoxic drug conjugate.  Multiagent 
chemotherapy or radiotherapy is reserved for patients with advanced, refractory disease and can 
result in partial disease regression but not full eradication.  Many treatments have serious side 
effects or lose efficacy over time.  Thus, there remains an unmet medical need for new therapies 
to treat CTCL. 


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2.1.2 
Human microRNA-155-5p 
2.1.2.1 
miR-155-5p in Normal Physiology and Immune Response 
miR-155-5p is a microRNA (miRNA) that, in humans, is encoded by the MIR155 host gene, 
MIR155HG.  This gene, also known as BIC (B-cell integration cluster) was originally identified 
as a common site for retroviral insertion in avian leukosis virus-induced lymphomas 
(Tam et al. 1997).  The 23 nucleotide, single-stranded miR-155-5p is encoded in exon 3 of the 
parent gene.  The sequence of miR-155-5p is highly conserved across species.  In non-human 
primates, the sequence of the microRNA is identical to the human sequence, while in mice and 
rats, the C at position 12 in the human sequence is replaced with a U in the rodent miRNA 
(miRbase, http://www.mirbase.org/). 
miR-155-5p is expressed in hematopoietic cells including B-cells, T-cells, monocytes and 
granulocytes (Landgraf et al. 2007).  miR-155-5p is an essential molecule in the control of both 
myelopoiesis and erythropoiesis.  This miRNA is highly expressed in hematopoietic 
stem-progenitor cells at an early stem-progenitor stage and blocks their differentiation into a 
more mature hematopoietic cell (e.g., lymphocyte, erythrocyte).  miR-155-5p expression 
progressively decreases as cells mature along these lineages and is ~200-fold lower in mature 
hematopoietic cells (Masaki et al. 2007; Lu et al. 2014; Burocchi et al. 2015; 
Kroesen et al. 2015). 
miR-155-5p plays an important role in mediating inflammatory and immune responses.  Mice 
lacking miR-155-5p show a normal number and distribution of T- and B-lymphocyte 
subpopulations, but display a deficient immune response, specifically in regulating T helper cell 
differentiation and the germinal center reaction to produce an optimal T-cell dependent antibody 
response (Rodriguez et al. 2007; Thai et al. 2007).  miR-155-5p controls differentiation of CD4+ 
T-cells into the T helper type 1 (Th1), Th2, and Th17 subsets of T helper cells, and affects the 
development of regulatory T-cells (Treg) (Baumjohann et al. 2013).  miR-155-5p also regulates 
effector and memory CD8+ T-cell responses to viral infection (Dudda et al. 2013; 
Gracias et al. 2013), as well as normal B-cell differentiation and antibody production.  In 
humans, miR-155-5p expression is low in nonlymphoid organs as well as in resting, naïve CD4+ 
T-cells.  miR-155-5p expression is greatly enhanced by antigen receptor stimulation of B- and 
T-cells (Tam 2001; Haasch et al. 2002; van den Berg et al. 2003; Rodriguez et al. 2007; 
Thai et al. 2007; Vigorito et al. 2007; Banerjee et al. 2010), and by Toll-like receptor agonist 
stimulation of macrophages and dendritic cells (Taganov et al. 2006; O’Connell et al. 2007; 
Ceppi et al. 2009; Mao et al. 2011).  MIR155HG activation involves both AP1- and NFB-
mediated mechanisms. 


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2.1.2.2 
miR-155-5p in Cutaneous T-Cell Lymphoma, Mycosis Fungoides Subtype 
miRNAs have been reported to be differentially expressed and potentially involved in the 
pathogenesis of CTCL.  miR-155-5p is among the miRNAs most up-regulated in MF 
(Kopp et al. 2013a; Kopp et al. 2013b).  Conversely, a distinct subset of dysregulated miRNAs is 
observed in SS, and miR155-5p is not up-regulated in this subtype of CTCL 
(Ballabio et al. 2010). 
Increased miR-155-5p in MF patient skin biopsies compared to control skin biopsies has been 
reported by several groups (van Kester et al. 2011; Maj et al. 2012; Kopp et al. 2013b; 
Moyal et al. 2013).  In one study, miR-155-5p levels were more than 4-fold higher in tumor-
stage biopsies compared to early MF biopsies (Moyal et al. 2013), suggesting that miR-155-5p 
levels may be correlated with disease progression.  In a second study to further define the 
specific cell types that express miR-155-5p, the miRNA was found by in situ hybridization to be 
expressed in both malignant and non-malignant T-cells in the CTCL lesions (Kopp et al. 2013b). 
miR-155-5p dysregulation is linked to signaling pathways that have been implicated in CTCL 
pathogenesis.  Specifically, malignant T-cells are reported to constitutively express the 
interleukin (IL)-2 receptor complex and the associated Janus kinases (JAK) that activate 
transcription via the STAT proteins.  miR-155-5p expression has been linked to the STAT5 
pathway in CTCL malignant T-cells in culture: chromatin immunoprecipitation experiments 
found STAT5 to be associated with the promoter of MIR155HG.  Inhibition of the JAK/STAT 
pathway resulted in down regulation of miR-155-5p expression, and treatment of cells with 
cytokines activating STAT5 resulted in increased miR-155-5p levels (Kopp et al. 2013a).  These 
results suggest that miR-155-5p may play a role in the pathogenesis of CTCL.  In support of this 
hypothesis, the authors showed that CTCL cells grown in the presence of an inhibitor to 
miR-155-5p had a reduction in cellular proliferation (Kopp et al. 2013a).  These data suggest that 
inhibition of miR-155-5p may have therapeutic effects by affecting the malignant T-cells of MF 
patients. 
2.1.3 
Investigational Product: Cobomarsen 
miRagen has identified an antagonist of miR-155-5p, cobomarsen (also referred to by the 
company code, MRG-106), by screening a panel of synthetic oligonucleotides for inhibitory 
activity as measured by target gene de-repression in cultured cells.  Cobomarsen is designed to 
interact with miR-155-5p through base-pairing complementarity to competitively inhibit the 
interaction of miR-155-5p with its mRNA targets.  


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In vitro pharmacology data demonstrate that exposure of cultured miR-155-5p-expressing MF 
cell lines to cobomarsen results in de-repression of miR-155-5p direct mRNA targets.  Further, 
two of three MF cell lines that were exposed to cobomarsen in culture showed significantly 
reduced proliferation and increases in protein markers of apoptosis.  An SS cell line that does not 
express high levels of miR-155-5p was not similarly responsive to the drug.  These data support 
the further evaluation of cobomarsen for its safety, tolerability and potential to provide 
therapeutic benefit in patients with MF.   
2.1.3.1 
Nonclinical Background 
miRagen has conducted in vitro and in vivo studies to investigate the pharmacology, 
pharmacokinetics (PK) and toxicology of cobomarsen.  Details of nonclinical studies conducted 
to date are provided in the cobomarsen (MRG-106) Investigator’s Brochure. 
Cobomarsen regulates miR-155-5p seed-matched target mRNAs in human CTCL cell lines, in a 
miR-155-5p-dependent and sequence-dependent manner.  Inhibition of miR-155-5p by 
cobomarsen reduces proliferation and cell survival, with induction of apoptosis, in human 
mycosis fungoides cell lines in a cobomarsen dose responsive manner.  Genome-wide expression 
analysis demonstrates that cobomarsen regulates numerous genes implicated in cell cycle and 
apoptosis, consistent with the pharmacologic impact on cell survival.  A subset of these genes 
has been identified as potentially translatable biomarkers to monitor cobomarsen activity in 
clinical samples. 
Experience with phosphorothioate and locked nucleic acid (LNA)-modified oligonucleotide 
drugs has been well described in the literature and much is understood about the relationship 
between toxicities observed in non-clinical studies and their potential clinical manifestations.  
Some of the class-related effects of oligonucleotides are known to be species specific, while 
others are related to PK, including plasma clearance time, and tissue accumulation and clearance.  
As such, monkeys are considered the most predictive toxicology species for humans because of 
their phylogenetic similarity to man and the ability to extrapolate plasma concentrations and 
clearance rates between primates and man on the basis of mg/kg dosing (Geary et al. 2003; 
FDA 2005; Yu et al. 2007). 
The toxicities observed in 28-day, repeat subcutaneous dose studies conducted in rats 
administered 10 cobomarsen doses of 3, 8 or 20 mg/kg and in monkeys administered 10 doses of 
3, 10 or 30 mg/kg were primarily those expected of LNA-modified phosphorothioate 
oligonucleotides.  The most notable adverse finding in rats was dose dependent (≥ 3 mg/kg) renal 
proximal tubule degeneration, characterized by vacuolation and fragmentation of the cytoplasm 


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of convoluted tubule epithelial cells, as well as changes in serum and urinary biochemical 
markers indicative of mild changes in renal function at doses ≥ 8 mg/kg.  These effects were 
largely reversed by 8 weeks after the last dose.  The rat is known to be more sensitive to renal 
toxicity from a variety of insults, including treatment with phosphorothioate oligonucleotides 
(Berman et al. 2014).  This is confirmed for cobomarsen as no similar changes in renal 
morphology or parameters of kidney function were observed in monkeys at doses up to and 
including 30 mg/kg. 
In monkeys, follicular atrophy in the thyroid gland with a concurrent decrease in thyroid organ 
weight was observed after subcutaneous administration of 30 mg/kg in males and ≥ 3 mg/kg in 
females.  Examination of thyroid-stimulating hormone (TSH) plasma levels demonstrated that 
this finding did not result in a significant difference in individual monkey’s TSH levels between 
predose Day 1 and Day 28.  Furthermore, no clinical indications of gross metabolic imbalance 
were observed in the monkeys over the course of the study.  Following the 28-day recovery 
period, there was evidence of partial recovery in both incidence and severity of the thyroid 
atrophy and organ weight.  No similar changes in the thyroid were observed in the rat at doses up 
to 20 mg/kg. 
In monkeys, a single 30 mg/kg dose administered as a subcutaneous injection or a 1-minute 
intravenous bolus injection was well tolerated, with no clinically significant effects on 
coagulation or complement activation.  Transient increases in liver transaminases (< 5-fold in 
aspartate aminotransferase [AST] and < 3-fold in alanine aminotransferase [ALT]), fibrinogen 
(< 2-fold) and creatine kinase (CK; < 5-fold intravenous and < 34-fold for subcutaneous dosing) 
values were observed 24 hours postdose but returned to within the normal range by Day 7, the 
next time point evaluated.  These clinical pathology findings were similar between intravenous 
bolus and subcutaneous dosing suggesting that the increased Cmax following intravenous 
injection did not contribute to the transient effects.  
Cobomarsen is considered to have a very low risk of genotoxicity based on literature reports and 
published regulatory opinion regarding the genotoxic potential of oligodeoxynucleotides 
(EMEA/CHMP/SWP/199726/2004) and LNA-containing oligonucleotides (Guérard et al. 2017).  
Cobomarsen has recently been evaluated for potential genotoxicity using standard in vitro testing 
methods, including the bacterial reverse mutation (Ames) assay and the micronucleus assay in 
human peripheral blood lymphocytes. The negative results of these studies confirm that the 
genotoxicity risk of cobomarsen is very low.  


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2.1.3.2 
Clinical Background 
Cobomarsen is being evaluated in a Phase 1 clinical trial to investigate its safety, tolerability and 
PK, as well as exploratory measures of pharmacodynamics (PD) and efficacy in subjects with 
CTCL, mycosis fungoides subtype. The study has also enrolled a limited number of subjects with 
chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and adult T-cell 
leukemia/lymphoma (ATLL).  Details of the Phase 1 clinical trial results are provided in the 
cobomarsen (MRG-106) Investigator’s Brochure. 
Study MRG106-11-101 has completed enrollment of subjects who had prior treatment for 
CTCL, mycosis fungoides subtype, stages I, II or III. As of 23 July 2019, 6 subjects with CTCL 
have been treated in Part A with 75 mg cobomarsen by intratumoral injection, and 37 subjects 
with CTCL have been treated in Part B with 300, 600 or 900 mg cobomarsen by subcutaneous 
injection, or intravenous infusion or injection. Of note, 2 subjects that had completed Part A were 
re-enrolled in Part B (with new unique identification numbers) following an 8-week washout 
period, as permitted in the protocol.  In addition, cobomarsen has been explored in other 
indications and at additional dose levels, as detailed in the Investigator’s Brochure. 
Overall, the study treatment has been well tolerated.  The majority of AEs have been mild or 
moderate in severity (grade 1 or 2) and there have been no safety signals indicative of clinically 
significant adverse effects on renal, liver, coagulation, platelets or thyroid function at the dosing 
regimens evaluated to date.  Two subjects experienced dose-limiting toxicities (pruritus and 
disease flare) resulting in study discontinuation, per protocol. Ninety-two percent (92%) of 
subjects treated with systemic administration showed improvement in skin disease as measured 
by the mSWAT score.  Sixty-three percent (63%) of subjects treated with 300 mg IV infusion (5 
of 8 subjects) achieved a partial response. Being well tolerated, this dose and mode of 
administration has been selected for the SOLAR trial. Full details on safety and efficacy of 
cobomarsen in CTCL are found in the Investigator’s Brochure. 
Pharmacodynamic effects of cobomarsen were assessed in lesion biopsies taken before and after 
treatment in both parts of the study.  In Part A of the clinical trial, high levels of cobomarsen 
(48-204 µg per gram of tissue) were detected in injected tumors 24 hours after the last dose.  
Accumulation of cobomarsen was also observed in a lesion distant from the site of injection at 
low levels (4 µg per gram of tissue).  Analysis of injected tumors also indicated an increased 
expression of several direct targets of miR-155, suggesting that the drug may be inhibiting its 
intended molecular target.  A similar pattern of gene regulation was observed in a lesion not 
directly injected with drug that had 4 µg cobomarsen per gram of tissue, suggesting the 
minimum effective dose level in skin lesions may be near this level.  After treatment, histology 


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revealed fewer cancerous cells or a reduction in cancer cell density or depth in most patients.  
Cobomarsen was also measured in skin biopsies collected from systemically-treated patients in 
Part B, at doses ranging from 300 to 900 mg.  Levels measured showed a mean of 12 µg per 
gram of tissue, with no clear dose response relationship.  Similar patterns of cobomarsen target-
gene expression changes were observed in patient biopsies after systemic dosing as were seen in 
the Part A lesions. 
In general, there has been no indication that cobomarsen is affecting the general leukocyte 
populations in patients that have been treated for up to 18 months except for an increase in 
natural killer (NK) cells in patients receiving 900 mg doses by multiple routes of administration.  
Analysis of the functional T-cell subsets have demonstrated that chronic dosing of cobomarsen 
does not affect the proportions of naïve, effector, and central or effector memory CD4+ and 
CD8+ T-cells, and the expected expansion and contraction of these effector cells occurs as would 
be expected during documented common respiratory or skin infections that occurred in several 
patients during the course of cobomarsen treatment.  For full details on pharmacodynamic effects 
of cobomarsen, please refer to the Investigator’s Brochure.  
Analysis of cobomarsen clinical PK data reveal biphasic plasma concentration time curves, 
indicative of multi-compartmental pharmacokinetics.  Apparent half-lives (t1/2) measured over 
the first 24-hours were similar for all routes of administration (ROA), ranging from 5.0 to 
8.2 hours.  Trough plasma samples collected once a month during prolonged administration of 
cobomarsen generally increased from the first extension cycle sample collection over the next 
one to two cycles, where they achieved maximum concentrations and then plateaued or declined 
over subsequent cycles. This may indicate steady state concentrations being achieved after 3 or 4 
cycles of dosing, or after approximately 12-16 weeks of regular cobomarsen administration, 
suggesting a terminal elimination half-life of approximately 2.5 to 3 weeks.  Despite the 
observed differences in Cmax and Tmax, dose normalized systemic exposure (AUC0-24/Dose) for 
all dose levels in the intratumoral, subcutaneous, and intravenous 2-hour infusion cohorts were 
similar, demonstrating good dose proportionality across those ROAs and dose concentrations.  
Accumulation ratios (multiple dose Cmax/first dose Cmax or multiple dose AUC0-24/first dose 
AUC0-24) indicated no significant accumulation at the 900 mg dose level for any route of 
administration. For full details on PK profile of cobomarsen in CTCL, please refer to the 
Investigator’s Brochure. 


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2.1.4 
Active Control: Vorinostat 
Vorinostat is a histone deacetylase (HDAC) inhibitor approved in the US, Canada and Australia 
for the treatment of CTCL.  This drug is not approved in Europe, and thus remains an 
investigational product for sites in that region.  Complete information on vorinostat, including 
risks, precautions and adverse effect profile are included in the package insert. 
2.2 
Scientific Rationale and Dose Selection 
Based on the nonclinical and clinical data collected to date, cobomarsen is hypothesized to offer 
clinical benefit to subjects with MF.  The current protocol is a randomized, open-label, parallel-
group, active comparator, multi-center, outpatient efficacy study designed to determine the 
efficacy, safety, and PK of cobomarsen compared with vorinostat in subjects with MF. 
Due to a lack of in vivo preclinical models to help define the optimal dose and route for 
cobomarsen administration, skin lesion biopsies have been collected from a subset of Phase 1 
human clinical trial participants dosed with cobomarsen by intralesional injection or systemically 
by the subcutaneous (SC) or intravenous (IV) routes at three dose levels. These samples are 
being analyzed for drug concentration and pharmacodynamic activity through molecular analysis 
of gene expression changes. The results obtained to date suggest that cobomarsen drug levels in 
individual lesions are highly variable from subject to subject, possibly due to differences in 
lesion morphology (patch, plaque, tumor) and the vascularity at each biopsy site.  The 
cobomarsen concentration in lesion biopsies collected 24 hours after the last dose ranged from 
48.6 to 206 µg/g after multiple 75 mg doses administered by direct intratumoral (IT) injection 
and from 3.10 to 53.2 µg/g after systemic administration of multiple doses by SC, IV infusion or 
IV bolus. Based on this small data set, there is not a strong correlation between dose or route of 
administration and skin biodistribution in systemically treated subjects. However, gene 
expression analysis demonstrates that concentrations as low as 3 µg/g tissue (0.6 µM) are 
sufficient to provide pharmacodynamically relevant exposure to the drug in the skin lesions of 
mycosis fungoides patients. The pharmacodynamic response to cobomarsen was evaluated by 
measuring the levels of approximately 600 mRNAs in skin lesion biopsies collected from study 
subjects before and after cobomarsen administration. This panel of mRNAs was identified in 
preclinical studies as potential direct or indirect targets of miR-155-5p based on their coordinated 
regulation in three MF cell lines following exposure to cobomarsen (refer to IB section 4.1.1.5).  
The data showed exposure-related changes in gene expression pathways expected to be 
modulated by inhibiting miR-155 and suggest that effective cobomarsen levels can be reached in 
MF lesions using either the subcutaneous or intravenous dosing routes and the 300 mg dose level 


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is sufficient to achieve the desired pharmacodynamic effects. For more details please see the 
Investigator’s Brochure. 
The dosing regimen of cobomarsen that will be administered in this study (282 mg active moiety, 
administered by intravenous infusion, equivalent to 300 mg of the sodium salt form) is based on 
above pharmacodynamic data, as well as safety and clinical efficacy data from Phase 1 study. 
This dose and mode of administration was well tolerated in the Phase 1 study in subjects with 
MF, who received systemic doses of up to 900 mg (sodium salt).  The 300 mg 2-hour 
intravenous infusion dose regimen was selected based on the generally favorable safety and 
tolerability data from the ongoing Phase 1 trial.  Additionally, compared to the 600 and 900 mg 
doses, the 300 mg dose appeared to have similar PD and clinical effects. For further efficacy 
data, please see Investigator’s Brochure. 
Vorinostat was selected as the active comparator.  As this clinical trial will be conducted at 
multiple sites within the European Union, North America and Australia, it is necessary to select 
an active comparator that is acceptable for use in all regions, but that is not first line of treatment 
in any region, as this would exclude many patients from participating in the study.  Vorinostat is 
more typically used as a second-line systemic treatment in the US, Canada and Australia and is 
not an approved therapy in the European Union.  Hence, the majority of the indicated study 
population in all regions will not have had previous exposure to the drug.  
Vorinostat is an HDAC inhibitor, a class of small molecules being evaluated in clinical trials for 
a number of different malignancies.  Vorinostat was the first HDAC inhibitor approved by the 
US Food and Drug Administration (FDA) in 2006 for treatment of cutaneous manifestations in 
patients with CTCL who have progressive, persistent or recurrent disease on or following two 
systemic therapies.  In two Phase 2 trials, vorinostat was safe and effective at an oral dose of 
400 mg/day with an overall response rate at one month of 31% in refractory advanced patients 
with CTCL, including large cell transformation and Sézary syndrome.  Vorinostat also has a 
significant symptomatic effect on pruritus, a major symptom in this patient population that 
directly impacts quality of life (Zinzani et al. 2016).  The most frequent side effects of vorinostat 
include gastrointestinal symptoms, fatigue and thrombocytopenia (Duvic and Ju, 2007).  The 
safety profile of the drug is well known, with clear guidelines for dose reduction to decrease 
gastrointestinal side effects (see vorinostat package insert).  Vorinostat is one of the drugs 
considered as standard of care in the US (Horwitz et al. 2018) and Australia for ≥ stage IB 
disease. 


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2.3 
Potential Risks and Benefits 
The potential risks and benefit of cobomarsen treatment are detailed in the Investigator’s 
Brochure.  The potential risks and benefit of vorinostat are in the package insert, which provides 
the full prescribing information for vorinostat in the US. 
2.3.1 
Known Potential Risks of Cobomarsen 
In clinical studies of phosphorothioate oligonucleotides, most of the observed side effects are 
believed to be hybridization-independent and related to the physical and chemical characteristics 
of this class of agents.  Certain adverse effects have been observed repeatedly during clinical 
investigations of systemically administered phosphorothioate oligonucleotide drugs, with the 
most commonly observed side effects including dermatological reactions at subcutaneous 
injection sites, constitutional symptoms such as fever, chills, and myalgia primarily associated 
with initial doses, and dose-dependent prolongation of activated partial thromboplastin time 
(aPTT) when the drugs are given intravenously, but not when administered subcutaneously.  In 
general, these effects are mild and transient, and resolve spontaneously. 
In the ongoing Phase 1 study of cobomarsen, there have been no safety signals indicative of 
clinically significant adverse effects on coagulation, platelets, or renal, liver, or thyroid function 
at the dosing regimens (300-900 mg) evaluated in CTCL patients. For full details of all 
cobomarsen Phase 1 safety data (across all indications) to date, refer to the current cobomarsen 
Investigator’s Brochure and any new safety updates.  
Potential risks of exaggerated pharmacology of miR-155 inhibition, specifically 
immunosuppression, have not been observed in the Phase 1 study in CTCL. 
2.3.2 
Known Potential Benefits of Cobomarsen 
The ongoing Phase 1 study in CTCL was designed primarily to evaluate safety, with efficacy 
collected as a secondary endpoint.  Preliminary evidence of antitumor activity has been observed 
and potentially outweighs the risks and warrants further investigation. 
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
3.1.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of cobomarsen in subjects with MF. 


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3.1.2 
Secondary Objectives 
Secondary study objectives are to: 
• Investigate the safety and tolerability of cobomarsen in subjects with MF. 
• Characterize the population PK of cobomarsen in subjects with MF.  
• During the crossover portion of the study: 
o Evaluate the efficacy, safety and tolerability of cobomarsen in subjects with MF 
who have shown disease progression following treatment with vorinostat. 
3.2 
Endpoints 
3.2.1 
Primary Endpoint 
Primary Efficacy Evaluation: 
• Proportion of subjects achieving an objective skin response (complete response [CR] or 
partial response [PR]) of at least 4 months duration (ORR4) using the mSWAT scoring 
(see Section 12.4.3 and Appendix F). 
3.2.2 
Secondary Endpoints 
Efficacy measures: 
• Progression-free survival (PFS).  
• Complete response rate (CRR). 
• Time to progression (TTP). 
• Time to maximal effect in skin (mSWAT). 
• Proportion of subjects achieving ≥ 50% improvement in mSWAT of at least 28-days 
duration (ORR1). 
• Proportion of subjects achieving ≥ 50% improvement in mSWAT from baseline at 28 
days and at 4 months. 
• Time to ≥ 50% improvement in mSWAT. 
• Duration of response in skin (no progression after achieving ≥ 50% improvement in 
mSWAT). 
• Change in pruritus medication utilization from baseline and incidence of pruritus 
medication utilization. 


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• During the crossover portion of the study: 
o Proportion of subjects achieving an objective skin response (complete response 
[CR] or partial response [PR]) of at least 4 months duration (ORR4) using the 
mSWAT scoring (see Appendix F). 
o Progression-free survival (PFS). 
o Complete response rate (CRR) 
o Time to progression (TTP). 
o Time to maximal effect in skin (mSWAT). 
o Proportion of subjects achieving ≥ 50% improvement in mSWAT of at least 
28-days duration (ORR1). 
o Proportion of subjects achieving ≥ 50% improvement in mSWAT from baseline 
at 28 days and at 4 months. 
o Time to ≥ 50% improvement in mSWAT. 
o Duration of response in skin (no progression after achieving ≥ 50% improvement 
in mSWAT). 
o Change in pruritus medication utilization from baseline and incidence of pruritus 
medication utilization. 
Safety and Tolerability Evaluations: 
• Incidence and severity of clinically significant AEs (including grade 3 and 4 AEs, 
treatment-related AEs, SAEs, and AEs requiring discontinuation), physical examination 
findings, changes in electrocardiogram (ECGs), changes in laboratory parameters and 
changes in vital signs. 
• Characterization of anti-drug antibody generation. 
Pharmacokinetic Evaluation: 
• Population PK parameters. 
• During the crossover portion of the study 
o Pharmacokinetic Cmax and trough concentration analysis 


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4 
STUDY DESIGN 
This is a Phase 2, randomized, open-label, parallel-group, active comparator, multi-center study 
to assess the efficacy and safety of cobomarsen compared to vorinostat in subjects with MF 
(Figure 1).  The randomization will be stratified based on subjects with at least one skin tumor at 
Screening vs. no skin tumors at Screening.  Subjects will also be stratified based on prognostic 
factors (age at diagnosis > 60 years and lactate dehydrogenase [LDH] level > the upper limit of 
normal [ULN] at diagnosis) (Scarisbrick et al., 2015).  Subjects will be stratified based on having 
0-1 vs 2 of these prognostic factors. 
This study will have 2 periods, a randomized period and a crossover period.  Subjects who are on 
the vorinostat arm in the randomized period and have confirmed skin disease progression may 
elect to participate in the crossover period of the study.  
4.1 
Randomized Period 
Approximately 126 subjects are expected to be enrolled.  An interim analysis will be conducted 
after approximately 40 subjects have been followed for a minimum of approximately 6 months; 
enrollment will be suspended after approximately 40 subjects have been enrolled until the 
completion of the interim analysis.    
Subjects will be randomized in a 1:1 ratio to receive cobomarsen or vorinostat.  Subjects will 
undergo Screening lasting up to 28 days from the time of informed consent, followed by active 
treatment, and then follow-up for response and disease progression. 
Figure 1. SOLAR Study Design Schematic 
 


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Subjects will remain on their assigned study treatment until one of the following occurs: 
1. 
Disease progression, defined as either (see Appendix F): 
a. Confirmed progression in skin 
b. Clinical progression in other compartments, documented by assessments (flow 
cytometry and/or CT scan) completed per investigator discretion 
c. Partial or complete skin response followed by a confirmed loss of skin response as 
defined by an increase of mSWAT of greater than the sum of nadir plus 50% baseline 
score. 
Progressions based on mSWAT will be confirmed by repeated measurement 28 days (±3 
days) after the first determination of progression.   
If confirmed, the date of progression will be based on the first determination of 
progression.  Subjects will continue the study treatment until disease progression is 
confirmed. 
2. Subject meets one of the other treatment discontinuation criteria (see Section 5.4.1). 
Safety assessments will include monitoring the incidence and severity of AEs and SAEs, 
physical examination findings, vital signs, ECG monitoring, and clinical laboratory assessments. 
Samples will be collected for PK in the cobomarsen group on Days 1, 2, 3, 5, 8, 15, 29, and 
every 4 weeks from Weeks 9 through 81, every 8 weeks thereafter, and at the follow-up/end of 
treatment visit. 
mSWAT evaluations will be completed on Days 1 and 29, every 4 weeks through Week 81, 
every 8 weeks thereafter, and at the End of Treatment and Follow-up visits. Every effort will be 
made to perform a final disease assessment for subjects who withdraw from the study early.  
4.2 
Crossover Period  
After completing the randomized period, subjects that have confirmed skin disease progression 
on the vorinostat arm can be assessed for eligibility for the crossover period.  Eligible subjects 
may elect to enter this optional crossover period and must sign an informed consent form to 
proceed.   
Potential subjects will need to complete the crossover screening activities and meet the entry 
criteria prior to enrollment into the crossover period of the study.   


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Subjects in the randomized period of the study who withdrew consent without confirmation of 
skin disease progression are not eligible to enroll in this period. In addition, subjects who 
received any subsequent systemic therapy for MF following confirmed disease progression in the 
randomized period are not eligible for the crossover period.  
Study procedures completed at the End of Treatment visit in the randomized period may be used 
for screening assessments in the crossover period, depending on the timing of the assessments. 
Subjects who initiate Screening in the crossover period > 28 days after completing the 
randomized period will need to complete all of the crossover Screening procedures.  
Subjects will undergo Screening lasting up to 28 days from the time of the first screening 
procedure, followed by active treatment and follow-up for response and disease progression.  
Subjects will remain on cobomarsen until one of the following occurs: 
1. Disease progression, defined as either (see Appendix F): 
a. Confirmed progression in skin 
b. Clinical progression in other compartments, documented by assessments (flow 
cytometry and/or CT scan) completed per investigator discretion 
c. Partial or complete skin response followed by a confirmed loss of skin response as 
defined by an increase of mSWAT of greater than the sum of nadir plus 50% baseline 
score. 
Progressions based on mSWAT will be confirmed by repeated measurement 28 days (±3 
days) after the first determination of progression.  If confirmed, the date of progression 
will be based on the first determination of progression.  Subjects will continue 
cobomarsen until disease progression is confirmed. 
2. Subject meets one of the other treatment discontinuation criteria (see Section 5.4.1). 
Safety assessments will include monitoring the incidence and severity of AEs and SAEs, 
physical examination findings, vital signs, ECG monitoring, and clinical laboratory assessments. 
Blood samples will be collected for PK on Days 1 and 29, every 4 weeks through Week 81, 
every 8 weeks thereafter, and at the End of Treatment and Follow-up visits.   
mSWAT evaluations will be completed on Days 1 and 29, every 4 weeks through Week 81, 
every 8 weeks thereafter, and at the End of Treatment and Follow-up visits.  


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4.3 
Treatments Administered 
Subjects will be treated and monitored in the outpatient setting for the duration of the study.   
Randomized Period 
On Day 1, subjects will visit the clinic to complete baseline assessments.  Upon confirmation of 
eligibility and completion of all predose assessments subjects will receive the first dose of study 
treatment (i.e., initiation of the randomized period) according to their randomized treatment 
assignment (cobomarsen or vorinostat).   
• Cobomarsen will be administered by intravenous 2-hour infusion at a dose of 282 mg on 
Days 1, 3, 5, 8, and weekly thereafter;  
• Vorinostat will be administered orally at a dose of 400 mg (four 100-mg capsules) once 
daily with food, at approximately the same time each day. 
o Subjects assigned to vorinostat with abnormal ALT/AST (> ULN) or bilirubin 
(> 1.0 × ULN) at Screening will start vorinostat dosing at 300 mg (three 100-mg 
capsules) once daily with food, at approximately the same time each day, per 
dosing guidelines.  
Subjects randomized to cobomarsen will remain in the clinic for PK sample collection and 
subjects in both groups will be monitored for safety 4 hours postdose. 
All subjects will return to the clinic on Day 2 for study assessments and on Days 3, 5, 8, 15, 22, 
and 29 for safety and study assessments.  The cobomarsen group will continue to receive study 
treatment weekly and undergo study assessments.  Infusions may be administered at satellite 
locations on dosing days without efficacy assessments. 
The vorinostat group will return to the clinic at Day 29, then weekly through Week 8 and every 
4 weeks thereafter for study assessments. 
Crossover Period 
On Day 1, subjects will visit the clinic to undergo baseline assessments.  Upon confirmation of 
eligibility and completion of all predose assessments, subjects will receive the first dose of 
cobomarsen (i.e., initiation of the crossover period) as a 2-hour intravenous infusion at a dose of 
282 mg. Subjects will remain in the clinic and will be monitored for safety for a minimum of 4 
hours postdose. 
Subjects will return to the clinic on Day 2 for study assessments and on Days 3, 5, and 8 for 
cobomarsen infusions and safety and study assessments.  Subjects will continue to receive 


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cobomarsen weekly and undergo study assessments. Infusions may be administered at satellite 
locations on dosing days without mSWAT assessments. 
4.3.1 
Research Home Infusions 
Randomized and Crossover Periods 
Subjects assigned cobomarsen in the randomized or crossover period of the study will have 
access to optional research home intravenous infusion services after 4 months of treatment with 
cobomarsen. In addition to completing at least 4 months of treatment at the study site, 
investigators must confirm the patient is suitable for home infusions based on the investigator’s 
clinical judgement. If a patient/site is deemed eligible for home infusion services, additional 
training of study site staff and coordination with the research home infusion vendor nurse will be 
required. 
Home infusions are optional to lighten the burden of the trial on eligible subjects. If site and/or 
IRB/IEC policies do not allow for the option of research home infusions, the option will not be 
presented to the subject. 
miRagen has chosen a Research Home Infusion Vendor to provide home infusion services in the 
study. Trained research nurses from the vendor will work in conjunction with the clinical sites’ 
staff to coordinate home infusion visits, facilitate the controlled management of investigational 
study drug, and transmit records from the home infusion visits to the clinical site staff. The 
research nurses will work collaboratively with the study site Principal Investigator and staff to 
identify, report, and manage adverse events documented during home visits. Detailed procedures 
for the research home infusion visits and the collection of study-related documentation during 
these visits are provided in the Off-Site Nursing Manual.  
5 
ENROLLMENT, DISCONTINUATION AND WITHDRAWAL OF 
STUDY SUBJECTS 
5.1 
Randomized Period Entry Criteria  
5.1.1 
Inclusion Criteria, Randomized Period 
Individuals must meet all of the following inclusion criteria to be eligible for participation in this 
study. 
1. Must provide written informed consent (signed and dated), and any authorizations 
required by law and be able to comply with all study requirements. 
2. Males or females, ≥ 18 years of age at the time of informed consent. 


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3. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. 
4. Biopsy-proven CTCL, MF subtype. 
5. Clinical stage IB, II, or III, with staging based on Screening assessments and following 
staging parameters set in this protocol (see Appendix H).   
6. Minimum mSWAT score of 10 at Screening (see Appendix F, Table F1). 
7. Receipt of at least one prior therapy for CTCL (per National Comprehensive Cancer 
Network [NCCN] guidelines for generalized skin involvement; e.g., topical, 
phototherapy, total skin electron beam therapy [TSEBT], or systemic therapy [see 
Appendix G]).  
8. Meets the following criteria per the central laboratory at Screening: 
a. Calculated creatinine clearance ≥ 40 mL/min using 24-hour creatinine clearance OR 
modified Cockcroft-Gault equation (using ideal body mass [IBM] instead of mass). 
b. AST and ALT ≤ 2.5 × the ULN; bilirubin ≤ 1.5 × ULN (except subjects with 
Gilbert’s Syndrome who may have bilirubin ≤ 3.0 × ULN following discussion with 
the Sponsor).  
9. Females who had a menstrual cycle within 2 years of Screening must have a negative 
serum pregnancy test at Screening and a negative urine pregnancy test on their first 
dosing day. 
10. Subjects of childbearing potential must agree to use highly effective methods of 
contraception as defined in Section 5.3.1. 
5.1.2 
Exclusion Criteria, Randomized Period 
Individuals who meet any of the following exclusion criteria are not to be enrolled in this study.  
1. Previous enrollment in a cobomarsen study. 
2. Prior therapy with vorinostat or other HDAC inhibitors, or contraindication to an HDAC 
inhibitor. 
3. Sézary syndrome or mycosis fungoides with B2 involvement, defined as a documented 
history of B2 and/or B2 staging at the Screening visit.  B2 means T-cell clone in 
peripheral blood + one of the following at Screening:  
a. ≥ 1000 Sézary cells by direct examination OR  


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b. ≥ 1000/µL CD4+ CD26- OR  
c. ≥ 1000/µL CD4+ CD7-  
4. Current evidence of large cell transformation (LCT), defined as > 25% of the 
lymphocytes at least 4 × the size of normal lymphocytes.  Current evidence refers to LCT 
diagnosis from biopsy performed within 4 months prior to randomization.  Subjects with 
a history of LCT but with a negative current biopsy (within 4 months) are eligible, 
provided there is no clinical indication for chemotherapy.  
5. Evidence of enlarged peripheral or central lymph node(s) > 1.5 cm in the long diameter 
or > 1.0 cm in the short diameter by radiographical imaging at Screening.  A subject with 
one or more enlarged lymph node(s) may be allowed, provided that a representative 
lymph node has been confirmed (via biopsy or positron emission tomography [PET]) 
scan) to be N0-N2 or SUV ≤ 5 within the 3 months prior to Day 1, and there has not been 
an appearance of new abnormal lymph nodes since the biopsy or PET scan.  Subjects 
with uncharacterized enlarged lymph nodes (i.e. not confirmed by biopsy or PET scan) 
will not be allowed. 
6. Any palpable peripheral node, regardless of size, that on physical examination is firm, 
irregular, clustered, or fixed, unless histologically confirmed to be non-malignant. 
7. Evidence of visceral involvement related to MF at Screening. 
8. Recent history of alcoholism (within the past 1 year). 
9. Known or suspected substance abuse within the past 1 year. 
10. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE, version 5.0), grade 0 or 1. 
11. Receipt of any of the following treatments: 
• Macrolide or tetracycline antibiotics within 28 days prior to Screening; 
• More than 3 short courses (≤ 7 days) of prednisone equivalent > 10 mg per day within 
8 weeks prior to Screening; however, a stable regimen of systemic prednisone 
equivalent to ≤ 10 mg per day (or steroid equivalent) is permitted; 
• Total skin electron beam therapy or radiotherapy within 4 weeks prior to Screening; 
• Investigational small molecule drug within 5 half-lives prior to Screening; 


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• Investigational biologic drug within 5 half-lives prior to Screening; 
• Phototherapy within 4 weeks prior to Screening; 
• Antibody-directed or immunoglobulin-based immune therapy or other monoclonal 
antibody therapies within 8 weeks prior to Screening; 
• Previous chronic (more than 20 days total) high potency topical corticosteroid use 
within 4 weeks of Screening.  Stable doses of low to medium potency topical 
corticosteroids are allowed; 
• Previous chronic (more than 20 days total) use of topical MF treatments (not listed in 
the bullets above) within 4 weeks prior to Screening; 
• Previous systemic MF treatments (not listed in the bullets above) within 4 weeks prior 
to Screening; 
• Previous treatment with an oligonucleotide. 
• Patients on chronic prophylactic (for prevention, more than 20 days per month) 
nonsteroidal antipruritic medications within 4 weeks of screening are excluded.  
Patients on symptomatic (for current symptoms) stable nonsteroidal antipruritic 
medications (dose and frequency remain the same for at least 1 month prior to 
screening) for symptomatic pruritus are allowed.   
12. Positive test for blood (including trace) on urinalysis considered by the investigator to be 
consistent with undiagnosed clinically significant renal pathology requiring further 
investigation.   
13. An active or uncontrolled infection defined as subjects who require systemic 
antibacterial, antiviral, or antifungal therapy within the last 7 days prior to Screening. 
14. Clinically significant liver disease within 1 year prior to Screening. 
15. Positivity for human immunodeficiency virus (HIV), Hepatitis B surface antigen, or 
Hepatitis C at the time of Screening, per central laboratory.  Subjects who are positive for 
Hepatitis C but have HCV RNA below the limit of quantitation, may be enrolled. 
16. Clinically significant anemia (hemoglobin < 8 g/dL), neutropenia (absolute neutrophil 
count [ANC] < 1000/mm3) or thrombocytopenia (platelets < 50,000/mm3) at Screening. 
17. Bleeding diathesis or unstable coagulopathy within 2 years prior to Screening. 


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18. Previous or concurrent malignancy with the following exceptions: 
• Adequately treated basal cell or squamous cell carcinoma of the skin (adequate 
wound healing is required prior to study entry), 
• In situ carcinoma of the cervix, treated curatively and without evidence of recurrence 
for at least 3 years prior to the study, 
• Or other solid tumor treated curatively, and without evidence of recurrence for at least 
3 years prior to study entry. 
19. Presence on ECG of QT interval corrected for heart rate using Fridericia’s formula 
(QTcF) > 450 msec for males or > 470 msec for females or > 480 msec for subjects with 
bundle branch block, based on a mean of the triplicate ECG measurements collected at 
Screening.   
20. History of long QT syndrome and/or a history of persistent hypokalemia. 
21. History of deep vein thrombosis and/or pulmonary embolism within 8 weeks of 
Screening. 
22. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or inability to communicate or cooperate fully with the Investigator. 
23. Lactating or pregnant. 
24. Major surgery within 4 weeks of first dose of study treatment. 
25. Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure, as defined by the New York Heart 
Association Functional Classification; or a history of myocardial infarction, unstable 
angina, or acute coronary syndrome within 6 months prior to enrollment. 
26. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
27. Unable to understand the purpose and risks of the study and to provide a signed and dated 
informed consent form (ICF) and authorization to use protected health information (in 
accordance with national and local subject privacy regulations). 
28. Psychiatric illness, disability or social situation that would compromise the subject’s 
safety or ability to provide consent, or limit compliance with study requirements. 


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29. Clinically significant abnormalities in medical history, physical examination, or 
laboratory values, which, in the opinion of the Investigator, would make the subject 
unsuitable for inclusion in the study.  
30. History of intolerance, or adverse or allergic reactions to oligonucleotide products and/or 
phosphate buffer solutions. 
5.2 
Crossover Period Entry Criteria 
5.2.1 
Inclusion Criteria, Crossover Period 
Individuals must meet all of the following inclusion criteria to be eligible for participation in the 
crossover period. 
1. Must provide or has provided written informed consent for the crossover period (signed 
and dated), and any authorizations required by law and be able to comply with all study 
requirements. 
2. Must have participated in the comparator arm of the randomized period and completed 
the randomized period (confirmed disease progression in skin). Subjects who 
discontinued from the randomized period of SOLAR for any reason other than confirmed 
skin disease progression on the comparator arm are not eligible. 
3. Meets the following criteria per the central laboratory at Screening: 
a. Calculated creatinine clearance ≥ 40 mL/min using 24-hour creatinine clearance 
OR modified Cockcroft-Gault equation (using ideal body mass [IBM] instead of 
mass). 
b. AST and ALT ≤ 2.5 × the ULN; bilirubin ≤ 1.5 × ULN (except subjects with 
Gilbert’s Syndrome who may have bilirubin ≤ 3.0 × ULN following discussion 
with the Sponsor). 
4. Females who had a menstrual cycle within 2 years of Screening must have a negative 
serum pregnancy test at Screening and a negative urine pregnancy test on their first 
dosing day. 
5. Subjects of childbearing potential must agree to use highly effective methods of 
contraception as defined in Section 5.3.1. 


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5.2.2 
Exclusion Criteria, Crossover Period  
Individuals who meet any of the following exclusion criteria are not to be enrolled in the 
crossover period.  
1. Sézary syndrome or mycosis fungoides with B2 involvement, defined as a documented 
history of B2 and/or B2 staging at the Screening visit. B2 means T-cell clone in 
peripheral blood + one of the following at Screening:  
a. ≥ 1000/µL Sézary cells by direct examination OR  
b. ≥ 1000/µL CD4+ CD26- OR  
c. ≥ 1000/µL CD4+ CD7-  
2. Current evidence of large cell transformation (LCT), defined as >25% of the lymphocytes 
at least 4 x the size of normal lymphocytes. Current evidence refers to LCT diagnosis 
from biopsy performed within 4 months prior to dosing in the crossover period. Subjects 
with a history of LCT but with a negative current biopsy (within 4 months) are eligible, 
provided there is no clinical indication for chemotherapy. 
3. History of visceral involvement related to MF at Screening. 
4. Unresolved toxicities from prior vorinostat treatment, defined as having not resolved to 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE, version 5.0), grade 0 or 1. 
5. Receipt of any of the following treatments: 
• Macrolide or tetracycline antibiotics within 28 days prior to Screening; 
• More than 3 short courses (≤ 7 days) of prednisone equivalent > 10 mg per day within 
8 weeks prior to Screening; however, a stable regimen of systemic prednisone 
equivalent to ≤ 10 mg per day (or steroid equivalent) is permitted; 
• Any CTCL systemic therapy after completion of the randomization period and prior 
to Day 1 for the crossover period.  
6. Positive test for blood (including trace) on urinalysis considered by the investigator to be 
consistent with undiagnosed clinically significant renal pathology requiring further 
investigation.   
7. An active or uncontrolled infection defined as subjects who require systemic 
antibacterial, antiviral, or antifungal therapy within the last 7 days prior to Screening. 


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8. Clinically significant anemia (hemoglobin < 8 g/dL), neutropenia (absolute neutrophil 
count [ANC] < 1000/mm3) or thrombocytopenia (platelets < 50,000/mm3) at Screening. 
9. Presence on ECG of QT interval corrected for heart rate using Fridericia’s formula 
(QTcF) > 450 msec for males or > 470 msec for females or > 480 msec for subjects with 
bundle branch block, based on a mean of the triplicate ECG measurements collected at 
Screening. 
10. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or inability to communicate or cooperate fully with the Investigator. 
11. Lactating or pregnant. 
12. Major surgery within 4 weeks of the first dose of study treatment. 
13. Unable to understand the purpose and risks of the study and to provide a signed and dated 
informed consent form (ICF) and authorization to use protected health information (in 
accordance with national and local subject privacy regulations). 
14. Clinically significant abnormalities in medical history, physical examination, or 
laboratory values that, in the opinion of the Investigator, would make the subject 
unsuitable for inclusion in the crossover period.  
15. History of intolerance, or adverse or allergic reactions to oligonucleotide products and/or 
phosphate buffer solutions. 
5.3 
Lifestyle Guidelines 
5.3.1 
Contraception Guidelines 
Female subjects must be either postmenopausal (absence of menses) for at least 1 year and have 
menopause confirmed by follicle-stimulating hormone (FSH) levels, or must be postmenopausal 
for at least 2 years (over 50 years old and absence of menses for 2 years, no confirmation by FSH 
required), or must be surgically sterile for at least 6 weeks, or must agree to take appropriate 
precautions to avoid pregnancy from Screening up to and including 105 days after the last dose 
of cobomarsen or 180 days after the last dose of vorinostat, if of childbearing potential. 
Males must agree to take appropriate precautions to avoid fathering a child from Screening up to 
and including 105 days after the last dose of study treatment and must consent to using an 
acceptable method of contraception such as a condom and a highly effective second method 


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(examples provided below), surgical sterilization (by one of the partners), postmenopausal 
partner (meeting the definition above), or abstinence. 
The following methods have been determined to be highly effective (< 1% failure rate per year 
when used consistently and correctly) (Trussell 2004; Clinical Trial Facilitation Group 2014) and 
are permitted under this protocol for use by the subject and his/her partner: 
• Complete abstinence from heterosexual intercourse during the entire period of risk 
associated with the study treatments, when this is in line with the preferred and usual 
lifestyle of the subject; 
• Oral, intravaginal, or transdermal combined (containing estrogen and progestogen) 
hormonal contraception associated with inhibition of ovulation; 
• Oral, injectable, or implanted progestogen-only hormonal contraception associated with 
inhibition of ovulation; 
o Note: Progestogen-only “mini-pills” are not considered highly effective methods 
of contraception for this protocol because inhibition of ovulation is not their 
primary mechanism of action. 
• Intrauterine device (IUD); 
• Intrauterine hormone-releasing system (IUS) 
• Vasectomy or vasectomized partner, provided that the partner is the sole sexual partner of 
the female trial participant and that the vasectomized partner has received medical 
assessment of the surgical success; 
• Bilateral oophorectomy with or without hysterectomy or tubal ligation at least 6 weeks 
prior to taking study treatment.  In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up levels of luteinizing 
hormone, FSH, and/or estradiol. 
o Female subjects who have undergone surgical sterilization by oophorectomy 
alone will have FSH levels assessed at Screening. 
5.3.2 
Exercise Guidelines 
Subjects should not embark on a new strenuous exercise regimen during Screening and while on 
study treatment.  Specifically, physical activities, such as strenuous, unusual or new type of 


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exercise, that can result in significant increases in plasma CK levels, should be avoided 48 hours 
prior to laboratory assessments, including Screening assessments. 
5.4 
Subject Discontinuation or Withdrawal from Study 
5.4.1 
Reasons for Subject Discontinuation or Withdrawal of Consent 
Subjects may withdraw their consent to participate in the study at any time for any reason 
without prejudice to their future medical care by the physician or at the institution.  If a subject 
withdraws consent, the date and reason for consent withdrawal should be documented.  The 
clinical site staff will also need to document from what portion of the study the subject is 
withdrawing consent: 
1. Withdrawing from treatment, but will continue to be followed for safety and progression; 
2. Withdrawing from treatment and all study procedures, but agrees to complete End of 
Treatment and 28 day post treatment follow-up visit;  
3. Complete study withdrawal with no additional follow-up.   
Subjects meeting any of the following criteria should discontinue study treatment: 
• Unacceptable AE(s) or failure to tolerate study treatment (see Section 10.2); 
• Prolonged dose delay (i.e., more than 4 missed consecutive doses of cobomarsen, or a 
dose interruption of > 14 consecutive days of vorinostat), due to an AE or clinically 
significant laboratory abnormality, or significant noncompliance with study treatment 
administration, unless judged by the Investigator and Sponsor Medical Monitor or 
designee to be in the best interest of the subject to continue treatment; 
• Changes in the subject’s condition or development of an intercurrent illness that renders 
the subject unsuitable for further study treatment in the judgment of the Investigator; 
• Disease progression (see Section 4); 
• Initiation of non-protocol CTCL treatment;  
• Withdrawal of consent; 
• Pregnancy; 
• Subject is lost to follow-up; 
• Discretion of the Investigator; 


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• Termination of the study by the Sponsor. 
Subjects meeting any of the following criteria should discontinue follow-up for disease 
progression: 
• Confirmed disease progression (see Section 4); 
• Withdrawal of consent; 
• Initiation of a subsequent CTCL treatment; 
• Subject is lost to follow-up; 
• Death. 
5.4.2 
Procedures for Subject Discontinuation or Withdrawal 
Wherever possible, the tests and evaluations listed for the post-treatment evaluation should be 
carried out and an effort should be made to continue follow-up.  The Sponsor should be notified 
of all study withdrawals through the designated electronic case report forms (eCRFs) in a timely 
manner. 
Subjects who discontinue prematurely will not be replaced. 
6 
STUDY PRODUCTS  
Throughout this protocol, “study treatment” refers to either cobomarsen or vorinostat. 
6.1 
Study Product(s) Management 
6.1.1 
Acquisition 
Cobomarsen and vorinostat will be supplied by the Sponsor and provided to clinical study sites. 
6.1.2 
Formulation, Appearance, Packaging, and Labeling 
The cobomarsen Drug Product is manufactured according to current Good Manufacturing 
Practice (cGMP) regulations for use in clinical trials.  The cobomarsen Drug Product is supplied 
as a sterile concentrate for solution for infusion.  The Drug Product is formulated in an isosmotic 
phosphate buffer, pH 7.4 ± 0.5, containing 141 mg/mL of the active moiety (equivalent to 
150 mg/mL of the active pharmaceutical ingredient or sodium salt form).  The Drug Product is 
packaged in sterile, single-dose, Type 1 glass vials with rubber stoppers and an aluminum 
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Vorinostat is available as 100 mg white, opaque, hard gelatin capsules for oral administration.  
The capsules have “568” over “100 mg” printed within a radial bar in black ink on the capsule 
body.  Capsules are packaged in plastic bottles, each containing 120 capsules. 
Study treatment will be labelled to comply with local labelling regulations.  
6.1.3 
Storage and Stability 
The cobomarsen Drug Product should be stored at 2 to 8°C (36 to 46°F), protected from light.   
Vorinostat capsules should be stored at 20 to 25°C (68 to 77°F) with excursions permitted 
between 15 to 30°C (59 to 86°F). 
6.1.4 
Accountability 
The investigator is responsible for ensuring adequate accountability of all used and unused study 
treatment.  All study treatment supplies and associated documentation will be reviewed and 
verified by the Clinical Research Associate (CRA).  Unused material cannot be disposed of until 
approval is obtained from the CRA.  The study site is responsible for the disposal and/or 
destruction of all unused study treatment supplies, according to the site’s standard operating 
procedures.  If the site cannot dispose of these materials, arrangements should be made between 
the site and Sponsor’s representative for destruction or return of the unused study treatment 
supplies. 
6.2 
Dosage, Preparation and Administration of Study Products 
6.2.1 
Dose and Regimen, Randomized Period 
As outlined in Section 4.3, the following study treatments will be administered according to 
randomized treatment assignment (cobomarsen or vorinostat): 
• Cobomarsen will be administered by 2-hour intravenous infusion at a dose of 282 mg on 
Days 1, 3, 5, 8, and weekly thereafter; 
• Vorinostat will be administered orally at a dose of 400 mg (four 100 mg capsules) once 
daily with food, at approximately the same time each day. 
o Subjects assigned to vorinostat with abnormal ALT/AST (> ULN) or bilirubin (> 1.0 
× ULN) at Screening will start vorinostat dosing at 300 mg (three 100 mg capsules) 
once daily with food, at approximately the same time each day, per dosing guidelines.  


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6.2.2 
Dose and Regimen, Crossover Period 
• Cobomarsen will be administered by 2-hour intravenous infusion at a dose of 282 mg on 
Days 1, 3, 5, 8, and weekly thereafter 
6.2.3 
Method of Assignment to Treatment 
During the randomized period, subjects will be randomized in the Interactive Web Response 
System (IWRS), in a 1:1 ratio, to receive either cobomarsen or vorinostat. In the crossover 
period, eligible subjects will be assigned open label cobomarsen through the IWRS.  
6.2.4 
Dose Preparation and Administration 
Cobomarsen must be prepared in accordance with local pharmacy practices using aseptic 
technique.  Complete details on the preparation and administration of study treatment are 
provided in a separate Pharmacy Manual. 
Subjects receiving intravenous doses of cobomarsen will have the total dose of study treatment 
administered via an intravenous infusion of approximately 2 hours (± 15 minutes).  The start 
time and end time of the infusion must be recorded.   
The subject should be observed for 4 hours following the Day 1 cobomarsen administrations.  
During this observation, an intravenous line could remain to allow administration of intravenous 
drugs, if necessary.  All supportive measures consistent with optimal subject care will be given 
throughout the study according to institution standards. 
Subjects assigned to vorinostat will receive an adequate supply of study treatment to last until the 
next scheduled study visit. 
6.2.5 
Assessment of Treatment Adherence 
All cobomarsen study treatments will be administered by qualified study personnel. 
Oral doses of vorinostat will be self-administered and subjects will record dosing information in 
paper subject diaries. 
7 
STUDY PROCEDURES 
The procedures and assessments that are outlined in this section will be performed at the time 
points specified by study visit in Section 8 (Randomized Period) and Section 9 (Crossover 
Period), and summarized in Appendix A (Schedule of Events (Screening, Randomized Period)),  


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Appendix B (On Treatment and Post-Treatment Follow-up – Cobomarsen Group), Appendix C 
(On Treatment and Post-Treatment Follow-up – Vorinostat Group), Appendix D (Screening, 
Crossover Period) and Appendix E (Crossover On Treatment and Post-Treatment Follow-up).   
Written informed consent must be provided by each subject prior to the initiation of any study 
procedure or assessment that is not part of standard of care. 
As part of the informed consent process, the investigational site personnel will review the study 
design with the subject and confirm the subject’s willingness and ability to participate in the 
clinical study if they are randomized to receive either cobomarsen or vorinostat, or if they elect 
to screen for the crossover period. 
7.1 
Clinical Assessments 
7.1.1 
Medical History 
Medical history will be recorded at Screening.  Any ongoing conditions and signs and symptoms 
observed prior to informed consent should be recorded as medical history with the relevant NCI 
CTCAE grade.  Any conditions and signs and symptoms occurring after the time of informed 
consent should be reported as AEs. 
Documentation of historical MF diagnosis by biopsy will be collected.  In addition, historical 
CD30 status will also be captured, if available.  
7.1.2 
CTCL Staging  
At Screening, CTCL staging will be assessed and recorded.   
In the randomized period, staging will be based on current screening assessments (mSWAT, CT 
scan and flow cytometry); historical compartment staging must not be used.   
In the crossover period, staging will be based on mSWAT and flow cytometry performed during 
the crossover screening period and the most recent CT scan performed during the study.  
7.1.3 
Prior MF Treatments  
Any prior therapy (topical, systemic, phototherapy or other) for the treatment of CTCL will be 
recorded at Screening, including dates of therapy and reason for discontinuation. 


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7.1.4 
Vital Signs 
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) will be measured 
at Screening and at the time points indicated in Appendix B, Appendix C and Appendix E. 
All vital sign measurements must be performed prior to every cobomarsen administration.   
7.1.5 
Physical Examination 
A complete physical examination will be performed by an investigator or sub-investigator at 
Screening and on Day 1.  At a minimum, the following body systems will be assessed: General 
Appearance, Dermatological, HEENT (head, eyes, ears, nose, and throat), Pulmonary, 
Cardiovascular, Gastrointestinal, Genito-Urinary, Musculoskeletal, Neurological and Lymphatic. 
Brief symptom-directed physical examinations should be performed at the subsequent time 
points specified in Appendix B, Appendix C and Appendix E. 
Body weight will be measured as part of the physical examination when indicated.  Height will 
be measured only at Screening.  Any treatment-emergent abnormal findings or worsening of a 
preexisting condition will be recorded as AEs. 
Subjects randomized to cobomarsen should have all physical examinations, occurring on dosing 
days, performed prior to receiving study treatment.  
7.1.6 
ECOG Performance Status 
Assessment of ECOG Performance Status (Table 2) will be performed at Screening. 
ECOG Performance Status should be obtained on the scheduled visit day, even if study treatment 
is being held. 
Table 2: 
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 
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 housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and about 
more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead 


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7.1.7 
Prior and Concomitant Medications 
All medications (including over-the-counter medicines, herbal treatments, supplements, and 
vitamins) administered within 30 days before the first administration of study treatment (Day 1) 
through the End of Treatment Visit will be recorded on the eCRF, using generic names when 
possible. Additionally, any concomitant medications taken for MF will be recorded throughout 
the study until confirmation of disease progression.  All medications taken for pruritus indication 
will be captured on a separate eCRF page.  
7.1.7.1 
Drug-Drug Interaction, Contraindications and Precautions 
Cobomarsen:  
Cobomarsen was neither an inhibitor nor an inducer of cytochrome P450 enzymes in cultured 
human hepatocytes treated with the drug.  
Cobomarsen is highly protein bound.  The interaction with other drugs with high protein affinity 
is not known.  Subjects receiving concomitant medications known to be highly protein bound 
should be carefully clinically monitored while being treated with cobomarsen, since free drug 
levels could increase.  When applicable, concomitant drug levels should be monitored. A non-
exhaustive list of some commonly used drugs known to be highly protein-bound in blood is 
provided in Table 3.  
Table 3: 
Medications Known to be Highly Protein-Bound in Blood 
Drug Class 
Drug Name 
Oral anticoagulants 
• Warfarin 
Oral antidiabetics 
• glimepiride, glipizide, glyburide 
Lipid lowering drugs 
• gemfibrozil, statins 
NSAIDs 
• indomethacine, phenylbutazone, ibuprofen, naproxen, 
diflunisal, diclophenac 
Loop diuretics 
• furosemide 
Antihypertensives 
• diazoxide, losartan 
Cardiovascular drugs 
• amiodarone, prazosin, felodipine, nicardipine, digitoxin, 
ticlopidine 
Antiinfectives 
• ceftriaxone, nalidixic acid, ketoconazole, itraconazole, 
suramin, nelfinavir 
Benzodiazepines 
• diazepam, midazolam 
Others 
• montelukast, zafirlukast, entacapone, leflunomide 
Source: aok.pte.hu/en/download/index/2736. Accessed 11 January 2019. 


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Similar to other oligonucleotide-based compounds, cobomarsen is metabolized by endo- and 
exonucleases in plasma and tissues and does not induce or inhibit cytochrome P450 (CYP) 
enzymes.  Therefore, it is not expected that cobomarsen will have clinical interactions with co-
medications cleared primarily by CYP-dependent metabolism. 
Vorinostat: 
Prescribing information, including risks of concomitant medications, can be found in the 
vorinostat package insert. 
Vorinostat is predominantly metabolized by the liver; therefore, use vorinostat with caution in 
subjects with hepatic disease or impairment.  Thrombocytopenia and anemia have been reported 
with vorinostat therapy.  Monitor complete blood counts closely throughout the study. 
Use vorinostat with caution in subjects with renal impairment. 
Dosage reduction or therapy discontinuation may be necessary in subjects who develop 
hematologic toxicity.  Severe thrombocytopenia has been reported with concomitant use of 
vorinostat and other HDAC inhibitors.  Concomitant use of vorinostat with other HDAC 
inhibitors is prohibited per protocol (see Section 7.1.7.2). However, subjects with prior history of 
thromboembolic disease, including pulmonary embolism and deep vein thrombosis, should be 
monitored closely during vorinostat therapy.   
Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) have been 
observed in patients receiving vorinostat concomitantly with coumarin-derivative anticoagulants. 
Investigators should monitor PT and INR more frequently in subjects concurrently administered 
vorinostat and coumarin derivatives. 
Pre-existing nausea and vomiting should be controlled prior to initiating vorinostat therapy.  
Gastrointestinal adverse effects including nausea, vomiting, and diarrhea have been reported 
during vorinostat therapy and may require antiemetic and antidiarrheal medication.  Fluids and 
electrolytes should be replaced to prevent dehydration.  Instruct subjects to drink at least 2 L/day 
of fluids for adequate hydration during vorinostat therapy.  Severe gastrointestinal bleeding has 
been reported with concomitant use of vorinostat and other histone deacetylases inhibitors, such 
as valproic acid.  Subjects with diabetes mellitus or glucose intolerance should be monitored 
closely during vorinostat therapy due to reports of hyperglycemia during treatment.  Adjustment 
of diet and/or therapy for glucose control may be necessary. 
Use vorinostat with caution in subjects with cardiac disease or other conditions that may increase 
the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial 


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infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, 
or in subjects receiving medications known to cause electrolyte imbalances. Subjects with a 
history of long QT syndrome and/or persistent hypokalemia should not be enrolled. Vorinostat 
should be used with caution with drugs known to induce QT interval prolongation.  See Table 4 
for a list of commonly used drugs known to induce QT interval prolongation. For complete and 
up to date information please visit the following website: https://crediblemeds.org/.  
Table 4: 
Medications Known to Prolong QT Interval and/or Cause Torsades de 
Pointes 
• Aclarubicin
• Disopyramide
• Ibutilide
• Propofol
• Amiodarone
• Dofetilide
• Levofloxacin
• Quinidine
• Anagrelide
• Domperidone
• Levomepromazine
(methotrimeprazine)
• Roxithromycin
• Arsenic trioxide
• Donepezil
• Levomethadyl acetate 
• Sevoflurane
• Astemizole
• Dronedarone
• Levosulpiride
• Sotalol
• Azithromycin
• Droperidol
• Mesoridazine
• Sparfloxacin
• Bepridil
• Erythromycin
• Methadone
• Sulpiride
• Chloroquine
• Escitalopram
• Moxifloxacin
• Sultopride
• Chlorpromazine
• Flecainide
• Ondansetron
• Terfenadine
• Cilostazol
• Fluconazole
• Oxaliplatin
• Terlipressin
• Ciprofloxacin
• Gatifloxacin
• Papaverine HCl
(Intracoronary)
• Terodiline
• Cisapride
• Grepafloxacin
• Pentamidine
• Thioridazine
• Citalopram
• Halofantrine
• Pimozide
• Vandetanib
• Clarithromycin
• Haloperidol
• Probucol
• Cocaine
• Ibogaine
• Procainamide
Source: https://crediblemeds.org/ Accessed 12 November 2018. 
7.1.7.2 
Prohibited and Limited Use of Concomitant Medications 
Topical and systemic treatment for CTCL will be prohibited during the study, except in 
exceptional circumstances as noted below. 
Systemic Corticosteroids 
In principle, initiation of systemic corticosteroid treatment or increase in corticosteroid dose for 
CTCL-related symptoms is prohibited during the study.  Subjects receiving a stable dose of oral 
prednisone of ≤ 10 mg daily (or steroid equivalent) at Screening are permitted to continue any 
such regimen, although the investigator should attempt to taper off or to decrease the dose to the 


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lowest dosage tolerable while on study.  In specific cases, and only after Medical Monitor 
approval, a transient systemic corticosteroid therapy course for symptoms related or unrelated to 
CTCL, limited to 7 days per course, and no more than one course per 60 days is allowed. 
Topical Corticosteroids and other Oral/Topical Medications 
Subjects that enter the study on a stable dose of medium or low potency topical corticosteroids 
for the treatment of pruritus may continue use at the same dose, although the investigator should 
attempt to taper off or decrease the use to the lowest dosage tolerable while on study.  
Initiation of new and transient topical high potency steroid therapy should be avoided 
unless needed to treat an acute non-CTCL condition. In this case, and only with Medical 
Monitor approval, a short course (≤ 7 days) of high potency topical corticosteroid is allowed, and 
not more than one short course per 60 days will be allowed.   
Initiation of new and transient topical, low or medium potency steroid therapy and/or oral 
antihistamines for pruritus is permitted, but should be limited to 7 days per course, and no more 
than one course per 30 days.   
Any new and transient use of topical corticosteroids should be recorded as a new medication in 
the concomitant medication or pruritus medication eCRF (depending on the indication), 
including the specific corticosteroid name, potency, formulation (ointment, cream, gel or lotion), 
indication and start and stop date. 
miRagen has evaluated topical corticosteroids potency used in all countries where SOLAR is 
being conducted. A comprehensive, but not exhaustive list of low, medium and high potency 
topical corticosteroid lotions, ointments, gels, solutions, foams and creams, as per miRagen’s 
determination, is provided in Appendix I. Though the determination of potency in few cases 
might slightly diverge from its clinical use in some countries, this list should be used to guide 
inclusion and exclusion criteria, prohibited medications, as well as exceptional new and transient 
use of topical corticosteroids during a subject’s participation in this trial. 
Use of topical emollients, moisturizers, camphor/menthol or pramoxine formulations (or other 
equivalent institutional standard of care therapies) should be limited where possible, but if used, 
should be recorded in the concomitant medication eCRF.  Any use of other methods (herbal 
supplements, ice baths, etc.) to treat pruritus should be avoided, but if used, should likewise be 
recorded in the concomitant medication eCRF. 
Nonsteroidal Anti-pruritic Medications 
The use of new prophylactic systemic anti-pruritic agents is prohibited.  


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The use of new daily symptomatic systemic anti-pruritic agents is discouraged.  Under 
exceptional circumstances, and only after Medical Monitor approval, these medications 
could be allowed.  These medications include, but are not limited to doxepin, gabapentin, 
aprepitrant, mirtazapine, selective serotonin reuptake inhibitors, or naltrexone.   
Short and intermittent courses of symptomatic systemic anti-pruritic agents should be avoided 
(with the exception of antihistamines, as noted above) including but not limited to doxepin, 
gabapentin, aprepitrant, mirtazapine, selective serotonin reuptake inhibitors, or naltrexone.  
However, in exceptional circumstances and with prior Medical Monitor approval, a short course 
(e.g. ≤ 7 days) of a new systemic anti-pruritic agent may be allowed.  Any medications used to 
treat symptomatic pruritus should be recorded on the pruritus concomitant medication eCRF.   
7.2 
Safety Assessments 
7.2.1 
Adverse Events 
AEs will be assessed at each study visit (in person or by telephone for telephone visits) by direct 
observation and subject interviews.  The severity of AEs will be evaluated using the NCI 
CTCAE version 5.0.  All AEs that occur from the time of informed consent up to and including 
60 days after the last dose of study treatment, regardless of causality to study treatment, must be 
reported.  Any treatment related AE reported by a subject during the clinical study, even if it 
occurs later than 60 days after the last dose of study treatment, should be reported in the eCRF.   
7.2.2 
Clinical Laboratory Assessments 
Blood and urine samples will be collected for the tests listed in Table 5 at Screening and at the 
time points specified in Appendix B, Appendix C and Appendix E.  Clinical laboratory 
assessments do not need to be performed on Day 1 if Screening laboratory assessments were 
performed within 3 days prior to Day 1 and subjects met inclusion/exclusion criteria based on 
Screening results. 
Screening for HIV, hepatitis B, and hepatitis C, will be performed at Screening in the 
randomized period. 
Female subjects who are not surgically sterile, must either have absence of menses for 1 year and 
have menopause confirmed by FSH levels at Screening, or must be postmenopausal for at least 
2 years (over 50 years old and absence of menses for 2 years; no confirmation by FSH required). 
Complement (C5a, Bb) testing will be performed on Day 1 and Day 2 only. 


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A central laboratory will be used for analysis of all blood and urine specimens collected, except 
for flow cytometry and a concomitant CBC used for calculation of absolute lymphocyte count, 
which will be performed by the site’s local laboratory.  At Screening, the central laboratory 
results will be used by the Investigator to determine the subject’s eligibility for the study.  Local 
laboratory results will not be used for eligibility determination, except for flow cytometry and 
the concomitant CBC used for calculation of absolute lymphocyte count. However, after 
Screening, results from the site’s local laboratory may be utilized if needed for timely review by 
the Investigator (if central laboratory results are not available).  Local site laboratory results 
obtained during the study will not be captured in the eCRF unless the Investigator determines 
they are needed to clarify why a treatment decision was made or if an AE was recorded based on 
the local results. 
Additional clinical laboratory tests may be obtained at any time during the study at the 
Investigator’s discretion. 
Site-specific handling instructions on the collection of blood and urine samples and their 
shipment to the central laboratory will be provided in the Laboratory Manual.  


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Table 5: 
Summary of Clinical Laboratory Tests 
Hematology a 
Chemistry 
Urinalysis 
Coagulation 
Others 
Abs Basophils 
Abs Eosinophils 
Abs Granulocytes 
Abs Lymphocytes 
Abs Monocytes 
Abs Neutrophils 
ANC 
Basophils 
Eosinophils 
Hematocrit 
Hemoglobin 
Lymphocytes 
Mean Corpuscular 
Hemoglobin 
Mean Corpuscular 
Hemoglobin 
Concentration 
Mean Corpuscular 
Volume 
Mean Platelet 
Volume 
Monocytes 
Neutrophils 
Platelets 
RBCs 
WBCs 
 
Albumin 
Alkaline phosphatase  
ALT  
AST  
Bicarbonate 
Calcium  
Chloride 
Cholesterol 
CKb 
C-Reactive Protein 
Creatinine  
Creatinine clearance 
(calculated)  
Bilirubin (total and 
direct)  
Glomerular Filtration 
Rate 
GGT 
GLDHc 
Glucose  
LDH 
Magnesium  
Phosphorus 
Potassium  
Sodium  
Total protein  
Triglyceride 
Urea (BUN) 
Uric acid  
Bilirubin 
Blood 
Color 
Glucose, Urine 
Ketones 
Leukocytes 
Nitrite 
pH 
Protein, Urine 
Specific gravity 
 
 
Urine Chemistry 
 
Myoglobin, Urine 
Protein, Urine 
Microalbuminuria 
Creatinine, Urine 
(Enzymatic) 
Protein/ 
Creatinine Ratio, 
Urine 
aPTT 
INR 
PT 
TSH  
 
Complement 
(C5a, Bb) 
 
For WOCBP: 
Serum/urine 
pregnancy test 
 
At Screening 
in the 
Randomized 
Period only: 
HIV 
Hepatitis B 
Hepatitis C 
 
For 
confirmation of 
menopause 
only: 
FSH 
 
 
Abbreviations: Abs = Absolute; ALT = alanine aminotransferase; ANC = absolute neutrophil count; 
aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CK = creatine kinase; GGT = gamma-glutamyl transferase; GLDH = glutamate dehydrogenase; FSH = follicle-
stimulating hormone; HIV = human immunodeficiency virus; INR = international normalized ratio; LDH = lactate 
dehydrogenase; PT = prothrombin time; RBC = red blood cell; TSH = thyroids-stimulating hormone; 
WBC = white blood cell; WOCBP = women of childbearing potential  
a Hematology will include CBCs performed at the central lab and locally when performed concurrently with the 
flow cytometry 
b For grade 2 or 3 total CK: measure CK, CK isoenzymes weekly for 3 weeks and if total CK remains ≤ the grade 
which triggered increased monitoring, continue to assess CK, CK isoenzymes along with regularly scheduled 
clinical chemistry assessments. 
c GLDH will be done as a reflex test if a grade 3 or 4 ALT or AST is observed. 


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7.2.2.1 
Pregnancy Test 
Female subjects of childbearing potential must have a negative serum pregnancy test at 
Screening and negative urine pregnancy tests on Day 1 and at the subsequent time points 
specified in Appendix B, Appendix C and Appendix E. 
Female subjects of nonchildbearing potential (see definitions in Section 5.3) do not require 
pregnancy tests.  
Female subjects who have undergone surgical sterilization by oophorectomy alone will have 
FSH levels assessed at Screening. 
All urine collections for pregnancy tests occurring on dosing days must be performed and 
assessed prior to study treatment administration.  A positive pregnancy test will result in 
immediate discontinuation of study treatment.  All pregnancies in study subjects or in female 
partners of male study subjects will be followed through to outcome and will be reported on the 
appropriate eCRFs. 
7.2.3 
Electrocardiograms 
A triplicate 12-lead ECG with lead II rhythm strip (3 serial ECGs conducted within 
approximately 5-10 minutes total time) will be performed at Screening.  The mean of the 
triplicate ECG measurement performed at Screening will be used to determine eligibility.  Single 
12-lead ECGs with lead II rhythm strip will be performed predose on Day 1 and during the 
active treatment and follow-up at the time points specified in Appendix B, Appendix C and 
Appendix E.  Prior to performing the 12-lead ECG, subjects should rest in the supine position for 
at least 5 minutes. 
Electrocardiogram parameters to be evaluated include the RR, QT, QRS, and PR intervals.  In 
addition, Fridericia’s formula should be used to calculate the QT interval corrected for heart rate 
(QTcF).  Abnormal ECG measurements will be recorded as AEs only if they are considered to be 
clinically significant by the Investigator.   
Post randomization 12-lead ECGs with non-clinically significant QTcF prolongation should be 
repeated in triplicate at the next dose visit with a lead II rhythm strip. Non-clinically significant 
QTcF prolongation is defined as a QTcF > 450 msec for males or > 470 msec for females or 
> 480 msec for subjects with bundle branch block but considered by the investigator to be non-
clinically significant.  
For subjects on cobomarsen, the repeat triplicate 12-lead ECG with a lead II rhythm strip 
should be performed after the end of the infusion (as soon as possible and ideally within 


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the 30 minutes following the infusion).  Subjects should also have a PK sample obtained 
5 minutes (± 5 minutes) before the end of infusion. 
For subjects on vorinostat, the repeat triplicate 12-lead ECG with a lead II rhythm strip 
should be performed at the next scheduled visit.    
If the QTc prolongation is considered clinically significant by the investigator, the subject should 
have a repeat triplicate 12-lead ECG immediately for confirmation, and if confirmed, the event 
should be entered as an AE.  Please refer to Section 10.2.1 (Cobomarsen Interruptions or 
Permanent Discontinuation - Other Grade 3 and 4 Adverse Events) and Section 10.2.2 
(Vorinostat Dose Modifications, Interruptions or Permanent Discontinuations) for additional 
instructions on dose delays or stopping rules due to clinically significant adverse events.  If 
further dosing with study treatment is deemed appropriate, triplicate 12-lead ECGs with a lead II 
rhythm strip should be repeated as described above for non-clinically significant QTcF 
prolongation.   
The sponsor may collect ECGs for central review during the course of the study.   
7.3 
Pharmacokinetic Sampling 
Plasma PK samples will be collected at the pre- and postdose time points specified in 
Appendix B and Appendix E to measure cobomarsen concentrations and metabolites.   
Pharmacokinetic samples will only be collected from subjects receiving cobomarsen in the 
randomized and crossover periods. 
7.4 
Pharmacodynamic and Anti-Drug Antibody Sampling 
7.4.1 
Blood Sample Collection 
Serum samples for PD biomarkers will be collected predose on Day 1 and on study days 
specified in Appendix B and Appendix E to investigate the effects of cobomarsen on miRNAs, 
miR-155-5p target mRNA and/or protein levels and/or downstream indirect targets.  Serum will 
also be collected to assess if anti-drug antibodies (ADA) are being generated over the course of 
cobomarsen treatment.  Pharmacodynamic samples will only be collected from subjects 
receiving cobomarsen in the randomized and crossover periods. 


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7.5 
Efficacy Assessments 
7.5.1 
Response and Disease Progression Evaluations and mSWAT 
Response to study treatment and disease progression will be evaluated using skin response 
criteria for MF (Olsen et al. 2011; see Appendix F). 
mSWAT evaluations should be performed per the visit schedule (see Appendix B, Appendix C, 
Appendix D and Appendix E) whether the subject is receiving study treatment or has 
discontinued treatment, until one of the following (whichever occurs first): disease progression 
in skin (confirmed by repeat measurement 28 days [± 3 days] after the first determination of 
progression), lymph nodes, blood or viscera, withdrawal of consent, initiation of subsequent MF 
treatment, lost to follow-up, or death.   
mSWAT evaluations may also be performed at any time the Investigator suspects there is clinical 
evidence of disease progression. 
In the event the investigator declares disease progression in other compartments, based on 
assessments (flow cytometry or CT scan) performed at his/her own discretion, documentation of 
progression by standard Olsen criteria (Appendix F) should be provided. 
7.5.1.1 
mSWAT Evaluations (Skin Component) 
mSWAT (see Appendix F) scoring will performed at Screening and before dosing at the time 
points outlined in Appendix B, Appendix C and Appendix E. 
Every effort should be made to have the same mSWAT evaluator conduct all assessments 
of mSWAT for a subject at Screening and throughout the study to ensure consistency.   
If the primary evaluator is not available during the visit window, the following should 
occur, in order of preference: 
1. The visit could be postponed or performed earlier by the primary evaluator.  
2. The visit could be performed by another locally trained evaluator. If a different 
evaluator conducts an mSWAT a review of the previous mSWAT should occur 
prior to the evaluation of the current mSWAT. If the new assessment impacts a 
response or progression there should be clear documentation (e.g. photography) to 
support the results.   


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7.5.1.2 
Process to Determine Skin Response and Confirmation  
Once the Investigator believes that the mSWAT evaluation has shown an objective response for 
4 consecutive months (i.e., a PR or CR as assessed per mSWAT criteria, without loss of 
response, for 4 consecutive months; see Table F2 in Appendix F), the Investigator must schedule 
the subject for a visit within 28 days (± 3 days) to perform a confirmatory mSWAT.  
Subjects who have a PR or CR cannot be downgraded to stable disease.  Subjects who have a PR 
or CR can only have their response downgraded if they meet the criteria of loss of response 
(progression) see Table F2 in Appendix F. 
Of note: An unconfirmed progression at any time during the study will not preclude the 
Investigator from assessing a future response (CR or PR). 
7.5.1.3 
Process to Determine Disease Progression  
As stated in Section 4, disease progression is defined as either: 
a. Confirmed progression in skin 
b. Clinical progression in in other compartments, documented by assessments (flow 
cytometry and/or CT scan) completed per investigator discretion  
c. Partial or complete skin response followed by a confirmed loss of skin response as 
defined by an increase of mSWAT of greater than the sum of nadir plus 50% baseline 
score. 
Progressions based on mSWAT will be confirmed by repeat measurement 28 days (± 3 days) 
after the first determination of progression. If the subject is currently on study treatment, the 
study treatment should not be discontinued until confirmation of disease progression.   
An unconfirmed progression would not preclude future responses (CR or PR). 
Upon reassessment, if the original findings have not changed, and there is no alternate clinical 
explanation or etiology for the suspected progression, then disease progression should be 
considered confirmed and the date of disease progression should be reported as the date that it 
was first suspected.   
Subjects who meet disease progression criteria in skin, or other compartment assessed per 
investigator discretion, should be discontinued from study treatment due to disease progression.  


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7.6 
Screening Staging Assessments  
7.6.1 
mSWAT Assessments  
See Section 7.5.1.1. 
7.6.2 
Radiological Imaging (Lymph Nodes and Viscera Components) 
Radiological imaging will be performed at Screening in the randomized period.   
While CT scans are the preferred method for radiological imaging, other modalities (e.g., MRI) 
can be used if needed.  PET scan should only be used to confirm an abnormal lymph node found 
by other modalities, if a nodal biopsy is not possible. Nodal biopsy is the preferred method for 
disease staging assessment, if possible.  
Radiological imaging will be performed locally (see Appendix A and Appendix D.  At 
Screening, a CT/MRI scan of the neck, chest, abdomen and pelvis (at minimum) must be 
performed.  The preferred radiologic technique is CT with intravenous contrast.  If a subject is 
known to have a contraindication to CT contrast media or develops a contraindication during the 
clinical study, a non-contrast CT should be performed. Scans will be reviewed by both the local 
site staff and by the blinded central imaging laboratory during screening in the randomized 
period.  A separate Imaging Manual will detail the collection, transfer and processing of the 
images to the central imaging laboratory.  The blinded independent review of scans for screening 
in the randomized period will be performed per the Imaging Charter. 
7.6.3 
Flow Cytometry (Blood Component) 
Whole blood will be collected and analyzed by flow cytometry (including a concomitant CBC 
used for calculation of absolute lymphocyte count) assessments performed by the site’s local 
laboratory at Screening as specified in Appendix A and Appendix D to evaluate the T-cell 
subpopulations to determine the extent of tumor cell blood involvement for eligibility assessment 
for the randomized and crossover periods of the study.  
The following flow cytometry markers will be used by the site’s local laboratory to determine 
eligibility and for CTCL staging at Screening: 
Antibodies to CD3, CD4, CD8, CD26, CD45 and CD7 


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8 
STUDY SCHEDULE (RANDOMIZED PERIOD) 
Before recruitment of subjects into the study, written Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) approval of the protocol, informed consent and any additional 
subject information must be obtained. 
The required visits for the clinical study are listed below.  The investigator can bring the subject 
into the clinic for an unscheduled visit, at any time. 
8.1 
Screening for the Randomized Period (Day -28 to Day -1) 
All Screening procedures to determine eligibility must be performed within the specific time 
windows.  Eligibility is determined by results of the Screening assessments performed prior to 
randomization.  Disease staging and eligibility will be confirmed by the Medical Monitor prior to 
randomization (24-48 hours should be allowed for Medical Monitor review).  
Subjects may be rescreened once at the discretion of the Investigator (i.e., if a subject does not 
meet the Inclusion/Exclusion criteria during the first Screening assessments).  Individual 
Screening assessments may be repeated, if the subject is still within the 28-day Screening 
window.  If a subject is outside of the 28-day Screening window, then the subject must be 
reconsented and all Screening procedures should be repeated.  If an assessment is repeated, the 
result obtained closest to randomization should be used for eligibility. 
Screening may last up to 28 days from the time the first study screening procedure is completed. 
During Screening, the IWRS will assign a unique subject identification number to each subject 
who signs informed consent for the study.  Once a subject is in Screening or is randomized into 
the study, s/he will only be identified by the assigned identification number throughout the study.  
Subjects who reconsent and rescreen per the procedure described above will receive a new 
subject identification number. 
The Investigator or designee is responsible for verifying that a subject is eligible before initiating 
the randomization.  Eligibility must also be confirmed by the Medical Monitor, prior to 
randomization.  Subjects must be treated within 3 working days of the date of randomization. 
Prior to performing study related procedures: 
Obtain informed consent of potential subject verified by written signature on an ICF. 
From Days -28 to -3, the following evaluations will occur: 
• Register the subject in the IWRS. 


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• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Perform MF disease evaluation using the mSWAT (see Appendix F). 
• Record medical history.  
• Record prior and concomitant medications administered from 30 days prior to the first 
dose of study treatment.  
• Record all prior MF treatments. 
• Record ECOG performance status. 
• Perform a complete physical examination (including documentation of height and 
weight). 
• Perform a triplicate 12-lead ECG (3 serial ECGs conducted within approximately 5-10 
minutes total time). 
• Perform CT/MRI scan of neck, chest, abdomen and pelvis (at minimum).  Must be 
performed within 28 days ± 7 days prior to randomization. 
• Collect blood for the following central laboratory analysis: 
o Screening for HIV, Hepatitis B, and Hepatitis C; 
o Confirmation of menopause by FSH (when required, see Section 5.3); 
o Serum pregnancy test (for females of childbearing potential); 
o Hematology; 
o Clinical chemistry; 
o TSH; 
o Coagulation. 
• Collect blood for flow cytometry and a concomitant CBC (performed locally; panels 
must include antibodies to CD3, CD4, CD8, CD26, CD45 and CD7). 
• Collect urine for central laboratory analysis of urinalysis (with microscopy). 
• Review eligibility of medical history and laboratory measurements according to 
inclusion/exclusion criteria. 
• Review and record AEs. 


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From Days -3 to -1, the following evaluations will occur: 
• Confirm eligibility of medical history and laboratory measurements according to 
inclusion/exclusion criteria. 
• Confirm CTCL staging based on Screening assessments (see Appendix H). 
• Re-review and record AEs. 
• Enter all Screening data in the eCRF and initiate Medical Monitor review in the IWRS 
(Allow 24-48 for Medical Monitor review). 
• After Medical Monitor approval, determine randomized treatment assignment using the 
IWRS. 
Note: Subjects must receive the first dose of study medication within 3 working days of 
randomization.  
8.2 
Randomized Period 
Subjects will be monitored and treated in the outpatient setting.  After all dosing and study 
procedures are completed at each study visit, subjects will return home until the next visit. 
8.2.1 
Day 1 (First Day of Study Treatment) 
• Perform CTCL disease evaluation using the mSWAT (predose) (see Appendix F). 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Perform a complete physical examination (including documentation of weight).  May be 
performed within 2 days prior to the Day 1 visit. 
• Collect blood for the following: 
o Complement C5a, Bb testing (cobomarsen predose and within the 10 minutes before 
the end of the infusion) (vorinostat predose and 2 hours post dose); 
o Hematology (predose); 
o Clinical chemistry (predose); 
o TSH (predose); 
o Coagulation (predose and at 3 hours [± 10 minutes] postdose); 
o Cobomarsen group only: PD and ADA  (predose); 


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o Cobomarsen group only: PK (pre-dose, 60 ± 5 minutes after the start of the infusion, 
5 ± 5 minutes before the end of the infusion, and 4 hours [± 10 minutes] after the end 
of the infusion). 
• Collect urine for the following:  
o Urinalysis (predose; only if Screening measurement was performed > 3 days before 
Day 1); 
o Pregnancy test (predose, for females of childbearing potential). 
• Perform a single 12-lead ECG 
o Cobomarsen group only: Predose and as soon as possible postdose, ideally within 30 
minutes of the end of infusion. 
• Vorinostat group only: Predose and 1 ± 0.5 hours postdose. 
• IWRS Transaction (Study Treatment Dispensation). 
• Cobomarsen group only: Administer intravenous infusion of cobomarsen with vital signs 
performed within 15 minutes of the end of the infusion and keep the subject in the clinic 
for 4 hours for observation.  
• Vorinostat group only: Administer first dose in the clinic with food following collection 
of laboratory samples and keep the subject in the clinic for 4 hours for observation. 
• Instruct subjects to record daily dosing in the provided diary (vorinostat group only).  
• Review and record AEs and concomitant medications. 
8.2.2 
Day 2 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Collect blood for the following: 
o Complement C5a, Bb testing (24 ± 4 hours) (predose for vorinostat); 
o Coagulation (predose for vorinostat); 
o Cobomarsen group only: PK (24 ± 4 hours after Day 1 dosing). 
• Vorinostat group only: Administer the dose in the clinic with food following collection of 
laboratory samples. 
• Instruct subjects to record daily dosing in the provided diary (vorinostat group only),  


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• Review and record AEs and concomitant medications. 
8.2.3 
Day 3 (+ 1 Day) 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Collect blood for the following: 
o Hematology (predose); 
o Clinical chemistry (predose); 
o TSH (predose); 
o Cobomarsen group only: PK (single predose sample). 
• Collect urine for urinalysis (predose). 
• Cobomarsen group only: IWRS Transaction (Study Treatment Dispensation). 
• Cobomarsen group only: Administer intravenous infusion of cobomarsen with vital signs 
performed within 15 minutes of the end of the infusion. 
• Vorinostat group only: Administer the dose in the clinic with food following collection of 
laboratory samples. 
• Instruct subjects to record daily dosing in the provided diary (vorinostat group only) 
• Review and record AEs and concomitant medications. 
8.2.4 
Day 5 (± 1 Day) 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Cobomarsen group only: PK (single predose sample). 
• Cobomarsen group only: IWRS Transaction (Study Treatment Dispensation). 
• Cobomarsen group only: Administer intravenous infusion of cobomarsen with vital signs 
performed within 15 minutes of the end of the infusion. 
• Vorinostat group only: Confirm that subject has taken daily dose in the morning with 
food and recorded it in their diary  
• Instruct subjects to record daily dosing in the provided diary (vorinostat group only) 
• Review and record AEs and concomitant medications. 


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8.2.5 
Day 8 (± 1 Day) 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Perform a brief, symptom-directed physical examination. 
• Collect blood for the following: 
o Hematology (predose); 
o Clinical chemistry (predose); 
o TSH (predose); 
o Coagulation (predose); 
o Cobomarsen group only: PK (predose, and 5 ± 5 minutes before the end of the 
infusion). 
• Collect urine for urinalysis (predose). 
• Cobomarsen group only: IWRS Transaction (Study Treatment Dispensation). 
• Cobomarsen group only: Administer intravenous infusion of cobomarsen with vital signs 
performed within 15 minutes of the end of the infusion. 
• Vorinostat group only: Administer the dose in the clinic with food following collection of 
laboratory samples. 
• Instruct subjects to record daily dosing in the provided diary (vorinostat group only) 
• Review and record AEs and concomitant medications. 
8.2.6 
Day 15 (± 1 Day) 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Perform a brief, symptom-directed physical examination. 
• Collect blood for the following: 
o Hematology (predose); 
o Clinical chemistry (predose); 
o TSH (predose); 
o Cobomarsen group only: PK (predose); 
o Cobomarsen group only: PD and ADA (predose). 


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• Collect urine for urinalysis (predose). 
• Cobomarsen group only: IWRS Transaction (Study Treatment Dispensation). 
• Cobomarsen group only: Administer intravenous infusion of cobomarsen with vital signs 
performed within 15 minutes of the end of the infusion. 
• Vorinostat group only: Administer the dose in the clinic with food following collection of 
laboratory samples. 
• Instruct subjects to record daily dosing in the provided diary (vorinostat group only) 
• Review and record AEs and concomitant medications. 
8.2.7 
Day 22 (± 2 Days) 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Cobomarsen group only: IWRS Transaction (Study Treatment Dispensation). 
• Cobomarsen group only:  Administer intravenous infusion of cobomarsen with vital signs 
performed within 15 minutes of the end of the infusion. 
• Vorinostat group only: Confirm that subject has taken daily dose in the morning with 
food and recorded it in their diary 
• Instruct subjects to record daily dosing in the provided diary (vorinostat group only) 
• Review and record AEs and concomitant medications. 
8.2.8 
Day 29 (± 3 Days) 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Perform CTCL disease evaluation using the mSWAT (predose) (see Appendix F). 
• Perform a brief, symptom-directed physical examination (including documentation of 
weight). 
• Collect blood for the following: 
o Hematology (predose); 
o Clinical chemistry (predose); 
o TSH (predose); 
o Coagulation (predose); 


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o
Cobomarsen group only: PD and ADA (predose);
o
Cobomarsen group only: PK (pre-dose, 60 ± 5 minutes after the start of the infusion,
5 ± 5 minutes before the end of the infusion, and 4 hours [± 10 minutes] after the end
of the infusion).
•
Collect urine for the following:
o
Urinalysis (predose);
o
Pregnancy test (for females of childbearing potential).
•
Perform a single 12-lead ECG
o
Cobomarsen group only: Predose and as soon as possible postdose, ideally within 30
minutes of the end of infusion.
o
Vorinostat group only: Predose and 1 ± 0.5 hours postdose
•
IWRS Transaction (Study Treatment Dispensation).
•
Cobomarsen group only: Administer intravenous infusion of cobomarsen with vital signs
performed within 15 minutes of the end of the infusion.
•
Vorinostat group only: Administer the dose in the clinic with food following collection of
laboratory samples. 
•
Instruct subjects to record daily dosing in the provided diary (vorinostat group only).
•
Review and record AEs and concomitant medications.
8.2.9 
Weekly Assessments Starting at Week 6 (± 3 Days) 
Starting at Week 6, the following assessments are required to be done weekly for subjects in both 
treatment groups.  The weekly study visits for the vorinostat group can be conducted via 
telephone (except for Week 7, see Section 8.2.10 below), unless the investigator feels it is in the 
best interest of the subject to visit the clinic. 
•
Cobomarsen group only: Obtain vital signs (blood pressure, heart rate, respiratory rate,
and body temperature). 
•
Cobomarsen group only: IWRS Transaction (Study Treatment Dispensation).
•
Cobomarsen group only: Administer intravenous infusion of cobomarsen with vital signs
performed within 15 minutes of the end of the infusion.


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• Vorinostat group only: Confirm that subject has taken daily dose in the morning with 
food and recorded it in their diary. 
• Instruct subjects to record daily dosing in the provided diary (vorinostat group only).  
• Review and record AEs and concomitant medications. 
8.2.10 
Week 7 Visit (± 3 Days) (for Vorinostat Subjects only)  
• Collect blood for the following: 
o Hematology (predose); 
o Clinical chemistry (predose); 
o Coagulation (predose); 
• Administer the dose in the clinic with food following collection of laboratory samples. 
8.2.11 
Every-4-Week Assessments from Weeks 9 through 81, then Every-8-Week 
Assessments Thereafter (± 3 Days) 
NOTE:  In addition to the weekly assessments listed above, the following additional assessments 
are required to be done every 4 weeks from Week 9 through Week 81 and then every 8 weeks 
thereafter, for subjects in both treatment groups: 
• Perform CTCL disease evaluation using the mSWAT (predose) (see Appendix F). 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Perform a brief, symptom-directed physical examination (including documentation of 
weight). 
• Collect blood for the following: 
o Hematology (predose); 
o Clinical chemistry (predose); 
o TSH (predose); 
o Cobomarsen group only: PD and ADA; 
o Cobomarsen group only: PK (predose, and 5 ± 5 minutes before the end of the 
infusion through Week 25.  Predose only from Weeks 29 through 81 and every 
8 weeks thereafter, and at the end of treatment visit). 


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• Collect urine for the following:  
o Urinalysis (predose); 
o Pregnancy test (performed every 4 weeks while on study treatment), for females of 
childbearing potential). 
• Perform a single 12-lead ECG (predose). 
• IWRS Transaction (Study Treatment Dispensation). 
• Cobomarsen group only:  Administer intravenous infusion of cobomarsen with vital signs 
performed within 15 minutes of the end of the infusion. 
• Vorinostat group only: Administer the dose in the clinic with food following collection of 
laboratory samples. 
• Instruct subjects to record daily dosing in the provided diary (vorinostat group only). 
• Review and record AEs and concomitant medications. 
8.3 
Post-treatment  
The following are the definitions for post-treatment visits in this study: 
• End of Treatment:  Time at which the subject is permanently discontinued from study 
treatment for any reason. 
o The End of Treatment Visit should be performed as soon as possible but ≤ 14 days 
after the last dose of study treatment.  See Section 8.4 for End of Treatment visit 
requirements. 
• Follow-up: The subject has completed study treatment but remains on study and is being 
followed for response and/or progression.  
o Subjects who had an ongoing response or stable disease at the time that they 
discontinued study treatment must continue to be followed for response and/or 
disease progression in the Follow-up Period.  See Section 8.5 and 8.6 for the 
follow-up visit frequency and requirements. 
• End of the Study:  The subject has completed all required follow-up on study and is no 
longer being followed for response or disease progression, in the study period.   
o If a subject withdraws consent for further follow-up at any time on study, the End of 
Study date is the date that consent is withdrawn. 


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8.4 
End of Treatment Visit 
At the time of study treatment discontinuation, the End of Treatment Visit should be completed 
for all subjects after the last dose of study treatment, and every effort should be made to perform 
the procedures listed below.  This visit should take place as soon as possible and ≤ 14 days after 
the last dose of study treatment.  The date and reason for stopping the study treatment will be 
reported.  The End of Treatment visit is not considered as the end of the study.  All subjects will 
enter the Follow-up unless they have withdrawn their consent to do so. 
• Perform CTCL disease evaluation using the mSWAT (see Appendix F). 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Perform a brief, symptom-directed physical examination (including documentation of 
weight). 
• Collect blood for the following: 
o Hematology; 
o Clinical chemistry; 
o TSH; 
o Cobomarsen group only: PD and ADA  
o Cobomarsen group only: PK. 
• Collect urine for the following:  
o Urinalysis; 
o Pregnancy test (for females of childbearing potential). 
• Perform a single 12-lead ECG. 
• IWRS Transaction (Discontinue the Subject in the System). 
• Review and record AEs and concomitant medications. 
8.5 
Long-term Follow-up for Subjects Who Have Not Progressed at the 
Time of End of Treatment Visit  
After the End of Treatment Visit, subjects who did not progress on study will be followed until  
progression (confirmed progression in skin, confirmed loss of response in skin or clinical 
progression in lymph nodes, blood or viscera assessed per investigator discretion), withdrawal of 


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consent, initiation of subsequent MF treatment, loss to follow-up, or death, and the subject’s final 
disposition is documented and reviewed by the Sponsor study team. 
8.5.1 
Every-4-Week Assessment through Week 81, then Every-8-Week Assessments 
Thereafter (± 3 Days) 
• Perform CTCL disease evaluation using the mSWAT (see Appendix F). 
• Review and record AEs and concomitant medications. 
8.6 
Follow-up Visit 28 ± 5 days after the End of Treatment or Early 
Termination 
For subjects who choose not to participate in the crossover period of the  study (or delay the start 
of the crossover period by > 28 days) or who discontinue cobomarsen treatment, the following 
assessments will be performed 28 ± 5 days after the End of Treatment Visit (assuming the 
subject has not withdrawn consent). 
• Perform CTCL disease evaluation using the mSWAT (does not need to be repeated if 
disease progression is already confirmed) (see Appendix F). 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Perform a brief, symptom-directed physical examination (including documentation of 
weight). 
• Collect blood for the following: 
o Hematology; 
o Clinical chemistry; 
o TSH; 
o Coagulation; 
o Cobomarsen group only: PD and ADA. 
o Cobomarsen group only: PK. 
• Collect urine for the following: 
o Urinalysis; 
o Pregnancy test (for females of childbearing potential). 
• Perform a single 12-lead ECG. 
• Review and record AEs and concomitant medications. 


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9 
CROSSOVER PERIOD 
9.1 
Crossover Period Design  
After completing the randomized period, subjects that have confirmed skin disease progression 
on the vorinostat arm can be assessed for eligibility for the crossover period.    Eligible subjects 
may elect to enter this optional crossover period and must have signed a study informed consent 
form (corresponding to the current version of the SOLAR protocol) to proceed.  Every effort will 
be made to perform final safety and disease assessments for subjects who withdraw from the 
study early. 
Potential subjects will need to complete the crossover screening activities and meet the entry 
criteria (see Section 5.2) prior to enrollment into the crossover period.   
Subjects in the randomized period of the study who withdrew consent without confirmation of 
skin disease progression are not eligible to enroll in this period. In addition, subjects who 
received any subsequent systemic therapy for MF following confirmed disease progression in the 
randomized period are not eligible for the crossover period.  
Study procedures completed at the End of Treatment visit in the randomized period may be used 
for screening assessments in the crossover period, depending on the timing of the assessments. 
Subjects who initiate Screening in the crossover period > 28 days after completing the 
randomized period will need to complete all of the crossover Screening procedures.  
Subjects will undergo Screening lasting up to 28 days from the time of the first screening 
procedure, followed by active treatment and follow-up for response and disease progression.  
Subjects who are currently on active treatment in the PRISM Study (MRG106-11-203) may 
enter the crossover period of this protocol, once the site has received necessary IRB/IEC and 
regulatory approvals for the current version of the SOLAR protocol.  In this case, site personnel 
will ensure the subject has provided written informed consent for the SOLAR crossover period.  
The subject will not need to be re-evaluated for the entry criteria for SOLAR crossover period 
and should enter the study at the next scheduled nominal study visit following the last study visit 
completed in the PRISM study.   
9.2 
Crossover Study Schedule 
Before recruitment of subjects into the crossover period, written Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval of the protocol, informed consent and 
any additional subject information must be obtained. 


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The required visits for the crossover period are listed below.  The investigator can bring the 
subject into the clinic for an unscheduled visit at any time. 
9.2.1 
Crossover Screening Period (Day -28 to Day -1) 
All Screening procedures to determine eligibility must be performed within the specific time 
windows.  Eligibility is determined by results of the assessments performed prior to enrollment.  
Disease staging and eligibility will be confirmed by the Medical Monitor prior to enrollment 
(24-48 hours should be allowed for Medical Monitor review).  
Subjects may be rescreened once at the discretion of the Investigator (i.e., if a subject does not 
meet the Inclusion/Exclusion criteria during the first Screening assessments).  Individual 
Screening assessments may be repeated, if the subject is still within the 28-day Screening 
window.  If a subject is outside of the 28-day Screening window, then the subject must be 
reconsented and all Screening procedures should be repeated.  If an assessment is repeated, the 
result obtained closest to enrollment should be used for eligibility. 
Screening may last up to 28 days from the time the first study screening procedure is completed. 
During Screening, the IWRS will assign a unique subject identification number to each subject 
who signs informed consent for the study.  Once a subject is in Screening or is enrolled into the 
study, s/he will only be identified by the assigned identification number throughout the crossover 
period.    
The Investigator or designee is responsible for verifying that a subject is eligible before initiating 
the enrollment.  Eligibility must also be confirmed by the Medical Monitor, prior to enrollment.  
Subjects must be treated within 3 working days of the date of enrollment. 
Prior to performing study related procedures: 
• Verify informed consent (including crossover procedures) of potential subject by written 
signature on an ICF. 
From Days -28 to -3, the following evaluations will occur: 
• Register the subject in the IWRS. 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature) (if 
not obtained within 14 days prior to Day 1). 
• Perform MF disease evaluation using the mSWAT (if not done within 28 days prior to 
Day 1) (see Appendix F).  


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• Record prior and concomitant medications administered from 30 days prior to the first 
dose of study treatment.  
• Record any new MF treatments following discontinuation of vorinostat in the randomized 
period.  
• Record ECOG performance status. 
• Perform a complete physical examination (including documentation of height and 
weight) (if not done within 14 days prior to Day 1) 
• Perform a triplicate 12-lead ECG (if not done within 14 days of Day 1).   
• Collect blood for the following central laboratory analysis (if not done within 14 days of 
Day 1): 
o FSH (for females who are not surgically sterile as confirmation of menopause for 
females who last menstrual cycle was within the last year) 
o Serum pregnancy test (for females of childbearing potential); 
o Hematology; 
o Clinical chemistry; 
o TSH; 
o Coagulation. 
• Collect blood for flow cytometry and a concomitant CBC (performed locally; panels 
must include antibodies to CD3, CD4, CD8, CD26, CD45 and CD7) (if not done within 
28 days of Day 1). 
• Collect urine for central laboratory analysis of urinalysis (with microscopy) (if not done 
within 14 days of Day 1). 
• Review eligibility of medical history and laboratory measurements according to 
inclusion/exclusion criteria. 
• Review and record AEs. 
From Days -3 to -1, the following evaluations will occur: 
• Confirm eligibility of medical history and laboratory measurements according to 
inclusion/exclusion criteria. 
• Re-review and record AEs. 


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• Enter all Screening data in the eCRF and initiate Medical Monitor review in the IWRS 
(allow 24-48 for Medical Monitor review).  
9.2.2 
Crossover Active Treatment 
Subjects will be monitored and treated in the outpatient setting.  After all dosing and study 
procedures are completed at each study visit, subjects will return home until the next visit. 
9.2.2.1 
Day 1 (First Day of Study Treatment) 
• Perform CTCL disease evaluation using the mSWAT (predose) (see Appendix F). 
• Obtain predose vital signs (blood pressure, heart rate, respiratory rate, and body 
temperature). 
• Perform a complete physical examination (including documentation of weight). This 
examination may be performed within 2 days prior to the Day 1 visit. 
• Collect blood for the following: 
o Complement C5a, Bb testing (predose and within the 10 minutes before the end of the 
infusion); 
o Hematology (predose; only if Screening measurement was performed > 3 days before 
Day 1); 
o Clinical chemistry (predose; only if Screening measurement was performed > 3 days 
before Day 1); 
o TSH (predose; only if Screening measurement was performed > 3 days before 
Day 1); 
o Coagulation (predose and at 3 hours [± 10 minutes] postdose);  
o PD and ADA (predose); 
o PK (predose, and 5 ± 5 minutes before the end of the infusion). 
• Collect urine for the following:  
o Urinalysis (predose; only if Screening measurement was performed > 3 days before 
Day 1); 
o Pregnancy test (predose, for females of childbearing potential). 


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• Perform a single 12-lead ECG (predose and as soon as possible postdose, ideally within 
30 minutes of the end of infusion). 
• IWRS transaction (cobomarsen dispensation). 
• Administer intravenous infusion of cobomarsen with vital signs performed within 
15 minutes of the end of the infusion. Monitor subject in the clinic for safety for a 
minimum of 4 hours postdose. 
• Review and record AEs and concomitant medications. 
9.2.2.2 
Day 2 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Collect blood for the following: 
o Complement C5a, Bb testing (24 ± 4 hours after Day 1 dosing); 
o Coagulation; 
• Review and record AEs and concomitant medications. 
9.2.2.3 
Day 3 (+ 1 Day) 
• Obtain predose vital signs (blood pressure, heart rate, respiratory rate, and body 
temperature). 
• Collect blood for the following: 
o Hematology (predose); 
o Clinical chemistry (predose); 
o TSH (predose); 
• Collect urine for urinalysis (predose). 
• IWRS transaction (cobomarsen dispensation). 
• Administer intravenous infusion of cobomarsen with vital signs performed within 
15 minutes of the end of the infusion. 
• Review and record AEs and concomitant medications. 


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9.2.2.4 
Day 5 (± 1 Day) 
• Obtain predose vital signs (blood pressure, heart rate, respiratory rate, and body 
temperature). 
• IWRS transaction (cobomarsen dispensation). 
• Administer intravenous infusion of cobomarsen with vital signs performed within 
15 minutes of the end of the infusion. 
• Review and record AEs and concomitant medications. 
9.2.2.5 
Day 8 (± 1 Day) 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Perform a brief, symptom-directed physical examination. 
• Collect blood for the following: 
o Hematology (predose); 
o Clinical chemistry (predose); 
o TSH (predose); 
o Coagulation (predose); 
• Collect urine for urinalysis (predose). 
• IWRS transaction (cobomarsen dispensation). 
• Administer intravenous infusion of cobomarsen with vital signs performed within 
15 minutes of the end of the infusion. 
• Review and record AEs and concomitant medications. 
9.2.2.6 
Day 15 (± 1 Day) 
• Obtain predose vital signs (blood pressure, heart rate, respiratory rate, and body 
temperature). 
• Perform a brief, symptom-directed physical examination. 
• Collect blood for the following: 
o Hematology (predose); 
o Clinical chemistry (predose); 


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o TSH (predose); 
o PD and ADA (predose). 
• Collect urine for urinalysis (predose). 
• IWRS transaction (cobomarsen dispensation). 
• Administer intravenous infusion of cobomarsen with vital signs performed within 
15 minutes of the end of the infusion. 
• Review and record AEs and concomitant medications. 
9.2.2.7 
Day 22 (± 2 Days) 
• Obtain predose vital signs (blood pressure, heart rate, respiratory rate, and body 
temperature). 
• IWRS transaction (cobomarsen dispensation). 
• Administer intravenous infusion of cobomarsen with vital signs performed within 
15 minutes of the end of the infusion. 
• Review and record AEs and concomitant medications. 
9.2.2.8 
Day 29 (± 3 Days) 
• Perform CTCL disease evaluation using the mSWAT (predose) (see Appendix F). 
• Obtain predose vital signs (blood pressure, heart rate, respiratory rate, and body 
temperature). 
• Perform a brief, symptom-directed physical examination (including documentation of 
weight). 
• Collect blood for the following: 
o Hematology (predose); 
o Clinical chemistry (predose); 
o TSH (predose); 
o Coagulation (predose); 
o PD and ADA (predose); 
o PK (predose, and 5 ± 5 minutes before the end of the infusion). 


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• Collect urine for the following: 
o Urinalysis (predose); 
o Pregnancy test (for females of childbearing potential). 
• Perform a single 12-lead ECG (predose and as soon as possible postdose, ideally within 
30 minutes of the end of infusion). 
• IWRS transaction (cobomarsen dispensation). 
• Administer intravenous infusion of cobomarsen with vital signs performed within 
15 minutes of the end of the infusion. 
• Review and record AEs and concomitant medications. 
9.2.2.9 
Weekly Assessments Starting at Week 6 (± 3 Days) 
Starting at Week 6, the following assessments are required to be done weekly.  
• Obtain predose vital signs (blood pressure, heart rate, respiratory rate, and body 
temperature). 
• IWRS transaction (cobomarsen dispensation). 
• Administer intravenous infusion of cobomarsen with vital signs performed within 
15 minutes of the end of the infusion. 
• Review and record AEs and concomitant medications. 
9.2.2.10 Every-4-Week Assessments from Weeks 9 through 81, then Every-8-Week 
Assessments Thereafter (± 3 Days) 
NOTE:  In addition to the weekly assessments listed above, the following additional assessments 
are required to be done every 4 weeks from Week 9 through Week 81 and then every 8 weeks 
thereafter: 
• Perform CTCL disease evaluation using the mSWAT (predose) (see Appendix F). 
• Perform a brief, symptom-directed physical examination (including documentation of 
weight). 
• Collect blood for the following: 
o Hematology (predose); 
o Clinical chemistry (predose); 


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o TSH (predose); 
o PD and ADA (predose); 
o PK (predose only through Week 81, and every 8 weeks thereafter). 
• Collect urine for the following:  
o Urinalysis (predose); 
o Pregnancy test (performed every 4 weeks while on study treatment), for females of 
childbearing potential. 
• Perform a single 12-lead ECG (predose). 
• Review and record AEs and concomitant medications. 
9.2.3 
End of Treatment Visit 
At the time of study treatment discontinuation, the End of Treatment Visit should be completed 
for all subjects after the last dose of study treatment, and every effort should be made to perform 
the procedures listed below.  This visit should take place as soon as possible and ≤ 14 days after 
the last dose of study treatment.  The date and reason for stopping the study treatment will be 
reported.  The End of Treatment visit is not considered as the end of the study.  All subjects will 
enter Follow-up unless they have withdrawn their consent to do so. 
• Perform CTCL disease evaluation using the mSWAT (see Appendix F). 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Perform a brief, symptom-directed physical examination (including documentation of 
weight). 
• Collect blood for the following: 
o Hematology; 
o Clinical chemistry; 
o TSH; 
o PD and ADA 
o PK. 
• Collect urine for the following:  
o Urinalysis; 


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o Pregnancy test (for females of childbearing potential). 
• Perform a single 12-lead ECG. 
• IWRS transaction (discontinue the subject in the system). 
• Review and record AEs and concomitant medications. 
9.3 
Long-term Follow-up for Subjects Who Have Not Progressed at the 
Time of End of Treatment Visit  
After the End of Treatment Visit, subjects who did not progress on study will be followed until 
progression (confirmed progression in skin, confirmed loss of response in skin or clinical 
progression in lymph nodes, blood or viscera assessed per investigator discretion), withdrawal of 
consent, initiation of subsequent MF treatment, loss to follow-up, or death, and the subject’s final 
disposition is documented and reviewed by the Sponsor study team. 
9.3.1 
Every-4-Week Assessment through Week 81, then Every-8-Week Assessments 
Thereafter (± 3 Days) 
• Perform CTCL disease evaluation using the mSWAT (see Appendix F). 
• Review and record AEs and concomitant medications. 
9.3.2 
Follow-up Visit 28 ± 5 days after the End of Treatment or Early Termination 
For subjects who discontinue treatment, the following assessments will be performed 28 ± 5 days 
after the End of Treatment Visit (assuming the subject has not withdrawn consent). 
• Perform CTCL disease evaluation using the mSWAT (does not need to be repeated if 
disease progression is already confirmed) (see Appendix F). 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and body temperature). 
• Perform a brief, symptom-directed physical examination (including documentation of 
weight). 
• Collect blood for the following: 
o Hematology; 
o Clinical chemistry; 
o TSH; 
o Coagulation; 


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o PD and ADA 
o PK. 
• Collect urine for the following: 
o Urinalysis; 
o Pregnancy test (for females of childbearing potential). 
• Perform a single 12-lead ECG. 
Review and record AEs and concomitant medications. 
10 
ASSESSMENT OF SAFETY 
10.1 
Specification of Safety Parameters 
Safety will be evaluated through continuous monitoring of AEs, vital signs, physical 
examinations, clinical laboratory measurements, and ECGs. 
Management of Infusion-related adverse events: 
Allergic events and/or infusion-related toxicities should be managed according to institutional 
guidelines.  If institutional guidelines are not available, the following recommendations apply.  
Rash, pruritus, urticaria and wheezing due to an infusion-related AE, may be treated with 
diphenhydramine hydrochloride and/or steroids as clinically appropriate.  Anaphylaxis or 
anaphylactoid signs or symptoms may be treated with steroids and/or epinephrine as clinically 
indicated.  Any concomitant therapies used must be recorded in the eCRF.  The Medical Monitor 
should be consulted prior to the use of steroids whenever possible.  Subjects should be treated in 
a facility equipped for cardiopulmonary resuscitation.  Infusion-related reactions (fever, rigors) 
should be treated per institutional guidelines but may be treated with acetaminophen and 
diphenhydramine hydrochloride. 
10.2 
Dose Modifications Interruptions and Stopping Rules  
More than 4 missed consecutive doses of cobomarsen, or a dose interruption of > 14 consecutive 
days of vorinostat, due to an AE or clinically significant laboratory abnormality, or other 
significant noncompliance with study treatment administration should result in permanent 
discontinuation of study treatment, unless it is judged by the Investigator and Sponsor Medical 
Monitor or designee to be in the best interest of the subject to continue treatment.  Regardless of 


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study treatment administration, subjects should continue to follow the study procedure schedule 
outlined in Section 8 and Section 9. 
10.2.1 
Cobomarsen Interruptions or Permanent Discontinuations 
There are no dose reductions allowed for the cobomarsen infusion.   
Infusion-related Adverse Events: 
• If any grade 2 infusion-related AE(s) are observed/reported at any time during the 
infusion, the infusion rate should be decreased by one-half and supportive care 
medications/procedures should be initiated as appropriate.  Upon resolution of the AE, 
the infusion rate should be increased to the rate used prior to the infusion-related AE.  If 
the AE does not resolve prior to the completion of the infusion, the current infusion rate 
should be used with subsequent study treatment administration.  Subjects who had 
grade 2 infusion-related reactions may receive premedication with subsequent infusions. 
• If any grade 3 infusion-related AE(s) are observed/reported at any time during the 
infusion, the infusion should be temporarily interrupted, and supportive care 
medications/procedures should be initiated as appropriate.  Once the symptoms decrease 
to baseline, the infusion may be resumed at one-half the rate and maintained at this rate 
for the remainder of the current infusion and subsequent infusions should be administered 
with premedication.  If a grade 3 infusion-related reaction re-occurs, the subject should 
be permanently discontinued.   
• If grade 4 infusion-related AE(s) are observed/reported at any time during the infusion, 
the infusion will be immediately discontinued, supportive care will be provided as 
needed, and no additional investigational product will be administered to the subject.  
Specific Grade 2 Renal Adverse Events of interest and Grade 3 and 4 Adverse Events of 
Interest (Hematological, Hepatic, TSH, and Constitutional)  
• If any renal grade 2 AE(s) of interest (e.g., creatinine elevation > 1.5 x baseline and 
above the ULN) a repeat serum creatinine level will be performed.  If the repeat 
creatinine level is still > 1.5 x baseline and above the ULN, and no other cause is 
identified for this elevation, study drug will be interrupted until the level returns to 
baseline.  Once the AE has decreased to baseline level, the infusion may be resumed.  If 
the grade 2 AE re-occurs, the subject should be permanently discontinued.   


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• If any grade 3 AE(s) of interest are ongoing at the time of the planned infusion, the 
infusion should be delayed, and supportive care medications/procedures should be 
initiated as appropriate.  Once the AE has decreased to baseline, the infusion may be 
resumed.  If the grade 3 AE re-occurs, the subject should be permanently discontinued.   
• If a grade 4 AE is observed/reported at any time and is felt to place the subject at life 
threatening risk, cobomarsen will be immediately discontinued, and the Medical Monitor 
should be contacted.  No additional investigational product will be administered to that 
subject.  
Other Grade 3 and 4 Adverse Events 
• If any clinically significant (symptomatic, requiring intervention) grade 3/4 AE(s) or 
laboratory abnormalities are ongoing at the time of the planned infusion, the infusion 
should be delayed, and supportive care medications/procedures should be initiated as 
appropriate.  Once the AE resolves or symptoms decrease to baseline, the infusion may 
be resumed.  If the grade 3/4 AE re-occurs, the subject should be permanently 
discontinued.   
• If any non-clinically significant (asymptomatic, not requiring an intervention) grade 
3/4 AE(s) or laboratory abnormalities are observed/reported at any time, the infusion may 
be temporarily interrupted based on the investigator’s opinion (in consultation with the 
Medical Monitor), and supportive care medications/procedures should be initiated as 
appropriate.  Once the symptoms decrease to baseline, the infusion may be resumed.   
10.2.2 
Vorinostat Dose Modifications, Interruptions, or Permanent Discontinuations 
In general, doses of vorinostat should not be adjusted, reduced or interrupted for grade 1 AEs, 
but treatment may be instituted to control symptoms.   
Vorinostat dose interruption or dose reduction may be considered if it is felt to be necessary 
(e.g., for AEs ≥ grade 2) (PDR 2018). 
• Dose Reduction 1:  If vorinostat therapy intolerance occurs and dose reduction is 
deemed appropriate, the dose may be reduced to 300 mg orally once daily with food. 
• Dose Reduction 2: If intolerance continues, the dose may be reduced to 300 mg once 
daily with food for 5 consecutive days each week. 
• No re-escalation of vorinostat dose or schedule is allowed during the study.  


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Grade 3 and 4 Adverse Events 
• If any clinically significant (symptomatic, requiring intervention) grade 3/4 AE(s) or 
laboratory abnormalities occur, the dose should be delayed, and supportive care 
medications/procedures should be initiated as appropriate.  Once the AE resolves or 
symptoms decrease to baseline, vorinostat may be resumed.  If the grade 3/4 AEs 
re-occurs, the subject should be permanently discontinued.   
• If any non-clinically significant (asymptomatic, not requiring an intervention) grade 
3/4 AE(s) or laboratory abnormalities are observed/reported at any time, vorinostat may 
be temporarily interrupted based on the investigator’s opinion and supportive care 
medications/procedures should be initiated as appropriate.  Once the symptoms decreased 
to baseline, vorinostat may be resumed.  
QT/QTc Prolongation Adverse Events 
Vorinostat is known to cause QT/QTc prolongation in patients.  Please use the following criteria 
in the management of vorinostat patients on the clinical study.   
• If any clinically significant QT/QTc interval prolongation of ≤ 500 msec is 
observed/reported at any time, vorinostat dosing should be interrupted and investigations 
about possible causes (electrolyte imbalance, concomitant medications, etc.), supportive 
care medications/procedures should be initiated.  If other cause is found, once the QTc is 
documented to be back into normal range, a re-challenge with vorinostat could be 
considered, based on the investigator’s discretion.   
• If any QT/QTc interval prolongation of > 500 msecs is observed, vorinostat should be 
permanently discontinued.  Consultation with a cardiologist is required and the subject 
should have continuous ECG monitoring until released by the cardiologist.   
If vorinostat is not tolerable and therapy must be discontinued, study assessments will be 
continued on an every-4-week visit schedule to follow the subject until confirmed progression, if 
the subject consents to continued follow-up visits.  
Whenever possible, additional therapies for MF should not be initiated until disease progression 
is documented.  Subjects will not be eligible for the  crossover period of the study unless: 
• Skin disease progression is confirmed;  
• No additional systemic therapies for MF have been initiated. 


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10.3 
Definition of Adverse Events  
10.3.1 
Adverse Event  
An AE is any untoward medical occurrence whether or not considered drug related.  An AE can 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a drug and does not imply any judgment about 
causality.  An AE can arise with any use of the drug (e.g., off-label use, use in combination with 
another drug) and with any route of administration, formulation, or dose, including an overdose.  
Please note that disease progression is not considered an AE. However, a primary adverse event 
associated with disease progression that meets the criteria for an SAE should be reported. 
10.3.2 
Suspected Adverse Reaction  
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE.  For the purposes of Investigational New Drug (IND) safety reporting, 
‘‘reasonable possibility’’ means there is evidence to suggest a causal relationship between the 
drug and the AE.  Suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any AE caused by a drug. 
10.3.3 
Life-Threatening Adverse Event or Life-Threatening Suspected Adverse Reaction  
An AE or suspected adverse reaction is considered ‘‘life-threatening’’ if, in the view of either the 
Investigator or Sponsor, its occurrence places the subject at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
10.3.4 
Serious Adverse Event or Serious Suspected Adverse Reaction  
An AE or suspected adverse reaction is considered ‘‘serious’’ if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
• Death; 
• A life-threatening AE (see Section 10.3.3); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• A persistent or significant disability or incapacity or substantial disruption of the ability 
to conduct normal life functions; 


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• A congenital anomaly/birth defect; 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization. 
10.3.5 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction  
An AE or suspected adverse reaction is considered ‘‘unexpected’’:  
• If it is not listed in the Investigator’s Brochure or is not listed at the specificity or severity 
that has been observed, or  
• If it is not consistent with the risk information described in the general investigational 
plan, or elsewhere in the current application, as amended.  
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the Investigator’s Brochure referred only to elevated hepatic enzymes or hepatitis.  
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the Investigator’s Brochure listed only cerebral vascular accidents.  
‘‘Unexpected,’’ as used in this definition, also refers to AEs or suspected adverse reactions that 
are mentioned in the Investigator’s Brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug but are not specifically mentioned as occurring 
with the particular drug under investigation. 
10.3.6 
Adverse Events of Special Interest  
Adverse events of special interest are those that have been identified in preclinical studies, as 
well as known AEs from oligonucleotides as a drug class and those from the cobomarsen 
emerging AE profile from the Phase 1 study.  These AEs of interest will be closely monitored, 
and specific dose interruption rules have been established.  These include: 
• Hematological: neutropenia, lymphopenia; 
• Hepatic: increase transaminases, gamma-glutamyl transferase (GGT), bilirubin consistent 
with hepatic involvement; 


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• Renal: increase serum creatinine, blood urea nitrogen (BUN) and hematuria, proteinuria, 
consistent with kidney involvement; 
• Increased TSH; 
• Constitutional symptoms: acute fever, chills, myalgias, fatigue. 
10.4 
Adverse Event Classification  
10.4.1 
Relationship to Study Treatments  
The Investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious).  An Investigator’s causality assessment is the determination of whether there exists 
a reasonable possibility that the investigational product caused or contributed to an AE. 
• Not related:  The AE is clearly not related or is unlikely to be related to the study 
treatment.  The temporal relationship of the onset of the AE relative to administration of 
the product is not reasonable, or the AE can be explained by another cause such as an 
underlying medical condition or other concomitant therapy, or the AE has no plausible 
relationship to study therapy. 
• Related:  The AE is related to the study treatment.  The temporal relationship of the AE 
to administration of the product is reasonable and there is no other cause to explain the 
event.  AEs should be classified as related if the Investigator feels the event may 
reasonably be regarded as caused by, or probably caused by, the study treatment. 
10.4.2 
Severity 
All AEs entered into the eCRF will be graded for severity using the NCI CTCAE, version 5.0.  If 
an AE is not listed in the CTCAE version 5.0, then the Investigator will use the terms:  Mild, 
Moderate, Severe, or Life-threatening to describe the maximum intensity of the AE.  For 
purposes of consistency, these intensity grades are defined as follows: 
Severity 
Definition 
Grade 0 
No change from Normal or Reference Range 
Grade 1 (Mild) 
No limitation of usual activities. 
Grade 2 (Moderate) 
Some limitation of usual activities. 
Grade 3 (Severe) 
Inability to carry out usual activities. 
Grade 4 (Life-threatening) 
Immediate risk of death. 
Grade 5 (Death) 
Resulting in death 


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10.5 
Collection and Reporting of Adverse Events 
10.5.1 
Reporting of Adverse Events 
Subjects will be evaluated and questioned generally to identify AEs during the course of the 
study.  Any AEs occurring prior informed consent will be recorded on the Medical History 
eCRF.  All AEs from the time of informed consent, including those deemed to be related to a 
study procedure, should be reported on the Adverse Event eCRF.  All AEs, including SAEs, will 
be reported from the time of informed consent.  All events occurring after administration of the 
first dose of study treatment or those that increase in severity or frequency will be considered 
treatment-emergent adverse events (TEAEs).  Adverse events that occur from the time of 
informed consent up to and including 60 days after the last dose of study treatment, regardless of 
causality to study treatment, must be reported. Any treatment related AE reported by a subject 
during the clinical study, even if it occurs later than 60 days after the last dose of study treatment, 
should be reported in the eCRF.   
All AEs spontaneously reported by the subject and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded on the Adverse Event eCRF.  Clinically significant changes in vital signs and 
clinically significant findings on physical examination will be recorded as AEs. 
Any clinically significant change in laboratory assessments or other clinical findings, as assessed 
by the Investigator, is considered an AE and must be recorded on the Adverse Event eCRF.  In 
addition, an abnormal test finding will be classified as an AE if one or more of the following 
criteria are met: 
• The test finding is accompanied by clinically significant symptoms; 
• The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention; including additional concomitant drug treatment or other therapy.  Note: 
simply repeating a test finding, in the absence of any of the other listed criteria, does not 
constitute an AE; 
• The test finding leads to a change in study treatment dosing or discontinuation of subject 
participation in the clinical research study; 
• The test finding is considered an AE by the Investigator. 
Wherever possible, a specific disease, diagnosis or syndrome rather than individual associated 
signs and symptoms should be identified.  However, if an observed or reported sign or symptom 


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is not associated with a documented disease or syndrome, the sign or symptom should be 
recorded as a separate AE.  Laboratory data are to be collected as stipulated in this protocol.  
Clinical syndromes associated with laboratory abnormalities are to be recorded as appropriate 
(e.g., diabetes mellitus rather than hyperglycemia). 
10.5.2 
Follow-up of Adverse Events 
All AEs considered to be related to study treatment will be followed until resolution or 
stabilization. 
10.6 
Collection and Reporting of Serious Adverse Events 
10.6.1 
Initial Serious Adverse Event Reports 
All SAEs that occur from the time of informed consent up to and including 60 days after the last 
dose of study treatment must be reported by the Investigator to the Sponsor or Sponsor’s 
designated representative immediately, and in no circumstances later than 24 hours after gaining 
awareness of the event by submission of a SAE Notification Form.  Investigators must report to 
the Sponsor or the Sponsor’s designated representative any SAE, whether or not considered drug 
related, including those listed in the protocol or Investigator’s Brochure.  The initial report must 
contain at a minimum a subject identifier code, an event term, and an assessment of causality.  
The SAE Notification Form should be faxed or e-mailed to: 
 
 
 
 
If the Investigator is unable to complete and send the SAE Notification Form within the 
timeframe required, the SAE must be reported via phone call to the Medical Monitor (see contact 
sheet in the study reference binder) and 
. 
An Investigator may be requested by the Sponsor or the Sponsor’s designated representative to 
obtain specific follow-up information in an expedited fashion.  This information may be more 
detailed than that captured on the Adverse Event eCRF.  In general, this will include a 
description of the SAE in sufficient detail to allow for a complete medical assessment of the case 
and independent determination of possible causality.  Information on other possible causes of the 
event, such as concomitant medications and illnesses must be provided.  In the case of a subject 


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death, a summary of available autopsy findings must be submitted as soon as possible to the 
Sponsor or the Sponsor’s designated representative. 
10.6.2 
Follow-up of Serious Adverse Events 
All SAEs should be followed up until resolution or stabilization.  The timelines and procedure 
for follow-up reports are the same as those for the initial report. 
New information regarding an SAE that becomes available after the submission of the initial 
SAE Notification Form must be reported by the Investigator to the Sponsor or the Sponsor’s 
designated representative by completion of a SAE Follow-up Report Form or through other 
written documentation (e.g., laboratory tests, discharge summary, postmortem results).  
Follow-up reports and/or written documentation must be provided to the Sponsor or the 
Sponsor’s designated representative immediately, and no later than 24 hours after the 
Investigator’s receipt of the information. 
10.7 
Post-Trial Adverse Events 
Any AE that occurs outside of the protocol-specified observation or after the end of the trial but 
is considered to be caused by the study treatment must be reported to the Sponsor or the 
Sponsor’s designated representative.  
10.8 
Pregnancy Reporting and Follow-up 
Pregnancy in a female clinical trial subject is not an SAE per se.  Complications of such 
pregnancies, for example, spontaneous abortion, may qualify as an SAE and should be reported 
as an SAE even if they occur after the SAE reporting period has ended.   
The Investigator must notify the Sponsor via telephone or e-mail immediately, and no later than 
24 hours after awareness of a pregnancy in a study subject and must complete the Pregnancy 
Notification Form and submit it to the Sponsor within 2 working days of being notified.  The 
subject will not receive any further doses of their assigned study treatment and will be 
permanently discontinued from study treatment.  The pregnancy must be followed to determine 
outcome, including spontaneous or voluntary termination, details of birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications.  This follow-up should occur even if the intended duration of safety follow-up for 
the trial has ended.  Information regarding the course of the pregnancy, including perinatal and 
postnatal offspring outcome up to 8 weeks of age should be reported as follow-up information on 
the Pregnancy Notification Form. 


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Male study subjects will be instructed to notify the Investigator if a female partner becomes 
pregnant during the study.  The Investigator must notify the Sponsor immediately and no later 
than 24 hours via telephone or e-mail and must complete the Pregnancy Notification Form and 
submit it to the Sponsor within 2 working days of being notified.  The Investigator should obtain 
informed consent from the subject’s partner allowing the Investigator to obtain information 
regarding the pregnancy and its outcome.  If the subject’s partner provides informed consent, the 
Investigator should follow the pregnancy until outcome as described above for female study 
subjects and report the follow-up information on the Pregnancy Notification Form. 
10.9 
Study Termination 
The Sponsor may suspend enrollment or terminate the study at any time for safety concerns or 
other reasons. 
10.10 
End of Study Definition  
The end of the study is defined as the timepoint when all study subjects meet at least one of the 
following criteria: 
1. Confirmed progression in the randomized period for subjects randomized to cobomarsen 
2. Confirmed progression in the randomized period for subjects randomized to vorinostat 
who choose not to participate in the crossover period 
3. Confirmed progression in the crossover period 
4. Full withdrawal of consent or lost to follow-up 
5. Death 
6. Duration on the study (from randomization) of at least 3 years.  
or, the study is terminated early by the Sponsor. 
10.11 
Emergency Sponsor Contact  
In a medical emergency (i.e., an event that requires immediate attention regarding operation of 
the clinical study and/or the use of investigational drug), study site staff will apply appropriate 
medical intervention according to current standards of care, and contact the Medical Monitor 
(see contact sheet in the study reference binder) or the designated Sponsor representative, as 
indicated in Section 1 of this protocol. 


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11 
TRIAL-SPECIFIC COMMITTEES 
11.1 
Data Monitoring Committee  
The Data Monitoring Committee (DMC) will be responsible for reviewing safety data at regular 
intervals as well as to perform the interim analysis.  A separate DMC Charter will be established 
that outlines DMC membership, precisely what data will be reviewed, along with the timing and 
frequency of the reviews.  DMC recommendations will be provided to the Sponsor in 
compliance with the DMC Charter. 
11.2 
Steering Committee  
The study Steering Committee (SC) will be appointed by the Sponsor prior to the initiation of the 
study.  The SC will include principal investigators from the study and Sponsor representatives.  
The SC will be involved in the oversight of the study and will ensure transparent management of 
the study according to the protocol through recommending modifications as circumstances 
require.  Details on the role of the SC and working procedures will be defined in the SC Charter. 
12 
STATISTICAL CONSIDERATIONS 
12.1 
Statistical and Analytical Plans 
Final statistical analysis will be completed after the last subject completes or discontinues the 
study and the study database has been cleaned, verified, and locked.  Based on timing of the 
primary and secondary endpoints, additional interim database locks may occur, before the final 
database lock. 
A statistical analysis plan (SAP) will be completed prior to the database lock.  This document 
will provide a technical and detailed description of the data analysis methods and procedures. 
The results of the final analysis will be presented in the clinical study report.  Any deviations 
from planned statistical analyses will be presented in the clinical study report. 
12.2 
Study Hypotheses 
The primary endpoint is objective response in skin of at least 4 months duration (ORR4).  
Response to cobomarsen will be compared to the control group using a Cochran-Mantel-Haenzel 
(CMH) statistic incorporating the stratification factors from the randomization.   


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The randomization will be stratified based on subjects with at least one skin tumor at Screening 
vs. no skin tumors at Screening.  Subjects will also be stratified based on prognostic factors (age 
at diagnosis > 60 years and LDH level > ULN at diagnosis) (Scarisbrick et al. 2015).  Subjects 
will be stratified based on having 0-1 vs 2 of these prognostic factors. 
There is only one primary and one key secondary endpoint (PFS) for analysis; a one-sided 
p=0.025 for response by CMH will establish statistical significance.  The study hypothesis is that 
response to cobomarsen is superior to the control group.  The null hypothesis (Ho) is that N (%) 
of responders to cobomarsen and N (%) of responders to control do not differ; the alternative 
hypothesis (Ha) is that N (%) of responders to cobomarsen is superior to N (%) of responders to 
control.  A step-down procedure will be used to assess the statistical significance of PFS, such 
that a statistically significant difference in PFS will be confirmatory of a treatment effect only if 
the analysis of the primary endpoint is statistically significant at the one-sided 0.025 level of 
significance. 
12.3 
Analysis Datasets 
Assignment of subjects to analysis sets will be done prior to database lock.  The following 
analysis sets will be defined: the Intent to Treat analysis set (ITT), the Safety set, the Per 
Protocol Set (PPS), and the PK Analysis Set (PKAS). 
12.3.1 
Intent to Treat Analysis Set (ITT) 
The ITT will include all randomized subjects who received at least one dose of study treatment 
(cobomarsen or vorinostat) and had at least one post-baseline assessment. 
12.3.2 
Safety Set  
The Safety set will include all randomized subjects who received at least one dose of study 
treatment (cobomarsen or vorinostat). 
12.3.3 
Per Protocol Set (PPS) 
The PPS will consist of all subjects randomized to the study, who received study treatment, and 
completed assessments necessary for the evaluation of the primary endpoint with no major 
protocol deviations that would affect endpoint analysis. 


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12.3.4 
Pharmacokinetic Analysis Set (PKAS) 
The PKAS will consist of subjects randomized to cobomarsen who received at least one dose of 
cobomarsen and had at least one post baseline PK sample taken and analyzed. 
12.4 
Statistical Methods and Sample Size Justification 
12.4.1 
General Approach 
All statistical analyses will be performed using SAS statistical software, unless otherwise noted.  
For categorical variables, the number and percent of each category within a parameter will be 
presented.  For continuous variables, the sample size (n), mean, median, standard deviation, 
minimum and maximum values will be presented.  Missing data will not be imputed unless 
otherwise stated. 
12.4.2 
Analysis of Demographics and Other Baseline Characteristics 
Demographics and other baseline disease characteristics will be summarized by treatment group. 
12.4.3 
Analysis of the Primary Efficacy Endpoint 
The analysis of the primary efficacy endpoint is the proportion of subjects in the randomized 
period achieving an ORR4 in skin using mSWAT assessments.  ORR4 is the proportion of 
subjects with a CR or PR for 4 consecutive months confirmed by repeat assessments no less than 
28 days (± 3 days) later (Olsen et al. 2011). 
12.4.4 
Analysis of the Secondary Endpoints 
The secondary endpoint of progression-free survival is defined as the time from randomization to 
the date of the earliest documented progression or death due to any cause.   
Time to event analyses (Kaplan-Meier) will be done for PFS, time to ≥ 50% mSWAT 
improvement, time to maximal effect in skin, duration of maintaining response in skin, CRR, and 
TTP.  For responding subjects, duration of response and duration of ≥ 50% improvement will be 
displayed.  
Summary statistics for change from Baseline for mSWAT scores will be presented by treatment 
and visit. 


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The percent of subjects achieving ≥ 50% improvement in mSWAT scores will be presented by 
treatment for: 
• ≥ 50% improvement for at least 28 days; 
• ≥ 50% improvement at 4 months; 
• ≥ 50% improvement at 28 days. 
The N (%) of complete responses will be presented by treatment. 
P-values generated from secondary analyses are supportive only.  The mean change from 
baseline in use of pruritus medication will be presented by treatment and visit.  
12.4.5 
Safety Analyses 
Treatment-emergent AEs will be coded by preferred term and system organ class using the 
Medical Dictionary for Regulatory Activities (MedDRA®) and summary tables for all AEs will 
be generated for the Safety Population.  Incidence rates and percentages will be summarized by 
preferred term and system organ class.  Additional summary tables will be generated for the 
following population subsets:  subjects with SAEs, subjects with treatment related AEs, subjects 
who discontinue due to AEs, and subjects with grade 3 or 4 AEs.  Severity will be assessed 
according to the NCI CTCAE version 5.0 and relationship to study treatment will be attributed 
by investigator. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD; March 2015 or later version).  A dictionary listing of all unique concomitant 
medications used in the study will be provided. 
12.4.5.1 Laboratory Data 
All hematology, chemistry, TSH, coagulation, and urinalysis results will be listed by subject for 
each assessment and descriptive statistics may be tabulated for select criteria.  Changes from 
baseline may be summarized by treatment. 
12.4.5.2 Physical Examination 
Clinically significant changes in vital signs and clinically significant findings on physical 
examination will be recorded as AEs.  Incidence of subjects with changes from normal physical 
examination findings at baseline to abnormal during the study may be generated. 


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12.4.5.3 Twelve-lead ECG 
Information on ECGs will be presented in listings.  The incidence of subjects with changes from 
normal ECG findings at baseline to abnormal during the study will be generated as appropriate.  
Summary of mean/median changes in ECG intervals may be generated on a data-driven basis. 
12.4.6 
Pharmacokinetic Analysis 
The concentration-time data will be used to prepare a population PK model for cobomarsen in 
subjects.  The actual elapsed time from dose will be used in the final PK modeling and parameter 
calculations.  The PK/PD analysis of the study will be used to describe the cobomarsen and its 
metabolite(s) (if applicable) concentration time profile(s) and exposure/response relationships 
with respect to PD/clinical/safety endpoints by means of modeling and simulation.  Full details 
of the relevant population PK modeling work (including objectives, relevant endpoints, 
methodology, software etc.) will be defined in a separate data analysis plan or the study 
integrated analysis plan.  The results of these analyses will be described in a separate report from 
the clinical study report. 
The exact date/time of sample collections (and dosing events) should be recorded (in the eCRF).  
Although every effort should be made to collect PK blood samples according to the Schedule of 
Events, blood samples collected outside of the planned window are not to be considered protocol 
deviations as long as the actual collection date and time is recorded, with the exception of the 
predose sample, which will be considered a deviation if it is not collected predose. 
12.4.7 
Planned Interim Analyses 
An interim analysis will be performed after approximately 40 subjects are followed for a 
minimum of approximately 6 months to allow assessment for a 4-month duration of response 
(ORR4) from the date of initial objective response. A decision to stop the study at interim 
analysis for superiority will be considered if the one-sided test statistic p-value is < 0.01 (Pocock, 
et al. 1977). The number of skin ORR4 events required to demonstrate superiority at the interim 
analysis are shown in Table 6. 


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Table 6: 
ORR4 Events Required to Demonstrate Superiority in Skin Objective 
Response for Interim Analysis (p < 0.01) 
Vorinostat 
(N = 18) 
Cobomarsen 
(N = 18) 
0/18 
6/18 
1/18 
8/18 
2/18 
10/18 
3/18 
11/18 
4/18 
12/18 
5/18 
13/18 
6/18 
14/18 
7/18 
15/18 
8/18 
16/18 
9/18 
17/18 
10/18 
18/18 
11/18 
18/18 
12/18 
18/18 
Enrollment will be halted if data from this study or other cobomarsen studies conclusively 
demonstrate that cobomarsen does not have significant activity in MF.   
12.5 
Sample Size Determination 
12.5.1 
Primary Endpoint Sample Size  
A sample size of 126 subjects (63 per group) provides greater than 80% power to detect a 
difference between cobomarsen and vorinostat, after accounting for the alpha spend at the 
interim analysis (interim alpha = 1%, one sided).  This power statement assumes a response rate 
of 35% in the cobomarsen group and 10% in the vorinostat group, using a one-sided, two sample 
binomial test of proportions at the adjusted final one-sided alpha of 1.5% (total alpha = 2.5%, 
one sided). The planned primary analysis will account for all randomized subjects. Power was 
computed using the normal approximation method. When the normal approximation method is 
used to compute power for Fisher's Exact Test, the results are based on the pooled, continuity-
corrected Chi-Square test (i.e. Z-Test C.C. (Pooled)). (Kim et al. 2017). 


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12.5.2 
Key Secondary Endpoint Sample Size 
The null hypothesis is that there is no difference in progression free survival (PFS) between 
cobomarsen and vorinostat. A sample size of 126 subjects (63 per group; 66 events) provides at 
least 80% power to detect a difference between vorinostat and cobomarsen, assuming a median 
PFS of 4 months for vorinostat and 8 months for cobomarsen. This calculation is based on a one-
sided, logrank test at the 0.025 level of significance, assuming 15 months of recruitment, 6 
months of follow-up, and 17% censoring. No interim analysis is planned for PFS. 
12.6 
Measures to Minimize Bias 
12.6.1 
Randomization Procedures 
The randomization will be stratified based on subjects with at least one skin tumor at Screening 
vs. no skin tumors at Screening.  Subjects will also be stratified based on prognostic factors (age 
at diagnosis > 60 years and LDH level > ULN at diagnosis) (Scarisbrick et al. 2015).  Subjects 
will be stratified based on 0-1 vs 2 of these prognostic factors. 
12.6.2 
Evaluation of Success of Blinding 
Not applicable 
12.6.3 
Breaking the Study Blind 
Not applicable 
13 
DATA HANDLING AND RECORD KEEPING 
13.1 
Study Files and Subject Source Documents 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents include 
the subject’s clinical source documents and Investigator’s Study Files. 
Subject clinical source documents may include, but are not limited to, hospital/clinic records, 
physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, radiograph, 
pathology and special assessment reports and consultant letters. 
The investigator will ensure the Study Files are maintained, including the eCRFs and query 
forms, protocol/amendments, IRB/IEC and regulatory approvals with associated correspondence, 
signed ICFs, study treatment records, staff curriculum vitae and authorization forms, all 


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correspondence and other appropriate documents.  Such data shall be secured in order to prevent 
loss. 
The investigator will allow personnel authorized by the Sponsor access to all study data at any 
time. 
13.2 
Data Collection Methods 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Investigator.  The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported.  An eCRF must be completed for each person who 
signs informed consent, regardless of the duration of their trial participation. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  When making changes or corrections, cross out the original entry with a 
single line, and initial and date the change.  DO NOT ERASE, OVERWRITE, OR USE 
CORRECTION FLUID OR TAPE ON THE ORIGINAL.  Documents (including laboratory 
reports, hospital records subsequent to SAEs, etc.) transmitted to the CRO or the Sponsor should 
include the assigned subject identifier but should not include the subject’s name in order to 
ensure confidentiality. 
Electronic CRFs will be provided for recording data for each subject enrolled in the study.  Data 
reported in the eCRF derived from source documents should be consistent with the source 
documents or the discrepancies should be explained and maintained in the subject’s official 
electronic study record.  The Investigator should consult the eCRF completion guidelines for 
comprehensive instructions for completing the eCRF. 
Clinical data will be entered into a 21 CFR Part 11-compliant electronic data capture system, 
unless otherwise specified.  The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate.  Clinical data will be entered directly from the source documents. 
13.3 
Retention of Records 
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an International Conference on Harmonization (ICH) 
region and until there are no pending or contemplated marketing applications in an ICH region; 
or, if no application is filed or if the application is not approved for such indication, until 2 years 
after the investigation is discontinued and regulatory authorities have been notified.  


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Investigators may need to retain documents longer if required by applicable regulatory 
requirements or if requested by the Sponsor.  The investigator must notify the Sponsor prior to 
destroying any clinical study records.  Should the investigator wish to assign the study records to 
another party or move them to another location, the Sponsor must be notified in advance.  It is 
the responsibility of the Sponsor to inform the investigator when these documents no longer need 
to be retained. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and miRagen to 
securely store the documents in an off-site storage location so that they can be returned to the 
investigator in case of a regulatory audit.  Where source documents are required for the 
continued care of the subject, appropriate copies should be made for off-site storage. 
13.4 
Protocol Deviations 
The investigator and the study site staff are responsible for ensuring the study is conducted in 
accordance with the schedule of procedures and assessments described in this protocol and in 
accordance with Good Clinical Practice (GCP).  The site must use continuous vigilance to 
identify and document any deviations that occur.  All deviations must be reviewed by the 
investigator to assess whether the safety of study participants or study integrity has been affected 
by the deviation. 
Intentional deviations from the protocol shall not be made except in a medical emergency, when 
the intent is to reduce immediate risk to the subject.  In such cases, the Sponsor, CRO, the 
IRB/IEC and regulatory authorities, as appropriate, should be notified, in accordance with local 
requirements.  In all other cases, the nature of the deviation, the justification for the deviation, 
and prior written approval of the Sponsor must be documented. 
Under no circumstance should the investigator contact the Sponsor or designee monitoring the 
study, to request approval of a protocol deviation, as no authorized deviations are permitted. 
Changes to the protocol may be made only when a written substantial protocol amendment has 
been approved by the Sponsor and submitted to the IRB/IEC and applicable regulatory agencies 
in accordance with local requirements.  Appropriate approval(s) must be obtained before changes 
can be implemented. 


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14 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality Control procedures will be implemented beginning with the data entry system, and data 
quality control checks will be run on the database.  Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
The Sponsor (or designee) is responsible for ensuring the proper conduct of the study with regard 
to protocol adherence and validity of data recorded in the eCRFs by assigning CRAs to each site.  
The CRA is responsible for reviewing the eCRFs at regular intervals throughout the study, 
verifying adherence to the protocol, assuring completeness, consistency and accuracy of the data, 
and reviewing study files and drug accountability.  The data will be verified against the original 
medical records and laboratory results as part of source document verification to ensure validity 
of the data.  The investigator’s responsibility is to ensure that any issues detected in the course of 
a monitoring visit are resolved. 
To ensure compliance with GCP and all applicable regulatory requirements, a quality assurance 
audit may be conducted by the Sponsor or the Sponsor’s designee.  Regulatory agencies may 
also conduct a regulatory inspection of this study.  Such audits/inspections can occur at any time 
during or after completion of the study.  If an audit or inspection occurs, the investigator and 
institution agree to allow the auditor/inspector direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues. 
The investigator and study staff are responsible for maintaining a comprehensive and accurate 
filing system of all study-related documentation that will be suitable for inspection at any time 
by the Sponsor, its designees, and/or regulatory agencies (see Section 13.3).  In signing this 
protocol, the investigator understands and agrees to give access to the necessary documentation 
and files. 
15 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
This Section 15 of the Clinical Trial Protocol is subject to the terms of the Clinical Trial 
Agreement between miRagen Therapeutics, Inc. and the study centers.  In the event of a 
discrepancy between the Clinical Trial Agreement and this Clinical Trial Protocol, the terms of 
the Clinical Trial Agreement shall control. 


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15.1 
Ethical Conduct of the Study 
This study will be conducted in compliance with the ICH GCP guidelines, US regulations for the 
ethical conduct of clinical studies under 21 Code of Federal Regulations (CFR; Parts 50, 56 and 
312), the European Clinical Trials Directive 2001/20/EC and implementing national regulations, 
the European Clinical Trials Regulation No. 536/2014, the Declaration of Helsinki, and with ICH 
guidelines regarding scientific integrity (E4, E8, E9 and E10).  This study will also adhere to all 
FDA, state and local regulatory requirements, and requirements for data protection. 
15.2 
Institutional Review Board/Independent Ethics Committee Review 
Before trial initiation, the investigator and institution must have written and dated approval from 
an accredited IRB/IEC for the study protocol, written ICF, subject recruitment procedures (e.g., 
advertisements), and any written information to be provided to subjects.  Any amendment to the 
protocol will require review and approval by the IRB/IEC before the changes are implemented to 
the study.  All changes to the consent form will be IRB/IEC approved prior to implementing the 
change; a determination will be made regarding whether previously consented subjects need to 
be re-consented using the amended form. 
Appropriate reports on the progress of the study will be made by the investigator to the IRB/IEC 
and the Sponsor in accordance with applicable regulations.  All correspondence with the 
IRB/IEC should be retained in the investigator’s Study File.  Copies of IRB/IEC approvals 
should be forwarded to miRagen or its designee. 
15.3 
Informed Consent Process 
An ICF template will be provided by the Sponsor to the investigator for submission to the 
IRB/IEC.  Any site-specific changes to the ICF must be approved by the Sponsor prior to its 
submission to the IRB/IEC.  The ICF must be approved by the IRB/IEC prior to being presented 
to potential study subjects. 
Individuals may agree to participate in the clinical trial only after the risks and possible benefits 
of their participation have been explained and extensively discussed.  The investigator will 
explain the purposes, procedures, and potential risks of the research study in terms suited to their 
comprehension, as well as their rights as a research subject.  Subjects will have the opportunity 
to carefully review the written ICF, discuss the study with their surrogates, and ask questions 
prior to signing.  Written informed consent must be obtained from each study subject or his/her 
legally acceptable representative prior to conducting any study-related procedures. 


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The investigator must use the most current IRB/IEC-approved ICF for documenting written 
consent.  Each informed consent will be appropriately signed and dated by the subject or the 
subject’s legally acceptable representative and by the person obtaining consent.  The site must 
retain the original signed ICF and provide a copy to the subject. 
15.4 
Confidentiality of Information 
Individual subject medical information obtained as a result of this study is considered 
confidential.  The investigator and the study center will adhere to all applicable laws relating to 
the protection of subject information.  To assure that subject confidentiality is maintained, 
subject data will be identified only by a study-assigned number on any Sponsor forms, reports, 
publications, or in any other disclosures, except where required by law. 
All personnel of miRagen Therapeutics, Inc. and its designees with access to the primary study 
data will handle subject data in a confidential manner in accordance with applicable regulations 
governing clinical research.  Subject records will be inspected only in connection with this 
research project.  Information generated as a result of a subject’s participation in this study may 
be disclosed to third parties for research, regulatory, and other purposes in any country as 
determined by miRagen Therapeutics, Inc.  However, subjects will not be individually identified 
but will be referred to by the study-assigned number. 
15.5 
Future Use of Stored Specimens 
Laboratory data collected for this study will be analyzed and stored at the central laboratory. 
With the subject’s approval and as approved by local IRBs, de-identified biological samples will 
be stored at the central laboratory for up to 2 years after the completion of the study.  These 
samples could be used for future research performed by miRagen or its collaborators into the 
causes of MF, its complications, and other conditions for which individuals with MF are at 
increased risk, and to improve treatment. 
16 
PUBLICATION POLICY 
Publication and/or disclosure of information or data related to this Clinical Trial Protocol is 
subject to and governed by the Clinical Trial Agreement between miRagen Therapeutics, Inc. 
and the study center to which the Principal Investigator is a signatory. 


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After conclusion of the study, investigators in this study may make oral presentations of study 
results or publish such results in scientific journals or other scholarly media without prior written 
approval from miRagen Therapeutics, Inc., only after the following conditions have been met: 
• The results of the study in their entirety have been publicly disclosed by or with the 
consent of miRagen Therapeutics, Inc. in an abstract, manuscript or presentation forum; 
• The investigator has complied with the terms of the Clinical Trial Agreement and all 
requests from miRagen Therapeutics, Inc. to delete any references to its confidential 
information (other than study results); 
• The study has been completed at all study sites for at least 1 year. 


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17 
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45. Thai TH, Calado DP, Casola S, et al. Regulation of the germinal center response by 
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18 
LIST OF APPENDICES 
Appendix A. Schedule of Events (Screening, Randomized Period) .........................................125 
Appendix B. Schedule of Events (On Treatment and Post-Treatment Follow-up – Cobomarsen 
Group) ..................................................................................................................127 
Appendix C. Schedule of Events (On Treatment and Post-Treatment Follow-up – Vorinostat 
Group) ..................................................................................................................130 
Appendix D. Crossover Period Schedule of Events (Screening, Crossover Period) .................132 
Appendix E. Crossover Period Schedule of Events (Crossover On Treatment and Post-
Treatment Follow-up) ..........................................................................................134 
Appendix F. Modified Severity Weighted Assessment Tool and Response Criteria ...............136 
Appendix G. National Comprehensive Cancer Network (NCCN) Guidelines for Treating 
Mycosis Fungoides/Sézary Syndrome .................................................................139 
Appendix H. TNMB Staging of Mycosis Fungoides ................................................................140 
Appendix I. 
Potency (Per Protocol) of Topical Corticosteroid Products .................................142 


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Appendix A. Schedule of Events (Screening, Randomized Period) 
Study Procedure or Assessment (completed after obtaining informed consent from the 
patient). 
Screening a 
Weeks Prior to Randomization 
-4
Time of Randomization 
Study Day Prior to Randomization 
-28 to -3
Day -3 to -1 
Registration in Interactive Web Response System 
X 
X i
Modified Severity Weighted Assessment Tool (mSWAT) 
X 
Medical History and Concomitant Medications b 
X 
Report Prior CTCL Treatments 
X 
ECOG Performance Status 
X 
Vital Signs 
X 
Complete Physical Examination Including Weight and Height 
X 
Triplicate 12-lead Electrocardiogram c 
X 
Radiological Imaging (CT/MRI Scans) d 
X 
HIV, Hepatitis B, Hepatitis C Screening e 
X 
Follicle-stimulating Hormone e, f 
X 
Serum Pregnancy Test e 
X 
Hematology, Chemistry, Coagulation and TSH e 
X 
Urinalysis with Microscopy e 
X 
Flow Cytometry and CBC (performed by the local laboratory) g 
X 
Review Inclusion/Exclusion Criteria 
X 
X (RECONFIRM) 
Confirm CTCL Staging based on Screening Assessments 
X 
Initiate Medical Monitor Review after all Screening Data are Entered in the eCRF h 
X 
Adverse Events 
Review on an ongoing basis 
Abbreviations: CT = computed tomography; CTCL = cutaneous T-cell lymphoma; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic 
case report form; HIV = human immunodeficiency virus; IWRS = Interactive Web Response System; MRI = magnetic resonance imaging; mSWAT = Modified Severity Weighted 
Assessment tool; TSH = thyroid-stimulating hormone 
a)
Subjects who do not meet the inclusion/exclusion criteria may rescreen once at the discretion of the Investigator.


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b) 
All medications (including over-the-counter medicines, herbal treatments, supplements, and vitamins) administered 30 days before the first administration of study treatment 
(Day 1) until the end of the study should be recorded on the eCRF. 
c) 
Triplicate 12-lead ECGs (3 serial ECGs conducted within approximately 5-10 minutes total time). 
d) 
CT/MRI scans collected by the local site and sent to the Central Laboratory for confirmation.  
e) 
Collected by the clinical site, processed and sent to the central laboratory.  Coagulation includes prothrombin time, partial thromboplastin time, and international normalized 
ratio. 
f) 
Only for women who are not surgically sterile as confirmation of menopause (for subjects whose last menstrual cycle was within the last year). 
g) 
Flow cytometry and CBC performed by the site’s local laboratory.  Panels must include antibodies to CD3, CD4, CD8, CD26, CD45 and CD7. 
h) 
To occur prior to initiating randomization procedures in IWRS. 
i) 
Randomization in IWRS will occur after Medical Monitor approval. 


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Appendix B. Schedule of Events (On Treatment and Post-Treatment Follow-up – Cobomarsen Group) 
Study Procedure or Assessment 
On Treatment Visits 
Follow-Up and End of Treatment 
Study Week 
1 
2 
3 
4 
5 
Weekly Visits 
from Week 6 
through End 
of Treatment 
(±3 days) 
Q4W 
Visits from 
Weeks 9 
through 81 
then Q8W 
thereafter 
(±3 days) 
End of 
Treatment 
Visit 
Follow-up 
visit:  
28 (±5)  
Days after 
End of 
Treatment 
Visit a 
Follow-up 
for Response 
 and 
Progression b 
 
Study Day 
1c 
2 
3 
(+1) 
5 
(±1) 
8 
(±1) 
15 
(±1) 
22 
(±2) 
29 
(±3) 
 
 
 
 
 
 
IWRS Transaction (Study 
Treatment Dispensation)  
X 
 
X 
X 
Weekly starting at Week 2 until End of 
Treatment Visit 
Xt 
 
 
 
mSWAT d 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
Xr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs s 
X 
X 
X 
X 
Weekly starting at Week 2 until End of  
Treatment Visit 
X 
X 
 
 
Physical Examination e 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
 
Weight 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
Complement (C5a, Bb)f 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test  
X 
 
 
 
 
 
 
X 
 
Xu 
X 
X 
 
 
Single 12-lead ECG g  
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
Laboratory Assessments h 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
 
Coagulation i 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Sample for PD and ADA  
(predose) 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Adverse Events j 
Review on an ongoing basis 
X 
 
Prior and Concomitant  
Medications k 
Review on an ongoing basis 
X 
 
Blood PK Sample   
Xl 
Xm 
Xn 
Xn 
Xo 
Xn 
 
Xl 
 
Xp 
X 
X 
 
 


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Study Procedure or Assessment 
On Treatment Visits 
Follow-Up and End of Treatment 
Study Week 
1 
2 
3 
4 
5 
Weekly Visits 
from Week 6 
through End 
of Treatment 
(±3 days) 
Q4W 
Visits from 
Weeks 9 
through 81 
then Q8W 
thereafter 
(±3 days) 
End of 
Treatment 
Visit 
Follow-up 
visit:  
28 (±5)  
Days after 
End of 
Treatment 
Visit a 
Follow-up 
for Response 
 and 
Progression b 
 
Study Day 
1c 
2 
3 
(+1) 
5 
(±1) 
8 
(±1) 
15 
(±1) 
22 
(±2) 
29 
(±3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cobomarsen Infusion q 
X 
 
X 
X 
Infusions performed weekly starting at Week 2 
until End of Treatment Visit  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ADA = anti-drug antibodies; AE = adverse event; aPTT = activated partial thromboplastin time; CR = complete response; CT = computed tomography; CTCL = 
cutaneous T-cell lymphoma; ECG = electrocardiogram; eCRF = electronic case report form; INR = international normalized ratio; IWRS = Interactive Web Response System; 
MRI = magnetic resonance imaging; mSWAT = Modified Severity Weighted Assessment tool; PD = pharmacodynamic(s); PK = pharmacokinetic(s); PR = partial response; 
PT = prothrombin time; Q4W = every 4 weeks; Q8W = every 8 weeks; SAE = serious adverse event;; TSH = thyroid-stimulating hormone 
a) Follow-up visit assessments to be performed 28 days after the last dose of study treatment and for subjects who discontinue treatment early (if the subject has not withdrawn 
consent). 
b) Subjects who did not progress on study will continue to be followed for response and progression every 4 weeks through Week 81, then every 8 weeks.   
c) Day 1 refers to the first dosing day. 
d) mSWAT assessment will be completed prior to dosing when applicable, at the indicated visits.  The Day 1 evaluator should conduct all subsequent mSWAT evaluations.  
e) Complete physical examination on Day 1 or within 2 days prior to the Day 1 visit; brief physical examination at all subsequent time points.  
f) To be collected on Day 1 (predose and within the 10 minutes before the end of the infusion) and on Day 2 (24 ± 4 hours after Day 1 dosing).  
g) To be performed predose and as soon as possible postdose (ideally within 30 minutes of the end of the infusion) on Days 1 and 29, and predose on indicated study days, and at 
the follow-up visit.  If the subject has an elevated QTcF during study treatment defined as (QTcF > 450 msec for males or > 470 msec for females or > 480 msec for subjects 
with bundle branch block, please see section 7.2.3 for additional guidance.   
h) Hematology, clinical chemistry, TSH and urinalysis (including microscopy) as indicated in the protocol will be collected predose on each of the indicated study days. 
Laboratory assessments do not need to be performed on Day 1 if Screening laboratory measurements were performed within 3 days prior to Day 1. 
i) Coagulation assessments (PT, aPTT, and INR) are to be performed on Day 1 predose and at 3 hours (± 10 minutes) postdose; on Day 2; on Day 8 predose; on Day 29 predose; 
and at the follow-up visit. 
j) All AEs, including SAEs, will be reported from the time of informed consent up to and including 60 days after the last dose of study treatment.  Treatment-related AEs ongoing 
at the end of treatment or follow-up visits should be followed to resolution or until the investigator considers them “chronic” or “stable.” 
k) All medications (including over-the-counter medicines, herbal treatments, supplements, and vitamins) administered 30 days before the first administration of study treatment 
(Day 1) until the end of the study should be recorded on the eCRF. 
l) On Day 1 and Day 29, plasma for PK will be drawn at (pre-dose, 60 ± 5 minutes after the start of the infusion, 5 ± 5 minutes before the end of the infusion, and 4 hours 
[± 10 minutes] after the end of the infusion).  
m) On Day 2, plasma for PK will be drawn 24 ± 4 hours after Day 1 dosing. 
n) A single PK sample will be drawn predose. 
o) Plasma for PK will be drawn at predose and 5 ± 5 minutes before the end of the infusion. 


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p) Plasma for PK will be drawn at predose and 5 ± 5 minutes before the end of the infusion though Week 25.  Plasma for PK will be drawn predose only from Week 29 through 
81 and every 8 weeks thereafter. 
q) Subjects randomized to cobomarsen will undergo intravenous infusions on Days 1, 3, and 5, and weekly thereafter starting at Week 2.  On Day 1, subjects will be monitored for 
4 hours postdose. 
r) mSWAT  performed at Every-4-Week Assessments through Week 81, then Every-8-Week Assessments Thereafter (± 3 days). 
s) Vital signs performed predose and within 15 minutes of the end of the cobomarsen infusion. 
t) Discontinue the subject in the IWRS.  
u) Urine pregnancy test to be completed every 4 weeks through end of treatment.  
 
 


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Appendix C. Schedule of Events (On Treatment and Post-Treatment Follow-up – Vorinostat Group) 
Study Procedure or Assessment 
On Treatment Visits 
Follow-Up and End of Treatment 
Study Week 
1 
2 
3 
4 
5 
Weekly Visits 
from Week 6 
through End 
of Treatment 
(±3 days) a 
Q4W Visits 
from Weeks 
9 through 
81 then 
Q8W 
thereafter 
(±3 days) 
End of 
Treatment 
Visit 
Follow-up 
visit:  
28 (±5) Days 
after End of 
Treatment 
Visit b 
Follow-up 
for Response 
 and 
Progression c 
 
Study Day 
1d 
2 
3 
(+1) 
5 
(±1) 
8 
(±1) 
15 
(±1) 
22 
(±2) 
29 
(±3) 
 
 
 
 
 
 
IWRS Transaction (Study 
Treatment Dispensation)  
X 
 
 
 
 
 
 
X 
 
X 
Xp 
 
 
 
mSWAT e 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Physical Examination f 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
 
Weight 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
Complement (C5a, Bb) g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test  
X 
 
 
 
 
 
 
X 
 
Xq 
X 
X 
 
 
Single 12-lead ECG h 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
Laboratory Assessments i 
X 
 
X 
 
X 
X 
 
X 
Week 7 
only j 
X 
X 
X 
 
 
Coagulation k 
X 
X 
 
 
X 
 
 
X 
Week 7 
only k 
 
 
X 
 
 
On treatment telephone contact l 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events m 
Review on an ongoing basis 
X 
 
Prior and Concomitant 
Medications n 
Review on an ongoing basis 
X 
 


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Study Procedure or Assessment 
On Treatment Visits 
Follow-Up and End of Treatment 
Study Week 
1 
2 
3 
4 
5 
Weekly Visits 
from Week 6 
through End 
of Treatment 
(±3 days) a 
Q4W Visits 
from Weeks 
9 through 
81 then 
Q8W 
thereafter 
(±3 days) 
End of 
Treatment 
Visit 
Follow-up 
visit:  
28 (±5) Days 
after End of 
Treatment 
Visit b 
Follow-up 
for Response 
 and 
Progression c 
 
Study Day 
1d 
2 
3 
(+1) 
5 
(±1) 
8 
(±1) 
15 
(±1) 
22 
(±2) 
29 
(±3) 
 
 
 
 
 
 
Vorinostat Dosing 
Taken orally once daily with food 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; CR = complete response; CT = computed tomography; CTCL = cutaneous T-cell lymphoma; ECG 
= electrocardiogram; eCRF = electronic case report form; INR = international normalized ratio; IWRS = Interactive Web Response System; MRI = magnetic resonance imaging; 
mSWAT = Modified Severity Weighted Assessment tool; PR = partial response; PT = prothrombin time; Q4W = every 4 weeks; Q8W = every 8 weeks;; SAE = serious adverse event; 
TSH = thyroid-stimulating hormone 
a) The weekly study visits for the vorinostat group can be conducted via telephone, unless the investigator feels it is in the best interest of the subject to visit the clinic. 
b) Follow-up visit assessments to be performed 28 days after the last dose of study treatment for subjects who choose not to participate in the crossover period.  and for subjects 
who discontinue treatment early (if the subject has not withdrawn consent). 
c) Subjects who did not progress on study will continue to be followed for response and progression.   
d) Day 1 refers to the first dosing day. 
e) mSWAT assessment will be completed prior to dosing when applicable, at the indicated visits.  The Day 1 evaluator should conduct all subsequent mSWAT evaluations. 
f) Complete physical examination on Day 1 or within 2 days prior to the Day 1 visit; brief physical examination at all subsequent time points. 
g) To be collected on Day 1 (predose and 2 hours [± 10 minutes] post dose) and on Day 2 (24 ± 4 hours after Day 1 dosing). 
h) To be performed predose and at 1 ± 0.5 hours postdose on Days 1 and 29, and predose on indicated study days.If the subject has an elevated QTcF during study treatment 
defined as QTcF > 450 msec for males or > 470 msec for females or > 480 msec for subjects with bundle branch block, please see section 7.2.3 for additional guidance.   
i) Hematology, clinical chemistry, TSH, and urinalysis (including microscopy) as indicated in the protocol will be collected predose on each of the indicated study days.  
Laboratory assessments do not need to be performed on Day 1 if Screening laboratory measurements were performed within 3 days prior to Day 1. 
j) Hematology and clinical chemistrywill be collected at the Week 7 visit for vorinostat subjects only. 
k) Coagulation assessments (PT, aPTT, and INR) are to be performed at on Day 1 predose and at 3 hours (± 10 minutes) postdose; on Day 2; on Day 8 predose; on Day 29 
predose; at week 7; and at the follow-up visit. 
l) Clinic visits may be scheduled instead of telephone contact, at the discretion of the investigator. 
m) All AEs, including SAEs, will be reported from the time of informed consent up to and including 60 days after the last dose of study treatment.  Treatment-related AEs ongoing 
at the end of treatment or follow-up visits should be followed to resolution or until the investigator considers them “chronic” or “stable.” 
n) All medications (including over-the-counter medicines, herbal treatments, supplements, and vitamins) administered 30 days before the first administration of study treatment 
(Day 1) until the end of the study should be recorded on the eCRF. 
. 
o) mSWAT,  performed at Every-4-Week Assessments through Week 81, then Every-8-Week Assessments Thereafter (± 3 days). 
p) Discontinue the subject in the IWRS 
q) Urine pregnancy test to be completed every 4 weeks through end of treatment.  
 


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Appendix D. Crossover Period Schedule of Events (Screening, Crossover Period) 
Study Procedure or Assessment (completed after obtaining informed consent from the 
patient). 
Screening a 
 
Weeks Prior to Enrollment  
-4  
Time of Enrollment 
Study Day Prior to Enrollment 
-28 to -3 
Day -3 to -1 
Registration in Interactive Web Response System 
X 
X b 
Modified Severity Weighted Assessment Tool (mSWAT) c 
X 
 
Medical History and Concomitant Medications d 
X 
 
Report Prior CTCL Treatments 
X 
 
ECOG Performance Status  
X 
 
Vital Signs e 
X 
 
Complete Physical Examination Including Weight and Height e 
X 
 
Triplicate 12-lead Electrocardiogram e, f 
X 
 
Follicle-stimulating Hormone e, g, h 
X 
 
Serum Pregnancy Test (for females of childbearing potential) e, h 
X 
 
Hematology, Chemistry, Coagulation and TSH e, g 
X 
 
Urinalysis with Microscopy e, g 
X 
 
Flow Cytometry and CBC (performed by the local laboratory) c, i 
X 
 
Review Inclusion/Exclusion Criteria 
X 
X (RECONFIRM) 
Initiate Medical Monitor Review after all Screening Data are Entered in the eCRF j 
 
X 
Adverse Events 
Review on an ongoing basis 
Abbreviations: App = application; CBC = complete blood count; CT = computed tomography; CTCL = cutaneous T-cell lymphoma; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; eCRF = electronic case report form; IWRS = Interactive Web Response System; MRI = magnetic resonance imaging; mSWAT = Modified Severity 
Weighted Assessment tool; TSH = thyroid-stimulating hormone 
a. 
Subjects who do not meet the inclusion/exclusion criteria may rescreen once at the discretion of the Investigator. 
b. 
Enrollment in IWRS will occur after Medical Monitor approval. 
c. 
Does not need to be repeated if completed within the 28 days prior to Day 1.  
d. 
All medications (including over-the-counter medicines, herbal treatments, supplements, and vitamins) administered 30 days before the first administration of cobomarsen 
(Day 1) will be recorded on the eCRF. 
e. 
Does not need to be repeated if completed within the 14 days prior to Day 1. 
f. 
Triplicate ECG (3 serial ECGs conducted within approximately 5-10 minutes total time). 
g. 
Collected by the clinical site, processed and sent to the central laboratory.  Coagulation includes prothrombin time, partial thromboplastin time, and international 
normalized ratio. 
h. 
Only for women who are not surgically sterile as confirmation of menopause (for subjects whose last menstrual cycle was within the last year). 


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i. 
Flow cytometry and CBC performed by the site’s local laboratory.  Panels must include antibodies to CD3, CD4, CD8, CD26, CD45 and CD7. 
j. 
To occur prior to initiating enrollment procedures in IWRS. 


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Appendix E. Crossover Period Schedule of Events (Crossover On Treatment and Post-Treatment Follow-up) 
Study Procedure or 
Assessment 
On Treatment Visits 
Follow up and End of Treatment 
Study Week 
1 
2 
3 
4 
5 
Weekly Visits 
from Week 6 
through End of 
Treatment 
(±3 days) 
Q4W Visits 
from Weeks 9 
through 81 
then Q8W 
thereafter 
(±3 days) 
End of 
Treatment 
Visit 
Follow-up 
visit: 28 (±5) 
Days after 
End of 
Treatment 
Visit a 
Follow-up 
for Response 
and 
Progression b 
Study Day 
1c 
2 
3 
(+1) 
5  
(±1) 
8 
(±1) 
15 
(±1) 
22 
(±2) 
29 
(±3) 
 
 
 
 
 
IWRS Transaction 
X 
 
X 
X 
Weekly starting at Week 2 until End of Treatment Visit 
X 
 
 
mSWAT d 
X 
 
 
 
 
 
 
X 
 
X 
X 
X e 
X f 
Vital Signs g 
X 
X 
X 
X 
Weekly starting at Week 2 until End of Treatment Visit 
X 
X 
 
Physical Examination h 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
Weight 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Complement (C5a, Bb) i 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test (for 
females of childbearing 
potential)  
X 
 
 
 
 
 
 
X 
 
Xr 
X 
X 
 
12-lead ECG j  
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Laboratory Assessments k 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Coagulation l 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Sample for PD and ADA 
(predose if applicable) 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
Adverse Events m 
Review on an ongoing basis 
X 
Prior and Concomitant 
Medications n 
Review on an ongoing basis 
X 
Blood PK Sample   
X o 
 
 
 
 
 
 
X o 
 
X p 
X 
X 
 
Cobomarsen Infusion q 
X 
 
X 
X 
Weekly starting at Week 2 until End of Treatment Visit 
 
 
 
Abbreviations: ADA = anti-drug antibodies; AE = adverse event; aPTT = activated partial thromboplastin time; CBC = complete blood count; CR = complete response; CT = 
computed tomography; ECG = electrocardiogram; eCRF = electronic case report form; INR = international normalized ratio; IWRS = Interactive Web Response System;; 


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MRI = magnetic resonance imaging; mSWAT = Modified Severity Weighted Assessment tool; PD = pharmacodynamic(s); PK = pharmacokinetic(s); PR = partial response; 
PT = prothrombin time; Q4W = every 4 weeks; Q8W = every 8 weeks; SAE = serious adverse event; TSH = thyroid-stimulating hormone 
 
a. 
Follow-up visit assessments to be performed 28 days after the last dose of cobomarsen for subjects who discontinue treatment early (if the subject has not withdrawn 
consent). 
b. 
Subjects who do not progress on study will continue to be followed for response and progression.   
c. 
Day 1 refers to the first dosing day. 
d. 
mSWAT assessment will be completed prior to dosing when applicable, at the indicated visits.  The Day 1 evaluator should conduct all subsequent mSWAT evaluations.  
e. 
mSWAT evaluations do not need to be repeated if disease progression is already confirmed. 
f. 
mSWAT performed at Every-4-Week Assessments through Week 81, then Every-8-Week Assessments Thereafter (± 3 days). 
g. 
Vital signs performed predose and within 15 minutes of the end of the cobomarsen infusion. 
h. 
Complete physical examination on Day 1 or within 2 days of the Day 1 visit; brief physical examination at all subsequent time points. 
i. 
To be collected on Day 1 (predose and within the 10 minutes before the end of the infusion) and on Day 2 (24 ± 4 hours after Day 1 dosing).  
j. 
To be performed predose and as soon as possible postdose on Days 1 and 29 (ideally within 30 minutes postdose on Day 1, predose on other indicated study days, and at 
the Follow-up Visit 28 ± 5 days after the End of Treatment Visit. 
k. 
Hematology, clinical chemistry, TSH and urinalysis (including microscopy) will be collected predose on each of the indicated study days. These assessments do not need 
to be repeated on Day 1 if the Screening assessments were performed within 3 days prior to Day 1 and satisfied eligibility criteria.  
l. 
Coagulation assessments (PT, aPTT, and INR) are to be performed on Day 1 predose and at 3 hours (± 10 minutes) postdose; on Day 2; on Day 8 predose; on Day 29 
predose; and at the Follow-up Visit 28 ± 5 days after the End of Treatment Visit. Coagulation does not need to be repeated on Day 1 if Screening coagulation 
assessments were performed within 3 days prior to Day 1 and satisfied eligibility criteria. 
m. All AEs, including SAEs, will be reported from the time of informed consent up to and including 60 days after the last dose of cobomarsen.  Treatment-related AEs 
ongoing at the end of treatment or follow-up visits should be followed to resolution or until the investigator considers them “chronic” or “stable.” 
n. 
All medications (including over-the-counter medicines, herbal treatments, supplements, and vitamins) administered 30 days before the first administration of study 
treatment (Day 1) until the end of the study should be recorded on the eCRF. 
o. 
On Day 1 and Day 29, blood for plasma PK will be drawn predose and 5 ± 5 minutes before the end of the infusion. 
p. 
Blood for plasma PK will be drawn, predose only, every 4 weeks from Week 9 through Week 81 and every 8 weeks thereafter. 
q. 
Subjects will undergo intravenous infusions with cobomarsen on Days 1, 3, 5, and 8 and weekly thereafter (starting at Week 2).  On Day 1, subjects will be monitored in 
the clinic for safety for 4 hours postdose. 
r. 
Urine pregnancy test to be completed every 4 weeks through end of treatment.  
 
 


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Appendix F. Modified Severity Weighted Assessment Tool and Response Criteria 
Derived from Olsen E, Whittaker S, Kim Y, et al. Clinical end points and response criteria in mycosis fungoides and 
Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States 
Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for 
Research and Treatment of Cancer. J Clin Oncol 2011; 29(18):2598-2607. 
 
Table F1: 
Modified Severity Weighted Assessment Tool 
Body Region 
% BSA in Body 
Region 
Assessment of Involvement in Subject’s Skin 
Patcha 
Plaqueb 
Tumorc 
Head 
7  
 
 
 
Neck 
2 
  
  
 
Anterior trunk 
13 
  
  
  
Arms 
8 
 
 
 
Forearms 
6 
 
 
 
Hands 
5 
 
 
 
Posterior trunk 
13 
 
 
 
Buttocks 
5 
 
 
 
Thighs 
19 
 
 
 
Legs 
14 
 
 
 
Feet 
7 
 
 
 
Groin 
1 
 
 
 
Subtotal of lesion BSA 
 
 
 
 
 
Weighting factor 
 
×1 
×2 
×4 
Subtotal lesion BSA x weighting factor 
 
 
 
 
NOTE: mSWAT score equals summation of each column line. 
Abbreviations:  BSA = body surface area; mSWAT = Modified Severity Weighted Assessment tool 
a) Any size lesion without induration or significant elevation above the surrounding uninvolved skin; poikiloderma 
may be present. 
b) Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present. 
c) Any solid or nodular lesion ≥ 1 cm in diameter with evidence of deep infiltration in the skin and/or vertical 
growth. 
 


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Table F2: 
Response in Skin Based on mSWAT Score 
Response 
Definition 
CR 
100% clearance of skin lesionsa 
PR 
50%-99% clearance of skin disease from baseline without new tumors (T3) in patients 
with T1, T2 or T4 only skin disease 
SD 
< 25% increase to < 50% clearance in skin disease from baseline without new tumors (T3) 
in patients with T1, T2, or T4 only skin disease 
PDb 
≥ 25% increase in skin disease from baseline or 
New tumors (T3) in patients with T1, T2 or T4 only skin disease or 
Loss of response: in those with complete or partial response, increase of skin score of 
greater than the sum of nadir plus 50% baseline score 
Relapse 
Any disease recurrence in those with complete response 
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease 
a)  A biopsy of normal appearing skin is unnecessary to assign a complete response. However, a skin biopsy should 
be performed of a representative area of the skin if there is any question of residual disease (persistent erythema 
or pigmentary change) where otherwise a complete response would exist. If histologic features are suspicious or 
suggestive of mycosis fungoides/Sézary syndrome, the response should be considered a partial response only. 
b) Whichever criterion occurs first. 
 
Table F3: 
Response Assessment in Lymph Nodesa 
Response 
Definition 
SD 
Fails to attain the criteria for PD 
PDb, c, d 
≥ 50% increase in SPD from baseline of lymph nodes that are proven to be N3 
histologically, or 
Any new node > 1.5 cm in the long axis or > 1 cm in the short axis, if 1-1.5 cm in the long 
axis that is proven to be N3 histologically  
Abbreviations: PD = progressive disease; SD = stable disease; SPD = sum of the maximum linear dimensions 
(major axis) × longest perpendicular dimension (minor axis) 
a)  Peripheral and central lymph nodes. 
b) Whichever criterion occurs first. 
c)  As an alternative to histological confirmation, PET scan > 5 SUV is also considered malignant. 
d) In exceptional circumstances where biopsy or PET scan cannot be done, the new enlarged node will be designated 
Nx and considered malignant.  
 
Table F4: 
Response Assessment in Viscera 
Response 
Definition 
SD 
Fails to attain the criteria for PD 
PD 
New organ involvement 
 
Abbreviations: PD = progressive disease; SD = stable disease;  


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Table F5: 
Response Assessment in Blooda 
Response 
Definition 
SD 
Fails to attain criteria for PD 
PD 
≥ 50% increase from baseline and at least 1,000 neoplastic cells/µL (B2)  
Abbreviations: PD = progressive disease; SD = stable disease 
a) As determined by absolute numbers of neoplastic cells/µL. 
 
 


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Appendix G. National Comprehensive Cancer Network (NCCN) Guidelines for Treating 
Mycosis Fungoides/Sézary Syndrome 
Skin-Directed Therapies 
Systemic Therapies 
For limited/localized skin involvement (Skin-Limited/Local) 
• Topical corticosteroidsa 
• Topical chemotherapy (mechlorethamine [nitrogen 
mustard]) 
• Local radiation (8–36 Gy) 
• Topical retinoids (bexarotene, tazarotene) 
• Phototherapy (UVB, NB-UVB for patch/thin plaques; 
PUVA for thicker plaques)b 
• Topical imiquimod 
For generalized skin involvement (Skin-Generalized) 
• Topical corticosteroidsa 
• Topical chemotherapy (mechlorethamine [nitrogen 
mustard]) 
• Phototherapy (UVB, NB-UVB for patch/thin plaques; 
PUVA for thicker plaques)b 
• Total skin electron beam therapy (TSEBT) (12–36 Gy)c, d 
Category A (SYST-CAT A) 
• Retinoids (bexarotene, all-trans retinoic acid, isotretinoin 
[13cis-retinoic acid], acitretin)d 
• Interferons (IFN-alpha, IFN-gamma) 
• HDAC-inhibitors (vorinostat, romidepsin)d 
• Extracorporeal photopheresise 
• Methotrexate (≤100 mg q week) 
• Brentuximab vedotinf 
Category B (SYST-CAT B) 
• Preferred therapies (alphabetical order) 
➢ Brentuximab vedotinf 
➢ Gemcitabine 
➢ Liposomal doxorubicin 
➢ Low-dose pralatrexate 
• Other therapies 
➢ Chlorambucil 
➢ Pentostatin 
➢ Etoposide 
➢ Cyclophosphamide 
➢ Temozolomide 
➢ Methotrexate (> 100 mg q week) 
➢ Pembrolizumabg (category 2B) 
➢ Bortezomib (category 3) 
Category C (SYST-CAT C)h (alphabetical order) 
• Bortezomib (category 3) 
• Brentuximab vedotinf 
• Gemcitabine 
• Liposomal doxorubin 
• Low- or standard-dose pralatrexate 
• Romidepsin 
Derived from the National Comprehensive Cancer Network Guidelines Version 1.2018. 
a)  Long-term use of topical steroid may be associated with skin atrophy and/or striae formation.  This risk worsens with 
increased potency of the steroid. High-potency steroid used on large skin surfaces may lead to systemic absorption. 
b) Cumulative dose of UV is associated with increased risk of UV-associated skin neoplasms; thus, phototherapy may not be 
appropriate in patients with a history of extensive squamoproliferative skin neoplasms or basal cell carcinomas or who have 
had melanoma. 
c) It is common practice to follow TSEBT with systemic therapies such as interferon or bexarotene to maintain response. 
d) Safety of combining TSEBT with systemic retinoids or HDAC inhibitors, such as vorinostat or romidepsin, or combining 
phototherapy with vorinostat or romidepsin is unknown. 
e) Photopheresis may be more appropriate as systemic therapy in patients with some blood involvement (B1 or B2). 
f) A randomized phase 3 trial comparing brentuximab vedotin (BV) with physician’s choice of oral bexarotene or methotrexate 
showed superior clinical outcome of BV in patients with CD30+ MF and pcALCL. CD30 positivity was defined as CD30 
expression≥ 10% of total lymphoid cells in at least 1 of minimal 2 skin biopsies required to evaluate for eligibility.  
Forty-four percent of eligible patients with MF had at least 1 Screening skin biopsy with CD30 <10%.  In the two previously 
reported investigator-initiated studies, clinical responses with BV was observed across all CD30 expression levels including 
in those with negligible CD30 expression. 
g) Preliminary phase II data in patients with MF and SS.  Disease flare is seen in some patients (especially in erythrodermic 
skin/SS patient) and should be distinguished from disease progression.  Khodadoust et al. Blood 2016; 125:Abstract 181. 
h) Patients with large cell transformed (LCT) MF and stage IV non-SS/visceral disease may present with more aggressive 
growth characteristics.  In general, agents listed in SYST-CAT C are preferred in these circumstances. 


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Appendix H. TNMB Staging of Mycosis Fungoides 
 
Modified ISCL/EORTC Revisions to the Staging of MF/SS 
Stage 
T 
N 
M 
B 
IA 
1 
0 
0 
0, 1 
IB 
2 
0 
0 
0, 1 
IIA 
1-2 
1, 2, X 
0 
0, 1 
IIB 
3 
0-2, X 
0 
0, 1 
IIIA 
4 
0-2, X 
0 
0 
IIIB 
4 
0-2, X 
0 
1 
IVA1 
1-4 
0-2, X 
0 
2 
IVA2 
1-4 
3 
0 
0-2 
IVB 
1-4 
0-3, X 
1 
0-2 
Derived from Olsen et al. 2011. 
Abbreviations: EORTC, European Organisation for Research and Treatment of Cancer; ISCL, International 
Society for Cutaneous Lymphomas; MF, mycosis fungoides; SS, Sézary syndrome; X, clinically abnormal lymph 
nodes without histologic confirmation or inability to full characterize histologic subcategories. 
 


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TNMB Stages 
Description of TNMB 
Skina 
 
T1 
Limited patches, papules, and/or plaques covering < 10% of the skin surface; may further 
stratify into T1a (patch only) v T1b (plaque ± patch) 
T2 
Patches, papules, or plaques covering ≥ 10% of the skin surface; may further stratify into T2a 
(patch only) v T2b (plaque ± patch) 
T3 
One or more tumors (≥ 1 cm diameter) 
T4 
Confluence of erythema covering ≥ 80% body surface area 
Nodeb 
 
N0 
No clinically abnormal lymph nodes; biopsy not required 
N1 
Clinically abnormal lymph nodes; histopathology Dutch grade 1 or NCI LN0-2 
N1a 
Clone negative 
N1b 
Clone positive 
N2 
Clinically abnormal lymph nodes; histopathology Dutch grade 2 or NCI LN3 
N2a 
Clone negative 
N2b 
Clone positive 
N3 
Clinically abnormal lymph nodes; histopathology Dutch grade 3-4 or NCI LN4; clone positive 
or negative 
Nx 
Clinically abnormal lymph nodes without histologic confirmation or inability to fully 
characterize the histologic subcategories 
Visceral 
 
M0 
No visceral organ involvement 
M1 
Visceral involvement (must have pathology confirmation and organ involved should be 
specified) 
Blood 
 
B0 
< 250/µL CD4+ CD26- or CD4+ CD7- 
B1 
250 to 1000/µL CD4+CD26- or CD4+ CD7-  
B2 
> 1000/µL CD4+ CD26- or CD4+ CD7- with T-cell blood clone 
Derived from Olsen et al. 2011 and Scarisbrick et al. 2018. 
Abbreviations: EORTC, European Organisation for Research and Treatment of Cancer; ISCL, International 
Society for Cutaneous Lymphomas; NCI, National Cancer Institute. 
a Patch = any size lesion without induration or significant elevation above the surrounding uninvolved skin: 
pokiloderma may be present. Plaque = any size lesion that is elevated or indurated: crusting or poikiloderma may 
be present. Tumor = any solid or nodular lesion ≥ 1 cm in diameter with evidence of deep infiltration in the skin 
and/or vertical growth. 
b Lymph node classification has been modified from 2007 ISCL/EORTC consensus revisions to include central 
nodes. Lymph nodes are qualified as abnormal if > 1.5 cm in diameter. 
c The clone in the blood should match that of the skin. The relevance of an isolated clone in the blood or a clone in 
the blood that does not match the clone in the skin remains to be determined. 
 
 
 


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Appendix I. Potency (Per Protocol) of Topical Corticosteroid Products 
Steroid Generic Name 
Trade Names 
miRagen 
Derived 
Potency 
Amcinonide Ointment, cream or lotion, 
0.1% 
CYCLOCORT, VISDERM 
High 
Augmented Betamethasone dipropionate , 
0.05% 
Diprolene Ointment / lotion / Diprolene AF Cream  
High 
Betamethasone butyrate propionate 0.05% 
ANTEBATE, Diprosone 
High 
Betamethasone dipropionate (Ointment, 
lotion) 0.05% 
DIPROLENE, Diprosone OV, Alphatrex, Beta 1 Kit, 
Beta Derm, Beta-Val, Betanate, Betatrex, Celestone, 
Del-Beta, Diprolene, Diprolene AF, Diprosone, Luxiq 
Foam, Maxivate, RRB Pak, Sernivo, Valisone, Taro-
sone, Topisone 
High 
Betamethasone dipropionate 0.064% 
RINDERON-DP 
High 
Betamethasone dipropionate Cream 0.05% 
+ Salicylic Acid 3% 
Diprosalic  
High 
Betamethasone dipropionate Cream, 
0.05% 
DIPROLENE, Diprosone, Taro-sone, Lotriderm, 
Maxivate, Betantate,  
High 
Betamethasone dipropionate glycol, 0.05% 
Diprolene Glycol, Topilene Glycol 
High 
Betamethasone dipropionate, Lotion, 
0.02% 
 
High 
Betamethasone valerate Ointment, 0.1% 
Beta-val, Betaderm, Lixiq, Valisone, Betatrex, 
Benovate, Celestone-V, Betnovate. Celestoderm 
High 
Clobetasol propionate Ointment/Cream/ 
topical 
solution/gel/foam/shampoo/spray/Lotion/ 
Emollient cream, 0.05% 
Dermovate, Dermaol cream, Dermol ointment, 
Clobevate, Cormax, Embeline E, Temovate -E, Ratio-
Clobetasol, Excel Cream,  
IMPOYZ (Encore Dermatology), Embeline, 
CLOBEX (Galderma Laboratories), , OLUX-E 
(Mylan Pharmaceuticals), OLUX (Mylan 
Pharmaceuticals), TEMOVATE (PharmaDerm), 
OLUX (Prestium Pharma), OLUX-E (Prestium 
Pharma), IMPOYZ (Promius Pharma) 
High 
Desoximatasone gel, 0.05% 
TOPICORT GEL 
High 
Desoximetasone Cream or ointment, 
0.25%  
Topicort, Topisone 
High 
Desoximetasone, 0.25% 
Topicort emollient cream, oint 
High 
Diflorasone diacetate (Ointment / Cream), 
0.05% 
Diflal, Diacort, PSCORON, Apexicon, PSCORON E, 
Apexicon E, Florone, Maxiflor, ApexiCon E 
Cream,Nerisone, Nerisone C (+ Chloqunaldol 1%) 
High 
Diflucortolone valerate 0.1% 
TEXMETEN, NERISONA, Nerisone ointment (NP) 
High 
Diflucortolone Valerate 0.3% 
Nerisone Forte  
High 
Difluprednate 0.05% 
MYSER 
High 
Fluocinolone acetonide ointment, 0.025% 
SYNLAR ointment, FLUCORT 
High 
Fluocinonide 0.1% 
VANOS CREAM 
High 


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Steroid Generic Name 
Trade Names 
miRagen 
Derived 
Potency 
Fluocinonide Cream, ointment, Lotion or 
gel, 0.05% 
LIDEX, VANOS, TOPSYM, Lyderm, Lidemol 
(emmolient base), Topsyn, Lidex-E,  
High 
Flurandrenolide Tape, (4mcg per cm2) 
Cordran 
High 
Fluticasone propionate (micro-ionized), 
0.005% 
CUTIVATE ointment 
High 
Halcinonide (Cream, Ointment, Solution) 
0.1% 
HALOG,Halciderm 
High 
Halobetasol propionate 0.05% 
ULTRAVATE, Lexette Foam. Halox 
High 
Halobetasol propionate lotion, 0.01% 
Bryhali Lotion, 0.01% 
High 
Hydrocortisone butyrate propionate 0.1% 
  
High 
Mometasone furoate ointment, 0.1%   
ELOCON, FULMETA, ASMANEX, Novasone 
High 
Triamcinolone acetonide (ointment, 
cream), 0.5% 
Cinalog, Kenalog 
High 
Triamcinolone acetonide, (Ointment, 
Cream, Lotion) 0.1% 
LEDERCORT, KENACORT-A, Triaderm, 
Aristocort-R, Kenalog, Oxacort, Triacet 
High 
Triamcinolone acetonide, Ointment, 0.1% 
+ chloroteracycline hydrochloride 3% 
Aureocort Ointment  
High 
Triamicinolone diacetate cream/ointment, 
0.1%  
Aristocort, Amcort 
High 
Alclometasone dipropionate Cream or 
Ointment, 0.1% 
ALMETA 
Medium 
Alclometasone dipropionate Ointment, 
0.05% 
ACLOVATE,  
Medium 
Beclometasone dipropionate 0.025%  
QVAR, Generic Beclometasone dipropionate 
cream/Ointment, Propaderm 
Medium 
Beclomethasone dipropionate lotion, 
0.025% 
Propaderm 
Medium 
Betamethasone valerate, 0.12% 
BETNEVATE, RINDERON-V, Lixiq Foam 
Medium 
Betamethasone valerate 0.025% 
Betnovate-RD cream/Ointment  
Medium 
Betamethasone valerate Cream, 0.1% 
Betnovate-1/2, Celestoderm-V, Celestoderm-V/2, 
Ectosone Mild-Lotion, Ectosone Regular-Cream, , 
Metaderm Regular, Novo-Betamet, Beta-Val 
Medium 
Betamethasone valerate Lotion or scalp 
lotion, 0.1%, Betamethosone valerate 
0.05% lotion 
Valisone, Ectosone, Betaderm, Ratio-Ectosone, Ratio-
Ectosone mild, Fucicort (+ fusidic acid 2%), 
Bentonovate C cream (+ clonquinol), Ectosone 
Regular-Lotion, Ectosone Scalp Lotion, Metaderm 
Mild,  
Medium 
Betamethasone valerate Lotion, 0.05% 
Ectosone Regular-Lotion, Ectosone Scalp Lotion, 
Metaderm Mild,  
Medium 
Betamethasone valerate, 0.05% 
Betonvate ½ 
Celestone- V1/2, Betaderm, Ratio-Ectosone,  
Medium 
Budesonide 
Paper from Belgium, Entocort C 
Medium 
Clobetasone butyrate, 0.05% 
KINDAVATE, Eumovate (cream/ointment) 
Medium 


miRagen Therapeutics, Inc. 
 
Protocol No. MRG106-11-201 
 
 
Version 4.0 
 
 
10 February 2020 
 
 
Proprietary and Confidential 
 
Page 144 of 146 
Steroid Generic Name 
Trade Names 
miRagen 
Derived 
Potency 
Clocortolone pivalate, 0.1% 
Cloderm cream 
Medium 
Deprodone propionate 0.3% 
ECLAR 
Medium 
Desonide Ointment, 0.05% 
Desocort, DesOwen ointment, Tridesilon 
Medium 
Desoximetasone Cream, 0.05% 
Topicort Mild (Cream), Desoxi (cream), Topicort LP, 
Topicort 0.05% Emollient cream 
Medium 
Desoximetasone Gel, 0.05% 
Topicort Gel 
Medium 
Dexamethasone propionate, 0.1% 
METHADERM 
Medium 
Dexamethasone valerate, 0.12% 
ZALUCS, VOALLA 
Medium 
Dexamethasone, 0.1% 
DECADRON 
Medium 
Diflucortolone valerate cream, 0.1% 
Nerisone Cr, Nerisone Oily, Nerisalic oily 
Medium 
Flucortolone, 0.25% 
Ultralanum plain cream/ointment 
Medium 
Fludroxycortide Cream or Ointment, 
0.05%  
  
Medium 
Fludroxycortide, 0.0125% 
Haelan Cream/ointment 
Medium 
Fluocinolone acetonide Cream , 0.025% 
SYNLAR cream, Fluoderm regular, Synemol 
Medium 
Fluocortin bultelester  
  
Medium 
Fluprednidene acetate 
Decoderm, Decoderm Comp, Crinohermal fem, 
Candio-hermal Plus, Sali-Decoderm, Vabaderm, 
Decoder Micoflu,  
Medium 
Flurandrenolide, 0.05% 
CORDORAN 
Medium 
Flurandrenolide ointment, 0.025% 
  
Medium 
Fluticasone propionate, 0.05% 
CUTIVATE cream, CUTIVATE Lotion  
Medium 
Halcinonide Cream, 0.025% 
Halog 
Medium 
Halometasone, 0.05% 
  
Medium 
Hydrocortisone buteprate, 0.1%, 
Hydrocortisone probutate 0.1% 
PANDEL (cream, Ointment, Solution)  
Medium 
Hydrocortisone butyrate Cream, 0.1% / 
Hydrocortisone 17- butyrate, 0.1%,  
LOCOID,Locoid Lipocream, Barriere-Hc, Cortate, 
Cort-Eze, Cortoderm Mild Ointment, Cortoderm 
Regular Ointment, Emo-Cort, Emo-Cort Scalp 
Solution, Hydrocortisone Cream, Novo-Hydrocort, 
Novo-Hydrocort Cream, Prevex Hc, Sarna Hc 
Medium 
Hydrocortisone valerate Cream or 
Ointment, 0.2% 
WESCORT cream, WESCORT ointment, Hydroval 
Medium 
Methylprednisolone aceponate, 0.1% 
Advantan cream/ointment 
Medium 
Mometasone furoate cream or lotion, 0.1% 
ELOCON, Elocom 
Medium 
Prednicarbate, 0.1% 
Dermatop (emollient cream, oint) 
Medium 
Prednisolone valerate acetate 0.3% 
LIDOMEX 
Medium 
Triamcinolone acetonide , 0.05%, 0.02% - 
Kenalone, Aristocort 1/2, Trianex (oint) 
Medium 
Triamcinolone acetonide, 0.025% 
Triaderm,Aristocort,Kenalog 
Medium 
Alclometasone dipropionate Cream, 0.05% 
ACLOVATE, LOGODERM, Modrasone cream 
Low 
Betamethasone valerate, 0.02% 
Betnovate 1/5 
Celestone-M 
Low 


miRagen Therapeutics, Inc. 
 
Protocol No. MRG106-11-201 
 
 
Version 4.0 
 
 
10 February 2020 
 
 
Proprietary and Confidential 
 
Page 145 of 146 
Steroid Generic Name 
Trade Names 
miRagen 
Derived 
Potency 
Desonide 
Cream/gel/Lotion/Solution/foam, 0.05% 
VERDESDO, Desocort, Desonate, Desowen, Versedo 
Foam, Lokara 
Low 
Dexamethasone sodium phosphate Cream, 
0.1% 
  
Low 
Fluocinolone acetonide, 
Cream/Solution/shampoo, 0.01% 
SYNLAR solution, Capex, Derma-smooth/FS 
Low 
Fluocinolone acetonide, 0.00625% 
Synalar 1 in 4 Dilution Cream, Capex, Derma-
Smoothe/FS, and Synalar,  Fluonid, Dermasmooth, 
Fluoderm Mild Cream, Fluoderm Mild Ointment, 
Fluoderm Regular Cream, Fluoderm Regular 
Ointment, Fluolar Mild, Fluolar Regular, Fluonide 
Mild-Cream, Synalar Mild, Synalar Regular, and 
Synamol 
Low 
Fluocinonide, 0.01% 
  
Low 
Flurandrenolide cream, 0.025% 
  
Low 
Hydrocortisone 2.5%, 1.85%, 1%, 0.5% 
(any formulation, Base or Acetate) 
Dermaid Cream, Soft cream, DP Lotion-HC 1%, 
Skincalm, Lemnis Fatty Acid Cream, Pimafucort 
Cream/Ointment, A-Hydrocort, Ala-Cort, Ala-Scalp, 
Anucort-HC, Anumed-HC, Anusol HC, Caldecort, 
Cetacort, Colocort, Cordate, Cortaid, Cortaid 
Advanced, Cortaid Intensive Therapy, Cortderm, 
Cortef, Cortenema, Corticaine, Corticool, Cortifoam, 
Cortizone, Cortizone-10, Cortizone-10 Cooling 
Relief, Cortizone-10 Intensive Healing, Cortizone-10 
Plus, Dermarest, Dricort, Dermarest Eczema, 
Dioderm, Emo-cort, Encort, First - Hydrocortisone, 
Gly-Cort, GRx HiCort, Hemmorex-HC, 
Hemorrhoidal-HC, Hemril, Hycort, Hyderm, Hydro 
Skin, Hydrocortisone in Absorbase, Hydrocortone, 
Hydroskin, Hytone, Instacort, Lacticare HC, Locoid, 
Locoid Lipocream, MiCort-HC, Monistat Complete 
Care Instant Itch Relief Cream, Neosporin Eczema, 
NuCort, Nutracort, NuZon, Pandel, Penecort, 
Preparation H Hydrocortisone, Pramosone 2.5%, 
Procto-Kit, Procto-Med HC, Procto-Pak, Proctocort, 
Proctocream-HC, Proctosert HC, Proctosol-HC, 
Proctozone-HC, Rectacort HC, Rectasol-HC, Rederm, 
Sarna-HC (camphor & menthol)Scalacort, Scalpicin 
Anti-Itch, Solu-Cortef, Texacort, Tucks HC, Vagisil 
Anti-Itch, Walgreens Intensive Healing, Westcort 
Low 
Hydrocortisone (+ Miconazole) 
Micreme H 
Low 
Hydrocortisone (+ neomycin, natamycin) 
Primafucort cream/ointment  
Low 
Hydrocortisone (alcohol or acetate) 0.5%, 
1%, 2% 
Cortic 0.5%, Cortaid, Derm-aid, Cortef, Egocort, 
Sigmacort, Squibb-HC, Analpram HC, Epifoam, 
Low 


miRagen Therapeutics, Inc. 
 
Protocol No. MRG106-11-201 
 
 
Version 4.0 
 
 
10 February 2020 
 
 
Proprietary and Confidential 
 
Page 146 of 146 
Steroid Generic Name 
Trade Names 
miRagen 
Derived 
Potency 
Pramosone 1%, Ucort, Proctofoam HC 1%, HC-
SLONE, Pediaderm HC (Lotion), Scalacort (lotion), 
(Cortaid, Cortef Feminine or Rectal Itch Cream, 
Gynecort, Lanacort, Wellcortin) 
Hydrocortisone/Urea 1%/10% 
  
Low 
Methylprednisolone 
  
Low 
Methylprednisolone acetate Cream, 0.25% 
  
Low 
Prednicarbate, 0.05% 
Dermatop (emollient cream, oint) 
Low 
Prednisolone 0.5% 
PREDONINE 
Low 
Tixocortol pivalate 
Pivalone 
Low