Conditions: Stage IV Melanoma Stage III Melanoma Advanced Melanoma
Keywords: Pembrolizumab All-Trans Retinoic Acid
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 26
Healthy volunteers: no

Brief summary:
This is a Phase I/Ib investigator-initiated open label of the combination of VESANOID and pembrolizumab treatment.

Detailed description:
Primary Objective

* To identify the MTD and RP2D of the combination of pembrolizumab and ATRA.

Secondary Objective:

* Describe the safety and toxicity of combined treatment with pembrolizumab and all-trans retinoic acid (ATRA) \[brand name VESANOID\] in melanoma patients.
* To assess the anti-tumor activity in terms of a). The reduction in MDSC (immunosuppressive myeloid -derived suppressor cells) frequency and suppressive function (measured as a continuous variable)in peripheral blood of advanced melanoma patients undergoing pembrolizumab and VESANOID combination therapy. b). progression free survival.

Exploratory Objective

* To determine the clinical outcomes with tumor-specific T cell responses.

Arms:
arm 1: Patients will receive pembrolizumab infusions every three weeks. Patients will also receive 3 days of all-trans retinoic acid treatment surrounding each of the first 4 infusions of pembrolizumab, beginning one day prior to the infusion (a total of 12 days of all-trans retinoic acid).

Interventions: intervention 1: Pembrolizumab with All-Trans Retinoic Acid
Intervention descriptions: intervention 1: All the patients will receive 200mg Q3W pembrolizumab treatment plus the supplemental treatment of 150 mg/m2 All-Trans Retinoic Acid orally for 3 days surrounding each of the first four infusions of pembrolizumab

Protocol document:
Prot_SAP_ICF_000.pdf: 
Study Drug:  PEMBROLIZUMAB 
Protocol Version:  08.14.2019 
Protocol Number: COMIRB 16-1080 
PI: Martin McCarter, MD 
 
Page 1 of 64 
 
 
 
PROTOCOL NUMBER: 
 
COMIRB 16-1080 
NCT: 
 
NCT03200847 
 
PROTOCOL TITLE:  
Pembrolizumab and All-Trans Retinoic Acid 
Combination Treatment of Advanced Melanoma 
 
VERSION DATE: 
August 14, 2019 
 
SPONSOR / 
PRINCIPAL INVESTIGATOR: 
Martin McCarter, MD  
 
Department of Surgery  
 
Mail Stop C313 
 
12631 East 17th Avenue 
 
Aurora, CO 80045 
 
P – 303-724-2725 
 
F – 303-724-2733 
 
STUDY SITES: 
University of Colorado Cancer Center 
 
Anschutz Cancer Pavilion 
 
1665 Aurora Court 
 
Aurora, CO 80045 
 
 
Poudre Valley Hospital 
 
1024 S. Lemay Avenue 
 
Fort Collins, CO 80524   
 
 
FUNDING SUPPORT:  
Merck & Co., Inc. 
 
STUDY REFERENCE NUMBER: 
MISP 54054  
 


Study Drug:  PEMBROLIZUMAB 
 
Protocol Version:  08.14.2019 
Protocol Number: COMIRB 16-1080 
PI: Martin McCarter, MD 
 
 
Page 2 of 64 
 
STATEMENT OF COMPLIANCE 
This is an investigator-initiated study. The Principal Investigator (PI), Martin McCarter, 
MD, is conducting the study and acting as the sponsor. As the Sponsor-Investigator, both the 
legal/ethical obligations of a PI and those of a sponsor will be followed. 
 
The trial will be carried out in accordance with Good Clinical Practice (GCP) as required by 
applicable United States (US) laws and applications, including but not limited to United 
States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/ or 21 CFR Part 812). 
 
The PI will assure that no changes to the protocol will take place without documented 
approval from the Institutional Review Board (IRB). All personnel involved in the conduct of 
this study have completed Human Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed 
about their obligations in meeting the above commitments. 
 
 
 
Sponsor-Lead Principal Investigator: __________________________________________ 
 
 
 
 
 
     Print/Type Name 
 
 
 
Signed: ____________________________________________ 
Date: _______________ 
 
 
Site Principal Investigator: __________________________________________ 
 
 
 
           Print/Type Name 
 
 
 
Signed: ____________________________________________ 
Date: _______________ 
 
 
 
 
 


Study Drug:  PEMBROLIZUMAB 
 
Protocol Version:  08.14.2019 
Protocol Number: COMIRB 16-1080 
PI: Martin McCarter, MD 
 
 
Page 3 of 64 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................ 8 
1.0 
PROTOCOL/TRIAL SUMMARY.......................................................................... 10 
2.0 
TRIAL DESIGN........................................................................................................ 11 
2.1 
Trial Design ........................................................................................................... 11 
2.2 
Trial Schema/Diagram ......................................................................................... 12 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................. 13 
3.1 
Primary Objective ................................................................................................. 13 
3.2 
Secondary Objective: ............................................................................................ 13 
3.3 
Exploratory Objective .......................................................................................... 13 
4.0 
BACKGROUND & RATIONALE .......................................................................... 13 
4.1 
Background ........................................................................................................... 13 
4.1.1 Pharmaceutical and Therapeutic Background..................................................... 14 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 14 
4.2 
Rationale ................................................................................................................ 15 
4.2.1 Rationale for the Trial and Selected Subject Population .................................... 15 
4.2.2 Rationale for Study Design/Dose Selection/Regimen/Modification .................. 15 
4.2.3 Efficacy Endpoints .............................................................................................. 17 
5.0 
STUDY ENROLLMENT AND WITHDRAWAL ................................................. 18 
5.1 
Trial Participation Criteria .................................................................................. 18 
5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 18 
5.1.2 Subject Inclusion Criteria ................................................................................... 18 
5.1.3 Subject Exclusion Criteria .................................................................................. 19 
6.0 
STUDY AGENT AND TRIAL TREATMENT ...................................................... 21 


Study Drug:  PEMBROLIZUMAB 
 
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6.1 
Study Drug Description and Trial Treatments .................................................. 21 
6.1.1 Dose Selection/Modification and Study Drug Risks .......................................... 22 
6.1.2 Timing of Dose Administration .......................................................................... 33 
6.1.3 Trial Blinding/Masking ....................................................................................... 33 
6.2 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 33 
6.2.1 Acceptable Concomitant Medications ................................................................ 33 
6.2.2 Prohibited Concomitant Medications ................................................................. 34 
6.3 
Rescue Medications & Supportive Care ............................................................. 35 
6.3.1 Supportive Care Guidelines ................................................................................ 35 
6.4 
Known Potential Benefits of the Trial ................................................................. 35 
6.5 
Diet/Activity/Other Considerations ..................................................................... 35 
6.5.1 Diet ...................................................................................................................... 35 
6.5.2 Contraception ...................................................................................................... 35 
6.5.3 Use in Pregnancy ................................................................................................ 37 
6.5.4 Use in Nursing Women ....................................................................................... 38 
6.6 
Subject Withdrawal, Treatment Discontinuation, or Study Termination 
Criteria ................................................................................................................... 38 
6.6.1 Subject Withdrawal ............................................................................................. 38 
6.6.2 Subject Discontinuation ...................................................................................... 38 
6.6.3 Discontinuation of Study Therapy after CR ....................................................... 39 
6.6.4 Discontinuation of Study Therapy after Disease Stability .................................. 39 
6.6.5 Toxicity and Study Discontinuation Criteria ...................................................... 39 
6.6.6 Clinical Criteria for Early Trial Termination ...................................................... 40 
7.0 
TRIAL SCHEDULE AND PROCEDURES ........................................................... 40 


Study Drug:  PEMBROLIZUMAB 
 
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7.1 
Trial Schedule of Events Chart ........................................................................... 40 
7.2 
Trial Procedures ................................................................................................... 41 
7.2.1 Administrative Procedures .................................................................................. 42 
7.2.2 Clinical Procedures / Assessments ...................................................................... 43 
7.2.3 Efficacy Measurement ........................................................................................ 44 
7.2.4 Tumor Tissue Collection and Correlative Studies Blood Sampling ................... 44 
7.2.5 Laboratory Procedures/Assessments................................................................... 44 
7.2.6 Other Procedures ................................................................................................. 45 
7.2.7 Visit Requirements .............................................................................................. 46 
7.3 
Adverse Events (AE) – Assessing, Recording and Reporting ........................... 46 
7.3.1 Definition of AE ................................................................................................. 46 
7.3.2 Assessment of AE ............................................................................................... 47 
7.3.3 Reporting of AEs ................................................................................................ 47 
7.4 
Serious Adverse Events (SAE) – Assessing, Recording and Reporting ........... 47 
7.4.1 Definition and Assessment SAEs ....................................................................... 47 
7.4.2 Immediate Reporting of SAEs ............................................................................ 48 
7.4.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting ................... 48 
7.5 
Events of Clinical Interest (ECI) ......................................................................... 48 
7.6 
Reporting of Pregnancy and Lactation ............................................................... 49 
7.7 
Sponsor-Investigator Responsibility for Reporting Adverse Events ............... 50 
7.7.1 Evaluating Adverse Events ................................................................................. 51 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 54 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 55 


Study Drug:  PEMBROLIZUMAB 
 
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9.1 
Investigational Product ........................................................................................ 55 
9.2 
Packaging and Labeling Information ................................................................. 55 
9.3 
Clinical Supplies Disclosure ................................................................................. 55 
9.4 
Storage and Handling Requirements .................................................................. 56 
9.5 
Returns and Reconciliation .................................................................................. 56 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 56 
10.1 
Ethics and Protection of Human Subjects .......................................................... 56 
10.1.1 Ethical Standard .................................................................................................. 56 
10.1.2 Institutional Review Board (IRB) ....................................................................... 56 
10.1.3 Informed Consent Process .................................................................................. 57 
10.1.4 Subject and Data Confidentiality ........................................................................ 57 
10.1.5 Future Use of Stored Specimens ......................................................................... 58 
10.2 
Data Management and Record Keeping ............................................................. 58 
10.2.1 Clinical Data Collection and Management Responsibilities: ............................. 58 
10.2.2 Database: ............................................................................................................. 59 
10.2.3 Study Records Retention: ................................................................................... 59 
10.2.4 Unanticipated Problems (UAP) including Protocol Deviations ......................... 59 
10.3 
Data and Safety Monitoring and Oversight ....................................................... 60 
10.3.1 Data Safety Monitoring Committee and Plan ..................................................... 60 
10.3.2 Quality Control and Quality Assurance .............................................................. 61 
11.0 
APPENDICES ........................................................................................................... 62 
11.1 
ECOG Performance Status .................................................................................. 62 
11.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ............... 62 


Study Drug:  PEMBROLIZUMAB 
 
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11.3 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ................................................................ 62 
12.0 
REFERENCES .......................................................................................................... 63 
 
 
 


Study Drug:  PEMBROLIZUMAB 
 
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LIST OF ABBREVIATIONS 
ACRONYM 
DESCRIPTION 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
APL 
acute promyelocytic leukemia 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATRA 
all-trans retinoic acid 
BCG 
Bacillus Calmette-Guerin 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
COMIRB 
Colorado Multiple Institutional Review Board 
CR 
Complete Response 
CrCl 
creatinine clearance 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
cytolytic T-lymphocyte 
CU 
University of Colorado 
DISC 
University of Colorado-Denver Development and Informatics Service Center 
DKA 
diabetic ketoacidosis 
dL 
Deciliter 
DSM 
data and safety monitoring 
DSMC 
Data and Safety Monitoring Committee 
ECI 
event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of Treatment 
EPO 
Erythropoietin 
ERC 
Ethics Resource Center 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
FDAMA 
Food and Drug Administration Modernization Act 
FSH 
follicle-stimulating hormone 
g 
Gram 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GI 
Gastrointestinal 
GM-CSF 
granulocyte-macrophage colony stimulating factor 
HCG 
human chorionic gonadotropin 


Study Drug:  PEMBROLIZUMAB 
 
Protocol Version:  08.14.2019 
Protocol Number: COMIRB 16-1080 
PI: Martin McCarter, MD 
 
 
Page 9 of 64 
 
HIV 
Human Immunodeficiency Virus 
HLA 
human leukocyte antigen 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IFM 
Interferon 
IL 
Interleukin 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
Intravenous 
kg 
Kilogram 
L 
Liter 
m 
Meter 
mAb 
monocolonal antibody 
mcL 
Microliter 
MDSC 
myeloid-derived suppressor cell 
mg 
Milligram 
mL 
Milliliter 
mmol 
Millimolar 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NSAID 
non-steroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
OTC 
over-the-counter 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PI 
principal investigator 
PK 
Pharmacokinetics 
po 
by mouth 
PT 
prothrombin time 
Q3W 
every three weeks 
RA-APL 
retinoic acid-acute promyelocytic leukemia 
RP2D 
Recommended Phase 2 dose 
SAE 
serious adverse event 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
T1DM 
Type 1 diabetes mellitus 
TB 
Tuberculosis 
TSH 
thyroid-stimulating hormone 
UAP 
unanticipated problem 
UCCC 
University of Colorado Cancer Center 
ULN 
upper limit of normal 
US 
United States 


Study Drug:  PEMBROLIZUMAB 
 
Protocol Version:  08.14.2019 
Protocol Number: COMIRB 16-1080 
PI: Martin McCarter, MD 
 
 
Page 10 of 64 
 
1.0 
PROTOCOL/TRIAL SUMMARY 
Protocol Title 
Pembrolizumab and All-Trans Retinoic Acid Combination 
Treatment of Stage IV Melanoma 
 
Protocol Number 
16-1080 
Trial Objectives: 
Objectives: 
Primary Objective 
To identify the MTD and RP2D of the combination of 
pembrolizumab and ATRA. 
Secondary Objective  
• Describe the safety and toxicity of combined 
treatment with pembrolizumab and all-trans retinoic 
acid (ATRA) [brand name VESANOID] in melanoma 
patients. 
• To assess the anti-tumor activity of the combination of 
pembrolizumab and all-trans retinoic acid (ATRA) 
[brand name VESANOID] in melanoma patients. 
Exploratory Objective 
To determine the clinical outcomes with tumor-specific 
T cell responses. 
Trial Efficacy Endpoints: 
1. Manipulation of MDSC subsets. 
2. Progression-free survival. 
Trial Population: 
• 24 subjects to be treated 
• Male and female subjects 
• Ages 18-100 
Trial Phase 
I/IB 
Clinical Indication 
Stage IV Melanoma 
Trial Type 
Interventional 
Type of Control 
N/A 
Description of Study Drug(s) 
Pembrolizumab 
(Keytruda 
®) 
will 
be 
administered 
Intravenous (IV) and Vesanoid will be administered orally. 
Trial Blinding 
Open Label Clinical Trial 
Treatment Groups  
One 
Number of Trial Subjects 
24 


Study Drug:  PEMBROLIZUMAB 
 
Protocol Version:  08.14.2019 
Protocol Number: COMIRB 16-1080 
PI: Martin McCarter, MD 
 
 
Page 11 of 64 
 
Estimated Enrollment Period 
1 year 
Estimated Duration of Trial 
5 years 
Duration of Subject 
Participation 
2 years 
Estimated Average Length of 
Treatment Per Patient 
VESANOID will be administered over 12 weeks. 
Pembrolizumab will be administered every 3 weeks until 
progression of disease, intolerance of therapy, or for up to two 
years. 
 
 
This is a multi-center study to be conducted at the University of Colorado Cancer Center 
(UCHealth central campus) and Poudre Valley Hospital (UCHealth north campus).  A 
complete and current listing of investigators, research personnel, and research facilities 
participating in this study will be maintained throughout the duration of this study on 
applicable study required forms such as an FDA Form 1572, the COMIRB Research Personnel 
Form, and/or a UCCC Protocol Contact List, incorporated herein by reference. 
 
2.0 
TRIAL DESIGN 
2.1 
Trial Design 
This is a Phase I/Ib investigator-initiated open label trial of the combination of VESANOID 
and pembrolizumab treatment.   
A total of 24 evaluable patients will be recruited into the study. All the patients will receive 
200mg Q3W pembrolizumab treatment plus the supplemental treatment of 150 mg/m2 
VESANOID orally for 3 days surrounding each of the first four infusions of pembrolizumab 
(day -1, day 0, day +1) for a total of 12 days of VESANOID treatment (Section 2.2 Trial 
Schema/Diagram).   
To closely monitor DLTs, subjects will be recruited into the study using a cohort size of 6. The 
toxicity monitoring design is to inform de-escalation decisions based on safety if needed. DLTs 
will be assessed during the DLT assessment window of 21 days following the first dose of 
Vesanoid and Pembrolizumab (Cycle 1 Day 0 to Cycle 2 Day 0). Patients who withdraw from 
the study prior to completing the DLT assessment window for any reason other than a DLT 
will be replaced. See Section 6.1.1.2.3 for DLT definition. 
After the first 6 subjects in cohort 1 complete the DLT period, the Sponsor-Investigator will 
review data pertaining to the dose de-escalation decision. Available adverse event data and 
laboratory assessments will be used to determine whether the Vesanoid dose should be 
continued at 150 mg/m2 or whether the Vesanoid dose should be de-escalated to 100 mg/m2in 
the subsequent six subjects to be enrolled in cohort 2.  
 


Study Drug:  PEMBROLIZUMAB 
 
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Dose de-escalation will proceed in accordance with the following rules: 
• 6 patients will be treated in cohort 1. 
o If 0-2 patients experience a DLT in cohort 1, the Vesanoid dose will be 
maintained. 
o If > 3 patients in cohort 1 experience a DLT, then dose de-escalation of 
Vesanoid will proceed. 
• 6 additional patients will be treated in cohort 2 at either the starting Vesanoid dose 
(150 mg/m2) or the reduced Vesanoid dose (100 mg/m2).  
o If 0-2 patients experience a DLT in cohort 2, the Vesanoid dose will be 
maintained. 
o If > 3 patients in cohort 2 experience a DLT, then the study will stop.  
• If it is determined that the dose will be maintained from Cohort 2, then an additional 
cohort (cohort 3) of up to 12 patients (depending on the number of patients required 
to achieve the enrollment goal of 24 patients, but not to exceed 30 patients) will be 
treated at either the starting Vesanoid dose (150 mg/m2), or the reduced Vesanoid 
dose (100 mg/m2).  
 
This trial will be conducted in compliance with this protocol, Good Clinical Practice, and local 
and federal regulations. 
 
Anticipated total number of enrolled research subjects: up to 30 to allow for screen fails or 
withdrawals 
 
Anticipated number to complete study: 24 (who receive at least one dose of VESANOID and 
Pembrolizumab) 
2.2 
Trial Schema/Diagram 
  
Figure 1. Diagram of the treatment and blood draw schedule for this study.  Patients will receive pembrolizumab infusions every three 
weeks.  Patients will also receive 3 days of VESANOID treatment surrounding each of the first 4 infusions of pembrolizumab, beginning 
one day prior to the infusion (a total of 12 days of VESANOID).  Six tubes of peripheral blood (for a total of approximately 40 ml) will be 
drawn at enrollment, at the 2rd and 4th infusions, and within 60 days of the final VESANOID dose for additional functional experiments.  


Study Drug:  PEMBROLIZUMAB 
 
Protocol Version:  08.14.2019 
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Page 13 of 64 
 
3.0 
OBJECTIVE(S) & HYPOTHESIS (ES) 
3.1 
Primary Objective 
To identify the MTD and RP2D of the combination of pembrolizumab and ATRA. 
3.2 
Secondary Objective:  
• Describe the safety and toxicity of combined treatment with pembrolizumab and all-
trans retinoic acid (ATRA) [brand name VESANOID] in melanoma patients. 
• To assess the anti-tumor activity in terms of a). The reduction in MDSC 
(immunosuppressive myeloid –derived suppressor cells) frequency and suppressive 
function (measured as a continuous variable) in peripheral blood of advanced 
melanoma patients undergoing pembrolizumab and VESANOID combination 
therapy.  b). progression free survival. 
3.3 
Exploratory Objective 
To determine the clinical outcomes with tumor-specific T cell responses. 
4.0 
BACKGROUND & RATIONALE 
4.1 
Background 
Melanoma elicits profound immune responses and is one of the few tumors for which 
immunotherapies have been successful (1). However, melanoma counters current 
immunotherapeutic approaches by inducing immune escape mechanisms, a critical barrier that 
may contribute to low response rates and treatment failure (1). Melanoma continues to be a 
leading cause of death among adult cancer patients (2, 3). Furthermore, the incidence of 
melanoma continues to increase across all age groups (4).  
The antibody therapy pembrolizumab, specific for programed cell death receptor 1 (PD-1), an 
inhibitory molecule expressed on activated T cells, has recently been shown to significantly 
improve overall survival and induce durable, long-lasting responses in approximately 45% of 
treated patients (5). Since pembrolizumab was granted approval as a first line treatment in 
metastatic melanoma patients, it has largely replaced Ipilimumab due to higher response rates 
with lower toxicities (5).  While the results of this monumental study highlight a crucial 
advantage of immunotherapies in achieving long-term immunity that is resistant to disease 
relapse, increased response rates to pembrolizumab could further enhance survival and clinical 
outcomes for patients with advanced-stage melanoma. One proven mechanism of action for 
this drug is eliciting the frequency and function of tumor-specific T cells (6). However, tumor 
induced immunosuppression may limit the development of effective immune responses in 
some patients treated with pembrolizumab. Improving clinical responses to pembrolizumab by 
enhancing other immune-mediated mechanisms in a combinatorial approach is essential for 
the future evolution of immunotherapeutic strategies. 


Study Drug:  PEMBROLIZUMAB 
 
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Page 14 of 64 
 
MDSCs are a mixed population of immunosuppressive myeloid cells that are key contributors 
to tumor-induced immunosuppression. Increased numbers of MDSCs are associated with 
larger tumor burdens, increased tumor progression, and shorter overall survival in several 
cancers, including melanoma (7-10). These data suggest that targeting MDSCs may improve 
tumor-specific immune responses, increase clinical responses to immunotherapy, and 
ultimately increase survival in melanoma patients. In this proposal, we aim to decrease the 
frequency and/or function of MDSCs in melanoma patients treated with all-trans retinoic acid 
(ATRA). 
4.1.1 Pharmaceutical and Therapeutic Background 
All-trans retinoic acid (ATRA) is a vitamin A derivative that binds the retinoic acid 
receptor on MDSCs and differentiates immature monocytes into more mature dendritic 
cells (11). VESANOID is a standard treatment currently approved for patients with acute 
promyelocytic leukemia (APL). 
 
VESANOID (tretinoin) is an FDA-approved commercially available retinoid that induces 
maturation of APL cells in culture. It is not approved in combination with pembrolizumab 
or for the treatment of patients with melanoma.  It is available in a 10 mg soft gelatin 
capsule for oral administration. The recommended dose (for APL) is 45 mg/m2/day 
administered as two evenly divided doses until complete remission is documented.  
 
Virtually all patients with APL experience some drug-related toxicity, especially headache, 
fever, weakness, and fatigue. These adverse effects are seldom permanent or irreversible 
nor do they usually require interruption of therapy. Some of the adverse events noted in 
patients with APL are associated with rapid tumor response and include hemorrhage, 
infections, 
gastrointestinal 
hemorrhage, 
disseminated 
intravascular 
coagulation, 
pneumonia, septicemia, and cerebral hemorrhage.  There are no reported adverse side 
effects in patients with solid tumors treated with a short course of 150 mg/m2 VESANOID 
combined with high dose IL-2 or a dendritic cell vaccine (12, 13).   
4.1.2 Preclinical and Clinical Trial Data 
Pre-clinical data suggest that VESANOID abrogates the suppressive effects of MDSCs 
isolated from both human cancer patients and mouse cancer models in vitro (14-16). 
Furthermore, mice treated with VESANOID have decreased frequencies of MDSCs and 
increased frequencies of dendritic cells that improve T cell responses against tumors (17-
19). 
Our preliminary research has identified a population of immunosuppressive MDSCs 
(Lineage negative, HLA-DR negative, CD11b positive, and CD33 positive) that are 
increased in Stage IV melanoma patients relative to healthy donors. To establish MDSCs 
as a potentially important contributor to immunosuppression in melanoma patients, we 
compared the frequency and function of immunosuppressive MDSCs in the peripheral 
blood of healthy donors, Stage I, and Stage IV melanoma patients (10). We found 
significant increases in the frequency of MDSCs in the peripheral blood of Stage IV 


Study Drug:  PEMBROLIZUMAB 
 
Protocol Version:  08.14.2019 
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Page 15 of 64 
 
melanoma patients compared to healthy donors. We showed that the frequency of these 
cells correlates with an increase in regulatory T cells and an increased level of IL-6 and IL-
8 cytokines in the peripheral blood. Furthermore, patients with clinical disease progression 
had an increased frequency of these cells.  We also found that patients with a high 
frequency of MDSCs had decreased overall survival and an increased risk of death (hazard 
ratio 4.83, p = 0.016). This increased risk of death was independent of other clinical factors 
including age, gender, and treatment regimens. Finally, we demonstrated that MDSCs 
isolated from Stage IV melanoma patients were significantly more immunosuppressive 
than those isolated from healthy donors. Overall, these data suggest that MDSCs may be a 
significant contributor to immunosuppression in melanoma patients and that targeting these 
cells in a combinatorial approach may improve immune responses against melanoma.  
 
VESANOID induces the differentiation of immature monocytes into more mature cells of 
the dendritic cell lineage (15, 16, 20). In agreement with these results, our preliminary data 
suggest that VESANOID induces maturation of in vitro-derived MDSCs. We cultured 
monocytes from healthy donors with GM-CSF/IL-4 or GM-CSF/IL-6 to generate mature 
monocytes of the dendritic cell lineage (a control population) or MDSCs, respectively (21, 
22).  In contrast to the control population, MDSCs express low levels of HLA-DR and 
maintain high expression of CD14, consistent with the phenotype of an immature 
monocyte. Furthermore, MDSCs express increased levels of molecules that inhibit T cell 
responses such as Arginase I, NOX1, iNOS, and PD-L1. Conversely, MDSCs cultured with 
VESANOID are phenotypically more similar to the control dendritic cell population, 
expressing decreased levels of inhibitory molecules and CD14 and increased levels of 
HLA-DR.  Most importantly, MDSCs derived in vitro with GM-CSF and IL-6 suppress T 
cell proliferation. However, treatment of these MDSCs with VESANOID eliminates their 
suppressive effects and restores T cell proliferation. Finally, MDSCs express higher levels 
of retinoic acid receptors RAR and RXR, suggesting that VESANOID treatment may 
selectively target these inhibitory cells. These preliminary data and our previous 
publications demonstrate that our research team has established the protocols necessary to 
accomplish the experiments outlined in this protocol. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Reducing immunosuppression by MDSCs during pembrolizumab treatment may 
maximize T cell activation and expansion, increasing the overall effectiveness and 
success of pembrolizumab treatment. This pilot clinical trial will demonstrate whether 
combinatorial immunotherapeutic approaches that target immunosuppressive MDSC’s 
can augment tumor-specific T cells and benefit melanoma patients. 
4.2.2 Rationale for Study Design/Dose Selection/Regimen/Modification 
Pembrolizumab Dose Selection  
Dosing of pembrolizumab has been evaluated in a variety of clinical settings. A 
population pharmacokinetic analysis has been performed using serum concentration time 


Study Drug:  PEMBROLIZUMAB 
 
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data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  Pembrolizumab has been 
found to have a wide therapeutic range based on the melanoma indication.  The 
differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body 
weight based regimen are anticipated to remain well within the established exposure 
margins of 0.5 – 5.0 for  pembrolizumab in the melanoma indication. The exposure 
margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg 
Q3W vs. 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK 
evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication 
settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab 
in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed 
at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the 
assumption that the dynamics of pembrolizumab target engagement will not vary 
meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab 
showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are 
optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will 
maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and 3) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. 
All the patients will receive 200mg Q3W pembrolizumab treatment plus the supplemental 
treatment of 150 mg/m2 VESANOID orally for 3 days surrounding each of the first four 
infusions of pembrolizumab (day -1, day 0, day +1) for a total of 12 days of VESANOID 
treatment (Section 2.2 Trial Schema/Diagram).  The total daily dose of VESANOID may 
be taken anytime on the day before the pembrolizumab infusion (day -1) according to the 
patient’s preferences, prior to the pembrolizumab infusion on the day of the infusion (day 
0), and anytime on the day after the pembrolizumab infusion (day 1) according to the 
patient’s preferences.   


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VESANOID Dose Selection  
Although VESANOID is a standard treatment for patients with acute promyelocytic 
leukemia, it has also been used to treat patients with solid tumors. We have selected the 
dose of VESANOID based on two prior clinical trials that combined VESANOID with 
other treatments. We have selected the same dose of VESANOID based on the 
pharmacokinetics and effects on MDSCs observed in these trials (11, 12). Renal cell 
carcinoma patients treated with VESANOID followed by high dose IL-2 had reduced 
frequencies of circulating MDSCs with reduced immunosuppressive function during the 
VESANOID phase of the treatment regimen (13).  However, the subsequent high-dose IL-
2 treatment abrogated these effects and resulted in a lack of clinical benefit overall (13). In 
another recent trial, VESANOID was used in combination with a dendritic cell vaccine 
targeting p53 mutations in small cell lung cancer patients (12). The survival outcomes have 
not yet been reported; however, the study demonstrated that the frequency and function of 
MDSCs was reduced following VESANOID treatment and that p53-specific T cell 
responses were increased in more patients receiving the combinatorial therapy compared 
to patients receiving the dendritic cell vaccine alone (12). These investigators performed a 
dose ranging pharmacokinetic analysis and correlated serum concentrations of ATRA with 
the desired target effect on MDSC’s and determined that the optimal oral dose of ATRA 
was 150mg/m2/day. Lower doses of ATRA generally resulted in lower serum 
concentrations and less reliable effects on MDSC’s. The authors also reported common 
side effects associated with the ATRA as dry skin, myalgia and headache that resolved 
when the ATRA was stopped. No specifics regarding the frequency or severity of these 
side effects were reported. (13)   
De-escalation Design 
The available data suggests that in order to target the MDSC’s, sufficient serum 
concentrations of ATRA are necessary to have the desired effect. Based on prior reported 
investigations (13), the dose of 150mg/m2/day of ATRA was considered optimal and used 
in a subsequent trial with a similar design of three days of high dose ATRA around 
administration of a vaccine (12). The choice of a de-escalation design was based on 
feedback and concern for the potential toxicity associated with the short term higher doses 
of ATRA.  In our prior trial combining three days of ATRA (150mg/m2/day) around 
administration of Ipilimumab, we noted headache as a significant common side effect that 
resolved with discontinuation of the ATRA. The de-escalation design was intended to aim 
for the effect on MDSC’s yet allow for a dose reduction for side effects with the hope of 
still observing at least some effect on the intended target of MDSC’s.  
 
4.2.3 Efficacy Endpoints 
We will monitor efficacy via two endpoints (1) manipulation of MDSC subsets and (2) 
progression free survival. 


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4.2.3.1 
Biomarker Research 
We will track MDSC populations throughout the study and will analyze banked plasma 
for exploratory cytokine and potentially other biomarker analysis that correlate with 
MDSC’s.   
5.0 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
Trial Participation Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Stage IV melanoma patients or patients who are being considered for pembrolizumab 
therapy. 
 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Diagnosis of advanced melanoma (unresectable Stage III or Stage IV Melanoma). 
2. Planned standard treatment with pembrolizumab.  
3. Be willing and able to provide written informed consent for the trial. 
4. State willingness to comply with all study procedures and be available for the 
duration of the trial. 
5. Be ≥ 18 years of age on day of signing informed consent. 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
7. Demonstrate adequate organ function as defined in Table 1, all screening labs 
should be performed within 10 days of treatment initiation.   
 
 
 
 
 
 
 


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Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 
7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
aCreatinine clearance should be calculated per institutional standard. 
8. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
9. Female subjects of childbearing potential (Section 6.5.2 - Contraception) must be 
willing to use an adequate method of contraception as outlined in Section 6.5.2 – 
Contraception, for the course of the study through 120 days after the last dose of study 
medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject. 
10. Male subjects of childbearing potential (Section 6.5.2- Contraception) must agree to 
use an adequate method of contraception as outlined in Section 6.5.2 - Contraception, 
starting with the first dose of study therapy through 120 days after the last dose of study 
therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 


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2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
3. Has a known history of active TB (Bacillus Tuberculosis). 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier.  
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. Subjects with 
chronic conditions such as vision changes from plaque radiation therapy for ocular 
melanoma or prior hearing loss, that is not reasonably expected to be exacerbated by 
the investigational product may be included.  
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 
Note:  If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.  
Note:  Subjects with Grade 2 adrenal insufficiency or thyroid conditions who are not 
expected to resolve to baseline, are on a stable dose of medication may be included  if 
it is not reasonably expected to be exacerbated by the investigational product, and 
asymptomatic whilst on treatment.  
7. Has known active CNS metastases and/or carcinomatous meningitis. Subjects with 
previously treated brain metastases may participate provided they are radiologically 
stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging 
(repeat imaging should be performed during study screening), clinically stable and 
without requirement of steroid treatment for at least 14 days prior to first dose of study 
treatment.  
8. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
9. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
10. Has known history of, or any evidence of active, non-infectious pneumonitis. 


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11. Has an active infection requiring systemic therapy. 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
18. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
19. Has known sensitivity to retinoic acid derivatives. 
20. Has a medical history of allogenic stem cell transplant or received a solid organ 
transplant. 
6.0 
STUDY AGENT AND TRIAL TREATMENT 
6.1 
Study Drug Description and Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 0 of each 3 
week cycle 
Standard 
agent 
All-trans 
retinoic acid 
150 
mg/m2 
Q3W 
Oral 
Day -1, 0, and 1 
of each 3 week 
cycle (first four 
cycles) 
Experimental 
agent 


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6.1.1 Dose Selection/Modification and Study Drug Risks 
6.1.1.1 
 
Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 
(Background and Rationale).   
Details on preparation and administration of pembrolizumab are provided in the 
Pharmacy Manual or investigational brochure.  
The selected dose of VESANOID is based on two prior studies (11, 12) and our own 
experience with VESANOID combined with ipilimumab. These trials combined 
VESANOID with other treatments. We have selected a dose based on the 
pharmacokinetics and effects on MDSCs observed in these trials (11, 12). Renal cell 
carcinoma patients treated with VESANOID followed by high dose IL-2 had reduced 
frequencies of circulating MDSCs with reduced immunosuppressive function during 
the VESANOID phase of the treatment regimen (13). 
6.1.1.2 
 
Dose Modification (Escalation/Titration/Other) 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, 
patient vacation, and/or holidays). Subjects should be placed back on study therapy 
within 3 weeks of the scheduled interruption, unless otherwise discussed with the 
Sponsor-Investigator. The reason for interruption should be documented in the patient's 
study record. 
The toxicity profile of VESANOID and Pembrolizumab may overlap causing difficulty 
in determining the causative agent. Our investigators have many years of prior 
experience treating patients with Pembrolizumab and their clinical judgement will be 
used to assess the toxicity and any potential relationship.  
 
Subjects who discontinue VESANOID treatment due to toxicity will be allowed to 
continue treatment with Pembrolizumab alone if the investigator feels the subject will 
continue to derive benefit from the treatment. 
 
6.1.1.2.1 Pembrolizumab – Risks and Dosing Modification Guidelines 
Pembrolizumab is generally well tolerated and demonstrates a favorable safety 
profile in comparison to chemotherapy. Pembrolizumab is an immunomodulatory 
agent, and based on this mechanism of action, immune-related adverse events 
(irAEs) are of primary concern. An irAE is defined as a clinically significant AE 
of any organ that is associated with study drug exposure, is of unknown etiology, 
and is consistent with an immune-related mechanism. If an irAE is suspected, a 
thorough evaluation should be conducted in an effort to possibly rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes before 


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diagnosing an irAE. Serological, immunological, and histological (biopsy) data 
should be considered to support the diagnosis of an immune-related toxicity. 
 
Immune-related AEs, including severe and fatal cases, have occurred in patients 
receiving pembrolizumab. Immune-related AEs can occur after discontinuation of 
treatment. 
 
Immune-related AEs affecting more than one body system can occur 
simultaneously. In clinical studies, most immune-mediated ARs were reversible 
and managed with interruptions of pembrolizumab, administration of 
corticosteroids, and/or supportive care.  
 
Consultation with the appropriate medical specialist should be considered when 
investigating a possible irAE. These events can occur at times ranging from after 
the first dose of treatment to several months after the last dose of treatment. Mild 
irAEs are usually treated symptomatically and infrequently require dosing delays 
or discontinuation. Higher grade and persistent lower grade irAEs typically 
necessitate withholding or discontinuing treatment, and administration of 
systemic steroids or other immunosuppressive agents (such as tumor 
necrosis factor blockers) when systemic steroids are not effective. Early 
recognition of irAEs and initiation of treatment are critical to reduce the risk of 
complications because the majority of irAEs are reversible with the use of steroids 
and other immune suppressants (please reference the clinical protocol for 
additional information regarding the management of irAEs). Therefore, early 
recognition and initiation of treatment is critical to reduce complications.  
 
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude 
other causes. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Dose modification and toxicity 
management guidelines for irAEs associated with pembrolizumab are provided in 
Table 3.  
 
Suggested supportive care measures for the management of adverse events related 
to pembrolizumab, including use of corticosteroids, are also outlined in Section 6.3 
- Rescue Medications & Supportive Care.  
 
In addition to the immune-related risks noted below, infusion-related reactions are 
also an important identified risk for pembrolizumab; however, they are not 
considered immune-mediated. 


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


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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper 
• 
Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Administer insulin for 
participants with T1DM  
• Administer anti-
hyperglycemic in participants 
with hyperglycemia until 
metabolic control is achieved 
 
• 
Monitor participants for hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids to 
treat adrenal insufficiency 
and other hormone 
replacements as clinically 
indicated.   
 
• 
Monitor patients for signs and symptoms of adrenal 
insufficiency and hypophysitis (including 
hypopituitarism)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyroinine) per standard 
of care 
• 
Monitor for signs and symptoms of thyroid disorders.  
 


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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
Severe skin 
reactions 
 
Withhold or 
permanently 
discontinue 
based on the type 
of event. Events 
that require 
discontinuation 
include and not 
limited to: 
Stevens-Johnson 
Syndrome (SJS) 
and toxic 
epidermal 
necrolysis (TEN) 
• Administer corticosteroids 
• 
Monitor patients for suspected severe skin reactions and 
exclude other causes. 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of 
AE administer 
corticosteroids  
• 
Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the type 
of event.  Events 
that require 
discontinuation 


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include and not 
limited to:  
Guillain-Barre 
Syndrome, 
pancreatitis, 
encephalitis, 
sarcoidosis, and 
myasthenic 
syndrome-
myasthenia 
gravis (including 
exacerbation) 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 


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Management of Infusion Reactions: 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.  
 
Following are treatment guidelines (Table 4) for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
 
Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (Pembrolizumab) 
with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 


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6.1.1.2.2 VESANOID - Risks 
Adverse events (both non-serious and serious) associated with VESANOID will be 
reported to the principal investigator, the University of Colorado Data Safety 
Monitoring Committee (DSMC), and COMIRB.  The treating medical oncologist 
and principal investigator will decide if VESANOID dose should be decreased or 
if VESANOID treatment should be discontinued. 
 
VESANOID Side Effects 
Below is a comprehensive list of reported side effects for VESANOID.  Much of 
the reported experience is in patients being treated for APL, which may differ for 
patients in this trial who do not have APL. 
Potential Side Effects 
Virtually all patients experience some drug-related toxicity, especially 
headache, fever, weakness, and fatigue. These adverse effects are seldom 
permanent or irreversible nor do they usually require interruption of therapy. 
Some of the adverse events are common in patients with APL, including 
hemorrhage, 
infections, 
gastrointestinal 
hemorrhage, 
disseminated 
intravascular coagulation, pneumonia, septicemia, and cerebral hemorrhage. 
The following describes the adverse events, regardless of drug relationship, that 
were observed in patients treated with VESANOID (tretinoin). 
Typical Retinoid Toxicity 
The most frequently reported adverse events were similar to those described in 
patients taking high doses of vitamin A and included headache (86%), fever 
(83%), skin/mucous membrane dryness (77%), bone pain (77%), 
nausea/vomiting (57%), rash (54%), mucositis (26%), pruritus (20%), increased 
sweating (20%), visual disturbances (17%), ocular disorders (17%), alopecia 
(14%), skin changes (14%), changed visual acuity (6%), bone inflammation 
(3%), visual field defects (3%). 
Body as a Whole 
General disorders related to VESANOID (tretinoin) administration and/or 
associated with APL included malaise (66%), shivering (63%), hemorrhage 
(60%), infections (58%), peripheral edema (52%), pain (37%), chest discomfort 
(32%), edema (29%), disseminated intravascular coagulation (26%), weight 
increase (23%), injection site reactions (17%), anorexia (17%), weight decrease 
(17%), myalgia (14%), flank pain (9%), cellulitis (8%), face edema (6%), fluid 
imbalance (6%), pallor (6%), lymph disorders (6%), acidosis (3%), 
hypothermia (3%), ascites (3%). 


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Respiratory System Disorders 
Respiratory system disorders were commonly reported in APL patients 
administered VESANOID (tretinoin). The majority of these events are 
symptoms of the RA-APL syndrome (see boxed WARNINGS). Respiratory 
system adverse events included upper respiratory tract disorders (63%), 
dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), 
pneumonia (14%), rales (14%), expiratory wheezing (14%), lower respiratory 
tract disorders (9%), pulmonary infiltration (6%), bronchial asthma (3%), 
pulmonary edema (3%), larynx edema (3%), unspecified pulmonary disease 
(3%). 
Ear Disorders 
Ear disorders were consistently reported, with earache or feeling of fullness in 
the ears reported by 23% of the patients. Hearing loss and other unspecified 
auricular disorders were observed in 6% of patients, with infrequent (<1%) 
reports of irreversible hearing loss. 
Gastrointestinal Disorders 
GI disorders included GI hemorrhage (34%), abdominal pain (31%), other 
gastrointestinal disorders (26%), diarrhea (23%), constipation (17%), dyspepsia 
(14%), abdominal distention (11%), hepatosplenomegaly (9%), hepatitis (3%), 
ulcer (3%), and unspecified liver disorder (3%). 
Cardiovascular and Heart Rate and Rhythm Disorders 
Arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%), 
phlebitis (11%), cardiac failure (6%) and for 3% of patients: cardiac arrest, 
myocardial infarction, enlarged heart, heart murmur, ischemia, stroke, 
myocarditis, pericarditis, pulmonary hypertension, secondary cardiomyopathy. 
Central and Peripheral Nervous System Disorders and Psychiatric 
Dizziness (20%), paresthesias (17%), anxiety (17%), insomnia (14%), 
depression (14%), confusion (11%), cerebral hemorrhage (9%), intracranial 
hypertension (9%), agitation (9%), hallucination (6%) and for 3% of patients: 
abnormal gait, agnosia, aphasia, asterixis, cerebellar edema, cerebellar 
disorders, convulsions, coma, CNS depression, dysarthria, encephalopathy, 
facial paralysis, hemiplegia, hyporeflexia, hypotaxia, no light reflex, neurologic 
reaction, spinal cord disorder, tremor, leg weakness, unconsciousness, 
dementia, forgetfulness, somnolence, slow speech. 
Urinary System Disorders 
Renal insufficiency (11%), dysuria (9%), acute renal failure (3%), micturition 
frequency (3%), renal tubular necrosis (3%), enlarged prostate (3%). 


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Miscellaneous Adverse Events 
Isolated cases of erythema nodosum, basophilia and hyperhistaminemia, 
Sweet's syndrome, organomegaly, hypercalcemia, pancreatitis and myositis 
have been reported. 
Cardiovascular 
Cases of thrombosis (both venous and arterial) involving various sites (e.g., 
cerebrovascular accident, myocardial infarction, renal infarct) have been 
reported rarely. 
Hematologic 
Rare cases of thrombocytosis have been reported. 
Skin 
Genital ulceration. 
Miscellaneous Adverse Events 
Rare cases of vasculitis, predominantly involving the skin, have been reported. 
6.1.1.2.3 Dose Modifications for VESANOID 
If patients experience grade 3 or 4 toxicity that is believed to be related to the 
VESANOID, then the VESANOID will be held until the toxicity resolves to grade 
0 or 1. In the case where the grade 3 or 4 toxicity is believed to be related to 
Pembrolizumab, the dose modification guidelines in table 3 will be followed. If the 
toxicity appears to be related to a combination of Pembrolizumab and VESANOID, 
the VESANOID will be held and the guidelines in table 3 will be followed. After 
the toxicity has resolved, the VESANOID will either be restarted at the next 
scheduled time at a reduced dose of 100mg/m2 or will be discontinued for serious 
toxicities. The decision to discontinue treatment will be based on what the treating 
physician feels is in the subjects’ best interest. If the grade 3 or 4 toxicity returns, 
the VESANOID will be held indefinitely.  
The severity of the adverse events will be rated on a scale of Grade 1-4 and reported 
according to the Data and Safety Monitoring Plan using CTCAE version 4.0. 
Medical oncologists at the University of Colorado Hospital Cutaneous Oncology 
Clinic specialize in melanoma and have extensive experience treating patients with 
immune-based therapies that cause immune-related adverse events. The Principal 
Investigator will be notified of all adverse events that occur during this trial and 
will work with the treating oncology team to determine the likelihood of 
VESANOID’s contribution to the adverse event.  
 
 
 


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VESANOID Related Toxicity 
Significant VESANOID related toxicity is defined as any >= grade 3 non-
hematologic toxicity related to VESANOID, > = grade 4 hematologic toxicity 
related to VESANOID or other grade VESANOID related adverse events that lead 
to treatment discontinuation. An exception is VESANOID related headache not 
optimally managed with supportive care therapies [acetaminophen, non-steroidal 
anti-inflammatory medication, or Imitrex (sumatriptan)] or that does not resolve 
within 72 hours of stopping the VESANOID. A patient’s choice to stop all 
VESANOID, with or without a dose reduction, due to headache alone will not be 
considered a dose limiting toxicity.  
 
Dose Limiting Toxicity and Study Discontinuation Criteria 
The trial stopping criteria outlined in the table found in Section 6.6.5 - Toxicity and 
Study Discontinuation Criteria will be followed to avoid posing undue risk to 
additional patients. Twenty four (24) patients will potentially be recruited to further 
evaluate safety and assess preliminary efficacy.  
Dose limiting toxicities are defined according to the AE profile observed during the 
first cycle (Cycle 1 Day 0 to Cycle 2 Day 0) of study drug administration. All AEs 
should be considered possibly related to the study drug unless such relationship can 
be definitively excluded.  
Toxicity will be evaluated according to NCI CTCAE Version 4.0. A DLT will be 
defined as any of the following events that are considered by the investigator to be 
at least possibly related to treatment with Vesanoid and Pembrolizumab: 
 
1. Any >= grade 3 non-hematologic toxicity related to VESANOID, > = 
grade 4 hematologic toxicity related to VESANOID or other grade 
VESANOID related adverse events that lead to treatment discontinuation. 
An exception is VESANOID related headache not optimally managed 
with supportive care therapies (acetaminophen or non-steroidal anti-
inflammatory medication) or that does not resolve within 72 hours of 
stopping the VESANOID. A patient’s choice to stop all VESANOID, with 
or without a dose reduction, due to headache alone will not be considered 
a dose limiting toxicity. 
2. Any >= grade 3 toxicity related to Pembrolizumab.   
 
 
 
 


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The dose levels will be as follows:  
Dose Level 
Number 
of 
Patients 
Vesanoid 
Pembrolizumab 
-1 
6 
100 mg/m2 PO on days -1, 0, and 1 
every 3 weeks for the first 4 cycles 
200 mg IV on Day 0 
every 3 weeks 
1 (Starting Dose) 6 
150 mg/m2 PO on days -1, 0, and 1 
every 3 weeks for the first 4 cycles 
200 mg IV on Day 0 
every 3 weeks 
6.1.2 Timing of Dose Administration 
Trial treatment with Pembrolizumab should be administered on Day 0 of each cycle after 
all procedures/assessments have been completed as detailed on the Trial Schedule of Events 
Chart (Section 7.1).  All trial treatments will be administered on an outpatient basis. 
VESANOID will be administered on day -1, 0 and 1 with each of the first four cycles of 
Pembrolizumab. VESANOID will be administered twice a day (75mg/m2 each dose for a 
total dose of 150mg/m2). 
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion every 3 weeks.  
Given the variability of infusion pumps from site to site, a window of -10 minutes and +10 
minutes is permitted (i.e., infusion time is 30 minutes: -10 min/+10 min). 
The Pharmacy Manual and investigational brochure contains specific instructions for the 
preparation of the pembrolizumab infusion fluid and administration of infusion solution. 
6.1.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor-Investigator, study personnel, and subject 
will know the treatment administered. 
6.2 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination rests 
with the Sponsor-Investigator and/or the subject's primary physician.  
6.2.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards 


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of medical care.  All concomitant medication will be recorded on the case report form 
(CRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids.  If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.5 – Events of Clinical Interest (ECI). 
6.2.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, 
BCG, and typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from 
an event of clinical interest of suspected immunologic etiology.  The use of 
physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor-Investigator. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications that are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 


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6.3 
Rescue Medications & Supportive Care 
6.3.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below). Refer to Section 6.1.1.2 - 
Dose Modification (Escalation/Titration/Other).  
6.4 
Known Potential Benefits of the Trial 
The risks to subjects are reasonable in relation to the anticipated benefits to subjects and/or 
society, and in relation to the importance of the knowledge that may reasonably be expected 
to result, thereby falling in favor of performing the study: 
 
• To Subject: The potential benefit to the study subject is decreased 
immunosuppressive action of MDSC’s and enhanced immunologic 
responses.  
• To Society: The potential benefit to society is generalizable knowledge 
regarding utilization of combinational immunotherapies.  
• Justify the importance of the knowledge gained: The potential knowledge 
to be gained includes a better understanding of mechanisms surrounding 
ongoing tumor induced immunosuppression. Information from this study 
may be used to further refine immunologic targets such as MDSC’s. 
6.5 
Diet/Activity/Other Considerations 
6.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
6.5.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known 
if pembrolizumab has transient adverse effects on the composition of sperm.   


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Animal reproduction studies have not been conducted with pembrolizumab; however, 
blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt 
tolerance to the fetus and to result in an increase in fetal loss. These results indicate a 
potential risk, based on its mechanism of action, that administration of pembrolizumab 
during pregnancy could cause fetal harm, including increased rates of abortion or 
stillbirth. Human IgG4 is known to cross the placental barrier and pembrolizumab is an 
IgG4; therefore, pembrolizumab has the potential to be transmitted from the mother to the 
developing fetus. Pembrolizumab is not recommended during pregnancy unless the 
clinical benefit outweighs the potential risk to the fetus. Women of childbearing potential 
should use effective contraception during treatment with pembrolizumab and for at least  
after the last dose of pembrolizumab. 
 
For this trial: 
• Male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
 
• Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
 
• Female and male subjects of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving study drug and for 
120 days after the last dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual 
activity.   
 


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• Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
o intrauterine device (IUD) 
o vasectomy of a female subject’s male partner  
o contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 
o diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
o cervical cap with spermicide (nulliparous women only)   
o contraceptive sponge (nulliparous women only)  
o male condom or female condom (cannot be used together) 
o hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
  
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.  
 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
 
Subjects should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study.  In order to 
participate in the study subjects of childbearing potential must adhere to the contraception 
requirement (described above) from the day of study medication initiation (or 14 days prior 
to the initiation of study medication for oral contraception) throughout the study period up 
to 120 days after the last dose of trial therapy.  If there is any question that a subject of 
childbearing potential will not reliably comply with the requirements for contraception, 
that subject should not be entered into the study. 
6.5.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor-Investigator, 
DSMC, COMIRB, and within 2 working days to Merck if the outcome is a serious adverse 
experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).   


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The study investigator will make every effort to obtain permission to follow the outcome 
of the pregnancy and report the condition of the fetus or newborn to the Sponsor-
Investigator, DSMC, COMIRB, and to Merck.   If a male subject impregnates his female 
partner the study personnel at the site must be informed immediately and the pregnancy 
reported to the investigator,  DSMC, COMIRB, and to Merck and followed as described 
above and in Section 7.4.2 – Immediate Reporting of SAEs. 
6.5.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
6.6 
Subject Withdrawal, Treatment Discontinuation, or Study Termination Criteria 
6.6.1 Subject Withdrawal 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be withdrawn by the investigator if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 7.2.6 - Other Procedures. 
6.6.2 Subject Discontinuation 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent 
• Confirmed radiographic disease progression (i.e. progressive disease per RECIST 
1.1 as documented by tumor imaging at any time point). Subjects with disease 
progression indicated on imaging should discontinue all study treatment, but may 
continue pembrolizumab according to standard of care outside of the study at 
investigator discretion. Subjects with suspected clinical progression may continue 
study treatment at investigator discretion until there is radiographic confirmation of 
disease progression.  
• Unacceptable adverse experiences as described in Section 6.1.1.2 (Dose 
Modification (Escalation/Titration/Other)) 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 


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• Administrative reasons 
 
The End of Treatment (EOT) and Follow-up visit procedures are listed in Section 7.1 (Trial 
Schedule of Events Chart) and Section 7.2.7 (Visit Requirements). Additionally, all subjects 
will be followed for overall survival until death, withdrawal of consent, or the end of the 
study, whichever occurs first. 
6.6.3 Discontinuation of Study Therapy after CR 
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
Complete Response (CR) that have had at least two treatments with pembrolizumab 
beyond the date when the initial CR was declared.  Subjects who then experience 
radiographic disease progression may be eligible for retreatment (200mg Q 3 weeks) for 
up to one additional year. 
6.6.4 Discontinuation of Study Therapy after Disease Stability 
Patients who achieve a partial response and prolonged disease stability may stay on 
Pembrolizumab (200mg Q3 weeks) for up to two years on study. In the absence of 
significant toxicity, the study drug may be discontinued at the discretion of the treating 
medical oncologist or Sponsor-Investigator after a prolonged period of disease stability. 
Subjects who then experience radiographic disease progression may be eligible for 
retreatment (200mg Q 3 weeks) for up to one additional year. 
6.6.5  Toxicity and Study Discontinuation Criteria  
The trial stopping criteria outlined in the Calculated Trial Stopping Criteria (Table 5) below 
will be followed to avoid posing undue risk to additional patients. Twenty-four patients 
will potentially be recruited in our study to evaluate DLTs and suggest RP2D. Toxicity is 
defined as AEs of grade 3 or higher. Historical data of similar patients show an overall 
grade 3 or 4 toxicity rate of approximately 14% for pembrolizumab treatment alone. It is 
estimated that the current trial (the combination) may increase toxicity rates an additional 
10% compared to pembrolizumab alone.  The DSMC will have oversight responsibilities 
for reviewing toxicities in patients associated with this trial.  
Table 5 Calculated Trial Stopping Criteria 
Number of Patients 
Stopping Criteria 
Dosing Action 
6 (Cohort 1) 
>=3 
Dose de-escalate in Cohort 2 (dose level -1) 
6 (Cohort 2) 
>=3 
Study Stop 
If the grade 3 or 4 toxicity exceeds 33% the stopping criteria, the next 6 enrolled patients will 
be put on the lower dose.  


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6.6.6 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete. 
2. Poor adherence to protocol and regulatory requirements. 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects. 
 
 
 
7.0 
TRIAL SCHEDULE AND PROCEDURES 
7.1 
Trial Schedule of Events Chart 
Trial Period: 
Screening 
Phase 
Treatment Cycles 
Post-Treatment 
Treatment Cycle/Title: 
Screening 
1 
2  
3 
4 
 
5+ 
EOTi 
Safety Follow-up 1 
Safety 
Follow-up 2b 
Survival 
Follow-up 
Scheduling Window (Days): 
-28 to -1 
 
± 7 
±7 
± 7 ± 7 
± 7 
30 days (+2 days) post 
last treatment or prior to 
starting new treatment 
90 days (+7 
days) post 
last treatment 
Every 12 
weeks (+14 
days) 
 
Administrative Procedures 
 
 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History 
x 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medication Review 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vesanoid Administrationa 
 
x 
x 
x 
x 
 
 
 
 
 
Pembrolizumab Administrationa 
 
x 
x 
x 
x 
x 
 
 
 
 
Post-study anticancer therapy 
status 
 
 
 
 
 
 
x 
x 
x 
x 
Survival Status 
 
 
 
 
 
 
 
x 
x 
x 
 
Clinical Procedures/Assessments 
 
 
 
Review Adverse Events 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
Full Physical Examination 
x 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
x 
x 
x 
x 
x 
 
x 
 
 
Vital Signs and Weight 
x 
x 
x 
x 
x 
x 
 
x 
 
 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
 
 
Pregnancy Test – Urine or 
Serum β-HCGh 
x 
 
 
 
 
 
 
 
 
 


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Trial Period: 
Screening 
Phase 
Treatment Cycles 
Post-Treatment 
Treatment Cycle/Title: 
Screening 
1 
2  
3 
4 
 
5+ 
EOTi 
Safety Follow-up 1 
Safety 
Follow-up 2b 
Survival 
Follow-up 
Scheduling Window (Days): 
-28 to -1 
 
± 7 
±7 
± 7 ± 7 
± 7 
30 days (+2 days) post 
last treatment or prior to 
starting new treatment 
90 days (+7 
days) post 
last treatment 
Every 12 
weeks (+14 
days) 
CBC with Differentialg 
x 
x 
x 
x 
x 
x 
 
 
 
 
Comprehensive Serum 
Chemistry Panele & g 
x 
x 
x 
x 
x 
x 
 
 
 
 
T3, FT4 and TSHg 
x 
x 
 
x 
 
xf 
 
 
 
 
 
Efficacy Measurements 
 
 
Tumor Imagingc 
x 
 
 
 
 
x 
x 
 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
 
 
Optional Archival or Newly 
Obtained Tissue Collectiond 
x 
 
 
 
 
 
 
x 
x 
x 
Correlative Studies Blood 
Collection 
x 
 
x 
 
x 
xj 
 
xj 
 
 
 
a Administered according to schedule outlined in table 2. Vesanoid drug supply will be dispensed in 
clinic on Cycle 1 Day -1 for Cycle 1, Cycle 1 Day 0 for Cycle 2, Cycle 2 Day 0 for Cycle 3 and Cycle 
3 Day 0 for Cycle 4.  
b To be completed only for subjects who have not initiated a new therapy. Can be collected at a regularly 
scheduled clinic visit or via patient contact by telephone. 
c Tumor imaging generally performed every 12 weeks per standard of care for the clinic and evaluated 
by RECIST 1.1 criteria (Section 11.3 - Appendices). Baseline tumor imaging should be completed 
within 28 days of starting treatment; however, exceptions may be approved after discussion with the 
principal investigator. Brain metastases that were radiated prior to starting the trial should be re-imaged 
at the standard 12 week frequency, or as deemed clinically appropriate, by the treating physician. 
d Optional additional tissue collection will be obtained from archival or future biopsies if available. 
e To include lactate dehydrogenase at screening. 
f To be collected every other cycle per standard of care for clinic. 
g Screening labs should be performed within 10 days of treatment initiation. 
h Within 72 hours prior to receiving the first dose of study medication. 
i To be completed when it is decided that the subject will discontinue study treatment. Tumor imaging 
is only required at investigator’s discretion. This visit can be combined with the first safety follow-up 
visit if the subject is planning to start a new treatment.  
j < 60 days after last Vesanoid treatment. 
 
7.2 
Trial Procedures 
Section 7.1 - The Trial Schedule of Events Chart - summarizes the trial procedures to be 
performed at each visit.  Individual trial procedures are described in detail below.  It may be 


Study Drug:  PEMBROLIZUMAB 
 
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necessary to perform these procedures at unscheduled time points if deemed clinically 
necessary by the investigator. 
Furthermore, 
additional 
evaluations/testing 
may 
be 
deemed 
necessary 
by 
the 
Sponsor/Principal-Investigator or treating physician for reasons related to subject safety. In 
some cases, such evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis 
C, etc.), and thus local regulations may require that additional informed consent be obtained 
from the subject.  In these cases, such evaluations/testing will be performed in accordance with 
those regulations. 
All trial procedures will be performed by the investigator, or a qualified designee (also an IRB 
approved research personnel for the study).   
7.2.1 Administrative Procedures 
7.2.1.1 
Informed Consent 
All subjects must first read, understand, and sign the IRB-approved informed consent 
form (ICF) before any study-specific screening procedures are performed. After 
signing the ICF, completing all screening procedures, and being deemed eligible for 
entry, subjects will be enrolled in the study.   
7.2.1.2 
Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed to ensure that the subject qualifies 
for the trial.  
7.2.1.3 
Medical History 
A medical history will be obtained and will include all active conditions, and any 
condition diagnosed within the prior 10 years that are considered to be clinically 
significant by the investigator.  Details regarding the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as medical history.   
7.2.1.4 
Prior Medications 
Prior medication taken by the subject within 28 days before the first dose of trial 
treatment, including any protocol-specified washout requirement, will be reviewed and 
recorded.  Treatment for the disease for which the subject has enrolled in this study will 
be recorded separately and not listed as a prior medication.  
7.2.1.5 
Concomitant Medications 
Medication, if any, taken by the subject during the trial will be recorded.  All 
medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 6.2 (Concomitant Medications/Vaccines (allowed & prohibited)). 


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7.2.1.6 
Disease Details and Treatments 
7.2.1.6.1 Disease Details 
Prior and current details regarding disease status will be obtained.  
7.2.1.6.2 Prior Treatment Details 
All prior cancer treatments including systemic treatments, radiation and surgeries 
will be reviewed. 
7.2.1.6.3 Subsequent Anti-Cancer Therapy Status 
All new anti-neoplastic therapy initiated after the last dose of trial treatment will be 
reviewed.  If a subject initiates a new anti-cancer therapy within 30 days after the 
last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated, the 
subject will move into survival follow-up. 
7.2.2 Clinical Procedures / Assessments 
7.2.2.1 
Adverse Event (AE) Monitoring 
Each subject will be assessed to evaluate for potential new or worsening AEs as 
specified in the Trial Schedule of Events Chart (Section 7.1) and more frequently if 
clinically indicated.  Adverse experiences will be graded and recorded throughout the 
study and during the follow-up period according to NCI CTCAE Version 4.0 (see 
Section 11.2 - Appendices).  Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment.  
Please refer to section 7.3 (Adverse Events (AE) – Assessment, Recording and 
Reporting) for detailed information regarding the assessment and recording of AEs.   
7.2.2.2 
Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during 
the screening period.  Clinically significant abnormal findings should be recorded as 
medical history.  A full physical exam should be performed during screening,  
7.2.2.3 
Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Schedule of Events 
Chart (Section 7.1), the investigator or qualified designee will perform a directed 
physical exam as clinically indicated prior to trial treatment administration.   
7.2.2.4 
Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as 


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specified in the Trial Schedule of Events Chart (Section 7.1).  Vital signs should include 
weight and other vital signs per standard of care.  
7.2.2.5 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status at screening, prior to 
the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Schedule of Events Chart (Section 7.1).   
7.2.3 Efficacy Measurement 
7.2.3.1 
Tumor Imaging and Assessment of Disease 
Following the standard of care for pembrolizumab treatment, imaging will be 
performed at the treating physician’s discretion.  The imaging will be reviewed by the 
investigator according to the RECIST criteria (version 1.1), to monitor the appearance 
of new metastatic lesions and the size of existing lesions. 
7.2.4 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Plasma will be banked from every patient for cytokine analysis, potential biomarker and 
other correlative studies.  Plasma will also be collected for potential analysis of plasma 
VESANOID levels in the event this could correlate with results from the immunologic 
analysis. Whenever possible, tumor samples will be cataloged and stored at the CU 
Melanoma Biorepository.  Additional correlative studies may include genomic analysis. 
7.2.5 Laboratory Procedures/Assessments 
7.2.5.1 
Standard safety laboratory tests. 
Will be obtained as outlined in section 7.1 - Trial Schedule of Events.  
7.2.5.2 
Experimental lab draws. 
Will be performed at regularly scheduled clinic visits as outlined in section 2.2 - Trial 
Schema/Diagram. Peripheral blood mononuclear cells (PBMCs) will be isolated and 
flow cytometry will be used to quantify MDSCs and T cells.  
- 
Baseline immune response determination. Subjects in the study will be 
asked to provide 40 mls of blood prior to initiating treatment to evaluate 
baseline immune responses and immune cell frequencies.  
- 
Immune response monitoring. Blood samples will be drawn prior to the 
administration of the 2nd and 4th doses of pembrolizumab and after the last 
dose of VESANOID for continued measurement of immune cell frequencies.  
- 
Cytokine analysis. Up to 20 ml of plasma will be stored for up to five years 
following study completion for subsequent cytokine analysis. 


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7.2.5.3 
Specimen Analysis 
Functional assays will be performed to assess the ability of isolated MDSCs to suppress 
T cell responses.  
- 
Determination of tumor-specific T cell response frequency. Peripheral 
blood mononuclear cells (PBMCs) will be isolated over a ficoll gradient and 
cells will be banked to analyze the frequency of MDSCs and T cells using 
flow cytometry as previously published. PBMCs will be used to determine the 
frequency of tumor-specific T cell responses by stimulating the cells with a 
mixture of peptides derived from known melanoma tumor antigens including 
NYESO, gp100, and tyrosinase as well as measuring IFN-gamma production 
by flow cytometry.  
- 
T cell suppression assay. The remaining PBMC will be used to perform T 
cell suppression assays using magnetically separated MDSC populations, 
comparing the suppressive function of MDSCs throughout treatment. Any 
remaining MDSCs will be flash frozen and banked for biomarker studies 
analyzing the expression of known suppressive molecules by real-time 
quantitative PCR.  
7.2.5.4 
Cytokine analysis.  
Multiplex cytokine array will be used for subsequent cytokine analysis. Concentration 
of cytokines related to the function of MDSCs (GM-CSF, VEGF, MIP-1 alpha, MIP-1 
beta, IL-10, IL-6, and IL-8) and T cells (IFN-gamma, TNF-alpha, IL-1-beta, IL-2, IL-
4, IL-5, IL-12p70, IL-17) will be analyzed. 
7.2.5.5 
Biomarker analysis.  
When available, representative histologic slides from each patient’s primary or 
metastatic melanoma will be procured and submitted to QualTek for PD-L1 analysis. 
Correlations between baseline PD-L1 staining and MDSC assessments, progression 
free survival and clinical outcomes will be analyzed.  
QualTek Molecular Laboratories 
300 Pheasant Run, Newtown, PA 18940 
(215) 504-7402 
7.2.6 Other Procedures 
7.2.6.1 
Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable 
activities scheduled for the final trial visit should be performed at the time of 
discontinuation. Any adverse events which are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety 
requirements outlined below at Assessing and Recording Adverse Events (Section 7.3) 
and then proceed to the Follow-Up Visits of the study (Section 7.2.8.).  


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7.2.7 Visit Requirements 
Visit requirements are outlined in Section 7.1 - Trial Schedule of Events Chart.   Specific 
procedure-related details are provided above in Section 7.2 - Trial Procedures. 
7.2.7.1 
Screening Period 
There will be a screening period of up to 28 days after subjects sign informed consent.  
7.2.7.2 
Treatment Period 
The treatment period is defined as the time that the patients are receiving VESANOID 
and/or Pembrolizumab treatment. 
7.2.7.3 
Post-Treatment Visits 
7.2.7.3.1 Safety Follow-Up Visits 
Subjects who discontinue trial treatment will move into the follow-up phase and 
other treatment decisions will be at the discretion of the treating physician.  
 
The first safety follow-up visit will be conducted for all subjects 30 days after the 
last dose of trial treatment (VESANOID and/or pembrolizumab) or before the 
initiation of a new anti-cancer treatment, whichever comes first.   
 
Should the subject not initiate a new anti-cancer treatment, the second safety 
follow-up visit will be conducted 90 days after the last dose of trial treatment.  
All AEs that occur prior to the Safety Follow-Up Visits should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to 
Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs 
first.  SAEs that occur within 90 days of the end of treatment or before initiation of 
a new anti-cancer treatment should also be followed and recorded.   
7.2.7.3.2 Survival Follow-up 
Subjects should be contacted at regularly scheduled clinic visits or by telephone 
every 12 weeks to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first. Every effort should be made to collect 
information regarding disease status and post-study anti-neoplastic treatment. 
 
Patients will be followed for up to 2 years or until recurrence or death. 
7.3 
Adverse Events (AE) – Assessing, Recording and Reporting 
7.3.1 Definition of AE 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment.  


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7.3.2 Assessment of AE 
An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with 
the use of a medicinal product or protocol-specified procedure, whether or not considered 
related to the medicinal product or protocol-specified procedure.  Any worsening (i.e., any 
clinically significant adverse change in frequency and/or intensity) of a preexisting 
condition that is temporally associated with the use of the study drug, is also an adverse 
event. 
 
Adverse events may occur during the course of the use of the study drug in clinical trials, 
or as prescribed in clinical practice, from overdose (whether accidental or intentional), 
from abuse and from withdrawal. 
 
Progression of the cancer under study is not considered an adverse event.  
7.3.3 Reporting of AEs 
All adverse events that occur after the consent form is signed but before treatment 
allocation must be reported by the investigator if they cause the subject to be excluded from 
the trial, or are the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
 
From the time of treatment allocation through 90 days following cessation of treatment, all 
adverse events must be reported by the investigator. Such events will be recorded at each 
examination on the adverse event case report forms/worksheets.  The reporting timeframe 
for adverse events meeting any serious criteria is described in Section 7.4 (Serious Adverse 
Events (SAE) – Assessing, Recording and Reporting). The investigator will make every 
attempt to follow all subjects with non-serious adverse events for outcome. 
 
7.4 
Serious Adverse Events (SAE) – Assessing, Recording and Reporting 
7.4.1 Definition and Assessment SAEs 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Pembrolizumab and VESANOID that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event.  
 
Refer to Table 6 for additional details regarding each of the above criteria. 


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7.4.2 Immediate Reporting of SAEs 
For the time period beginning when the consent form is signed until treatment allocation, 
any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study (reference section 7.4.3 below 
- Protocol Specific Exceptions to Serious Adverse Event Reporting for additional details) 
that occurs to any subject must be reported within 24 hours to the Sponsor-Investigator, 
within 2 business days to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 
993-1220), within 5 business days to the DSMC, and in accordance with COMIRB 
reporting requirements (within 5 business days or during continuing review) if it causes 
the subject to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. 
 
For the time period beginning at treatment allocation through 90 days following cessation 
of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under 
study (reference section 7.4.3 below - Protocol Specific Exceptions to Serious Adverse 
Event Reporting for additional details), whether or not related to the study drug, must be 
reported within 24 hours to the Sponsor-Investigator, within 2 business days to Merck 
Global Safety, within 5 business days to the DSMC, and in accordance with COMIRB 
reporting requirements (within 5 business days or during continuing review). 
  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the study drug, that is brought to the attention of the investigator 
at any time following consent through the end of the specified safety follow-up period 
specified in the paragraph above, or at any time outside of the time period specified in the 
previous paragraph also must be reported within 24 hours to the Sponsor-Investigator, 
within 2 business days to Merck Global Safety, within 5 business days to the DSMC, and 
in accordance with COMIRB reporting requirements (within 5 business days or during 
continuing review).   
 
All subjects with serious adverse events must be followed up for outcome. 
7.4.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
The suspected/actual events covered in this exception include any event that is disease 
progression of the cancer under study. Additionally, hospitalization related to convenience 
(e.g., transportation issues etc.) will not be considered a SAE. 
7.5 
Events of Clinical Interest (ECI) 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported be within 24 hours to the Sponsor-Investigator, within 2 working 


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days to Merck Global Safety, within 5 business days to the DSMC, and in accordance with 
COMIRB reporting requirements (within 5 business days or during continuing review).  
For the time period beginning when the consent form is signed until treatment allocation, any 
ECI, or follow up to an ECI, that occurs to any subject must be reported within 24 hours to the 
investigator if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any ECI, or follow up to an ECI, must be reported within 24 
hours to the Sponsor-Investigator, within 2 working days to Merck Global Safety, within 5 
business days to the DSMC, and in accordance with COMIRB reporting requirements (within 
5 business days or during continuing review). 
Events of clinical interest for this trial include: 
1. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  
7.6 
Reporting of Pregnancy and Lactation 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation must be reported by the investigator if they cause the subject to be excluded from 
the trial, or are the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.   
 
Pregnancies and lactations that occur from the time of treatment allocation through 120 
days following cessation of the study drugs, or 30 days following cessation of treatment if 
the subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.  All reported pregnancies must be followed to the completion/termination of 
the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues 


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to term, the outcome (health of infant) must also be reported. Such events must be reported 
within 24 hours to the Sponsor-Investigator, within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 993-1220), within 5 days to the DSMC and 
within 5 days to COMIRB. 
7.7 
Sponsor-Investigator Responsibility for Reporting Adverse Events 
The Sponsor-Investigator will report all Adverse Events to regulatory authorities and 
COMIRB, in accordance with all applicable laws and regulations.  


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7.7.1 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI Common Terminology for Adverse Events 
(CTCAE), version 4.0. Any adverse event which changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
Table 6 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of study drug product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of study drug and is documented in the 
patient’s medical history.); or 


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†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the investigator within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the investigator and 
to Merck Global Safety, the DSMC, and COMIRB within 2 working days. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken 
Did the adverse event cause study drug to be discontinued? 
Relationship to 
Study Drug 
Did study drug cause the adverse event? The determination of the likelihood that study drug caused the adverse event will be provided by an investigator who is a 
qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information. 
The following components are to be used to assess the relationship between study drug and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely study drug caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to study drug such as: reliable history, acceptable compliance assessment (pill count, diary, 
etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 
 


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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Study Drug 
(continued) 
Dechallenge 
Was study drug discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to study drug in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY STUDY DRUG, OR IF REEXPOSURE TO STUDY DRUG POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE 
SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE MODIFICATION 
GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding study drug or drug class pharmacology or 
toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is 
reasonable.  The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable OR 
the AE is more likely explained by another cause than the Merck product.  (Also entered for a subject with overdose without an associated AE.) 


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8.0 
STATISTICAL ANALYSIS PLAN 
The primary goal of the study is to characterize the safety and establish the recommended 
phase 2 dose (RP2D) and preliminary efficacy evaluation with a total of 24 evaluable 
subjects. A modified 3+3 design with a cohort size of 6 with a continuous toxicity 
monitoring. The design is to inform de-escalation decisions based on safety if needed. For the 
purposes of this trial, a target toxicity rate of approximately 33% will be used to establish the 
RP2D. Table 7 below provides the probability of detecting the number of DLTs based on true 
toxicity rates with 24 subjects: 
 
Table 7 Number of DLTs and the Corresponding Cumulative Probability for Several 
Toxicity Rates with 24 Subjects  
True toxicity rate (%) 
Corresponding Number of 
DLTs (# DLT) 
Cumulative Probability for 
Detecting #DLT 
20 
5 
0.66 
25 
6 
0.56 
30 
7 
0.56 
35 
8 
0.53 
40 
10 
0.65 
 
Safety Analyses 
All patients who received any protocol therapy will be employed for safety analyses.  
Patient incidence of all treatment-emergent AEs will be tabulated by dose and system organ 
class and preferred term. Tables of fatal adverse events, serious adverse events, treatment-
related AEs, and adverse events leading to withdrawal from investigation product will also be 
provided. The MedDRA will be used to code adverse events and the NCI CTCAE version 
4.0 will be used to grade severity of adverse events and laboratory toxicities.  
 
Summary statistic will be provided for total number of subjects treated under each dose, 
average dose administered, and duration of treatment.  
 
For select laboratory parameters, changes of laboratory values over time (eg, change from 
baseline summary statistics), grade shifts in laboratory values from baseline to worst on-
study value, and grade 3 or higher laboratory toxicities will be summarized. The ECG 
measurements from this study will be performed as per standard of care for routine safety 
monitoring.  
 
Efficacy analysis 
The efficacy analysis population consists of all subjects who receive at least one cycle 
treatment (3-day doses of study treatment). 
 


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Tcell subsets (CD4, CD8, Treg) and MDSC subsets (CD14+, CD15+) will be analyzed by flow 
cytometry at each of the blood draws time points and compared to whole blood cells, total 
lymphocytes and monocytes populations between time points and compared between 
pretreatment, on treatment and post treatment. T cell activation will be assessed by CD107 and 
IFNg production in response to PMA and ionomycin and compared between pretreatment, on 
treatment and post treatment. MDSC functional assays will assess the ability of MDSC’s to 
suppress stimulated T cell proliferation as a percent of positive control and will be compared 
between time points and compared between pretreatment, on treatment and post treatment.  
Linear mixed effects models will be used to assess the frequency of MDSC subsets over 
times. Contrast statements will be used to estimate changes in the frequency of MDSC 
subsets and its suppressive function from baseline after treatment at different time points.  
For PFS endpoint, Kaplan-Meier (KM) curves and median estimates from the KM curves 
will be provided as appropriate. Subjects without efficacy evaluation data or without survival 
data will be censored at Day 1. The change in frequency of T cell subsets, the expression of 
activation markers, and the CTL response will be evaluated using paired t-test. Correlations 
between the frequencies of MDSCs and T cell subsets or expression of activation markers 
will be evaluated using Pearson or Spearman Correlation Coefficients at a specified time 
points. Alternatively, Intraclass correlation coefficients will be used to assess the potential 
correlations among those measurements over time.  
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF 
CLINICAL SUPPLIES 
9.1 
Investigational Product  
VESANOID will be supplied through the University of Colorado Cancer Center’s 
investigational pharmacy. VERSANOID is supplied as 10 mg capsules, two-tone (lengthwise), 
orange-yellow and reddish-brown and imprinted VERSANOID 10 ROCHE. It is packaged in 
high-density polyethylene opaque bottles of 100 capsule with child-resistance closure.  
Pembrolizumab (200mg dosing Q3 weeks) will be supplied by Merck. 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor-Investigator, 
and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the 
label text; random code/disclosure envelopes or lists are not provided. 


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9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The Sponsor-Investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount of VESANOID and Pembrolizumab dispensed 
to and returned by the subjects and the amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational 
product (study drug) will be destroyed at the site per institutional policy. It is the Sponsor-
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 
Ethics and Protection of Human Subjects 
10.1.1 Ethical Standard 
The PI will ensure that this study is conducted in full conformity with regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 
CFR Part 56. ICH E6 may also be followed to the extent it has been adopted by and is in 
accordance with FDA regulations. 
 
10.1.2 Institutional Review Board (IRB) 
The protocol, informed consent form(s), recruitment materials, and all subject materials 
will be submitted to the Colorado Multiple Institutional Review Board (COMIRB) for review 
and approval. Approval of both the protocol and the consent form must be obtained before 
any subject is enrolled. Any amendment to the protocol will require review and approval 
by COMIRB before the changes are implemented to the study. All changes to the consent 
form will COMIRB-approved. 


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10.1.3 Informed Consent Process 
10.1.3.1 Informed Consent Form(s) (ICF) 
Informed Consent Form(s) (ICF) describing in detail the study drug, study procedures, 
and risks are given to the subject and written documentation of informed consent is 
required prior to starting intervention/ administering study drug. 
10.1.3.2 Informed Consent Procedures and Documentation 
The informed consent process will be initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the subject’s study participation. 
Extensive discussion of risks and possible benefits of participation will be provided to 
the subjects and their families.  
 
ICFs will be IRB-approved and the subject will be asked to read and review the 
document. The investigator, or qualified research study personnel, will explain the 
clinical trial to the subject and answer any questions that may arise. All subjects will 
receive a verbal explanation in terms suited to their comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research subjects. 
Subjects will have the opportunity to carefully review the written consent form and ask 
questions prior to signing. The subjects will have the opportunity to discuss the study 
with their surrogates or think about it prior to agreeing to participate. The subject will 
sign the informed consent document prior to any procedures being done specifically 
for the study.  
 
The subjects may withdraw consent at any time throughout the course of the trial. A 
copy of the informed consent document will be given to the subjects for their records. 
The rights and welfare of the subjects will be protected by emphasizing to them that 
the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
 
The study allows the inclusion of non-English speaking and non-reading subjects. 
Witnesses to these consent processes will be individuals not associated with the trial 
and will not have a conflict of interest. 
10.1.4  Subject and Data Confidentiality 
Subject confidentiality is strictly held in trust by the Sponsor-Investigator, their staff, 
and their agents. This confidentiality is extended to cover testing of biological samples 
and genetic tests in addition to the clinical information relating to subjects. Therefore, 
the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be 
released to any unauthorized third party without prior written approval of the Sponsor-
Investigator. 
 


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The study monitor, other authorized representatives of the Sponsor-Investigator, 
representatives of the IRB or pharmaceutical company supplying study product or 
funding may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the subjects in this study. The clinical study site will permit 
access to such records. 
 
The study subject’s contact information will be securely stored at the clinical site for 
internal use during the study. At the end of the study, all records will continue to be 
kept in a secure location for as long a period as dictated by local IRB and Institutional 
regulations. 
 
Study subject research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the University of Colorado Cancer Center.  
This will not include the subject’s contact or identifying information. Rather, individual 
subjects and their research data will be identified by a unique study identification 
number. The study data entry and study management systems used by the University 
of Colorado Cancer Center research staff will be secured and password protected. At 
the end of the study, all study databases will be de-identified and archived at the 
University of Colorado Cancer Center. 
10.1.5 Future Use of Stored Specimens 
Any remaining specimens will be banked for future studies. 
10.2 
Data Management and Record Keeping 
10.2.1 Clinical Data Collection and Management Responsibilities:  
Clinical data collection is the responsibility of the site’s clinical trial staff under the 
supervision of the PI.  The PI is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported.  
Clinical data will be collected during each visit by the clinical provider and stored in a 
locked office or cabinet with access limited to the study coordinator and/or data manager. 
Age, gender, pathologic features of the melanoma, co-morbid conditions, and concomitant 
medications will be recorded. 
All paper form source documents will be recorded neatly and legibly 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. Clinical data will be used 
for the initial recording of clinical data. Corrections will be made legibly, initialed, and 
dated. Correction fluid and covering labels will not be used. Data quality will be monitored 
by random inspection of the completed forms by a research assistant and any problems will 
be discussed with the PI.  


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10.2.2 Database:  
Study data will be collected and managed using OnCore. OnCore is a secure web 
application designed to support data capture for research studies, providing user-friendly 
web-based case report forms, real-time data entry validation (e.g. for data types and range 
checks), audit trails and a de-identified data export mechanism to common statistical 
packages.  
The database will be designed and maintained by the University of Colorado Cancer Center 
Clinical Protocol and Data Management (CPDM) team.  The study/data coordinator will 
enter the data at the conclusion of each clinic visit. 
10.2.3 Study Records Retention: 
Study documents will be retained per applicable regulations, and/or institution policies. No 
records will be destroyed without the written consent of the Sponsor-Investigator, if 
applicable. It is the responsibility of the Sponsor-Investigator to determine when these 
documents no longer need to be retained.  
10.2.4 Unanticipated Problems (UAP) including Protocol Deviations 
10.2.4.1 Definition of UAP 
This study will use the Office of Human Research Protection (OHRP) definition of a 
UAP, which considers unanticipated problems involving risks to subjects or others to 
include, in general, any incident, experience, or outcome that meets all of the following 
criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• Related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and 
• Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
10.2.4.2 Definition of Protocol Deviation 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or 
SOP requirements. The noncompliance may be either on the part of the subject, the 
investigator, or the study site personnel. As a result of deviations, corrective actions are 
to be developed by the site in compliance with this protocol and implemented promptly.  
 


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It is the responsibility of the study team to use continuous vigilance to identify and 
report protocol deviations. All protocol deviations must be addressed in study source 
documents, and reported as required by COMIRB UAP Reporting Guidelines. The 
Sponsor-Investigator and study personnel are responsible for knowing and adhering to 
the IRB requirements. Further details about the handling of protocol deviations may be 
included in the study procedures manual.  
10.2.4.3 Reporting a UAP 
The study will follow COMIRB’s guidance for UAP reporting and the DSMC’s 
requirements (discussed below). AEs, noncompliance and protocol violations will be 
recorded and reported as required either promptly (within 5 days of Sponsor-
Investigator’s knowledge) or at the time of the study’s continuing review.  
 
10.3 
Data and Safety Monitoring and Oversight 
10.3.1 Data Safety Monitoring Committee and Plan 
The Sponsor-Investigator will be responsible for monitoring the trial per the trial 
monitoring plan, in addition to overseeing the safety and efficacy of the trial including any 
specimens collected, executing the data and safety monitoring (DSM) plan, and complying 
with all reporting requirements to local and federal authorities. This oversight will be 
accomplished through additional oversight from the Data and Safety Monitoring 
Committee (DSMC) at the University of Colorado Cancer Center (CU Cancer Center).  
The DSMC is responsible for ensuring data quality and study subject safety for all clinical 
studies at the CU Cancer Center, which is the coordinating institution of this trial.   A 
summary of the DSMC’s activities is as follows: 
 
• Conduct of internal audits 
• Ongoing review of all serious adverse events (SAEs), unanticipated problems 
(UAPs) and reportable adverse events (AEs) 
• Has the authority to close and/or suspend trials for safety or trial conduct issues 
• May submit recommendations for corrective actions to the CU Cancer Center’s 
Executive Committee 
 
Per the CU Cancer Center Institutional DSM Plan, SAEs, UAPs and reportable AEs are 
reported to the DSMC, IRB and the Sponsor-Investigator per protocol.  All SAEs, UAPs 
and reportable AEs are to be reported to the DSMC within 5 business days of the 
investigator receiving notification of the occurrence. 
Each subject’s treatment outcomes will be discussed by the investigator and appropriate 
staff at weekly meetings. Toxicity will be addressed in real time and communicated to the 
team, then submitted to DSMC as indicated.  Data regarding number of subjects, significant 
toxicities, dose modifications, and treatment responses will be discussed. 


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The Sponsor-Investigator will provide a DSM report to the CU Cancer Center DSMC on a 
six-month basis. The DSM report will include a protocol summary; current enrollment 
numbers; summary of toxicity data to include specific SAEs, UAPs and AEs; any dose 
modifications; all protocol deviations; and protocol amendments. The DSM report 
submitted to the DSMC will also include, if applicable, the results of any efficacy data 
analysis conducted.  Results and recommendations from the review of this six-month report 
by the DSMC will then be provided to the Sponsor-Investigator in a DSMC review letter.  
The Sponsor-Investigator is then responsible for ensuring this letter is submitted to the 
site’s IRB of record at the time of IRB continuing review. 
10.3.2 Quality Control and Quality Assurance 
10.3.2.1 Clinical Monitoring 
Clinical site monitoring will be conducted to ensure that the rights and well-being of 
human participants are protected, that the reported trial data are accurate, complete, and 
verifiable, and that the conduct of the trial is in compliance with the currently approved 
protocol/ amendment(s), with GCP, and with applicable regulatory requirement(s). 
Monitoring for this study will be performed by the CU Cancer Center Clinical Monitor 
on a regular basis, and pursuant to the Clinical Monitoring Plan (CMP), incorporated 
herein by reference. The CMP describes in detail who will conduct the monitoring, at 
what frequency monitoring will be done, at what level of detail monitoring will be 
performed, and the distribution of the monitoring reports.  As necessary, requests for 
data clarification or correction will be sent to the PI. 
10.3.2.2 Independent Auditing. 
Independent auditors from the UCCC DSMC will be allowed to audit this study.  In 
addition, audits may be conducted at any time by appropriate regulatory authorities 
and/or the IRB.  
The PI will be notified of any recommendation in order that he may alert all sub-
investigators involved in the trial with regard to the action plan.  
 


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11.0 APPENDICES 
11.1 
ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. 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 
In bed <50% of the time. 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 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
11.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
11.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study.  
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 


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12.0 REFERENCES 
1. 
R. L. Siegel, K. D. Miller, A. Jemal, Cancer statistics, 2016. CA Cancer J Clin 66, 7-
30 (2016). 
2. 
D. U. Ekwueme et al., The health burden and economic costs of cutaneous melanoma 
mortality by race/ethnicity-United States, 2000 to 2006. J Am Acad Dermatol 65, S133-
143 (2011). 
3. 
C. Eheman et al., Annual Report to the Nation on the status of cancer, 1975-2008, 
featuring cancers associated with excess weight and lack of sufficient physical activity. 
Cancer 118, 2338-2366 (2012). 
4. 
A. C. Geller et al., Melanoma Epidemic: An Analysis of Six Decades of Data From the 
Connecticut Tumor Registry. J Clin Oncol,  (2013). 
5. 
C. Robert et al., Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J 
Med 372, 2521-2532 (2015). 
6. 
J. M. Chauvin et al., TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in 
melanoma patients. J Clin Invest 125, 2046-2058 (2015). 
7. 
K. R. Jordan et al., Myeloid-derived suppressor cells are associated with disease 
progression and decreased overall survival in advanced-stage melanoma patients. 
Cancer Immunol Immunother 62, 1711-1722 (2013). 
8. 
D. I. Gabrilovich, S. Nagaraj, Myeloid-derived suppressor cells as regulators of the 
immune system. Nat Rev Immunol 9, 162-174 (2009). 
9. 
J. D. Fontenot, M. A. Gavin, A. Y. Rudensky, Foxp3 programs the development and 
function of CD4+CD25+ regulatory T cells. Nat Immunol 4, 330-336 (2003). 
10. 
K. R. Jordan et al., Myeloid-derived suppressor cells are associated with disease 
progression and decreased overall survival in advanced-stage melanoma patients. 
Cancer Immunol Immunother,  (2013). 
11. 
Y. Nefedova et al., Mechanism of all-trans retinoic acid effect on tumor-associated 
myeloid-derived suppressor cells. Cancer research 67, 11021-11028 (2007). 
12. 
C. Iclozan, S. Antonia, A. Chiappori, D. T. Chen, D. Gabrilovich, Therapeutic 
regulation of myeloid-derived suppressor cells and immune response to cancer vaccine 
in patients with extensive stage small cell lung cancer. Cancer Immunol Immunother 
62, 909-918 (2013). 
13. 
N. Mirza et al., All-trans-retinoic acid improves differentiation of myeloid cells and 
immune response in cancer patients. Cancer research 66, 9299-9307 (2006). 
14. 
E. S. Van Amersfoort, T. J. Van Berkel, J. Kuiper, Receptors, mediators, and 
mechanisms involved in bacterial sepsis and septic shock. Clin Microbiol Rev 16, 379-
414 (2003). 
15. 
S. Nagaraj et al., Regulatory myeloid suppressor cells in health and disease. Cancer 
Res 69, 7503-7506 (2009). 
16. 
D. Sendo, Y. Takeda, H. Ishikawa, F. Sendo, Y. Araki, Localization of GPI-80, a beta2-
integrin-associated glycosylphosphatidyl-inositol anchored protein, on strongly CD14-
positive human monocytes. Immunobiology 207, 217-221 (2003). 


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17. 
S. Kusmartsev et al., All-trans-retinoic acid eliminates immature myeloid cells from 
tumor-bearing mice and improves the effect of vaccination. Cancer research 63, 4441-
4449 (2003). 
18. 
J. M. Lee et al., The restoration of myeloid-derived suppressor cells as functional 
antigen-presenting cells by NKT cell help and all-trans-retinoic acid treatment. Int J 
Cancer 131, 741-751 (2012). 
19. 
X. Song et al., A tritherapy combination of a fusion protein vaccine with immune-
modulating doses of sequential chemotherapies in an optimized regimen completely 
eradicates large tumors in mice. Int J Cancer 128, 1129-1138 (2011). 
20. 
T. R. Breitman, S. J. Collins, B. R. Keene, Terminal differentiation of human 
promyelocytic leukemic cells in primary culture in response to retinoic acid. Blood 57, 
1000-1004 (1981). 
21. 
M. G. Lechner, D. J. Liebertz, A. L. Epstein, Characterization of cytokine-induced 
myeloid-derived suppressor cells from normal human peripheral blood mononuclear 
cells. J Immunol 185, 2273-2284 (2010). 
22. 
T. F. Tedder, P. J. Jansen, Isolation and generation of human dendritic cells. Curr 
Protoc Immunol Chapter 7, Unit 7 32 (2001). 
23. 
P. F. Thall, R. M. Simon, E. H. Estey, Bayesian sequential monitoring designs for 
single-arm clinical trials with multiple outcomes. Stat Med 14, 357-379 (1995). 
24. 
P. F. Thall, R. M. Simon, E. H. Estey, New statistical strategy for monitoring safety 
and efficacy in single-arm clinical trials. J Clin Oncol 14, 296-303 (1996). 
25. 
P. F. Thall, H. G. Sung, Some extensions and applications of a Bayesian strategy for 
monitoring multiple outcomes in clinical trials. Stat Med 17, 1563-1580 (1998). 
 


Consent and Authorization Form
Principal Investigator: Martin McCarter, MD 
COMIRB No:
16-1080
Version Date:
August 14, 2019
Study Title:
Pembrolizumab and All-Trans Retinoic Acid Combination 
Treatment of Advanced Melanoma
You are being asked to be in a research study. This form provides you with information 
about the study. A member of the research team will describe this study to you and answer 
all of your questions. Please read the information below and ask questions about anything 
you don’t understand before deciding whether or not to take part.
Why is this study being done?
This study plans to learn more about melanoma treatment. Melanoma is one of the few 
tumors for which immunotherapy can be effective. Pembrolizumab is one type of 
immunotherapy approved by the Food and Drug Administration (FDA) for first line 
treatment in metastatic melanoma patients. ATRA is an All-trans retinoic acid and is 
commercially available Vitamin A derivative that is approved by the FDA as a standard 
treatment for leukemia. ATRA has also been shown to alter the immune response. ATRA 
has previously been used to treat different types of cancer; however, the combination of 
these two drugs for melanoma is considered experimental. We are hoping to learn if the 
combination of pembrolizumab and ATRA will be effective in treating melanoma.
This study will evaluate the effects of ATRA on tumor-induced immunosuppression. We 
believe that adding ATRA to standard pembrolizumab therapy will increase patients’ 
responses to the immunotherapy. Throughout the rest of this consent form ATRA will be 
referred to as the “study drug”. The doses of study drug that will be given on this study will 
start at a higher dose and may be reduced if subjects experience significant side effects. If 
certain serious or severe side effects are seen, the study will be stopped.
You are being asked to be in this research study because you have advanced melanoma 
and will receive pembrolizumab therapy as part of your standard melanoma treatment.
Other people in this study
Up to 30 people will participate in the study.
What happens if I join this study?
If you join the study, you will be asked to sign this consent form. You will be given a copy 
to keep and the original form will be kept at the clinic. You can withdraw from the study at 
any time and without giving a reason. This will not affect the standard medical care you 
receive.
Page 1 of 21
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
COMIRB
APPROVED
For Use
23-Oct-2019
23-Jul-2020


Consent and Authorization Form
Page 2 of 22
COMIRB 16-1080
PI:  Martin McCarter MD
Version Date: 08/14/2019
There are three (3) sections to this study:
1. Before starting the study (Screening)
2. During the study (Treatment)
3. Post-treatment (After last dose of ATRA and/or Pembrolizumab)
There are also optional parts of this study. These optional procedures are voluntary and 
are not required. You can still take part in the main study if you choose not to take part in 
the optional study procedures. You will be given the choice later in this consent form to 
decide if you would like to take part in these optional procedures.
This next section is an overview of what will be expected of you, and what you can expect 
if you take part in this study.
Study Procedures:
Below are the study procedures and schedule of events (when each procedure will take 
place). Some procedures you receive while taking part in this study are “standard of care 
procedures” for treatment of your disease.
If you have had some of these procedures recently, they may not need to be repeated.
Some procedures are required only for this research and are called “research procedures”, 
which are described here.
The time points when these study procedures will take place are specified in the next 
section called “Study Visits”.
Informed Consent (research)
This informed consent form will be discussed with you and you will be given a copy 
of this document. If you join the study, you will be asked to sign this consent form 
before you receive any study related tests or procedures.
Medical and Cancer History
Before you start the study, we will record your date of birth, race, ethnicity, and 
complete medical history. This history will look at the background and progress of 
your cancer and any treatments you have received for your disease.
Physical Examination
A physical examination will be completed at the beginning of the study and 
throughout the duration of the study. After you join the study, we will assess if the 
study drug is affecting your bodily functions including lungs, heart, abdomen, 
extremities, skin, head (eyes, ears, noses, hair, etc.), and nervous system.


Consent and Authorization Form
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COMIRB 16-1080
PI:  Martin McCarter MD
Version Date: 08/14/2019

Blood and Urine Samples
One of the main components of the study is to collect blood samples for both safety 
testing and to look at your immune response to the drug combination. These will 
occur at the study visits as listed in the study visit descriptions later in this form. 
These tests will consist of some standard of care tests and some research tests and 
include:
o
Pregnancy test - women who are able to become pregnant will be given 
either a urine or blood pregnancy test. A positive pregnancy test prior to 
being given the study drugs, will exclude you from starting or continuing to 
take part in the study.
o
Complete blood count (CBC) with differential
o
Comprehensive serum chemistry panel
o
Thyroid function tests (T3, FT4 and TSH)
o
Blood collection - to check for immune response (research)
o
Lactase Dehydrogenase (LDH) (research)
Your doctor may order additional blood tests for planning treatment administrations, dose 
modification, or further evaluation.

CT
A computed tomography scan uses x-rays to make detailed pictures of parts of the 
body and the structures inside the body.

MRI
Magnetic resonance imaging is a test that uses a magnetic field and pulses of radio 
wave energy to make pictures of organs and structures inside the body.

Vital Signs
We will collect your vital signs including blood pressure, heart rate, respiratory rate, 
body temperature and weight per standard of care. 

Performance Status 
We will assess how well you are performing your daily activities.

Review of other medications
Your study doctor will let you know which other medications you can and cannot 
take while taking part in this study. You will need to check with the study doctor 
before taking any new medications. From the time you first receive the study drugs 
through 30 days after the last dose, we will record other medications you may be 
taking.


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COMIRB 16-1080
PI:  Martin McCarter MD
Version Date: 08/14/2019

Review Adverse Events 
Some risks have been identified because of the disease process or through 
use of the study drugs. These are commonly called side effects and will be 
followed very closely by your doctor and study staff. More information about 
these will be provided in the Risk section of this consent form.
Study Visits:
1. SCREENING
After signing this consent form you will have the following done to see if you can be in this 
study:

Review your medical history

Review your current medications

Full physical examination

Vital signs

Performance status

Urine or serum pregnancy test to make sure you are not pregnant for women 
who can get pregnant (within 72 hours of your first dose of study drug)

Blood tests – CBC with differential, comprehensive serum chemistry panel and 
thyroid function test

Tumor imaging (CT or MRI) will be done

Tumor tissue collections of archived and recent biopsies
2. TREATMENT
In addition to your standard treatment with pembrolizumab, all patients will also receive 
treatment with ATRA (both study drugs provided by Merck). The study drugs will be given 
on a 3 week treatment cycle.
Pembrolizumab:
You will receive an intravenous (IV) treatment of pembrolizumab every three weeks. You 
will receive a dose (200 mg) on the first day of each cycle.
ATRA:
You will receive an oral dose of ATRA every three weeks. You will receive three doses of 
150 mg/m2 at the beginning of the first four cycles. ATRA treatments will be given twice a 
day:

on the day before pembrolizumb infusion (Day -1)

the day of pembrolizumab infusion (Day 0)

the day after pembrolizumab infusion (Day 1)


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Day -1 of treatment cycle 1

You will be dispensed your ATRA supply for cycle 1 and receive a drug 
diary to record dosing information
Day 0 of treatment cycle 1

Review of medications you are taking

Review of Adverse Events (AEs)

Directed physical examination

Performance Status

Vital signs including weight

Blood tests – CBC with differential, comprehensive serum chemistry 
panel and thyroid function test

You will take your Day 0 dose of ATRA once instructed and 
receive your pembrolizumab infusion

You will be dispensed your ATRA supply for cycle 2 and receive a new drug 
diary to record dosing information
Day 0 of treatment cycle 2

Review of medications you are taking

Review of AEs

Directed physical examination

Performance Status

Vital signs including weight

Blood tests – CBC with differential and comprehensive serum chemistry panel

Research blood samples

You will return your drug bottles and diary from cycle 1

You will take your Day 0 dose of ATRA once instructed and 
receive your pembrolizumab infusion

You will be dispensed your ATRA supply for cycle 3 and receive a new drug 
diary to record dosing information
Day 0 of treatment cycle 3

Review of medications you are taking

Review of AEs

Directed physical examination

Performance Status

Vital signs including weight

Blood tests – CBC with differential, comprehensive serum chemistry 
panel and thyroid function test

You will return your drug bottles and diary from cycle 2

You will take your Day 0 dose of ATRA once instructed and 


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receive your pembrolizumab infusion

You will be dispensed your ATRA supply for cycle 4 and receive a new drug 
diary to record dosing information
Day 0 of treatment cycle 4

Review of medications you are taking

Review of AEs

Directed physical examination

Performance Status

Vital signs including weight

Blood tests – CBC with differential and comprehensive serum chemistry panel

Research blood samples

You will return your drug bottles and diary from cycle 3

You will take your Day 0 dose of ATRA once instructed and receive 
your pembrolizumab infusion
Day 0 of treatment cycle 5+

Review of medications you are taking

Review of AEs

Directed physical examination

Performance Status

Vital signs  including weight

Blood tests – CBC with differential and comprehensive serum chemistry panel

Research blood samples will be collected within 60 days of last ATRA dose

Thyroid function test will be collected every other cycle per standard of 
care for clinic

Tumor imaging (CT or MRI) will generally be performed every 12 
weeks per standard of care for clinic

You will return your drug bottles and diary from cycle 4 at the cycle 5 day 0 
visit

You will continue to receive pembrolizumab infusions as long as you are 
receiving benefit or up to 2 years
3. AFTER TREATMENT FOLLOW-UP
End of Treatment (EOT) +/-7 days

Review of medications you are taking

Review of AEs

Performance Status

Post-study therapy status

Tumor Imaging


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Safety Follow-up Visit (30 days after last treatment or prior to starting 
new treatment):

Review of medications you are taking

Review of AEs

Directed physical exam

Vital signs including weight

Research blood samples will be collected within 60 days of last ATRA dose

Post-study therapy status

Survival status

Archival tissue collection for newly obtained tissue - optional
Safety Follow-up Visit (90 days after last treatment unless a new anti-
cancer treatment was initiated, can be collected at a regularly scheduled 
clinic visit or by telephone):

Review of medications you are taking

Review of AEs

Post-study therapy status

Survival status

Archival tissue collection for newly obtained tissue - optional
Survival Follow-up Visit (every 12 weeks until end of study, can be 
collected at a regularly scheduled clinic visit or by telephone):

Review medications you are taking

Post-study therapy status

Survival status

Archival tissue collection for newly obtained tissue - optional
Optional Data and Specimen Banking for Future Research
Dr. Martin McCarter would like to collect archival tissue and some of the data, blood 
and tissue that is taken during the study but is not used for other tests. If you agree, 
the data and samples will be kept and may be used in future research to learn more 
about melanoma. The research that is done with your data and samples is not 
designed to specifically help you. It might help people who have melanoma and 
other diseases in the future. Reports about research done with your data and 
samples will not be given to you or your doctor. These reports will not be put in your 
health records. The research using your data and samples will not affect your care.


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The choice to let Dr. McCarter keep the data and samples for future research is up 
to you. No matter what you decide to do, it will not affect the care that you will 
receive as part of the study. If you decide now that your data and samples can be 
kept for research, you can 
change your mind at any time and contact your study doctor to let him or her know 
that you do not want Dr. McCarter to use your data and samples any longer, and 
they will no longer be used for research. Otherwise, they may be kept until they are 
used up, or until Dr. McCarter decides to destroy them.
When your data and samples are given to other researchers in the future, Dr. 
McCarter will not give them your name, address, phone number or any other 
information that will let the researchers know who you are.
Sometimes data and samples are used for genetic research (about diseases that 
are passed on in families). Even if your data and samples are used for this kind of 
research, the results will not be told to you and will not be put in your health records. 
Your data and samples will only be used for research and will not be sold. The 
research done with your data and samples may help to develop new products in the 
future, but there is no plan for you to be paid.
Please read each sentence below and think about your choice. After reading each 
sentence, check “yes” or “no” and initial next to your selection. If you have questions, 
please talk to your doctor or nurse. Remember, no matter what you decide to do 
about the storage and future use of your data and samples, you may still take part in 
the study.
I give my permission for my data, blood and tissue to be stored in a central tissue 
bank at the University of Colorado Cancer Center for future use by the study 
investigators:
1. I give my permissions for my data, blood and tissue samples taken 
during the study to be kept by Dr. McCarter for use in future research to 
learn more about how to prevent, detect, or treat melanoma.
Yes
No
 
Initials
2. I give my permissions for my archival tissue samples to be kept by Dr. 
McCarter for use in future research to learn more about how to prevent, 
detect, or treat melanoma.
Yes
No
 
Initials


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3. I give my permissions for my data, blood and tissue samples to be 
used for research about other health problems (for example: causes of 
heart disease, osteoporosis, and diabetes).
Yes
No
 
Initials
4. I give my permission for my study doctor (or someone he or she 
chooses) to contact me in the future to ask me to take part in more 
research.
Yes
No
 
Initials
How long will I be in the study?
Your study participation is expected to last at least 2 years. The amount of time you 
participate in this study will depend on how your disease responds and how you 
tolerate the treatment. You will continue in the study until there is evidence that your 
disease has relapsed, your side effects are too severe, you request to stop 
participation, the study doctor feels that you will not benefit from further dosing, you do 
not follow the study instructions, or (for women) you become pregnant.
What are the possible discomforts or risks?
As with any study drug, side effects may occur when taking this study drug. While 
taking part in this study, and being treated with the study drugs, you will be watched 
carefully for any side effects. Some side effects may go away after you stop taking 
the study drug. Some side effects can be long lasting and may never go away or 
may even lead to death.
You should talk to your study doctor about any side effects or discomfort you may 
have. The study doctor may give you some medicine that will help with some side 
effects. The study doctor may also interrupt or discontinue the study drug.
You will be notified by your study doctor of any new side effects seen in other 
patients that occur during the time you are on the study. This may affect you 
wanting to continue in this research study.
Based on animal studies and/or other studies with similar types of drugs, side 
effects or discomforts you may experience while in this study include:
Risks of Pembrolizumab (KEYTRUDA)
Pembrolizumab, which is approved in the USA and some other countries, is 
available by prescription to treat several different cancers, but may not be 
approved to treat your type of cancer.


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Pembrolizumab works by helping your immune system to fight your cancer.
However, pembrolizumab can also cause your immune system to attack normal 
organs and tissues in your body and can affect the way they work, which can result in 
side effects. These side effects may be serious (i.e. causing hospitalization or be life-
threatening), may result in death, and/or may occur after you stop taking 
pembrolizumab. These side effects can affect more than one of your normal organs 
and tissues at the same time.
VERY COMMON, SOME MAY BE SERIOUS (i.e. causing hospitalization, life-
threatening or where noted, may cause death) – occurring in more than 20 people 
out of 100 people:
Itching of the skin
Loose or watery stools
Cough
COMMON, SOME MAY BE SERIOUS (i.e. causing hospitalization, life-
threatening, or where noted, may cause death) occurring in at least 5 but less 
than 20 people out of 100 people:
Joint pain
Rash
Fever
Back pain
Pain in your belly
Loss of skin color
Not enough thyroid hormone so you may feel tired, gain weight, feel 
cold, have infrequent or hard stools
Low level of salt in the blood that may cause you to feel tired, 
confused, headache, muscle cramps or upset stomach
UNCOMMON, SOME MAY BE SERIOUS - i.e. causing hospitalization, life-
threatening, or where noted, may cause death) – occurring in at least 1 to less 
than 5 people out of 100 people:
Inflammation of the lungs so you may feel short of breath and cough. 
Rarely this might lead to death.
Too much thyroid hormone so you may feel anxious, angry, have trouble 
sleeping, feel weak, tremble, sweat, feel tired, have loose and watery stools
Infusion reaction, where you may feel dizzy or faint, flushed, get a rash, 
have a fever, feel short of breath, experience a decrease in your blood 
pressure at the time of receiving your infusion (IV) or just after, or pain at 
the site of infusion


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Inflammation of the bowels/gut that can cause severe stomach pain with 
loose or watery stools, or stools that are black, tarry, sticky or stools with 
blood or mucus
A condition called Stevens Johnson Syndrome (SJS) or Toxic Epidermal 
Necrosis (TEN). This condition involves inflammation of the skin, which may 
cause peeling of the skin, itchiness, and/or skin redness. The skin 
inflammation (i.e. peeling, itching and redness) could also be widespread 
throughout your body. More severe skin reactions may involve the inside of 
your mouth, the surface of your eye and genital areas, and/or may cause 
the top layer of your skin to peel from all over your body, which can cause 
severe infection. These severe conditions can rarely lead to death.
RARE, SOME MAY BE SERIOUS (i.e. causing hospitalization, life-threatening, or 
where noted, may cause death) – in less than 1 out of 100 people:

Inflammation of the nerves that may cause
o
Pain
o
Weakness or tingling in the hands and feet, and may spread to 
the legs, arms and upper body leading to severe muscle 
weakness and possible temporary paralysis

Inflammation of the muscles so you may feel weak or have pain in the 
muscles, sometimes referred to a myasthenic syndrome

Inflammation of the pancreas (a gland in your abdomen that controls 
sugar levels)
o
Severe pain in the top part of your belly that may move to the back
o
Sick to your stomach
o
Vomiting that gets worse when you eat

Inflammation of the eye
o
Redness of the eye
o
Blurred vision
o
Sensitivity to light
o
Have eye pain
o
See floaters
o
Have headaches
   Inflammation of the liver
o
Upset stomach and vomiting
o
Feel like not eating
o
Feel tired
o
Mild fever
o
Pain in the right side of your belly
o
Yellow eyes and skin
o
Dark urine
  Inflammation of the pituitary gland (a gland in the head)
o
Headaches


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o
Upset stomach
o
Changes in behavior
o
Double vision
o
Few to no menstrual cycles
o
Weakness
o
Vomiting
o
Dizziness or fainting

Adrenal glands (glands on top of the kidneys) may not produce enough 
hormone
o
Tiredness
o
Weight loss
o
Muscle weakness
o
Feeling faint
o
Joint, muscle and belly aches
o
Nausea
o
Vomiting
o
Loose or watery stools
o
Fever
o
Salt craving
o
Darkening of the skin like a suntan

Type 1 Diabetes, a condition that can cause too much sugar in the blood 
which may make you:
o
Feel thirstier than usual
o
Frequent urination
o
Weight Loss
o
May need regular insulin shots

Inflammation of the kidney, you may:
o
pass less urine
o
have cloudy or bloody urine
o
swelling
o
low back pain

Inflammation of the middle layer of your heart (myocarditis)
o
Difficulty pumping blood throughout your body
o
Chest pain
o
Shortness of breath
o
Swelling of the legs
o
Fast or irregular heartbeat (that may cause dizziness or fainting)
o
Death

Inflammation of the thyroid gland, an organ that makes and stores thyroid 
hormones. This condition may lead to change in your:
o
 heart rate
o
 blood pressure
o
body temperature


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o
metabolism (the rate at which food is converted into energy)

A condition that may make you feel weak and tired and might have 
drooping of the eyelids, blurred or double vision, difficulty swallowing, 
slurred speech, weakness in your arms and legs, or difficulty breathing

Formation of small clusters of immune cells (granulomas) in parts of 
your body such as your lymph nodes, eyes, skin, or lungs

Inflammation of the brain which may include:
o
Confusion
o
Fever
o
Disorientation
o
Memory problems
o
Seizures (fits)
o
Changes in personality and behavior
o
Difficulty speaking
o
Weakness or loss of movement in some parts of your body
o
Loss of consciousness
Additionally, since pembrolizumab was approved in September 2014, the following 
side effects have been reported by people receiving pembrolizumab. These side 
effects were voluntarily reported from a group of people of unknown size. It is not 
possible to estimate the frequency of this side effect:

Inflammation of the joints which may include joint pain, stiffness and/or 
swelling

Severe responses of the immune system that cause the body to attack its 
own blood cells, spleen, liver, lymph nodes, skin and brain. This may 
include fever, rash, inflammation of the liver, yellowing of the skin, an 
enlarged liver and spleen, low blood counts, and enlarged lymph nodes. 
The nervous system may also be affected and cause confusion, seizures, 
and even coma.
Risks of ATRA
ATRA is approved by the Food and Drug Administration for the treatment of 
leukemia. Patients with acute promyelocytic leukemia (APL) treated with ATRA 
every day for many weeks at a time reported the following: 
In this study, you will receive a higher dose of ATRA for a shorter period of time than 
patients with APL. The most common side effect of ATRA treatment is a limited 
headache that typically resolves when ATRA treatment stops.
COMMON SIDE EFFECTS – in 30 people out of 100 people
Which may include the following symptoms:
o Headache
o Fever


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o Dry skin
o Dry mouth and nose
o Bone pain
o Nausea and vomiting
o Rash
o Mouth sores
o Itching
o Sweating
o Eyesight changes
Flu-like symptoms such as malaise and chills
Bleeding problems
Vulnerability to infections
Swelling of feet or ankles
Bone and joint pain
Chest discomfort
Abdominal pain
LESS COMMON SIDE EFFECTS – in 10 to 29 people out of 100 people
Weight increase
Heart rate irregularities
Flushing
Poor appetite
Weight loss
Earache or feeling of fullness in the ears
Diarrhea
Dizziness
Constipation
Numbness and tingling in hands and feet
Anxiety
Heartburn
Low blood pressure
Insomnia
Depression
High blood pressure
Confusion
RARE BUT SERIOUS SIDE EFFECTS – in 3 people out of 100 people
Brain disease, damage, or malfunction (encephalopathy)
Cardiac arrest
Inflammation of the blood vessels (vasculitis)
Neurologic reaction
Stroke


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Risks of Having an IV Inserted in Your Vein
In this study, we will insert a needle, connected to a plastic tube, into a vein in 
your arm. You will feel some pain when we first insert the tube into your vein. You 
may have some redness, swelling, or bruising where the tube goes under your 
skin. In some cases, this type of tube can cause an infection where it goes under 
the skin. In rare cases, it can cause a blood clot in the vein.
Risks of Having Blood Taken
In this study, depending on study visit, we will need to get about ¾ of a cup (24 
tubes) of blood from you over the course of the study. We will get blood by putting a 
needle into one of your veins and letting the blood flow into a vacuum tube. You may 
feel some pain when the needle goes into your vein. A day or two later, you may 
have a small bruise where the needle went under the skin.
Computed Tomography (CT) Risk
As part of this study, we will perform a CT scan. CT is a way of taking detailed 
pictures inside your body by using X-rays. X-rays are a type of radiation.
You get some radiation from your environment.  You get radiation from bricks and 
concrete, from some foods, and from radon gas, which is an invisible gas that seeps 
out of the ground.  The amount of radiation that this CT scan will deliver to your body 
(give you) is about the same as you would get from living in your environment. This 
is an estimate.
The amount of radiation you get could be higher or lower, depending on the 
machine, the power setting, and your body weight. Exposure to radiation at high 
levels increases a risk of developing cancer. There is no evidence of such risks for 
diagnostic procedures.
Risks of Having an MRI
In this study, we will take Magnetic Resonance Images (MRI’s) of your affected 
area. The MRI machine uses powerful magnetic waves to take pictures inside the 
body. The waves themselves are not harmful, but they can cause metal to heat up 
and electronics to stop working. You should NOT have an MRI if you have metal 
or electronic devices inside your body.
Heart pacemakers and insulin 
pumps are examples of electronic devices.
The MRI machine is a small round tube. It might make you uncomfortable if you do 
not like tight spaces.
The most common side effect of having an MRI is flashing lights in the eyes. This 
is caused by the magnetic waves and is not harmful. Some people also experience 


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warmth and reddening of the skin.  This usually goes away after a few minutes.
If you are pregnant, be sure to tell the person giving you the MRI.
Risk of Loss of Confidentiality
There is a risk that people outside of the research team will see your research 
information. We will do all that we can to protect your information, but it cannot be 
guaranteed.
Reproductive Risks
The use of the study drugs in pregnant females and nursing mothers has not been 
studied. The effects of the study drugs on human eggs and sperm has not been 
studied. The risks to a human fetus are unknown. However, based on the way the 
drugs work, it cannot be ruled out that there is potential for the study drugs to 
cause birth defects in humans. If the study drugs are taken during pregnancy, they 
may cause birth defects or death to an unborn baby.
Females must not become pregnant while taking the study drugs. Women who are 
able to get pregnant must use effective birth control while taking pembrolizumab 
and for at least 4 months after the last dose of pembrolizumab.
Before you begin study treatment, your doctor will discuss acceptable forms of birth 
control with you.
The study may also include risks that are unknown at this time.
What are the possible benefits of the study?
This study is designed for the researcher to learn more about the effects of 
Pembrolizumab and the study drug on your disease. However, there is no 
guarantee that your health will improve if you join this study. Also, there could be 
risks to being in this study. If there are risks, these are described in the section 
describing the discomforts or risks.
Are there alternative treatments?
There may be other ways of treating your Melanoma. These other ways include:

You may choose to receive treatment with another experimental therapy

You may choose to receive treatment with another approved therapy

You may choose to receive comfort/palliative care

You could also choose to get no treatment at all


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You should talk to your doctor about your choices. Make sure you understand all of 
your choices before you decide to take part in this study. You may leave this study 
and still have these other choices available to you.
Who is paying for this study?
Merck is providing funding support for this trial. This research is being sponsored by 
the University of Colorado Cancer Center.
Dr. Karl Lewis (investigator) has a significant financial interest due to his role as an 
Advisory Board Member with Merck & Co., Inc.. Merck & Co., Inc. is the sponsor of 
this study and the manufacturer of one of the study drugs (pembrolizumab).
Dr. Rene Gonzalez (investigator) and Dr. Karl Lewis (investigator) have financial 
interests with Roche/Genetech. Roche/Genetech is the manufacturer of one of the 
study drugs (ATRA). Please feel free to ask any questions you have about this 
matter.
Will I be paid for being in the study?
You will not be paid to be in the study.
Will I have to pay for anything?
Merck will pay for the cost of the Pembrolizumab, ATRA and research blood work. 
The sponsor will also pay for any tests or procedures that are related to the research 
study.
You will need to pay for any tests and procedures that are considered standard of 
care. These include the CT scans, MRIs and some clinic visits and laboratory tests. 
You may be responsible for co-payments and deductibles that are standard for your 
insurance coverage.
Ask your study doctor to discuss the costs that will or will not be covered by the 
sponsor. This discussion should include the costs of treating possible side effects. 
Otherwise, you might have unexpected expenses from being in this study.
Is my participation voluntary?
Taking part in this study is voluntary. You have the right to choose not to take part in 
this study. If you choose to take part, you have the right to stop at any time. If you 
refuse or decide to withdraw later, you will not lose any benefits or rights to which you 
are entitled.


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If you leave this study, you will still receive your normal medical care. The only 
medical care that you will lose is the medical care you are getting as part of this 
study. You might be able to get that same kind of medical care outside of the study.  
Ask your study doctor.
If there are any new findings during the study that may affect whether you want to 
continue to take part, you will be told about them.
Can I be removed from this study?
The study doctor may decide to stop your participation without your permission if the 
study doctor thinks that being in the study may cause you harm, or for any other 
reason. Also, the sponsor may stop the study at any time.
What happens if I am injured or hurt during the study?
If you have an injury while you are in this study you should call your study 
investigator immediately. Dr. Martin McCarter’s phone number is (303) 724 2728. 
You may also call Dr. Schuster at 970-493-6337, Dr. Rene Gonzalez at (720) 848-
0564 or Dr. Karl Lewis at (720) 848-0584.
If you are hurt by this research, we will arrange to get you medical care if you have 
an injury that is caused by this research. However, you or your insurance company 
will have to pay for that care.
Who do I call if I have questions?
The researcher carrying out this study is Martin McCarter, MD. You may ask any 
questions you have now. If you have questions, concerns, or complaints later, 
you may call Dr. McCarter at (303) 724-2728 or Dr. Schuster at (970)493-6337. 
You will be given a copy of this form to keep.
You may have questions about your rights as someone in this study. You 
can call Dr. McCarter at (303) 724-2728 or Dr. Schuster at (970) 493-6337 
with questions. You can also call the responsible Institutional Review Board 
(COMIRB). You can call them at (303) 724-1055.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This Web site will not include information that can 
identify you. At most, the Web site will include a summary of the results. You can 
search this Web site at any time.
Who will see my research information?


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PI:  Martin McCarter MD
Version Date: 08/14/2019
The University of Colorado Denver (UCD) and its affiliated hospital(s) have rules to 
protect information about you. Federal and state laws including the Health 
Insurance Portability and Accountability Act (HIPAA) also protect your privacy.
This part of the consent form tells you what information about you may be collected 
in this study and who might see or use it.
The institutions involved in this study include:
University  of Colorado Denver
University of Colorado Hospital
University of Colorado-North Poudre Valley Hospital
We cannot do this study without your permission to see, use and give out your 
information. You do not have to give us this permission.  If you do not, then you may 
not join this study.
We will see, use and disclose your information only as described in this form and in 
our Notice of Privacy Practices; however, people outside the UCD and its affiliate 
hospitals may not be covered by this obligation.
We will do everything we can to maintain the confidentiality of your personal 
information but confidentiality cannot be guaranteed.
The use and disclosure of your information has no time limit. You can cancel your 
permission to use and disclose your information at any time by writing to the study’s 
Principal Investigator (PI), at the name and address listed below. If you do cancel 
your permission to use and disclose your information, your part in this study will end 
and no further information about you will be collected. Your cancellation would not 
affect information already collected in this study.
Martin McCarter, MD
University of Colorado Denver Anschutz Medical 
Campus 12631 E. 17th Avenue, Mail Stop C325
Aurora, CO 80045
Steven Schuster, MD
UCH-North Poudre Valley Hospital
2121 E. Harmony Road, Suite 170


Consent and Authorization Form
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COMIRB 16-1080
PI:  Martin McCarter MD
Version Date: 08/14/2019
Fort Collins, CO 80528
Both the research records that identify you and the consent form signed by you may 
be looked at by others who have a legal right to see that information, such as:

Federal offices such as the Food and Drug Administration (FDA) and the 
Office of Human Research Protections (OHRP) that protect research 
subjects like you.

People at the Colorado Multiple Institutional Review Board (COMIRB).

The study doctor and the rest of the study team.

Merck who is the company paying for this research study.

Officials at the institution where the research is conducted and officials at 
other institutions involved in this study who are in charge of making sure that 
we follow all of the rules for research
We might talk about this research study at meetings. We might also print the results 
of this research study in relevant journals, but we will always keep the names of the 
research subjects, like you, private.
You have the right to request access to your personal health information from the 
Investigator.
The investigator (or staff acting on behalf of the investigator) will use your 
information for the research outlined in this consent form. They will also 
make all or some of the following health information about you collected in 
this study available to: 
Merck - the company providing Pembrolizumab and VESANOID and QualTek 
laboratories for biomarker analysis.
Some of the research procedures involve genetic testing or the use of your 
genetic information.  Your genetic information will not be released to others.
Information about you that will be seen, collected, used and disclosed in this 
study:

Name and Demographic Information (age, sex, ethnicity, address, phone 
number, etc.

Portions of your previous and current Medical Records that are relevant to 
this study, including but not limited to Diagnosis(es), History and Physical, 
laboratory or tissue studies, radiology studies, procedure results

Research Visit and Research Test records

Tissue samples and the data with the samples.


Consent and Authorization Form
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COMIRB 16-1080
PI:  Martin McCarter MD
Version Date: 08/14/2019

Billing or financial information
What happens to Data, Tissue, Blood and Specimens that are collected 
in this study?
Scientists at the University of Colorado Denver and the hospitals involved in this 
study work to find the causes and cures of disease. The data, tissue, blood and 
specimens collected from you during this study are important to this study and to 
future research. If you join this study:

The data, tissue, blood, or other specimens given by you to the 
investigators for this research no longer belong to you.

Both the investigators and any sponsor of this research may study 
your data, tissue, blood, or other specimens collected from you.

If data, tissue, blood, or other specimens are in a form that identifies you, 
UCD or the hospitals involved in this study may use them for future 
research only with your consent or Institutional Review Board (IRB) 
approval.

Any product or idea created by the researchers working on this study 
will not belong to you.

There is no plan for you to receive any financial benefit from the creation, 
use or sale of such a product or idea.
HIPAA Authorization for Optional Additional Study Procedures –
In this form, you were given the option to agree to additional, optional research 
procedures. You must also give us your permission, under HIPAA rules, to use 
and disclose the information collected from these optional procedures, as 
described above.
Some of these optional procedures may involve genetic testing or the use of your 
genetic information.  Your genetic information will not be released to others.
If you decline to give us permission to use and disclose your information, you 
cannot take part in these optional procedures, but you can still participate in the 
main study. Please initial next to your choice:
 
I give permission for my information, from the optional procedures I have 
agreed to above, to be used and disclosed as described in this section.
 
I do not give permission for my information for any optional 
procedures to be used and disclosed; I understand that I will not 


Consent and Authorization Form
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COMIRB 16-1080
PI:  Martin McCarter MD
Version Date: 08/14/2019
participate in any optional procedures.
Agreement to be in this study and use my data
I have read this paper about the study or it was read to me. I understand the 
possible risks and benefits of this study.  I understand and authorize the access, 
use and disclosure of my information as stated in this form. I know that being in this 
study is voluntary.  I choose to be in this study: I will get a signed and dated copy of 
this consent form.
Signature: _______________________________________ Date: ________
Print Name:  
Consent form explained by: _________________________
Date: ________
Print Name:  
Witness Signature: 
Date:  
Witness Print Name:   
                                           Witness of Signatur
Witness of consent process: ______________________
A signature line for a witness is required for consent of 
non-reading subjects and consent using a short form.