Clinical trial NCT03875859
Conditions: Squamous Cell Carcinoma
Sponsor: Kavita Sarin
Start date: 2019-12-12; Completion date: 2021-01-30
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary purpose of this study is to determine if 8 weeks of topical remetinostat applied three times daily will suppress Squamous Cell Carcinoma.

Detailed description:
The primary purpose of this study is:

* to determine if 8 weeks of topical remetinostat gel applied 3 times daily (TID) under occlusion will suppress SCC growth
* to determine the overall response rate (ORR) of SCCs after 8 weeks of treatment with topical remetinostat gel 1%, as measured by at least 30% decrease in greatest area (in mm2).

  * Subjects with at least 1 biopsy-proven cutaneous SCC will be recruited for this study.
  * Subjects will apply remetinostat gel 1% to at least 1 SCC.
  * Non-invasive cutaneous SCC lesions, including Bowen's disease, are also eligible for this study
  * There is 1 treatment option: Topical remetinostat gel 1% applied 3 times daily.
  * The study is a single arm, open label design
  * For purposes of ClinicalTrials.gov, there is no secondary outcome.

Arms: arm 1: Subjects will apply remetinostat gel 1% to at least 1 SCC: Topical remetinostat gel 1% applied 3 times daily.
Interventions: intervention 1: Remetinostat
Intervention descriptions: intervention 1: Topical 1% remetinostat gel

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL:   
IRB-49542  
Page 1 of 34 
19 July 2019 
Version # 1 
A Phase 2 Open-label, Single-arm Trial to Investigate the 
Efficacy and Safety of Topical Remetinostat Gel as 
Neoadjuvant Therapy in Patients Undergoing Surgical 
Resection of Squamous Cell Carcinoma (SCC)  
Coordinating Center 
Stanford Cancer Institute 
Medical Dermatology 
450 Broadway St  
Redwood City, CA  94063-5334 
Protocol Director  
Kavita Y Sarin, MD, PhD 
Stanford Cancer Institute 
Medical Dermatology 
450 Broadway St  
 
Redwood City, CA  94063-5334 
Phone xxx-xxx-xxxx;  Fax xxx-xxx-xxxx 
ksarin@stanford.edu  
Sub-Investigators 
Sumaira Aasi, MD 
450 Broadway St. 
Pavilion C, 2nd Floor 
Redwood City, CA 
Phone:  xxx-xxx-xxxx  
Fax:  xxx-xxx-xxxx 
aasi@stanford.edu  
Aatman Shah, MD 
455 Broadway St. 
Discovery Hall 
Redwood City, CA 94063 
Phone:  xxx-xxx-xxxx 
Fax:  xxx-xxx-xxxx 
aatmans@stanford.edu 
James Kilgour, MBBS  
455 Broadway St. 
Discovery Hall, Room, 
Redwood City, CA 94063 
Phone:  xxx-xxx-xxxx  
Fax:  xxx-xxx-xxxx 
jkilgour@stanford.edu 
Biostatistician 
Shufeng Li, MS 
780 Welch Road, 
Palo Alto, CA  94304 
Stanford, California 94305 
Phone: xxx-xxx-xxxx 
Fax: xxx-xxx-xxxx 
shufeng@stanford.edu 
Study Coordinator 
Irene Bailey 
450 Broadway St. 
Pavilion C, 
Redwood City, CA 
Phone: xxx-xxx-xxxx 
Fax:  xxx-xxx-xxxx 
baileyhi@stanford.edu    
 
IRB-49542 
SKIN0050 
NCT03875859 
IND 134521 
Version Date:  
19 July 2019 
Version: 
1 
SRC approval date: 
pending  


CONFIDENTIAL:   
IRB-49542  
Page 2 of 34 
19 July 2019 
Version # 1 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................................ 4 
SCHEMA ....................................................................................................................................... 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................ 6 
1. 
OBJECTIVES ....................................................................................................................... 7 
1.1. 
PRIMARY OBJECTIVE ...................................................................................................... 7 
1.2. 
SECONDARY OBJECTIVES ............................................................................................... 7 
2. 
BACKGROUND ................................................................................................................... 7 
2.1 
STUDY DISEASE .............................................................................................................. 7 
2.2 
STUDY AGENT ................................................................................................................. 8 
2.3 
RATIONALE .................................................................................................................... 10 
2.4 
STUDY DESIGN .............................................................................................................. 11 
2.5 
CORRELATIVE STUDIES BACKGROUND ........................................................................ 11 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ........................ 12 
3.2 
INFORMED CONSENT PROCESS ................................................................................... 15 
3.3 
RANDOMIZATION PROCEDURES .................................................................................... 15 
3.4 
STUDY TIMELINE ........................................................................................................... 15 
4. 
TREATMENT PLAN .......................................................................................................... 15 
4.1 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............ 17 
4.2 
CRITERIA FOR REMOVAL FROM STUDY ........................................................................ 17 
4.3 
ALTERNATIVES .............................................................................................................. 18 
5. 
INVESTIGATIONAL DRUG INFORMATION ................................................................ 18 
5.1 
INVESTIGATIONAL DRUG ............................................................................................... 18 
5.2 
AVAILABILITY ................................................................................................................. 19 
5.3 
AGENT ORDERING ........................................................................................................ 19 
5.4 
STORAGE CONDITIONS ................................................................................................. 19 
5.5 
AGENT ACCOUNTABILITY .............................................................................................. 19 
6. 
DOSE MODIFICATIONS .................................................................................................. 19 
6.1. 
DOSE MODIFICATIONS DUE TO TOXICITY AND STOPPING CRITERIA ............................ 20 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES .......................................... 21 
7.1 
POTENTIAL ADVERSE EVENTS ...................................................................................... 21 
7.2 
ADVERSE EVENT REPORTING....................................................................................... 23 
8. 
EXPLORATIVE / CORRELATIVE / SPECIAL STUDIES ........................................... 23 
9. 
STUDY CALENDAR ......................................................................................................... 24 
10. 
MEASUREMENTS......................................................................................................... 25 
10.1 
PRIMARY OUTCOME ...................................................................................................... 25 
10.1.1 RELEVANT SUBSET ....................................................................................................... 25 
10.1.2 MEASUREMENT DEFINITION .......................................................................................... 25 
10.1.3 MEASUREMENT METHODS ............................................................................................ 25 
10.2 
SECONDARY OUTCOMES .............................................................................................. 25 
11. 
REGULATORY CONSIDERATIONS ......................................................................... 26 
11.1 
INSTITUTIONAL REVIEW OF PROTOCOL ........................................................................ 26 
11.2 
DATA AND SAFETY MONITORING PLAN ........................................................................ 26 
11.3 
DATA MANAGEMENT PLAN ........................................................................................... 27 
12. 
STATISTICAL CONSIDERATIONS ........................................................................... 27 
12.1 
STATISTICAL DESIGN .................................................................................................... 27 


CONFIDENTIAL:   
IRB-49542  
Page 3 of 34 
19 July 2019 
Version # 1 
12.1.1 
RANDOMIZATION ....................................................................................................... 27 
12.2 
INTERIM ANALYSES ........................................................................................................ 27 
12.3 
DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS ................................. 27 
12.6 
SAMPLE SIZE ................................................................................................................. 28 
13. 
REFERENCES ............................................................................................................... 30 
APPENDIX A:  STUDY IRB-49542 PARTICIPANT MEDICATION APPLICATION DIARY ........... 32 
APPENDIX B:  STUDY IRB-49542 PARTICIPANT INFORMATION SHEET ............................... 34 


CONFIDENTIAL:   
IRB-49542  
Page 4 of 34 
19 July 2019 
Version # 1 
PROTOCOL SYNOPSIS 
TITLE 
A Phase 2 Open-label, Single-arm Trial of the Efficacy 
and Safety of Topical Remetinostat Gel as Neoadjuvant 
Therapy in Patients with Squamous Cell Carcinoma 
Undergoing Surgical Resection 
STUDY PHASE 
Phase 2 
INDICATION 
Treatment of squamous cell carcinoma (SCC) and 
squamous cell carcinoma in situ (SCC-IS) 
INVESTIGATIONAL PRODUCT  
Topical remetinostat gel 1% 
PRIMARY OBJECTIVE 
• 
To determine if topical remetinostat gel treatment 
3-times-daily (TID) for 8 weeks will decrease 
SCC tumor area (in mm2) by at least 30%  
• 
To determine the overall response rate (ORR) of 
SCC tumors to 8 weeks of TID treatment with topical 
remetinostat gel  
SECONDARY OBJECTIVE 
To assess the safety and tolerability of remetinostat gel 
1% when applied topically TID under occlusion for 
8 weeks as follows: 
• 
Incidence, type, and severity of adverse events (AEs)  
• 
Incidence and nature of serious adverse 
events (SAEs)  
• 
Incidence of AEs leading to remetinostat 
discontinuation or interruption  
• 
Adherence to the treatment, measured by number of 
patients discontinuing the treatment (for any reason) 
and treatment interruptions  
TREATMENT SUMMARY 
Apply topical remetinostat gel 1% 3 times daily (TID) 
under bandage occlusion for 8 weeks 
STUDY POPULATION  
Adults of either gender with squamous cell carcinoma 
(SCC) lesions ≥ 5 mm.  See Section 3.1 for detailed 
eligibility.  
SAMPLE SIZE  
30 SCC per-protocol evaluable tumors.  The maximum 
number of subjects contributing evaluable tumors will be 
40, but can be less to obtain the 30 SCC per-protocol 
evaluable tumors.  Participating subjects that do not 
contribute evaluable tumors will not be counted towards 
this total.  It is anticipated that no more than 40 subjects 
will participate overall.  


CONFIDENTIAL:   
IRB-49542  
Page 5 of 34 
19 July 2019 
Version # 1 
STATISTICAL 
CONSIDERATIONS 
Overall response rate of SCC tumors (Primary Objective 
and Primary Outcome) in subjects will be defined as at 
least a 30% decrease in the area of each SCC lesion(s).  
With a planned analysis on 30 per-protocol evaluable 
SCCs, this study would provide 91% power to reject an 
ORR of 15% if the true ORR is 40% or better, at 
one-sided alpha level of 0.05 with at least 9 responders.  
For the Secondary Objective 1, toxicities will be graded 
according to the National Cancer Institute CTCAE v5.0.  
SCHEMA 
 


CONFIDENTIAL:   
IRB-49542  
Page 6 of 34 
19 July 2019 
Version # 1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
ADL 
Activities of daily living 
AE 
Adverse event 
BID 
Twice daily 
CBC 
Complete blood count 
CI 
Confidence interval 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCL 
Cutaneous T-cell lymphoma 
DLT 
Dose-limiting toxicity 
DSMC 
Data Safety Monitoring Committee 
EKG 
Electrocardiogram 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HDAC 
Histone deacetylase  
HH 
Hedgehog 
IRB 
Institutional Review Board 
IV 
Intravenous 
LLN 
Lower limit of normal  
OS 
Overall survival  
PLT 
Platelet 
PD 
Progressive disease 
PR 
Partial response 
PTCH1 
Protein patched homolog 1 
QD 
Once daily 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SCC 
Squamous cell cancer / carcinoma 
SCC-IS 
Squamous cell cancer/carcinoma in situ 
SD 
Stable disease 
Shh pathway 
Sonic hedgehog pathway 
SMO 
Smoothened 
TID 
Three times daily 
ULN 
Upper limit of normal 


CONFIDENTIAL:   
IRB-49542  
Page 7 of 34 
19 July 2019 
Version # 1 
1. 
OBJECTIVES 
1.1. 
Primary Objective  
Overall response rate of SCC in subjects defined by at least a 30% decrease in SCC tumor area 
(in mm2) at end of study measurement as compared with baseline measurements.  The 
threshold for positive response will be at least 30% decrease in tumor area (Note:  RECIST v1.1 
criteria have limited utility for SCCs under 10 mm, and will not be used for that reason). 
1.2. 
Secondary Objectives 
 
• 
Safety assessment of remetinostat after 8 weeks of topical treatment will be evaluated 
as follows: 
o Incidence, type, and severity of adverse events (AEs)  
o Incidence and nature of serious adverse events (SAEs)  
o Incidence of AEs leading to treatment discontinuation or interruption  
o Adherence to the treatment, measured by number of patients discontinuing the 
treatment (for any reason) and treatment interruptions  
2. 
BACKGROUND 
2.1 
Study Disease 
Cutaneous squamous cell carcinoma (SCC) is one of the most common human cancers and is 
the second most common skin cancer, comprising at least 20% of all non-melanoma skin 
cancers, affecting approximately 700,000 Americans each year (as non-melanoma skin cancers 
are not reported to cancer registries, the exact incidence of SCC is not known)1.  Similar to other 
skin cancers, risk factors for development of SCC include age, lighter skin tones, and 
importantly, chronic exposure to ultraviolet light2.  Exposure to ionizing radiation, arsenic, 
chronic inflammatory processes (such as in chronic wounds), and HPV infection also 
predispose patients to developing cutaneous SCC2.  SCC is also more common in patients who 
have been exposed to arsenic3,4, or have taken photo-sensitizing drugs such as thiazide 
diuretics5.  Up to 50% of transplant patients on immunosuppressive therapy develop cutaneous 
SCC after long-term therapy; these SCCs also tend to behave more aggressively2. 
Given their frequencies, treatment of non-melanoma skin cancers (NMSC) represents a 
significant annual cost to the United States health care system.  Amongst all cancers treated in 
the Medicare population, NMSC represented the 5th-most-costly cancer to Medicare overall and 
represented 4.5% of all Medicare cancer costs6.  This high expenditure is largely influenced by 
the high frequency of NMSC rather than a high per-patient cost.  The incidence of NMSC has 
increased since the mid-1960s at a rate of approximately 2% to 8% per year6,7, so overall 
healthcare spending to treat SCC, with its continually-increasing incidence, is very likely to 
continue to rise. 
While the exact mechanism of pathogenesis in SCC is unknown8, multiple genetic mutations 
have been associated with and are thought to contribute to the development of SCC.  Mutations 
in p53, CDK2NA, RAS, MYC, and KNSTRN, NOTCH1, and NOTCH2 have all been associated 
with SCC2,9-11 and MC1R polymorphisms can influence individuals’ risk for developing SCC12.  
EGFR and IKK expression have been found to be predictive of metastatic capability in SCC7.  A 
study of conjunctival epithelial tumors suggested that Sonic hedgehog signaling (Shh) pathway 


CONFIDENTIAL:   
IRB-49542  
Page 8 of 34 
19 July 2019 
Version # 1 
alterations could lead to transformation of intraepithelial neoplasia into invasive squamous cell 
carcinoma8.  
2.2 
Study Agent  
Histone deacetylase (HDAC) inhibitors are anticancer agents.  Two HDAC inhibitors, vorinostat 
and romidepsin, were approved by the US FDA for the treatment of cutaneous T-cell 
lymphoma (CTCL)13.  HDAC inhibitors antagonize tumors by altering the expression of 
oncogenes or tumor suppressors by modulating the level of acetylation/deacetylation of 
histones and/or non-histone proteins such as transcription factors.  Preclinical studies suggest 
that HDAC inhibitors may potentially be effective anti-SCC agents, as murine studies have 
shown HDAC inhibitors can inhibit the growth of SCC cells and SCC tumors both in vitro and 
in vivo14. 
Remetinostat is also known as suberohydroxamic acid phenyl ester (SHAPE); SHAPE Gel; SHP 
141; and 4 [[8 (hydroxyamino) 1,8 dioxooctyl]oxy] benzoic acid methyl ester.  Remetinostat is a 
histone deacetylase inhibitor (HDACi) that was designed with a metabolically labile ester bond 
so that topical application would produce effective local histone deacetylase (HDAC) inhibition in 
cutaneous lesions while resulting in only negligible systemic HDAC inhibition. 
Preclinical studies have demonstrated a role for histone deacetylase 1 and 2 (HDAC1/2) in 
modulating Gli1 transcription and basal cell carcinoma (BCC) growth in cell lines and mouse 
models. We conducted an open-label clinical trial of the pan-HDAC inhibitor, remetinostat, as a 
neoadjuvant treatment for basal cell carcinoma (BCC). Participants applied topical remetinostat 
1% gel three times per day under bandage occlusion to BCC(s) for six weeks prior to 
undergoing surgical excision. The primary outcome was overall response rate (ORR) as 
measured by at least a thirty percent decrease in BCC greatest diameter. In addition, tumor 
area was assessed as well as percent of tumors with complete response. Secondary objectives 
include suppression of Gli1 expression in post-treatment tumors and remetinostat tolerability. 
This trial has enrolled 17 BCCs tumors, ranging in baseline size from 6-25 mm greatest 
diameter, with enrollment goal of 30 tumors. Among the 14 BCCs that have completed the trial, 
the ORR is 64%. The longest tumor diameter of BCCs shrank by an average of 62%, and tumor 
area was reduced by an average of 70%. 43% (6) of tumors reached clinical resolution. Side 
effects associated with treatment included grade 1-2 eczematous reaction in 71% (10), and 
application site pain in 36% (5). Remetinostat gel for BCC offer a potentially effective, non-
surgical intervention for treatment of localized BCCs. 
HDAC inhibitors can suppress growth of SCC tumor xenografts 
In one study14, vorinostat was found to suppress the proliferation of epidermoid carcinoma cells 
in vitro.  Highly-immunosuppressed female athymic mice were injected with epidermoid 
carcinoma A431 cells; once tumors were palpable, vorinostat or placebo vehicle was injected 
intraperitoneally.  After three weeks, the mice were sacrificed and their tumors analyzed.  
Treated tumors demonstrated increased acetylation of histone H3 and p53 and apoptosis of 
tumor cells.  Consistent with this finding, histologic evaluation of treated tumors demonstrated 
large necrotic areas.  Further evaluation demonstrated that vorinostat inhibits cell cycle 
regulatory proteins (with notable reduction in the production of cyclins A (p = 0.002) and E 
(p = 0.015).  Expression of total and phosphorylated ERK, activation of which is known to 
regulate cell proliferation15, was also assessed.  Treatment with vorinostat resulted in significant 
reduction of ERK1/2 phosphorylation.  Additional anti-tumor effect is thought to be due to 


CONFIDENTIAL:   
IRB-49542  
Page 9 of 34 
19 July 2019 
Version # 1 
reduction in phosphorylation of Akt, resulting in reduction of mTOR and its downstream targets 
(S6 ribosomal protein, p70S6 kinase, and 4E-BP1)14.  
HDAC inhibitors are well-tolerated and have resulted in promising clinical responses in 
patients with advanced stage head and neck squamous cell carcinoma 
A phase 1 study of 26 patients with advanced stage head and neck SCCs of mixed etiology 
demonstrated similar to more-favorable safety and tolerability profiles when compared to 
pre-existing chemoradiation regimens that did not include a HCAC inhibitor.  While clinical 
response to therapy was not the primary endpoint of this phase 1 study, encouraging tumor 
responses were observed despite the subjects’ advanced-stage tumors16.  
Altogether, the preliminary data suggests HDAC inhibitors are a promising new candidate 
therapy for SCC.   
Remetinostat is a novel histone deacetylase inhibitor (HDACi) that was designed with a 
metabolically-labile ester bond so that topical application would produce effective local histone 
deacetylase (HDAC) inhibition in cutaneous lesions while resulting in only negligible systemic 
HDAC inhibition.  Remetinostat is rapidly degraded into primary metabolites SHP-100 and 
methylparaben.  Three studies (an in vitro Franz Diffusion Cell assay; a 28-day study in 
minipigs; and a 90-day study in minipigs) showed that uptake of remetinostat through skin into 
the systemic circulation was minimal.  In both dermal and intravenous (IV) studies in animals, 
remetinostat was metabolized in the blood rapidly to the primary metabolites.  These findings 
suggest that dermal application of remetinostat largely obviates systemic exposure to the HDAC 
inhibitor remetinostat and, consequently, sequelae from systemic inhibition of HDAC.  This 
observation was supported by the fact that in a Phase 1 study in patients with cutaneous T-cell 
lymphoma (CTCL), plasma concentrations of remetinostat were minimal and at or below the 
lower limit of quantitation of the assay indicating minimal systemic exposure.  The lack of 
measurable levels of remetinostat in blood is consistent with the rapid conversion of 
remetinostat to its metabolites. 
Remetinostat has been tested in a battery of safety pharmacology studies.  Remetinostat did 
not affect the functional observational battery (FOB) parameters in rats given IV doses of up 
100 mg/kg/day, which is equivalent to a dose of approximately 970 mg in a 60-kg human 
subject.  Remetinostat also did not inhibit human ether à-go-go-related gene (hERG) current 
in vitro at concentrations up to approximately 32,000 ng/mL and did not affect cardiovascular 
function in minipigs given IV doses of up to 100 mg/kg, which is equivalent to a dose of 
approximately 5,700 mg in a 60-kg human subject.  Based on the lack of effect observed in 
these studies, it was anticipated that remetinostat would be unlikely to adversely affect nervous 
system or cardiovascular system function when administered topically to humans.  This 
observation has been supported by the clinical data, to date. 
A program of Good Laboratory Practice (GLP) - compliant toxicity studies evaluated the safety 
of multiple doses of remetinostat administered IV to rats and administered topically to minipigs.  
In addition, the genotoxicity of remetinostat and the local tolerance and sensitizing potential of 
remetinostat and placebo gel solutions were assessed.  Remetinostat and placebo gel were 
tolerated, with only excipient-related local irritation when applied topically, and renal 
histopathologic changes not relevant in humans when administered IV.  The 28-day 
No-Observed-Adverse-Effect-Level (NOAEL) for remetinostat administered IV to rats was 


CONFIDENTIAL:   
IRB-49542  
Page 10 of 34 
19 July 2019 
Version # 1 
30 mg/kg/day.  When remetinostat gel 1.5% was applied topically in minipigs, the 28-day and 
90-day NOAEL of 150 μg/cm2 of skin yielded a total dose of approximately 6 mg/kg. 
Based on these findings, a phase 1 (SHP-141-001) study was conducted (NCT01433731) in 
18 patients with stage IA-IIA MF-CTCL.  This randomized, double-blind, placebo-controlled 
dose-escalating study was designed to evaluate the safety, pharmacokinetics and 
pharmacodynamics of remetinostat gel administered topically twice-daily up to 28 days in 
patients. Escalating doses of remetinostat gel, 0.1%, 0.5% and 1%, were administered BID for a 
maximum of 28 days to 3 cohorts of patients (n = 6 patients per cohort, active:placebo ratio 5:1). 
A phase 2, multicenter, open-label, randomized study (SHP-141-003, NCT02213861) to 
evaluate the efficacy and safety of remetinostat applied topically in 60 patients with stage IA to 
IIA MF-CTCL was completed in September 2016. Three doses of remetinostat were evaluated 
in three treatment arms (n = 20 per treatment arm, 1:1:1 randomization). The three dosing 
regimens of remetinostat (1% QD, 0.5% BID and 1% BID) were tested in this study for between 
6 to 12 months. 
All doses and schedules of remetinostat were well tolerated. There were three CTCAE 
Grade ≥3 remetinostat treatment related AEs, with 2/20 patients discontinuing treatment due to 
remetinostat related AEs, for the highest dose group of 1% gel BID (2/20 and 6/20 for the 
1% gel QD and 0.5% gel BID dose groups respectively).  There were no remetinostat treatment 
related systemic adverse events reported in either clinical study, which is consistent with the 
minimal systemic exposure and very short half-life of remetinostat in human blood. 
A phase 1 study in patients with psoriasis resulted in limited efficacy but the safety profile was 
similar to the MF-CTCL studies; no serious adverse events were seen on this study.   
Remetinostat is not currently approved by FDA for any use, and an Investigational New Drug 
application (IND) is required.  This protocol is submitted to IND 134521. 
2.3 
Rationale 
The severity of SCC burden differs widely among patients from those who develop early SCCs, 
have advanced SCC, or suffer from numerous SCC lesions.  In the more severely-affected, 
such as those who have undergone organ transplantation or are otherwise immunosuppressed, 
or those with extensive chronic sun exposure, their quality of life is severely affected by the 
need for frequent, repetitive surgical procedures.  Procedures can be time-consuming and 
expensive, and they inevitably produce scarring.  Other patients may have fewer tumor lesions, 
but they occur in cosmetically-disfiguring areas or near functional areas, where surgery is 
not ideal.  
SCCs are usually treated with surgical excision, with resultant scars that can be disfiguring.  
Several non-surgical treatments are sometimes utilized to treat SCC and SCC-IS.  Cryotherapy 
can be used for low-risk invasive cutaneous SCCs and SCC-IS, but is less effective than 
surgery and can be complicated by post-procedure hypopigmentation, hypertrophic scaring, or 
hair loss of the treated area17.  Photodynamic therapy (PDT) is an option for patients with 
non-invasive SCC, but is not a suitable option for invasive SCC given high recurrence rates17.  
Similarly, topical fluorouracil and imiquimod are both used to treat SCC-IS, especially amongst 
patients who refuse surgical treatment.  However, both of these uses are off-label and have 
significant inflammatory reactions that can cause patients to discontinue their use18,19.  For 
patients with SCCs in areas not suitable for surgical resection, for those who are not surgical 


CONFIDENTIAL:   
IRB-49542  
Page 11 of 34 
19 July 2019 
Version # 1 
candidates, or for tumors with significant perineural or large nerve involvement, radiation 
therapy can be considered20,21.  However, limitations exist with each of these non-surgical 
modalities.  Additionally, patients who develop multiple SCCs and/or tumors in sensitive areas 
would likely greatly benefit from additional non-surgical treatment options.  
Given the limitations of current treatment modalities and the pre-clinical murine and phase 1 
studies that demonstrate HDAC inhibitors impact the proliferation and survival of SCC cells, the 
topical HDAC inhibitor remetinostat is promising potential therapy for cutaneous SCCs. 
2.4 
Study Design 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
(see Section 10 for additional information) 
• 
The primary purpose of this study is:  
o To determine if 8 weeks of topical remetinostat gel applied TID under occlusion will 
suppress SCC growth 
o To determine the overall response rate (ORR) of SCCs after 8 weeks of treatment 
with topical remetinostat gel 1%, as measured by at least 30% decrease in greatest 
area (in mm2).   
• 
Subjects with at least 1 biopsy-proven cutaneous SCC will be recruited for this study.   
• 
Subjects will apply remetinostat gel 1% to at least 1 SCC.   
• 
Non-invasive cutaneous SCC lesions, including Bowen’s disease, are also eligible for this 
study 
• 
There is 1 treatment option:  Topical remetinostat gel 1% applied 3 times daily.   
• 
The study is a single-arm, open-label design 
• 
For purposes of ClinicalTrials.gov, there is no secondary outcome.  
2.5 
Correlative Studies Background 
There are no planned correlative studies. 


CONFIDENTIAL:   
IRB-49542  
Page 12 of 34 
19 July 2019 
Version # 1 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 
Participant Eligibility Checklist 
Participant Eligibility Checklist must be completed in its entirety for each subject prior to 
registration.  The completed, signed, and dated checklist must be retained in the subject’s study 
file and the study’s Regulatory Binder.   
The study coordinator, treating physician and an independent reviewer must verify that the 
participant’s eligibility is accurate, complete, and legible in source records.  A description of the 
eligibility verification process should be included in the EPIC or other Electronic Medical Record 
progress note.  
Protocol Title: 
A Phase 2 Open-label, Single-arm Trial to Investigate the Efficacy and 
Safety of Topical Remetinostat Gel as Neoadjuvant Therapy in Patients 
Undergoing Surgical Resection of Squamous Cell Carcinoma (SCC) 
Protocol Number: 
IRB-49542 / OnCore TBD 
Principal Investigator: Kavita Sarin, MD, PhD 
II.  Subject Information: 
Subject Name / ID: 
 
Gender:    
 Male     
 Female 
III.  Study Information: 
SRC-approved 
    IRB-approved 
   Contract signed 
   
Inclusion Criteria 
(From IRB-approved protocol) 
Yes No N/A 
Supporting 
Documentation* 
1 
Must have at least one cutaneous SCC or SCC in situ lesion 
greater than or equal to 5 mm.  Non-invasive SCC lesion(s), 
including (SCC-IS), are eligible, but must be amenable to 
surgical resection. 
 
 
 
 
2 
18 years of age or older 
 
 
 
 
3 
Must be willing to apply the topical remetinostat 3 times daily 
for 8 weeks and cover with an occlusive bandage. 
 
 
 
 
4 
Negative serum pregnancy test within 14 days prior to the first 
dose of study therapy [for women of child-bearing potential 
(WCBP), defined as a sexually mature woman who has not 
undergone a hysterectomy or who has not been naturally 
postmenopausal for at least 24 consecutive months (e.g., who 
has had menses any time in that period)] 
 
 
 
 
5 
Sexually-active women of child bearing potential and male 
patients with a female partner of child-bearing potential must 
agree to use acceptable methods of contraception to avoid 
pregnancy (e.g., oral;  injectable;  or implantable hormonal 
contraceptive;  tubal ligation;  intra-uterine device;  barrier 
contraceptive with spermicide;  or vasectomized male) before 
the 1st dose of study therapy and for 3 months after the 
last dose of study therapy 
 
 
 
 


CONFIDENTIAL:   
IRB-49542  
Page 13 of 34 
19 July 2019 
Version # 1 
Inclusion Criteria 
(From IRB-approved protocol) 
Yes No N/A 
Supporting 
Documentation* 
6 
Has signed and dated the current IRB-approved informed 
consent document 
 
 
 
 
 
Exclusion Criteria 
(From IRB-approved protocol) 
Yes No N/A 
Supporting 
Documentation* 
1 
Any large (> 20 mm) SCC lesion.  Patients with large SCC 
lesion(s) will be referred for evaluation for surgical resection. 
 
 
 
 
2 
Inoperable locally-advanced and/or non-cutaneous 
metastatic SCC 
 
 
 
 
3 
SCC lesion(s) in cosmetically-sensitive areas (e.g., tip of 
nose, eyelid).  If a prospective subject has SCC lesion(s) in 
other areas, those tumor(s) may be considered for 
enrollment. 
 
 
 
 
4 
Taking any medication known to affect SCC growth 
 
 
 
 
5 
Within the past 6 months, has used topical or systemic 
therapies that might interfere with the evaluation of the 
study medication during the study.  Specifically, these 
include the topical use at the site of the study tumors:   
o 
Glucocorticoids  
o 
Retinoids either systemically or topically at the tumor 
site (e.g., etretinate, isotretinoin, tazarotene, tretinoin, 
adapalene)  
o 
Alpha-hydroxy acids (e.g., glycolic acid, lactic acid) to 
the tumor site 
o 
5-fluorouracil or imiquimod:  -- 
 
 
 
 
6 
Has received treatment with systemic chemotherapy within 
60 days prior to starting study medication 
 
 
 
 
7 
Currently receiving systemic medications that could affect 
SCC tumors (e.g., oral retinoids) or might interact with 
remetinostat 
 
 
 
 
8 
Uncontrolled intercurrent illness including, but not limited to, 
ongoing or active infection, recurrent seizure history or 
psychiatric illness/social situations that would limit 
compliance with study requirements 
 
 
 
 
9 
Moderate to significant immunosuppression (e.g., active 
cancer, significant autoimmune disease) and/or receiving 
immunosuppressive drugs that result in moderate to 
significant immunosuppression (e.g., low dose oral 
glucocorticoids do not necessarily exclude a patient)  
 
 
 
 
10 
Known or previous hypersensitivity to HDACi 
 
 
 
 
11 
History of congestive heart failure, cardiac arrhythmias, or 
other findings of ventricular dysfunction 
 
 
 
 
12 
Pregnancy or breast-feeding 
 
 
 
 


CONFIDENTIAL:   
IRB-49542  
Page 14 of 34 
19 July 2019 
Version # 1 
IV.  Statement of Eligibility 
By signing this form of this trial, I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study.  This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
Investigator Signature: 
Date: 
Printed Name: 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
Tertiary Reviewer Signature: 
Date: 
Printed Name: 
 


CONFIDENTIAL:   
IRB-49542  
Page 15 of 34 
19 July 2019 
Version # 1 
3.2 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.  Participants must 
sign the IRB-approved informed consent prior to participation in any study-specific procedure.  
The participant must receive a copy of the signed and dated consent document.  The original 
signed copy of the consent document must be retained in the subject’s research file.   
3.3 
Randomization Procedures 
This study does not have randomization.  All subjects must at least have one cutaneous SCC 
lesion and will apply topical remetinostat to SCC(s).  If the subject has more than one SCC, a 
body map will remind subjects where to apply gel. 
3.4 
Study Timeline 
Primary Completion: 
The study will reach primary completion 18 months from the time the study opens to accrual.  
Individual subjects will reach primary completion 8 weeks after starting topical remetinostat 
treatment.  
Study Completion: 
The study will reach study completion 24 months from the time the study opens to accrual, 
e.g., allowing 6 months from Primary Completion for data analysis.  Individual subjects will 
complete the study about 14 to 18 weeks after starting topical remetinostat treatment 
(e.g., Screening; 8 weeks treatment; post-treatment visit and surgical excision at Week 10 to 14, 
4 weeks follow-up).   
4. 
TREATMENT PLAN 
Adult subjects in the clinic who have one or more biopsy-proven cutaneous SCC or SCC-in situ 
(hereafter referred to as “SCC”) lesions greater than or equal to 5 mm in diameter, at least one 
of which is being biopsied as a normal course of care, will be invited to participate in this trial.  
Eligibility of prospective participants will be confirmed, and subjects will enroll according to 
stated inclusion and exclusion criteria. 
Screening visits may be combined with or without day 1 visit.   
Prospective participants must be willing to sign a consent form.  Subjects will also give consent 
to donate their SCC tissue for biomarker measurement and apply medication 3-times daily 
under bandage occlusion for 8 weeks.  The anticipated bandage will be an adhesive bandage 
(e.g., “Band-Aid”) with a non-adherent dressing, or paper tape with a non-adherent dressing. 
Drug treatment:  Subjects will be instructed to apply topical remetinostat to individual SCCs 
3-times daily (TID) for 8 weeks.  Patients will be asked to discontinue application of the 
medication at 8 weeks, approximately 2 weeks prior to their surgical excision(s), as dermal 
irritation from study drug may interfere with lesion identification at excision.  
At least 1 target SCC will be identified requiring surgical excision per standard of care.  In 
addition to being measured and photographed, this lesion(s) may be biopsied.  Week 8 biopsy 
may be collected at the time of surgical excision of lesion(s).  Histopathological evaluation of the 
specimen may be performed. 


CONFIDENTIAL:   
IRB-49542  
Page 16 of 34 
19 July 2019 
Version # 1 
After an initial treatment application demonstration by the study team, treatment applications will 
be self-administered by the subject or a caregiver.  Patients will receive oral and written 
administration instructions at the outset of the trial as follows: 
“Study medication is to be applied to dry skin.  Apply the study medication to the SCC 
lesion(s) designated by your physician, 3 times daily for 8 weeks, using clean washed 
finger(s)/ hand as applicable.  Cover the treated SCC lesions(s) with a sticky strip bandage, 
such as a Band-Aid.  If you start to treat new lesions or stop treating any lesion, please 
inform your physician so a record can be kept of which lesions are being treated with study 
medication.  There is no need to leave large amounts of residue on your skin.  If someone 
else helps apply the study medication, they should follow the same instructions.  
Immediately following application, wipe the finger(s) and hands you have used to apply the 
study drug with a disposable tissue and wash your hands using soap and water.  If the study 
medication gets on the skin of other people, they should wash with soap and water.  
Alternatively, you or a caregiver can wear disposable gloves to apply the study medication, 
which will be supplied to subject on request.” 
Diary:  after an initial explanation by the study team at the first visit, patients will be requested to 
fill out a medication diary to document application of the study drug (see Appendix A.)  Patients 
will be requested to fill this out daily and requested to bring their diary with them to each study 
visit for review by the study team. 
Tumors to be treated will be clearly identified.  Patients will be instructed to store research 
medication in a refrigerator (see Appendix B).  Patients will be offered a small portable 
medication cooler to utilize to keep their study drug cold.  
All tumors will be measured and photographed at baseline, 4 weeks and after applying 
remetinostat for 8 weeks (at the Week 10 visit).  
Paper case report forms will be used to capture source data for this study.  A physician note will 
also be entered into Stanford’s electronic medical record system for each of the study visits. 
Patients may be contacted periodically to check on compliance and to follow up on AEs.  
Additional clinic visit(s) may be scheduled to assess AEs. 
Given the absence of any remetinostat treatment related systemic AEs, together with the lack of 
effect on laboratory parameters or EKG, the minimal levels of remetinostat detected 
systemically reported in clinical studies to date, and the small BSA (< 0.5%) that will be treated 
with remetinostat gel, no lab assessments will be performed with the exception of a serum 
pregnancy test for women of child-bearing potential at baseline to assess eligibility for 
enrollment.  
It is anticipated that the entire target tumor(s) will be surgically removed after the 8th week of 
treatment, in accordance with regular medical care; it is estimated that the surgical excision will 
occur between Weeks 10 to 14, depending on surgeon availability.  A dose of remetinostat will 
be applied to the SCC by study personnel in clinic 30 mins before surgical excision.  If surgical 
excision is delayed, i.e., does not occur at Week 10, remetinostat application may be continued 
for up to 4 additional weeks until surgical excision.  
A follow-up visit will occur between Weeks 12 to 18 (approximately 2 to 4 weeks after 
Mohs/surgical excision), which may be in conjunction with surgery or a surgical follow-up visit, 


CONFIDENTIAL:   
IRB-49542  
Page 17 of 34 
19 July 2019 
Version # 1 
or the visit may be conducted by phone. Patients may be contacted after completion of the 
study for additional follow up if deemed necessary by the Study Doctor. 
SCC tissue biopsies will be collected from those who consent at baseline and Week 10 to 
evaluate the tumors treated with topical remetinostat gel 1%.  The SCC biopsy will be collected 
in RNA later. 
4.1 
General Concomitant Medication and Supportive Care Guidelines 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a subject between 1 month preceding the screening evaluation and the end of study 
visit. 
Subjects who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy will continue their use.  All concomitant medications will be reported to the investigator 
and recorded on the appropriate CRF. 
4.2 
Criteria for Removal from Study 
The trial will be terminated in the event of an SAE (Serious Adverse Event) related to the 
intervention.  A Serious Adverse Event is any of the following:   
• 
Fatal (i.e., the AE actually causes or leads to death).   
• 
Life-threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death).  It does not include an AE that, had it occurred in a more 
severe form, might have caused death (life-threatening does not include events such as 
blood values that do not by themselves represent an immediate risk of death).  
• 
Requires or prolongs inpatient hospitalization.   
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions).   
• 
Any occurrence considered by the investigator to be a significant medical event 
(e.g., may jeopardize the subject or may require medical/surgical intervention to prevent 
one of the medical outcomes listed above).  All AEs that do not meet any of the criteria 
for serious should be regarded as non-serious AEs.   
The investigator will use the following definitions to assess the relationship of the adverse event 
to the use of the study drug:   
• 
Probably-related:  An adverse event has a strong temporal relationship to the study 
drug or recurs on re-challenge and another etiology is unlikely or significantly less likely.   
• 
Possibly-related:  An adverse event has a strong temporal relationship to the study 
drug and an alternative etiology is equally or less likely compared the potential 
relationship to study drug.   
• 
Probably Not Related:  An adverse event has little or no temporal relationship to the 
study drug and/or a more likely alternative etiology exists. 
• 
Not Related:  An adverse even is due to an underlying or concurrent illness or effect of 
another drug and is not related to the study drug. 


CONFIDENTIAL:   
IRB-49542  
Page 18 of 34 
19 July 2019 
Version # 1 
Subjects may be removed from the study because of subject wishes, non-compliance, or 
development of any medical condition that puts the subject at increased risk, in the opinion of 
the investigator.   
The investigator has the right to discontinue a patient from study drug or withdraw a patient from 
the study at any time.  In addition, patients have the right to voluntarily discontinue study drug or 
withdraw from the study at any time for any reason.  Reasons for discontinuation of study drug 
or withdrawal from the study may include, but are not limited to, the following:   
• 
Any subject who presents at screening or during treatment with a large (> 20 mm) SCC 
lesion:  such a lesion will be discontinued from treatment (if applicable) and referred for 
evaluation for surgical resection.  (If the patient has other, smaller lesions, these smaller 
lesions may be considered for enrollment in the study.) 
• 
Subject withdrawal of consent at any time   
• 
Any medical condition that the investigator or Sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study   
• 
Investigator determines it is in the best interest of the patient   
• 
Surgical or other treatment of target SCC before Week 8 
• 
Pregnancy  
4.3 
Alternatives 
Alternatives to participation in the study include participating in a different clinical study, 
receiving medical care outside of a research study (including immediate surgical treatment), or 
no treatment. 
5. 
INVESTIGATIONAL DRUG INFORMATION 
5.1 
Investigational Drug  
Remetinostat is also known as suberohydroxamic acid phenyl ester (SHAPE); SHAPE Gel;  
SHP-141; and 4-[[8-(hydroxyamino)-1,8-dioxooctyl]oxy]-benzoic acid methyl ester.  
Remetinostat is a histone deacetylase inhibitor (HDACi) that was designed with a 
metabolically-labile ester bond so that topical application would produce effective local histone 
deacetylase (HDAC) inhibition in cutaneous lesions while resulting in only negligible systemic 
HDAC inhibition.  
In this single-arm study, remetinostat is formulated at a strength of 1.0% in a gel consisting of 
dehydrated alcohol; propylene glycol; hexylene glycol; glycerin; oleyl alcohol; 
diisopropyl adipate; hydroxypropylcellulose; butylated hydroxytoluene and citric acid 
(anhydrous). The overall concentration of ethanol in the gel is approximately 50% (w/w). The 
primary packaging for remetinostat gel is aluminum tubes with plastic screw-on caps. The 60-g 
tubes are packaged in paper cartons (both labeled with identical labels). 
See the remetinostat Investigator Brochure for additional information including the mechanism 
of action; summaries of animal and clinical studies; non-clinical and clinical pharmacokinetic; 
major route of elimination; safety profile; and the non-clinical and clinical data supporting the 
dose and regimen chosen for this study. 


CONFIDENTIAL:   
IRB-49542  
Page 19 of 34 
19 July 2019 
Version # 1 
5.2 
Availability 
Medivir AB is providing drug for this study. 
5.3 
Agent Ordering 
Remetinostat will be ordered by the Principal Investigator and shipped directly to the Stanford 
Dermatology Clinic, where it will be stored per manufacturer’s guidelines and Stanford SOPs.  
Investigational drug will not be shipped to or held by Stanford Investigational Drug Services.  
The contact for drug ordering is: 
Medivir AB  
Box 1086 
141 22 Huddinge, Sweden 
Tel:  +46(0)8-5468 31 00 
E-mail:  Torbjorn.larsson@medivir.com  
5.4 
Storage Conditions 
The Investigator is responsible for the control of the drug under investigation.  The study agent 
will be kept in a locked refrigerator (2 to 8ºC) in a secure area.  Only trained research staff will 
have access to the locked refrigerator.   
5.5 
Agent Accountability 
Adequate records for the receipts (e.g., Drug Receipt Record) and disposition (eg, Drug 
Dispensing Log) of the study drug will be maintained.  Accountability and subject compliance 
will be assessed by maintaining adequate “drug dispensing” and return records. 
Accurate records must be kept for each study drug provided by the Sponsor.  These records 
must contain the following information:   
• 
Documentation of drug shipments received from the Sponsor (date received, quantity, 
and tube number)  
• 
Disposition of unused study drug not dispensed to subject  
A Drug Dispensing Log will be kept current and will contain the following information:   
• 
The identification of the subject to whom the study medication was dispensed  
• 
The date(s), quantity, and kit number of the study medication dispensed to the subject.   
• 
The date(s), quantity and kit number of the study medication returned by the subject  
Subjects will be asked to return all used and unused drug supply containers during and at the 
end of the treatment.  
The investigational product will be returned to the Sponsor for disposal, or with the agreement of 
the drug manufacturer, destroyed in accordance with institutional SOPs. 
6. 
DOSE MODIFICATIONS 
Detectable systemic levels of remetinostat after topical application for 8 weeks are not 
anticipated.  Treatment with topical remetinostat may be interrupted or dose modified as 
detailed below.  Subjects who require discontinuation of treatment for any reason will go 


CONFIDENTIAL:   
IRB-49542  
Page 20 of 34 
19 July 2019 
Version # 1 
off-study.  The Study Doctor will assess and determine if an individual subject needs to be taken 
off the study due to side effects.   
6.1. 
Dose Modifications due to Toxicity and Stopping Criteria 
Patients experiencing any treatment-related Grade 3 or higher local dermal irritation will be 
required to have their treatment exposure suspended until the irritation reduces to at least 
Grade 2.  Guidelines for dose reduction, interruption and discontinuation are provided below: 
Table 1:  Dose Modification 
Grade of 
Local Dermal 
Irritation 
Defining 
Clinical Signs 
Proposed Treatment Modification 
0 (No 
Reaction) 
None 
No action required; observation 
1 (Mild) 
Definite pink to 
red coloration 
2 (Moderate) 
Increased 
redness, with or 
without edema 
3 
(Moderately 
Severe) 
Very red, with 
edema and 
vesiculation 
Treatment must be suspended until irritation improves to 
Grade 2 or lower (this must occur within 2 weeks).  After 
the irritation improves to Grade 2 or lower, treatment may 
be re-started, initially TID every second day, then 
increased to TID daily, if tolerated.  If dermal irritation does 
not improve to Grade 2 or lower after 2 weeks, treatment 
should be discontinued, and the patient withdrawn.  If 
event re-occurs, consider discontinuation of treatment. 
4 (Severe) 
Deep red, 
swelling and 
edema with 
bullae 
formation and 
necrosis 
Treatment must be suspended until irritation improves to 
Grade 2 or lower (this must occur within 2 weeks).  After 
the irritation improves to Grade 2 or lower, treatment may 
be re-started, initially TID every second day, then 
increased to TID daily, if tolerated.  If dermal irritation does 
not improve to Grade 2 or lower after 2 weeks, treatment 
should be discontinued, and the patient withdrawn.  If 
event re-occurs, consider discontinuation of treatment. 
Treatment may be stopped approximately 2 weeks before surgical excision if the PI determines 
that local dermal irritation may interfere with lesion identification at excision. 
Based on remetinostat safety data collected to date in earlier MF-CTCL studies, systemic 
adverse events are not anticipated. 
In the unlikely event that a patient experiences any systemic AE which is consistent with the 
effects of systemic HDAC inhibition, such as diarrhea or thrombocytopenia and the AE is 
considered possibly related to treatment with remetinostat gel, their treatment will be modified, 
as follows: 


CONFIDENTIAL:   
IRB-49542  
Page 21 of 34 
19 July 2019 
Version # 1 
Thrombocytopenia CTC Grade 2 (platelet count ≥ 50 to ≤ 75 x 109/L):  Reduce treatment 
frequency of remetinostat gel to BID every second day. Recommence TID daily treatment once 
platelet count reaches ≥ 75 x 109/L.  If platelet count does not recover after 2 weeks’ every 
2nd day dosing, suspend treatment until platelet count reaches ≥ 75 x 109/L (maximum period of 
treatment suspension is 4 weeks). 
Thrombocytopenia CTC Grade ≥ 3 (platelet count ≤ 50 x 109/L):  Treatment must be 
discontinued for up to 4 weeks, by which time treatment must be permanently discontinued if 
the platelet count does not recover to ≥ 75 x 109/L.  On recovery of platelet count to 
≥ 75 x 109/L, treatment with remetinostat should initially be re-started BID every second day and 
then increased to BID daily application if tolerated. If event re-occurs, consider discontinuation 
of treatment. 
Diarrhea CTC Grade 1, an increase of < 4 stools per day over baseline; mild increase in 
ostomy output compared to baseline:  Reduce treatment frequency of remetinostat gel to 
every second day.  Recommence BID daily treatment once diarrhea has resolved/returned to 
baseline status.  If diarrhea does not recover after 4 weeks’ every second day BID dosing, 
suspend treatment until diarrhea has resolved/returned to baseline status (maximum period of 
treatment suspension is 4 weeks). 
Diarrhea CTC Grade ≥ 2, an increase of 4 to 6 stools per day over baseline;  moderate 
increase in ostomy output compared to baseline;  limiting instrumental activities of daily 
life (ADL):  Treatment must be discontinued for up to 4 weeks, by which time treatment must be 
permanently discontinued if diarrhea does not resolve/recover to baseline status. Once diarrhea 
has recovered/returned to baseline status, treatment with remetinostat should initially be 
re-started BID every second day and then increased to BID daily application if tolerated.  If 
event re-occurs, consider discontinuation of treatment. 
If a patient lesion grows by 30% at the 4 week observation point, the patient would be directed 
to surgery instead of continued therapy on trial. 
If 50% of total lesions being treated per protocol have grown, we would stop the study early.  
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
Slight irritation of the skin was observed in some animal studies and was likely related to the 
ethanol in the formulation.  
Escalating doses of remetinostat gel were administered to different cohorts of patients to assess 
safety and tolerability in a Phase 1 study in patients with CTCL.  A total of 18 patients with 
CTCL were sequentially enrolled into one of three study cohorts consisting of six patients each.  
Within each study cohort of six patients, 5 were randomly assigned to receive remetinostat gel 
and 1 was randomly assigned to receive placebo.  Patients received treatment for a maximum 
of 28 days.  Three dose levels of remetinostat gel were evaluated at 0.1%, 0.5% and 1%.   
The study drug was well-tolerated.  Eight patients, including one who received placebo, 
experienced 11 treatment-related adverse events.  The adverse events consisted of a skin 
burning or warming sensation, paraesthesia, and contact dermatitis and were all related to 
topical application of study drug to the index lesion treatment sites.  Ten of the treatment-related 


CONFIDENTIAL:   
IRB-49542  
Page 22 of 34 
19 July 2019 
Version # 1 
adverse events were mild (Grade 1) and one event (contact dermatitis) was Grade 2.  Only the 
Grade 2 event of contact dermatitis required treatment, for which topical steroid and moisturizer 
were applied after the patient completed the 28-day course of remetinostat gel treatment, which 
resolved.  All treatment-related adverse events had resolved prior to the Day 42 End-of-Study 
visit. 
There were no hematological findings among the 18 treated patients.  Among the 5 clinical 
laboratory changes reported as adverse events and the 4 clinical laboratory values that reached 
≥ Grade 2, none was related to study drug administration. 
For the phase 2 study, 60 patients were randomised in a 1:1:1 ratio to three treatment regimens 
of remetinostat gel (1% QD, 0.5% BID and 1% BID).  Patients received treatment for 6 months 
and could continue on treatment for a further 6 months (12 months in total) if they received 
clinical benefit during the first 6-month period. 
Remetinostat gel at dosing regimens of 1% QD, 0.5% BID and 1% BID was generally well 
tolerated, with no reports of adverse events associated with systemic HDAC inhibitors. There 
were 2 SAEs (acute heart failure and fracture), observed during the study, considered unrelated 
to treatment with remetinostat. 
The most common adverse events were pruritus and skin irritation.   
Approximately half of the patients in each group reported AEs considered related to treatment; 
4 of these met CTCAE Grade ≥ 3 for severity and all were skin-related:  The rate of 
discontinuations due to treatment-related AEs was low, with no indication of a higher rate in the 
highest (1% BID) dose group. Overall, the patients who had dose reduction/interruptions due to 
remetinostat related skin AEs in the 1% BID dose group stayed on treatment for a long time. 
The CTC Grade 3 events resolved, patients wanted to stay on treatment despite these AEs 
(except for a single patient) and most of the patients (4 of 6) in this highest dose group who 
remained on drug for > 6 months received benefit, in terms of objective CAILS and/or pruritus 
responses. 
In the current study, skin will be carefully evaluated during treatment.  Patients who develop 
contact dermatitis caused by the strip bandage adhesive per PI determination may discontinue 
bandage use. 
No systemic abnormalities were found at any dose level in the nonclinical studies and no 
treatment-related observations other than those above were noted in any clinical trial.  Thus, no 
special precautions are anticipated. 
The effect of remetinostat in pregnancy has not been studied.  Similarly, excretion of 
remetinostat into breast milk has not been examined.  Therefore, pregnant and lactating women 
are excluded from clinical trials at this time. 
Remetinostat is considered unlikely to be a photo-irritant as remetinostat absorbs light at a 
maximum of 234 nm in the UV/visible spectrum and does not meaningfully absorb light above 
290 nm.  Photo-irritation has not been observed in clinical trials of remetinostat gel.  There is no 
information to indicate that abuse or dependency would occur with exposure to remetinostat gel.  
Detectable systemic levels of remetinostat after topical application are not anticipated.   
See the Investigator Brochure for details on AEs captured to date from CTCL study. 


CONFIDENTIAL:   
IRB-49542  
Page 23 of 34 
19 July 2019 
Version # 1 
7.2 
Adverse Event Reporting 
For guidance on reporting adverse events, refer to the Stanford Cancer Institute Clinical 
Trials Office Adverse Event SOP.  
Adverse events will be graded according to CTCAE v5.0.  Both Serious and Non-Serious 
Adverse Events will be clearly noted in source documentation and listed on study specific Case 
Report Forms (CRFs).  The Protocol Director (PD) or designee will assess each Adverse 
Event (AE) to determine whether it is unexpected according to the Investigator’s Brochure 
and/or protocol and related to the a) study drug or b) the investigation.  All Serious Adverse 
Events (SAEs) will be tracked until resolution or until 30 days after the last dose of the study 
treatment.  
All AE and SAEs will be reported to the Principal Investigator.  The Stanford Cancer Institute 
Data and Safety Monitoring Committee (DSMC) will be informed of all SAEs.  An AE is any 
unfavorable and unintended sign, symptom, or disease temporally associated with the use of an 
investigational medicinal product (IMP) or other protocol-imposed intervention, in this study 
topical remetinostat, regardless of attribution.  This includes the following:  AEs not previously 
observed in the subject that emerge during the protocol specified AE reporting period, 
complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies); and preexisting medical conditions judged by the investigator to 
have worsened in severity or frequency or changed in character during the protocol-specified 
AE reporting period. 
SAEs CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to the 
Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the 
study-specific CRF regardless of the event’s relatedness to the investigation.  Following review 
by the DSMC, events meeting the IRB definition of ‘Unanticipated Problem’ will be reported to 
the IRB using eProtocol within 10 working days of DSMC review, or within 5 working days for 
deaths or life-threatening experiences. 
Female patients of childbearing potential will be instructed to immediately inform the investigator 
if they become pregnant during the study or within 3 months after the last application of study 
drug.  The investigator will discontinue study drug and counsel the patient, discussing the risks 
of the pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any SAEs associated with the pregnancy 
(eg, an event in the fetus;  an event in the mother during or after the pregnancy;  or a congenital 
anomaly/birth defect in the child) will be reported per Stanford SOPs.  
Male patients will be instructed to immediately inform the investigator if their partner becomes 
pregnant during the study or within 3 months after the last application of study drug.  
8. EXPLORATIVE / CORRELATIVE / SPECIAL STUDIES  
None.   


CONFIDENTIAL:   
IRB-49542  
Page 24 of 34 
19 July 2019 
Version # 1 
9. STUDY CALENDAR 
  
Pre-treatment 
Day -2 to -30 
Pre-treatment 
Day -1 
Treatment 
Day 1 
Treatment 
Week 4  
(+/- 1 week) 
Week 10 
Visit* 
(+ 4 weeks) 
Follow-up 
Week 12-18*
* 
Early 
termination 
Remetinostat 
treatment 
 
 
X 
X 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Concurrent meds 
X------------------------------------------------------------------------------------------------------► 
Physical exam 
X 
X 
 
X 
X 
 
X 
Vital signs 
X 
X 
 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
X 
 
X 
ECOG score 
X 
 
 
X 
X 
 
X 
Serum pregnancy test  
X 
 
 
 
 
 
 
Adverse event 
evaluation 
 
 
X---------------------------------------------------------------------► 
Tumor measurements 
and photographs 
 
X 
 
X 
X 
 
X 
Tumor Biopsy  
 
X 
 
 
(X) 
 
Patient Calls 
 
 
X-----------------------------------------------► 
 
*Week 10 visit may occur between weeks 10-14, depending on surgeon availability. Study drug will be applied for 8 weeks in total; if 
surgical excision is delayed, the study drug may be applied for up to 4 additional weeks (for a total of up to 12 weeks)  
 
**Follow up visit or phone call will occur between weeks 12-18 (approximately 2-4 weeks after Mohs/surgical excision)


CONFIDENTIAL:   
IRB-49542  
Page 25 of 34 
19 July 2019 
Version # 1 
10. 
MEASUREMENTS 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
10.1 Primary Outcome  
Title:  Overall Response Rate (ORR) 
Description:  The primary objective of this study is to determine if topical remetinostat will 
reduce squamous cell carcinoma (SCC) tumor size (measured in mm2).  Tumors will be 
measured with calipers throughout the study.  The associated outcome is reported as the 
number of tumors who achieve a partial response (PR) or complete response (CR), and 
overall response (OR).  CR and PR are defined below, and OR is the sum of PR and CR. 
• CR = undetectable tumor lesion(s).   
• PR = ≥ 30% decrease in total tumor area. 
Timeframe:  Up to 10 weeks 
Safety Outcome?:  No 
10.1.1 Relevant Subset 
All tumors with study drug application at 80% compliance and above will be included in analysis.  
10.1.2 Measurement Definition 
Tumor size will be measured by measuring the tumor with calipers at study visits week 0, 4, and 
8.  
10.1.3 Measurement Methods 
Tumor size will be measured with calipers and will be recorded in millimeters. 
10.1.4 Measurement Time Points 
Tumor size will be measured at study visits week 0, 4, and 8.  
10.1.5 Response Review 
The primary outcome (tumor size) is measured in real time by a physician during the clinic visit; 
no radiologic images are obtained for later review in this study. 
10.2 
Secondary Outcomes  
10.2.1 Overall Adverse Events (AEs) 
Title:  Overall Adverse Events (AEs) 
Description:  Participants will be monitored for adverse events (AEs) throughout the study 
period.  The outcome will be reported as the number of participants who experience any AE, 
serious or non-serious, a number without dispersion. 
Timeframe:  Up to 10 weeks 
Safety Outcome?:  Yes 
10.2.2 Serious Adverse Events (SAEs) 
Title:  Serious Adverse Events (SAEs) 


CONFIDENTIAL:   
IRB-49542  
Page 26 of 34 
19 July 2019 
Version # 1 
Description:  Participants will be monitored for serious adverse events (SAEs) throughout 
the study period.  The outcome will be reported as the number of participants who 
experience any SAE, a number without dispersion. 
Timeframe:  Up to 10 weeks 
Safety Outcome?:  Yes 
10.2.3 Adverse Event-related Treatment Discontinuation or Interruption 
Title:   Adverse Event-related Treatment Discontinuation or Interruption.  
Description:  Incidence of AEs leading to remetinostat discontinuation or interruption.  
Participants will be monitored for adverse events (SAEs) throughout the study period, and 
the relationship of remetinostat discontinuation or interruption to adverse events will be 
evaluated for all remetinostat discontinuation or interruption.  The outcome will be reported 
as the number of participants who discontinued remetinostat or experienced treatment 
interruption due to an adverse event, a number without dispersion. 
Timeframe:  Up to 10 weeks 
Safety Outcome?:  Yes 
10.2.4  
Title:  Treatment Schedule Compliance 
Description:  Participant adherence to the treatment schedule will be assessed as the 
number of patients who discontinue the treatment, or experience treatment interruption, for 
any reason.  The outcome will be reported as a number without dispersion. 
Timeframe:  Up to 10 weeks 
Safety Outcome?:  Yes 
11. 
REGULATORY CONSIDERATIONS 
11.1 Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to 
the study (eg, advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes 
made to the protocol will be submitted as a modification and will be approved by the IRB prior to 
implementation.  The Protocol Director will disseminate the protocol amendment information to 
all participating investigators. 
11.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study.  The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  This may include review of the 
following types of documents participating in the study:  regulatory binders, case report forms, 
eligibility checklists, and source documents.  In addition, the DSMC will regularly review serious 
adverse events and protocol deviations associated with the research to ensure the protection of 


CONFIDENTIAL:   
IRB-49542  
Page 27 of 34 
19 July 2019 
Version # 1 
human subjects.  Results of the DSMC audit will be communicated to the IRB and the 
appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as 
needed.  
11.3 
Data Management Plan 
The Protocol Director, or a designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study-specific case 
report forms (CRFs) will be developed to document treatment outcomes for data analysis.  
These CRFs will initially be developed on paper forms by the study coordinator but may 
transition to electronic forms (ie, in OnCore or RedCap).  Subject charts will be kept in a locked 
office, only accessible to the research team.  
12. 
STATISTICAL CONSIDERATIONS 
Shufeng Li, MS, is the statistician for this clinical trial.  
12.1 
Statistical Design 
The Primary Objective and Primary Outcome of this study is to determine if topical remetinostat 
will reduce SCC tumor size, as defined by at least 30% decrease in SCC tumor area (in mm2) at 
end of study as compared with baseline.  Complete response (CR) will be defined as no 
clinically detectable tumor at EOS.  ORR is defined as the proportion of tumors with either a 
complete response or a partial response (PR) among all eligible and treated lesions.  Exact 
binomial 90% confidence intervals (CIs) will be computed for the ORR.  With a planned analysis 
on 30 per-protocol SCCs, this study should provide 91% power to reject an ORR of 15% if the 
true ORR is 40% or better, at one-sided-alpha level of 0.05 with at least 9 responders.  
12.1.1 Randomization 
Not applicable, as this is a single-arm trial.  
12.2 
Interim analyses 
None planned 
12.3 
Descriptive Statistics and Exploratory Data Analysis 
The baseline characteristics of study subjects (age; gender; skin type; number of tumors;  
average size of tumors;  tumor location;  tumor histology;  and prior treatments) will be 
summarized in tables.  Wilcoxon signed rank tests for continuous variables and chi-square tests 
for dichotomous variables will be used.  CONSORT guidelines will be followed to describe the 
number of subjects screened; enrolled; and completed the treatment.  All AEs will be described 
in tabular format. 
12.4 Primary Analysis 
The primary endpoint is the overall response rate of SCC lesions as defined by at least 
30% decrease in tumor area at EOS as compared to baseline.  Note:  RECIST v1.1 criteria 
have limited utility for SCCs under 10 mm, and will not be used for that reason. 
12.4.1 Analysis Population 
We will first analyze the data by intention to treat analysis and then per-protocol analysis by only 
including tumors ≥ 80% compliant with drug treatment.  Tumors with 79% or less compliant with 


CONFIDENTIAL:   
IRB-49542  
Page 28 of 34 
19 July 2019 
Version # 1 
drug treatment will be reported as a deviation; tumors at least 80% compliant with drug 
treatment will not be recorded as a deviation. Patients will be instructed to use a band-aid or 
other form of occlusion. If the patient has difficulty with band-aid usage, the patient may stop 
and this will be documented.  
For subjects who drop out, we will use data from their last study visit if they contribute a biopsy.  
The analysis population will include participants who have consented to undergo remetinostat 
treatment and who have at least 1 SCC tumor.   
Safety analyses will include all subjects who received at least one dose of study treatment.  
Graded AEs (number and percent) will be summarized and reported according to the NCI 
CTCAE v5.0. 
12.4.2 Analysis Plan 
We will analyze the overall response rate of SCC based on the change in tumor area.  Objective 
response rate (ORR) will be defined as the proportion of tumors with either a complete response 
or a partial response (PR) among all eligible and treated tumors.  Toxicities will be graded 
according to the National Cancer Institute CTCAE v5.0.  Exact binomial 90% confidence 
intervals (CIs) will be computed for the ORR.  With a planned analysis on 30 per-protocol SCCs, 
this study would provide 91% power to reject an ORR of 15% if the true ORR is 40% or better, 
at one-sided alpha level of 0.05 with at least 9 responders. 
12.5 Secondary Analysis 
12.5.1 Analysis Population 
Data from all enrolled patients will be included in the below safety evaluations.  
12.5.2 Analysis plan  
For Secondary Objective 1, toxicities will be graded according to the National Cancer Institute 
CTCAE v5.0.   
The safety of remetinostat when applied topically for 8 weeks will be assessed as follows: 
• 
Incidence, type, and severity of adverse events (AEs)  
• 
Incidence and nature of serious adverse events (SAEs)  
• 
Incidence of AEs leading to treatment discontinuation or interruption  
• 
Adherence to the treatment, measured by number of patients discontinuing the treatment 
(for any reason) and treatment interruptions  
12.6 
Sample Size 
12.6.1 Overall Accrual estimates 
Subjects will be enrolled from Stanford Dermatology (Adult) clinic which sees approximately 
4,000 dermatology patients per month (or 48,000 visits per year).  Approximately 20% of these 
patients have current or past skin cancer.  Enrollment of SCC subjects for Stanford clinical trials 
has been rapid.  30 per-protocol SCC lesions are anticipated to be evaluated within the first 
12 months.  We will only advertise and enroll from Stanford Dermatology clinic.  It is anticipated 
that at least 10 subjects will consent to baseline and post-treatment biopsies.   


CONFIDENTIAL:   
IRB-49542  
Page 29 of 34 
19 July 2019 
Version # 1 
12.6.2 Sample size justification 
For primary objective analysis, with a planned analysis on 30 per-protocol SCCs, this study 
would provide 91% power to reject an ORR of 15% if the true ORR is 40% or better, at 
one-sided alpha level of 0.05 with at least 9 responders. 
12.6.3 Effect size justification 
This is a single-arm (non-randomized) study of topical remetinostat.  SCCs are not anticipated 
to self-regress in the absence of any treatment. 
12.7 
Criteria for future studies 
If topical remetinostat reduces SCC size, it is anticipated that a larger, randomized, controlled 
trial will be proposed. 


CONFIDENTIAL:   
IRB-49542  
Page 30 of 34 
19 July 2019 
Version # 1 
13. 
REFERENCES 
1. 
Miller DL, Weinstock MA. Nonmelanoma skin cancer in the United States: incidence. J 
Am Acad Dermatol. May 1994;30(5 Pt 1):774-778. 
2. 
Kraft S, Granter SR. Molecular pathology of skin neoplasms of the head and neck. Arch 
Pathol Lab Med. Jun 2014;138(6):759-787. 
3. 
Guo HR, Yu HS, Hu H, Monson RR. Arsenic in drinking water and skin cancers: cell-
type specificity (Taiwan, ROC). Cancer Causes Control. Dec 2001;12(10):909-916. 
4. 
Karagas MR, Stukel TA, Morris JS, et al. Skin cancer risk in relation to toenail arsenic 
concentrations in a US population-based case-control study. Am J Epidemiol. Mar 15 
2001;153(6):559-565. 
5. 
Pedersen SA, Gaist D, Schmidt SAJ, Holmich LR, Friis S, Pottegard A. 
Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-
control study from Denmark. J Am Acad Dermatol. Apr 2018;78(4):673-681 e679. 
6. 
Housman TS, Feldman SR, Williford PM, et al. Skin cancer is among the most costly of 
all cancers to treat for the Medicare population. J Am Acad Dermatol. Mar 
2003;48(3):425-429. 
7. 
Burton KA, Ashack KA, Khachemoune A. Cutaneous Squamous Cell Carcinoma: A 
Review of High-Risk and Metastatic Disease. Am J Clin Dermatol. Oct 2016;17(5):491-
508. 
8. 
Celebi AR, Kiratli H, Soylemezoglu F. Evaluation of the 'Hedgehog' signaling pathways 
in squamous and basal cell carcinomas of the eyelids and conjunctiva. Oncol Lett. Jul 
2016;12(1):467-472. 
9. 
Tsai KY, Tsao H. The genetics of skin cancer. Am J Med Genet C Semin Med Genet. Nov 
15 2004;131C(1):82-92. 
10. 
Lee CS, Bhaduri A, Mah A, et al. Recurrent point mutations in the kinetochore gene 
KNSTRN in cutaneous squamous cell carcinoma. Nat Genet. Oct 2014;46(10):1060-
1062. 
11. 
Wang NJ, Sanborn Z, Arnett KL, et al. Loss-of-function mutations in Notch receptors in 
cutaneous and lung squamous cell carcinoma. Proc Natl Acad Sci U S A. Oct 25 
2011;108(43):17761-17766. 
12. 
Rees JL. The genetics of sun sensitivity in humans. Am J Hum Genet. Nov 
2004;75(5):739-751. 
13. 
Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R. FDA approval summary: 
vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist. 
Oct 2007;12(10):1247-1252. 
14. 
Kurundkar D, Srivastava RK, Chaudhary SC, et al. Vorinostat, an HDAC inhibitor 
attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling 
pathway in a human xenograft murine model. Toxicol Appl Pharmacol. Jan 15 
2013;266(2):233-244. 
15. 
Karam M, Legay C, Auclair C, Ricort JM. Protein kinase D1 stimulates proliferation and 
enhances tumorigenesis of MCF-7 human breast cancer cells through a MEK/ERK-
dependent signaling pathway. Exp Cell Res. Mar 10 2012;318(5):558-569. 
16. 
Teknos TN, Grecula J, Agrawal A, et al. A phase 1 trial of Vorinostat in combination 
with concurrent chemoradiation therapy in the treatment of advanced staged head and 
neck squamous cell carcinoma. Invest New Drugs. Dec 19 2018. 


CONFIDENTIAL:   
IRB-49542  
Page 31 of 34 
19 July 2019 
Version # 1 
17. 
Lansbury L, Bath-Hextall F, Perkins W, Stanton W, Leonardi-Bee J. Interventions for 
non-metastatic squamous cell carcinoma of the skin: systematic review and pooled 
analysis of observational studies. BMJ. Nov 4 2013;347:f6153. 
18. 
Mackenzie-Wood A, Kossard S, de Launey J, Wilkinson B, Owens ML. Imiquimod 5% 
cream in the treatment of Bowen's disease. J Am Acad Dermatol. Mar 2001;44(3):462-
470. 
19. 
Morton C, Horn M, Leman J, et al. Comparison of topical methyl aminolevulinate 
photodynamic therapy with cryotherapy or Fluorouracil for treatment of squamous cell 
carcinoma in situ: Results of a multicenter randomized trial. Arch Dermatol. Jun 
2006;142(6):729-735. 
20. 
Locke J, Karimpour S, Young G, Lockett MA, Perez CA. Radiotherapy for epithelial skin 
cancer. Int J Radiat Oncol Biol Phys. Nov 1 2001;51(3):748-755. 
21. 
NCCN Clinical Practice Guidelines in Oncology: Squamous Cell Skin Cancer. 2018; 
2.2019:https://http://www.nccn.org/professionals/physician_gls/pdf/squamous.pdf. 
Accessed 16 January 2019. 
 


CONFIDENTIAL:   
IRB-49542  
Page 32 of 34 
19 July 2019 
Version # 1 
APPENDIX A:  Study IRB-49542 Participant Medication Application Diary 
Study Participant Study Drug Application Diary 
 
 
 
 
Participant Identifier:  SCC-_______ 
STUDY DRUG INSTRUCTIONS: 
Study Drug:  Remetinostat 1% gel 
How Much:  Apply a thin layer over the tumor(s) identified by the 
study doctor. 
How Often:  Three times daily. 
When:  You should apply the gel in the morning, at mid-day, and in 
the evening. 
SPECIAL INSTRUCTIONS: 
This medication must remain refrigerated at all times. 
Cover the area with a bandage after you apply the gel. 
Wash your hands after you apply the gel. 
APPLICATION LOG 
Please indicate if you applied the gel for each dose listed below. 
Please bring this diary to your next clinic visit. 
 
  
Date 
Gel Applied 
Comments 
  
Dose 1 
Dose 2 
Dose 3 
 
Example 
4/1/19 
x 
x 
x 
Stinging after medication 
applied 
Day 1 
<prepopulated date> 
 
 
 
 
Day 2 
<prepopulated date> 
 
 
 
 
Day 3 
<prepopulated date> 
 
 
 
 
Day 4 
<prepopulated date> 
 
 
 
 
Day 5 
<prepopulated date> 
 
 
 
 
Day 6 
<prepopulated date> 
 
 
 
 
Day 7 
<prepopulated date> 
 
 
 
 
Day 8 
<prepopulated date> 
 
 
 
 
Day 9 
<prepopulated date> 
 
 
 
 
Day 10 
<prepopulated date> 
 
 
 
 
Day 11 
<prepopulated date> 
 
 
 
 
Day 12 
<prepopulated date> 
 
 
 
 
Day 13 
<prepopulated date> 
 
 
 
 


CONFIDENTIAL:   
IRB-49542  
Page 33 of 34 
19 July 2019 
Version # 1 
  
Date 
Gel Applied 
Comments 
  
Dose 1 
Dose 2 
Dose 3 
 
Day 14 
<prepopulated date> 
 
 
 
 
Day 15 
<prepopulated date> 
 
 
 
 
Day 16 
<prepopulated date> 
 
 
 
 
Day 17 
<prepopulated date> 
 
 
 
 
Day 18 
<prepopulated date> 
 
 
 
 
Day 19 
<prepopulated date> 
 
 
 
 
Day 20 
<prepopulated date> 
 
 
 
 
Day 21 
<prepopulated date> 
 
 
 
 
Day 22 
<prepopulated date> 
 
 
 
 
Day 23 
<prepopulated date> 
 
 
 
 
Day 24 
<prepopulated date> 
 
 
 
 
Day 25 
<prepopulated date> 
 
 
 
 
Day 26 
<prepopulated date> 
 
 
 
 
Day 27 
<prepopulated date> 
 
 
 
 
Day 28 
<prepopulated date> 
 
 
 
 
Day 29 
<prepopulated date> 
 
 
 
 
Day 30 
<prepopulated date> 
 
 
 
 
Day 31 
<prepopulated date> 
 
 
 
 
Day 32 
<prepopulated date> 
 
 
 
 
Day 33 
<prepopulated date> 
 
 
 
 
Day 34 
<prepopulated date> 
 
 
 
 
Day 35 
<prepopulated date> 
 
 
 
 
Day 36 
<prepopulated date> 
 
 
 
 
Day 37 
<prepopulated date> 
 
 
 
 
Day 38 
<prepopulated date> 
 
 
 
 
Day 39 
<prepopulated date> 
 
 
 
 
Day 40 
<prepopulated date> 
 
 
 
 
Day 41 
<prepopulated date> 
 
 
 
 
Day 42 
<prepopulated date> 
 
 
 
 
Day 43 
<prepopulated date> 
 
 
 
 
Day 44 
<prepopulated date> 
 
 
 
 
Day 45 
<prepopulated date> 
 
 
 
 
Day 46 
<prepopulated date> 
 
 
 
 
Day 47 
<prepopulated date> 
 
 
 
 
Day 48 
<prepopulated date> 
 
 
 
 
Day 49 
<prepopulated date> 
 
 
 
 


CONFIDENTIAL:   
IRB-49542  
Page 34 of 34 
19 July 2019 
Version # 1 
APPENDIX B:  Study IRB-49542 Participant Information Sheet 
Remetinostat Participant Information Sheet 
Remetinostat Application instructions:   
Remetinostat gel 1% is to be applied to dry skin.  Wash your hands and squeeze the 
amount of study medication that was demonstrated by the study team from the tube 
onto your index finger and apply to the SCC lesion(s) identified by your physician.  
Apply to the SCC lesion(s) 3 times daily for 8 weeks as specified by your physician.  
Cover the treated SCC lesions(s) with a sticky strip bandage, such as a Band-Aid.   
There is no need to leave large amounts of residue on your skin.  Immediately following 
application, wipe the finger(s) and hands you have used to apply the study drug with a 
disposable tissue and wash your hands using soap and water.  If the study medication 
gets on the skin of other people, they should wash with soap and water. 
If someone else helps apply the study medication, they should follow the same 
instructions.  
If you start to treat new lesions or stop treating any lesion, please inform your physician 
so a record can be kept of which lesions are being treated with study medication. 
Remetinostat Storage Instructions:   
• Do not store the study medication in your car.  
• Study medication should be stored in the refrigerator, away from heat or open 
flame.  
• The study medication should be kept out of reach of children and unauthorized 
persons (not being patients participating in this study or their caregiver).  
Risks from Remetinostat: 
In prior studies, remetinostat caused some people to have some skin irritation such as a 
tingling or tickling feeling (“pins and needles”) on their skin, a warm or burning feeling on 
their skin or inflammation (redness and swelling).  This may be due to the ingredients 
the drug is mixed in, or the drug itself.  If you have any concerns, contact the study 
team.