Clinical trial NCT03646188
Conditions: Basal Cell Carcinoma
Sponsor: SkinJect, Inc.
Start date: 2020-06-10; Completion date: 2021-05-04
Enrollment: 13 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase I study in participants with superficial or nodular Basal Cell Carcinoma (BCC), designed to assess dose limiting toxicities and maximum tolerated dose, efficacy, safety, and tolerability of dissolvable, tip-loaded, microneedle arrays containing doxorubicin (D-MNA).

Detailed description:
This is a Phase I study in participants with superficial or nodular Basal Cell Carcinoma (BCC), designed to assess dose limiting toxicities and maximum tolerated dose, efficacy, safety, and tolerability of dissolvable, tip-loaded, microneedle arrays containing doxorubicin (D-MNA). Doxorubicin is a cytotoxic anthracycline antibiotic and is currently approved for the treatment of a broad range of cancers, including but not limited to: breast, bladder, gastric, and ovarian cancers; small cell lung cancer; acute lymphoblastic leukemia; and acute myelo blastic leukemia. SkinJect, Inc. has developed a novel delivery system in the form of a tip-loaded dissolvable microneedle array (MNA) which will allow for topical delivery of doxorubicin directly to the lesion at concentrations that are far below standard systemic dosing, thereby reducing the adverse events associated with systemic delivery. The primary objective of this investigation is to establish the highest safe and tolerable dose of single applications of D-MNA, one application per week for three weeks in placebo, 25 µg, 50 µg, 100 µg, and 200 µg dose groups in participants with BCC.

Arms: arm 1: Placebo arm 2: D-MNA's containing 25 µg of doxorubicin hydrochloride arm 3: D-MNA's containing 50 µg of doxorubicin hydrochloride arm 4: D-MNA's containing 100 µg of doxorubicin hydrochloride arm 5: D-MNA's containing 200 µg of doxorubicin hydrochloride
Interventions: intervention 1: Placebo-containing MNA intervention 2: 25 µg doxorubicin-containing MNA intervention 3: 50 µg doxorubicin-containing MNA intervention 4: 100 µg doxorubicin-containing MNA intervention 5: 200 µg doxorubicin-containing MNA
Intervention descriptions: intervention 1: A 15 x 15 mm array containing 400 tip-loaded, dissolvable microneedles delivering a placebo. intervention 2: A 15 x 15 mm array containing 400 tip-loaded, dissolvable microneedles delivering 25 µg of doxorubicin hydrochloride. intervention 3: A 15 x 15 mm array containing 400 tip-loaded, dissolvable microneedles delivering 50 µg of doxorubicin hydrochloride. intervention 4: A 15 x 15 mm array containing 400 tip-loaded, dissolvable microneedles delivering 100 µg of doxorubicin hydrochloride. intervention 5: A 15 x 15 mm array containing 400 tip-loaded, dissolvable microneedles delivering 200 µg of doxorubicin hydrochloride.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
An Open-Label Dose Escalation Trial to Evaluate 
Dose Limiting Toxicity (DLT), Maximum Tolerated 
Dose (MTD), Safety, and Tolerability of Microneedle 
Arrays containing Doxorubicin (D-MNA) in 
Participants with Basal Cell Carcinoma (BCC) 
Protocol Number: SKNJCT-001 
National Clinical Trial (NCT) Identified Number:  NCT03646188 
IND #: 139837 
Sponsor: SkinJect, Inc. 
Funded by: SkinJect, Inc. 
Administrative Change: 04 
Version Number:  v. 3.4 
Version Date: 09 February 2021 
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Protocol Number: SKNJCT-001 
Version and Date: 3.4 (09 February 2021) 
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Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.3 
8.3.3.1 
12.2 
ALL 
Updated the schedule of activities . 
Updated the language to reference the 
appropriate scale for pain related adverse 
events as recorded on the Numerical Rating 
Scale (NRS).   
NRS scale with adverse event severity added to 
the appendix. 
Grammatical and formatting revisions. 
To be consistent with the information in 
the table footers. 
Adverse event severity terms are 
required for capturing of the AE in the 
case report forms. 
A reference tool for consistent recorded 
of adverse events. 
Appropriate corrections. 
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 4 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 5 
2 
INTRODUCTION ............................................................................................................................................ 7 
2.1 
Study Rationale .................................................................................................................................... 7 
2.2 
Background......................................................................................................................................... 10 
2.3 
Risk/Benefit Assessment .................................................................................................................. 13 
2.3.1 
Known Potential Risks ................................................................................................... 13 
2.3.2 
Known Potential Benefits .............................................................................................. 15 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 15 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 16 
4.1 
Overall Design .................................................................................................................................... 18 
4.2 
Scientific Rationale for Study Design.............................................................................................. 18 
4.3 
Justification for Dose ......................................................................................................................... 18 
4.4 
End of Study Definition ..................................................................................................................... 18 
5 
STUDY POPULATION ................................................................................................................................ 19 
5.1 
Inclusion Criteria ................................................................................................................................ 19 
5.2 
Exclusion Criteria ............................................................................................................................... 19 
5.3 
Lifestyle Considerations .................................................................................................................... 20 
5.4 
Screen Failures .................................................................................................................................. 20 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 20 
6 
STUDY INTERVENTION ............................................................................................................................ 21 
6.1 
Study Intervention(s) Administration ............................................................................................... 21 
6.1.1 
Study Intervention Description ..................................................................................... 21 
6.1.2 
Dosing and Administration ............................................................................................ 21 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 22 
6.2.1 
Acquisition and accountability ...................................................................................... 22 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 22 
6.2.3 
Product Storage and Stability ....................................................................................... 23 
6.2.4 
Preparation ...................................................................................................................... 23 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 23 
6.4 
Study Intervention Compliance ........................................................................................................ 24 
6.5 
Concomitant Therapy ........................................................................................................................ 24 
6.5.1 
Rescue Medicine ............................................................................................................ 24 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 24 
7.1 
Discontinuation of Study Intervention ............................................................................................. 24 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 24 
7.3 
Lost to Follow-Up ............................................................................................................................... 25 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 25 
8.1 
Efficacy Assessments ....................................................................................................................... 25 
8.2 
Safety and Other Assessments ....................................................................................................... 26 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 27 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 27 
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8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 27 
8.3.3 
Classification of an Adverse Event .............................................................................. 27 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 29 
8.3.5 
Adverse Event Reporting .............................................................................................. 29 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 29 
8.3.7 
Reporting Events to Participants ................................................................................. 30 
8.3.8 
Events of Special Interest ............................................................................................. 30 
8.3.9 
Reporting of Pregnancy ................................................................................................ 30 
8.4 
Unanticipated Problems .................................................................................................................... 30 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 30 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 31 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 31 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 31 
9.1 
Statistical Hypotheses ....................................................................................................................... 31 
9.2 
Sample Size Determination .............................................................................................................. 31 
9.3 
Populations for Analyses .................................................................................................................. 32 
9.4 
Statistical Analyses............................................................................................................................ 32 
9.4.1 
General Approach .......................................................................................................... 32 
9.4.2 
Analysis of the Primary Endpoint(s) ............................................................................ 32 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 32 
9.4.4 
Safety Analyses .............................................................................................................. 33 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 33 
9.4.6 
Planned Interim Analyses ............................................................................................. 33 
9.4.7 
Sub-Group Analyses ..................................................................................................... 33 
9.4.8 
Tabulation of Individual participant Data .................................................................... 33 
9.4.9 
Exploratory Analyses ..................................................................................................... 34 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 34 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 34 
10.1.1 
Informed Consent Process ........................................................................................... 34 
10.1.2 
Study Discontinuation and Closure ............................................................................. 35 
10.1.3 
Confidentiality and Privacy ........................................................................................... 35 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 36 
10.1.5 
Key Roles and Study Governance .............................................................................. 36 
10.1.6 
Safety Oversight ............................................................................................................. 36 
10.1.7 
Clinical Monitoring .......................................................................................................... 37 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 37 
10.1.9 
Data Handling and Record Keeping ............................................................................ 37 
10.1.10 
Protocol Deviations ........................................................................................................ 38 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 38 
10.1.12 
Conflict of Interest Policy .............................................................................................. 39 
10.2 
Additional Considerations ................................................................................................................. 39 
10.3 
Abbreviations ...................................................................................................................................... 40 
10.4 
Protocol Amendment History ........................................................................................................... 42 
11 
REFERENCES ............................................................................................................................................. 43 
12 
AppendiCEs .................................................................................................................................................. 45 
12.1 
Appendix 1 .......................................................................................................................................... 45 
12.2 
Appendix 2 .......................................................................................................................................... 48 
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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and applicable United States (US) Code of Federal Regulations (CFR).  
The Principal Investigator will assure that no deviation from or changes to the protocol will take place 
without prior agreement from the Investigational New Drug (IND) sponsor, and documented approval 
from the Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) 
to the trial participants. All personnel involved in the conduct of this study have completed Human 
Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled.   
Any amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  All changes to the consent form will be IRB approved; a determination will 
be made regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form. 
1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
An Open-Label Dose Escalation Trial to Evaluate Dose Limiting Toxicity 
(DLT), Maximum Tolerated Dose (MTD), Safety, and Tolerability of 
Microneedle Arrays containing Doxorubicin (D-MNA) in Participants with 
Basal Cell Carcinoma (BCC)  
Study Description: 
This study is designed as an open-label dose escalation trial of D-MNA in 
Participants with BCC (subtype: superficial or nodular). The goal of the 
dose escalation is to determine the maximum tolerated dose and assess 
lesion responses in the different dose groups to inform a decision on the 
doses to be tested in a subsequent Phase II study.  
Escalation will follow a traditional 3+3 design with a sentinel patient 
dosing approach for each cohort as documented in the Data Monitoring 
Committee (DMC) charter.  Specifically, in each dose group N=3 
participants will be treated. If no dose-limiting toxicities (DLTs) are 
observed, the study will escalate to the next dose level. If DLTs are 
observed in 2 or more participants, then the maximum tolerated dose 
(MTD) will have been exceeded. If 1 DLT is observed, an additional 3 
participants will be treated at the same dose level. If no DLTs are 
observed in the additional 3 participants, the study will escalate to the 
next dose level. If DLTs are observed in 1 or more of the 3 additional 
participants, the MTD will have been exceeded. The first 2 groups, 
placebo and 25 µg, may  screen and enroll patients concurrently.   
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A Data Monitoring Committee (DMC) will be in place to monitor 
participant safety during the study including dose escalation decisions. 
Objectives: 
Primary Objective: 
•
To establish the highest safe and tolerable dose of single applications
of D-MNA, one application  administered weekly, three times over a
two week period,in placebo, 25 µg, 50 µg, 100 µg, and 200 µg dose
groups in participants with BCC
Secondary Objectives: 
•
To evaluate the efficacy of single applications of D-MNA, one
application  administered weekly, three times over a two week
period,in participants with BCC
•
To evaluate safety and tolerability and to characterize the adverse
events profile of the different D-MNA dose groups
Exploratory Objectives: 
•
To quantify the approximate amount of doxorubicin released after
application of the  MNA
•
To evaluate by photographic assessment the efficacy of single
applications of D-MNA, one application administered weekly, three
times over a two week, period in participants with BCC
Endpoints: 
Primary Endpoint: 
•
Assessment of Dose limiting toxicity (DLT) and Maximum Tolerated
Dose (MTD) as defined in Appendix 1 using the LSR grading scale or
any systemic ≥ Grade 3 adverse event according to CTCAE v 5.0 that
cannot be attributed to another cause
Secondary Endpoints: 
•
Lesion response as assessed by a central reader after the 3-week
course of treatment will be categorized as either absence or
presence of Complete Response (CR) defined as no histologically
proven BCC cells in excised tissue.
•
Visual evidence of BCC at the treatment site pre and post MNA
application by visual and dermatoscopic inspection and of the
treatment site
•
Local tolerance of the MNA on the skin according to the Local Skin
Response (LSR) Grading Scale (Appendix 1)
•
Pain assessment using an 11-point numerical rating scale (NRS)
(Appendix 2)
Exploratory Endpoint: 
•
Compare the listed dosage for each doxorubicin cohort to the
amount of doxorubicin  remaining in each MNA after use, such
amounts being determined by the validated analytical method.
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• 
Visual evidence of BCC at the treatment site pre and post MNA 
application by photographic assessment of the treatment site 
 
Study Population: 
Men and women with BCC (superficial or nodular sub-type) age 18 or 
older and in general good health. 15 participants (3 in each of the 5 dose 
groups) are planned. Up to 15 additional participants may be recruited in 
case of emergence of dose limiting toxicities. 
 
Three study treatments are planned  
Phase: 
I 
Description of 
Sites/Facilities Enrolling 
Participants: 
Clinical trial to be conducted by qualified dermatologists (or other sub-
specialty physicians with equivalent qualifications) 
 
One study site in the United States will participate in this clinical trial. 
Description of Study 
Intervention: 
The participant will be treated with microneedle arrays containing 
doxorubicin (D-MNA) or microneedle arrays containing placebo. 
 
The D-MNA or MNA-placebo  is applied to the BCC lesion and secured to 
the skin with a  bandage applying constant pressure.  The D-MNA is 
removed from the skin after 30 minutes.  Each participant will receive 
three (3) weekly applications of the D-MNA unless a dose limiting toxicity 
(DLT) requires skipping or postponement of an application.  
The investigational product is chemotherapeutic agent doxorubicin (25 
µg, 50 µg, 100 µg, or 200 µg) delivered to specific skin strata by a novel 
delivery system, MNA or placebo  delivered to specific skin strata by 
MNA. 
Study Duration: 
Recruitment of 15 to 30 participants is expected to complete in 
approximately 5-7 months 
Participant Duration: 
Individual participant participation is expected to be approximately up to 
11 weeks (4 weeks screening + 7 weeks from the first treatment to the 
final follow up visit).  
 
 
 
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1.2 
SCHEMA 
Refer to Section 1.3 for the Schedule of Activities 
 
 
 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
  
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
PROCEDURE 
Screening 
Visit 
Treat-
ment #1 
Treat-
ment #2 
Treat-
ment #3 
End of 
Treatment 
Follow-
up #1 
Follow-
up #2 
Final  
Follow-up 
Day -28 
(+/- 2 
days) 
Day 1 
Day 7 
(+/- 2 
days) 
Day 14 
(+/- 2 
days) 
Day 21 
(+/- 2 
days) 
Day 22  
(1 day 
post 
excision) 
Day 35 
(+/- 2 
days) 
Day 50 
(+/- 2 
days) 
Study Assessments 
  
  
  
  
  
  
  
  
Informed Consent  
X 
Review of inclusion/exclusion criteria 
X 
Medical history including prior & concomitant medication 
X 
Concomitant medication review  
X 
X 
X 
X 
X 
X 
X 
Initial Full Physical exam (including height and weight)1 
X 
 
 
 
 
 
 
 
Adverse Event(s), assessment 
 
X 
X 
X 
X 
X 
X 
X 
Follow-up Visit w/ Physical Exam (including weight) 
 
 
 
 
X 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Administer IP to BCC lesion for 30 minutes (+/- 3 minutes) 
X 
X 
X 
Local Skin Response (LSR) of MNA4 
X 
X 
X 
 Dermatological inspection of the lesion pre-MNA 
application     
X 
X 
X 
Dermatological inspection of the lesion post-MNA 
application    
 
X 
X 
X 
X5 
 
 
 
 Dermatoscopic evaluation of the lesion pre-MNA 
application     
X 
X 
X 
Dermatoscopic evaluation of the lesion post-MNA 
application3 
 
X 
X 
X 
X5 
 
 
 
 Photography of lesion site pre-MNA application  
X 
X 
X 
 Photography of lesion site post-MNA application  
X 
X 
X 
X5 
Shave biopsy of the BCC lesion w/ interpretation 
X2 
Excision of the BCC lesion / treatment site  
X 
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Preparation and shipment of excision 
X 
 Suture Removal  
X 
 Wound Healing  
X 
X 
X 
Hematology (Sample collection only) 
X 
X 
Serum chemistry (Sample collection only) 
X 
X 
Urinalysis (Sample collection only) 
X 
X 
Urine pregnancy test   
X 
 
 
 
X 
 
 
 
ECG 
X 
 
 
 
X 
 
 
 
Dermpath biopsy analysis 
 
 
 
 
X 
 
 
 
Administration of Pain Assessment Scale 
X 
X 
X 
X6 
Investigational Product Dispensing 
X 
X 
X 
 
 
1 Height collected at Visit 0 only 
2 Diagnostic shave biopsies will be performed at least 7 days before the 1st MNA application if patient not previously diagnosed with an eligible lesion.   
3 Dermatoscopic evaluation is to be conducted ≤5 minutes after removal of the MNA.  
4 Assess treatment area at removal of the MNA at V1; pre-application and post removal of MNA at V2, V3 and V4.  To be obtained ≤15 minutes after removal of MNA for V1 – V3. 
5 Final dermatology, dermatoscopic and photography evaluation of treatment area prior to excision of the lesion 
6 Pain assessment to be completed prior to standard of care excision 
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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
This is a Phase I study in participants with superficial or nodular Basal Cell Carcinoma (BCC), designed to 
assess dose limiting toxicities and maximum tolerated dose, efficacy, safety, and tolerability of 
dissolvable, tip-loaded, microneedle arrays containing doxorubicin (D-MNA). Doxorubicin is a cytotoxic 
anthracycline antibiotic and is currently approved for the treatment of a broad range of cancers, 
including but not limited to: breast, bladder, gastric, and ovarian cancers; small cell lung cancer; acute 
lymphoblastic leukemia; and acute myelo blastic leukemia. SkinJect, Inc. has developed a novel delivery 
system in the form of a dissolvable microneedle array (MNA) which is intended to allow topical delivery 
of doxorubicin directly to the lesion at concentrations that are far below standard systemic dosing, 
thereby reducing the adverse events associated with systemic delivery.  
 
The primary objective of this investigation is to establish the highest safe and tolerable dose of single 
applications of D-MNA, one application administered weekly, three times over a two week period in 
placebo, 25 µg, 50 µg, 100 µg, and 200 µg dose groups in participants with BCC.  
 
Safety, efficacy and tolerability of the different doses will be evaluated, and additionally, quantification 
of the doxorubicin delivered to the BCC lesion and doxorubicin remaining in the microneedle array after 
use will be performed.   
 
Doxorubicin’s mechanism of action has not been fully elucidated, but it is generally accepted to be 
largely due to its ability to intercalate with DNA base pairs, resulting in inhibition of topoisomerase II, 
and subsequent DNA breakage1,2.  Additional antineoplastic effects are thought to be attributable to a P-
450-mediated one-electron reduction resulting in the formation of an unstable and reactive radical 
species3. It is anticipated that the mechanism of action of locally administered doxorubicin is 
comparable to systemic administration. Enhanced local anti-tumor effects are a result of direct tumor 
lysis, acute phase inflammation, and local recruitment of innate and tumor specific immune effectors. 
Basal cell carcinoma is the most common cancer in humans, with an estimated annual global incidence 
of 2.75 million cases4.  Basal cell carcinoma arises from the basal cells in the epidermis and are 
associated with both chronic and intermittent acute UV exposure.  The development of basal cell 
carcinoma is thought to be attributable, in part, to a deregulation of the Hedgehog (Hh) signaling 
pathway.  The Hedgehog pathway is involved in stem cell maintenance, regulation of cell proliferation 
and differentiation, and carcinogenesis, and dysfunctional activation has been implicated in the 
 
 
1Yang F, Teves SS, Kemp CJ, Henikoff S. Doxorubicin, DNA torsion, and chromatin dynamics. Biochim Biophys Acta . 
2014;1845(1):84-89. . 
2. Fornari FA, Randolph JK, Yalowich JC, Ritke MK, Gewirtz DA. Interference by doxorubicin with DNA unwinding in 
MCF-7 breast tumor cells. Mol Pharmacol. 1994;45(4):649-56. 
3. Sinha BK. Is Metabolic Activation of Topoisomerase II Poisons Important In The Mechanism Of Cytotoxicity? 
Journal of Drug Metabolism & Toxicology. 2015;06(03):186-186. 
4 Verkouteren JAC, Ramdas KHR, Wakkee M, Nijsten T. Epidemiology of basal cell carcinoma: scholarly review. Br J 
Dermatol. 2017;177(2):359-372. 
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development of multiple cancers, including BCC5.  Chemotherapeutic inhibition of Hedgehog signaling 
has been demonstrated to be effective against advanced BCC6. 
 
While BCC is highly-curable and only rarely metastasizes, it can result in significant morbidity in terms of 
cosmetic and functional loss. Current standard of care for localized BCC is typically surgical, either via 
standard excision or Mohs micrographic surgery.  While surgical excision remains the standard-of-care 
for the treatment of BCC, it carries risks typically associated with surgical procedures, including bleeding, 
scarring, and infection.  Surgical treatment may not be desirable or indicated for all participants, 
resulting in a demand for non-surgical treatment options.  Commonly used topical treatments for BCC 
include:  imiquimod; 5-fluorouracil; and tazarotene.   
 
Imiquimod primarily acts as an agonist of toll-like receptors (TLR) 7 and 8, leading to activation of 
nuclear factor-kappa B (NF-kappaB).  This activation results in the induction of pro-inflammatory 
cytokines and chemokines, ultimately resulting in a T-cell-mediated anti-tumor immune response.7  
Imiquimod has demonstrated efficacy in the treatment of both superficial and nodular BCC; however, 
imiquimod’s efficacy is significantly inferior to surgery, with 84% of imiquimod-treated patients 
remaining tumor-free after 3-years, compared to 98% of surgically-treated patients8. 
 
5-Fluorouracil is an antimetabolite and blocks DNA replication by inhibiting thymidylate synthase9.  
Three-year tumor-free status following treatment with 5-Fluorouracil is inferior to that of imiquimod, 
with 68% of patients remaining tumor-free after 3-years10. 
 
Tazarotene’s mechanism-of-action as an anti-neoplastic agent is not fully understood, but it is believed 
to be related to its ability to cause caspase-dependent apoptosis11.  Tazarotene is a less-promising 
surgical alternative, with only 30.5% of patients remaining tumor-free at 3 years12 
 
 
 
5 Gupta S, Takebe N, Lorusso P. Targeting the Hedgehog pathway in cancer. Ther Adv Med Oncol. 2010;2(4):237-
50. 
6 Soura E, Chasapi V, Stratigos AJ. Pharmacologic treatment options for advanced epithelial skin cancer. Expert 
Opin Pharmacother. 2015;16(10):1479-93.. 
7 Schön MP, Schön M. Imiquimod: mode of action. Br J Dermatol. 2007;157 Suppl 2:8-13. 
8 Bath-hextall F, Ozolins M, Armstrong SJ, et al. Surgical excision versus imiquimod 5% cream for nodular and 
superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial. Lancet Oncol. 
2014;15(1):96-105. 
9 Nakamura A, Nakajima G, Okuyama R, et al. Enhancement of 5-fluorouracil-induced cytotoxicity by leucovorin in 
5-fluorouracil-resistant gastric cancer cells with upregulated expression of thymidylate synthase. Gastric Cancer. 
2014;17(1):188-95. 
10 Roozeboom MH, Arits AH, Mosterd K, et al. Three-Year Follow-Up Results of Photodynamic Therapy vs. 
Imiquimod vs. Fluorouracil for Treatment of Superficial Basal Cell Carcinoma: A Single-Blind, Noninferiority, 
Randomized Controlled Trial. J Invest Dermatol. 2016;136(8):1568-74. 
11 Wu CS, Chen GS, Lin PY, et al. Tazarotene induces apoptosis in human basal cell carcinoma via activation of 
caspase-8/t-Bid and the reactive oxygen species-dependent mitochondrial pathway. DNA Cell Biol. 
2014;33(10):652-66. 
12 Bianchi L, Orlandi A, Campione E, et al. Topical treatment of basal cell carcinoma with tazarotene: a 
clinicopathological study on a large series of cases. Br J Dermatol. 2004;151(1):148-56. 
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The goal of the present study is to determine the maximum tolerated dose and to assess whether D-
MNA represents an alternative to the currently available non-surgical, and in some cases, surgical 
treatments for BCC.  
 
Treatment of BCC with D-MNA is intended to treat local visible tumor.  Based on the potential for D-
MNA to induce immunogenic effects, future clinical trials will assess the potential of the D-MNA to 
prevent recurrence at the treated site, the growth of additional primary tumors, or both.  
 
The proposed approach relies on localized delivery of doxorubicin to the accessible tumor 
microenvironment. In the mouse melanoma model, doxorubicin delivered by the MNAs caused local, 
acute tumor cell death at low doses (e.g., 25 µg).  Such a dose delivered systemically would be sub-
therapeutic and non-toxic. 
 
This investigation’s therapeutic approach is intended to eradicate basal cell carcinoma cells locally; the 
potential of inducing long-lasting systemic, anti-tumor immunity will be evaluated in future studies. 
Enhanced local anti-tumor effects are believed to be the result of direct tumor lysis, acute phase 
inflammation, and local recruitment of innate and tumor specific immune effectors. It is thought that 
adaptive immunity may result from the immunogenic tumor cell death, which will stimulate the 
activation of innate immune mechanisms capable of overcoming local immunosuppression to induce 
antigen-specific effector and memory cellular immune responses.1 
Doxorubicin is a particularly well-
suited chemotherapeutic drug for this purpose as it creates an immunogenic “good death” for tumor 
cells13.  Doxorubicin chemotherapy has been shown to result in innate immune activation, including the 
attraction and activation of antigen presenting cells.  The simultaneous cell death process facilitates the 
activation of these antigen presenting cells and their internalization and processing of dying tumor cell 
derivatives through underlying mechanisms that include ATP and HMGB1 release, and calreticulin 
exposure. 
 
Microneedle Arrays (MNAs) are intended to enable in situ alteration of the tumor microenvironment. 
Drug delivery is a major barrier for skin cancer therapy. User variability and irregular diffusion kinetics 
make traditional intradermal injection an inefficient and highly variable method for localized drug 
delivery to specific skin strata. On the other hand, the potential for skin penetration for an active drug 
delivered topically is quite variable and largely dependent on its physiochemical properties. 
Reproducibility is dependent on several factors, from variability in stratum corneum 
penetration/retention to user variability. Very few chemotherapeutics or adjuvants have been 
successfully formulated for topical use.  
 
Based on pre-clinical and clinical studies (see Pharmacology and Toxicology, section 2.3.1 and 2.3.2), it 
appears that the D-MNA, at doxorubicin doses of 25-200 µg per MNA, will be well-tolerated and will 
demonstrate certain local tumoricidal activity. 
 
 
 
 
13 Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev 
Drug Discov. 2012;11(3):215-33. 
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2.2 
BACKGROUND  
 
Basal cell carcinoma is the most common skin cancer, with more than 4-million cases diagnosed each 
year in the US 14.  Despite its relatively low mortality rate, BCC is responsible for approximately 3000 
deaths annually15, and, along with SCC, results in $4.8-billion/year in healthcare spending in the US16.  
The development of a successful chemo-immunotherapy for the treatment of BCC represents an 
alternative, non-invasive treatment of this disease, particularly for individuals for whom surgical 
resection is contra-indicated or is done with elevated risk.  The introduction of a safe, locally-
administered, effective non-surgical treatment has the potential to reduce morbidity, mortality, and 
healthcare expenditures. 
 
PRECLINICAL STUDIES 
 
Basal Cell Carcinoma 
The development of a viable and replicable animal model of BCC has presented a challenge to 
researchers; there are currently no models appropriate for assessing an immune-modulating treatment 
for BCC17. Until such time that a viable animal model of BCC is developed, it is necessary to rely on data 
from other dermatological malignances to support BCC research. Data regarding the use of D-MNA in 
murine models of squamous cell carcinoma and melanoma are presented below. 
 
Squamous Cell Carcinoma 
Dr. Louis Falo at the University of Pittsburgh has developed both a murine model and a human ex-vivo 
model for Squamous Cell Carcinoma (SCC) and has used these models to demonstrate the efficacy of D-
MNA at 25 µg in the treatment of SCC lesions.  In the murine model, mice inoculated with SCC cells were 
treated with either D-MNA (n=5) or MNA-Blank (n=5); 20-days post-inoculation, 100% of the D-MNA-
treated mice survived, compared with 0% of the MNA-Blank-treated mice.  Additionally, D-MNA-treated 
mice demonstrated increased levels of pro-inflammatory cytokine gene expression, increased cell death, 
and decreased tumor growth.  Similarly, D-MNA treated ex-vivo human SCCs showed increased levels of 
cell death.  These results suggest that D-MNA is capable of inducing tumor cell death and increasing 
survival in an animal model18.   
 
A subsequent study conducted by Dr. Falo attempted to further elucidate the mechanisms by which D-
MNA at 25 µg exerted its anti-tumor effects, specifically by examining the expression of genes 
 
 
14 Cancer Facts and Figures 2018. American Cancer Society. https://www.cancer.org/content/dam/cancer-
org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. 
Accessed May 15, 2018. 
15 . Gould A, Missailidis S. Targeting the hedgehog pathway: the development of cyclopamine and the development 
of anti-cancer drugs targeting the hedgehog pathway. Mini Rev Med Chem. 2011;11(3):200-13. 
16 Guy GP, Machlin SR, Ekwueme DU, Yabroff KR. Prevalence and costs of skin cancer treatment in the U.S., 2002-
2006 and 2007-2011. Am J Prev Med. 2015;48(2):183-7. 
17 Hochberg M. Experimental Models for BCC. Journal of Dermatology and Clinical Research. 2013;1(1):1002.  
18 Friedman B, Donahue C, Erdos G, Falo LD. A topical chemo-immunotherapy for squamous cell carcinoma. The 
Journal of Immunology. 2016;196(1):213.9. 
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associated with pro- and anti-tumor environments in both normal human tissue and in ex-vivo human 
cutaneous SCCs, both untreated (n=5) and D-MNA-treated (n=5). They found that relative to untreated 
cutaneous SCCs, D-MNA-treated cutaneous SCCs demonstrated a significant decrease in pro-
tumorigenic genes (IDO, ARG2, S100A7 and VEGF-A) and a significant increase in anti-tumorigenic genes 
(CXCL14, HMGB1, and Caspase-8).  D-MNA-treated cutaneous SCCs phenotypically resembled normal 
human tissue, suggesting that D-MNA was able to induce a reversion of cutaneous SCCs to normal, 
healthy tissue19.   
 
Melanoma 
Early research20 into the efficacy of D-MNA on a murine model of melanoma also demonstrates activity.   
Prof. Louis Filo’s laboratory at the University of Pittsburgh used a subcutaneous model of B16 melanoma 
which results in visible tumors 14 – 21 days following injection.  As shown in Figure A (below), treatment 
with D-MNA at 25 µg resulted in a reduction in tumor area.  Figure B (below) compares survival 
percentages over time of animals that received no treatment (n=10), D- MNAs (n=10), Poly(I:C) via 
MNAs (n=10), and both doxorubicin and Poly(I:C) incorporated into the array matrix (n=10). 
 
In summary, the preclinical D-MNA data reported for both cutaneous SCC and melanoma provides 
hypothetical justification for the investigation of its use as a potential treatment for BCC.  
 
 
 
19 Friedman B, Carey C, Edros G, Falo LD. Topical chemo-immunotherapy converts a pro-tumorigenic tumor 
microenvironment to a pro-inflammatory phenotype in human cutaneous squamous cell carcinoma. The Journal of 
Immunology. 2017;198(1):66.21 
20  Falo LD, Erdos G, Ozdoganlar B. Microneedle Arrays for Cancer Therapy Applications. May 2016. 
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FIGURE A 
FIGURE B 
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CLINICAL STUDIES 
Early clinical data demonstrates the potential efficacy of D-MNA in treatment of mycosis fungoides, a 
common subtype of cutaneous T-Cell lymphoma (CTCL). An early clinical study is currently being 
conducted by Professor Louis Falo at University of Pittsburgh (IND #122448221). The primary objective of 
the study is to evaluate the safety of escalating, low doses (25-200 µg) of doxorubicin delivered directly 
into CTCL lesions using a MNA system. Secondary objectives include evaluations of the pharmacokinetics 
and pharmacodynamics (PK/PD) of doxorubicin when delivered using the D-MNA system; and 
evaluations of local, locoregional, and distant responses, biologic responses, and effects of treatment on 
the tumor microenvironment. This initial Phase 1 clinical trial incorporates a single-arm, placebo-
controlled (within patient), open-label, accelerated dose escalation study design to determine the 
maximum tolerated dose (MTD) (or effective dose) of doxorubicin; followed by an extended evaluation 
of safety and effectiveness at the determined MTD (or Effective Dose). 
 
The first cohort of 3 patients was treated with 25 µg of doxorubicin via MNA. Patients were treated 
once/week for 4-weeks, followed by a one-week break. No toxicities were observed at the 25-µg dose, 
and the original cohort, plus a new 3-patient cohort was escalated to the 50-µg dose. Dose-limiting 
toxicity (DLT), a cutaneous reaction, was observed in one patient at the 50-µg dose and the cohort was 
expanded to 2 additional patients, with no additional DLT reported. One patient in the 50-µg cohort 
exhibited a complete resolution of mycosis fungoides in response to D-MNA22 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Known Risks Specific to D-MNA 
Doxorubicin hydrochloride and the excipients used in D-MNA were formulated to specific requirements 
and studied in model systems of sensitization (the murine local lymph node assay), pyrogenicity, and 
irritation (the New Zealand rabbit model).  The test articles in the mouse and rabbit study generated no 
remarkable findings at any of the doses studied in either model.   
A placebo- controlled, 14-day toxicity and toxicokinetic study23 of Yucatan minipigs was conducted to 
assess cutaneous reactions to placebo-MNA, 3 doses of D-MNA (25 µg, 50 µg, and 200 µg), and 
parenteral doxorubicin hydrochloride at 2 mg/kg. All D-MNA dose groups exhibited some macroscopic 
findings at the dose site; the placebo-treated minipigs exhibited findings that were similar to, though 
milder than, the D-MNA-treated minipigs. Red discoloration of the epidermis of the dose site was 
 
 
21 Clinicaltrials.gov. (2018). Micro Needle Array-Doxorubicin (MNA-D) in Patients With Cutaneous T-cell Lymphoma 
(CTCL) - Full Text View - ClinicalTrials.gov. [online] Available at: 
https://clinicaltrials.gov/ct2/show/NCT02192021?term=doxorubicin+dermal&draw=2&rank=1 [Accessed 14 Jun. 
2018]. 
22 Akilov O, Mccann S, Chao E, Cullison SJ, Erdos G, Falo L. 581 Phase 1, single-arm, open-label, dose escalation trial 
of microneedle array-doxorubicin in patients with mycosis fungoides. Journal of Investigative Dermatology. 
2018;138(5 
23 SRC Study No.: S15055: A 14-Day Toxicity and Toxicokinetic Study of Doxorubicin Delivered Topically by Microneedle Array 
(MNA) to Yucatan Minipigs 
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identified in four animals, in the 50 µg and 200 µg groups.  In two of the 200 µg group female animals, 
the red discoloration correlated microscopically with serocellular crust, and additionally with dermis 
congestion in one of those animals. The other two animals (males) did not have a microscopic correlate.  
Abnormal surface (scabbing) of the epidermis of the dose site was observed in a 200-µg group male 
animal and correlated microscopically with serocellular crust.  One minipig receiving parenteral 
doxorubicin exhibited hemorrhage of the right axillary region, which corresponded to microscopic 
hemorrhage.  This finding was believed to be related to either blood collection or injection procedures. 
Hemorrhage of the right axillary region was observed in a single animal in Group 5 (intravenous 
Doxorubicin) and correlated microscopically to hemorrhage.  It was believed to be related to blood 
collection or injection procedures. 
Other macroscopic findings represented incidental background findings typical for this species, or else 
did not have a microscopic correlate. 
Known Risks Specific to Parenteral Doxorubicin 
The foregoing information from a standard package insert for doxorubicin hydrochloride assumes a 
parenteral use of the compound at doses designed for systemic distribution and utility against solid 
tumors.  The D-MNA, it must be emphasized, is introducing microgram quantities of doxorubicin into the 
epidermal space, limiting systemic exposure to the compound and the associated systemic and regional 
side effects.  Studies in both mice and minipigs demonstrate that treatment with D-MNA did not result 
in any measurable blood levels of doxorubicin.  In the murine model, mice were 100 µg or 200 µg of 
doxorubicin (iv), or 200 µg D-MNA. Blood samples were collected 5, 20, and 60 minutes post-dose. 
Blood levels of doxorubicin were measured by spectrofluorimetry and quantitated against a calibration 
curve, with a lower limit of quantitation (LLOQ) of 0.1 µg/ml. No detectable quantities of doxorubicin 
were observed in the mice receiving the 200 µg D-MNA, while doxorubicin levels were detectable in the 
intravenously injected mice.  In the minipig, all D-MNA-treated groups (25, 50, and 200 µg) showed 
doxorubicin plasma levels below the LLOQ) which for this LC-MS/MS method was 0.25 ng/ml. In 
contrast, doxorubicin was detectable in the plasma following parenteral administration. The Sponsor 
concludes that there was no measurable systemic exposure to doxorubicin when administered by D-
MNA23. 
 
In standard chemotherapeutic regimens, doxorubicin hydrochloride can cause myocardial damage, 
including acute left ventricular failure.  The risk of cardiomyopathy is generally proportional to the 
cumulative exposure.  The clinician should include prior doses of other anthracyclines or 
anthracenediones in calculations of total cumulative dosage for doxorubicin hydrochloride.  
Cardiomyopathy may develop during treatment or up to several years after completion of treatment 
and can include decrease in left ventricular ejection fraction (LVEF) and signs and symptoms of 
congestive heart failure (CHF). The probability of developing cardiomyopathy is estimated to be 1 to 2% 
at a total cumulative dose of 300 mg/m2 of doxorubicin hydrochloride, 3 to 5% at a dose of 400 mg/m2, 
5 to 8% at a dose of 450 mg/m2, and 6 to 20% at a dose of 500 mg/m2, when doxorubicin hydrochloride 
is administered every 3 weeks. There is an additive or potentially synergistic increase in the risk of 
cardiomyopathy in patients who have received radiotherapy to the mediastinum or concomitant 
therapy with other known cardiotoxic agents such as cyclophosphamide and trastuzumab.  Pericarditis 
and myocarditis have also been reported during or following doxorubicin hydrochloride treatment. 
 
The clinician should assess left ventricular cardiac function (e.g., multigated acquisition scan or 
echocardiogram) prior to initiation of doxorubicin hydrochloride, during treatment to detect acute 
changes, and after treatment to detect delayed cardiotoxicity. Increase the frequency of assessments as 
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the cumulative dose exceeds 300 mg/m2 . The same method of assessment of LVEF should be used at all 
time points. 
 
Other known risks of parenteral doxorubicin hydrochloride therapy include arrhythmias, secondary 
malignancies, and extravasation from the i.v. needle and tissue necrosis.     
 
2.3.2 KNOWN POTENTIAL BENEFITS  
The cytotoxic effect of doxorubicin HCl on malignant cells and its toxic effects on various organs are 
thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of 
doxorubicin.  Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The 
interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an 
important mechanism of doxorubicin HCl cytocidal activity24 .  Based on preclinical data in SCC and 
melanoma, the Sponsor concludes that doxorubicin in the microgram amounts being delivered by the 
microneedles is causing an environment hostile to basal cell carcinoma and inducing tumor lysis. 
 
Based on the animal studies performed to date, the D-MNA system may offer an effective alternative to 
the current standard of care.  Excisionalstandard of care surgery can be painful and time-consuming, 
while the time and expense of Mohs micrographic surgery can be quite high if multiple procedures are 
required.   Other topical dosage forms, such as 5-fluorouracil and imiquimod, can produce unpleasant 
topical side effects and may not be particularly effective.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
An independent Data Monitoring Committee (DMC) will be set up prior to the start of this study. 
Membership to this committee will include qualified clinicians- dermatologists with expertise in treating 
skin cancer and a statistician.  The DMC will review data for each dose escalation for dose limiting 
toxicities and determine when maximum tolerated dose has been exceeded. Details of the safety review 
as well as recommended dose selection for future clinical trials will be defined by the DMC. 
 
The IRB(s) will be kept informed of the DMC decisions during the study.
 
 
24 Doxorubicin Package Insert: Accessdata.fda.gov. (2018). [online] Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050629s022lbl.pdf [Accessed 8 Jun. 2018]. 
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3 
OBJECTIVES AND ENDPOINTS 
 
Primary Objective 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary Objective 
 
 
• 
To establish the highest safe 
and tolerable dose of single 
applications of D-MNA, one 
application administered 
weekly, three times over a two 
week period, in placebo, 25 
µg, 50 µg, 100 µg, and 200 µg 
dose groups in participants 
with BCC 
 
 
• 
Escalation will follow a traditional 3+3 design. Specifically, in 
each dose group n=3 participants will be treated. If no DLTs are 
observed, the study will escalate to the next dose level. If DLTs 
are observed in 2 or more participants, then the maximum 
tolerated dose (MTD) will have been exceeded. If 1 DLT is 
observed, an additional 3 participants will be treated at the 
same dose level. If no DLTs are observed in the additional 3 
participants, the study will escalate to the next dose level. If 
DLTs are observed in 1 or more of the 3 additional participants, 
the MTD will have been exceeded. The first 2 groups, placebo 
and 25 µg, may screen and enroll patients concurrently in the 
study. 
• 
Dose escalation follows a traditional 3+3 
design to evaluate DLTs and identify the 
MTD.  
 
Secondary and Exploratory Objectives 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Secondary 
 
 
• 
To evaluate the efficacy of 
single applications of D-MNA, 
one administered weekly, 
three times over a two week 
period, in participants with 
BCC 
• 
To evaluate safety and 
tolerability and to characterize 
• 
Clinical response as assessed by a central reader after the 3-
week course of treatment will be categorized as either absence 
or presence of Complete Response (CR) defined as no 
histologically proven BCC cells in excised tissue. 
• 
Visual evidence of BCC at the treatment site pre and post MNA 
application by visual and dermatoscopic inspection of the 
treatment site 
• Reporting of complete histological response 
to treatment is standard per literature 
review and consistent with the clinical trial 
evaluation of Imiquimod indicated for 
treatment of superficial BCC25.    
• Clinical response will be assessed by 
independent central reader as detailed in 
the Central Reader Manual.  
 
 
25 Geisse J, Rich P, Pandya A et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: A double-blind, randomized, vehicle-controlled 
study*. J Am Acad Dermatol. 2002;47(3):390-398. 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
the adverse events profile of 
the different D-MNA dose 
groups  
• 
Local tolerance of the MNA on the skin according to the Local 
Skin Response (LSR) Grading Scale  
• 
Pain assessment using an 11-point numerical rating scale (NRS) 
• Dermatologic inspection, dermatoscopic 
evaluation photography of the lesion are 
routine evaluations for BCC lesions  
Exploratory 
 
 
• 
 To quantify the 
approximate amount of 
doxorubicin released after 
application of the  MNA 
• 
To evaluate by 
photographic assessment, 
the efficacy of single 
applications of D-MNA, 
one application 
administered weekly, 
three times over a two 
week period, in 
participants with BCC 
• Compare the listed dosage for each doxorubicin dosing cohort to 
the amount of doxorubicin  remaining in each MNA after use as 
determined by the validated analytical method.  
• Visual evidence of BCC at the treatment site pre and post MNA 
application by photographic assessment of the treatment site 
• To gain additional information on the 
microneedle array delivery system 
• Photography of the lesion is a routine 
evaluation for BCC lesions 
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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
This is a Phase I open-label dose escalation trial to evaluate dose limiting toxicity, maximum tolerated 
dose, safety, and tolerability of Microneedle Arrays containing Doxorubicin (D-MNA) in participants with 
Basal Cell Carcinoma (BCC). 
 
It is expected that one study site in the US will enroll all participants in the study. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
We hypothesize that treatment with D-MNA will result in tumor destruction and the induction of 
potent, immunogenic anti-tumor responses. Because MNAs enable this agent to be delivered at very 
low doses to a confined tumor microenvironment we expect only minimal, if any, systemic drug toxicity; 
thus, facilitating optimal local dose levels and durable clinical responses. 
 
4.3 
JUSTIFICATION FOR DOSE 
The current dosing regimen is partly based on animal efficacy data performed to date and the toxicology 
studies performed in mice, rabbits, and minipigs to assess the risk of dermal irritation at dose ranges (25 
µg, 50 µg, 100 µg, and 200 µg ) These doses are also currently being tested in Prof. Falo’s CTCL study, in 
which these doses have been well tolerated with minimal dose-limiting toxicity.  
 
The study design also includes a placebo group (placebo-MNA). Inclusion of placebo-MNA will allow the 
evaluation of two questions: 
• 
Tolerability: to assess if there is a cutaneous response to microneedle penetration that is 
independent of microneedle delivery of doxorubicin to the target tissue   
• 
Efficacy:  to assess if a placebo-containing array can stimulate a non-specific immune response in 
reaction to microneedle penetration of the skin, and compare to the response with the active 
compound doxorubicin delivered by the D-MNA 
 
The BCC lesion will be excised in all the dose groups at the end of the study. All BCC cells will be 
removed regardless of the dose group the participants were assigned.  
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study when (s)he has completed the final study visit  
including the standard of care excision of the treatment site as shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
 
 
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5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
The participant must meet all the following criteria to be eligible to participate in this study: 
1. Adult males and females, 18+ years in general good health as assessed by the investigator.  
2. BCC (subtype: superficial or nodular) confirmed histologically by diagnostic shave biopsy at the 
Screening Visit.  If previously confirmed, participants can only have diagnosed BCC via shaved 
biopsy within 6 months of first study treatment.  
3. Primary BCC (i.e., no previous treatment) 
4. Lesion size ≥ 64 mm2 or 8 x 8 mm and ≤ 169 mm2 or 13 x 13 mm, i.e., the entire lesion must be 
covered by 13X13 mm area of the array containing the microneedles 
5. Clinical laboratory results within the following ranges: 
a. granulocytes ≥2,000/mm3 
b. platelets >50,000/mm3 
c. serum creatinine ≤2X the upper limit of normal (ULN) 
d. Aspartate aminotransferase (AST), alanine aminotransferase (ALT),  lactate dehydrogenase 
(LDH), alkaline phosphatase ≤3X the ULN. 
6. Participant must have no other “clinically significant” abnormal findings in his/her medical 
history, physical examination or clinical laboratory test results as assessed by the investigator 
7. Female participants must be either postmenopausal (no menstrual period for a minimum of 12 
months) or surgically sterile upon entry into the study. Female patients of childbearing potential 
must have a negative pregnancy test upon entry into this study and agree to use a highly 
effective method of contraception from Screening until the final follow-up visit. 
8. Male participants with female partners of child bearing potential must be either surgically sterile 
or agree to use a double-barrier contraception method (i.e., condom + diaphragm, condom or 
diaphragm + spermicidal gel or foam) from screening until until the final follow-up visit. 
9. Participant must to be willing to adhere to the instructions of the investigator and his or her 
research team 
10. Participant must sign an Informed Consent Form prior to any study specific procedures and 
entry into the study  
 
5.2 
EXCLUSION CRITERIA 
 
A participant who meets any of the following criteria will be excluded from participation in this study: 
1. Evidence of clinically significant, unstable medical conditions as assessed by the investigator 
2. Excisional biopsy performed on the lesion to be treated in this study 
3. Recent therapy(ies) to the BCC treatment area 
4. Recurrent BCC (previously treated) at the site presented for treatment 
5. BCC lesion to be treated is located in an area where excisional biopsy is undesired or 
aesthetically unacceptable to the participant 
6. Previously demonstrated sensitivity to doxorubicin or carboxymethyl cellulose. 
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7. Participant with other active malignancies except for non-metastatic prostate cancer and 
carcinoma in situ of the skin or cervix 
8. Participant with evidence of metastatic malignancies 
9. Concomitant disease requiring systemic immunosuppressive treatment 
10. Genetic skin cancer disorder, e.g., basal cell nevus syndrome 
11. Participant is pregnant or breastfeeding 
12. Treatment with another investigational drug, device, or other intervention within 3 months 
prior to the Screening Visit  
13. Existing condition or treatment within 3 months prior to the Screening Visit that may have 
impact on clinical outcome for the treatment of BCC or delay in wound healing from the 
standard of care excision 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
 Female patients of childbearing potential must agree to use a highly effective method of contraception 
from Screening until the final follow-up visit. 
 
• 
Highly effective methods of contraception that result in a low failure rate (i.e., <1% per year) when 
used consistently and correctly include combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal), 
progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, 
or implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal 
occlusion, vasectomized partner, or sexual abstinence; 
• 
True abstinence, when in line with the preferred and usual lifestyle of the patient, is considered a 
highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of study participation (i.e., Screening until the final follow-up visit). The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, and post-ovulation method) and withdrawal are not acceptable methods of 
contraception 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
treated at least one time with the investigational product. 
 
Individuals or Screen Failures who do not initially meet the criteria for participation in this trial due to 
logistic reasons, e.g., planned Treatment Day 1 is more than 28 (+/- 7 days) days after the Screening 
Visit, may be rescreened.  
 
Rescreened participants should be assigned a different Participant Number as for the initial screening. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Standard of care excision of the BCC site will be performed on all participants. There are no additional 
benefits in participating in this study.  Participants may be compensated for the additional time, e.g., 
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weekly treatment visits and expenses to participate in the study. Compensation for the participant 
should be reasonable and not excessive. The amount of participant compensation will be reviewed and 
approved by the IRB prior to the start of the study. 
 
One study site in the United States is planned, and this study site is expected to have an adequate pool 
of participants available for screening and enrollment into the study.  
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
The investigational product is chemotherapeutic agent, doxorubicin (25 µg, 50 µg, 100 µg, or 200 µg) 
delivered to the basal layer of skin by a novel delivery system, a MNA. 
The delivery system is a square patch 15 x 15 mm in dimension edge to edge. The dissolvable array of 
400 microneedles is in a 13 x 13 mm area. The microneedles are 750 microns in length. Each MNA patch 
delivers 9.6 µL of drug product into the peri-epidermal space.  
 
The microneedles are formed by dissolving an active compound in citric acid, dibasic sodium phosphate, 
trehalose, and water; by mixing these materials with carboxymethyl cellulose; by plating them on 
precisely designed molds; and by centrifuging the molds until the arrays have dried and can be extruded 
from the mold.  In this study, doxorubicin is embedded in this matrix at specific doses, tip loaded, so that 
the needles deliver the doxorubicin sub epidermally to the BCC. A similar process, excluding doxorubicin, 
is used to make placebo arrays.  The dissolvable MNA has the appearance of a “square patch” the size of 
one’s thumbprint. 
6.1.2 DOSING AND ADMINISTRATION 
 
The D-MNA or MNA-placebo  is applied to the BCC lesion with the following instructions: 
 
1. Prepare the lesion for the study drug administration by manually rubbing the surface of the lesion 
and may include a liquid interface. 
2. The study personnel must use gloves while handling the MNA.  
3. The study personnel will hold the skin taut with one hand while placing the MNA over the lesion 
with the other hand, ensuring the entire lesion is under the area of the MNA. 
4. The time of MNA application is documented. 
5. The study personnel push the MNA firmly into the skin with manual pressure for 3 minutes 
immediately after which the MNA is secured to the skin with a bandage that applies constant 
pressure over the microneedle array.    
 
The MNA is removed from the skin after 30 minutes (+/- 3 minutes) and the time of removal is recorded 
in the subject’s source documents.  After the array’s removal from skin, the participant should wear a 
small self-adhesive bandage for the remainder of the day to keep the application site clean and 
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protected from infection. The participant should be instructed to avoid sun exposure to the treated area 
for the duration of the study.  
 
Participant will receive up to three (3) weekly (+/- 2 days) applications of the D-MNA or placebo-MNA .   
 
The Sponsor will provide the investigator training on the application of the investigational product prior 
to the start of the study. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
The investigational product will be shipped under controlled temperature conditions (2-8℃).  
 
The Sponsor will supply the different doses of D-MNA and MNA-placebo  for use in this study to 
approved study sites with an authorized investigational pharmacist or delegate as designated by the 
Investigator. The Investigator or delegate is responsible for the accurate documentation of receipt, 
inventory, storage, treatment assignment, and dispensing of the investigational product.  
 
After removal from the treatment area, the used MNA is to be stored at refrigerated temperature (2-
8°C). These MNAs will be sent to a central laboratory for quantification of doxorubicin remaining in the 
microneedles. 
 
 Detailed information will be provided in the Study Pharmacy Manual. 
 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
D-MNAs are are red in appearance due to the color of liquid doxorubicin. Red dye is not being added to 
the MNA-placebo in order to eliminate the genotoxicity risk associated with the addition of red dye. 
 
 Four (4) MNAs of the same dosage (25 µg, 50 µg, 100 µg, or 200 µg or placebo ) are contained in 
individual foil-sealed“cubes,” and each cube is contained in a 2” x 3” opaque, heat-sealed Uline packet 
labeled with standard investigational drug text.  Four of these packets are stored in a 4” x 6” Ziplock 
Uline bag packet labeled with standard investigational drug text.  This packaging provides 3 MNAs for 3 
treatments in a 14-day period, and one additional MNA in case of damage to one of the other 3 arrays.   
 
 Each array is contained in individual foil-sealed“cubes,” and each cube is contained in a heat-sealed 2” x 
3” opaque Uline packet labeled with standard investigational drug text.  Four of these packets are stored 
in a 4” x 6” Ziplock Uline bag labeled with standard investigational drug text.   
 
An example of the investigational product label below will also include language that corresponds to 
each dosage (i.e., 25 µg, 50 µg, 100 µg, or 200 µg or placebo).  
 
 
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6.2.3 PRODUCT STORAGE AND STABILITY 
 
The unopened D-MNA should be stored under refrigeration (2-8°C) and protected from exposure to 
light. 
 
 
Stability of the D-MNA for 3 months at refrigerated temperature (2-8°C) has been established in a non-
GLP pilot study. 
 
 
6.2.4 PREPARATION 
 
The health care provider must follow all standard precautions for handling chemotherapy agents 
including the use of gloves.  
 
The D-MNAs and MNAs are supplied ready to be applied to the treatment area. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Study treatment is not randomized, and the study design is open-label dose escalation.  
 
While safety evaluation is the primary objective in this Phase I study, preliminary efficacy evaluations 
will also be conducted. The placebo (without the addition of red dye) is not a matching placebo to the 
active investigational product. However, a process to blind the central reader who will assess the clinical 
response to study treatment will be detailed in the Central Reader Manual. The steps to minimize bias in 
evaluation of visual and histologic responses include: 
• 
All pre and post treatment biopsies will be centrally read after the end of study excision biopsy is 
performed in the last study participant. 
• 
Each set of slides/digital images will be randomly assigned a second unique identifier before they 
are sent to the central reader for assessment. 
• 
The central reader will not have access to the Subject ID or the treatment assignment associated 
with each set of slides/digital images, i.e., the central reader will not have access to the key linking 
the Subject ID with the second unique identifier. 
 
 
 
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6.4 
STUDY INTERVENTION COMPLIANCE 
 
The investigational product is dispensed and placed on the treatment area by the investigator or 
delegated site staff during the clinic visit. Date and time of application and time of removal of the 
investigational product is to be documented in the participant’s file and in the Case Report Form (CRF). 
 
6.5 
CONCOMITANT THERAPY 
 
Medications to be reported in the CRF are concomitant prescription medications, over-the-counter 
medications and supplements.  
 
Systemic immunosuppressive treatment is prohibited during the study. 
 
6.5.1 RESCUE MEDICINE 
 
Not-applicable 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
A DMC will be established to monitor participant safety and the dose escalation , and an DMC charter 
including safety stopping rules will be finalized prior to the first participant enrolled into the study. The 
DMC will be notified of all treatment discontinuationsDMC. 
 
The Investigator may delay/skip a study treatment or prematurely terminate the study treatment 
according to guideline in Appendix 1.  
 
Additionally, pain at the treatment site will be assessed by the participant using an 11-point numerical 
response scale (NRS), and the investigator will take into consideration the pain level as assessed by the 
study participant to determine if treatment should be delayed/skipped or prematurely terminated. 
 
Discontinuation from study treatment does not mean discontinuation from the study. Remaining study 
procedures should be completed as indicated by the study protocol.  If a clinically significant finding is 
identified after enrollment, e.g., change from baseline or anytime during the study, the investigator or 
qualified designee will determine if any change in medical management is needed. Any new clinically 
relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include assessments listed 
for all follow-up visits. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
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• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event, laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to receive study treatment for more than 2 weeks (+/- 2 days) since the last 
treatment. 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF).  To allow for subjects who discontinue or withdrawal  prior to treatment or receiving 
the 3 planned treatments, additional participants may be enrolled to ensure that each cohort is 
evaluable. Additional participants will be added according to Section 1.2 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 2 consecutive scheduled 
visits and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 2 days and 
counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address). These contact attempts should 
be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
A visual and dermatoscopic evaluation of the treatment area for visible evidence of BCC will be performed 
pre and post each application of the D-MNA and at the End-of-Treatment visit prior to excision of the 
lesion. 
 
An standard of care excision of the treatment site will be performed at Visit 4. The biopsy slide (prepared 
per standard operation procedures at the site) will be sent to a central reader to assess clinical response 
to the study treatment. The clinical response will be assessed by a central reader after the 3-week 
course of treatment and will be categorized as either absence or presence of Complete Response (CR) 
defined as no histologically proven BCC cells in excised tissue.  
 
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Preparation of the biopsy slide and the blinded central reading process are detailed in a Central Reading 
Procedure Manual. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Participants will undergo a physical examination including assessment of vital signs at screening and at 
Visit 4. 
 
Safety laboratory tests (hematology, serum chemistry, urinalysis) will also be performed at the local 
laboratory at screening and at the Visit 4 follow up visit: 
 
Hematology 
• 
White blood count (WBC) 
• 
Platelet count 
• 
Hematocrit 
• 
Hemoglobin 
  
Serum Chemistry 
• 
Creatinine 
• 
Blood urea nitrogen (BUN) 
• 
Glucose 
• 
Aspartate aminotransferase (AST) 
• 
Alanine aminotransferase (ALT) 
• 
Albumin 
• 
Amylase 
• 
Lipase 
• 
Total bilirubin 
• 
Alkaline phosphatase 
• 
Potassium 
• 
Calcium 
• 
Phosphate 
• 
Lactate dehydrogenase 
 
Urinalysis 
• 
Macroscopic 
• 
Microscopic  
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Glucose 
• 
Ketones 
• 
Hemoglobin 
• 
Leukocyte esterase 
• 
Nitrite 
• 
Bilirubin 
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Additionally, ECG will also be performed locally according to standard practice at screening and at the 
Visit 4 27pEnd-of-Treatment visit.  
 
Pregnancy test will be performed for women of childbearing pontential at Screening  and End-of -
Treatment visit. 
 
After each application of the MNA, the investigator will visually inspect the skin/treatment area to 
assess tolerance of the study treatment. Dermatoscopic evaluation and photography of the lesion will 
be completed pre and post array application. Assessment of dose-limiting toxicity according to the local 
skin responses grading scale in Appendix 1 of the protocol will be performed.  Assessment of wound 
healing will be performed at all follow-up visits according to standard of care for a typical standard of 
care excision procedure.  
 
Quantification of the doxorubicin remaining in the used MNA will be performed.    
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or Sponsor, it results in any of the following outcomes:  
• 
Death 
• 
Life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• 
Congenital anomaly/birth defect 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition.  
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
Except for subject-reported pain AEs via the NRS referenced in Appendix 2, Common Terminology 
Criteria for Adverse Events (CTCAE) Version 5.0 will be used for severity grading of adverse events (Aes).  
The CTCAE is not provided as a part of the protocol, but can be accessed and downloaded at the 
following website:  
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https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.
pdf 
 
For  subject-reported pain AEs via the NRS, the numerical rating will be assigned a severity (e.g., mild, 
moderate, severe) based upon pain intensity-to-severity grading in Appendix 2.  
    
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (Aes) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (challenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it can 
be flagged as requiring more information and later be upgraded to “probably related” or “definitely 
related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship improbable 
(e.g., the event did not occur within a reasonable time after administration of the study 
intervention) and in which other drugs or chemicals or underlying disease provides plausible 
explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician. 
 
8.3.3.3 EXPECTEDNESS  
 
Treatment with D-MNA is expected to elicit local skin reactions which are the most common adverse 
effects of this non-systemic treatment.  Some cutaneous responses (e.g., erythema, flaking/scaling, 
crusting, swelling, vesiculation/pustulation, erosion/ulceration) to the D-MNA are indicative of drug 
dispersal. 
 
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The investigator will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. Aes characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The investigator will record all adverse events with start dates occurring any time after informed 
consent is obtained until  the  Visit 7 Final Follow-up.  If a participant discontinues for any reason prior to 
Vist 7, all Aes ≥ “Potentially Related” (see Section 8.3.3.2) will continue to be followed as defined in 
Section 8.3.5.   At each study visit, the investigator will inquire about the occurrence of AE/SAEs since 
the last visit.  Events will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
All Aes including local and systemic reactions and abnormal clinically significant laboratory values not 
meeting the criteria for SAEs will be captured on the appropriate case report form (CRF). Information to 
be collected includes event description, time of onset, clinician’s assessment of severity, relationship to 
study product (assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All Aes occurring while on study must be documented 
appropriately regardless of relationship. All related (i.e., ≥ Potentially Related) Aes will be followed to 
adequate resolution or stabilization to a grade acceptable to the Investigator and has concurrence by 
the Sponsor or the subject is lost to follow-up (as defined in Section 7.3). 
 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
The investigator will immediately report to the sponsor any serious adverse event within 24 hours of 
becoming aware of the event, whether or not considered study intervention related, including those 
listed in the protocol or investigator brochure and must include an assessment of whether there is a 
reasonable possibility that the study intervention caused the event. All SAEs will be reported to the IRB 
per local regulatory requirements. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the investigator 
deems the event to be chronic or the participant is stable or is lost to follow-up (as defined in Section 
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7.3). Other supporting documentation of the event may be requested by the Independent Data 
Monitoring Committee and/or the study sponsor and should be provided as soon as possible. 
 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor’s initial receipt of the information.  In addition, the sponsor must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
New information gathered during the study that may affect participant’s consent to continue 
participation will be provided to the participants. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
Not Applicable 
 
8.3.9 REPORTING OF PREGNANCY  
 
All female participants of child bearing potential will have negative pregnancy test during the screening 
process before enrollment into this study. Women with a positive pregnancy test are not eligible to 
participate in this study.  
 
If a participant becomes pregnant during the study, she will continue to be followed at the scheduled 
study visit as described in SECTION 7.2,  Participant Discontinuation/Withdrawal from the Study.  
 
Male participants with a partner of child-bearing potential should be informed of the reproductive risk 
per the Product Insert for doxorubicin and to take prophylactic measures to prevent pregnancy. 
 
Pregnancy is not reported as an adverse event, pregnancy will be documented on a specific CRF.  
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all 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 Institutional Review Board (IRB)-approved 
research protocol and informed consent document; and (b) the characteristics of the participant 
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 
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• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (Ups) to the reviewing Institutional Review Board 
(IRB) and the sponsor. The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, Ups will be reported using the following timeline:   
 
• 
Ups that are serious adverse events (SAEs) will be reported to the IRB and to the study sponsor 
immediately and within 24 hours of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the study sponsor as soon as possible and within 5 
business days of the investigator becoming aware of the problem.  
• 
All Ups should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures) and other regulatory agencies according to national and local 
regulations.  
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
As applicable, national and local regulations will be followed to inform the trial participants of relevant 
Ups. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
No hypothesis testing or inferential statistical analyses are planned in this Phase I dose escalation study. 
All statistical analyses will be descriptive. Summary statistics and associated confidence intervals will be 
calculated for the primary, secondary and safety endpoints for each dose group. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
The study will follow a traditional 3+3 dose escalation design with 4 dose groups plus placebo  to define 
a MTD by evaluating DLTs as described in Section 1.2. Based on this design, between 15 and 30 subjects 
will be required to be evaluable for the primary DLT endpoint.  
 
 
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9.3 
POPULATIONS FOR ANALYSES 
• 
DLT evaluable population: 
Defined as subjects who complete the study without experiencing a DLT or subjects who experience 
a DLT regardless of discontinuation. Participants who discontinue the study prior to Visit 4 without 
experiencing a DLT will not be considered evaluable for the primary DLT endpoint. 
 
• 
Safety Population:  
Defined as all enrolled subjects who receive treatment. The safety population will be included in all 
safety analyses and summaries.   
 
• 
Efficacy Population: 
Defined as all subjects in the safety population without major protocol deviations. Efficacy analyses 
will be conducted on the efficacy population. 
 
9.4 
STATISTICAL ANALYSES 
 
A formal Statistical Analysis Plan (SAP) will be a separate document and will be updated as required, in 
association with any protocol amendments. The plan will provide additional details of the statistical 
methodology as well as tables, listings, graphs and statistical programming considerations. The SAP will 
be completed prior to database lock and unblinding of the study data. 
 
9.4.1 GENERAL APPROACH 
 
All statistical analyses will be descriptive. No hypothesis testing is planned. Descriptive statistics will 
include n, mean, median, standard deviation, minimum and maximum for continuous data and n and 
percentages for categorical data. All efficacy analyses will be conducted for the efficacy population. 
Missing clinical response data at Visit 4 (21 days) will be imputed from the clinical response based on 
biopsy results of standard of care excision at the time of discontinuation, when available. All safety 
analyses will be conducted on the safety population.  
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 
The primary study endpoint will be the assessment of DLT through Visit 4 (21 days) as defined in 
Appendix 1 using the LSR grading scale. All DLTs will be summarized for each dose group including 
placebo. The MTD will be defined as the highest dose with a DLT rate below 33%.  
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Lesion Response 
The proportion of participants achieving a histological complete response (CR) at Visit 4 (21 days) will be 
summarized with the associated 95% exact 1-sided confidence interval (CI) for each dose group 
including placebo.  
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Additional Endpoints 
The following endpoints will be summarized by dose group (including placebo) using descriptive 
statistics at each study visit: 
 
• 
Visual evidence of BCC at the treatment site pre and post MNA application by visual and 
dermatoscopic inspection of the treatment site  
• 
Local tolerance of the MNA on the skin as measured by the LSR grading scale  
• 
Pain assessment using an 11-point numerical rating scale (NRS) 
 
9.4.4 SAFETY ANALYSES 
 
All enrolled participants who receive treatment will be included in the safety analysis and summaries. 
Adverse events will be coded using MedDRA and summarized by dose group for number of participants 
reporting the adverse event and the number of adverse events reported. A by-subject adverse event 
data listing including verbatim term, preferred term, dose group, severity, and relationship to study 
medication will be provided. 
 
Wound healing at the surgical standard of care excision site will be assessed during the suture removal 
visit according to standard of care. 
 
Safety endpoints will include skin evaluations, clinical laboratory tests, urinalysis, physical examination, 
vital signs, ECG, and adverse events. Descriptive statistics will be used to summarize safety endpoints 
overall and separately by dose group.  
 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Demographics and baseline disease characteristics will be summarized by dose group using descriptive 
statistics. 
 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
Interim safety summaries will be prepared for review by the DMC prior to each dose escalation.  
 
 
9.4.7 SUB-GROUP ANALYSES 
 
No subgroup analyses are planned. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
All individual subject data will be reported in data listings by time point. 
 
 
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9.4.9 EXPLORATORY ANALYSES 
 
Quantification of the doxorubicin remaining in the used MNA will be summarized by dose group 
including placebo using descriptive statistics. 
 
Additional exploratory analyses may be conducted. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
In obtaining and documenting informed consent, the investigator must comply with applicable 
regulatory requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and should adhere to ICH 
GCP. Prior to the beginning of the trial, the investigator should have the IRB’s written approval for the 
protocol and the written informed consent form(s) and any other written information to be provided to 
the participants.  
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to any study specific 
procedures and administration of study intervention.   
 
An standard of care excision of the BCC lesion will be performed for all subjects. There is no benefit from 
participation in this study other than contribution to research. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator or designee will explain the research study to the participant and answer any questions that 
may arise. A verbal explanation will be provided in terms suited to the participant’s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
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and welfare of the participants 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. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, the Investigational 
New Drug (IND) sponsor and regulatory authorities.  If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional 
Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension.  Study 
participants will be contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their representatives. This confidentiality is extended to cover testing of 
biological samples in addition to the clinical information relating to participants. 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.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), and regulatory agencies 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 participants in this study. The clinical study site will permit access to such 
records. 
 
The study participant’s contact information will be securely stored at each 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 the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored in a database at the Sponsor and/or Clinical Research Organization (CRO) 
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designated by the sponsor. This will not include the participant’s contact or identifying information. 
Rather, individual participants and their research data will be identified by a unique study identification 
number. The study data entry and study management systems used by clinical sites and by the CRO 
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 CRO designated by the sponsor. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at the sponsor and/or designated CRO. After 
the study is completed, the de-identified, archived data will be transmitted to and stored at the sponsor 
designated CRO. The data may be used by other researchers including those outside of the study.  
 
Any publication of results obtained from this study will not identify the participant by name.  
 
Absolute participant confidentiality cannot be guaranteed due to the requirements to release 
information to authorized representatives of the sponsor, representatives of the Institutional Review 
Board (IRB), and regulatory agencies. In any event, the sponsor will use reasonable efforts to preserve 
participant confidentiality. 
 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), images of 
de-identified biopsy slides, will be stored with the study archive. Tissues collected for the experimental 
endpoints may also be stored with the participant and IRB approval.  
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biopsy slides stored for future research.  
 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Study Management 
Medical Monitor 
Gregory R Suplick 
Senior Director, Clinical Operations 
Susan Tansey, MD 
Chief Medical Officer 
InClinica 
InClinica  
Ph:  484.636.9333 
Email: 
susan.tansey@boydconsultants.com 
Email: gsuplick@inclinica.com 
 
 
 
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of an Data Monitoring Committee (DMC) composed of 
individuals with the appropriate expertise, including dermatologists, and statistician.DMC  The DMC will 
oversee safety in the study including the dose escalations. The DMC will operate under the rules of an 
approved charter that will be written prior to enrollment of the first participant.  
 
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The IRB(s) and relevant health authority(ies) will be notified of decisions of the DMC in accordance with 
local regulatory requirements. 
 
10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial 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 International 
Conference on Harmonisation Good Clinical Practice (ICH GCP E6 (R2)), and with applicable regulatory 
requirement(s).  
 
Monitoring for this study will be performed by the sponsor’s designated CRO, InClinica. Details of clinical 
site monitoring are documented in a Clinical Monitoring Plan (CMP). 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 monitoring reports. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The study site staff should be trained in Good Clinical Practice (GCP) and operate under GCP principles 
for the conduct of the study. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Independent audits may be conducted by Sponsor representative to ensure monitoring practices are 
performed consistently across all participating sites and that monitors are following the CMP. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted, and data are generated, and biological specimens are collected, documented (recorded), 
and reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible and indelible manner to ensure accurate 
interpretation of data.   
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Hardcopies of the study visit worksheets may be used to supplement other source document 
worksheets for recording data for each participant enrolled in the study.  Data recorded in the electronic 
case report form (eCRF) derived from source documents should be consistent with the data recorded on 
the source documents.  
 
Clinical data (including adverse events (Aes), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into an electronic data capture system which is 21 CFR 
Part 11-compliant. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical 
data will be entered directly from the source documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or study specific manual requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, 4.5.3 and 4.5.4.   
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report major 
deviations, especially those affecting safety of the participants, within one (1) working days of 
identification of the protocol deviation.  All deviations must be addressed in study source documents.  
Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per its policies. The 
site investigator is responsible for knowing and adhering to the reviewing IRB requirements.  
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
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• 
All manuscripts, abstracts, or presentations developed from the results of this study must been 
reviewed and approved in writing by the sponsor in advance of submission or public presentation. 
The review is intended to protect sponsor proprietary information.  
• 
Investigator may not publish results from his/her study site until after the publication of the primary 
manuscript describing the full trial results. 
• 
This trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov.  
 
The obligations regarding the publication of any data, material results or other information that is 
generated or created in relation to the trial will be detailed in the clinical trial agreement between the 
investigator and sponsor. 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  
  
10.2 ADDITIONAL CONSIDERATIONS 
Not-applicable 
 
 
 
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10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase  
AST 
Aspartate Aminotransferase 
AUC 
Area Under Curve 
BCC 
Basal Cell Carcinoma 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum Plasma Concentration  
CMP 
Clinical Monitoring Plan 
CR 
Complete Response 
CRO 
Clinical Research Organization 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria  for Adverse Events 
CTLC 
Cutaneous T-Cell Lymphoma  
DLT 
Dose-Limiting Toxicity  
D-MNA 
Doxorubicin-Microneedle Array 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Forms 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
ICH 
International Conference on Harmonisation  
IND 
Investigational New Drug Application 
IMP 
Investigational Medicical Product 
IRB 
Institutional Review Board 
LVEF 
Left Ventricular Ejection Fraction  
LSR 
Local Skin Responses 
MNA 
Microneedle Array 
MTD 
Maximum Tolerated Dose 
NCT 
National Clinical Trial 
NR 
No Response 
OHRP 
Office for Human Research Protections 
ORR 
Objective Response Rate 
PI 
Principal Investigator 
PD 
Pharmacodynamics  
PK 
Pharmacokinetics  
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
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SAP 
Statistical Analysis Plan 
SCC 
Squamous Cell Carcinoma  
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
Tmax 
Time of Maximum Plasma Concentration 
t1/2 
Half-Life 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problem 
US 
United States 
WBC 
White Blood Count 
 
 
 
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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the pages before the Table of Contents.  
 
Version 
Date 
Description of Change  
Brief Rationale 
3.0 
11 Feb 2020 
Updates to the trial: 
• 
Endpoints and objectives 
(make consistent throughout 
the document) 
• 
Entrance criteria 
• 
General update to the 
document 
Clarify and make sections 
consistent. 
 
3.1 
08 Jun 2020 
• 
Update to Schedule of 
Activities 
• 
Revision to inclusion 
criterion #2 
• Clarify and make consistent 
with the language in the body 
of the protocol 
• Clarify and adjust previously 
diagnosed BCC inclusion 
criterion 
3.2 
06 Aug 2020 
• 
Update to the DLT 
assessment language 
assocoiated with local skin 
reactions (LSR). 
 
• Clarify the language and 
criteria for subjects entering 
the trial with baseline LSRs. 
 
3.3 
28 Dec 2020 
• 
Revision to the study drug 
administration language 
• Clarify the steps that study 
personnel are to follow for 
administering the study drug. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11 REFERENCES  
 
1. Yang F, Teves SS, Kemp CJ, Henikoff S. Doxorubicin, DNA torsion, and chromatin dynamics. Biochim 
Biophys Acta . 2014;1845(1):84-89. 
 
2. Fornari FA, Randolph JK, Yalowich JC, Ritke MK, Gewirtz DA. Interference by doxorubicin with DNA 
unwinding in MCF-7 breast tumor cells. Mol Pharmacol. 1994;45(4):649-56. 
 
3. Sinha BK. Is Metabolic Activation of Topoisomerase II Poisons Important In The Mechanism Of 
Cytotoxicity? Journal of Drug Metabolism & Toxicology. 2015;06(03):186-186. 
 
4. Verkouteren JAC, Ramdas KHR, Wakkee M, Nijsten T. Epidemiology of basal cell carcinoma: scholarly 
review. Br J Dermatol. 2017;177(2):359-372. 
 
5. Gupta S, Takebe N, Lorusso P. Targeting the Hedgehog pathway in cancer. Ther Adv Med Oncol. 
2010;2(4):237-50. 
 
6. Soura E, Chasapi V, Stratigos AJ. Pharmacologic treatment options for advanced epithelial skin cancer. 
Expert Opin Pharmacother. 2015;16(10):1479-93.. 
 
7. Schön MP, Schön M. Imiquimod: mode of action. Br J Dermatol. 2007;157 Suppl 2:8-13. 
 
8. Bath-hextall F, Ozolins M, Armstrong SJ, et al. Surgical excision versus imiquimod 5% cream for nodular 
and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial. 
Lancet Oncol. 2014;15(1):96-105. 
 
9. Nakamura A, Nakajima G, Okuyama R, et al. Enhancement of 5-fluorouracil-induced cytotoxicity by 
leucovorin in 5-fluorouracil-resistant gastric cancer cells with upregulated expression of thymidylate 
synthase. Gastric Cancer. 2014;17(1):188-95. 
 
10. Roozeboom MH, Arits AH, Mosterd K, et al. Three-Year Follow-Up Results of Photodynamic Therapy vs. 
Imiquimod vs. Fluorouracil for Treatment of Superficial Basal Cell Carcinoma: A Single-Blind, 
Noninferiority, Randomized Controlled Trial. J Invest Dermatol. 2016;136(8):1568-74. 
 
11. Wu CS, Chen GS, Lin PY, et al. Tazarotene induces apoptosis in human basal cell carcinoma via activation 
of caspase-8/t-Bid and the reactive oxygen species-dependent mitochondrial pathway. DNA Cell Biol. 
2014;33(10):652-66. 
 
12. Bianchi L, Orlandi A, Campione E, et al. Topical treatment of basal cell carcinoma with tazarotene: a 
clinicopathological study on a large series of cases. Br J Dermatol. 2004;151(1):148-56. 
 
13. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat 
Rev Drug Discov. 2012;11(3):215-33. 
 
14. Cancer Facts and Figures 2018. American Cancer Society. https://www.cancer.org/content/dam/cancer-
org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-
2018.pdf. Accessed May 15, 2018. 
 
15. Gould A, Missailidis S. Targeting the hedgehog pathway: the development of cyclopamine and the 
development of anti-cancer drugs targeting the hedgehog pathway. Mini Rev Med Chem. 2011;11(3):200-
13. 
 
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16. Guy GP, Machlin SR, Ekwueme DU, Yabroff KR. Prevalence and costs of skin cancer treatment in the U.S., 
2002-2006 and 2007-2011. Am J Prev Med. 2015;48(2):183-7. 
 
17. Hochberg M. Experimental Models for BCC. Journal of Dermatology and Clinical Research. 2013;1(1):1002.  
 
18. Friedman B, Donahue C, Erdos G, Falo LD. A topical chemo-immunotherapy for squamous cell carcinoma. 
The Journal of Immunology. 2016;196(1):213.9. 
 
19. Friedman B, Carey C, Edros G, Falo LD. Topical chemo-immunotherapy converts a pro-tumorigenic tumor 
microenvironment to a pro-inflammatory phenotype in human cutaneous squamous cell carcinoma. The 
Journal of Immunology. 2017;198(1):66.21 
 
20. Falo LD, Erdos G, Ozdoganlar B. Microneedle Arrays for Cancer Therapy Applications. May 2016. 
 
21. Clinicaltrials.gov. (2018). Micro Needle Array-Doxorubicin (MNA-D) in Patients With Cutaneous T-cell 
Lymphoma (CTCL) - Full Text View - ClinicalTrials.gov. [online] Available at: 
https://clinicaltrials.gov/ct2/show/NCT02192021?term=doxorubicin+dermal&draw=2&rank=1 [Accessed 
14 Jun. 2018]. 
 
22. Akilov O, Mccann S, Chao E, Cullison SJ, Erdos G, Falo L. 581 Phase 1, single-arm, open-label, dose 
escalation trial of microneedle array-doxorubicin in patients with mycosis fungoides. Journal of 
Investigative Dermatology. 2018;138(5) 
 
23. SRC Study No.: S15055: A 14-Day Toxicity and Toxicokinetic Study of Doxorubicin Delivered Topically by 
Microneedle Array (MNA) to Yucatan Minipigs 
 
24. Doxorubicin Package Insert: Accessdata.fda.gov. (2018). [online] Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050629s022lbl.pdf [Accessed 8 Jun. 2018]. 
25. Geisse J, Rich P, Pandya A et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: 
A double-blind, randomized, vehicle-controlled study*. J Am Acad Dermatol. 2002;47(3):390-398. 
26. Common Terminology Criteria for Adverse Events (CTCAE). Common Terminology Criteria for Adverse 
Events (CTCAE), Version 5. Published October 17, 2017.  
 
 
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12 APPENDICES  
 
12.1 Appendix 1  
Guidelines for skipping/delaying and discontinuation of study treatment and definition of Dose 
Limiting Toxicity Using the LSR Grading Scale 
GUIDELINE 1 
For subjects who enter the trial with LSR evaluations =Grade 0 and experience an increase in severity during their 
participation, the guidelines below will be applied: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GUIDELINE 2 
For subjects who enter the trial with any LSR evaluation ≥Grade 1 and experience an increase in severity during 
their participation, the guidelines below will be applied: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any 1 of the following 
• Vesiculation / Pustulation ≥ 3 
• Erosion/Ulceration ≥ 3 
• Crusting ≥ 3 
• Scaling ≥ 3 
• Erythema = 4 
Two (2) or more of the following 
• Vesiculation / Pustulation ≥ 2 
• Erosion/Ulceration ≥ 2 
• Crusting ≥ 2 
• Scaling ≥ 3 
• Erythema ≥ 3 
OR 
 
Assessed at one (1) clinic visit 
h 
Assessed at two (2) consecutive protocol 
defined evaluations at two (2) consecutive 
clinic visits 
Skip/Delay 
Study Treatment 
Dose Limiting 
Toxicity is Reached; 
Discontinue  
Study Treatment 
Any 1 of the following 
• Vesiculation / Pustulation ≥ 3 
• Erosion/Ulceration ≥ 3 
• Crusting ≥ 3 
• Scaling ≥ 3 
• Erythema = 4 
Two (2) or more of the following 
• Vesiculation / Pustulation =4 
• Erosion/Ulceration =4 
• Crusting =4 
• Scaling =4 
• Erythema =4 
OR
 
Assessed at two (2) consecutive protocol 
defined evaluations at two (2) consecutive 
clinic visits 
 
Assessed at one (1) clinic visit 
Skip/Delay 
Study Treatment 
Dose Limiting 
Toxicity is Reached; 
Discontinue  
Study Treatment 
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The LSR evaluation and assessment of any potential change in treatment and/or DLT determination is to be 
conducted on an individual LSR category.  For example, a subject may have two (2) grade 0 and three (3) grade 1 
LSRs at pre-treatment Visit 1, Day 1.  Subsequent evaluations will require use of both guidelines above. 
 
Local Skin Responses (LSR) Grading Scale 
 
 
 
0 
1 
2 
3 
4 
Erythema 
Not Present 
Slightly Pink 
Pink or Light Red 
>50% 
Red, Restricted 
to Treatment 
Area 
Red Extending Outside 
of Treatment Area 
Flaking / 
Scaling 
Not Present 
Isolated Scale, 
Specific to Lesions 
Scale < 50% 
Scale >50% 
Scaling Extending 
Outside Treatment Area 
Crusting 
Not Present 
Isolated Crusting 
Crusting < 50% 
Crusting >50% 
Crusting Extending 
Outside Treatment Area 
Swelling 
Not Present 
Slight Lesion 
Specific Edema 
Palpable Edema 
Extending Beyond 
Individual Lesions 
Confluent 
and/or Visible 
Edema 
Marked Swelling 
Extending Outside 
Treatment Area 
Vesiculation / 
Pustulation 
Not Present 
Vesicles Only 
Transudate or Pustules, 
With or Without 
Vesicles < 50% 
Transudate or 
Pustules, With 
or Without 
Vesicles >50% 
Transudate or Pustules, 
With or Without 
Vesicles Extending 
Outside Treatment Area 
Erosion / 
Ulceration 
Not Present 
Lesion Specific 
Erosion 
Erosion Extending 
Beyond Individual 
Lesions 
Erosion >50% 
Black Eschar or 
Ulceration 
 
Appendix 1 (continued next page) 
Grade 
Categories 
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Rosen, Robert, Marmur, Ellen, Anderson, Lawrence, Welburn, Peter, Katsamas, Janelle. A New, Objective, Quantitative Scale for 
Measuring Local Skin Responses Following Topical Actinic 
Keratosis Therapy with Ingenol Mebutate. Dermatol Ther (Heidelb) (2014) 4:207–219 DOI 10.1007/s13555-014-0059-9 
 
 
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12.2 Appendix 2 
 
 
 
 
https://www.physio-pedia.com/Numeric_Pain_Rating_Scale 
 
 
Pain Intensity-to-Severity Grading 
 
 
Breivik H, Borchgrevik P, Allen S, Rosseland L, Romundstad L, Breivik Hals E, Kvarstein G, Stubhaug A.  Assessment of pain.  
British Journal of Anaesthesia. 2008; 101(1):17-24 
 
 
 
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SAP_001.pdf: 
 
SkinJect, Inc. 
Protocol SKNJCT-001 
Statistical Analysis Plan  
03May2021 
 
Confidential 
Page 1 of 22 
 
 
Protocol SKNJCT-001 
 
 
An Open-Label Dose Escalation Trial to Evaluate Dose Limiting Toxicity (DLT), Maximum 
Tolerated Dose (MTD), Safety and Tolerability of Microneedle Arrays containing Doxorubicin 
(D-MNA) in Participants with Basal Cell Carcinoma (BCC) 
 
 
 
 
 
Document type: 
Statistical Analysis Plan  
Document status: 
FINAL v1.0 
Release date: 
03 May 2021 
Protocol: 
SKNJCT-001 - Protocol Version 3.4 dated 09February 2021 
National Clinical 
Trial Number: 
NCT03646188  
 
 
 
 
 
 


 
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03May2021 
 
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Table of Contents 
Table of Contents................................................................................................................... 2 
1 
Glossary and Abbreviations ............................................................................................ 5 
2 
Introduction ................................................................................................................... 6 
3 
Study Rationale, Background and Objectives .................................................................. 6 
3.1 
Study Rationale .................................................................................................................6 
3.2 
Background .......................................................................................................................7 
3.3 
Data Monitoring Committee (DMC) ....................................................................................8 
4 
Study Objectives ............................................................................................................. 8 
4.1 
Primary Objective ..............................................................................................................8 
4.2 
Secondary and Exploratory Objectives ................................................................................8 
5 
Study Design .................................................................................................................. 9 
5.1 
Overall Study Design ..........................................................................................................9 
5.2 
Dose Justification ...............................................................................................................9 
5.3 
Subjects ........................................................................................................................... 10 
5.4 
Study Design Summary .................................................................................................... 10 
6 
Determination of Sample Size ....................................................................................... 10 
7 
Randomization ............................................................................................................. 10 
8 
Analysis Populations .................................................................................................... 11 
9 
Statistical Analysis ....................................................................................................... 11 
9.1 
General Considerations .................................................................................................... 11 
9.2 
Baseline Values ................................................................................................................ 13 
9.3 
Maximum Tolerated Dose (MTD)...................................................................................... 13 
9.4 
Handling of Missing Data.................................................................................................. 13 
10 Background Characteristics .......................................................................................... 13 
10.1 
Subject Disposition .......................................................................................................... 13 
10.2 
Demographic and Baseline Characteristics ........................................................................ 13 
10.3 
Prior and Concomitant Medications ................................................................................. 13 


 
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10.4 
Medical History ................................................................................................................ 14 
11 Study Treatment .......................................................................................................... 15 
12 Primary and Secondary Endpoint Analysis .................................................................... 15 
12.1 
Primary Endpoint Analysis:  Assessment of DLT................................................................. 15 
12.2 
Secondary Endpoint Analysis ............................................................................................ 15 
12.2.1 
Lesion Response .............................................................................................................................. 15 
12.2.2 
Additional Endpoints ....................................................................................................................... 15 
13 Safety Analysis ............................................................................................................. 16 
13.1 
Adverse Events ................................................................................................................ 16 
13.2 
Laboratory Data ............................................................................................................... 17 
13.3 
Vital Signs and Body Measurements ................................................................................. 17 
14 Exploratory Analyses .................................................................................................... 18 
15 Interim Summaries and Data Monitoring ...................................................................... 18 
16 References ................................................................................................................... 19 
17 Planned Tables and Listings .......................................................................................... 20 
17.1 
Planned Tables ................................................................................................................ 20 
17.2 
Planned Listings ............................................................................................................... 22 
 
 


 
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Signature Page 
 
 


 
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1 
Glossary and Abbreviations 
Abbreviation 
Definition 
AE 
Adverse Event 
ALL 
All Subjects Population 
BCC 
Basal Cell Carcinoma 
CI 
Confidence Interval 
CRF 
Case Record Form 
CTCL 
Cutaneous T-cell lymphoma 
DLT 
Dose Limiting Toxicity 
DLTP 
Dose Limiting Toxicity population 
DMC 
Data Monitoring Committee 
DOX 
Doxorubicin 
D-MNA 
Doxorubicin microneedle array 
EFF 
Efficacy population 
ICH 
International Council for Harmonisation 
LSR 
Local skin reaction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNA 
Microneedle array 
MTD 
Maximum Tolerated Dose 
NRS 
Numerical Rating Scale 
PT 
Preferred Term 
SAE 
Serious Adverse Events 
SAF 
Safety Population 
TEAE 
Treatment Emergent Adverse Event 
TL 
Tables and Listings 
 
 
 


 
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2 
Introduction 
This study is a Phase I study designed as an open-label dose escalation trial of D-MNA in subjects 
with BCC (subtype: superficial or nodular). The goal of the dose escalation is to determine the 
maximum tolerated dose (MTD) and assess lesion responses in the different dose groups to 
inform a decision on the doses to be tested in a subsequent Phase II study.  
The statistical methods to be implemented during the analyses of data collected within the scope 
of this study will be outlined in this document.  The purpose of this plan is to provide specific 
guidelines from which the statistical analysis will proceed.  Any deviations from this plan will be 
documented in the clinical study report. 
3 
Study Rationale, Background and Objectives 
3.1 
Study Rationale 
This is a Phase I study in subjects with superficial or nodular Basal Cell Carcinoma (BCC), designed 
to assess dose limiting toxicities (DLTs) and MTD, efficacy, safety, and tolerability of dissolvable, 
tip-loaded, microneedle arrays containing doxorubicin (D-MNA). Doxorubicin (DOX) is a cytotoxic 
anthracycline antibiotic and is currently approved for the treatment of a broad range of cancers, 
including but not limited to:  breast, bladder, gastric, and ovarian cancers; small cell lung cancer; 
acute lymphoblastic leukemia; and acute myeloblastic leukemia. SkinJect, Inc. has developed a 
novel delivery system in the form of a dissolvable microneedle array (MNA) which is intended to 
allow subepidermal delivery of doxorubicin directly to the lesion at concentrations that are far 
below standard systemic dosing, thereby reducing the adverse events associated with systemic 
delivery.  
The primary objective of this investigation is to establish the highest safe and tolerable dose of 
single applications of D-MNA, one application administered weekly, three times over a two- week 
period in placebo, 25 μg, 50 μg, 100 μg, and 200 μg DOX dose groups in subjects with BCC.  
Safety, efficacy and tolerability of the different doses will be evaluated, and additionally, 
quantification of the DOX delivered to the BCC lesion and DOX remaining in the MNA after use 
will be performed.  


 
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We hypothesize that treatment with D-MNA will result in tumor destruction and the induction of 
potent, immunogenic anti-tumor responses. Because MNAs enable this agent to be delivered at 
very low doses to a confined tumor microenvironment we expect only minimal, if any, systemic 
drug toxicity; thus, facilitating optimal local dose levels and durable clinical responses.  
3.2 
Background 
BCC is the most common skin cancer, with more than 4-million cases diagnosed each year in the 
US1. Despite its relatively low mortality rate, BCC is responsible for approximately 3000 deaths 
annually2, and, along with SCC, results in $4.8 billion/year in healthcare spending in the US3. The 
development of a successful chemo-immunotherapy for the treatment of BCC represents an 
alternative, non-invasive treatment of this disease, particularly for individuals for whom surgical 
resection is contra-indicated or is done with elevated risk. The introduction of a safe, locally- 
administered, effective non-surgical treatment has the potential to reduce morbidity, mortality, 
and healthcare expenditures.  
Early clinical data demonstrates the potential efficacy of D-MNA in treatment of mycosis 
fungoides, a common subtype of cutaneous T-Cell lymphoma (CTCL). An early clinical study is 
currently being conducted by Professor Louis Falo at University of Pittsburgh (IND #12244824). 
The primary objective of the study is to evaluate the safety of escalating, low doses (25-200 μg) 
of DOX delivered directly into CTCL lesions using a MNA system. Secondary objectives include 
evaluations of the pharmacokinetics and pharmacodynamics of DOX when delivered using the D-
MNA system; and evaluations of local, locoregional, and distant responses, biologic responses, 
and effects of treatment on the tumor microenvironment. The initial Phase 1 clinical trial by Prof. 
Falo incorporates a single-arm, placebo- controlled (within subjects), open-label, accelerated 
dose escalation study design to determine the MTD (or effective dose) of DOX. This is followed 
by an extended evaluation of safety and effectiveness at the determined MTD or effective dose.  
In Prof. Falo’s trial, the first cohort of three subjects was treated with 25 μg of DOX via MNA. 
Subjects were treated once/week for four weeks, followed by a one-week break. No toxicities 
were observed at the 25-μg dose, and the original cohort, plus a new three-subject cohort were 
escalated to the 50-μg dose. DLT, a cutaneous reaction, was observed in one subject at the 50-
μg dose and the cohort was expanded to two additional subjects, with no additional DLT 
reported. One subject in the 50-μg cohort exhibited a complete resolution of mycosis fungoides 
in response to D-MNA5.  


 
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SkinJect’s trial uses a 3+3 design, enrolling five dosing cohorts, namely, placebo MNAs, 25 µg D-
MNA, 50 µg D-MNA, 100 µg D-MNA, and a 200 µg D-MNA. 
3.3 
Data Monitoring Committee (DMC) 
A DMC has been chartered for this study. Membership in this committee includes qualified 
physicians who are dermatologists with expertise in treating skin cancer and sponsor’s medical 
monitor, as well as individuals with DMC expertise. The DMC will review the safety data at the 
end of each cohort during the dose escalation phase of the study.  After the last end-of-treatment 
(i.e., Day 21) visit for the last subject in the trial has occurred, the DMC will review the safety data 
for all of the subjects for DLTs and determine when a MTD has been reached. Details of the safety 
review as well as recommended dose selection for future clinical trials will be defined by the 
DMC.  
4 
Study Objectives 
4.1 
Primary Objective 
The primary objective is to establish the highest safe and tolerable dose of single applications of 
D-MNA, one application administered weekly, three times over a two-week period (Time 0, Week 
1 and Week 2 timepoints), in placebo, 25 μg, 50 μg, 100 μg and 200 μg DOX dose groups in 
subjects with BCC.  
4.2 
Secondary and Exploratory Objectives 
Secondary objectives are: 
 
● To evaluate the efficacy of single applications of D-MNA, once administered weekly, 
three times over a two-week period, in subjects with BCC; 
● To evaluate safety and tolerability and to characterize the adverse events profile of 
the different D-MNA dose groups. 
 
Exploratory objectives are: 
 
● To quantify the approximate amount of DOX released after application of the MNA; 


 
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● To evaluate by photographic assessment, the efficacy of single applications of D-
MNA, one application administered weekly, three times over a two-week period, in 
subjects with BCC. 
5 
Study Design 
5.1 
Overall Study Design 
This is a Phase I open-label dose-escalation trial to evaluate DLT, MTD, safety, and tolerability of 
MNAs containing DOX in subjects with BCC.  
One study site in the US will enroll all subjects in the study.  
5.2 
Dose Justification 
The current dosing regimen is partly based on animal efficacy data performed to date and the 
toxicology studies performed in mice, rabbits, and minipigs to assess the risk of dermal irritation 
at dose ranges (25 μg, 50 μg, 100 μg and 200 μg). These doses are also currently being tested in 
Prof. Falo’s CTCL study, in which these doses have been well tolerated with minimal DLT.  
The study design also includes a placebo-MNA (P-MNA) group. Inclusion of P-MNA will allow the 
evaluation of two questions:  
● Tolerability: to assess if there is a cutaneous response to microneedle penetration that is 
independent of microneedle delivery of DOX to the target tissue; 
● Efficacy: to assess if a placebo-containing array can stimulate a non-specific immune 
response in reaction to microneedle penetration of the skin and compare to the response 
with the active compound DOX delivered by the D-MNA.  
As each subject completes his or her treatment course in any given dosing cohort, the BCC lesion 
is excised. All BCC cells will be removed regardless of the dose group to which the subjects were 
assigned.  


 
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5.3 
Subjects 
Qualified subjects are men and women with BCC (superficial or nodular sub-type) age 18 or older 
and in general good health. Fifteen subjects (three in each of the five dose groups) are planned. 
Up to 15 additional subjects may be recruited in case of emergence of DLTs.  
5.4 
Study Design Summary 
One study site in the United States is participating in this clinical trial.  The trial is being conducted 
by qualified dermatologists (or other sub-specialty physicians with equivalent qualifications). 
 
The participating subjects are treated with MNAs containing DOX or MNAs containing placebo. 
The D-MNA or P-MNA is applied to the BCC lesion and secured to the skin with a bandage. The 
D-MNA and P-MNA are removed from the skin after 30 minutes. Each subject will receive three 
(3) weekly applications of the D-MNA unless a DLT requires skipping or postponement of an 
application.  
The investigational product is chemotherapeutic agent DOX (25 μg, 50 μg, 100 μg, or 200 μg) 
delivered to specific skin strata by a novel delivery system, MNA or placebo delivered to specific 
skin strata by MNA.  
Individual subject participation is expected to be approximately up to 11 weeks (4 weeks 
screening + 7 weeks from the first treatment to the final follow up visit).  
6 
Determination of Sample Size 
The study will follow a traditional 3+3 dose escalation design with 4 dose groups plus placebo to define a 
MTD by evaluating DLTs as described in Section 1.2 of the study protocol. Based on this design, between 
15 and 30 subjects will be required to be evaluable for the primary DLT endpoint.  
7 
Randomization 
Study treatment is not randomized and the study design is open-label dose escalation.  
While safety evaluation is the primary objective in this Phase I study, preliminary efficacy evaluations 
will also be conducted. The P-MNA is not a matching placebo to the active investigational product. 
However, a process to blind the central reader who will assess the clinical response to study treatment 


 
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will be detailed in the Central Reader Manual. The steps to minimize bias in evaluation of visual and 
histologic responses include:  
● 
All pre- and post-treatment biopsies will be centrally read after the end of study excision biopsy 
is performed in the last study subject; 
● 
Each set of slides/digital images will be randomly assigned a second unique identifier before 
they are sent to the central reader for assessment; 
● 
The central reader will not have access to the subject identification information or the treatment 
assignment associated with each set of slides/digital images, i.e., the central reader will not have 
access to the key linking the subject identification number with the second unique identifier.  
8 
Analysis Populations 
Three subject populations will be defined for this study. 
● DLTP evaluable population (DLT): All subjects who complete the study through the Day-
21 visit (End of Treatment) without experiencing a DLT or subjects who experience a DLT 
regardless of discontinuation. Subjects who discontinue the study prior to Visit 4 
without experiencing a DLT will not be considered evaluable for the primary DLT      
endpoint; 
 
● Safety population (SAF): All enrolled subjects who receive at least one treatment. The 
SAF population will be included in all safety analyses and summaries; 
 
● All subjects population (ALL):  All randomized subjects; 
 
● Efficacy population (EFF): All subjects in the safety population with at least one dose of 
study medication (active or placebo). Efficacy analyses will be conducted on the efficacy 
population.  
9 
Statistical Analysis 
9.1 
General Considerations 
The statistical analyses will be reported using summary tables and listings (TLs).  Numbering for 
TLs will be based on the recommended numbering convention provided by the International 
Council for Harmonisation (ICH).  All summary tables will be presented by treatment group.  


 
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Select baseline tables may also include a total column summary. Tables and listings will be 
presented in PDF format. 
Continuous (quantitative) variable summaries will include the number of subjects (n) with non-
missing values, mean, standard deviation (SD), median, minimum and maximum.  Categorical 
(qualitative) variables will be summarized by frequencies and percentages of subjects in 
corresponding categories.  The denominator for the percentage calculation will be based upon 
the total number of subjects in the study population for the treatment group with non-missing 
data for the variable of interest. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data.  Measures of location (mean and median) will 
be reported to one degree of precision more than the observed data and measures of spread 
(standard deviation) will be reported to two degrees of precision more than the observed data. 
Percentages will be presented to one decimal place unless otherwise specified. Assessments 
done on unscheduled visits will not be summarized but will be listed.  
No hypothesis testing is planned, so no P-values will be reported. 
For analysis purposes, repeat laboratory rest results will not be used unless the original 
laboratory value is missing or indicated as invalid, in which case the first non-missing repeat 
laboratory value will be used for data analysis. 
All collected data will be presented in listings and will be sorted by subject.  CDISC‑compliant 
datasets (STDM and ADAM) will also be provided to the sponsor. 
All analyses and tabulations will be performed using SAS® version 9.3 or higher.  Upon 
completion, all SAS programs will be validated by an independent programmer.  The validation 
process will be used to confirm that statistically valid methods have been implemented and that 
all data manipulations and calculations are accurate.  Checks will be made to ensure accuracy, 
consistency with this plan, consistency with tables, and consistency between tables and 
corresponding data listings. 


 
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9.2 
Baseline Values 
Unless otherwise noted, baseline is defined as the last non-missing value recorded prior to the 
administration of the first study treatment.  When applicable, unscheduled visits will be used in 
the determination of baseline values. 
9.3 
Maximum Tolerated Dose (MTD) 
The MTD is defined as the highest dose with a DLT rate below 33%. 
 
9.4 
Handling of Missing Data 
Missing clinical response data at Visit 4 (21 days) will be imputed from the clinical response based 
on biopsy results of standard of care excision at the time of discontinuation, when available.  
In general, with the exception of the clinical response data at Visit 4, missing values are not 
considered for percentage calculations, unless stated otherwise.  In these cases, footnotes will 
specify the percentage denominator definition.  
10 Background Characteristics 
10.1 Subject Disposition 
Study completion and reasons for discontinuation for all subjects in the study will be summarized 
for each treatment group.  Discontinuations by reason will be tabulated for each treatment 
group.  All subjects and study completion status will be presented in a listing.  
10.2 Demographic and Baseline Characteristics 
Continuous demographic variables (e.g., age, height, weight) will be summarized by descriptive 
statistics for each treatment group.  Qualitative demographic characteristics (e.g., gender, race, 
ethnicity) will be summarized by counts and percentages for each treatment group.  
Demographics will also be presented in a subject listing. 
10.3 Prior and Concomitant Medications 
All medications taken during the course of the study with a start date or an end date on or after 
the date of the first study treatment administration or marked as ongoing will be considered 
concomitant.  Medications stopped prior to the date of the first study treatment administration 
will be considered prior medications.  


 
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If start and/or end dates for medications are missing, the dates will be imputed as described 
below.   
Imputing partial or missing start dates: 
● If the year is unknown, the start date will not be imputed.  The data will remain missing. 
● If the month is unknown, and the year is the same as the first treatment date of the study, 
and the corresponding stop date is not prior to the first treatment date of the study, then 
impute the month and day of the date to be equal to the first dose month and day.  
Otherwise, impute the month as January. 
● If the day is unknown and the month and year are the same as the first treatment date of 
the study, and the corresponding stop date is not prior to the first treatment date of the 
study, then impute the day to be equal to the day of the first treatment.  Otherwise, 
impute the day as ‘01’. 
Imputing partial or missing end dates: 
● If the year is unknown, the end date will not be imputed.  The data will remain missing. 
● If the month is unknown, impute the month as December. 
● If the day is unknown, impute the day to be the last day of the month. 
If an imputed stop date is greater than the last medication date or study 
completion/discontinuation date of the study, then the imputed stop date will be set equal to 
the maximum of these two dates (last medication date or completion/discontinuation date). 
The number and percentage of subjects using each concomitant medication will be summarized 
for each dose group according to the World Health Organization Drug Dictionary (WHODRUG) 
(Version March 1, 2019) Anatomical Therapeutic Chemical (ATC) Classification preferred term 
(PT).  Subjects with multiple use of a concomitant medication during a treatment period will be 
counted only once for a given drug class or PT for the treatment period.  Medication summaries 
will be based on the SAF and presented in summary tables and a subject listing. 
10.4 Medical History 
Medical history (past and ongoing medical illness) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA, Version 22.0) coding dictionary.  Medical history is defined as any 


 
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illness documented at the screening visit that the subject may have had prior to first application 
of the study treatment.  
Prior (conditions ending prior to the first application of the study treatment) and ongoing 
(conditions present while receiving study treatment) medical conditions will be summarized by 
presenting for each group the number and percentage of subjects having any condition.  Prior 
and ongoing conditions will be presented in separate Medical History tables. 
Subject data listing of all medical history will also be presented. 
11 Study Treatment 
A summary table will be provided detailing counts of subjects and dispensation of investigational 
product as well as dose levels and treatment exposure.  
12 Primary and Secondary Endpoint Analysis 
12.1 Primary Endpoint Analysis:  Assessment of DLT 
The primary efficacy endpoint is the assessment of DLT through Visit 4 (21 days) as defined in 
Appendix 1 of the Protocol using the LSR grading scale. or any systemic ≥ Grade 3 adverse event 
according to Common Terminology Criteria for Adverse Events v 5.0 that cannot be attributed to 
another cause   All DLTs will be summarized by dose group, including placebo.  A subject-level 
listing of DLT assessment will also be presented. 
12.2  Secondary Endpoint Analysis 
12.2.1 Lesion Response 
The proportion of subjects achieving a histological complete response (CR) at Visit 4 (21 days) will 
be summarized with the associated 95% exact lower, 1-sided confidence interval (CI) for each 
dose group including placebo.  Lesion Response results will also be presented in a subject-level 
listing. 
12.2.2 Additional Endpoints 
The following endpoints will be summarized by dose group using descriptive statistics at each 
study visit: 


 
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● Evidence of BCC at the treatment site pre and post MNA application by dermatoscopic 
inspection of the treatment site  
● Local tolerance of the MNA on the skin as measured by the LSR grading scale  
● Pain assessment using an 11-point numerical rating scale (NRS).  
13 Safety Analysis 
All enrolled subjects who receive at least one treatment will be included in the safety analysis 
and summaries. Adverse events will be coded using MedDRA and summarized by dose group.  
Summaries by the number of subjects reporting the adverse event and the number of adverse 
events reported will be presented. A by-subject adverse event data listing including verbatim 
term, preferred term, dose group, severity, and relationship to study medication will be 
provided.  
Wound healing at the surgical standard of care excision site will be assessed during the suture 
removal visit according to standard of care and reported in a subject-level listing.  
Safety endpoints will include skin evaluations, clinical laboratory tests, urinalysis, physical 
examination, vital signs, ECG and adverse events. Descriptive statistics will be used to 
summarize safety endpoints overall and separately by dose group.  
13.1 Adverse Events 
Adverse events (AEs) will be recorded throughout the study and at early discontinuation.  AEs 
and medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) (Version 22.0) and summarized by dose group.  Summaries by the number of subjects 
reported the AE and the number of AEs reported will be presented.  A by-subject AE listing 
including verbatim term, PT, dose group, severity and relationship to study n will be provided.   
Adverse events will further be categorized by severity and relationship to study medication.  
Serious adverse events will also be summarized.  Other information collected will be listed, as 
appropriate.  
Treatment-emergent adverse events (TEAEs) will be defined as any event not present prior to the 
initiation of treatment or any event already present that worsens in either intensity or frequency 
following exposure to treatment.  TEAEs will be summarized by dose group, presenting the 
number and percentage of subjects having any treatment-emergent AE, having an AE in each 


 
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body system and having an individual AE.  (Note:  In any given category [e.g., body system], a 
subject will only be counted once.) 
13.2 Laboratory Data 
The summary statistics of raw data (hematology, chemistry and applicable urinalysis) and change 
from baseline values (means, medians, standard deviations, min, and max) will be presented.  For 
urinalysis parameters that are categorical, the number and percentage of subjects falling under 
each category of the test will be presented.  Clinical laboratory tests to be performed are: 
 
Category 
Parameters 
Hematology 
hemoglobin, hematocrit, platelets, and white blood cell (WBC) 
count 
 
Chemistry 
blood urea/blood urea nitrogen (BUN), creatinine, glucose, 
potassium, chloride, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (ALP), albumin, 
amylase, lipase, total bilirubin, potassium, calcium, phosphate, 
lactate dehydrogenase 
 
Urinalysis  
 
          macroscopic, microscopic, specific gravity, pH, protein,  
 
 
 
 
          glucose, ketones, hemoglobin. 
 
13.3 Vital Signs and Body Measurements 
Data from vital signs and body measurements (see below) will be listed and any other information 
collected will be listed.  Data will be summarized by treatment group using mean change from 
baseline.  Variables to be summarized are: 
 
 
 


 
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Measurement 
Heart Rate 
Diastolic Blood Pressure 
Systolic Blood Pressure 
Respiratory Rate 
Body Temperature 
Weight 
 
14 Exploratory Analyses 
Quantification of the DOX remaining in the used MNA will be summarized by dose group using 
descriptive statistics.  Additional exploratory analyses may be defined at a later date.  
15 Interim Summaries and Data Monitoring 
There is no planned statistical output for DMC review.   
 
 


 
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16 References  
1. Cancer Facts and Figures 2018.  American Cancer Society.  
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-
statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf.  
Accessed May 15, 2018. 
2. Gould A, Missailidis S.  Targeting the hedgehog pathway:  the development of cyclopamine 
and the development of anti-cancer drugs targeting the hedgehog pathway.  Mini Rev Med 
Chem.  2011;11(3):200-13. 
3. Guy GP, Machlin SR, Ekwueme DU, Yabroff KR.  Prevalence and costs of skin cancer 
treatment in the U.S., 2002-2006 and 2007-2011.  Am J Prev Med. 2015;48(2):183-7. 
4. Clinicaltrials.gov. (2018).  Micro Needle Array-Doxorubicin (MNA-D) in Patients With 
Cutaneous T-cell Lymphoma (CTCL) - Full Text View - ClinicalTrials.gov. [online] Available at:  
http://clinicaltrials.gov/ct2/show/NCT02192021?term=doxorubicin+dermal&draw=2&rank=
1 [Accessed 14 Jun.2018]. 
5. Akilov O, Mccann S, Chao E, Cullison SJ, Erdos G, Falo L. 581 Phase 1, single-aarm, open-
label, dose escalation trial of microneedle array-doxorubicin in patients with mycosis 
fungoides.  Journal of Investigative Dermatology.  2018;138(5). 
 
 
 


 
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17 Planned Tables and Listings 
17.1 Planned Tables 
Table Number 
Table Title 
14.1.1 
Subject Disposition (ALL) 
14.1.2 
Demographics and Baseline Characteristics (ALL) 
14.1.3.1 
Prior Medication (ALL) 
14.1.3.2 
Concomitant Medication (ALL) 
14.1.4.1 
Medical History at Baseline (ALL) 
14.1.4.2 
Ongoing Medical History (ALL) 
14.1.4.3 
Summary of Study Procedure Administration (ALL) 
14.2.1.1 
Primary Endpoint Summary:  DLT through Visit 4 (21 days) (EFF) 
14.2.1.2 
Primary Endpoint Summary:  DLT through Visit 4 (21 days) (ALL) 
14.2.1.3 
Primary Endpoint Summary:  DLT through Visit 4 (21 days) (DLTP) 
14.2.2.1.1 
Secondary Endpoint Summary:  Lesion Response Based on Clinical Response 
Assessment at Visit 4 (21 days) (EFF) 
14.2.2.1.2 
Secondary Endpoint Summary:  Lesion Response Based on Clinical Response 
Assessment at Visit 4 (21 days) (ALL) 
14.2.2.1.3 
Secondary Endpoint Summary:  Lesion Response Based on Clinical Response 
Assessment at Visit 4 (21 days) (DLTP) 
14.2.2.2.1 
Secondary Endpoint Summary:  Evidence of BCC by Dermatoscopic Inspection (EFF) 
14.2.2.2.2 
Secondary Endpoint Summary:  Evidence of BCC by Dermatoscopic Inspection (ALL) 
14.2.2.2.3 
Secondary Endpoint Summary:  Evidence of BCC by Dermatoscopic Inspection (DLTP) 
14.2.2.3.1 
Secondary Endpoint Summary:  Local Tolerance of the MNA as Measured by the LSR 
Grading Scale (EFF) 
14.2.2.3.2 
Secondary Endpoint Summary:  Local Tolerance of the MNA as Measured by the LSR 
Grading Scale (SAF) 
14.2.2.4.1 
Secondary Endpoint Summary:  Pain Assessment from 11-Point NRS (EFF) 
14.2.2.4.2 
Secondary Endpoint Summary:  Pain Assessment from 11-Point NRS (SAF) 
14.2.2.4.3 
Secondary Endpoint Summary:  Pain Assessment from 11-Point NRS (DLTP) 
14.3.1.1 
Overall Adverse Event Summary (SAF) 
14.3.1.2.1 
Adverse Events by System Organ Class and Preferred Term (SAF) 
14.3.1.3.1 
Adverse Events by System Organ Class, Preferred Term, Severity (SAF) 
14.3.1.3.2 
Adverse Events by System Organ Class, Preferred Term, Relationship to Study 
Treatment (SAF) 
14.3.1.4.1 
Subroup Analysis:  Adverse Events Related to Treatment by System Organ Class and 
Preferred Term (SAF) 
14.3.1.4.2 
Subroup Analysis: Grade III/IV Adverse Events by System Organ Class and Preferred 
Term (SAF) 
14.3.1.5.1 
Serious Adverse Events by System Organ Class and Preferred Term (SAF) 


 
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14.3.1.5.2 
Adverse Events Related to Treatment by System Organ Class and Preferred Term (SAF) 
14.3.1.5.3 
Treatment-emergent Adverse Events by System Organ Class and Preferred Term (SAF) 
14.3.1.5.4 
Grade III/IV Adverse Events by System Organ Class and Preferred Term (SAF) 
14.3.4.1 
Chemistry Laboratory Summary -- Actual Value and Change from Baseline (SAF) 
14.3.4.2 
Hematology Laboratory Summary - Actual Value and Change from Baseline (SAF) 
14.3.4.3 
Urinalysis Summary (Continuous Variables) - Actual Value and Change from Baseline 
(SAF) 
14.3.4.4 
Urinalysis Summary (Categorical Variables – SAF) 
14.3.4.5 
Summary of Abnormal Laboratory Values (SAF) 
14.3.5 
Vital Signs Summary - Actual Value and Change from Baseline (SAF) 
14.3.6 
Summary of ECG - Actual Value and Change from Baseline (SAF) 
 
 


 
SkinJect, Inc. 
Protocol SKNJCT-001 
Statistical Analysis Plan  
03May2021 
 
Confidential 
Page 22 of 22 
 
17.2 Planned Listings 
Listing Number 
Listing Title 
16.2.1 
Subject Disposition 
16.2.2 
Protocol Deviations 
16.2.4.1 
Demographics 
16.2.4.2 
Medical History 
16.2.4.3 
Prior and Concomitant Medications 
16.2.5.1 
Study Drug and MNA Administration 
16.2.5.2 
Local Skin Response (LSR) of MNA 
16.2.5.3 
Dermatoscopic Evaluation of Lesion 
16.2.5.4 
Photography of Lesion Site 
16.2.5.5 
Shave Biopsy of the BCC Lesion 
16.2.5.6 
Excision of BCC Lesion/Treatment Site 
16.2.5.7 
Clinical Response Assessment 
16.2.5.8 
Concurrent Procedures 
16.2.6.1 
Adverse Events 
16.2.6.2 
Treatment-emergent Adverse Events 
16.2.6.3 
Treatment-related Adverse Events 
16.2.6.4 
Grade III/IV Adverse Events 
16.2.6.5 
Serious Adverse Events 
16.2.7 
Suture Removal and Wound Healing 
16.2.8.1 
Hematology Laboratory Parameters 
16.2.8.2 
Chemistry Laboratory Parameters 
16.2.8.3 
Urinalysis Laboratory Parameters 
16.2.8.4 
Urine Pregnancy Test 
16.2.8.5 
ECG 
16.2.9 
Vital Signs 
16.2.10 
Physical Examination 
16.2.11 
Pain Assessment Scale