Clinical trial NCT02838628
Conditions: Actinic Keratosis
Sponsor: Almirall, S.A.
Start date: 2016-04-11; Completion date: 2017-12-22
Enrollment: 168 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this study, the activity, safety, and pharmacokinetics (PK) of KX2-391 Ointment was evaluated in adult participants with a clinical diagnosis of stable, clinically typical actinic keratosis (AK) on the face or scalp.

Detailed description:
This study was an open-label, multicenter, activity, safety, tolerability, and PK study of KX2-391 Ointment administered topically to the face or scalp of participants with AK.

The study consists of Screening, Treatment, and Follow-up Periods. Eligible participants were received 3 or 5 consecutive days of topical treatment, applied at the study site. Blood samples for PK analysis were collected. Activity (lesion counts) and safety evaluations were performed.

Arms: arm 1: Participants were applied 50 milligrams (mg) of KX2-391 Ointment 1% topically on face or scalp in 25 centimeter square (cm\^2) treatment area, once daily for 5 consecutive days. arm 2: Participants were applied 50 mg of KX2-391 Ointment 1% topically on face or scalp in 25 cm\^2 treatment area, once daily for 3 consecutive days.
Interventions: intervention 1: 50 mg of KX2-391 Ointment 1% intervention 2: 50 mg of KX2-391 Ointment 1%
Intervention descriptions: intervention 1: Dose: 50 mg; Route of administration: Topical intervention 2: Dose: 50 mg; Route of administration: Topical

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol Amendment 2 
KX01-AK-002 
Kinex Pharmaceuticals, Inc. 
FINAL v3.0_26 Sep 2016 
i 
CONFIDENTIAL 
REVISION HISTORY 
Revisions to KX01-AK-002 protocol v2.0_26 Apr 2016 (Amendment 1 protocol) 
Current Version and Date:  v3.0_26 Sep 2016 (Amendment 2) 
Change 
Rationale 
Affected Protocol Sections 
Revised the length of time a female 
subject must be amenorrheic in the 
definition of postmenopausal (from 
18 months to 12 months). 
Revised the length of time before 
study treatment during which a 
highly effective means of 
contraception must be used (from 
90 days to at least 30 days or 
1 menstrual cycle, whichever is 
longer). 
To align with current guidelines. 
A minimum of 1 menstrual cycle 
prior to dosing is sufficient for 
subjects using highly effective 
contraception. 
x
Synopsis / Inclusion Criteria
x
Section 9.3.1
Revised the length of time after 
which an investigational product 
was taken in a previous clinical trial 
as exclusionary in this study (from 
14 days to 30 days). 
Clinical trial subjects are followed 
for safety up to 30 days after their 
last study visit. 
x
Synopsis / Exclusion Criteria
x
Section 9.3.2
Specified KX2-391 1% as study 
drug. 
Included treatment area borders as 
part of the application site. 
Clarification. 
x
Section 9.4.2.4
x
Section 9.4.4
Added measurement of height as 
part of the screening physical 
examination. 
BSA may need to be calculated 
for interpretation of PK data, so 
height measurement is needed. 
x
Table 1
x
Table 2
x
(new) Section 9.5.1.2.4
x
Section 9.5.1.5.5
Heading name was revised to 
remove “…and Exposure to study 
Drug through Breastfeeding”. 
Specified pregnancies include those 
occurring in a subject or in the 
female partner of a male subject. 
Revised withdrawal from study to 
discontinuation from treatment. 
Correction; section text makes no 
reference to exposure through 
breastfeeding. 
Clarification. 
Clarification. 
x
Section 9.5.3.2
Stipulated that pigment-related 
changes or scarring should be 
followed until resolution or deemed 
stabilized by the Investigator. 
Additional safety monitoring. 
x
Section 9.5.1.5.8
Revised language about reporting of 
significant treatment-emergent 
laboratory abnormalities. 
Clarification. 
x
Section 9.5.1.5.1
x
Section 9.5.1.5.2


Clinical Study Protocol Amendment 2 
KX01-AK-002 
 
 
Kinex Pharmaceuticals, Inc. 
FINAL v3.0_26 Sep 2016 
 
ii 
CONFIDENTIAL 
 
Revisions to KX01-AK-002 protocol v2.0_26 Apr 2016 (Amendment 1 protocol) 
Current Version and Date:  v3.0_26 Sep 2016 (Amendment 2) 
Change 
Rationale 
Affected Protocol Sections 
Stipulated that subjects with a 
history of HIV, chronic hepatitis C, 
or chronic hepatitis B infection will 
be excluded from the study. 
The effect of KX2-391 ointment 
on subjects who have these 
chronic infections for which they 
are on treatment is unknown. 
x 
Synopsis / Exclusion Criteria 
x 
Section 9.3.2 
Added additional ECG 
measurements for Cohort 2. 
Additional safety monitoring. 
x 
Table 2 
x 
Section 9.5.1.5.6 
Corrected miscellaneous 
punctuation/grammar errors. 
Administrative. 
x 
Throughout protocol 
 
 


Clinical Study Protocol Amendment 2 
KX01-AK-002 
 
 
Kinex Pharmaceuticals, Inc. 
FINAL v3.0_26 Sep 2016 
 
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CONFIDENTIAL 
 
Revisions to KX01-AK-002 protocol v1.0_23 Jan 2016 (original protocol) 
Current Version and Date:  v2.0_26 Apr 2016 (Amendment 1) 
Change 
Rationale 
Affected Protocol Sections 
Added a second cohort with a 3-day 
dosing regimen. 
If the 5-day treatment regimen 
(Cohort 1) has sufficient activity 
and safety, a 3-day regimen 
(Cohort 2) will be evaluated. 
x 
Throughout protocol 
x 
Table 1 
x 
(new) Table 2 
x 
List of In-Text Tables 
Added a secondary objective. 
To accommodate addition of a 
3-day regimen (Cohort 2). 
x 
Synopsis / Objectives 
x 
Section 8.2 
Made sustained response an 
exploratory objective; removed it as 
a primary endpoint and revised 
exploratory endpoints and analyses 
to align with it as an exploratory 
objective; revised wording to 
describe analysis of recurrence 
rates. 
Sustained response is more 
appropriate as exploratory 
because it is assessed post-
Day 57; clarification 
x 
Synopsis  
- Objectives 
- Statistical Methods / Study 
Endpoints 
- Activity Analyses 
x 
Section 8.3 
x 
Section 9.7.1.1.1 
x 
Section 9.7.1.1.3 
x 
Section 9.7.1.6 
Revised the number of subjects in 
the study. 
To accommodate addition of a 
3-day regimen (Cohort 2). 
x 
Synopsis / Number of subjects 
x 
Section 9.1 
x 
Section 9.1.1 
Revised PK sampling timepoints. 
To accommodate addition of a 
3-day regimen (Cohort 2). 
x 
Synopsis / Pharmacokinetic 
Assessments 
x 
Table 4 
Removed reference to a Safety 
Management Plan; revised text 
regarding reporting of SAEs, deaths, 
and life-threatening events, and 
corresponding follow-up 
information. 
Clarification. 
x 
Section 9.5.3.1 
Revised statistical-related text to 
reflect increased number of subjects 
based on the addition of Cohort 2; 
revised text regarding interim 
analysis. 
To accommodate addition of a 
3-day regimen (Cohort 2). 
x 
Synopsis 
 
- Analysis Sets 
 
- Activity Analyses 
 
- Safety Analyses 
 
- Interim Analysis 
 
- Sample Size Rationale 
x 
Sections 9.7.1.2 - 9.7.1.6 
x 
Section 9.7.1.8 (entirety) 
x 
Section 9.7.2 
x 
Section 9.7.3 
Added immunosuppressants and 
immunomodulators as exclusionary 
medications. 
 
These medications may affect the 
intended effects of the study drug. 
x 
Synopsis / Exclusion Criteria 
x 
Section 9.3.2 
Increased the duration of the study 
period overall and enrollment 
To accommodate addition of a 
x 
Synopsis / Study Period and 
Phase of Development 


Clinical Study Protocol Amendment 2 
KX01-AK-002 
 
 
Kinex Pharmaceuticals, Inc. 
FINAL v3.0_26 Sep 2016 
 
iv 
CONFIDENTIAL 
 
Revisions to KX01-AK-002 protocol v1.0_23 Jan 2016 (original protocol) 
Current Version and Date:  v2.0_26 Apr 2016 (Amendment 1) 
Change 
Rationale 
Affected Protocol Sections 
period. 
3-day regimen (Cohort 2). 
x 
Synopsis / Duration of 
Participation and Treatment 
Increased the number of sites 
conducting the study. 
 
 
 
With addition of additional sites, 
specified that enrollment among 
sites would be monitored to avoid 
imbalance. 
To accommodate increased 
number of subjects due to 
addition of Cohort 2; to facilitate 
enrollment. 
 
Clarification. 
x 
Synopsis / Sites 
x 
Section 6 
 
 
 
x 
Synopsis / Study Design 
x 
Section 9.1 
x 
Section 9.4.3 
Revised description of study 
treatment. 
Clarification. 
x 
Table 3 
Specified “during the Treatment 
Period” with regard to withdrawal 
of subjects who become pregnant. 
Clarification of timeframe. 
x 
Section 9.5.3.2 
Revised text regarding collection 
and following of adverse events. 
 
Removed reference to Screening 
Disposition CRF/eCRF. 
Clarification of timeframe; only 
study drug-related AEs will be 
followed. 
There is no Screening Disposition 
CRF/eCRF in the study. 
x 
Section 9.5.1.5.1 
Removed Appendix 1 and 
renumbered remaining appendix; 
added appropriate literature citation 
for reference. 
Investigators are familiar with the 
method for skin typing; 
questionnaire and scoring system 
in Appendix 1 is not validated. 
x 
List of Appendices 
x 
Section 9.5.1.2.2 
x 
Section 9.5.1.5.8 
x 
Section 10 
x 
(original) Appendix 1 (deleted) 
Revised text regarding removal of 
subjects from the therapy or 
assessment; modified some of the 
reasons for discontinuation. 
Clarification. 
x 
Section 9.3.3 
Modified text regarding restrictions 
on the use of concomitant 
medication/therapies/topical 
products during the study; referred 
the reader to an FDA draft guidance. 
Per recommendation of the 
Investigators and subject matter 
experts; to provide further 
guidance to the investigators. 
x 
Synopsis / Concomitant 
Drug/Therapy 
x 
Section 9.4.7.3 
Revised description of the Final 
Visit; specified when the Final Visit 
is for those who do not have 
complete response at Day 57. 
 
Clarification. 
x 
Table 1 / Footnote c 
x 
Section 9.1.3 
x 
Section 9.1.4 
Specified that use of sunblock in the 
treatment area will be recorded in 
To be able to evaluate the activity 
of study drug in the presence and 
x 
Section 9.4.7.2 
x 
Section 9.5.1.5.8 


Clinical Study Protocol Amendment 2 
KX01-AK-002 
 
 
Kinex Pharmaceuticals, Inc. 
FINAL v3.0_26 Sep 2016 
 
v 
CONFIDENTIAL 
 
Revisions to KX01-AK-002 protocol v1.0_23 Jan 2016 (original protocol) 
Current Version and Date:  v2.0_26 Apr 2016 (Amendment 1) 
Change 
Rationale 
Affected Protocol Sections 
the Concomitant Medication CRF. 
 
Removed text regarding subjects not 
changing their use of concomitant 
medications. 
absence of sunblock. 
 
Subjects will be able to change 
concomitant medications per the 
Investigator’s instructions. 
Removed use of body charts for 
identifying the location and shape of 
the treatment area. 
Not needed; this will be done 
with the acetate sheets. 
x 
Section 9.1.1 
x 
Section 9.1.2 
Specified minimum timeframe 
during which subjects cannot touch 
or wet the treatment area after study 
treatment application; removed 
information regarding shower times; 
revised text about instructions to the 
subjects for care of the treatment 
area. 
Clarification. 
x 
Section 9.4.2.4 
Revised description of sun 
exposure. 
Clarification. 
x 
Synopsis / Inclusion Criteria 
x 
List of Abbreviations and 
Definition of Terms 
x 
Section 9.3.1 
Revised description of Medical 
History. 
Clarification. 
x 
Section 9.5.1.2.1 
Revised description of the Final 
Visit; specified when the Final Visit 
is for those who do not have 
complete response at Day 57. 
Clarification. 
x 
Table 1 / Footnote c 
x 
Section 9.1.3 
x 
Section 9.1.4 
Removed exclusionary use of 
moisturizers or emollients on the 
face or scalp within 12 hours prior 
to Visit 1. 
Not necessary to exclude before 
Visit 1. 
x 
Synopsis / Exclusion Criteria 
x 
Section 9.3.2 
Revised Medical Monitor signatory. 
Administrative. 
x 
Protocol Signature page 
Specified that scarring, in addition 
to pigmentation, will be assessed at 
the visits cited. 
Clarification. 
x 
Section 9.5.1.5.8 / 
Pigmentation and Scarring 
Revised description of procedures 
related to treatment area 
identification. 
Clarification to align with 
streamlined procedures. 
x 
Section 9.1.1 
Revised text to ensure the signing of 
ICF prior to study procedures. 
Clarification. 
x 
Section 5.3 
Revised the definition of the 
Evaluable Set. 
Clarification. 
x 
Synopsis / Number of Subjects 


Clinical Study Protocol Amendment 2 
KX01-AK-002 
Kinex Pharmaceuticals, Inc. 
FINAL v3.0_26 Sep 2016 
vi 
CONFIDENTIAL 
Revisions to KX01-AK-002 protocol v1.0_23 Jan 2016 (original protocol) 
Current Version and Date:  v2.0_26 Apr 2016 (Amendment 1) 
Change 
Rationale 
Affected Protocol Sections 
Revised definition of ICH. 
Clarification to align with recent 
ICH organizational changes. 
x
Investigator Signature Page
x
Title Page
x
List of Abbreviations and
Definition of Terms
x
Section 5.1
Corrected 
typographical/punctuation/grammar 
errors. 
Administrative. 
x
Throughout protocol


PPD
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Clinical Study Protocol Amendment 2 
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FINAL v3.0_26 Sep 2016 
viii 
CONFIDENTIAL 
INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
KX01-AK-002 
Study Protocol Title: 
A Phase 2a, Open-Label, Multicenter, Activity and Safety Study of 
KX2-391 Ointment 1% in Subjects with Actinic Keratosis on the Face 
or Scalp 
Investigational Product 
Name: 
KX2-391 Ointment 1% 
UTN Number: 
U1111-1173-5677 
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
<Name, degree(s)> 
Investigator 
Signature 
Date 
<Name of study site> 
Study Site 


Clinical Study Protocol Amendment 2 
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FINAL v3.0_26 Sep 2016 
 
Page 1  
CONFIDENTIAL 
 
1 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
Study Protocol 
Number: 
KX01-AK-002 
Study Protocol Title: 
A Phase 2a, Open-Label, Multicenter, Activity and Safety Study of 
KX2-391 Ointment 1% in Subjects with Actinic Keratosis on the Face or 
Scalp 
Sponsor: 
United States: 
Kinex Pharmaceuticals, Inc. 
20 Commerce Drive 
Cranford, New Jersey 07016, US 
Tel:  +1 908-272-0628 
Investigational 
Product Name: 
KX2-391 Ointment 1% 
Indication: 
Actinic keratosis on the face or scalp 
Phase: 
2a 
Approval Date:  
v1.0 
v2.0 
v3.0 
23 Jan 2016 (original protocol) 
26 Apr 2016 (Amendment 1) 
26 Sep 2016 (Amendment 2) 
UTN Number: 
U1111-1173-5677 
GCP Statement: 
This study is to be performed in full compliance with International Council 
for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information of Kinex 
Pharmaceuticals, Inc. (the Sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly 
prohibited.  Such information may be used solely for the purpose of 
reviewing or performing this study. 


Clinical Study Protocol Amendment 2 
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FINAL v3.0_26 Sep 2016 
 
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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No. 
KX2-391 
Name of Active Ingredient: 
N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl) acetamide 
Study Protocol Title 
A Phase 2a, Open-Label, Multicenter, Activity and Safety Study of KX2-391 Ointment 1% in Subjects 
with Actinic Keratosis on the Face or Scalp 
Investigators 
, MD, Lead Principal Investigator 
Sites 
Approximately 8 to 16 sites in the United States 
Study Period and Phase of Development 
First subject in to last subject out, approximately 24 months 
Phase 2a 
Objectives 
Primary Objective: 
• To evaluate the activity of KX2-391 Ointment 1% administered topically to the face or scalp in 
subjects with actinic keratosis (AK) by determining complete response rate, defined as 100% 
clearance at Day 57 
Secondary Objectives:  
• To assess the activity of KX2-391 Ointment 1% during Days 1-57 
• To assess the safety and tolerability of KX2-391 Ointment 1% in subjects with AK on the face or 
scalp 
• To assess the pharmacokinetics (PK) of KX2-391 Ointment 1% in subjects with AK on the face or 
scalp 
• To assess dose regimens by contrasting 5-day treatment with 3-day treatment in terms of the activity 
and safety of KX2-391 Ointment 1% in subjects with AK on the face or scalp 
Exploratory Objectives: 
• To determine recurrence rates up to 12 months post-Day 57 for subjects who show response at 
Day 57 
• To determine sustained response rates at 12 months post-Day 57 for subjects who show response at 
Day 57 
Study Design 
This study will be an open-label, multicenter, activity, safety, tolerability, and PK study of KX2-391 
Ointment 1% administered topically to the face or scalp of subjects with actinic keratosis in 2 sequential 
cohorts:  a 5-day dosing regimen (Cohort 1) and a 3-day dosing regimen (Cohort 2). 
The study consists of Screening, Treatment, and Follow-up Periods. 
In Cohort 1, eligible subjects will receive 5 consecutive days of topical treatment, to be applied at the 
PPD


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study site, with 50 mg of KX2-391 Ointment 1% each day.  Blood samples for PK analysis will be 
collected on Day 1 and Day 5.  Subjects will return for Follow-up visits until Day 57.  Thereafter, only 
Day 57 complete responders will continue Recurrence Follow-up Visits every 3 months for an additional 
12 months after Day 57.  Activity (lesion counts) and safety evaluations will be performed. 
The Sponsor will review accumulating data.  If the 5-day regimen (Cohort 1) has sufficient activity and 
safety to warrant evaluating a 3-day regimen, enrollment of Cohort 2 will start after there are 60 evaluable 
subjects or up to 80 subjects are enrolled (whichever comes first) in Cohort 1.  For the most part, protocol 
procedures for Cohort 1 will be duplicated for Cohort 2, except PK samples will be collected on Days 1 
and 3, and subjects will not return for Visits 5 and 6. 
The same study sites for the most part of Cohort 1 will be used for Cohort 2.  The Sponsor study team 
will monitor the enrollment status closely and ensure that any individual site does not enroll too many 
subjects. 
Number of Subjects 
In each cohort, approximately 80 subjects will be enrolled to provide approximately 60 subjects in the 
Evaluable Set, defined as subjects who complete all planned treatments and most evaluations, including 
the Day 57 Follow-up visit.  Therefore, a total of 160 subjects in 2 cohorts may be enrolled, but the 
sample size of Cohort 2 may be adjusted, depending on the results of Cohort 1. 
Inclusion Criteria 
Eligible subjects must have/be: 
1. Males and females ≥18 years old 
2. Clinical diagnosis of stable, clinically typical actinic keratosis 
3. A treatment area on the face or scalp that: 
x 
is a continuous area measuring 25 cm2 
x 
contains 4 to 8 AK lesions 
4. Females must be postmenopausal (>50 years of age with at least 12 months of amenorrhea), 
surgically sterile (by hysterectomy, bilateral oophorectomy or tubal ligation) or otherwise incapable 
of pregnancy for at least 1 year; or, if of childbearing potential, must be using highly effective 
contraception for at least 30 days or 1 menstrual cycle, whichever is longer, prior to treatment with 
KX2-391 Ointment 1% and must agree to continue to use highly effective contraception for at least 
90 days following their last dose of KX2-391 Ointment 1%.  Highly effective contraception includes 
oral hormonal contraceptives, hormonal contraceptive implant or patch, or intrauterine device.  
Abstinence and double barrier methods do not qualify as highly effective methods of contraception. 
5. Males who have not had a vasectomy must agree to use barrier contraception from Screening through 
90 days after their last dose of KX2-391 Ointment 1%. 
6. All subjects must agree not to donate sperm or eggs or attempt conception from Screening through 
90 days following their last dose of KX2-391 Ointment 1%. 
7. Females of childbearing potential must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on Day 1 prior to administration of study treatment. 
8. Subjects who in the judgment of the Investigator, are in good general health based on: 
x 
medical history 
x 
no physical examination (PE) findings that the Principal Investigator (PI) determines would 
interfere with interpretation of study results 
x 
screening electrocardiogram (ECG) without clinically significant abnormalities  


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x 
clinical chemistry, hematology, and urinalysis results that are within the reference ranges; clinical 
laboratory values outside the reference ranges that are considered by the PI to be clinically 
insignificant are also acceptable 
9. Willing to avoid direct sun or ultraviolet (UV) light exposure to the face or scalp 
10. Able to comprehend and are willing to sign an informed consent form (ICF) 
Exclusion Criteria 
Eligible subjects must not have/be: 
1. Clinically atypical and/or rapidly changing AK lesions on the treatment area 
2. Malignancy within 5 years prior to Screening except basal or squamous cell carcinoma not on the 
treatment area that were treated with curative intent and are without recurrence 
3. Used any of the following systemic therapies within the specified period before Visit 1: 
x 
retinoids; 90 days 
x 
glucocorticosteroids; 28 days (intra-articular and inhaled steroids are allowed) 
x 
methotrexate or other anti-metabolites; 28 days 
x 
immunosuppressants or immunomodulators; 28 days 
4. Used any of the following topical therapies on the treatment area within the specified period before 
Visit 1: 
x 
retinoids; 90 days 
x 
glucocorticosteroids; 14 days 
x 
analgesic and/or anti-inflammatory medication on the face or scalp; 72 hours 
5. Had any of the following on the treatment area within 90 days (or until the site has healed, whichever 
is longer) before Visit 1: 
x 
ingenol mebutate (eg, Picato) 
x 
5-fluorouracil (eg, 5-FU; Efudex) 
x 
imiquimod (eg, Aldara; Zyclara) 
x 
diclofenac with or without hyaluronic acid (eg, Solaraze) 
6. Surgical or destructive modalities on the treatment area within 30 days (or until the site has healed 
following treatment, whichever is longer) before Visit 1: 
x 
cryotherapy 
x 
electrodesiccation 
x 
laser, light (eg, photodynamic therapy, intense pulsed light) or any other energy-based therapy 
x 
chemical peels (eg, tricholoracetic acid) 
x 
dermabrasion 
x 
surgical removal (eg, curettage, excision) 
7. Currently, or has experienced any of the following on the treatment area within the specified period 
before Visit 1: 
x 
cutaneous malignancy; 180 days 
x 
sunburn; 28 days 
x 
body art (eg, tattoo, piercing); currently 
8. A history of sensitivity and/or allergy to any of the ingredients in the study medication 
9. A skin disease (eg, atopic dermatitis, psoriasis, eczema) or condition (eg, scarring, open wounds) that, 
in the opinion of the Investigator, might interfere with the study conduct or evaluations, or which 


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exposes the subject to an unacceptable risk by study participation 
10. Other significant uncontrolled or unstable medical diseases or conditions that, in the opinion of the 
Investigator, would expose the subject to unacceptable risk by study participation 
11. Females who are pregnant or nursing 
12. Participated in an investigational drug trial during which an investigational study medication was 
administered within 30 days or 5 half-lives of the investigational product, whichever is longer, before 
dosing 
13. A known history of human immunodeficiency virus (HIV), chronic hepatitis C, or chronic hepatitis B 
infection 
Study Treatment 
50 mg of KX2-391 Ointment 1% will be applied topically once daily for 5 consecutive days (Cohort 1) or 
3 consecutive days (Cohort 2) to the 25 cm2 treatment area (2 mg/cm2; 0.5 mg KX2-391 total). 
Duration of Participation and Treatment 
• Planned enrollment period for each cohort:  approximately 3 months (90 days) 
• Planned subject participation is approximately 64 weeks:  
o Screening Period:  up to 28 days 
o Treatment Period:  For Cohort 1, 5 consecutive treatment days (Days 1-5); for Cohort 2, 
3 consecutive treatment days (Days 1-3) 
o Follow-up Period:  Visits at Days 8, 15, 29, and 57 
o Recurrence Follow-up Period:  only for complete responders at Day 57, visits every 3 months for 
12 months after Day 57 (ie, at 3, 6, 9, and 12 months post-Day 57). 
Length of stay:  On Day 1 (Visit 2, Cohorts 1 and 2) and Day 5 (Visit 6, Cohort 1) or Day 3 (Visit 4, 
Cohort 2), subjects may stay for approximately 5 hours at the investigational center until after the last PK 
blood sample is collected. 
Concomitant Drug/Therapy 
Use of any non-study drug treatment for AK lesions on the treatment area is prohibited until Day 57.  Any 
lesion in the treatment area that is treated during the Recurrence Follow-up Period will be considered as a 
recurrence. 
Assessments 
Activity Assessments 
The Investigator will perform a count of AK lesions for all subjects at Visits 1 and 2, Visits 7 through 10, and 
for Day 57 complete responders, also at Visits 11 through 14. 
Safety Assessments 
Safety will be assessed by recording all adverse events (AEs), serious adverse events (SAEs), laboratory 
evaluation of hematology, biochemistry, and urinalysis values, measurement of weight and vital signs, 
evaluation of ECGs, and the performance of physical examinations. 
Subjects will be queried for spontaneously reported AEs at each study visit, before assessment of local 
skin reactions (LSRs).  AEs will be reported separately from LSRs. 
Subject-reported LSRs will not be reported as adverse events.  
Other Assessments 
The LSR assessment is the Investigator’s (or trained designee’s) assessment of the following signs on the 
treatment area:  erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration.  


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These 
signs 
will 
be 
assessed 
using 
a 
grading 
scale 
ranging 
from 
0 
(not 
present)  
to 4 (worst).  In addition to LSRs, hypo- and hyper- pigmentation and scarring on the treatment area will 
be assessed as being present or absent.  Application site reactions not classified as LSRs (eg, pruritus, 
pain, infection) will be reported as adverse events.  All application site reactions and LSRs will be 
followed to resolution, or if resolution is unlikely, to stabilization.  LSRs will be reported separately from 
AEs. 
Standardized photography will be performed at Screening (Visit 1), Day 1 (Visit 2), Day 8 (Visit 7), 
Day 57 (Visit 10), and during the Recurrence Follow-up (at 3, 6, 9, and 12 months post-Day 57).  Before 
study medication application on Day 1, the Investigator or a qualified staff member must obtain 
standardized photography of each subject’s treatment area before application of study medication. 
Pharmacokinetic Assessments 
PK samples will be collected at the following timepoints for Cohort 1: 
• Day 1:  predose, 0.5 (±5 minutes), 1 and 4 hours (±10 minutes) postdose  
• Day 5:  predose, 0.5 (±5 minutes), 1 and 4 hours (±10 minutes) postdose 
PK samples will be collected at the following timepoints for Cohort 2: 
• Day 1:  predose, 0.5 (±5 minutes), 1 and 4 hours (±10 minutes) postdose  
• Day 3:  predose, 0.5 (±5 minutes), 1 and 4 hours (±10 minutes) postdose 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments 
Not applicable 
Bioanalytical Methods 
Plasma concentrations of study drug will be measured using a validated liquid chromatography/tandem 
mass spectrometry (LC-MS/MS) assay. 
Statistical Methods 
Study Endpoints 
Primary Endpoint 
x Activity will be evaluated by reduction in lesion count.  Complete response rate will be defined as 
the proportion of subjects achieving 100% complete clearance of all treated AK lesions on the face 
or scalp at Day 57.   
Secondary Endpoints 
• Activity:  Reduction in lesion counts during Days 1-57 
• Safety:  Evaluation of AEs and clinical laboratory data; the results of other safety assessments (vital 
signs, physical examinations, ECGs) will also be evaluated. 
• Pharmacokinetic:  Determination of Cmax and where applicable, AUCt, Cmin, and accumulation  
ratio R 
Exploratory Endpoints 
• Recurrence rate will be defined as the proportion of subjects who achieved 100% complete clearance 
at Day 57 (Visit 10) with any identified AK lesions on the treatment area at 3, 6, 9, and 12 months 
post-Day 57. 
• Sustained response rate will be defined as the proportion of subjects who achieved 100% complete 


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clearance at Day 57 (Visit 10) without any identified AK lesions on the treatment area at 12 months 
post-Day 57. 
Analysis Sets 
• Per-Protocol Set:  the group of protocol-eligible subjects who receive 5 days (Cohort 1) or 3 days 
(Cohort 2) of study treatment and complete at least one scheduled post-treatment evaluation. 
• Evaluable Set:  the group of subjects who receive 5 days (Cohort 1) or 3 days (Cohort 2) of treatment 
and complete most evaluations including the Day 57 Follow-up Visit. 
• Safety Analysis/Full Analysis Set:  the group of subjects who receive at least one dose of study 
treatment. 
• PK Analysis Set: the group of subjects who receive study treatment and complete at least one 
scheduled post-treatment PK evaluation. 
Activity Analyses 
AK lesion counts will be summarized by cohort at Day 1 (pretreatment) and at each subsequent timepoint 
for subjects in the Full Analysis Set and the Per-Protocol Set. 
A 95% confidence interval (CI) for the complete clearance (response rate) at Day 57 will be estimated by 
cohort in the Evaluable Set. 
Recurrence rates for all subjects who achieved complete clearance at Day 57 will be estimated by 
timepoint and cohort in the Evaluable Set. 
A 95% CI for the sustained response rate at 12 months post-Day 57 will be estimated by cohort in the 
Evaluable Set. 
Both cohorts will be analyzed with the same statistical methods.  Since this is not a dose regimen 
randomized study, any contrast between the 2 cohorts will mainly be noninferential and consist of 
listings, graphs, and descriptive statistics. 
Safety Analyses 
All subjects who receive at least one dose of KX2-391 Ointment 1% will be included in the safety 
analyses.  Treatment-emergent AEs (TEAEs) are defined as either those AEs with an onset after dosing or 
those pre-existing AEs that worsen after dosing.  For AEs, verbatim terms on the case report 
form/electronic case report form (CRF/eCRF) will be mapped to preferred terms (PTs) and system organ 
classes (SOCs) using the Medical Dictionary for Regulatory Activities (MedDRA; v 16.0 or higher).  
Subject incidence of AEs will be displayed by SOC.  The incidence of AEs will be summarized by 
cohort.  Adverse events will also be summarized by severity, relationship to study drug, and cohort.  
Subject incidence of SAEs will also be displayed by cohort.  Laboratory parameters will be summarized 
using descriptive statistics at baseline and at each subsequent timepoint by cohort.  Changes from baseline 
will also be summarized by cohort.  In addition, shift tables (ie, low-normal-high at baseline versus low-
normal-high at follow-up in a 3-by-3 contingency table) will be provided to assess changes in laboratory 
values from baseline to follow-up in each cohort. 
Local skin reactions, pigmentation, and scarring as reported by the Investigator, will be displayed and 
summarized by visit and cohort for all subjects. 
Similar to the activity analyses, any contrast between the 2 cohorts will mainly be noninferential in the 
safety analyses. 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Pharmacokinetic Analyses 


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Plasma concentrations for KX2-391 will be analyzed to determine applicable PK parameters. 
Individual timepoints will be tabulated and displayed graphically and listed for all subjects.  Summary PK 
parameters will be analyzed as applicable. 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Not applicable 
Interim Analysis 
A formal interim analysis is not planned. Since this is an open-label study, after each group of 
approximately 20 subjects, ongoing analyses will be performed with tabulation of activity, LSRs, and 
adverse events. The decision to open Cohort 2 will be documented. 
Statistical Methods 
Statistical analyses will be reported using summary tables, graphs, and data listings. Continuous variables 
will be summarized using the mean, standard deviation (SD), median, minimum, and maximum.  
Categorical variables will be summarized by counts and by percentage of subjects in corresponding 
categories.  All raw data obtained from the CRF/eCRF, as well as any derived data will be included in 
data listings. 
Sample Size Rationale 
For either cohort, a sample size of 60 subjects is sufficient to detect a 100% complete clearance rate at 
Day 57 greater than 20% with 80% power, based on a two-sided (alpha=0.05) binomial test, assuming a 
response rate of 35%, and less than a 25% dropout rate.  This corresponds to a two-sided 95% CI with a 
half-width of less than 15% (ie, lower boundary of the CI above 20%).  The sample size of Cohort 2 may 
be adjusted, depending on the results of Cohort 1. 
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Table 1 
Schedule of Procedures/Assessments in Study KX01-AK-002 (Cohort 1) 
Period 
Screening 
Treatment 
Follow-up 
Recurrence Follow-up a 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 b/ 
Early 
Term  
11, 12, 13, 14 a 
Day 
-28 to -1 
1 
2 
3 
4 
5 
8 
15 
29 
57b 
3, 6, 9, 12 Months Post-Day 57c 
Visit time window (days) 
None 
None 
None 
None 
None 
None 
±2 
±2 
±2 
±2 
±14 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion & exclusion criteria 
X 
Xd 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
AK history/AK treatment history 
X 
 
 
 
 
 
 
 
 
 
 
Fitzpatrick skin-type scale 
X 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
Prior and concomitant medications/therapies 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination, including weight and 
heightf 
X 
 
 
 
 
 
 
 
 
X 
 
Treatment area identification 
X 
Xd 
 
 
 
 
 
 
 
  
 
AK lesion count 
X 
Xd 
 
 
 
 
X 
X 
X 
X 
X 
ECGg 
X 
 
 
 
 
 
X 
 
 
X 
 
Clinical chemistry, hematology, and urinalysish 
X 
 
 
 
 
 
X 
 
 
X 
 
Pregnancy test  
X 
Xd,i 
 
 
 
 
X 
 
 
X 
 
PK blood samples 
 
Xj 
 
 
 
Xj 
 
 
 
 
 
Study medication application 
 
X 
X 
X 
X 
X 
 
 
 
 
 
AEsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
LSRs 
 
Xd 
Xd 
Xd 
Xd 
Xd 
X 
X 
X 
X 
 
Pigmentation and scarring 
 
Xd 
Xd 
Xd 
Xd 
Xd 
X 
X 
X 
X 
 
Standardized photography 
X 
Xd 
 
 
 
 
X 
 
 
X 
X 


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Table 1 
Schedule of Procedures/Assessments in Study KX01-AK-002 (Cohort 1) 
AE = adverse event; AK = actinic keratosis; ECG = electrocardiogram; HEENT = head, eyes, ears, nose, and throat; LSR = local skin reaction; PK = pharmacokinetic; 
Term = Termination. 
a 
For Day 57 complete responders only. 
b 
For subjects who do not have complete response at Day 57, Day 57 is the Final Visit. 
c 
For subjects who have complete response at Day 57 and no recurrence, 12 months post-Day 57 is the Final Visit.  Those subjects who have AK recurrence in the treatment area will 
have their Final Visit at the visit when the AK recurrence is identified. 
d 
Assessment performed before study medication application.  Day 1 evaluation will serve as baseline for these assessments. 
e 
Vital signs measurements will be taken after the subject has been seated for at least 5 minutes. 
f 
A complete PE will include weight and an assessment of HEENT, integumentary, gastrointestinal, cardiovascular, respiratory, musculoskeletal, and neurological systems.  Height 
will be measured at Screening only. 
g 
Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG. 
h 
Except for those diagnosed as having diabetes, subjects must be fasted for laboratory assessments. 
i 
For females of childbearing potential; urine pregnancy test on Day 1 before study medication application.  All other pregnancy tests are performed with serum. 
j 
PK assessments on Day 1 and Day 5 at 0 hour (just before study medication application) and at 0.5 (±5 min), 1 and 4 hours (±10 min) after study drug application.  
k 
Before LSR assessment, subjects will be queried for spontaneously reported AEs. 
l 
Only AEs in the selected treatment area will be recorded. 


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Table 2 
Schedule of Procedures/Assessments in Study KX01-AK-002 (Cohort 2) 
Period 
Screening 
Treatment 
Follow-up 
Recurrence Follow-up a 
Visit 
1 
2 
3 
4 
5 b 
6 b 
7 
8 
9 
10c/ 
Early 
Term  
11, 12, 13, 14 a 
Day 
-28 to -1 
1 
2 
3 
4 
5 
8 
15 
29 
57c 
3, 6, 9, 12 Months Post-Day 57d 
Visit time window (days) 
None 
None 
None 
None 
±2 
±2 
±2 
±2 
±14 
Informed consent 
X 
Inclusion & exclusion criteria 
X 
Xe 
Demographics 
X 
Medical/surgical history 
X 
AK history/AK treatment history 
X 
Fitzpatrick skin-type scale 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications/therapies 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
Physical examination, including weight and 
heightg 
X 
X 
Treatment area identification 
X 
Xe 
AK lesion count 
X 
Xe 
X 
X 
X 
X 
X 
ECGh 
X 
Xh 
Xh 
X 
X 
Clinical chemistry, hematology, and urinalysisi 
X 
X 
X 
Pregnancy test 
X 
Xe,j 
X 
X 
PK blood samples 
Xk 
Xk 
Study medication application 
X 
X 
X 
AEsl 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
LSRs 
Xe 
Xe 
Xe 
X 
X 
X 
X 
Pigmentation and scarring 
Xe 
Xe 
Xe 
X
X
X
X
Standardized photography 
X 
Xe 
X 
X 
X 


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Table 2 
Schedule of Procedures/Assessments in Study KX01-AK-002 (Cohort 2) 
AE = adverse event; AK = actinic keratosis; ECG = electrocardiogram; HEENT = head, eyes, ears, nose, and throat; LSR = local skin reaction; PK = pharmacokinetic; 
Term = Termination. 
a 
For Day 57 complete responders only. 
b 
These visits are not required for Cohort 2 subjects. 
c 
For subjects who do not have complete response at Day 57, Day 57 is the Final Visit. 
d 
For subjects who have complete response at Day 57 and no recurrence, 12 months post-Day 57 is the Final Visit.  Those subjects who have AK recurrence in the treatment area will 
have their Final Visit at the visit when the AK recurrence is identified. 
e 
Assessment performed before study medication application.  Day 1 evaluation will serve as baseline for these assessments. 
f 
Vital signs measurements will be taken after the subject has been seated for at least 5 minutes. 
g 
A complete PE will include weight and an assessment of HEENT, integumentary, gastrointestinal, cardiovascular, respiratory, musculoskeletal, and neurological systems.  Height 
will be measured at Screening only. 
h 
Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.  On Days 1 and 3, ECGs will be performed 4 hours postdose. 
i 
Except for those diagnosed as having diabetes, subjects must be fasted for laboratory assessments. 
j 
For females of childbearing potential; urine pregnancy test on Day 1 before study medication application.  All other pregnancy tests are performed with serum. 
k 
PK assessments on Day 1 and Day 3 at 0 hour (just before study medication application) and at 0.5 (±5 min), 1 and 4 hours (±10 min) after study drug application.  
l 
Before LSR assessment, subjects will be queried for spontaneously reported AEs. 
m 
Only AEs in the selected treatment area will be recorded. 


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3 
TABLE OF CONTENTS 
REVISION HISTORY............................................................................................................... I 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................2 
3 
TABLE OF CONTENTS .................................................................................................13 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................17 
5 
ETHICS............................................................................................................................18 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................18 
5.2 
Ethical Conduct of the Study .................................................................................18 
5.3 
Subject Information and Informed Consent ...........................................................19 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................19 
7 
INTRODUCTION ...........................................................................................................19 
7.1 
Indication ...............................................................................................................19 
7.1.1 
Mechanism of Action ...................................................................................20 
7.1.2 
Clinical Experience with KX2-391 ..............................................................20 
7.2 
Study Rationale ......................................................................................................21 
8 
STUDY OBJECTIVES ....................................................................................................21 
8.1 
Primary Objective ..................................................................................................21 
8.2 
Secondary Objectives.............................................................................................21 
8.3 
Exploratory Objectives ..........................................................................................22 
9 
INVESTIGATIONAL PLAN ..........................................................................................22 
9.1 
Overall Study Design and Plan ..............................................................................22 
9.1.1 
Screening Period ..........................................................................................23 
9.1.2 
Treatment Period ..........................................................................................24 
9.1.3 
Follow-up Period .........................................................................................24 
9.1.4 
Recurrence Follow-up Period ......................................................................24 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................25 
9.3 
Selection of Study Population ................................................................................25 
9.3.1 
Inclusion Criteria .........................................................................................25 
9.3.2 
Exclusion Criteria ........................................................................................26 
9.3.3 
Removal of Subjects from Therapy or Assessment .....................................27 
9.4 
Treatments..............................................................................................................28 
9.4.1 
Treatment Administered ..............................................................................28 
9.4.2 
Identity of Investigational Products .............................................................29 
Chemical Name and Structural Formula of KX2-391 .........................29 
Labeling for Study Drug ......................................................................29 
Storage Conditions ...............................................................................30 


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Administration of Investigational Products .........................................30 
9.4.3 
Method of Assigning Subjects to Treatment Groups ...................................31 
9.4.4 
Selection of Doses in the Study ...................................................................31 
9.4.5 
Selection and Timing of Dose for Each Subject ..........................................31 
9.4.6 
Blinding........................................................................................................31 
9.4.7 
Prior and Concomitant Therapy ...................................................................31 
Prior Therapy .......................................................................................31 
Concomitant Medication/Therapy .......................................................31 
Prohibited Medication/Therapy ...........................................................32 
9.4.8 
Prohibitions and Restrictions during Study Period ......................................33 
9.4.9 
Treatment Compliance .................................................................................33 
9.4.10 
Drug Supplies and Accountability ...............................................................33 
9.5 
Study Assessments .................................................................................................34 
9.5.1 
Assessments .................................................................................................34 
Demography .........................................................................................34 
Baseline Assessments ..........................................................................34 
9.5.1.2.1 
Medical/Surgical and Actinic Keratosis History ...........................34 
9.5.1.2.2 
Fitzpatrick Skin-Type Classification .............................................34 
9.5.1.2.3 
Prior Medications ...........................................................................35 
9.5.1.2.4 
Height .............................................................................................35 
Activity Assessments ...........................................................................35 
9.5.1.3.1 
Actinic Keratosis Lesion Count .....................................................35 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments .............................................................36 
9.5.1.4.1 
Pharmacokinetic Assessments .......................................................36 
9.5.1.4.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments ...................................................................................36 
Safety Assessments ..............................................................................36 
9.5.1.5.1 
Adverse Events and Other Events of Interest ................................37 
9.5.1.5.2 
Serious Adverse Events and Other Events of Interest ...................39 
9.5.1.5.3 
Laboratory Measurements .............................................................40 
9.5.1.5.4 
Vital Signs ......................................................................................41 
9.5.1.5.5 
Physical Examinations ...................................................................41 
9.5.1.5.6 
Electrocardiograms ........................................................................42 
9.5.1.5.7 
Pregnancy Testing ..........................................................................42 
9.5.1.5.8 
Other Assessments .........................................................................42 
9.5.2 
Appropriateness of Measurements ...............................................................44 


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9.5.3 
Reporting of Serious Adverse Events, Pregnancy, and Other Events of 
Interest..........................................................................................................44 
Reporting of Serious Adverse Events ..................................................44 
Reporting of Pregnancy .......................................................................45 
Reporting of Other Events of Interest ..................................................46 
9.5.3.3.1 
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................46 
Expedited Reporting ............................................................................46 
Breaking the Blind ...............................................................................46 
Regulatory Reporting of Adverse Events ............................................46 
9.5.4 
Completion/Discontinuation of Subjects .....................................................46 
9.5.5 
Abuse or Diversion of Study Drug ..............................................................47 
9.5.6 
Confirmation of Medical Care by another Physician ..................................47 
9.6 
Data Quality Assurance .........................................................................................47 
9.6.1 
Data Collection ............................................................................................47 
9.6.2 
Clinical Data Management ..........................................................................48 
9.7 
Statistical Methods .................................................................................................48 
9.7.1 
Statistical and Analytical Plans ....................................................................48 
Study Endpoints ...................................................................................48 
9.7.1.1.1 
Primary Endpoints .........................................................................48 
9.7.1.1.2 
Secondary Endpoints .....................................................................49 
9.7.1.1.3 
Exploratory Endpoints ...................................................................49 
Definitions of Analysis Sets.................................................................49 
Subject Disposition ..............................................................................50 
Demographic and Other Baseline Characteristics ...............................50 
Prior and Concomitant Therapy ...........................................................50 
Activity Analyses .................................................................................50 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...................................................................51 
9.7.1.7.1 
Pharmacokinetic Analyses .............................................................51 
9.7.1.7.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .........................................................................................51 
Safety Analyses ....................................................................................51 
9.7.1.8.1 
Extent of Exposure .........................................................................51 
9.7.1.8.2 
Adverse Events ..............................................................................51 
9.7.1.8.3 
Laboratory Values ..........................................................................52 
9.7.1.8.4 
Vital Signs ......................................................................................52 
9.7.1.8.5 
Electrocardiograms ........................................................................52 


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9.7.1.8.6 
Physical Examinations ...................................................................52 
9.7.1.8.7 
Pregnancy Tests .............................................................................52 
9.7.1.8.8 
Other Analyses ...............................................................................52 
9.7.2 
Determination of Sample Size .....................................................................53 
9.7.3 
Interim Analysis ...........................................................................................53 
9.7.4 
Other Statistical/Analytical Issues ...............................................................53 
9.7.5 
Procedure for Revising the Statistical Analysis Plan ...................................53 
10 REFERENCE LIST .........................................................................................................54 
11 APPENDICES .................................................................................................................56 
LIST OF IN-TEXT TABLES 
Table 1 
Schedule of Procedures/Assessments in Study KX01-AK-002 
(Cohort 1) .....................................................................................................9 
Table 2 
Schedule of Procedures/Assessments in Study KX01-AK-002 
(Cohort 2) ...................................................................................................11 
Table 3 
Treatment Administered in KX01-AK-002 ...............................................29 
Table 4 
Blood Sample Collection Times for Pharmacokinetic Analyses ...............36 
Table 5 
Clinical Laboratory Tests ...........................................................................41 
Table 6 
Local Skin Reaction Grading Criteria ........................................................43 
LIST OF APPENDICES 
Appendix 1 
Photographs of Local Skin Reactions ........................................................57 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Terms 
AE 
adverse event 
AK 
actinic keratosis 
AUC 
area under the plasma concentration-time curve  
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
Cmin 
minimum (trough) plasma concentration 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LC-MS/MS 
liquid chromatography/tandem mass spectrometry 
LSR 
local skin reaction 
MedDRA 
Medical Dictionary for Regulatory Activities 
PE 
physical examination 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PT 
preferred term 
R 
accumulation ratio 
SAE 
serious adverse event 
SCC 
squamous cell carcinoma 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
US 
United States 
UV 
ultraviolet (light) 
 


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5 
ETHICS 
5.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, any protocol amendments, informed consent form (ICF), and appropriate 
related documents must be reviewed and approved before subjects are screened for entry by 
an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) constituted and 
functioning in accordance with International Council for Harmonisation (ICH) E6 (Good 
Clinical Practice [GCP]1), Section 3, and any local regulations (eg, Federal Regulations, Title 
21 Code of Federal Regulations [CFR] Part 56).  Documentation of IRB/IEC compliance 
with the ICH E6 and any local regulations regarding constitution and review conduct will be 
provided to the Sponsor. 
A signed letter of study approval from the IRB/IEC chairman must be sent to the Principal 
Investigator (PI) with a copy to the Sponsor before study start and the release of any study 
drug to the site by the Sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the Investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the Sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the Investigator or 
Sponsor, depending on local regulatory obligations.  If the Investigator is required to report 
to the IRB/IEC, he/she will forward a copy to the Sponsor at the time of each periodic report.  
The Investigator(s) or the Sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the Investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required. 
5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures (SOPs) of the 
Sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following: 
• Principles of the World Medical Association Declaration of Helsinki (2013) 
• ICH E6: Guidance for Industry - E6 Good Clinical Practice: Consolidated Guidance, US 
Department of Health and Human Services, Food and Drug Administration, April 1996.  
• Title 21 of the United States CFR (US 21 CFR) regarding clinical studies, including Part 
50 and Part 56 concerning informed subject consent and IRB regulations and applicable 
sections of US 21 CFR Part 312 
 


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5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the Investigator must explain to 
each subject the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the subject, and the extent of 
maintaining confidentiality of the subject’s records.  Each subject must be informed that 
participation in the study is voluntary, that he/she may withdraw from the study at any time, 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it, and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject provides verbal consent to the subject’s participation in the 
study and has signed and personally dated the ICF, the witness should sign and personally 
date the consent form.  The subject will be asked to sign an ICF and all authorizations required 
by local law (eg, Protected Health Information in North America) before any study-specific 
procedures are performed.  No subject can enter the study before his/her informed consent 
has been obtained. 
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with 
ICH E6, Section 4, and all applicable local regulations.  The original, signed ICF for each 
subject will be verified by the Sponsor and kept on file according to local procedures at the 
site. 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified Investigators under the sponsorship of Kinex 
Pharmaceuticals, Inc. at approximately 8 to 16 investigational sites in the United States (US). 
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the Sponsor and of any contract research organizations (CROs) will be listed in the 
Regulatory Binder provided to the site. 
7 
INTRODUCTION 
7.1 
Indication 
In this study, the activity, safety, and pharmacokinetics (PK) of KX2-391 Ointment 1% will 
be evaluated in adult subjects with a clinical diagnosis of stable, clinically typical actinic 
keratosis (AK) on the face or scalp. 


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7.1.1 
Mechanism of Action 
KX2-391 (also referred to as KX01) is a synthetic and highly selective inhibitor of Src 
tyrosine kinase signaling and tubulin polymerization. KX2-391 ointment is being developed 
as a topical treatment for actinic keratosis.  KX2-391 is also being developed as an oral agent 
for oncology indications.  In defining its pharmacological activity in tumor cells, both in vitro 
and in vivo, KX2-391 has been shown to have potent activity against a wide range of solid 
tumors as well as leukemia cell lines, including cell lines that are resistant to commonly used 
cancer drugs.  Clinically, the safety, tolerability and pharmacokinetics of KX2-391 have been 
studied in approximately 120 patients in both solid and liquid tumors using either once or 
twice daily dosing.  The best overall response in these early studies has been ‘stable disease’ 
in 25-30% of patients. 
KX2-391 promotes the induction of p53, G2/M arrest of proliferating cell populations and 
subsequent apoptosis via the stimulation of Caspase-3 and PARP cleavage. Data from pre-
clinical dermatology studies coupled with an understanding of the mechanism of action of 
KX2-391 suggests that this compound will have clinical activity in dermatology indications 
such as actinic keratosis.  Potent inhibition of the growth of primary human keratinocytes and 
several melanoma cell lines in vitro (50% growth inhibition [GI50 values] ≤50 nM), suggests 
that KX2-391 has the potential to inhibit the proliferative expansion and promote apoptosis 
of abnormally proliferating cells in the epidermal and dermal layers upon topical application. 
KX2-391 has also been observed to inhibit T cell migration and endothelial tubule formation 
in vitro, suggesting additional potential therapeutic benefits for conditions where pathology is 
supported by lymphocyte infiltration, inflammation, and/or angiogenesis. 
Information regarding KX2-391 nonclinical studies is provided in the Investigator’s 
Brochure. 
7.1.2 
Clinical Experience with KX2-391 
KX2-391 Ointment 1% has been administered to humans in ongoing study KX01-AK-01-
US.  Based on preliminary PK data from this study in AK lesions on the forearm, the 
systemic exposure to KX2-391 following topical administration is limited, and is 
considerably lower than observed in previous clinical studies of oral KX2-391.  Patients 
should be monitored for the occurrence of application site reactions and systemic toxicity. 
KX2-391 has been administered orally to approximately 120 patients with malignancy. 
The Kinex studies of oral KX2-391 are as follows: 
KX2-391 was evaluated in a Phase I clinical trial, Study No. KX01-01-07, entitled “A 
Combined Rising Single-Dose (RSD) and Rising Multiple-Dose (RMD) Phase I Study to 
Evaluate Safety, Tolerability, and Pharmacokinetics of KX2-391 in Patients with Advanced 
Malignancies That Are Refractory to Conventional Therapies”. 
KX2-391 has been evaluated in Study No. KX01-002-09, entitled “A Phase II, Open-Label, 
Single-Arm Study Evaluating the Safety, Efficacy and Pharmacokinetics of KX2-391 in 


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Patients with Bone-Metastatic, Castration-Resistant Prostate Cancer Who Have Not Received 
Prior Chemotherapy.” 
KX2-391 was evaluated in Study No, KX01-03-11, “A Phase 1b Rising Multiple-Dose 
Clinical Study to Evaluate Safety, Tolerability and Activity of Oral Monotherapy with 
KX2-391 in Elderly Subjects with Acute Myeloid Leukemia (AML) Who Are Refractory to 
or Have Declined Standard Induction Therapy”. 
7.2 
Study Rationale 
Actinic keratoses represent the initial intra-epidermal manifestation of abnormal keratinocyte 
proliferation having the potential to progress to squamous cell carcinoma (SCC).  Squamous 
cell carcinoma is the second leading cause of skin cancer deaths in the US, with up to 65% of 
SCC arising from pre-existing actinic keratoses.2,3  The risk of progression has been 
determined to be between 0.025% and 16% per year,2,4 and the calculated lifetime risk of 
malignant transformation for a patient with AKs followed up for 10 years is between 6.1% 
and 10.2%.5  The rationale behind treating every AK is based on the difficulty in predicting 
which single AK will progress to squamous cell carcinoma.6,7  Suchniak et al8 reported 36% 
of lesions previously diagnosed clinically as AKs being in fact SCC, with 14% being in situ 
SCC.  Ehrig et al9 showed that 4% of AKs clinically diagnosed by board-certified 
dermatologists were in fact SCC and 5% were considered occult early stage of cutaneous 
malignancy.  Spontaneous regression has been reported in up to 25.9% of AKs over a 
12-month period, although 15% later reappeared.10,11,12  The goals of treatment are to 
completely eliminate AKs, minimizing their risk of progression to invasive SCC, reducing 
the potential to metastasize and cause death, while obtaining the best cosmetically acceptable 
outcomes.  Current approved/marketed treatment has shown up to approximately 60% 
efficacy, with a recurrence rate of approximately 35%. 
8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
The primary objective of the study is: 
• To evaluate the activity of KX2-391 Ointment 1% administered topically to the face or 
scalp in subjects with AK by determining complete response rate, defined as 100% 
clearance at Day 57 
8.2 
Secondary Objectives 
The secondary objectives of the study are: 
x To assess the activity of KX2-391 Ointment 1% during Days 1-57 
x To assess the safety and tolerability of KX2-391 Ointment 1% in subjects with AK on 
the face or scalp 
x To assess the PK of KX2-391 Ointment 1% in subjects with AK on the face or scalp 


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x To assess dose regimens by contrasting 5-day treatment with 3-day treatment in terms 
of the activity and safety of KX2-391 Ointment 1% in subjects with AK on the face 
or scalp 
8.3 
Exploratory Objectives 
The exploratory objectives of the study are: 
x To determine recurrence rates up to 12 months post-Day 57 for subjects who show 
response at Day 57 
x To determine sustained response rates at 12 months post-Day 57 for subjects who 
show response at Day 57 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This study will be an open-label, multicenter, activity, safety, tolerability, and PK study of 
KX2-391 Ointment 1% administered topically to the face or scalp of subjects with actinic 
keratosis in 2 sequential cohorts:  a 5-day dosing regimen (Cohort 1) and a 3-day dosing 
regimen (Cohort 2). 
The study consists of Screening, Treatment, and Follow-up Periods. 
Cohort 1:  
Eligible subjects will receive 5 consecutive days of topical treatment, to be applied at the 
study site, with 50 mg of KX2-391 Ointment 1% each day.  Blood samples for PK analysis 
will be collected on Day 1 and Day 5.  Subjects will return for Follow-up visits until Day 57.  
Thereafter, only Day 57 complete responders will continue Recurrence Follow-up Visits 
every 3 months for an additional 12 months after Day 57.  Activity (lesion counts) and safety 
evaluations will be performed. 
Cohort 2: 
Eligible subjects will receive 3 consecutive days of topical treatment, to be applied at the 
study site, with 50 mg of KX2-391 Ointment 1% each day.  Blood samples for PK analysis 
will be collected on Day 1 and Day 3.  Subjects will return for Follow-up visits until Day 57.  
Thereafter, only Day 57 complete responders will continue Recurrence Follow-up Visits 
every 3 months for an additional 12 months after Day 57.  Activity (lesion counts) and safety 
evaluations will be performed. 
For both cohorts, subjects may stay for approximately 5 hours at the investigational center 
until after the last PK blood sample is collected on Days 1 and 5 (Cohort 1) or Days 1 and 3 
(Cohort 2). 


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The Sponsor will review accumulating data.  If the 5-day regimen (Cohort 1) has sufficient 
activity and safety to warrant evaluating a 3-day regimen, enrollment of Cohort 2 will start 
after there are 60 evaluable subjects or up to 80 subjects are enrolled (whichever comes first) 
in Cohort 1.  For the most part, protocol procedures for Cohort 1 will be duplicated for 
Cohort 2, except PK samples will be collected on Days 1 and 3, and subjects will not return 
for Visits 5 and 6. 
The same study sites for the most part of Cohort 1 will be used for Cohort 2.  The Sponsor 
study team will monitor the enrollment status closely and ensure that any individual site does 
not enroll too many subjects. 
In each cohort, approximately 80 subjects will be enrolled to provide approximately 
60 subjects in the Evaluable Set, defined as subjects who complete all planned treatments and 
most evaluations, including the Day 57 Follow-up visit.  Therefore, a total of 160 subjects in 
2 cohorts may be enrolled, but the sample size of Cohort 2 may be adjusted, depending on 
the results of Cohort 1. 
9.1.1 
Screening Period 
The Screening Period may last up to 28 days for each cohort. 
Subject eligibility will be established during the Screening Period.  Subjects will be screened 
within 28 days of the first dose of study drug.  All screening assessments/evaluations, as 
presented in Table 1 and Table 2 will be performed after the subject provides informed 
consent and eligibility criteria are met. 
Treatment Area Identification 
At Screening (Visit 1), the Investigator will select a continuous treatment area affected with 
AK on the face or scalp for each subject that: 
x measures 25 cm2 
x contains 4 to 8 AK lesions that are clinically typical 
The location and approximate shape of the treatment area will be recorded on an acetate 
transparency sheet. 
At Visit 1, the Investigator and an investigational center staff member will identify the 
treatment area by:  
x Examining the face or scalp and locating each AK with a dot of removable marker. 
x Using an 8 x 11 acetate transparency sheet with 1x1 cm squares.   
x Mapping at least 2 anatomical landmarks on the acetate sheet.  Example of landmarks 
could be bony prominences, scars, moles, seborrheic keratosis, and veins. 
x Indicating the location of AK lesions with permanent marker dots on the acetate 
transparency sheet. 


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x Outlining the treatment area on the transparency sheet with the permanent marker. 
x Removing marker dots on the face/scalp with alcohol swabs or water (after taking the 
screening photo). 
9.1.2 
Treatment Period 
The inclusion/exclusion criteria will be reviewed again prior to treatment on Day 1, to 
re-confirm subjects’ eligibility to participate in the study. 
Subjects in Cohort 1 will be treated for 5 consecutive days (Days 1-5 [Visits 2-6]) during the 
Treatment Period.  Visits 2 through 6 should be scheduled to occur at approximately the 
same time each day. 
Subjects in Cohort 2 will be treated for 3 consecutive days (Days 1-3 [Visits 2-4]) during the 
Treatment Period.  Subjects will not return on Day 4 (Visit 5) or Day 5 (Visit 6).  Visits 2 
through 4 should be scheduled to occur at approximately the same time each day.  
At Visit 2 (Day 1), prior to study drug application, the Investigator and any appropriate 
investigational staff member(s) (Investigator-trained designee) will confirm the location of 
the treatment area using the Visit 1 acetate sheet.  The Investigator should re-mark the 
treatment area borders as needed so the study evaluations may be effectively completed. 
Once the treatment area has been re-identified at Visit 2, photographs will be taken 
(Section 9.5.1.5.8).  50 mg of KX2-391 Ointment 1% will be applied topically once daily for 
5 consecutive days (Cohort 1) or 3 consecutive days (Cohort 2) to the 25 cm2 treatment area 
(2 mg/cm2; 0.5 mg KX2-391 total).  See Section 9.4.2.4 for a detailed description of study 
medication application. 
Pharmacokinetic blood sampling, activity, safety assessments, and local skin reaction (LSR) 
assessments (see Section 9.5 for details) will be performed (Table 1 and Table 2).  
Pigmentation and scarring in the treatment area also will be assessed by the Investigator (or a 
trained designee). 
Standardized photography will be performed at designated visits throughout the study 
(Table 1 and Table 2). 
9.1.3 
Follow-up Period 
After the Treatment Period for both cohorts, there will be Follow-up Visits at Days 8, 15, 29, 
and 57 to assess safety, activity, LSRs, pigmentation, and scarring. 
For subjects who do not have complete response at Day 57, Day 57 is their Final Visit. 
9.1.4 
Recurrence Follow-up Period 
For both cohorts, only for subjects who show complete response at Day 57, there will be 
additional visits every 3 months up to 12 months post-Day 57 (ie, at 3, 6, 9, and 12 months 


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post-Day 57) to assess recurrence of AK lesions.  These subjects will continue to undergo 
scheduled activity and safety assessments (Table 1 and Table 2). 
For subjects who have complete response at Day 57 and no recurrence, 12 months 
post-Day 57 is the Final Visit.  Those subjects who have AK recurrence in the treatment area 
will have their Final Visit at the visit when the AK recurrence is identified. 
9.2 
Discussion of Study Design, Including Choice of Control Groups 
This is a nonrandomized, open-label study.  No control group has been included. 
9.3 
Selection of Study Population 
Eligible subjects will be adults (≥18 years of age) with a clinical diagnosis of stable, 
clinically typical AK on the face or scalp. 
9.3.1 
Inclusion Criteria 
Inclusion criteria will be reviewed at Screening (Visit 1). 
Subjects must meet all of the following criteria to be included in this study: 
1. Males and females ≥18 years old 
2. Clinical diagnosis of stable, clinically typical actinic keratosis 
3. A treatment area on the face or scalp that: 
x is a continuous area measuring 25 cm2 
x contains 4 to 8 AK lesions 
4. Females must be postmenopausal (>50 years of age with at least 12 months of 
amenorrhea), surgically sterile (by hysterectomy, bilateral oophorectomy or tubal 
ligation) or otherwise incapable of pregnancy for at least 1 year; or, if of childbearing 
potential, must be using highly effective contraception for at least 30 days or 
1 menstrual cycle, whichever is longer, prior to treatment with KX2-391 Ointment 1% 
and must agree to continue to use highly effective contraception for at least 90 days 
following their last dose of KX2-391 Ointment 1%.  Highly effective contraception 
includes oral hormonal contraceptives, hormonal contraceptive implant or patch, or 
intrauterine device.  Abstinence and double barrier methods do not qualify as highly 
effective methods of contraception. 
5. Males who have not had a vasectomy must agree to use barrier contraception from 
Screening through 90 days after their last dose of KX2-391 Ointment 1%. 
6. All subjects must agree not to donate sperm or eggs or attempt conception from 
Screening through 90 days following their last dose of KX2-391 Ointment 1%. 
7. Females of childbearing potential must have a negative serum pregnancy test at 
Screening and a negative urine pregnancy test on Day 1 prior to administration of study 
treatment. 


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8. Subjects who in the judgment of the Investigator, are in good general health based on: 
x medical history 
x no physical examination (PE) findings that the Principal Investigator (PI) determines 
would interfere with interpretation of study results 
x screening electrocardiogram (ECG) without clinically significant abnormalities  
x clinical chemistry, hematology, and urinalysis results that are within the reference 
ranges; clinical laboratory values outside the reference ranges that are considered by 
the PI to be clinically insignificant are also acceptable 
9. Willing to avoid direct sun or ultraviolet (UV) light exposure to the face or scalp 
10. Able to comprehend and are willing to sign an informed consent form 
9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Clinically atypical and/or rapidly changing AK lesions on the treatment area 
2. Malignancy within 5 years prior to Screening except basal or squamous cell carcinoma 
not on the treatment area that were treated with curative intent and are without 
recurrence 
3. Used any of the following systemic therapies within the specified period before Visit 1: 
x retinoids; 90 days 
x glucocorticosteroids; 28 days (intra-articular and inhaled steroids are allowed) 
x methotrexate or other anti-metabolites; 28 days 
x immunosuppressants or immunomodulators; 28 days 
4. Used any of the following topical therapies on the treatment area within the specified 
period before Visit 1: 
x retinoids; 90 days 
x glucocorticosteroids; 14 days 
x analgesic and/or anti-inflammatory medication on the face or scalp; 72 hours 
5. Had any of the following on the treatment area within 90 days (or until the site has 
healed, whichever is longer) before Visit 1: 
x ingenol mebutate (eg, Picato) 
x 5-fluorouracil (eg, 5-FU; Efudex) 
x imiquimod (eg, Aldara; Zyclara) 
x diclofenac with or without hyaluronic acid (eg, Solaraze) 
6. Surgical or destructive modalities on the treatment area within 30 days (or until the site 
has healed following treatment, whichever is longer) before Visit 1: 
x cryotherapy 


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x electrodesiccation 
x laser, light (eg, photodynamic therapy, intense pulsed light) or any other energy-based 
therapy 
x chemical peels (eg, tricholoracetic acid) 
x dermabrasion 
x surgical removal (eg, curettage, excision) 
7. Currently, or has experienced any of the following on the treatment area within the 
specified period before Visit 1: 
x cutaneous malignancy; 180 days 
x sunburn; 28 days 
x body art (eg, tattoo, piercing); currently 
8. A history of sensitivity and/or allergy to any of the ingredients in the study medication 
9. A skin disease (eg, atopic dermatitis, psoriasis, eczema) or condition (eg, scarring, open 
wounds) that, in the opinion of the Investigator, might interfere with the study conduct 
or evaluations, or which exposes the subject to an unacceptable risk by study 
participation 
10. Other significant uncontrolled or unstable medical diseases or conditions that, in the 
opinion of the Investigator, would expose the subject to unacceptable risk by study 
participation 
11. Females who are pregnant or nursing 
12. Participated in an investigational drug trial during which an investigational study 
medication was administered within 30 days or 5 half-lives of the investigational 
product, whichever is longer, before dosing 
13. A known history of human immunodeficiency virus (HIV), chronic hepatitis C, or 
chronic hepatitis B infection 
9.3.3 
Removal of Subjects from Therapy or Assessment 
The Investigator may discontinue treating a subject with study treatment or withdraw the 
subject from the study at any time for safety or administrative reasons.  The subject may 
decide to discontinue study treatment or withdraw from the study at any time for any reason. 
The Investigator will document the reason for discontinuing a subject from treatment or from 
the study. 
The Investigator may discontinue treatment or discontinue a subject from the study for any of 
the reasons listed below:  
x Occurrence of AEs 
x Occurrence of pregnancy  


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x Use of a prohibited concomitant medication or treatment (see Section 9.4.7.3) 
x Conditions that, in the opinion of the Investigator, would make the subject’s 
continued participation in the study inadvisable (actual condition must be 
documented) 
x Noncompliance (Investigator must describe) 
x Withdrawal of consent (subject asked, but not required to give a reason) 
x Other (Investigator must describe) 
If the study is terminated by the Sponsor, the Investigator will promptly explain to the subject 
involved that the study will be discontinued and provide appropriate medical treatment and 
other necessary measures for the subject. 
9.4 
Treatments 
The investigational product in the study is KX2-391 Ointment 1%. 
9.4.1 
Treatment Administered 
Information regarding study treatment is provided in Table 3. 
 
 


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Table 3 
Treatment Administered in KX01-AK-002 
Investigational Product 
Strength 
Size of 
Treatment 
Area 
Quantity study 
medication/ 
KX2-391 
Number 
Applications 
and Frequency 
Study Days 
Administered 
KX2-391 Ointment 1% 
1% 
25 cm2 
50 mg of study 
drug = 0.5 mg 
of KX2-391 
1 application 
daily for 
5 consecutive 
days (Cohort 1) 
or 3 consecutive 
days (Cohort 2) 
Days 1-5 (Cohort 1) 
Days 1-3 (Cohort 2) 
 
9.4.2 
Identity of Investigational Products 
 
Chemical Name and Structural Formula of KX2-391 
x Study drug code:  KX2-391 Ointment 1% 
x Drug Product:  KX2-391 free base ointment formulated with glyceryl 
monostearate and propylene glycol 
x Chemical name:  N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl) 
acetamide   
x Molecular formula:  C26H29N3O3 
x Molecular weight:  431.53 g/mole 
x Structural formula:   
 
 
Labeling for Study Drug 
Investigational product will be packaged and labeled in a manner consistent with the study 
and will be designed by:  
Kinex Pharmaceuticals, Inc. 
1001 Main Street 
Suite 600 
Buffalo, NY 14203 
Labels will be nonremovable in nature. 


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Labels for the investigational product will be in accordance with US regulations and will 
include (but will not be limited to) the following information: 
• 
 For clinical study use only 
• Name and address of the Sponsor 
• Chemical name/drug identifier 
• Lot number/batch number 
• Storage conditions, expiration date if necessary 
 
Storage Conditions 
Study drug will be stored in accordance with labeled storage conditions. Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The Investigator is responsible for ensuring that the 
temperature is monitored throughout the total duration of the trial and that records are 
maintained; the temperature should be monitored continuously by using either an in house 
validated data acquisition system, a mechanical recording device, such as a calibrated chart 
recorder, or by manual means, such that minimum and maximum thermometric values over a 
specific time period can be recorded and retrieved as required. 
 
Administration of Investigational Products 
The study medication is for external topical use on the treatment area.  An investigational 
center staff member will perform the study medication applications.  The staff member must 
wash her/his hands before and after each study medication application. 
50 mg of KX2-391 Ointment 1% will be applied topically to a 25 cm2 treatment area.  This 
amount contains a total of 0.5 mg KX2-391 free base.  KX2-391 Ointment 1% will be 
applied once daily for 5 consecutive days (Cohort 1) or 3 consecutive days (Cohort 2) (see 
Table 3). 
The staff member will weigh the appropriate amount of study medication into a weighing 
boat (or equivalent) using a calibrated scale.  The amount of study medication applied will be 
calculated by determining the difference of the weight of the weighing boat with study 
medication before and after application.  The amount of study medication weighed will be as 
close to the intended dose as possible. 
A study staff member will perform and document a scale accuracy check at least every day 
before weighing study medication. 
KX2-391 Ointment 1% will be applied to the subject’s treatment area using a fingertip 
protected with a powder-free finger cot or examination glove.  The study medication will be 
gently and evenly rubbed over the treatment area, including its borders, until no visible 
accumulation is evident. The time when the study medication application is completed 
(Application Completion Time) will be recorded. 


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The study medication should remain on the treatment area. Subjects must avoid touching or 
wetting the treatment area for at least 12 hours from time of last application and are not 
allowed to apply any topical products to the treatment area (see Section 9.4.7.3).  Instructions 
will be sent home with the subject clarifying on how to care for the treatment area. 
9.4.3 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study with 2 sequential cohorts.  Each site will enroll subjects for 
Cohort 1 (5-day regimen) first, and will not assign any subjects to Cohort 2 (3-day regimen) 
until being notified.  The Sponsor will review accumulating data on Cohort 1 to decide if, 
when, and where to start Cohort 2.  In addition, the Sponsor study team will monitor the 
enrollment status closely and ensure that any individual site does not enroll too many 
subjects. 
9.4.4 
Selection of Doses in the Study 
The dose of 50 mg of KX2-391 Ointment 1% applied to a 25 cm2 area on the face or scalp 
for 5 or 3 consecutive days is based on a previous study using the same dose regimen for the 
treatment of AK on the forearm (study KX01-AK-01-US).  Preliminary data show that this 
regimen had an acceptable LSR and safety profile, with efficacy outcomes considered to 
warrant further investigation. 
9.4.5 
Selection and Timing of Dose for Each Subject 
Section 9.4.2.4 provides detailed instructions for administering KX2-391 Ointment 1% in 
this study.  Study medication should be applied at about the same time each day. 
9.4.6 
Blinding 
The study will not be blinded. 
9.4.7 
Prior and Concomitant Therapy 
 
Prior Therapy 
All medications (prescription and nonprescription including vitamins and dietary 
supplements), treatments, and therapies including radiotherapy taken 28 days before Day 1 
through the final study visit must be recorded in the case report form/electronic case report 
form (CRF/eCRF).  A complete AK treatment history will be recorded on the AK Treatment 
History CRF/eCRF (see Section 9.5.1.2.1). 
 
Concomitant Medication/Therapy 
Concomitant medication/therapies are any new or existing therapy received by the subject 
after signing the ICF until discharge from the study. 


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Any medication (including nonprescription medications) or therapy administered to the 
subject during the course of the study (starting at the date of informed consent) will be 
recorded on the Concomitant Medication CRF/eCRF. 
Use of sunblock or any topical products in the treatment area allowed by the Investigator will 
be recorded in the Concomitant Medication CRF/eCRF. 
The Investigator will record any AE on the Adverse Events CRF/eCRF for which the 
concomitant medication/therapy was administered.  
Subjects will refrain from receipt of any therapy in accordance with the inclusion/exclusion 
criteria. 
 
Prohibited Medication/Therapy 
Use of any non-study drug treatment for AK lesions on the treatment area is prohibited until 
Day 57.  AK lesions located outside the treatment area may be treated by lesion-directed 
treatment only, eg, cryotherapy or biopsy, as determined by the Investigator.  A list of 
prohibited medications follows. 
Prohibited drug products and treatments that might influence or mask the effects of treatment 
until Day 57 include:  immunomodulators or immunosuppressive therapies, cytotoxic drugs, 
interferon/interferon inducers, topical or systemic steroids, 5-FU, ingenol mebutate, 
imiquimod, diclofenac, topical or systemic retinoids, topical salicylic acid, bichloroacetic 
acid, trichloroacetic acid, acid-containing therapeutic products, benzoyl peroxide, 
chemodestruction, medicated/therapeutic topical salves or topical steroids, photodynamic 
therapy, psoralen plus UVA or UVB therapy, artificial tanner, excessive or prolonged 
exposure to UV light source.13 
During the Recurrence Follow-up Period, lesion-directed treatment such as cryotherapy or 
biopsy, and topical treatment is allowed for treatment of AK lesions emerging in any part of 
the body.  Any lesion in the treatment area that is treated during the Recurrence Follow-up 
Period will be considered as a recurrence. 
Subjects are prohibited from applying any topical products, including but not limited to, 
lotions, creams, and ointments to the treatment area up until the end of Visit 10 (Day 57), 
except when those medications are prescribed by the Investigator for the management of 
local skin reactions.  All other routinely used topical products can be used on the treatment 
area from Day 57 onward, at the discretion of the Investigator. 
All subjects should be reminded to avoid direct sun or UV exposure to the treatment area 
throughout the study.  From Day 15 onward, if a subject is unable to avoid direct sun or UV 
exposure to the treatment area, the Investigator may allow the use of sunblock only. 
Subjects have unrestricted use of nonmedicated topical products on areas outside of the 
treatment area during the study.  After Day 57, all routinely used topical products can be 
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Any subjects who start systemic therapies for the treatment of AK will be withdrawn from 
the study. 
Any subjects who start topical therapies for AK on the treatment area will be withdrawn from 
the study. 
The decision to administer a prohibited medication/treatment is done with the safety of the 
study subject as the primary consideration. 
9.4.8 
Prohibitions and Restrictions during Study Period 
Except for those diagnosed as having diabetes, subjects must be fasted for laboratory 
assessments (see Section 9.5.1.5.3); otherwise there are no food, water, beverage, or physical 
activity restrictions during the study. 
9.4.9 
Treatment Compliance 
Records of treatment administration for each subject will be kept during the study.  The 
clinical research associates (CRAs) will review treatment administration throughout the 
course of the study. 
9.4.10 
Drug Supplies and Accountability 
The Investigator and study staff will be responsible for the accountability of all clinical 
supplies (dispensing, inventory, and record keeping) following the Sponsor’s instructions.  In 
this matter, the Investigator and study staff must adhere to GCP guidelines, as well as 
national requirements. 
Under no circumstances will the Investigator allow the study drugs to be used other than as 
directed by this protocol.  Clinical supplies will be dispensed only by an appropriately 
qualified person and will not be dispensed to any individual who is not enrolled in the study. 
An accurate and timely record of the receipt of all clinical supplies and dispensing of study 
drug to the subject must be maintained.  This includes, but is not limited to: 
x documentation of receipt of clinical supplies 
x study drugs dispensing/return reconciliation log, including amount and date of 
dispensing 
x study drugs accountability log 
x all shipping service receipts 
x documentation of study drug returned to the Sponsor 
All forms will be provided by the Sponsor (or its designee).  Any comparable forms that the 
investigational site wishes to use must be approved by the Sponsor.  A copy of the drug 
accountability record must be provided to the Sponsor at the end of the study. 


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The supplies and inventory records must be made available, on request, for inspection by the 
Sponsor (or its designee) or a representative of a health authority.  If applicable, all unused 
study drugs and empty containers, are to be returned to the Investigator by the subject and 
ultimately to the Sponsor at the conclusion of the study unless provision is made by the 
Sponsor for destruction of supplies and containers at the investigational site.  On completion 
of drug accountability and reconciliation procedures by investigational site personnel and 
documentation procedures by Sponsor personnel, study drug that is to be returned to the 
Sponsor, if necessary must be boxed and sealed and shipped back to the Sponsor following 
all local regulatory requirements. 
The CRA(s) will review drug accountability during monitoring site visits and at the 
completion of the study. 
9.5 
Study Assessments 
9.5.1 
Assessments 
All assessments and timing of the assessments should be performed according to the 
Schedule of Procedures and Assessments (Table 1 and Table 2). 
 
Demography 
Subject demographic information will be collected at the Screening Visit.  Demographic 
information includes date of birth (or age), sex, race/ethnicity. 
 
Baseline Assessments 
9.5.1.2.1 MEDICAL/SURGICAL AND ACTINIC KERATOSIS HISTORY 
Medical and surgical history and current medical conditions will be recorded at Screening 
(Visit 1).  All pertinent medical history must be noted in the CRF/eCRF.  A complete AK 
medical history will also be recorded. 
Medical history will include:  
x Significant medical and surgical history; childhood diseases and common colds are 
not required unless it is ongoing at Screening 
x A complete AK history from the time of initial diagnosis 
x A complete AK treatment history including all commercial and investigational 
products, including medical therapies and surgical modalities, and other prescribed 
and nonprescription therapies dating back to the initial diagnosis.  
9.5.1.2.2 FITZPATRICK SKIN-TYPE CLASSIFICATION 
The Fitzpatrick Skin-Type is a skin classification system14 which measures 2 components 
(genetic disposition and reaction to sun exposure).  Skin-types range from very fair (Type I) 
to very dark (Type VI). 


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Subjects’ skin will be typed using this classification system at Screening (Visit 1). 
9.5.1.2.3 PRIOR MEDICATIONS 
Prior medications taken within 28 days before Day 1, including nonprescription remedies, 
vitamins, etc, will be recorded at Screening (Visit 1). 
9.5.1.2.4 HEIGHT 
Height will be measured only during the screening physical examination. 
 
Activity Assessments 
9.5.1.3.1 ACTINIC KERATOSIS LESION COUNT 
The Investigator will perform a count of AK lesions (lesion count) for all subjects at Visits 1 
and 2, Visits 7 through 10, and for Day 57 complete responders, also at Visits 11 through 14. 
The AK lesion count is the Investigator’s assessment of the number of AK lesions in the 
treatment area.  A subject must have 4 to 8 AK lesions in the treatment area to be eligible to 
continue in the study at Visit 1. 
For this assessment, an AK lesion is considered to be on the treatment area, and should be 
counted if it is completely inside the treatment area or is touching any of the borders of the 
treatment area.  These lesions will be treated during the study medication application process. 
The Investigator must NOT refer to any other evaluation to assist with the AK lesion count.  
This is not a comparison with the AK lesion count at any other timepoint. 


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Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
9.5.1.4.1 PHARMACOKINETIC ASSESSMENTS 
Blood samples (3 mL at each timepoint) for PK analysis of KX2-391 will be collected at the 
following timepoints (Table 4): 
Table 4 
Blood Sample Collection Times for Pharmacokinetic Analyses  
Application Day 
Time (hours) 
 
0 
predose 
0.5 
postdose 
1 
postdose 
4 
postdose 
Window 
 
±5 minutes 
±10 minutes 
±10 minutes 
Both cohorts: Day 1 (Visit 2)  
Xa 
X 
X 
X 
Cohort 1:  Day 5 (Visit 6) 
Xa 
X 
X 
X 
Cohort 2:  Day 3 (Visit 4) 
Xa 
X 
X 
X 
a 
Prior to application of study treatment. 
Approximately 24 mL will be collected for measurement of plasma concentrations of 
KX2-391. 
The actual times of PK sampling will be recorded. 
A description of collection, handling, and shipping procedures for PK samples will be 
provided to the sites. 
Plasma concentrations of KX2-391 will be analyzed to determine Cmax, and where applicable, 
AUCt, Cmin, and accumulation ratio R. 
Plasma concentrations of study drug will be measured using a validated liquid 
chromatography/tandem mass spectrometry (LC-MS/MS) assay. 
9.5.1.4.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS 
Not applicable 
 
Safety Assessments 
Safety assessments will include recording all AEs and serious adverse events (SAEs). 
Safety assessments also include laboratory evaluation of hematology, biochemistry, and 
urinalyses; periodic measurement of weight, vital signs, ECGs, and performance of PEs, as 
detailed in the sections below and shown in Table 1 and Table 2. 


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Subjects will be queried for spontaneously reported AEs at each study visit, before 
assessment of local skin reactions.  AEs will be reported separately from LSRs. 
Subject-reported LSRs will not be reported as adverse events.  Treatments administered for 
LSRs will be recorded on the Concomitant Medications CRF. 
9.5.1.5.1 ADVERSE EVENTS AND OTHER EVENTS OF INTEREST 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is KX2-391 
Ointment 1%. 
Treatment-emergent AEs are defined as: 
x either those AEs with an onset after dosing or  
x those pre-existing conditions that worsen after dosing 
The criteria for identifying AEs are: 
• any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product 
• any new disease or exacerbation of an existing disease  
• any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation from study drug 
• recurrence of an intermittent medical condition (eg, headache) not present at baseline 
All AEs, regardless of relationship to study drug or procedure, should be collected beginning 
from the time the subject signs the study ICF through the final contact in the Follow-up 
Period on Day 57.  For subjects participating in the Recurrence Follow-up Period, only AEs 
at the treatment area will be collected. 
Subjects with study drug-related AEs will be followed until resolution, resolved with 
sequelae, or under medical care.  All SAEs must be followed to resolution or, if resolution is 
unlikely, to stabilization. 
All AEs observed during the study will be reported on the CRF/eCRF. 
Laboratory Adverse Events 
A treatment-emergent abnormal laboratory test result should be considered as a treatment-
emergent AE (TEAE) if the identified laboratory abnormality leads to any type of 
intervention whether prescribed in the protocol or not. 


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An abnormal laboratory result should be considered by the Investigator to be an AE if it: 
x results in the withdrawal of study drug 
x results in withholding of study drug pending some investigational outcome 
x results in the initiation of an intervention, based on medical evaluation (eg, 
potassium supplement for hypokalemia) 
x results in any out of range laboratory value that in the Investigator’s judgment 
fulfills the definitions of an AE with regard to the subject’s medical profile 
x increases in severity compared with baseline 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
Investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF/eCRF. 
For significant treatment-emergent laboratory abnormalities meeting criteria as SAEs, the 
study site must submit an SAE report to the Sponsor or designee using the SAE reporting 
procedures described in Section 9.5.3.1.  However, if a significant treatment-emergent 
laboratory abnormality is accompanied by, and is part of the syndrome of, a serious clinical 
event or diagnosis, it is the clinical event/diagnosis that should be reported as the SAE and 
not the significant treatment-emergent laboratory abnormality. 
ECG changes and associated clinical symptoms determined to be clinically significant by the 
Investigator will be reported as AEs.  An ECG abnormality in a subject with symptoms may 
meet the criteria for an AE as described in this protocol.  In these instances, the AE 
corresponding to the symptomatic ECG abnormality will be recorded on the Adverse Events 
CRF/eCRF. 
For symptomatic ECG abnormalities meeting criteria as SAEs, the study site must submit an 
SAE report, including the ECG report to the Sponsor, or designee, using the SAE reporting 
procedures (Section 9.5.3.1). 
Assessing Severity of Adverse Events 
Every effort must be made by the Investigator to categorize each AE according to its severity 
and its relationship to the study treatment. 
Adverse events will be graded for severity as follows: 
Mild 
An event that is easily tolerated by the patient, causing minimal discomfort 
and not interfering with everyday activities 
Moderate 
An event that is sufficiently discomforting to interfere with everyday 
activities 


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Severe 
An event that prevents normal everyday activities 
Investigators will assess severity for all AEs (for both increasing and decreasing severity).  
The criteria for assessing severity are different from those used for seriousness (see 
Section 9.5.1.5.2). 
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
x temporal relationship of the onset of the event to the initiation of the study treatment 
x the course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
x whether the event is known to be associated with the study treatment or with other 
similar treatments 
x the presence of risk factors in the study subject known to increase the occurrence of 
the event 
x the presence of nonstudy treatment-related factors that are known to be associated 
with the occurrence of the event 
Classification of Causality 
The relationship of each AE to the study drug will be recorded on the CRF/eCRF using the 
following criteria: 
Definitely Related:  A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to drug administration, and which cannot be explained by 
concurrent or underlying disease or other drugs or conditions 
Probably Related:  A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to concurrent or 
underlying disease or other drugs or conditions  
Possibly Related:  A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, but which could also be explained by concurrent 
or underlying disease or other drugs or conditions 
Unlikely Related:  A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship improbable, and in 
which other drugs, conditions or concurrent or underlying disease provide plausible 
explanations 
9.5.1.5.2 
 SERIOUS ADVERSE EVENTS AND OTHER EVENTS OF INTEREST 
An SAE is any untoward medical occurrence that at any dose: 
• results in death 


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• is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death) 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, other events of interest, which include pregnancy and overdose, are 
to be captured using the SAE procedures described in Section 9.5.3.1, but are to be 
considered as SAEs only if they met one of the above criteria.  All events of these types are 
to be reported on the Adverse Events CRF/eCRF whether or not they meet the criteria for 
SAEs. 
The following hospitalization is not considered to be an SAE because there is no “AE” (ie, 
there is no untoward medical occurrence) associated with the hospitalization: 
• hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 
9.5.1.5.3 LABORATORY MEASUREMENTS 
Blood will be collected for clinical laboratory tests at Screening (Visit 1), Day 8 (Visit 7), 
and Day 57 (Visit 10) (Table 1 and Table 2).  Collection of blood and urine (including 
samples for pregnancy testing, where applicable) will be conducted at the clinic site.  
Approximately 20 mL of blood will be collected for clinical laboratory testing, including 
pregnancy testing, when required.  Except for those diagnosed as having diabetes, subjects 
must be fasted for laboratory assessments.  Fasting status must be documented for all 
laboratory samples. 
Microscopic urinalysis will be conducted only when clinically indicated based on dipstick 
results (laboratory protocol) or as determined by the Investigator.  When conducted, 
microscopic urinalysis results will be recorded on the CRF/eCRF. 
The clinical laboratory tests to be measured during the study are provided in Table 5. 


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Table 5 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
red blood cells (RBC), hemoglobin, hematocrit, platelets, and white 
blood cells (WBC) with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils), mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), RBC distribution width (RDW) 
Chemistry 
 
 Electrolytes 
chloride, potassium, sodium, bicarbonate (HCO3) 
 Liver function tests 
alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), gamma glutamyl transpeptidase (GGT), direct 
bilirubin, total bilirubin 
 Renal function tests 
blood urea/blood urea nitrogen, creatinine 
 Other 
Albumin, calcium, cholesterol, glucose, lactate dehydrogenase (LDH), 
phosphorus, total protein, triglycerides, uric acid 
Urinalysis (dipstick)a 
hydrogen ion concentration (pH), specific gravity, protein, glucose, 
ketones, leukocyte esterase, nitrite, bilirubin, urobilinogen, blood 
Pregnancy Testing 
serum pregnancy test, urine pregnancy test (where applicable) 
a 
Microscopic urinalysis will be conducted only when clinically indicated based on dipstick results 
(laboratory protocol) or as determined by the Investigator. 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1).  In these instances, the AE corresponding to the laboratory 
abnormality will be recorded on the Adverse Event CRF/eCRF. 
For laboratory abnormalities meeting the criteria of SAEs (see Section 9.5.1.5.2), the site 
must electronically transmit the SAE report including the laboratory report to the Sponsor 
using the SAE form (see Section 9.5.3.1). 
9.5.1.5.4 VITAL SIGNS 
Vital sign (pulse rate, systolic and diastolic blood pressure, respiratory rate, and body 
temperature) measurements will be taken after the subject has been seated for at least 
5 minutes at Screening (Visit 1), Day 5 (Visit 6) for Cohort 1 or Day 3 (Visit 4) for Cohort 2, 
Day 8 (Visit 7), Day 15 (Visit 8), Day 29 (Visit 9), and Day 57 (Visit 10) (Table 1 and 
Table 2).  Serial vital signs may be obtained to confirm accurate readings. 
9.5.1.5.5 PHYSICAL EXAMINATIONS 
A complete PE will be performed at Screening (Visit 1) and Day 57 (Visit 10) (Table 1 and 
Table 2). 
A complete PE will include weight and an assessment of head, eyes, ears, nose, and throat 
(HEENT), integumentary, gastrointestinal, cardiovascular, respiratory, musculoskeletal, and 
neurological systems. 


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Height will be measured only during the screening physical examination. 
Documentation of the PE will be included in the source documentation at the site.  Only 
changes from screening PE findings that meet the definition of an AE will be recorded on the 
Adverse Events CRF/eCRF. 
9.5.1.5.6 ELECTROCARDIOGRAMS 
A 12-lead ECG will be completed at Screening (Visit 1), Day 8 (Visit 7), and Day 57 
(Visit 10) (Table 1 and Table 2), at a convenient time during the visit.  ECGs will also be 
performed in Cohort 2 subjects at 4 hours postdose on Day 1 (Visit 2) and Day 3 (Visit 4).  
Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.  The 
ECG data recorded on the CRF/eCRF must include rate, rhythm, intervals, and QTc/QTcF. 
ECG changes and associated clinical symptoms determined to be clinically significant by the 
Investigator will be reported as AEs. 
9.5.1.5.7 PREGNANCY TESTING 
Serum pregnancy tests will be obtained in females of childbearing potential at Screening 
(Visit 1), Day 8 (Visit 7), and Day 57 (Visit 10) (Table 1 and Table 2). 
A urine pregnancy test will be performed on females of childbearing potential before study 
medication application on Day 1 (Visit 2).  Visit 1 and Visit 2 test results must be reviewed 
before dosing. 
9.5.1.5.8 OTHER ASSESSMENTS 
Concomitant Medications 
Concomitant medications will be assessed at all clinic visits (Table 1 and Table 2).  Any 
medication (including nonprescription medications) or therapy administered to the subject 
during the course of the study (starting at the date of informed consent) will be recorded on 
the Concomitant Medication CRF/eCRF.  The Investigator will record any AE on the 
Adverse Events CRF/eCRF for which the concomitant medication/therapy was administered. 
Use of sunblock or any topical products in the treatment area allowed by the Investigator will 
be recorded in the Concomitant Medication CRF/eCRF. 
Local Skin Reactions 
At every post-Screening clinic visit through Day 57 (Visit 10), the Investigator or trained 
designee will assess any LSR on the treatment area for signs: 
x Before study medication application (on dosing days) 
x After the assessment of adverse events 
The LSR assessment is the Investigator’s (or trained designee’s) assessment of the following 
signs 
on 
the 
treatment 
area: 
 
erythema, 
flaking/scaling, 
crusting, 
swelling, 


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vesiculation/pustulation, and erosion/ulceration.  These signs will be assessed using a grading 
scale ranging from 0 (not present) to 4 (worst) (Table 6). 
Table 6 
Local Skin Reaction Grading Criteria 
 
Grading Criteria 
Local Skin 
Response 
0 
1 
2 
3 
4 
Erythema 
Not present 
Slightly pink 
<50% 
Pink or light red 
>50% 
Red, restricted to 
treatment area 
Red extending 
outside treatment 
area 
Flaking / 
Scaling 
Not present 
Isolated scale, 
specific to lesion 
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 
 
Examples of LSR signs are shown in photographs in Appendix 1.15 
Application site reactions not classified as LSRs (eg, pruritus, pain, infection) will be 
reported as adverse events. 
All application site reactions and LSRs will be followed to resolution, or if resolution is 
unlikely, to stabilization. 
Treatment for any LSR or interruption/discontinuation of study treatment for an LSR will be 
recorded on the CRF/eCRF. 
LSRs will be reported separately from adverse events. 


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Pigmentation and Scarring 
Hypo- and hyper- pigmentation and scarring on the treatment area will be assessed by the 
Investigator (or a trained designee) as being present or absent.   
Pigmentation and scarring will be assessed at every post-Screening clinic visit through 
Day 57 (Visit 10) (Table 1 and Table 2).  Pigment-related changes or scarring should be 
followed until resolution or deemed stabilized by the Investigator. 
Standardized Photography 
Standardized photography will be performed at Screening (Visit 1), Day 1 (Visit 2), Day 8 
(Visit 7), Day 57 (Visit 10), and during the Recurrence Follow-up (at 3, 6, 9, and 12 months 
post-Day 57).  Before study medication application on Day 1, the Investigator or a qualified 
staff member must obtain standardized photography of each subject’s treatment area before 
application of study medication. 
Care must be taken to ensure the same lighting, background, subject positioning relative to 
the camera and camera settings are used for each photograph.  Equipment, supplies and 
detailed instructions for obtaining and managing the photographs will be provided to the 
investigational center prior to the initiation of subject enrollment. 
The photographs are to document the appearance of the subjects’ treatment area and to assist 
with the identification and confirmation of the location of the treatment area throughout the 
study (Section 9.1.1). 
Equipment, supplies and detailed instructions for obtaining and managing the photographs 
will be provided to the investigational center prior to the initiation of subject enrollment. 
9.5.2 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in dermatology studies 
as well as in the routine clinical care of patients with actinic keratosis. 
9.5.3 
Reporting of Serious Adverse Events, Pregnancy, and Other Events of 
Interest 
 
Reporting of Serious Adverse Events 
All SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by electronic transmission as soon as possible but no later than 
1 business day from the date the Investigator becomes aware of the event.  SAE 
reporting requirements will be provided in the Investigator File.  
All SAEs, regardless of causality assessment, must be collected through the last subject 
contact and followed to resolution or, if resolution is unlikely, to stabilization.  SAEs 
reported to the site from the time of the last subject contact up to 30 days after the last 
contact, will be collected (ie, Day 57 plus 30 days).  During the Recurrence Follow-up 
Period, all AEs, including SAEs in the treatment area will be collected until the last subject 


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contact.  These SAEs will be discussed in the clinical study report.  Any SAE event judged 
by the Investigator to be related to the study treatment should be reported to the Sponsor 
regardless of the length of time that has passed since study completion. 
Deaths and life-threatening events should be reported immediately by telephone.  The 
initial report must be submitted within 1 business day by electronically transmitting the 
completed SAE form. 
The detailed contact information for reporting of SAEs will be provided in the Investigator 
File. 
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report. This includes the Investigator’s assessment of causality.  All 
supporting documents should be sent de-identified and should contain the assigned subject 
number.  Only supporting documents directly related to the event should be sent. 
Any follow-up information received on SAEs should be forwarded as soon as possible.  If the 
follow-up information changes the Investigator’s assessment of causality, this should also be 
noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the Sponsor. 
 
Reporting of Pregnancy 
Any pregnancy, whether occurring in a subject or in the female partner of a male subject, for 
which the estimated date of conception was either before the last visit or within 30 days of 
last study treatment must be reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same timeframe and in 
the same format as all other SAEs (see Section 9.5.3.1). 
Pregnancies must be reported by electronic transmission as soon as possible but no later than 
1 business day from the date the Investigator becomes aware of the pregnancy.  The contact 
information for the reporting of pregnancies is provided in the Investigator File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the Investigator becomes aware of the outcome. 
A subject who becomes pregnant during the Treatment Period must be discontinued from 
treatment but continue to participate in the study per the protocol.   


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Reporting of Other Events of Interest 
9.5.3.3.1 REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, 
MISUSE, ABUSE, OR MEDICATION ERROR 
Study drug overdose is defined as the accidental or intentional use of the drug in an amount 
higher than the dose being studied. 
Any study drug overdose should be noted on the Study Medication CRF/eCRF. 
All AEs associated with overdose, or medication error should be captured on the Adverse 
Event CRF/eCRF and also reported using the procedures detailed in Section 9.5.3.1 even if 
the AEs do not meet serious criteria.  If the AE associated with an overdose or medication 
error does not meet serious criteria, it must still be reported using the SAE form and in an 
expedited manner, but should be noted as nonserious on the SAE form and the Adverse 
Event CRF/eCRF. 
 
Expedited Reporting 
The Sponsor (or its designee) must inform Investigators and regulatory authorities of 
reportable events, in compliance with applicable regulatory requirements, on an expedited 
basis (ie, within specific timeframes).  For this reason, it is imperative that sites provide 
complete SAE information in the manner described above. 
In determining what SAEs meet criteria for expedited reporting, the current version of the 
Investigator’s Brochure will be used for reference safety information. 
 
Breaking the Blind 
Not applicable 
 
Regulatory Reporting of Adverse Events 
Adverse events will be reported by the Sponsor or a third party acting on behalf of the 
Sponsor to regulatory authorities in compliance with local law and established guidance.  The 
format of these reports will be dictated by the local and regional requirements. 
9.5.4 
Completion/Discontinuation of Subjects 
A subject may elect to discontinue from the study at any time for any reason.  See 
Section 9.3.3 for reasons why Investigators may discontinue subjects from the study.  
Investigators must document the actual reason(s) why they decided to discontinue subjects, 
or why subjects withdrew consent, as applicable.  Study disposition information will be 
collected on the Disposition CRF/eCRF. 
Subjects who withdraw from study treatment (with the exception of death or withdrawal of 
consent) will be encouraged to complete the Early Termination assessments at the time of 
withdrawal as indicated in Table 1 and Table 2.  A subject who has ceased to return for visits 


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will be followed up by mail, phone, or other means to gather information such as the reason 
for failure to return, the status of treatment compliance, the presence or absence of AEs, and 
clinical courses of signs and symptoms.  This information will be recorded in the CRF/eCRF.  
9.5.5 
Abuse or Diversion of Study Drug 
Not applicable 
9.5.6 
Confirmation of Medical Care by another Physician 
The Investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the Investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the Investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study. 
9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
may be made periodically by the Sponsor’s or the CRO’s qualified compliance auditing 
team, which is an independent function from the study team responsible for conduct of the 
study. 
9.6.1 
Data Collection 
Data required by the protocol will be documented in the subject source documentation, 
collected on the CRF/eCRFs and entered into a validated data management system that is 
compliant with all regulatory requirements.  A CRF/eCRF or a select CRF/eCRF page may 
be used as a source document.  CRF/eCRFs used as source documents will be listed in the 
Data Management Plan.  As defined by ICH E6 guidelines (Section 1.11), the CRF is a 
printed, optical, or electronic document designed to record all of the protocol-required 
information to be reported to the Sponsor on each study subject.  In this study, the CRF may 
refer to either a paper (CRF) or electronic data collection form (eCRF), or both. 
Data collected on the CRF/eCRF must be completed following the instructions described in 
the CRF/eCRF Completion Guidelines, which will be based on the Data Management Plan.  
The Investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRF/eCRF.  The PI must sign the CRF/eCRF to 
attest to its accuracy, authenticity, and completeness. 
Completed, original CRFs/eCRFs are the sole property of the Sponsor and should not be 
made available in any form to third parties without written permission from the Sponsor, 
except for authorized representatives of the Sponsor or appropriate regulatory authorities. 


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Responsible site personnel will enter the information required by the protocol onto the 
CRF/eCRFs in accordance with the CRF/eCRF Completion Guidelines that are provided.  A 
CRA will visit each site as documented in the monitoring plan to review the CRF/eCRFs for 
completeness and accuracy against the source documents. They will identify any 
discrepancies and ensure that appropriate site personnel address the discrepancies. 
The original CRFs/eCRFs will be maintained at the site in a central document repository. If 
used, a copy of the CRF will be forwarded to the Sponsor. 
At the end of the study an electronic copy of the database along with appropriate system 
version will be archived. 
Uniform procedures will be discussed at the Investigator meetings or at site initiation and/or 
will be documented in the CRF/eCRF Completion Guidelines. 
9.6.2 
Clinical Data Management 
All data, both CRF/eCRF and external data, will be loaded into a clinical system as specified 
in the Data Management Plan. 
Quality control and data validation procedures will be applied to ensure the validity and 
accuracy of the clinical data. 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements. 
9.7 
Statistical Methods 
All statistical analyses will be performed by the Sponsor or designee after the study is 
completed and the database is locked.  Statistical analyses will be performed using Phoenix 
WinNonlin and SAS software or other validated statistical software as required. 
Statistical analyses will be reported using summary tables, graphs, and data listings. 
Continuous variables will be summarized using the mean, standard deviation (SD), median, 
minimum, and maximum.  Categorical variables will be summarized by counts and by 
percentage of subjects in corresponding categories.  All raw data obtained from the 
CRF/eCRF, as well as any derived data will be included in data listings. 
For all analyses, study Day 1 will be defined as the date of the first dose of study drug. 
9.7.1 
Statistical and Analytical Plans 
 
Study Endpoints 
9.7.1.1.1 PRIMARY ENDPOINTS 
The primary endpoint is activity. 


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Activity will be evaluated by reduction in lesion count.  Complete response rate will be 
defined as the proportion of subjects achieving 100% complete clearance of all treated AK 
lesions on the face or scalp at Day 57. 
9.7.1.1.2 SECONDARY ENDPOINTS 
Activity 
Reduction in lesion counts at each visit during Days 1-57 will be assessed as the secondary 
endpoint for activity. 
Safety 
Safety will be evaluated primarily by assessment of AEs and clinical laboratory data.  The 
results of other safety assessments (vital signs, PEs, ECGs) will also be evaluated. 
Pharmacokinetic 
Secondary endpoints include the following PK parameters derived by noncompartmental 
analysis using the plasma concentration-time data of KX2-391:  Cmax, and where applicable, 
AUCt, Cmin, and accumulation ratio R. 
9.7.1.1.3 EXPLORATORY ENDPOINTS 
Exploratory endpoints include recurrence and sustained response rates. 
Recurrence rate will be defined as the proportion of subjects who achieved 100% complete 
clearance at Day 57 (Visit 10) with any identified AK lesions on the treatment area at 3, 6, 9, 
and 12 months post-Day 57. 
Sustained response rate will be defined as the proportion of subjects who achieved 100% 
complete clearance at Day 57 (Visit 10) without any identified AK lesions on the treatment 
area at 12 months post-Day 57. 
 
Definitions of Analysis Sets 
The Per-Protocol Set is the group of protocol-eligible subjects who receive 5 days (Cohort 1) 
or 3 days (Cohort 2) of study treatment and complete at least one scheduled post-treatment 
evaluation.  
The Evaluable Set is the group of subjects who receive 5 days (Cohort 1) or 3 days 
(Cohort 2) of treatment and complete most evaluations including the Day 57 Follow-up Visit. 
The Safety Analysis/Full Analysis Set is the group of subjects who receive at least one dose 
of study treatment. 
The PK Analysis Set is the group of subjects who receive study treatment and complete at 
least one scheduled post-treatment PK evaluation. 


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Subject Disposition 
All subjects will be tabulated by cohort as to study discontinuation and the reasons for 
discontinuation as described in Section 9.3.3. 
 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized by cohort.  For continuous 
demographic variables, results will be summarized by cohort as well, and presented as N, 
mean, SD, median, and minimum and maximum values.  For categorical (nominal or ordinal) 
variables, the number and percentage of subjects will be used in each cohort.  No statistical 
testing will be performed. 
 
Prior and Concomitant Therapy 
All Investigator terms for medications recorded in the CRF/eCRF will be coded to an 
11-digit code using the World Health Organization Drug Dictionary drug codes. 
Prior medications will be defined as medications that stopped before the first dose of study 
drug. 
Concomitant medications will be defined as medications that (1) started before the first dose 
of study drug and were continuing at the time of the first dose of study drug, or (2) started on 
or after the date of the first dose of study drug.  Prior and concomitant medications will be 
further coded to the appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating 
therapeutic classification.  A listing of prior and concomitant medications by drug and drug 
class will be included in the clinical study report for this protocol. 
All medications will be presented by cohort in subject data listings. 
 
Activity Analyses 
AK lesion counts will be summarized by cohort at Day 1 (pretreatment) and at each 
subsequent timepoint for subjects in the Full Analysis Set and the Per-Protocol Set. 
A 95% confidence interval (CI) for the complete clearance (response rate) at Day 57 will be 
estimated by cohort in the Evaluable Set. 
Recurrence rates for all subjects who achieved complete clearance at Day 57 will be 
estimated by timepoint and cohort in the Evaluable Set. 
A 95% CI for the sustained response rate at 12 months post-Day 57 will be estimated by 
cohort in the Evaluable Set. 
Both cohorts will be analyzed with the same statistical methods.  Since this is not a dose 
regimen randomized study, any contrast between the 2 cohorts will mainly be noninferential 
and consist of listings, graphs, and descriptive statistics. 


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Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
9.7.1.7.1 PHARMACOKINETIC ANALYSES 
PK analyses will be performed on the PK Analysis Set. 
Plasma concentrations of KX2-391 will be analyzed to determine Cmax, and where applicable, 
AUCt, Cmin, and accumulation ratio R. 
Individual timepoints will be tabulated and displayed graphically and listed for all subjects.  
Summary PK parameters will be analyzed as applicable. 
9.7.1.7.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
Not applicable 
 
Safety Analyses 
All subjects in the Safety Analysis Set will be included in the safety analyses. 
Safety data will be summarized by cohort using descriptive statistics (eg, n, mean, SD, 
median, minimum, maximum for continuous variables; n [%] for categorical variables).  
Safety variables include AEs, clinical laboratory parameters, weight, vital signs, 12-lead 
ECG results, and physical examination findings. 
Similar to the activity analyses, any contrast between the 2 cohorts will mainly be 
noninferential in the safety analyses. 
9.7.1.8.1 EXTENT OF EXPOSURE 
The actual number of doses for each subject will be summarized by cohort. 
9.7.1.8.2 ADVERSE EVENTS 
For AEs, verbatim terms on the CRFs/eCRFs will be mapped to preferred terms (PTs) and 
system organ classes (SOCs) using the Medical Dictionary for Regulatory Activities 
(MedDRA; version 16.0 or higher).  Subject incidence of AEs will be displayed by SOC.  
The incidence of AEs will be summarized by cohort.  Adverse events will also be 
summarized by severity, relationship to study drug, and cohort.  Subject incidence of SAEs 
will also be displayed by cohort. 
Only those AEs that were treatment-emergent will be included in summary tables.  
Treatment-emergent AEs are defined as: 
x either those AEs with an onset after dosing or  
x those pre-existing AEs that worsen after dosing 


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All AEs, treatment emergent or otherwise, will be presented in subject data listings. 
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC, PT, and cohort.  A subject data listing of all AEs leading to death will be 
provided. 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC, PT, and cohort.  A subject data listing of all AEs 
leading to discontinuation from study drug will be provided. 
9.7.1.8.3 LABORATORY VALUES 
Laboratory parameters will be summarized using descriptive statistics at baseline and at each 
subsequent timepoint by cohort.  Changes from baseline will also be summarized by cohort. 
In addition, shift tables (ie, low-normal-high at baseline versus low-normal-high at follow-up 
in a 3-by-3 contingency table) will be provided to assess changes in laboratory values from 
baseline to follow-up in each cohort. 
9.7.1.8.4 VITAL SIGNS 
Vital sign values will be evaluated by cohort on an individual basis by subject.  Abnormal 
vital sign values will be identified as those outside (above or below) the reference range. 
9.7.1.8.5 ELECTROCARDIOGRAMS 
ECG data will be tabulated by cohort for each individual subject. 
9.7.1.8.6 PHYSICAL EXAMINATIONS 
Physical examination findings will be listed by cohort for each subject. 
9.7.1.8.7 PREGNANCY TESTS 
Results of pregnancy tests will be listed by cohort for all subjects, as applicable. 
9.7.1.8.8 OTHER ANALYSES 
Local Skin Reactions 
Local skin reactions as reported by the Investigator will be displayed and summarized by 
visit and cohort for all subjects. 
Pigmentation and Scarring 
Pigmentation and scarring as reported by the Investigator will be displayed and summarized 
by visit and cohort for all subjects. 


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9.7.2 
Determination of Sample Size 
For either cohort, a sample size of 60 subjects is sufficient to detect a 100% complete 
clearance rate at Day 57 greater than 20% with 80% power, based on a two-sided 
(alpha=0.05) binomial test, assuming a response rate of 35%, and less than a 25% dropout 
rate.  This corresponds to a two-sided 95% CI with a half-width of less than 15% (ie, lower 
boundary of the CI above 20%). 
The sample size of Cohort 2 may be adjusted, depending on the results of Cohort 1. 
9.7.3 
Interim Analysis 
A formal interim analysis is not planned. Since this is an open-label study, after each group 
of approximately 20 subjects, ongoing analyses will be performed with tabulation of activity, 
LSRs, and adverse events.  The decision to open Cohort 2 will be documented. 
9.7.4 
Other Statistical/Analytical Issues 
Not applicable 
9.7.5 
Procedure for Revising the Statistical Analysis Plan 
If the prespecified plans need to be revised after the study starts, the Sponsor will determine 
how the revision impacts the study and how the revision should be implemented.  The details 
of the revision will be documented and described in the clinical study report. 


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10 REFERENCE LIST 
1. ICH E6: Guidance for Industry - E6 Good Clinical Practice: Consolidated Guidance, 
US Department of Health and Human Services, Food and Drug Administration, April 
1996. 
2. Marks R, Rennie G, Selwood TS.  Malignant transformation of solar keratoses to 
squamous cell carcinoma.  Lancet 1988;1(8589):795-7. 
3. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: natural history 
and risk of malignant transformation in the Veterans Affairs Topical Tretinoin 
Chemoprevention Trial. Cancer 2009;115(11):2523-30. 
4. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol 
2000;42(1 Pt 2):23-4. 
5. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am 
Acad Dermatol 2000;42(1 Pt 2):4-7. 
6. Guidelines for the Management of Actinic Keratoses.  2004/2005 European 
Dermatology Forum.  Available from: http://www.euroderm.org  [Accessed 02 July 
2012]. 
7. Drake LA, Ceilley RI, Cornelison RL, et al. Guidelines of care for actinic keratoses. 
Committee on Guidelines of Care. J Am Acad Dermatol 1995;32(1):95-8. 
8. Suchniak JM, Baer S, Goldberg LH. High rate of malignant transformation in 
hyperkeratotic actinic keratoses. J Am Acad Dermatol 1997;37(3 Pt 1):392-4. 
9. Ehrig T, Cockerell C, Piacquadio D, et al. Actinic keratoses and the incidence of 
occult squamous cell carcinoma: a clinical-histopathologic correlation. Dermatol Surg 
2006;32(10):1261-5. 
10. Berman B, Bienstock L, Kuritzky L, et al. Primary Care Education Consortium; 
Texas Academy of Family Physicians. Actinic keratoses: sequelae and treatments. 
Recommendations from a consensus panel.  J Fam Pract 2006;55(5 Suppl):1-8. 
11. Quaedvlieg PJ, Tirsi E, Thissen MR, et al. Actinic keratosis: how to differentiate the 
good from the bad ones? Eur J Dermatol 2006;16(4):335-9. 
12. Marks R, Foley P, Goodman G, et al.  Spontaneous remission of solar keratoses:  the 
case for conservative management. Br J Dermatol 1986;115(6):649-55. 
13. Food and Drug Administration Draft Guidance on Ingenol Mebutate; Recommended 
Jan 2016. 


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14. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through IV. 
Arch Dermatol 1998;124(6):869-71. 
15. Rosen R, Marmur E, Anderson L, et al. A new, objective, quantitative scale for 
measuring local skin responses following topical actinic keratosis therapy with 
ingenol mebutate. Dermatol Ther (Heidelb) 2014;4:207-19. 


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11 APPENDICES 
 


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Appendix 1 
Photographs of Local Skin Reactions 
 
 
Source:  Rosen R, Marmur E, Anderson L, et al. A new, objective, quantitative scale for measuring local skin 
responses following topical actinic keratosis therapy with ingenol mebutate. Dermatol Ther (Heidelb) 
2014;4:207-19. 
 


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REVISION HISTORY 
Revisions to KX01-AK-002 protocol v1.0_23 Jan 2016 (original protocol) 
Current Version and Date:  v2.0_26 Apr 2016 (Amendment 1) 
Change 
Rationale 
Affected Protocol Sections 
Added a second cohort with a 3-day 
dosing regimen. 
If the 5-day treatment regimen 
(Cohort 1) has sufficient activity 
and safety, a 3-day regimen 
(Cohort 2) will be evaluated. 
x 
Throughout protocol 
x 
Table 1 
x 
(new) Table 2 
x 
List of In-Text Tables 
Added a secondary objective. 
To accommodate addition of a 
3-day regimen (Cohort 2). 
x 
Synopsis / Objectives 
x 
Section 8.2 
Made sustained response an 
exploratory objective; removed it as 
a primary endpoint and revised 
exploratory endpoints and analyses 
to align with it as an exploratory 
objective; revised wording to 
describe analysis of recurrence 
rates. 
Sustained response is more 
appropriate as exploratory 
because it is assessed post-
Day 57; clarification 
x 
Synopsis  
- Objectives 
- Statistical Methods / Study 
Endpoints 
- Activity Analyses 
x 
Section 8.3 
x 
Section 9.7.1.1.1 
x 
Section 9.7.1.1.3 
x 
Section 9.7.1.6 
Revised the number of subjects in 
the study. 
To accommodate addition of a 
3-day regimen (Cohort 2). 
x 
Synopsis / Number of subjects 
x 
Section 9.1 
x 
Section 9.1.1 
Revised PK sampling timepoints. 
To accommodate addition of a 
3-day regimen (Cohort 2). 
x 
Synopsis / Pharmacokinetic 
Assessments 
x 
Table 4 
Removed reference to a Safety 
Management Plan; revised text 
regarding reporting of SAEs, deaths, 
and life-threatening events, and 
corresponding follow-up 
information. 
Clarification. 
x 
Section 9.5.3.1 
Revised statistical-related text to 
reflect increased number of subjects 
based on the addition of Cohort 2; 
revised text regarding interim 
analysis. 
To accommodate addition of a 
3-day regimen (Cohort 2). 
x 
Synopsis 
 
- Analysis Sets 
 
- Activity Analyses 
 
- Safety Analyses 
 
- Interim Analysis 
 
- Sample Size Rationale 
x 
Sections 9.7.1.2 - 9.7.1.6 
x 
Section 9.7.1.8 (entirety) 
x 
Section 9.7.2 
x 
Section 9.7.3 
Added immunosuppressants and 
immunomodulators as exclusionary 
medications. 
 
These medications may affect the 
intended effects of the study drug. 
x 
Synopsis / Exclusion Criteria 
x 
Section 9.3.2 


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Revisions to KX01-AK-002 protocol v1.0_23 Jan 2016 (original protocol) 
Current Version and Date:  v2.0_26 Apr 2016 (Amendment 1) 
Change 
Rationale 
Affected Protocol Sections 
Increased the duration of the study 
period overall and enrollment 
period. 
To accommodate addition of a 
3-day regimen (Cohort 2). 
x 
Synopsis / Study Period and 
Phase of Development 
x 
Synopsis / Duration of 
Participation and Treatment 
Increased the number of sites 
conducting the study. 
 
 
 
With addition of additional sites, 
specified that enrollment among 
sites would be monitored to avoid 
imbalance. 
To accommodate increased 
number of subjects due to 
addition of Cohort 2; to facilitate 
enrollment. 
 
Clarification. 
x 
Synopsis / Sites 
x 
Section 6 
 
 
 
x 
Synopsis / Study Design 
x 
Section 9.1 
x 
Section 9.4.3 
Revised description of study 
treatment. 
Clarification. 
x 
Table 3 
Specified “during the Treatment 
Period” with regard to withdrawal 
of subjects who become pregnant. 
Clarification of timeframe. 
x 
Section 9.5.3.2 
Revised text regarding collection 
and following of adverse events. 
 
Removed reference to Screening 
Disposition CRF/eCRF. 
Clarification of timeframe; only 
study drug-related AEs will be 
followed. 
There is no Screening Disposition 
CRF/eCRF in the study. 
x 
Section 9.5.1.5.1 
Removed Appendix 1 and 
renumbered remaining appendix; 
added appropriate literature citation 
for reference. 
Investigators are familiar with the 
method for skin typing; 
questionnaire and scoring system 
in Appendix 1 is not validated. 
x 
List of Appendices 
x 
Section 9.5.1.2.2 
x 
Section 9.5.1.5.8 
x 
Section 10 
x 
(original) Appendix 1 (deleted) 
Revised text regarding removal of 
subjects from the therapy or 
assessment; modified some of the 
reasons for discontinuation. 
Clarification. 
x 
Section 9.3.3 
Modified text regarding restrictions 
on the use of concomitant 
medication/therapies/topical 
products during the study; referred 
the reader to an FDA draft guidance. 
Per recommendation of the 
Investigators and subject matter 
experts; to provide further 
guidance to the investigators. 
x 
Synopsis / Concomitant 
Drug/Therapy 
x 
Section 9.4.7.3 
Revised description of the Final 
Visit; specified when the Final Visit 
is for those who do not have 
complete response at Day 57. 
 
Clarification. 
x 
Table 1 / Footnote c 
x 
Section 9.1.3 
x 
Section 9.1.4 


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Revisions to KX01-AK-002 protocol v1.0_23 Jan 2016 (original protocol) 
Current Version and Date:  v2.0_26 Apr 2016 (Amendment 1) 
Change 
Rationale 
Affected Protocol Sections 
Specified that use of sunblock in the 
treatment area will be recorded in 
the Concomitant Medication CRF. 
 
Removed text regarding subjects not 
changing their use of concomitant 
medications. 
To be able to evaluate the activity 
of study drug in the presence and 
absence of sunblock. 
 
Subjects will be able to change 
concomitant medications per the 
Investigator’s instructions. 
x 
Section 9.4.7.2 
x 
Section 9.5.1.5.8 
Removed use of body charts for 
identifying the location and shape of 
the treatment area. 
Not needed; this will be done 
with the acetate sheets. 
x 
Section 9.1.1 
x 
Section 9.1.2 
Specified minimum timeframe 
during which subjects cannot touch 
or wet the treatment area after study 
treatment application; removed 
information regarding shower times; 
revised text about instructions to the 
subjects for care of the treatment 
area. 
Clarification. 
x 
Section 9.4.2.4 
Revised description of sun 
exposure. 
Clarification. 
x 
Synopsis / Inclusion Criteria 
x 
List of Abbreviations and 
Definition of Terms 
x 
Section 9.3.1 
Revised description of Medical 
History. 
Clarification. 
x 
Section 9.5.1.2.1 
Revised description of the Final 
Visit; specified when the Final Visit 
is for those who do not have 
complete response at Day 57. 
Clarification. 
x 
Table 1 / Footnote c 
x 
Section 9.1.3 
x 
Section 9.1.4 
Removed exclusionary use of 
moisturizers or emollients on the 
face or scalp within 12 hours prior 
to Visit 1. 
Not necessary to exclude before 
Visit 1. 
x 
Synopsis / Exclusion Criteria 
x 
Section 9.3.2 
Revised Medical Monitor signatory. 
Administrative. 
x 
Protocol Signature page 
Specified that scarring, in addition 
to pigmentation, will be assessed at 
the visits cited. 
Clarification. 
x 
Section 9.5.1.5.8 / 
Pigmentation and Scarring 
Revised description of procedures 
related to treatment area 
identification. 
Clarification to align with 
streamlined procedures. 
x 
Section 9.1.1 
Revised text to ensure the signing of 
ICF prior to study procedures. 
Clarification. 
x 
Section 5.3 


Clinical Study Protocol_Amendment 1 
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Kinex Pharmaceuticals, Inc. 
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iv 
CONFIDENTIAL 
 
Revisions to KX01-AK-002 protocol v1.0_23 Jan 2016 (original protocol) 
Current Version and Date:  v2.0_26 Apr 2016 (Amendment 1) 
Change 
Rationale 
Affected Protocol Sections 
Revised the definition of the 
Evaluable Set. 
Clarification. 
x 
Synopsis / Number of Subjects 
Revised definition of ICH. 
Clarification to align with recent 
ICH organizational changes. 
x 
Investigator Signature Page 
x 
Title Page 
x 
List of Abbreviations and 
Definition of Terms 
x 
Section 5.1 
Corrected 
typographical/punctuation/grammar 
errors. 
Administrative. 
x 
Throughout protocol 


PPD
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Clinical Study Protocol_Amendment 1 
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INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
KX01-AK-002 
Study Protocol Title: 
A Phase 2a, Open-Label, Multicenter, Activity and Safety Study of 
KX2-391 Ointment 1% in Subjects with Actinic Keratosis on the Face 
or Scalp 
Investigational Product 
Name: 
KX2-391 Ointment 1% 
UTN Number: 
U1111-1173-5677 
 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
 
 
 
<Name, degree(s)> 
 
 
 
 
Investigator 
 
Signature 
 
Date 
<Name of study site> 
 
 
 
 
Study Site  
 
 
 
 
 
 


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1 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
Study Protocol 
Number: 
KX01-AK-002 
Study Protocol Title: 
A Phase 2a, Open-Label, Multicenter, Activity and Safety Study of 
KX2-391 Ointment 1% in Subjects with Actinic Keratosis on the Face or 
Scalp 
Sponsor: 
United States: 
Kinex Pharmaceuticals, Inc. 
20 Commerce Drive 
Cranford, New Jersey 07016, US 
Tel:  +1 908-272-0628 
Investigational 
Product Name: 
KX2-391 Ointment 1% 
Indication: 
Actinic keratosis on the face or scalp 
Phase: 
2a 
Approval Date:  
v1.0 
v2.0 
23 Jan 2016 (original protocol) 
26 Apr 2016 (Amendment 1) 
UTN Number: 
U1111-1173-5677 
GCP Statement: 
This study is to be performed in full compliance with International Council 
for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information of Kinex 
Pharmaceuticals, Inc. (the Sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly 
prohibited.  Such information may be used solely for the purpose of 
reviewing or performing this study. 


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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.
KX2-391
Name of Active Ingredient:
N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl) acetamide
Study Protocol Title
A Phase 2a, Open-Label, Multicenter, Activity and Safety Study of KX2-391 Ointment 1% in Subjects 
with Actinic Keratosis on the Face or Scalp
Investigators
, MD, Lead Principal Investigator
Sites
Approximately 8 to 16 sites in the United States
Study Period and Phase of Development
First subject in to last subject out, approximately 24 months
Phase 2a
Objectives
Primary Objective:
•
To evaluate the activity of KX2-391 Ointment 1% administered topically to the face or scalp in 
subjects with actinic keratosis (AK) by determining complete response rate, defined as 100% 
clearance at Day 57
Secondary Objectives: 
•
To assess the activity of KX2-391 Ointment 1% during Days 1-57
•
To assess the safety and tolerability of KX2-391 Ointment 1% in subjects with AK on the face or 
scalp
•
To assess the pharmacokinetics (PK) of KX2-391 Ointment 1% in subjects with AK on the face or 
scalp
•
To assess dose regimens by contrasting 5-day treatment with 3-day treatment in terms of the activity 
and safety of KX2-391 Ointment 1% in subjects with AK on the face or scalp
Exploratory Objectives:
•
To determine recurrence rates up to 12 months post-Day 57 for subjects who show response at 
Day 57
•
To determine sustained response rates at 12 months post-Day 57 for subjects who show response at 
Day 57
Study Design
This study will be an open-label, multicenter, activity, safety, tolerability, and PK study of KX2-391
Ointment 1% administered topically to the face or scalp of subjects with actinic keratosis in 2 sequential 
cohorts:  a 5-day dosing regimen (Cohort 1) and a 3-day dosing regimen (Cohort 2).
The study consists of Screening, Treatment, and Follow-up Periods.
In Cohort 1, eligible subjects will receive 5 consecutive days of topical treatment, to be applied at the 
PPD


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study site, with 50 mg of KX2-391 Ointment 1% each day.  Blood samples for PK analysis will be 
collected on Day 1 and Day 5.  Subjects will return for Follow-up visits until Day 57.  Thereafter, only 
Day 57 complete responders will continue Recurrence Follow-up Visits every 3 months for an additional 
12 months after Day 57.  Activity (lesion counts) and safety evaluations will be performed. 
The Sponsor will review accumulating data.  If the 5-day regimen (Cohort 1) has sufficient activity and 
safety to warrant evaluating a 3-day regimen, enrollment of Cohort 2 will start after there are 60 evaluable 
subjects or up to 80 subjects are enrolled (whichever comes first) in Cohort 1.  For the most part, protocol 
procedures for Cohort 1 will be duplicated for Cohort 2, except PK samples will be collected on Days 1 
and 3, and subjects will not return for Visits 5 and 6. 
The same study sites for the most part of Cohort 1 will be used for Cohort 2.  The Sponsor study team 
will monitor the enrollment status closely and ensure that any individual site does not enroll too many 
subjects. 
Number of Subjects 
In each cohort, approximately 80 subjects will be enrolled to provide approximately 60 subjects in the 
Evaluable Set, defined as subjects who complete all planned treatments and most evaluations, including 
the Day 57 Follow-up visit.  Therefore, a total of 160 subjects in 2 cohorts may be enrolled, but the 
sample size of Cohort 2 may be adjusted, depending on the results of Cohort 1. 
Inclusion Criteria 
Eligible subjects must have/be: 
1. Males and females ≥18 years old 
2. Clinical diagnosis of stable, clinically typical actinic keratosis 
3. A treatment area on the face or scalp that: 
x 
is a continuous area measuring 25 cm2 
x 
contains 4 to 8 AK lesions 
4. Females must be postmenopausal (>50 years of age with at least 18 months of amenorrhea), 
surgically sterile (by hysterectomy, bilateral oophorectomy or tubal ligation) or otherwise incapable 
of pregnancy for at least 1 year; or, if of childbearing potential, must be using highly effective 
contraception for at least 90 days prior to treatment with KX2-391 Ointment 1% and must agree to 
continue to use highly effective contraception for at least 90 days following their last dose of 
KX2-391 Ointment 1%.  Highly effective contraception includes oral hormonal contraceptives, 
hormonal contraceptive implant or patch, or intrauterine device.  Abstinence and double barrier 
methods do not qualify as highly effective methods of contraception. 
5. Males who have not had a vasectomy must agree to use barrier contraception from Screening through 
90 days after their last dose of KX2-391 Ointment 1%. 
6. All subjects must agree not to donate sperm or eggs or attempt conception from Screening through 
90 days following their last dose of KX2-391 Ointment 1%. 
7. Females of childbearing potential must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on Day 1 prior to administration of study treatment. 
8. Subjects who in the judgment of the Investigator, are in good general health based on: 
x 
medical history 
x 
no physical examination (PE) findings that the Principal Investigator (PI) determines would 
interfere with interpretation of study results 
x 
screening electrocardiogram (ECG) without clinically significant abnormalities  


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x
clinical chemistry, hematology, and urinalysis results that are within the reference ranges; clinical 
laboratory values outside the reference ranges that are considered by the PI to be clinically 
insignificant are also acceptable 
9.
Willing to avoid direct sun or ultraviolet (UV) light exposure to the face or scalp 
10. Able to comprehend and are willing to sign an informed consent form (ICF) 
Exclusion Criteria
Eligible subjects must not have/be:
1.
Clinically atypical and/or rapidly changing AK lesions on the treatment area
2.
Malignancy within 5 years prior to Screening except basal or squamous cell carcinoma not on the 
treatment area that were treated with curative intent and are without recurrence
3.
Used any of the following systemic therapies within the specified period before Visit 1:
x
retinoids; 90 days
x
glucocorticosteroids; 28 days (intra-articular and inhaled steroids are allowed)
x
methotrexate or other anti-metabolites; 28 days
x
immunosuppressants or immunomodulators; 28 days
4.
Used any of the following topical therapies on the treatment area within the specified period before 
Visit 1:
x
retinoids; 90 days
x
glucocorticosteroids; 14 days
x
analgesic and/or anti-inflammatory medication on the face or scalp; 72 hours
5.
Had any of the following on the treatment area within 90 days (or until the site has healed, whichever 
is longer) before Visit 1:
x
ingenol mebutate (eg, Picato)
x
5-fluorouracil (eg, 5-FU; Efudex)
x
imiquimod (eg, Aldara; Zyclara)
x
diclofenac with or without hyaluronic acid (eg, Solaraze)
6.
Surgical or destructive modalities on the treatment area within 30 days (or until the site has healed 
following treatment, whichever is longer) before Visit 1:
x
cryotherapy
x
electrodesiccation
x
laser, light (eg, photodynamic therapy, intense pulsed light) or any other energy-based therapy
x
chemical peels (eg, tricholoracetic acid)
x
dermabrasion
x
surgical removal (eg, curettage, excision)
7.
Currently, or has experienced any of the following on the treatment area within the specified period 
before Visit 1:
x
cutaneous malignancy; 180 days
x
sunburn; 28 days
x
body art (eg, tattoo, piercing); currently
8.
A history of sensitivity and/or allergy to any of the ingredients in the study medication 
9.
A skin disease (eg, atopic dermatitis, psoriasis, eczema) or condition (eg, scarring, open wounds) that, 
in the opinion of the Investigator, might interfere with the study conduct or evaluations, or which 


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exposes the subject to an unacceptable risk by study participation
10. Other significant uncontrolled or unstable medical diseases or conditions that, in the opinion of the 
Investigator, would expose the subject to unacceptable risk by study participation
11. Females who are pregnant or nursing
12. Participated in an investigational drug trial during which an investigational study medication was 
administered within 14 days or 5 half-lives of the investigational product, whichever is longer, before 
Screening
Study Treatment
50 mg of KX2-391 Ointment 1% will be applied topically once daily for 5 consecutive days (Cohort 1) or 
3 consecutive days (Cohort 2) to the 25 cm2 treatment area (2 mg/cm2; 0.5 mg KX2-391 total).
Duration of Participation and Treatment
•
Planned enrollment period for each cohort:  approximately 3 months (90 days)
•
Planned subject participation is approximately 64 weeks: 
o
Screening Period:  up to 28 days
o
Treatment Period:  For Cohort 1, 5 consecutive treatment days (Days 1-5); for Cohort 2, 
3 consecutive treatment days (Days 1-3)
o
Follow-up Period:  Visits at Days 8, 15, 29, and 57
o
Recurrence Follow-up Period:  only for complete responders at Day 57, visits every 3 months for 
12 months after Day 57 (ie, at 3, 6, 9, and 12 months post-Day 57).
Length of stay:  On Day 1 (Visit 2, Cohorts 1 and 2) and Day 5 (Visit 6, Cohort 1) or Day 3 (Visit 4, 
Cohort 2), subjects may stay for approximately 5 hours at the investigational center until after the last PK 
blood sample is collected.
Concomitant Drug/Therapy
Use of any non-study drug treatment for AK lesions on the treatment area is prohibited until Day 57.  Any 
lesion in the treatment area that is treated during the Recurrence Follow-up Period will be considered as a 
recurrence.
Assessments
Activity Assessments
The Investigator will perform a count of AK lesions for all subjects at Visits 1 and 2, Visits 7 through 10, and 
for Day 57 complete responders, also at Visits 11 through 14.
Safety Assessments
Safety will be assessed by recording all adverse events (AEs), serious adverse events (SAEs), laboratory 
evaluation of hematology, biochemistry, and urinalysis values, measurement of weight and vital signs, 
evaluation of ECGs, and the performance of physical examinations.
Subjects will be queried for spontaneously reported AEs at each study visit, before assessment of local 
skin reactions (LSRs).  AEs will be reported separately from LSRs.
Subject-reported LSRs will not be reported as adverse events. 
Other Assessments
The LSR assessment is the Investigator’s (or trained designee’s) assessment of the following signs on the 
treatment area:  erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration.  
These 
signs 
will 
be 
assessed 
using
a 
grading 
scale 
ranging 
from 
0 
(not 
present) 
to 4 (worst). In addition to LSRs, hypo- and hyper- pigmentation and scarring on the treatment area will 


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be assessed as being present or absent.  Application site reactions not classified as LSRs (eg, pruritus, 
pain, infection) will be reported as adverse events.  All application site reactions and LSRs will be 
followed to resolution, or if resolution is unlikely, to stabilization.  LSRs will be reported separately from 
AEs. 
Standardized photography will be performed at Screening (Visit 1), Day 1 (Visit 2), Day 8 (Visit 7), 
Day 57 (Visit 10), and during the Recurrence Follow-up (at 3, 6, 9, and 12 months post-Day 57).  Before 
study medication application on Day 1, the Investigator or a qualified staff member must obtain 
standardized photography of each subject’s treatment area before application of study medication. 
Pharmacokinetic Assessments 
PK samples will be collected at the following timepoints for Cohort 1: 
• Day 1:  predose, 0.5 (±5 minutes), 1 and 4 hours (±10 minutes) postdose  
• Day 5:  predose, 0.5 (±5 minutes), 1 and 4 hours (±10 minutes) postdose 
PK samples will be collected at the following timepoints for Cohort 2: 
• Day 1:  predose, 0.5 (±5 minutes), 1 and 4 hours (±10 minutes) postdose  
• Day 3:  predose, 0.5 (±5 minutes), 1 and 4 hours (±10 minutes) postdose 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments 
Not applicable 
Bioanalytical Methods 
Plasma concentrations of study drug will be measured using a validated liquid chromatography/tandem 
mass spectrometry (LC-MS/MS) assay. 
Statistical Methods 
Study Endpoints 
Primary Endpoint 
x Activity will be evaluated by reduction in lesion count.  Complete response rate will be defined as 
the proportion of subjects achieving 100% complete clearance of all treated AK lesions on the face 
or scalp at Day 57.   
Secondary Endpoints 
• Activity:  Reduction in lesion counts during Days 1-57 
• Safety:  Evaluation of AEs and clinical laboratory data; the results of other safety assessments (vital 
signs, physical examinations, ECGs) will also be evaluated. 
• Pharmacokinetic:  Determination of Cmax and where applicable, AUCt, Cmin, and accumulation  
ratio R 
Exploratory Endpoints 
• Recurrence rate will be defined as the proportion of subjects who achieved 100% complete clearance 
at Day 57 (Visit 10) with any identified AK lesions on the treatment area at 3, 6, 9, and 12 months 
post-Day 57. 
• Sustained response rate will be defined as the proportion of subjects who achieved 100% complete 
clearance at Day 57 (Visit 10) without any identified AK lesions on the treatment area at 12 months 
post-Day 57. 


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Analysis Sets 
• Per-Protocol Set:  the group of protocol-eligible subjects who receive 5 days (Cohort 1) or 3 days 
(Cohort 2) of study treatment and complete at least one scheduled post-treatment evaluation. 
• Evaluable Set:  the group of subjects who receive 5 days (Cohort 1) or 3 days (Cohort 2) of treatment 
and complete most evaluations including the Day 57 Follow-up Visit. 
• Safety Analysis/Full Analysis Set:  the group of subjects who receive at least one dose of study 
treatment. 
• PK Analysis Set: the group of subjects who receive study treatment and complete at least one 
scheduled post-treatment PK evaluation. 
Activity Analyses 
AK lesion counts will be summarized by cohort at Day 1 (pretreatment) and at each subsequent timepoint 
for subjects in the Full Analysis Set and the Per-Protocol Set. 
A 95% confidence interval (CI) for the complete clearance (response rate) at Day 57 will be estimated by 
cohort in the Evaluable Set. 
Recurrence rates for all subjects who achieved complete clearance at Day 57 will be estimated by 
timepoint and cohort in the Evaluable Set. 
A 95% CI for the sustained response rate at 12 months post-Day 57 will be estimated by cohort in the 
Evaluable Set. 
Both cohorts will be analyzed with the same statistical methods.  Since this is not a dose regimen 
randomized study, any contrast between the 2 cohorts will mainly be noninferential and consist of 
listings, graphs, and descriptive statistics. 
Safety Analyses 
All subjects who receive at least one dose of KX2-391 Ointment 1% will be included in the safety 
analyses.  Treatment-emergent AEs (TEAEs) are defined as either those AEs with an onset after dosing or 
those pre-existing AEs that worsen after dosing.  For AEs, verbatim terms on the case report 
form/electronic case report form (CRF/eCRF) will be mapped to preferred terms (PTs) and system organ 
classes (SOCs) using the Medical Dictionary for Regulatory Activities (MedDRA; v 16.0 or higher).  
Subject incidence of AEs will be displayed by SOC.  The incidence of AEs will be summarized by 
cohort.  Adverse events will also be summarized by severity, relationship to study drug, and cohort.  
Subject incidence of SAEs will also be displayed by cohort.  Laboratory parameters will be summarized 
using descriptive statistics at baseline and at each subsequent timepoint by cohort.  Changes from baseline 
will also be summarized by cohort.  In addition, shift tables (ie, low-normal-high at baseline versus low-
normal-high at follow-up in a 3-by-3 contingency table) will be provided to assess changes in laboratory 
values from baseline to follow-up in each cohort. 
Local skin reactions, pigmentation, and scarring as reported by the Investigator, will be displayed and 
summarized by visit and cohort for all subjects. 
Similar to the activity analyses, any contrast between the 2 cohorts will mainly be noninferential in the 
safety analyses. 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Pharmacokinetic Analyses 
Plasma concentrations for KX2-391 will be analyzed to determine applicable PK parameters. 
Individual timepoints will be tabulated and displayed graphically and listed for all subjects.  Summary PK 
parameters will be analyzed as applicable. 


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Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Not applicable 
Interim Analysis 
A formal interim analysis is not planned. Since this is an open-label study, after each group of 
approximately 20 subjects, ongoing analyses will be performed with tabulation of activity, LSRs, and 
adverse events. The decision to open Cohort 2 will be documented. 
Statistical Methods 
Statistical analyses will be reported using summary tables, graphs, and data listings. Continuous variables 
will be summarized using the mean, standard deviation (SD), median, minimum, and maximum.  
Categorical variables will be summarized by counts and by percentage of subjects in corresponding 
categories.  All raw data obtained from the CRF/eCRF, as well as any derived data will be included in 
data listings. 
Sample Size Rationale 
For either cohort, a sample size of 60 subjects is sufficient to detect a 100% complete clearance rate at 
Day 57 greater than 20% with 80% power, based on a two-sided (alpha=0.05) binomial test, assuming a 
response rate of 35%, and less than a 25% dropout rate.  This corresponds to a two-sided 95% CI with a 
half-width of less than 15% (ie, lower boundary of the CI above 20%).  The sample size of Cohort 2 may 
be adjusted, depending on the results of Cohort 1. 
FINAL  
v2.0_26 Apr 2016 


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Table 1
Schedule of Procedures/Assessments in Study KX01-AK-002 (Cohort 1)
Period
Screening
Treatment
Follow-up
Recurrence Follow-up a
Visit
1
2
3
4
5
6
7
8
9
10 b/
Early 
Term
11, 12, 13, 14 a
Day
-28 to -1
1
2
3
4
5
8
15
29
57b
3, 6, 9, 12 Months Post-Day 57c
Visit time window (days)
None
None
None
None
None
None
±2
±2
±2
±2
±14
Informed consent
X
Inclusion & exclusion criteria
X
Xd
Demographics
X
Medical/surgical history
X
AK history/AK treatment history
X
Fitzpatrick skin-type scale
X
Vital signse
X
X
X
X
X
X
Prior and concomitant 
medications/therapies
X
Xd
X
X
X
X
X
X
X
X
X
Physical examination, including weightf
X
X
Treatment area identification
X
Xd
AK lesion count
X
Xd
X
X
X
X
X
ECGg
X
X
X
Clinical chemistry, hematology, and 
urinalysish
X
X
X
Pregnancy test 
X
Xd,i
X
X
PK blood samples
Xj
Xj
Study medication application
X
X
X
X
X
AEsk
X
X
X
X
X
X
X
X
X
X
Xl
LSRs
Xd
Xd
Xd
Xd
Xd
X
X
X
X
Pigmentation and scarring
Xd
Xd
Xd
Xd
Xd
X
X
X
X
Standardized photography
X
Xd
X
X
X


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Table 1 
Schedule of Procedures/Assessments in Study KX01-AK-002 (Cohort 1) 
AE = adverse event; AK = actinic keratosis; ECG = electrocardiogram; HEENT = head, eyes, ears, nose, and throat; LSR = local skin reaction; PK = pharmacokinetic; 
Term = Termination. 
a 
For Day 57 complete responders only. 
b 
For subjects who do not have complete response at Day 57, Day 57 is the Final Visit. 
c 
For subjects who have complete response at Day 57 and no recurrence, 12 months post-Day 57 is the Final Visit.  Those subjects who have AK recurrence in the treatment area will 
have their Final Visit at the visit when the AK recurrence is identified. 
d 
Assessment performed before study medication application.  Day 1 evaluation will serve as baseline for these assessments. 
e 
Vital signs measurements will be taken after the subject has been seated for at least 5 minutes. 
f 
A complete PE will include weight and an assessment of HEENT, integumentary, gastrointestinal, cardiovascular, respiratory, muscular-skeleton, and neurological systems. 
g 
Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG. 
h 
Except for those diagnosed as having diabetes, subjects must be fasted for laboratory assessments. 
i 
For females of childbearing potential; urine pregnancy test on Day 1 before study medication application.  All other pregnancy tests are performed with serum. 
j 
PK assessments on Day 1 and Day 5 at 0 hour (just before study medication application) and at 0.5 (±5 min), 1 and 4 hours (±10 min) after study drug application.  
k 
Before LSR assessment, subjects will be queried for spontaneously reported AEs. 
l 
Only AEs in the selected treatment area will be recorded. 


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Table 2
Schedule of Procedures/Assessments in Study KX01-AK-002 (Cohort 2)
Period
Screening
Treatment
Follow-up
Recurrence Follow-up a
Visit
1
2
3
4
5 b
6 b
7
8
9
10c/
Early 
Term
11, 12, 13, 14 a
Day
-28 to -1
1
2
3
4
5
8
15
29
57c
3, 6, 9, 12 Months Post-Day 57d
Visit time window (days)
None
None
None
None
±2
±2
±2
±2
±14
Informed consent
X
Inclusion & exclusion criteria
X
Xe
Demographics
X
Medical/surgical history
X
AK history/AK treatment history
X
Fitzpatrick skin-type scale
X
Vital signsf
X
X
X
X
X
X
Prior and concomitant 
medications/therapies
X
Xe
X
X
X
X
X
X
X
Physical examination, including weightg
X
X
Treatment area identification
X
Xe
AK lesion count
X
Xe
X
X
X
X
X
ECGh
X
X
X
Clinical chemistry, hematology, and 
urinalysisi
X
X
X
Pregnancy test 
X
Xe,j
X
X
PK blood samples
Xk
Xk
Study medication application
X
X
X
AEsl
X
X
X
X
X
X
X
X
Xm
LSRs
Xe
Xe
Xe
X
X
X
X
Pigmentation and scarring
Xe
Xe
Xe
X
X
X
X
Standardized photography
X
Xe
X
X
X


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Table 2 
Schedule of Procedures/Assessments in Study KX01-AK-002 (Cohort 2) 
AE = adverse event; AK = actinic keratosis; ECG = electrocardiogram; HEENT = head, eyes, ears, nose, and throat; LSR = local skin reaction; PK = pharmacokinetic; 
Term = Termination. 
a 
For Day 57 complete responders only. 
b 
These visits are not required for Cohort 2 subjects. 
c 
For subjects who do not have complete response at Day 57, Day 57 is the Final Visit. 
d 
For subjects who have complete response at Day 57 and no recurrence, 12 months post-Day 57 is the Final Visit.  Those subjects who have AK recurrence in the treatment area will 
have their Final Visit at the visit when the AK recurrence is identified. 
e 
Assessment performed before study medication application.  Day 1 evaluation will serve as baseline for these assessments. 
f 
Vital signs measurements will be taken after the subject has been seated for at least 5 minutes. 
g 
A complete PE will include weight and an assessment of HEENT, integumentary, gastrointestinal, cardiovascular, respiratory, muscular-skeleton, and neurological systems. 
h 
Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG. 
i 
Except for those diagnosed as having diabetes, subjects must be fasted for laboratory assessments. 
j 
For females of childbearing potential; urine pregnancy test on Day 1 before study medication application.  All other pregnancy tests are performed with serum. 
k 
PK assessments on Day 1 and Day 3 at 0 hour (just before study medication application) and at 0.5 (±5 min), 1 and 4 hours (±10 min) after study drug application.  
l 
Before LSR assessment, subjects will be queried for spontaneously reported AEs. 
m 
Only AEs in the selected treatment area will be recorded. 


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3 
TABLE OF CONTENTS 
REVISION HISTORY............................................................................................................... I 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................2 
3 
TABLE OF CONTENTS .................................................................................................13 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................17 
5 
ETHICS............................................................................................................................18 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................18 
5.2 
Ethical Conduct of the Study .................................................................................18 
5.3 
Subject Information and Informed Consent ...........................................................19 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................19 
7 
INTRODUCTION ...........................................................................................................19 
7.1 
Indication ...............................................................................................................19 
7.1.1 
Mechanism of Action ...................................................................................20 
7.1.2 
Clinical Experience with KX2-391 ..............................................................20 
7.2 
Study Rationale ......................................................................................................21 
8 
STUDY OBJECTIVES ....................................................................................................21 
8.1 
Primary Objective ..................................................................................................21 
8.2 
Secondary Objectives.............................................................................................21 
8.3 
Exploratory Objectives ..........................................................................................22 
9 
INVESTIGATIONAL PLAN ..........................................................................................22 
9.1 
Overall Study Design and Plan ..............................................................................22 
9.1.1 
Screening Period ..........................................................................................23 
9.1.2 
Treatment Period ..........................................................................................24 
9.1.3 
Follow-up Period .........................................................................................24 
9.1.4 
Recurrence Follow-up Period ......................................................................25 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................25 
9.3 
Selection of Study Population ................................................................................25 
9.3.1 
Inclusion Criteria .........................................................................................25 
9.3.2 
Exclusion Criteria ........................................................................................26 
9.3.3 
Removal of Subjects from Therapy or Assessment .....................................27 
9.4 
Treatments..............................................................................................................28 
9.4.1 
Treatment Administered ..............................................................................28 
9.4.2 
Identity of Investigational Products .............................................................29 
Chemical Name and Structural Formula of KX2-391 .........................29 
Labeling for Study Drug ......................................................................29 
Storage Conditions...............................................................................30 


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Administration of Investigational Products .........................................30 
9.4.3 
Method of Assigning Subjects to Treatment Groups ...................................30 
9.4.4 
Selection of Doses in the Study ...................................................................31 
9.4.5 
Selection and Timing of Dose for Each Subject ..........................................31 
9.4.6 
Blinding........................................................................................................31 
9.4.7 
Prior and Concomitant Therapy ...................................................................31 
Prior Therapy .......................................................................................31 
Concomitant Medication/Therapy .......................................................31 
Prohibited Medication/Therapy ...........................................................32 
9.4.8 
Prohibitions and Restrictions during Study Period ......................................33 
9.4.9 
Treatment Compliance .................................................................................33 
9.4.10 
Drug Supplies and Accountability ...............................................................33 
9.5 
Study Assessments .................................................................................................34 
9.5.1 
Assessments .................................................................................................34 
Demography .........................................................................................34 
Baseline Assessments ..........................................................................34 
9.5.1.2.1 
Medical/Surgical and Actinic Keratosis History ...........................34 
9.5.1.2.2 
Fitzpatrick Skin-Type Classification .............................................34 
9.5.1.2.3 
Prior Medications ...........................................................................34 
Activity Assessments...........................................................................35 
9.5.1.3.1 
Actinic Keratosis Lesion Count .....................................................35 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................35 
9.5.1.4.1 
Pharmacokinetic Assessments .......................................................35 
9.5.1.4.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments ...................................................................................36 
Safety Assessments ..............................................................................36 
9.5.1.5.1 
Adverse Events and Other Events of Interest ................................36 
9.5.1.5.2 
Serious Adverse Events and Other Events of Interest ...................39 
9.5.1.5.3 
Laboratory Measurements .............................................................40 
9.5.1.5.4 
Vital Signs ......................................................................................41 
9.5.1.5.5 
Physical Examinations ...................................................................41 
9.5.1.5.6 
Electrocardiograms ........................................................................41 
9.5.1.5.7 
Pregnancy Testing ..........................................................................41 
9.5.1.5.8 
Other Assessments .........................................................................41 
9.5.2 
Appropriateness of Measurements ...............................................................43 
9.5.3 
Reporting of Serious Adverse Events, Pregnancy, and Other Events of 
Interest..........................................................................................................44 


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Reporting of Serious Adverse Events..................................................44 
Reporting of Pregnancy and Exposure to Study Drug through
Breastfeeding .......................................................................................44 
Reporting of Other Events of Interest ..................................................45 
9.5.3.3.1 
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................45 
Expedited Reporting ............................................................................45 
Breaking the Blind ...............................................................................45 
Regulatory Reporting of Adverse Events ............................................46 
9.5.4 
Completion/Discontinuation of Subjects .....................................................46 
9.5.5 
Abuse or Diversion of Study Drug ..............................................................46 
9.5.6 
Confirmation of Medical Care by another Physician ..................................46 
9.6 
Data Quality Assurance .........................................................................................46 
9.6.1 
Data Collection ............................................................................................46 
9.6.2 
Clinical Data Management ..........................................................................47 
9.7 
Statistical Methods .................................................................................................47 
9.7.1 
Statistical and Analytical Plans ....................................................................48 
Study Endpoints ...................................................................................48 
9.7.1.1.1 
Primary Endpoints .........................................................................48 
9.7.1.1.2 
Secondary Endpoints .....................................................................48 
9.7.1.1.3 
Exploratory Endpoints ...................................................................48 
Definitions of Analysis Sets.................................................................49 
Subject Disposition ..............................................................................49 
Demographic and Other Baseline Characteristics ...............................49 
Prior and Concomitant Therapy ...........................................................49 
Activity Analyses.................................................................................50 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...................................................................50 
9.7.1.7.1 
Pharmacokinetic Analyses .............................................................50 
9.7.1.7.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .........................................................................................50 
Safety Analyses ....................................................................................50 
9.7.1.8.1 
Extent of Exposure .........................................................................51 
9.7.1.8.2 
Adverse Events ..............................................................................51 
9.7.1.8.3 
Laboratory Values ..........................................................................51 
9.7.1.8.4 
Vital Signs ......................................................................................51 
9.7.1.8.5 
Electrocardiograms ........................................................................51 
9.7.1.8.6 
Physical Examinations ...................................................................52 


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9.7.1.8.7 
Pregnancy Tests .............................................................................52 
9.7.1.8.8 
Other Analyses ...............................................................................52 
9.7.2 
Determination of Sample Size .....................................................................52 
9.7.3 
Interim Analysis ...........................................................................................52 
9.7.4 
Other Statistical/Analytical Issues ...............................................................52 
9.7.5 
Procedure for Revising the Statistical Analysis Plan ...................................52 
10 REFERENCE LIST .........................................................................................................53 
11 APPENDICES .................................................................................................................55 
LIST OF IN-TEXT TABLES
Table 1 
Schedule of Procedures/Assessments in Study KX01-AK-002 
(Cohort 1) .....................................................................................................9 
Table 2 
Schedule of Procedures/Assessments in Study KX01-AK-002 
(Cohort 2) ...................................................................................................11 
Table 3 
Treatment Administered in KX01-AK-002 ...............................................28 
Table 4 
Blood Sample Collection Times for Pharmacokinetic Analyses ...............35 
Table 5 
Clinical Laboratory Tests ...........................................................................40 
Table 6 
Local Skin Reaction Grading Criteria ........................................................42 
LIST OF APPENDICES 
Appendix 1 
Photographs of Local Skin Reactions ........................................................56 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Terms 
AE 
adverse event 
AK 
actinic keratosis 
AUC 
area under the plasma concentration-time curve  
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
Cmin 
minimum (trough) plasma concentration 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LC-MS/MS 
liquid chromatography/tandem mass spectrometry 
LSR 
local skin reaction 
MedDRA 
Medical Dictionary for Regulatory Activities 
PE 
physical examination 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PT 
preferred term 
R 
accumulation ratio 
SAE 
serious adverse event 
SCC 
squamous cell carcinoma 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
US 
United States 
UV 
ultraviolet (light) 
 


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5 
ETHICS 
5.1
Institutional Review Boards/Independent Ethics Committees 
The protocol, any protocol amendments, informed consent form (ICF), and appropriate 
related documents must be reviewed and approved before subjects are screened for entry by 
an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) constituted and 
functioning in accordance with International Council for Harmonisation (ICH) E6 (Good 
Clinical Practice [GCP]1), Section 3, and any local regulations (eg, Federal Regulations, Title
21 Code of Federal Regulations [CFR] Part 56).  Documentation of IRB/IEC compliance 
with the ICH E6 and any local regulations regarding constitution and review conduct will be 
provided to the Sponsor. 
A signed letter of study approval from the IRB/IEC chairman must be sent to the Principal 
Investigator (PI) with a copy to the Sponsor before study start and the release of any study 
drug to the site by the Sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the Investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the Sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the Investigator or 
Sponsor, depending on local regulatory obligations.  If the Investigator is required to report 
to the IRB/IEC, he/she will forward a copy to the Sponsor at the time of each periodic report.  
The Investigator(s) or the Sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the Investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required. 
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures (SOPs) of the 
Sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following: 
•
Principles of the World Medical Association Declaration of Helsinki (2013) 
•
ICH E6: Guidance for Industry - E6 Good Clinical Practice: Consolidated Guidance, US
Department of Health and Human Services, Food and Drug Administration, April 1996.
•
Title 21 of the United States CFR (US 21 CFR) regarding clinical studies, including Part 
50 and Part 56 concerning informed subject consent and IRB regulations and applicable 
sections of US 21 CFR Part 312 


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5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the Investigator must explain to 
each subject the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the subject, and the extent of 
maintaining confidentiality of the subject’s records.  Each subject must be informed that 
participation in the study is voluntary, that he/she may withdraw from the study at any time, 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it, and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject provides verbal consent to the subject’s participation in the 
study and has signed and personally dated the ICF, the witness should sign and personally 
date the consent form.  The subject will be asked to sign an ICF and all authorizations required 
by local law (eg, Protected Health Information in North America) before any study-specific 
procedures are performed.  No subject can enter the study before his/her informed consent 
has been obtained. 
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with 
ICH E6, Section 4, and all applicable local regulations.  The original, signed ICF for each 
subject will be verified by the Sponsor and kept on file according to local procedures at the 
site. 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified Investigators under the sponsorship of Kinex 
Pharmaceuticals, Inc. at approximately 8 to 16 investigational sites in the United States (US). 
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the Sponsor and of any contract research organizations (CROs) will be listed in the 
Regulatory Binder provided to the site. 
7 
INTRODUCTION 
7.1 
Indication 
In this study, the activity, safety, and pharmacokinetics (PK) of KX2-391 Ointment 1% will 
be evaluated in adult subjects with a clinical diagnosis of stable, clinically typical actinic 
keratosis (AK) on the face or scalp. 


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7.1.1 
Mechanism of Action 
KX2-391 (also referred to as KX01) is a synthetic and highly selective inhibitor of Src 
tyrosine kinase signaling and tubulin polymerization. KX2-391 ointment is being developed 
as a topical treatment for actinic keratosis.  KX2-391 is also being developed as an oral agent 
for oncology indications.  In defining its pharmacological activity in tumor cells, both in vitro 
and in vivo, KX2-391 has been shown to have potent activity against a wide range of solid 
tumors as well as leukemia cell lines, including cell lines that are resistant to commonly used 
cancer drugs.  Clinically, the safety, tolerability and pharmacokinetics of KX2-391 have been 
studied in approximately 120 patients in both solid and liquid tumors using either once or 
twice daily dosing.  The best overall response in these early studies has been ‘stable disease’ 
in 25-30% of patients. 
KX2-391 promotes the induction of p53, G2/M arrest of proliferating cell populations and 
subsequent apoptosis via the stimulation of Caspase-3 and PARP cleavage. Data from pre-
clinical dermatology studies coupled with an understanding of the mechanism of action of 
KX2-391 suggests that this compound will have clinical activity in dermatology indications 
such as actinic keratosis.  Potent inhibition of the growth of primary human keratinocytes and 
several melanoma cell lines in vitro (50% growth inhibition [GI50 values] ≤50 nM), suggests 
that KX2-391 has the potential to inhibit the proliferative expansion and promote apoptosis 
of abnormally proliferating cells in the epidermal and dermal layers upon topical application. 
KX2-391 has also been observed to inhibit T cell migration and endothelial tubule formation 
in vitro, suggesting additional potential therapeutic benefits for conditions where pathology is 
supported by lymphocyte infiltration, inflammation, and/or angiogenesis. 
Information regarding KX2-391 nonclinical studies is provided in the Investigator’s 
Brochure. 
7.1.2 
Clinical Experience with KX2-391 
KX2-391 Ointment 1% has been administered to humans in ongoing study KX01-AK-01-
US.  Based on preliminary PK data from this study in AK lesions on the forearm, the 
systemic exposure to KX2-391 following topical administration is limited, and is 
considerably lower than observed in previous clinical studies of oral KX2-391.  Patients 
should be monitored for the occurrence of application site reactions and systemic toxicity. 
KX2-391 has been administered orally to approximately 120 patients with malignancy. 
The Kinex studies of oral KX2-391 are as follows: 
KX2-391 was evaluated in a Phase I clinical trial, Study No. KX01-01-07, entitled “A 
Combined Rising Single-Dose (RSD) and Rising Multiple-Dose (RMD) Phase I Study to 
Evaluate Safety, Tolerability, and Pharmacokinetics of KX2-391 in Patients with Advanced 
Malignancies That Are Refractory to Conventional Therapies”. 
KX2-391 has been evaluated in Study No. KX01-002-09, entitled “A Phase II, Open-Label, 
Single-Arm Study Evaluating the Safety, Efficacy and Pharmacokinetics of KX2-391 in 


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Patients with Bone-Metastatic, Castration-Resistant Prostate Cancer Who Have Not Received 
Prior Chemotherapy.” 
KX2-391 was evaluated in Study No, KX01-03-11, “A Phase 1b Rising Multiple-Dose 
Clinical Study to Evaluate Safety, Tolerability and Activity of Oral Monotherapy with KX2-
391 in Elderly Subjects with Acute Myeloid Leukemia (AML) Who Are Refractory to or 
Have Declined Standard Induction Therapy”.
7.2 
Study Rationale 
Actinic keratoses represent the initial intra-epidermal manifestation of abnormal keratinocyte 
proliferation having the potential to progress to squamous cell carcinoma (SCC).  Squamous 
cell carcinoma is the second leading cause of skin cancer deaths in the US, with up to 65% of 
SCC arising from pre-existing actinic keratoses.2,3  The risk of progression has been 
determined to be between 0.025% and 16% per year,2,4 and the calculated lifetime risk of 
malignant transformation for a patient with AKs followed up for 10 years is between 6.1% 
and 10.2%.5 The rationale behind treating every AK is based on the difficulty in predicting 
which single AK will progress to squamous cell carcinoma.6,7  Suchniak et al8 reported 36% 
of lesions previously diagnosed clinically as AKs being in fact SCC, with 14% being in situ 
SCC.  Ehrig et al9 showed that 4% of AKs clinically diagnosed by board-certified 
dermatologists were in fact SCC and 5% were considered occult early stage of cutaneous 
malignancy.  Spontaneous regression has been reported in up to 25.9% of AKs over a 
12-month period, although 15% later reappeared.10,11,12
The goals of treatment are to 
completely eliminate AKs, minimizing their risk of progression to invasive SCC, reducing 
the potential to metastasize and cause death, while obtaining the best cosmetically acceptable 
outcomes.  Current approved/marketed treatment has shown up to approximately 60% 
efficacy, with a recurrence rate of approximately 35%. 
8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
The primary objective of the study is: 
•
To evaluate the activity of KX2-391 Ointment 1% administered topically to the face or 
scalp in subjects with AK by determining complete response rate, defined as 100% 
clearance at Day 57 
8.2 
Secondary Objectives 
The secondary objectives of the study are: 
x
To assess the activity of KX2-391 Ointment 1% during Days 1-57 
x
To assess the safety and tolerability of KX2-391 Ointment 1% in subjects with AK on 
the face or scalp 
x
To assess the PK of KX2-391 Ointment 1% in subjects with AK on the face or scalp 


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x To assess dose regimens by contrasting 5-day treatment with 3-day treatment in terms 
of the activity and safety of KX2-391 Ointment 1% in subjects with AK on the face 
or scalp 
8.3 
Exploratory Objectives 
The exploratory objectives of the study are: 
x To determine recurrence rates up to 12 months post-Day 57 for subjects who show 
response at Day 57 
x To determine sustained response rates at 12 months post-Day 57 for subjects who 
show response at Day 57 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This study will be an open-label, multicenter, activity, safety, tolerability, and PK study of 
KX2-391 Ointment 1% administered topically to the face or scalp of subjects with actinic 
keratosis in 2 sequential cohorts:  a 5-day dosing regimen (Cohort 1) and a 3-day dosing 
regimen (Cohort 2). 
The study consists of Screening, Treatment, and Follow-up Periods. 
Cohort 1:  
Eligible subjects will receive 5 consecutive days of topical treatment, to be applied at the 
study site, with 50 mg of KX2-391 Ointment 1% each day.  Blood samples for PK analysis 
will be collected on Day 1 and Day 5.  Subjects will return for Follow-up visits until Day 57.  
Thereafter, only Day 57 complete responders will continue Recurrence Follow-up Visits 
every 3 months for an additional 12 months after Day 57.  Activity (lesion counts) and safety 
evaluations will be performed. 
Cohort 2: 
Eligible subjects will receive 3 consecutive days of topical treatment, to be applied at the 
study site, with 50 mg of KX2-391 Ointment 1% each day.  Blood samples for PK analysis 
will be collected on Day 1 and Day 3.  Subjects will return for Follow-up visits until Day 57.  
Thereafter, only Day 57 complete responders will continue Recurrence Follow-up Visits 
every 3 months for an additional 12 months after Day 57.  Activity (lesion counts) and safety 
evaluations will be performed. 
For both cohorts, subjects may stay for approximately 5 hours at the investigational center 
until after the last PK blood sample is collected on Days 1 and 5 (Cohort 1) or Days 1 and 3 
(Cohort 2). 


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The Sponsor will review accumulating data.  If the 5-day regimen (Cohort 1) has sufficient 
activity and safety to warrant evaluating a 3-day regimen, enrollment of Cohort 2 will start 
after there are 60 evaluable subjects or up to 80 subjects are enrolled (whichever comes first) 
in Cohort 1.  For the most part, protocol procedures for Cohort 1 will be duplicated for 
Cohort 2, except PK samples will be collected on Days 1 and 3, and subjects will not return 
for Visits 5 and 6. 
The same study sites for the most part of Cohort 1 will be used for Cohort 2.  The Sponsor 
study team will monitor the enrollment status closely and ensure that any individual site does 
not enroll too many subjects. 
In each cohort, approximately 80 subjects will be enrolled to provide approximately 
60 subjects in the Evaluable Set, defined as subjects who complete all planned treatments and 
most evaluations, including the Day 57 Follow-up visit.  Therefore, a total of 160 subjects in 
2 cohorts may be enrolled, but the sample size of Cohort 2 may be adjusted, depending on 
the results of Cohort 1. 
9.1.1 
Screening Period 
The Screening Period may last up to 28 days for each cohort. 
Subject eligibility will be established during the Screening Period.  Subjects will be screened 
within 28 days of the first dose of study drug.  All screening assessments/evaluations, as 
presented in Table 1 and Table 2 will be performed after the subject provides informed 
consent and eligibility criteria are met. 
Treatment Area Identification 
At Screening (Visit 1), the Investigator will select a continuous treatment area affected with 
AK on the face or scalp for each subject that: 
x
measures 25 cm2 
x
contains 4 to 8 AK lesions that are clinically typical 
The location and approximate shape of the treatment area will be recorded on an acetate 
transparency sheet.
At Visit 1, the Investigator and an investigational center staff member will identify the 
treatment area by:  
x
Examining the face or scalp and locating each AK with a dot of removable marker. 
x
Using an 8 x 11 acetate transparency sheet with 1x1 cm squares.   
x
Mapping at least 2 anatomical landmarks on the acetate sheet.  Example of landmarks 
could be bony prominences, scars, moles, seborrheic keratosis, and veins. 
x
Indicating the location of AK lesions with permanent marker dots on the acetate 
transparency sheet. 


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x
Outlining the treatment area on the transparency sheet with the permanent marker. 
x
Removing marker dots on the face/scalp with alcohol swabs or water (after taking the 
screening photo). 
9.1.2 
Treatment Period 
The inclusion/exclusion criteria will be reviewed again prior to treatment on Day 1, to 
re-confirm subjects’ eligibility to participate in the study. 
Subjects in Cohort 1 will be treated for 5 consecutive days (Days 1-5 [Visits 2-6]) during the 
Treatment Period.
Visits 2 through 6 should be scheduled to occur at approximately the 
same time each day. 
Subjects in Cohort 2 will be treated for 3 consecutive days (Days 1-3 [Visits 2-4]) during the 
Treatment Period.  Subjects will not return on Day 4 (Visit 5) or Day 5 (Visit 6).  Visits 2 
through 4 should be scheduled to occur at approximately the same time each day.  
At Visit 2 (Day 1), prior to study drug application, the Investigator and any appropriate 
investigational staff member(s) (Investigator-trained designee) will confirm the location of 
the treatment area using the Visit 1 acetate sheet.  The Investigator should re-mark the 
treatment area borders as needed so the study evaluations may be effectively completed. 
Once the treatment area has been re-identified at Visit 2, photographs will be taken 
(Section 9.5.1.5.8).  50 mg of KX2-391 Ointment 1% will be applied topically once daily for 
5 consecutive days (Cohort 1) or 3 consecutive days (Cohort 2) to the 25 cm2 treatment area 
(2 mg/cm2; 0.5 mg KX2-391 total).  See Section 9.4.2.4 for a detailed description of study 
medication application. 
Pharmacokinetic blood sampling, activity, safety assessments, and local skin reaction (LSR) 
assessments (see Section 9.5 for details) will be performed (Table 1 and Table 2).  
Pigmentation and scarring in the treatment area also will be assessed by the Investigator (or a 
trained designee).
Standardized photography will be performed at designated visits throughout the study 
(Table 1 and Table 2). 
9.1.3 
Follow-up Period 
After the Treatment Period for both cohorts, there will be Follow-up Visits at Days 8, 15, 29, 
and 57 to assess safety, activity, LSRs, pigmentation, and scarring. 
For subjects who do not have complete response at Day 57, Day 57 is their Final Visit. 


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9.1.4 
Recurrence Follow-up Period 
For both cohorts, only for subjects who show complete response at Day 57, there will be 
additional visits every 3 months up to 12 months post-Day 57 (ie, at 3, 6, 9, and 12 months 
post-Day 57) to assess recurrence of AK lesions. These subjects will continue to undergo 
scheduled activity and safety assessments (Table 1 and Table 2).
For subjects who have complete response at Day 57 and no recurrence, 12 months 
post-Day 57 is the Final Visit.  Those subjects who have AK recurrence in the treatment area 
will have their Final Visit at the visit when the AK recurrence is identified.
9.2 
Discussion of Study Design, Including Choice of Control Groups 
This is a nonrandomized, open-label study.  No control group has been included. 
9.3
Selection of Study Population
Eligible subjects will be adults (≥18 years of age) with a clinical diagnosis of stable, 
clinically typical AK on the face or scalp. 
9.3.1 
Inclusion Criteria 
Inclusion criteria will be reviewed at Screening (Visit 1). 
Subjects must meet all of the following criteria to be included in this study: 
1. Males and females ≥18 years old
2. Clinical diagnosis of stable, clinically typical actinic keratosis 
3. A treatment area on the face or scalp that: 
x
is a continuous area measuring 25 cm2
x
contains 4 to 8 AK lesions 
4. Females must be postmenopausal (>50 years of age with at least 18 months of 
amenorrhea), surgically sterile (by hysterectomy, bilateral oophorectomy or tubal 
ligation) or otherwise incapable of pregnancy for at least 1 year; or, if of childbearing 
potential, must be using highly effective contraception for at least 90 days prior to 
treatment with KX2-391 Ointment 1% and must agree to continue to use highly 
effective contraception for at least 90 days following their last dose of KX2-391 
Ointment 1%.  Highly effective contraception includes oral hormonal contraceptives, 
hormonal contraceptive implant or patch, or intrauterine device.  Abstinence and double 
barrier methods do not qualify as highly effective methods of contraception.
5. Males who have not had a vasectomy must agree to use barrier contraception from 
Screening through 90 days after their last dose of KX2-391 Ointment 1%. 
6. All subjects must agree not to donate sperm or eggs or attempt conception from 
Screening through 90 days following their last dose of KX2-391 Ointment 1%. 


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7. Females of childbearing potential must have a negative serum pregnancy test at 
Screening and a negative urine pregnancy test on Day 1 prior to administration of study 
treatment. 
8. Subjects who in the judgment of the Investigator, are in good general health based on: 
x
medical history 
x
no physical examination (PE) findings that the Principal Investigator (PI) determines 
would interfere with interpretation of study results 
x
screening electrocardiogram (ECG) without clinically significant abnormalities  
x
clinical chemistry, hematology, and urinalysis results that are within the reference 
ranges; clinical laboratory values outside the reference ranges that are considered by 
the PI to be clinically insignificant are also acceptable 
9. Willing to avoid direct sun or ultraviolet (UV) light exposure to the face or scalp 
10. Able to comprehend and are willing to sign an informed consent form 
9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Clinically atypical and/or rapidly changing AK lesions on the treatment area 
2. Malignancy within 5 years prior to Screening except basal or squamous cell carcinoma 
not on the treatment area that were treated with curative intent and are without 
recurrence 
3. Used any of the following systemic therapies within the specified period before Visit 1: 
x
retinoids; 90 days 
x
glucocorticosteroids; 28 days (intra-articular and inhaled steroids are allowed) 
x
methotrexate or other anti-metabolites; 28 days 
x
immunosuppressants or immunomodulators; 28 days 
4. Used any of the following topical therapies on the treatment area within the specified 
period before Visit 1: 
x
retinoids; 90 days 
x
glucocorticosteroids; 14 days 
x
analgesic and/or anti-inflammatory medication on the face or scalp; 72 hours 
5. Had any of the following on the treatment area within 90 days (or until the site has 
healed, whichever is longer) before Visit 1: 
x
ingenol mebutate (eg, Picato) 
x
5-fluorouracil (eg, 5-FU; Efudex) 
x
imiquimod (eg, Aldara; Zyclara) 
x
diclofenac with or without hyaluronic acid (eg, Solaraze) 


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6. Surgical or destructive modalities on the treatment area within 30 days (or until the site 
has healed following treatment, whichever is longer) before Visit 1: 
x
cryotherapy 
x
electrodesiccation 
x
laser, light (eg, photodynamic therapy, intense pulsed light) or any other energy-based 
therapy 
x
chemical peels (eg, tricholoracetic acid) 
x
dermabrasion 
x
surgical removal (eg, curettage, excision) 
7. Currently, or has experienced any of the following on the treatment area within the 
specified period before Visit 1: 
x
cutaneous malignancy; 180 days 
x
sunburn; 28 days 
x
body art (eg, tattoo, piercing); currently 
8. A history of sensitivity and/or allergy to any of the ingredients in the study medication 
9. A skin disease (eg, atopic dermatitis, psoriasis, eczema) or condition (eg, scarring, open 
wounds) that, in the opinion of the Investigator, might interfere with the study conduct 
or evaluations, or which exposes the subject to an unacceptable risk by study 
participation 
10. Other significant uncontrolled or unstable medical diseases or conditions that, in the 
opinion of the Investigator, would expose the subject to unacceptable risk by study 
participation 
11. Females who are pregnant or nursing 
12. Participated in an investigational drug trial during which an investigational study 
medication was administered within 14 days or 5 half-lives of the investigational 
product, whichever is longer, before Screening 
9.3.3 
Removal of Subjects from Therapy or Assessment 
The Investigator may discontinue treating a subject with study treatment or withdraw the 
subject from the study at any time for safety or administrative reasons.  The subject may 
decide to discontinue study treatment or withdraw from the study at any time for any reason. 
The Investigator will document the reason for discontinuing a subject from treatment or from 
the study. 


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The Investigator may discontinue treatment or discontinue a subject from the study for any of 
the reasons listed below:  
x
Occurrence of AEs 
x
Occurrence of pregnancy  
x
Use of a prohibited concomitant medication or treatment (see Section 9.4.7.3) 
x
Conditions that, in the opinion of the Investigator, would make the subject’s 
continued participation in the study inadvisable (actual condition must be 
documented) 
x
Noncompliance (Investigator must describe) 
x
Withdrawal of consent (subject asked, but not required to give a reason) 
x
Other (Investigator must describe) 
If the study is terminated by the Sponsor, the Investigator will promptly explain to the subject
involved that the study will be discontinued and provide appropriate medical treatment and 
other necessary measures for the subject. 
9.4 
Treatments 
The investigational product in the study is KX2-391 Ointment 1%.
9.4.1 
Treatment Administered 
Information regarding study treatment is provided in Table 3.
Table 3
Treatment Administered in KX01-AK-002
Investigational Product
Strength
Size of 
Treatment 
Area
Quantity study 
medication/
KX2-391
Number 
Applications 
and Frequency
Study Days 
Administered
KX2-391 Ointment 1%
1%
25 cm2
50 mg of study 
drug = 0.5 mg
of KX2-391
1 application 
daily for 
5 consecutive 
days (Cohort 1) 
or 3 consecutive 
days (Cohort 2)
Days 1-5 (Cohort 1)
Days 1-3 (Cohort 2)


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9.4.2 
Identity of Investigational Products 
 
Chemical Name and Structural Formula of KX2-391 
x Study drug code:  KX2-391 Ointment 1% 
x Drug Product:  KX2-391 free base ointment formulated with glyceryl 
monostearate and propylene glycol 
x Chemical name:  N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl) 
acetamide   
x Molecular formula:  C26H29N3O3 
x Molecular weight:  431.53 g/mole 
x Structural formula:   
 
 
Labeling for Study Drug 
Investigational product will be packaged and labeled in a manner consistent with the study 
and will be designed by:  
Kinex Pharmaceuticals, Inc. 
1001 Main Street 
Suite 600 
Buffalo, NY 14203 
Labels will be nonremovable in nature. 
Labels for the investigational product will be in accordance with US regulations and will 
include (but will not be limited to) the following information: 
• 
 For clinical study use only 
• Name and address of the Sponsor 
• Chemical name/drug identifier 
• Lot number/batch number 
• Storage conditions, expiration date if necessary 


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Storage Conditions
Study drug will be stored in accordance with labeled storage conditions. Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The Investigator is responsible for ensuring that the 
temperature is monitored throughout the total duration of the trial and that records are 
maintained; the temperature should be monitored continuously by using either an in house 
validated data acquisition system, a mechanical recording device, such as a calibrated chart 
recorder, or by manual means, such that minimum and maximum thermometric values over a 
specific time period can be recorded and retrieved as required. 
Administration of Investigational Products
The study medication is for external topical use on the treatment area.  An investigational 
center staff member will perform the study medication applications.  The staff member must 
wash her/his hands before and after each study medication application. 
50 mg of KX2-391 Ointment 1% will be applied topically to a 25 cm2 treatment area.  This 
amount contains a total of 0.5 mg KX2-391 free base.  KX2-391 Ointment 1% will be 
applied once daily for 5 consecutive days (Cohort 1) or 3 consecutive days (Cohort 2) (see 
Table 3).
The staff member will weigh the appropriate amount of study medication into a weighing 
boat (or equivalent) using a calibrated scale.  The amount of study medication applied will be 
calculated by determining the difference of the weight of the weighing boat with study 
medication before and after application. The amount of study medication weighed will be as 
close to the intended dose as possible. 
A study staff member will perform and document a scale accuracy check at least every day 
before weighing study medication. 
The study medication will be applied to the subject’s treatment area using a fingertip 
protected with a powder-free finger cot or examination glove. The study medication will be 
gently and evenly rubbed over the treatment area until no visible accumulation is evident. 
The time when the study medication application is completed (Application Completion 
Time) will be recorded. 
The study medication should remain on the treatment area. Subjects must avoid touching or 
wetting the treatment area for at least 12 hours from time of last application and are not 
allowed to apply any topical products to the treatment area (see Section 9.4.7.3).  Instructions 
will be sent home with the subject clarifying on how to care for the treatment area. 
9.4.3 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study with 2 sequential cohorts.  Each site will enroll subjects for 
Cohort 1 (5-day regimen) first, and will not assign any subjects to Cohort 2 (3-day regimen) 
until being notified.  The Sponsor will review accumulating data on Cohort 1 to decide if, 


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when, and where to start Cohort 2.  In addition, the Sponsor study team will monitor the 
enrollment status closely and ensure that any individual site does not enroll too many 
subjects. 
9.4.4 
Selection of Doses in the Study 
The dose of 50 mg of KX2-391 applied to a 25 cm2 area on the face or scalp for 5 or 
3 consecutive days is based on a previous study using the same dose regimen for the 
treatment of AK on the forearm (study KX01-AK-01-US). Preliminary data show that this 
regimen had an acceptable LSR and safety profile, with efficacy outcomes considered to 
warrant further investigation.
9.4.5 
Selection and Timing of Dose for Each Subject 
Section 9.4.2.4 provides detailed instructions for administering KX2-391 Ointment 1% in 
this study.  Study medication should be applied at about the same time each day. 
9.4.6 
Blinding 
The study will not be blinded. 
9.4.7 
Prior and Concomitant Therapy 
Prior Therapy
All medications (prescription and nonprescription including vitamins and dietary 
supplements), treatments, and therapies including radiotherapy taken 28 days before Day 1 
through the final study visit must be recorded in the case report form/electronic case report 
form (CRF/eCRF).  A complete AK treatment history will be recorded on the AK Treatment 
History CRF/eCRF (see Section 9.5.1.2.1).
Concomitant Medication/Therapy
Concomitant medication/therapies are any new or existing therapy received by the subject 
after signing the ICF until discharge from the study. 
Any medication (including nonprescription medications) or therapy administered to the 
subject during the course of the study (starting at the date of informed consent) will be 
recorded on the Concomitant Medication CRF/eCRF. 
Use of sunblock or any topical products in the treatment area allowed by the Investigator will 
be recorded in the Concomitant Medication CRF/eCRF. 
The Investigator will record any AE on the Adverse Events CRF/eCRF for which the 
concomitant medication/therapy was administered. 
Subjects will refrain from receipt of any therapy in accordance with the inclusion/exclusion 
criteria 


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Prohibited Medication/Therapy
Use of any non-study drug treatment for AK lesions on the treatment area is prohibited until 
Day 57.  AK lesions located outside the treatment area may be treated by lesion-directed 
treatment only, eg, cryotherapy or biopsy, as determined by the Investigator.  A list of 
prohibited medications follows. 
Prohibited drug products and treatments that might influence or mask the effects of treatment 
until Day 57 include:  immunomodulators or immunosuppressive therapies, cytotoxic drugs, 
interferon/interferon inducers, topical or systemic steroids, 5-FU, ingenol mebutate, 
imiquimod, diclofenac, topical or systemic retinoids, topical salicylic acid, bichloroacetic 
acid, trichloroacetic acid, acid-containing therapeutic products, benzoyl peroxide, 
chemodestruction, medicated/therapeutic topical salves or topical steroids, photodynamic 
therapy, psoralen plus UVA or UVB therapy, artificial tanner, excessive or prolonged 
exposure to UV light source.13
During the Recurrence Follow-up Period, lesion-directed treatment such as cryotherapy or 
biopsy, and topical treatment is allowed for treatment of AK lesions emerging in any part of 
the body.  Any lesion in the treatment area that is treated during the Recurrence Follow-up 
Period will be considered as a recurrence. 
Subjects are prohibited from applying any topical products, including but not limited to, 
lotions, creams, and ointments to the treatment area up until the end of Visit 10 (Day 57), 
except when those medications are prescribed by the Investigator for the management of 
local skin reactions.  All other routinely used topical products can be used on the treatment 
area from Day 57 onward, at the discretion of the Investigator. 
All subjects should be reminded to avoid direct sun or UV exposure to the treatment area 
throughout the study.  From Day 15 onward, if a subject is unable to avoid direct sun or UV 
exposure to the treatment area, the Investigator may allow the use of sunblock only. 
Subjects have unrestricted use of nonmedicated topical products on areas outside of the 
treatment area during the study.  After Day 57, all routinely used topical products can be 
used. 
Any subjects who start systemic therapies for the treatment of AK will be withdrawn from 
the study. 
Any subjects who start topical therapies for AK on the treatment area will be withdrawn from 
the study. 
The decision to administer a prohibited medication/treatment is done with the safety of the 
study subject as the primary consideration. 


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9.4.8 
Prohibitions and Restrictions during Study Period 
Except for those diagnosed as having diabetes, subjects must be fasted for laboratory 
assessments (see Section 9.5.1.5.3); otherwise there are no food, water, beverage, or physical 
activity restrictions during the study. 
9.4.9 
Treatment Compliance 
Records of treatment administration for each subject will be kept during the study.  The 
clinical research associates (CRAs) will review treatment administration throughout the 
course of the study. 
9.4.10 
Drug Supplies and Accountability 
The Investigator and study staff will be responsible for the accountability of all clinical 
supplies (dispensing, inventory, and record keeping) following the Sponsor’s instructions.  In 
this matter, the Investigator and study staff must adhere to GCP guidelines, as well as 
national requirements. 
Under no circumstances will the Investigator allow the study drugs to be used other than as 
directed by this protocol.  Clinical supplies will be dispensed only by an appropriately 
qualified person and will not be dispensed to any individual who is not enrolled in the study. 
An accurate and timely record of the receipt of all clinical supplies and dispensing of study 
drug to the subject must be maintained.  This includes, but is not limited to: 
x
documentation of receipt of clinical supplies 
x
study drugs dispensing/return reconciliation log, including amount and date of 
dispensing 
x
study drugs accountability log 
x
all shipping service receipts
x
documentation of study drug returned to the Sponsor 
All forms will be provided by the Sponsor (or its designee).  Any comparable forms that the 
investigational site wishes to use must be approved by the Sponsor.  A copy of the drug 
accountability record must be provided to the Sponsor at the end of the study. 
The supplies and inventory records must be made available, on request, for inspection by the 
Sponsor (or its designee) or a representative of a health authority.  If applicable, all unused 
study drugs and empty containers, are to be returned to the Investigator by the subject and 
ultimately to the Sponsor at the conclusion of the study unless provision is made by the 
Sponsor for destruction of supplies and containers at the investigational site.  On completion 
of drug accountability and reconciliation procedures by investigational site personnel and 
documentation procedures by Sponsor personnel, study drug that is to be returned to the 


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Sponsor, if necessary must be boxed and sealed and shipped back to the Sponsor following 
all local regulatory requirements. 
The CRA(s) will review drug accountability during monitoring site visits and at the 
completion of the study. 
9.5 
Study Assessments 
9.5.1 
Assessments 
All assessments and timing of the assessments should be performed according to the 
Schedule of Procedures and Assessments (Table 1 and Table 2).
Demography
Subject demographic information will be collected at the Screening Visit.  Demographic
information includes date of birth (or age), sex, race/ethnicity. 
Baseline Assessments
9.5.1.2.1 MEDICAL/SURGICAL AND ACTINIC KERATOSIS HISTORY
Medical and surgical history and current medical conditions will be recorded at Screening 
(Visit 1).  All pertinent medical history must be noted in the CRF/eCRF.  A complete AK
medical history will also be recorded. 
Medical history will include:  
x
Significant medical and surgical history; childhood diseases and common colds are 
not required unless it is ongoing at Screening 
x
A complete AK history from the time of initial diagnosis 
x
A complete AK treatment history including all commercial and investigational 
products, including medical therapies and surgical modalities, and other prescribed 
and nonprescription therapies dating back to the initial diagnosis. 
9.5.1.2.2 FITZPATRICK SKIN-TYPE CLASSIFICATION
The Fitzpatrick Skin-Type is a skin classification system13 which measures 2 components 
(genetic disposition and reaction to sun exposure).  Skin-types range from very fair (Type I) 
to very dark (Type VI). 
Subjects’ skin will be typed using this classification system at Screening (Visit 1). 
9.5.1.2.3 PRIOR MEDICATIONS
Prior medications taken within 28 days before Day 1, including nonprescription remedies, 
vitamins, etc, will be recorded at Screening (Visit 1).


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Activity Assessments
9.5.1.3.1 ACTINIC KERATOSIS LESION COUNT
The Investigator will perform a count of AK lesions (lesion count) for all subjects at Visits 1
and 2, Visits 7 through 10, and for Day 57 complete responders, also at Visits 11 through 14.
The AK lesion count is the Investigator’s assessment of the number of AK lesions in the 
treatment area.  A subject must have 4 to 8 AK lesions in the treatment area to be eligible to 
continue in the study at Visit 1. 
For this assessment, an AK lesion is considered to be on the treatment area, and should be 
counted if it is completely inside the treatment area or is touching any of the borders of the 
treatment area.  These lesions will be treated during the study medication application process. 
The Investigator must NOT refer to any other evaluation to assist with the AK lesion count.  
This is not a comparison with the AK lesion count at any other timepoint. 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1 PHARMACOKINETIC ASSESSMENTS
Blood samples (3 mL at each timepoint) for PK analysis of KX2-391 will be collected at the 
following timepoints (Table 4): 
Table 4
Blood Sample Collection Times for Pharmacokinetic Analyses 
Application Day
Time (hours) 
0
predose
0.5
postdose
1
postdose
4
postdose
Window
±5 minutes
±10 minutes
±10 minutes
Both cohorts: Day 1 (Visit 2)
Xa
X
X
X
Cohort 1:  Day 5 (Visit 6)
Xa
X
X
X
Cohort 2:  Day 3 (Visit 4)
Xa
X
X
X
a
Prior to application of study treatment.
Approximately 24 mL will be collected for measurement of plasma concentrations of 
KX2-391. 
The actual times of PK sampling will be recorded. 
A description of collection, handling, and shipping procedures for PK samples will be 
provided to the sites. 


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Plasma concentrations of KX2-391 will be analyzed to determine Cmax, and where applicable, 
AUCt, Cmin, and accumulation ratio R. 
Plasma concentrations of study drug will be measured using a validated liquid 
chromatography/tandem mass spectrometry (LC-MS/MS) assay. 
9.5.1.4.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS
Not applicable 
Safety Assessments
Safety assessments will include recording all AEs and serious adverse events (SAEs).
Safety assessments also include laboratory evaluation of hematology, biochemistry, and 
urinalyses; periodic measurement of weight, vital signs, ECGs, and performance of PEs, as 
detailed in the sections below and shown in Table 1 and Table 2. 
Subjects will be queried for spontaneously reported AEs at each study visit, before 
assessment of local skin reactions.  AEs will be reported separately from LSRs. 
Subject-reported LSRs will not be reported as adverse events. Treatments administered for 
LSRs will be recorded on the Concomitant Medications CRF. 
9.5.1.5.1 ADVERSE EVENTS AND OTHER EVENTS OF INTEREST
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is KX2-391 
Ointment 1%.
Treatment-emergent AEs are defined as: 
x
either those AEs with an onset after dosing or  
x
those pre-existing conditions that worsen after dosing 
The criteria for identifying AEs are: 
•
any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product 
•
any new disease or exacerbation of an existing disease  
•
any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation from study drug 


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•
recurrence of an intermittent medical condition (eg, headache) not present at baseline 
All AEs, regardless of relationship to study drug or procedure, should be collected beginning 
from the time the subject signs the study ICF through the final contact in the Follow-up 
Period on Day 57. For subjects participating in the Recurrence Follow-up Period, only AEs 
at the treatment area will be collected. 
Subjects with study drug-related AEs will be followed until resolution, resolved with 
sequelae, or under medical care.  All SAEs must be followed to resolution or, if resolution is 
unlikely, to stabilization. 
All AEs observed during the study will be reported on the CRF/eCRF. 
Laboratory Adverse Events 
A treatment-emergent abnormal laboratory test result should be considered as a treatment-
emergent AE (TEAE) if the identified laboratory abnormality leads to any type of 
intervention whether prescribed in the protocol or not. 
An abnormal laboratory result should be considered by the Investigator to be an AE if it: 
x
results in the withdrawal of study drug 
x
results in withholding of study drug pending some investigational outcome 
x
results in the initiation of an intervention, based on medical evaluation (eg, 
potassium supplement for hypokalemia) 
x
results in any out of range laboratory value that in the Investigator’s judgment 
fulfills the definitions of an AE with regard to the subject’s medical profile
x
increases in severity compared with baseline 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
Investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF/eCRF. 
ECG changes and associated clinical symptoms determined to be clinically significant by the 
Investigator will be reported as AEs.  An ECG abnormality in a subject with symptoms may 
meet the criteria for an AE as described in this protocol.  In these instances, the AE 
corresponding to the symptomatic ECG abnormality will be recorded on the Adverse Events 
CRF/eCRF. 
For symptomatic ECG abnormalities meeting criteria as SAEs, the study site must submit an 
SAE report, including the ECG report to the Sponsor, or designee, using the SAE reporting 
procedures (Section 9.5.3.1).


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Assessing Severity of Adverse Events 
Every effort must be made by the Investigator to categorize each AE according to its severity 
and its relationship to the study treatment.
Adverse events will be graded for severity as follows: 
Mild 
An event that is easily tolerated by the patient, causing minimal discomfort 
and not interfering with everyday activities 
Moderate 
An event that is sufficiently discomforting to interfere with everyday 
activities 
Severe 
An event that prevents normal everyday activities
Investigators will assess severity for all AEs (for both increasing and decreasing severity).  
The criteria for assessing severity are different from those used for seriousness (see 
Section 9.5.1.5.2).
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
x
temporal relationship of the onset of the event to the initiation of the study treatment 
x
the course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
x
whether the event is known to be associated with the study treatment or with other 
similar treatments 
x
the presence of risk factors in the study subject known to increase the occurrence of 
the event 
x
the presence of nonstudy treatment-related factors that are known to be associated 
with the occurrence of the event 
Classification of Causality 
The relationship of each AE to the study drug will be recorded on the CRF/eCRF using the 
following criteria: 
Definitely Related: A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to drug administration, and which cannot be explained by 
concurrent or underlying disease or other drugs or conditions 
Probably Related: A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to concurrent or 
underlying disease or other drugs or conditions  


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Possibly Related: A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, but which could also be explained by concurrent 
or underlying disease or other drugs or conditions 
Unlikely Related: A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship improbable, and in 
which other drugs, conditions or concurrent or underlying disease provide plausible 
explanations 
9.5.1.5.2 
SERIOUS ADVERSE EVENTS AND OTHER EVENTS OF INTEREST
An SAE is any untoward medical occurrence that at any dose: 
•
results in death 
•
is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death) 
•
requires inpatient hospitalization or prolongation of existing hospitalization 
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, other events of interest, which include pregnancy, overdose, and 
significant treatment-emergent laboratory abnormality (See Section 9.5.1.5.1), are to be 
captured using the SAE procedures but are to be considered as SAEs only if they met one of 
the above criteria. All events of these types are to be reported on the CRF/eCRF whether or 
not they meet the criteria for SAEs. 
The following hospitalization is not considered to be an SAE because there is no “AE” (ie, 
there is no untoward medical occurrence) associated with the hospitalization: 
•
hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 


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9.5.1.5.3 LABORATORY MEASUREMENTS
Blood will be collected for clinical laboratory tests at Screening (Visit 1), Day 8 (Visit 7), 
and Day 57 (Visit 10) (Table 1 and Table 2).  Collection of blood and urine (including 
samples for pregnancy testing, where applicable) will be conducted at the clinic site.  
Approximately 20 mL of blood will be collected for clinical laboratory testing, including 
pregnancy testing, when required.  Except for those diagnosed as having diabetes, subjects 
must be fasted for laboratory assessments.  Fasting status must be documented for all 
laboratory samples. 
Microscopic urinalysis will be conducted only when clinically indicated based on dipstick 
results (laboratory protocol) or as determined by the Investigator.  When conducted, 
microscopic urinalysis results will be recorded on the CRF/eCRF. 
The clinical laboratory tests to be measured during the study are provided in Table 5.
Table 5
Clinical Laboratory Tests
Category
Parameters
Hematology
red blood cells (RBC), hemoglobin, hematocrit, platelets, and white 
blood cells (WBC) with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils), mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), RBC distribution width (RDW)
Chemistry
Electrolytes
chloride, potassium, sodium, bicarbonate (HCO3)
Liver function tests
alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), gamma glutamyl transpeptidase (GGT), direct
bilirubin, total bilirubin
Renal function tests
blood urea/blood urea nitrogen, creatinine
Other
Albumin, calcium, cholesterol, glucose, lactate dehydrogenase (LDH),
phosphorus, total protein, triglycerides, uric acid
Urinalysis (dipstick)a
hydrogen ion concentration (pH), specific gravity, protein, glucose, 
ketones, leukocyte esterase, nitrite, bilirubin, urobilinogen, blood
Pregnancy Testing
serum pregnancy test, urine pregnancy test (where applicable)
a
Microscopic urinalysis will be conducted only when clinically indicated based on dipstick results 
(laboratory protocol) or as determined by the Investigator.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1).  In these instances, the AE corresponding to the laboratory 
abnormality will be recorded on the Adverse Event CRF/eCRF. 
For laboratory abnormalities meeting the criteria of SAEs (see Section 9.5.1.5.2), the site 
must electronically transmit the SAE report including the laboratory report to the Sponsor 
using the SAE form (see Section 9.5.3.1).


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9.5.1.5.4 VITAL SIGNS
Vital sign (pulse rate, systolic and diastolic blood pressure, respiratory rate, and body 
temperature) measurements will be taken after the subject has been seated for at least 
5 minutes at Screening (Visit 1), Day 5 (Visit 6) for Cohort 1 or Day 3 (Visit 4) for Cohort 2, 
Day 8 (Visit 7), Day 15 (Visit 8), Day 29 (Visit 9), and Day 57 (Visit 10) (Table 1 and
Table 2).  Serial vital signs may be obtained to confirm accurate readings.  
9.5.1.5.5 PHYSICAL EXAMINATIONS
A complete PE will be performed at Screening (Visit 1) and Day 57 (Visit 10) (Table 1 and
Table 2).
A complete PE will include weight and an assessment of head, eyes, ears, nose, and throat 
(HEENT), integumentary, gastrointestinal, cardiovascular, respiratory, muscular-skeleton, 
and neurological systems. 
Documentation of the PE will be included in the source documentation at the site.  Only 
changes from screening PE findings that meet the definition of an AE will be recorded on the 
Adverse Events CRF/eCRF. 
9.5.1.5.6 ELECTROCARDIOGRAMS
A 12-lead ECG will be completed at Screening (Visit 1), Day 8 (Visit 7), and Day 57
(Visit 10) (Table 1 and Table 2). ECGs may be performed at a convenient time during the 
visit.  Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.  
The ECG data recorded on the CRF/eCRF must include rate, rhythm, intervals, and 
QTc/QTcF. 
ECG changes and associated clinical symptoms determined to be clinically significant by the 
Investigator will be reported as AEs. 
9.5.1.5.7 PREGNANCY TESTING
Serum pregnancy tests will be obtained in females of childbearing potential at Screening 
(Visit 1), Day 8 (Visit 7), and Day 57 (Visit 10) (Table 1 and Table 2).
A urine pregnancy test will be performed on females of childbearing potential before study 
medication application on Day 1 (Visit 2). Visit 1 and Visit 2 test results must be reviewed 
before dosing. 
9.5.1.5.8 OTHER ASSESSMENTS
Concomitant Medications 
Concomitant medications will be assessed at all clinic visits (Table 1 and Table 2).  Any 
medication (including nonprescription medications) or therapy administered to the subject 
during the course of the study (starting at the date of informed consent) will be recorded on 


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the Concomitant Medication CRF/eCRF.  The Investigator will record any AE on the 
Adverse Events CRF/eCRF for which the concomitant medication/therapy was administered. 
Use of sunblock or any topical products in the treatment area allowed by the Investigator will 
be recorded in the Concomitant Medication CRF/eCRF. 
Local Skin Reactions 
At every post-Screening clinic visit through Day 57 (Visit 10), the Investigator or trained 
designee will assess any LSR on the treatment area for signs: 
x
Before study medication application (on dosing days) 
x
After the assessment of adverse events 
The LSR assessment is the Investigator’s (or trained designee’s) assessment of the following 
signs 
on 
the 
treatment 
area: 
 
erythema, 
flaking/scaling, 
crusting, 
swelling, 
vesiculation/pustulation, and erosion/ulceration.  These signs will be assessed using a grading 
scale ranging from 0 (not present) to 4 (worst) (Table 6).
Table 6
Local Skin Reaction Grading Criteria
Grading Criteria
Local Skin 
Response
0
1
2
3
4
Erythema
Not present
Slightly pink 
<50%
Pink or light red 
>50%
Red, restricted to 
treatment area
Red extending 
outside treatment 
area
Flaking / 
Scaling
Not present
Isolated scale, 
specific to lesion
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


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Examples of LSR signs are shown in photographs in Appendix 1.15
Application site reactions not classified as LSRs (eg, pruritus, pain, infection) will be 
reported as adverse events. 
All application site reactions and LSRs will be followed to resolution, or if resolution is 
unlikely, to stabilization. 
Treatment for any LSR or interruption/discontinuation of study treatment for an LSR will be 
recorded on the CRF/eCRF.
LSRs will be reported separately from adverse events.
Pigmentation and Scarring 
Hypo- and hyper- pigmentation and scarring on the treatment area will be assessed by the 
Investigator (or a trained designee) as being present or absent.   
Pigmentation and scarring will be assessed at every post-Screening clinic visit through 
Day 57 (Visit 10) (Table 1 and Table 2).
Standardized Photography 
Standardized photography will be performed at Screening (Visit 1), Day 1 (Visit 2), Day 8 
(Visit 7), Day 57 (Visit 10), and during the Recurrence Follow-up (at 3, 6, 9, and 12 months 
post-Day 57).  Before study medication application on Day 1, the Investigator or a qualified 
staff member must obtain standardized photography of each subject’s treatment area before 
application of study medication. 
Care must be taken to ensure the same lighting, background, subject positioning relative to 
the camera and camera settings are used for each photograph.  Equipment, supplies and 
detailed instructions for obtaining and managing the photographs will be provided to the 
investigational center prior to the initiation of subject enrollment. 
The photographs are to document the appearance of the subjects’ treatment area and to assist 
with the identification and confirmation of the location of the treatment area throughout the 
study (Section 9.1.1).
Equipment, supplies and detailed instructions for obtaining and managing the photographs 
will be provided to the investigational center prior to the initiation of subject enrollment.
9.5.2 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in dermatology studies 
as well as in the routine clinical care of patients with actinic keratosis. 


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9.5.3 
Reporting of Serious Adverse Events, Pregnancy, and Other Events of 
Interest 
 
Reporting of Serious Adverse Events 
All SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by electronic transmission as soon as possible but no later than 
1 business day from the date the Investigator becomes aware of the event.  SAE 
reporting requirements will be provided in the Investigator File.  
All SAEs, regardless of causality assessment, must be collected through the last subject 
contact and followed to resolution or, if resolution is unlikely, to stabilization.  SAEs 
reported to the site from the time of the last subject contact up to 30 days after the last 
contact, will be collected (ie, Day 57 plus 30 days).  During the Recurrence Follow-up 
Period, all AEs, including SAEs in the treatment area will be collected until the last subject 
contact.  These SAEs will be discussed in the clinical study report.  Any SAE event judged 
by the Investigator to be related to the study treatment should be reported to the Sponsor 
regardless of the length of time that has passed since study completion. 
Deaths and life-threatening events should be reported immediately by telephone.  The 
initial report must be submitted within 1 business day by electronically transmitting the 
completed SAE form. 
The detailed contact information for reporting of SAEs will be provided in the Investigator 
File. 
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report. This includes the Investigator’s assessment of causality.  All 
supporting documents should be sent de-identified and should contain the assigned subject 
number.  Only supporting documents directly related to the event should be sent. 
Any follow-up information received on SAEs should be forwarded as soon as possible.  If the 
follow-up information changes the Investigator’s assessment of causality, this should also be 
noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the Sponsor. 
 
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding 
Any pregnancy for which the estimated date of conception was either before the last visit or 
within 30 days of last study treatment must be reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 


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A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same timeframe and in 
the same format as all other SAEs (see Section 9.5.3.1).
Pregnancies must be reported by electronic transmission as soon as possible but no later than 
1 business day from the date the Investigator becomes aware of the pregnancy.  The contact 
information for the reporting of pregnancies is provided in the Investigator File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the Investigator becomes aware of the outcome. 
A subject who becomes pregnant during the Treatment Period must be withdrawn from the 
study. 
Reporting of Other Events of Interest
9.5.3.3.1 REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Study drug overdose is defined as the accidental or intentional use of the drug in an amount 
higher than the dose being studied. 
Any study drug overdose should be noted on the Study Medication CRF/eCRF. 
All AEs associated with overdose, or medication error should be captured on the Adverse 
Event CRF/eCRF and also reported using the procedures detailed in Section 9.5.3.1 even if 
the AEs do not meet serious criteria.  If the AE associated with an overdose or medication 
error does not meet serious criteria, it must still be reported using the SAE form and in an 
expedited manner but should be noted as nonserious on the SAE form and the Adverse Event 
CRF/eCRF. 
Expedited Reporting
The Sponsor (or its designee) must inform Investigators and regulatory authorities of 
reportable events, in compliance with applicable regulatory requirements, on an expedited 
basis (ie, within specific timeframes).  For this reason, it is imperative that sites provide 
complete SAE information in the manner described above. 
In determining what SAEs meet criteria for expedited reporting, the current version of the 
Investigator’s Brochure will be used for reference safety information. 
Breaking the Blind
Not applicable 


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Regulatory Reporting of Adverse Events
Adverse events will be reported by the Sponsor or a third party acting on behalf of the 
Sponsor to regulatory authorities in compliance with local law and established guidance.  The 
format of these reports will be dictated by the local and regional requirements. 
9.5.4 
Completion/Discontinuation of Subjects 
A subject may elect to discontinue from the study at any time for any reason.  See 
Section 9.3.3 for reasons why Investigators may discontinue subjects from the study.  
Investigators must document the actual reason(s) why they decided to discontinue subjects, 
or why subjects withdrew consent, as applicable.  Study disposition information will be 
collected on the Disposition CRF/eCRF. 
Subjects who withdraw from study treatment (with the exception of death or withdrawal of 
consent) will be encouraged to complete the Early Termination assessments at the time of 
withdrawal as indicated in Table 1 and Table 2.  A subject who has ceased to return for visits 
will be followed up by mail, phone, or other means to gather information such as the reason 
for failure to return, the status of treatment compliance, the presence or absence of AEs, and 
clinical courses of signs and symptoms.  This information will be recorded in the CRF/eCRF.  
9.5.5 
Abuse or Diversion of Study Drug 
Not applicable 
9.5.6 
Confirmation of Medical Care by another Physician 
The Investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the Investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the Investigator, with the consent of the subject, will inform the other physician
that the subject is participating in the clinical study. 
9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
may be made periodically by the Sponsor’s or the CRO’s qualified compliance auditing 
team, which is an independent function from the study team responsible for conduct of the 
study. 
9.6.1 
Data Collection 
Data required by the protocol will be documented in the subject source documentation, 
collected on the CRF/eCRFs and entered into a validated data management system that is 
compliant with all regulatory requirements.  A CRF/eCRF or a select CRF/eCRF page may 


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be used as a source document.  CRF/eCRFs used as source documents will be listed in the 
Data Management Plan.  As defined by ICH E6 guidelines (Section 1.11), the CRF is a 
printed, optical, or electronic document designed to record all of the protocol-required 
information to be reported to the Sponsor on each study subject.  In this study, the CRF may 
refer to either a paper (CRF) or electronic data collection form (eCRF), or both. 
Data collected on the CRF/eCRF must be completed following the instructions described in 
the CRF/eCRF Completion Guidelines, which will be based on the Data Management Plan.  
The Investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRF/eCRF.  The PI must sign the CRF/eCRF to 
attest to its accuracy, authenticity, and completeness. 
Completed, original CRFs/eCRFs are the sole property of the Sponsor and should not be 
made available in any form to third parties without written permission from the Sponsor, 
except for authorized representatives of the Sponsor or appropriate regulatory authorities. 
Responsible site personnel will enter the information required by the protocol onto the 
CRF/eCRFs in accordance with the CRF/eCRF Completion Guidelines that are provided.  A 
CRA will visit each site as documented in the monitoring plan to review the CRF/eCRFs for 
completeness and accuracy against the source documents. They will identify any 
discrepancies and ensure that appropriate site personnel address the discrepancies. 
The original CRFs/eCRFs will be maintained at the site in a central document repository. If 
used, a copy of the CRF will be forwarded to the Sponsor. 
At the end of the study an electronic copy of the database along with appropriate system 
version will be archived. 
Uniform procedures will be discussed at the Investigator meetings or at site initiation and/or 
will be documented in the CRF/eCRF Completion Guidelines. 
9.6.2 
Clinical Data Management 
All data, both CRF/eCRF and external data, will be loaded into a clinical system as specified 
in the Data Management Plan. 
Quality control and data validation procedures will be applied to ensure the validity and 
accuracy of the clinical data. 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements. 
9.7 
Statistical Methods 
All statistical analyses will be performed by the Sponsor or designee after the study is 
completed and the database is locked.  Statistical analyses will be performed using Phoenix 
WinNonlin and SAS software or other validated statistical software as required. 


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Statistical analyses will be reported using summary tables, graphs, and data listings. 
Continuous variables will be summarized using the mean, standard deviation (SD), median, 
minimum, and maximum.  Categorical variables will be summarized by counts and by 
percentage of subjects in corresponding categories.  All raw data obtained from the 
CRF/eCRF, as well as any derived data will be included in data listings. 
For all analyses, study Day 1 will be defined as the date of the first dose of study drug. 
9.7.1 
Statistical and Analytical Plans 
 
Study Endpoints 
9.7.1.1.1 PRIMARY ENDPOINTS 
The primary endpoint is activity. 
Activity will be evaluated by reduction in lesion count.  Complete response rate will be 
defined as the proportion of subjects achieving 100% complete clearance of all treated AK 
lesions on the face or scalp at Day 57. 
9.7.1.1.2 SECONDARY ENDPOINTS 
Activity 
Reduction in lesion counts at each visit during Days 1-57 will be assessed as the secondary 
endpoint for activity. 
Safety 
Safety will be evaluated primarily by assessment of AEs and clinical laboratory data.  The 
results of other safety assessments (vital signs, PEs, ECGs) will also be evaluated. 
Pharmacokinetic 
Secondary endpoints include the following PK parameters derived by noncompartmental 
analysis using the plasma concentration-time data of KX2-391:  Cmax, and where applicable, 
AUCt, Cmin, and accumulation ratio R. 
9.7.1.1.3 EXPLORATORY ENDPOINTS 
Exploratory endpoints include recurrence and sustained response rates. 
Recurrence rate will be defined as the proportion of subjects who achieved 100% complete 
clearance at Day 57 (Visit 10) with any identified AK lesions on the treatment area at 3, 6, 9, 
and 12 months post-Day 57. 
Sustained response rate will be defined as the proportion of subjects who achieved 100% 
complete clearance at Day 57 (Visit 10) without any identified AK lesions on the treatment 
area at 12 months post-Day 57. 


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Definitions of Analysis Sets
The Per-Protocol Set is the group of protocol-eligible subjects who receive 5 days (Cohort 1) 
or 3 days (Cohort 2) of study treatment and complete at least one scheduled post-treatment 
evaluation.  
The Evaluable Set is the group of subjects who receive 5 days (Cohort 1) or 3 days 
(Cohort 2) of treatment and complete most evaluations including the Day 57 Follow-up Visit. 
The Safety Analysis/Full Analysis Set is the group of subjects who receive at least one dose 
of study treatment. 
The PK Analysis Set is the group of subjects who receive study treatment and complete at 
least one scheduled post-treatment PK evaluation. 
Subject Disposition
All subjects will be tabulated by cohort as to study discontinuation and the reasons for 
discontinuation as described in Section 9.3.3.
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized by cohort.  For continuous 
demographic variables, results will be summarized by cohort as well, and presented as N, 
mean, SD, median, and minimum and maximum values.  For categorical (nominal or ordinal) 
variables, the number and percentage of subjects will be used in each cohort.  No statistical 
testing will be performed. 
Prior and Concomitant Therapy
All Investigator terms for medications recorded in the CRF/eCRF will be coded to an 
11-digit code using the World Health Organization Drug Dictionary drug codes. 
Prior medications will be defined as medications that stopped before the first dose of study 
drug. 
Concomitant medications will be defined as medications that (1) started before the first dose 
of study drug and were continuing at the time of the first dose of study drug, or (2) started on 
or after the date of the first dose of study drug.  Prior and concomitant medications will be 
further coded to the appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating 
therapeutic classification.  A listing of prior and concomitant medications by drug and drug 
class will be included in the clinical study report for this protocol. 
All medications will be presented by cohort in subject data listings. 


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Activity Analyses 
AK lesion counts will be summarized by cohort at Day 1 (pretreatment) and at each 
subsequent timepoint for subjects in the Full Analysis Set and the Per-Protocol Set. 
A 95% confidence interval (CI) for the complete clearance (response rate) at Day 57 will be 
estimated by cohort in the Evaluable Set. 
Recurrence rates for all subjects who achieved complete clearance at Day 57 will be 
estimated by timepoint and cohort in the Evaluable Set. 
A 95% CI for the sustained response rate at 12 months post-Day 57 will be estimated by 
cohort in the Evaluable Set. 
Both cohorts will be analyzed with the same statistical methods.  Since this is not a dose 
regimen randomized study, any contrast between the 2 cohorts will mainly be noninferential 
and consist of listings, graphs, and descriptive statistics. 
 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
9.7.1.7.1 PHARMACOKINETIC ANALYSES 
PK analyses will be performed on the PK Analysis Set. 
Plasma concentrations of KX2-391 will be analyzed to determine Cmax, and where applicable, 
AUCt, Cmin, and accumulation ratio R. 
Individual timepoints will be tabulated and displayed graphically and listed for all subjects.  
Summary PK parameters will be analyzed as applicable. 
9.7.1.7.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
Not applicable 
 
Safety Analyses 
All subjects in the Safety Analysis Set will be included in the safety analyses. 
Safety data will be summarized by cohort using descriptive statistics (eg, n, mean, SD, 
median, minimum, maximum for continuous variables; n [%] for categorical variables).  
Safety variables include AEs, clinical laboratory parameters, weight, vital signs, 12-lead 
ECG results, and physical examination findings. 
Similar to the activity analyses, any contrast between the 2 cohorts will mainly be 
noninferential in the safety analyses. 


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9.7.1.8.1 EXTENT OF EXPOSURE 
The actual number of doses for each subject will be summarized by cohort. 
9.7.1.8.2 ADVERSE EVENTS 
For AEs, verbatim terms on the CRFs/eCRFs will be mapped to preferred terms (PTs) and 
system organ classes (SOCs) using the Medical Dictionary for Regulatory Activities 
(MedDRA; version 16.0 or higher).  Subject incidence of AEs will be displayed by SOC.  
The incidence of AEs will be summarized by cohort.  Adverse events will also be 
summarized by severity, relationship to study drug, and cohort.  Subject incidence of SAEs 
will also be displayed by cohort. 
Only those AEs that were treatment-emergent will be included in summary tables.  
Treatment-emergent AEs are defined as: 
x either those AEs with an onset after dosing or  
x those pre-existing AEs that worsen after dosing 
All AEs, treatment emergent or otherwise, will be presented in subject data listings. 
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC, PT, and cohort.  A subject data listing of all AEs leading to death will be 
provided. 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC, PT, and cohort.  A subject data listing of all AEs 
leading to discontinuation from study drug will be provided. 
9.7.1.8.3 LABORATORY VALUES 
Laboratory parameters will be summarized using descriptive statistics at baseline and at each 
subsequent timepoint by cohort.  Changes from baseline will also be summarized by cohort. 
In addition, shift tables (ie, low-normal-high at baseline versus low-normal-high at follow-up 
in a 3-by-3 contingency table) will be provided to assess changes in laboratory values from 
baseline to follow-up in each cohort. 
9.7.1.8.4 VITAL SIGNS 
Vital sign values will be evaluated by cohort on an individual basis by subject.  Abnormal 
vital sign values will be identified as those outside (above or below) the reference range. 
9.7.1.8.5 ELECTROCARDIOGRAMS 
ECG data will be tabulated by cohort for each individual subject. 


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9.7.1.8.6 PHYSICAL EXAMINATIONS 
Physical examination findings will be listed by cohort for each subject. 
9.7.1.8.7 PREGNANCY TESTS 
Results of pregnancy tests will be listed by cohort for all subjects, as applicable. 
9.7.1.8.8 OTHER ANALYSES 
Local Skin Reactions 
Local skin reactions as reported by the Investigator will be displayed and summarized by 
visit and cohort for all subjects. 
Pigmentation and Scarring 
Pigmentation and scarring as reported by the Investigator will be displayed and summarized 
by visit and cohort for all subjects. 
9.7.2 
Determination of Sample Size 
For either cohort, a sample size of 60 subjects is sufficient to detect a 100% complete 
clearance rate at Day 57 greater than 20% with 80% power, based on a two-sided 
(alpha=0.05) binomial test, assuming a response rate of 35%, and less than a 25% dropout 
rate.  This corresponds to a two-sided 95% CI with a half-width of less than 15% (ie, lower 
boundary of the CI above 20%). 
The sample size of Cohort 2 may be adjusted, depending on the results of Cohort 1. 
9.7.3 
Interim Analysis 
 A formal interim analysis is not planned. Since this is an open-label study, after each group 
of approximately 20 subjects, ongoing analyses will be performed with tabulation of activity, 
LSRs, and adverse events.  The decision to open Cohort 2 will be documented. 
9.7.4 
Other Statistical/Analytical Issues 
Not applicable 
9.7.5 
Procedure for Revising the Statistical Analysis Plan 
If the prespecified plans need to be revised after the study starts, the Sponsor will determine 
how the revision impacts the study and how the revision should be implemented.  The details 
of the revision will be documented and described in the clinical study report. 


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10 REFERENCE LIST 
1. ICH E6: Guidance for Industry - E6 Good Clinical Practice: Consolidated Guidance,
US Department of Health and Human Services, Food and Drug Administration, April 
1996.
2. Marks R, Rennie G, Selwood TS.  Malignant transformation of solar keratoses to 
squamous cell carcinoma.  Lancet 1988;1(8589):795-7.
3. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: natural history 
and risk of malignant transformation in the Veterans Affairs Topical Tretinoin 
Chemoprevention Trial. Cancer 2009;115(11):2523-30.
4. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol 
2000;42(1 Pt 2):23-4.
5. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am 
Acad Dermatol 2000;42(1 Pt 2):4-7.
6. Guidelines for the Management of Actinic Keratoses.  2004/2005 European 
Dermatology Forum.  Available from: http://www.euroderm.org [Accessed 02 July 
2012]. 
7. Drake LA, Ceilley RI, Cornelison RL, et al. Guidelines of care for actinic keratoses. 
Committee on Guidelines of Care. J Am Acad Dermatol 1995;32(1):95-8. 
8. Suchniak JM, Baer S, Goldberg LH. High rate of malignant transformation in 
hyperkeratotic actinic keratoses. J Am Acad Dermatol 1997;37(3 Pt 1):392-4.
9. Ehrig T, Cockerell C, Piacquadio D, et al. Actinic keratoses and the incidence of 
occult squamous cell carcinoma: a clinical-histopathologic correlation. Dermatol Surg
2006;32(10):1261-5.
10. Berman B, Bienstock L, Kuritzky L, et al. Primary Care Education Consortium; 
Texas Academy of Family Physicians. Actinic keratoses: sequelae and treatments. 
Recommendations from a consensus panel.  J Fam Pract 2006;55(5 Suppl):1-8.
11. Quaedvlieg PJ, Tirsi E, Thissen MR, et al. Actinic keratosis: how to differentiate the 
good from the bad ones? Eur J Dermatol 2006;16(4):335-9.
12. Marks R, Foley P, Goodman G, et al.  Spontaneous remission of solar keratoses:  the 
case for conservative management. Br J Dermatol 1986;115(6):649-55.
13. Food and Drug Administration Draft Guidance on Ingenol Mebutate; Recommended 
Jan 2016. 


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14. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through IV. 
Arch Dermatol 1998;124(6):869-71. 
15. Rosen R, Marmur E, Anderson L, et al. A new, objective, quantitative scale for 
measuring local skin responses following topical actinic keratosis therapy with 
ingenol mebutate. Dermatol Ther (Heidelb) 2014;4:207-19. 


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11 APPENDICES 
 


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Appendix 1 
Photographs of Local Skin Reactions 
 
 
Source:  Rosen R, Marmur E, Anderson L, et al. A new, objective, quantitative scale for measuring local skin 
responses following topical actinic keratosis therapy with ingenol mebutate. Dermatol Ther (Heidelb) 
2014;4:207-19. 
 


PPD
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CONFIDENTIAL 
 
INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
KX01-AK-002 
Study Protocol Title: 
A Phase 2a, Open-Label, Multicenter, Activity and Safety Study of 
KX2-391 Ointment 1% in Subjects with Actinic Keratosis on the Face 
or Scalp 
Investigational Product 
Name: 
KX2-391 Ointment 1% 
UTN Number: 
U1111-1173-5677 
 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
 
 
 
<Name, degree(s)> 
 
 
 
 
Investigator 
 
Signature 
 
Date 
<Name of study site> 
 
 
 
 
Study Site  
 
 
 
 
 
 


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1 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
Study Protocol 
Number: 
KX01-AK-002 
Study Protocol Title: 
A Phase 2a, Open-Label, Multicenter, Activity and Safety Study of 
KX2-391 Ointment 1% in Subjects with Actinic Keratosis on the Face or 
Scalp 
Sponsor: 
United States: 
Kinex Pharmaceuticals, Inc. 
20 Commerce Drive 
Cranford, New Jersey 07016, US 
Tel:  +1 908-272-0628 
Investigational 
Product Name: 
KX2-391 Ointment 1% 
Indication: 
Actinic keratosis on the face or scalp 
Phase: 
2a 
Approval Date:  
v1.0 
23 Jan 2016 (original protocol) 
UTN Number: 
U1111-1173-5677 
GCP Statement: 
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information of Kinex 
Pharmaceuticals, Inc. (the Sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly 
prohibited.  Such information may be used solely for the purpose of 
reviewing or performing this study. 


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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No. 
KX2-391 
Name of Active Ingredient: 
N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl) acetamide 
Study Protocol Title 
A Phase 2a, Open-Label, Multicenter, Activity and Safety Study of KX2-391 Ointment 1% in Subjects 
with Actinic Keratosis on the Face or Scalp 
Investigators 
, MD, Lead Principal Investigator 
Sites 
Approximately 4 to 6 sites in the United States 
Study Period and Phase of Development 
First subject in to last subject out, approximately 18 months 
Phase 2a 
Objectives 
Primary Objective: 
• To evaluate the activity of KX2-391 Ointment 1% administered topically to the face or scalp in 
subjects with actinic keratosis (AK) by determining complete response rate, defined as 100% 
clearance at Day 57 
Secondary Objectives:  
• To assess the activity of KX2-391 Ointment 1% during Days 1-57 
• To assess the safety and tolerability of KX2-391 Ointment 1% in subjects with AK on the face or 
scalp 
• To assess the pharmacokinetics (PK) of KX2-391 Ointment 1% in subjects with AK on the face or 
scalp 
Exploratory Objective: 
• To determine recurrence rates to 12 months post-Day 57 for subjects who show response at Day 57 
Study Design 
This study will be an open-label, multicenter, activity, safety, tolerability, and PK study of KX2-391 
Ointment 1% administered topically to the face or scalp of subjects with actinic keratosis. 
The study consists of Screening, Treatment, and Follow-up Periods. 
Eligible subjects will receive 5 consecutive days of topical treatment, to be applied at the study site, with 
50 mg of KX2-391 Ointment 1% each day.  Blood samples for PK analysis will be collected on Day 1 
and Day 5.  Subjects will return for Follow-up visits until Day 57.  Thereafter, only Day 57 complete 
responders will continue Recurrence Follow-up Visits every 3 months for an additional 12 months after 
Day 57.  Activity (lesion counts) and safety evaluations will be performed. 
Number of Subjects 
Approximately 80 subjects will be enrolled to provide approximately 60 subjects in the Evaluable Set, 
PPD


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defined as subjects who complete 5 days of treatment and the Day 57 Follow-up visit. 
Inclusion Criteria 
Eligible subjects must have/be: 
1. Males and females ≥18 years old 
2. Clinical diagnosis of stable, clinically typical actinic keratosis 
3. A treatment area on the face or scalp that: 
x 
is a continuous area measuring 25 cm2 
x 
contains 4 to 8 AK lesions 
4. Females must be postmenopausal (>50 years of age with at least 18 months of amenorrhea), 
surgically sterile (by hysterectomy, bilateral oophorectomy or tubal ligation) or otherwise incapable 
of pregnancy for at least 1 year; or, if of childbearing potential, must be using highly effective 
contraception for at least 90 days prior to treatment with KX2-391 Ointment 1% and must agree to 
continue to use highly effective contraception for at least 90 days following their last dose of 
KX2-391 Ointment 1%.  Highly effective contraception includes oral hormonal contraceptives, 
hormonal contraceptive implant or patch, or intrauterine device).  Abstinence and double barrier 
methods do not qualify as highly effective methods of contraception. 
5. Males who have not had a vasectomy must agree to use barrier contraception from Screening through 
90 days after their last dose of KX2-391 Ointment 1%. 
6. All subjects must agree not to donate sperm or eggs or attempt conception from Screening through 
90 days following their last dose of KX2-391 Ointment 1%. 
7. Females of childbearing potential must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on Day 1 prior to administration of study treatment. 
8. Subjects who in the judgment of the Investigator, are in good general health based on: 
x 
medical history 
x 
no physical examination (PE) findings that Principal Investigator (PI) determines would interfere 
with interpretation of study results 
x 
screening electrocardiogram (ECG) without clinically significant abnormalities  
x 
clinical chemistry, hematology, and urinalysis results that are within the reference ranges; clinical 
laboratory values outside the reference ranges that are considered by the PI to be clinically 
insignificant are also acceptable 
9. Willing to avoid excessive sun exposure 
10. Able to comprehend and are willing to sign an informed consent form (ICF) 
Exclusion Criteria 
Eligible subjects must not have/be: 
1. Clinically atypical and/or rapidly changing AK lesions on the treatment area 
2. Malignancy within 5 years prior to Screening except basal or squamous cell carcinoma not on the 
treatment area that were treated with curative intent and are without recurrence 
3. Used any of the following systemic therapies within the specified period before Visit 1: 
x 
retinoids; 90 days 
x 
glucocorticosteroids; 28 days (intra-articular and inhaled steroids are allowed) 
x 
methotrexate or other anti-metabolites; 28 days 


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4. Used any of the following topical therapies on the treatment area within the specified period before 
Visit 1: 
x 
retinoids; 90 days 
x 
glucocorticosteroids; 14 days 
x 
analgesic and/or anti-inflammatory medication on the face or scalp; 72 hours 
x 
moisturizers or emollients on the face or scalp; 12 hours 
5. Had any of the following on the treatment area within 90 days (or until the site has healed, whichever 
is longer) before Visit 1: 
x 
ingenol mebutate (eg, Picato) 
x 
5-fluorouracil (eg, 5-FU; Efudex) 
x 
imiquimod (eg, Aldara; Zyclara) 
x 
diclofenac with or without hyaluronic acid (eg, Solaraze) 
6. Surgical or destructive modalities on the treatment area within 30 days (or until the site has healed 
following treatment, whichever is longer) before Visit 1: 
x 
cryotherapy 
x 
electrodesiccation 
x 
laser, light (eg, photodynamic therapy, intense pulsed light) or any other energy-based therapy 
x 
chemical peels (eg, tricholoracetic acid) 
x 
dermabrasion 
x 
surgical removal (eg, curettage, excision) 
7. Currently, or has experienced any of the following on the treatment area within the specified period 
before Visit 1: 
x 
cutaneous malignancy; 180 days 
x 
sunburn; 28 days 
x 
body art (eg, tattoo, piercing); currently 
8. A history of sensitivity and/or allergy to any of the ingredients in the study medication 
9. A skin disease (eg, atopic dermatitis, psoriasis, eczema) or condition (eg, scarring, open wounds) that, 
in the opinion of the Investigator, might interfere with the study conduct or evaluations, or which 
exposes the subject to an unacceptable risk by study participation 
10. Other significant uncontrolled or unstable medical diseases or conditions that, in the opinion of the 
Investigator, would expose the subject to unacceptable risk by study participation 
11. Females who are pregnant or nursing 
12. Participated in an investigational drug trial during which an investigational study medication was 
administered within 14 days or 5 half-lives of the investigational product, whichever is longer, before 
Screening 
Study Treatment 
50 mg of KX2-391 Ointment 1% will be applied topically once daily to the 25 cm2 treatment area 
(2 mg/cm2; 0.5 mg KX2-391 total). 
KX2-391 Ointment 1% will be applied once daily for 5 consecutive days. 
Duration of Participation and Treatment 
• Planned enrollment period:  approximately 3 months (90 days) 


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• Planned subject participation is approximately 64 weeks:  
o Screening Period:  up to 28 days 
o Treatment Period:  5 consecutive treatment days (Days 1-5) 
o Follow-up Period:  Visits at Days 8, 15, 29, and 57 
o Recurrence Follow-up Period:  only for complete responders at Day 57, visits every 3 months for 
12 months after Day 57 (ie, at 3, 6, 9, and 12 months post-Day 57). 
Length of stay:  On Day 1 (Visit 2) and Day 5 (Visit 6), subjects will stay for approximately 5 hours at the 
investigational center until after the last PK blood sample is collected. 
Concomitant Drug/Therapy 
Use of any non-study drug treatment for AK lesions on the face or scalp is prohibited during the study.  
During the Recurrence Follow-up Period, isolated lesion treatment such as cryotherapy or biopsy is 
allowed for treatment of AK lesions emerging in the selected treatment area.  Any treated lesion will be 
considered as a recurrence. 
Assessments 
Activity Assessments 
The Investigator will perform a count of AK lesions for all subjects at Visits 1 and 2, Visits 7 through 10, and 
for Day 57 complete responders, also at Visits 11 through 14. 
Safety Assessments 
Safety will be assessed by recording all adverse events (AEs), serious adverse events (SAEs), laboratory 
evaluation of hematology, biochemistry, and urinalysis values, measurement of weight and vital signs, 
evaluation of ECGs, and the performance of physical examinations. 
Subjects will be queried for spontaneously reported AEs at each study visit, before assessment of local 
skin reactions (LSRs).  AEs will be reported separately from LSRs. 
Subject-reported LSRs will not be reported as adverse events.  
Other Assessments 
The LSR assessment is the Investigator’s (or trained designee’s) assessment of the following signs on the 
treatment area:  erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration.  
These 
signs 
will 
be 
assessed 
using 
a 
grading 
scale 
ranging 
from 
0 
(not 
present)  
to 4 (worst).  In addition to LSRs, hypo- and hyper- pigmentation and scarring on the treatment area will 
be assessed as being present or absent.  Application site reactions not classified as LSRs (eg, pruritus, 
pain, infection) will be reported as adverse events.  All application site reactions and LSRs will be 
followed to resolution, or if resolution is unlikely, to stabilization.  LSRs will be reported separately from 
AEs. 
Standardized photography will be performed at Screening (Visit 1), Day 1 (Visit 2), Day 8 (Visit 7), 
Day 57 (Visit 10), and during the Recurrence Follow-up (at 3, 6, 9, and 12 months post-Day 57).  Before 
study medication application on Day 1, the Investigator or a qualified staff member must obtain 
standardized photography of each subject’s treatment area before application of study medication. 
Pharmacokinetic Assessments 
PK samples will be collected at the following timepoints: 
• Day 1:  predose, 0.5 (±5 minutes), 1 and 4 hours (±10 minutes) postdose  
• Day 5:  predose, 0.5 (±5 minutes), 1 and 4 hours (±10 minutes) postdose 
 


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Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments 
Not applicable 
Bioanalytical Methods 
Plasma concentrations of study drug will be measured using a validated liquid chromatography/tandem 
mass spectrometry (LC-MS/MS) assay. 
Statistical Methods 
Study Endpoints 
Primary Endpoint 
x Activity will be evaluated by reduction in lesion count.  Complete response rate will be defined as 
the proportion of subjects achieving 100% complete clearance of all treated AK lesions on the face 
or scalp at Day 57.  Sustained response will be defined as the proportion of subjects achieving 100% 
(complete) clearance at Day 57 without any identified AK lesions on the treatment area at 12 months 
post-Day 57. 
Secondary Endpoints 
• Activity:  Reduction in lesion counts during Days 1-57 
• Safety:  Evaluation of AEs and clinical laboratory data; the results of other safety assessments (vital 
signs, physical examinations, ECGs) will also be evaluated. 
• Pharmacokinetic:  Determination of Cmax,  and where applicable, AUCt, Cmin, and accumulation  
ratio R 
Exploratory Endpoint 
• Recurrence rate will be defined as the proportion of subjects who achieved 100% complete clearance 
at Day 57 (Visit 10) with any identified AK lesions on the face or scalp at 3, 6, 9, and 12 months 
post-Day 57. 
Analysis Sets 
• Per-Protocol Set:  the group of protocol-eligible subjects who receive 5 days of study treatment and 
complete at least one scheduled post-treatment evaluation. 
• Evaluable Set:  the group of subjects who receive 5 days of treatment and complete most evaluations 
including the Day 57 Follow-up Visit. 
• Safety Analysis/Full Analysis Set:  the group of subjects who receive at least one dose of study 
treatment. 
• PK Analysis Set: the group of subjects who receive study treatment and complete at least one 
scheduled post-treatment PK evaluation. 
Activity Analyses 
AK lesion counts will be summarized at Day 1 (pretreatment) and at each subsequent timepoint for 
subjects in the Full Analysis Set and the Per-Protocol Set. 
A 95% confidence interval (CI) for the complete clearance (response rate) at Day 57 and 12 months 
post-Day 57 will be estimated in the Evaluable Set. 
Recurrence rates for all subjects who achieved complete clearance at Day 57 will be summarized by 
timepoint in the Evaluable Set. 


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Safety Analyses 
All subjects who receive at least one dose of KX2-391 Ointment 1% will be included in the safety 
analyses.  Treatment-emergent AEs (TEAEs) are defined as either those AEs with an onset after dosing or 
those pre-existing AEs that worsen after dosing.  For AEs, verbatim terms on the case report 
form/electronic case report form (CRF/eCRF) will be mapped to preferred terms (PTs) and system organ 
classes (SOCs) using the Medical Dictionary for Regulatory Activities (MedDRA; v 16.0 or higher).  
Subject incidence of AEs will be displayed by SOC.  Adverse events will also be summarized by severity 
and relationship to study drug.  Subject incidence of SAEs will also be displayed.  Laboratory parameters 
will be summarized using descriptive statistics at baseline and at each subsequent timepoint.  Changes 
from baseline will also be summarized.  In addition, shift tables (ie, low-normal-high at baseline versus 
low-normal-high at follow-up in a 3-by-3 contingency table) will be provided to assess changes in 
laboratory values from baseline to follow-up. 
Local skin reactions, pigmentation, and scarring as reported by the Investigator, will be displayed and 
summarized by visit for all subjects. 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Pharmacokinetic Analyses 
Plasma concentrations for KX2-391 will be analyzed to determine applicable PK parameters. 
Individual timepoints will be tabulated and displayed graphically and listed for all subjects.  Summary PK 
parameters will be analyzed as applicable. 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Not applicable 
Interim Analysis 
Since this is an open-label study, after each group of approximately 20 subjects completes Day 57 
assessments, activity data will be tabulated. 
Statistical Methods 
Statistical analyses will be reported using summary tables, graphs, and data listings. Continuous variables 
will be summarized using the mean, standard deviation (SD), median, minimum, and maximum.  
Categorical variables will be summarized by counts and by percentage of subjects in corresponding 
categories.  All raw data obtained from the CRF/eCRF, as well as any derived data will be included in 
data listings. 
Sample Size Rationale 
A sample size of 60 subjects is sufficient to detect a 100% complete clearance rate at Day 57 greater than 
20% with 80% power, based on a two-sided (alpha=0.05) binomial test, assuming a response rate of 35%, 
and less than a 25% dropout rate.  This corresponds to a two-sided 95% CI with a half-width of less than 
15% (ie, lower boundary of the CI above 20%). 
FINAL  
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Table 1 
Schedule of Procedures/Assessments in Study KX01-AK-002 
Period 
Screening 
Treatment 
Follow-up 
Recurrence Follow-up a 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 b/ 
Early 
Term  
11, 12, 13, 14 a 
Day 
-28 to -1 
1 
2 
3 
4 
5 
8 
15 
29 
57b 
3, 6, 9, 12 Months Post-Day 57c 
Visit time window (days) 
None 
None 
None 
None 
None 
None 
±2 
±2 
±2 
±2 
±14 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion & exclusion criteria 
X 
Xd 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
AK history/AK treatment history 
X 
 
 
 
 
 
 
 
 
 
 
Fitzpatrick skin-type scale 
X 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
Prior and concomitant 
medications/therapies 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination, including weightf 
X 
 
 
 
 
 
 
 
 
X 
 
Treatment area identification 
X 
Xd 
 
 
 
 
 
 
 
  
 
AK lesion count 
X 
Xd 
 
 
 
 
X 
X 
X 
X 
X 
ECGg 
X 
 
 
 
 
 
X 
 
 
X 
 
Clinical chemistry, hematology, and 
urinalysish 
X 
 
 
 
 
 
X 
 
 
X 
 
Pregnancy test  
X 
Xd,i 
 
 
 
 
X 
 
 
X 
 
PK blood samples 
 
Xj 
 
 
 
Xj 
 
 
 
 
 
Study medication application 
 
X 
X 
X 
X 
X 
 
 
 
 
 
AEsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
LSRs 
 
Xd 
Xd 
Xd 
Xd 
Xd 
X 
X 
X 
X 
 
Pigmentation and scarring 
 
Xd 
Xd 
Xd 
Xd 
Xd 
X 
X 
X 
X 
 
Standardized photography 
X 
Xd 
 
 
 
 
X 
 
 
X 
X 


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Table 1 
Schedule of Procedures/Assessments in Study KX01-AK-002 
AE = adverse event; AK = actinic keratosis; ECG = electrocardiogram; HEENT = head, eyes, ears, nose, and throat; LSR = local skin reaction; PK = pharmacokinetic; Term = 
Termination. 
a 
For Day 57 complete responders only. 
b 
For subjects who do not have complete response at Day 57, Day 57 is the Final Visit. 
c 
For subjects who have complete response at Day 57, 12 months post-Day 57 is the Final Visit. 
d 
Assessment performed before study medication application.  Day 1 evaluation will serve as baseline for these assessments. 
e 
Vital signs measurements will be taken after the subject has been seated for at least 5 minutes. 
f 
A complete PE will include weight and an assessment of HEENT, integumentary, gastrointestinal, cardiovascular, respiratory, muscular- skeleton, and neurological systems. 
g 
Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG. 
h 
Except for those diagnosed as having diabetes, subjects must be fasted for laboratory assessments. 
i 
For females of childbearing potential; urine pregnancy test on Day 1 before study medication application.  All other pregnancy tests are performed with serum. 
j 
PK assessments on Day 1 and Day 5 at 0 hour (just before study medication application) and at 0.5 (±5 min), 1, and 4 hours (±10 min) after study drug application.  
k 
Before LSR assessment, subjects will be queried for spontaneously reported AEs. 
l 
Only AEs in the selected treatment area will be recorded. 


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TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................2 
3 
TABLE OF CONTENTS .................................................................................................10 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................14 
5 
ETHICS............................................................................................................................15 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................15 
5.2 
Ethical Conduct of the Study .................................................................................15 
5.3 
Subject Information and Informed Consent ...........................................................16 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................16 
7 
INTRODUCTION ...........................................................................................................16 
7.1 
Indication ...............................................................................................................16 
7.1.1 
Mechanism of Action ...................................................................................17 
7.1.2 
Clinical Experience with KX2-391 ..............................................................17 
7.2 
Study Rationale ......................................................................................................18 
8 
STUDY OBJECTIVES ....................................................................................................18 
8.1 
Primary Objective ..................................................................................................18 
8.2 
Secondary Objectives.............................................................................................18 
8.3 
Exploratory Objective ............................................................................................19 
9 
INVESTIGATIONAL PLAN ..........................................................................................19 
9.1 
Overall Study Design and Plan ..............................................................................19 
9.1.1 
Screening Period ..........................................................................................19 
9.1.2 
Treatment Period ..........................................................................................20 
9.1.3 
Follow-up Period .........................................................................................21 
9.1.4 
Recurrence Follow-up Period ......................................................................21 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................21 
9.3 
Selection of Study Population ................................................................................21 
9.3.1 
Inclusion Criteria .........................................................................................21 
9.3.2 
Exclusion Criteria ........................................................................................22 
9.3.3 
Removal of Subjects from Therapy or Assessment .....................................23 
9.4 
Treatments..............................................................................................................24 
9.4.1 
Treatment Administered ..............................................................................24 
9.4.2 
Identity of Investigational Products .............................................................24 
Chemical Name and Structural Formula of KX2-391 .........................24 
Labeling for Study Drug ......................................................................25 
Storage Conditions ...............................................................................25 
Administration of Investigational Products .........................................26 


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9.4.3 
Method of Assigning Subjects to Treatment Groups ...................................26 
9.4.4 
Selection of Doses in the Study ...................................................................26 
9.4.5 
Selection and Timing of Dose for Each Subject ..........................................27 
9.4.6 
Blinding........................................................................................................27 
9.4.7 
Prior and Concomitant Therapy ...................................................................27 
Prior Therapy .......................................................................................27 
Concomitant Medication/Therapy .......................................................27 
Prohibited Medication/Therapy ...........................................................27 
9.4.8 
Prohibitions and Restrictions during Study Period ......................................29 
9.4.9 
Treatment Compliance .................................................................................29 
9.4.10 
Drug Supplies and Accountability ...............................................................29 
9.5 
Study Assessments .................................................................................................30 
9.5.1 
Assessments .................................................................................................30 
Demography .........................................................................................30 
Baseline Assessments ..........................................................................30 
9.5.1.2.1 
Medical/Surgical and Actinic Keratosis History ...........................30 
9.5.1.2.2 
Fitzpatrick Skin-Type Classification .............................................30 
9.5.1.2.3 
Prior Medications ...........................................................................31 
Activity Assessments ...........................................................................31 
9.5.1.3.1 
Actinic Keratosis Lesion Count .....................................................31 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments .............................................................31 
9.5.1.4.1 
Pharmacokinetic Assessments .......................................................31 
9.5.1.4.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments ...................................................................................32 
Safety Assessments ..............................................................................32 
9.5.1.5.1 
Adverse Events and Other Events of Interest ................................32 
9.5.1.5.2 
Serious Adverse Events and Other Events of Interest ...................35 
9.5.1.5.3 
Laboratory Measurements .............................................................36 
9.5.1.5.4 
Vital Signs ......................................................................................37 
9.5.1.5.5 
Physical Examinations ...................................................................37 
9.5.1.5.6 
Electrocardiograms ........................................................................37 
9.5.1.5.7 
Pregnancy Testing ..........................................................................37 
9.5.1.5.8 
Other Assessments .........................................................................37 
9.5.2 
Appropriateness of Measurements ...............................................................39 
9.5.3 
Reporting of Serious Adverse Events, Pregnancy, and Other Events of 
Interest..........................................................................................................39 
Reporting of Serious Adverse Events ..................................................39 


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Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding .......................................................................................40 
Reporting of Other Events of Interest ..................................................41 
9.5.3.3.1 
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................41 
Expedited Reporting ............................................................................41 
Breaking the Blind ...............................................................................41 
Regulatory Reporting of Adverse Events ............................................41 
9.5.4 
Completion/Discontinuation of Subjects .....................................................41 
9.5.5 
Abuse or Diversion of Study Drug ..............................................................42 
9.5.6 
Confirmation of Medical Care by another Physician ..................................42 
9.6 
Data Quality Assurance .........................................................................................42 
9.6.1 
Data Collection ............................................................................................42 
9.6.2 
Clinical Data Management ..........................................................................43 
9.7 
Statistical Methods .................................................................................................43 
9.7.1 
Statistical and Analytical Plans ....................................................................44 
Study Endpoints ...................................................................................44 
9.7.1.1.1 
Primary Endpoints .........................................................................44 
9.7.1.1.2 
Secondary Endpoints .....................................................................44 
9.7.1.1.3 
Exploratory Endpoints ...................................................................44 
Definitions of Analysis Sets.................................................................44 
Subject Disposition ..............................................................................45 
Demographic and Other Baseline Characteristics ...............................45 
Prior and Concomitant Therapy ...........................................................45 
Activity Analyses .................................................................................45 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...................................................................46 
9.7.1.7.1 
Pharmacokinetic Analyses .............................................................46 
9.7.1.7.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .........................................................................................46 
Safety Analyses ....................................................................................46 
9.7.1.8.1 
Extent of Exposure .........................................................................46 
9.7.1.8.2 
Adverse Events ..............................................................................46 
9.7.1.8.3 
Laboratory Values ..........................................................................47 
9.7.1.8.4 
Vital Signs ......................................................................................47 
9.7.1.8.5 
Electrocardiograms ........................................................................47 
9.7.1.8.6 
Physical Examinations ...................................................................47 
9.7.1.8.7 
Pregnancy Tests .............................................................................47 


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9.7.1.8.8 
Other Analyses ...............................................................................47 
9.7.2 
Determination of Sample Size .....................................................................47 
9.7.3 
Interim Analysis ...........................................................................................48 
9.7.4 
Other Statistical/Analytical Issues ...............................................................48 
9.7.5 
Procedure for Revising the Statistical Analysis Plan ...................................48 
10 REFERENCE LIST .........................................................................................................49 
11 APPENDICES .................................................................................................................50 
LIST OF IN-TEXT TABLES 
Table 1 
Schedule of Procedures/Assessments in Study KX01-AK-002...................8 
Table 2 
Treatment Administered in KX01-AK-002 ...............................................24 
Table 3 
Blood Sample Collection Times for Pharmacokinetic Analyses ...............31 
Table 4 
Clinical Laboratory Tests ...........................................................................36 
Table 5 
Local Skin Reaction Grading Criteria ........................................................38 
LIST OF APPENDICES 
Appendix 1 
Fitzpatrick Skin-Type Classification .........................................................51 
Appendix 2 
Photographs of Local Skin Reactions ........................................................52 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Terms 
AE 
adverse event 
AK 
actinic keratosis 
AUC 
area under the plasma concentration-time curve  
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
Cmin 
minimum (trough) plasma concentration 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LC-MS/MS 
liquid chromatography/tandem mass spectrometry 
LSR 
local skin reaction 
MedDRA 
Medical Dictionary for Regulatory Activities 
PE 
physical examination 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PT 
preferred term 
R 
accumulation ratio 
SAE 
serious adverse event 
SCC 
squamous cell carcinoma 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
US 
United States 


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5 
ETHICS 
5.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, any protocol amendments, informed consent form (ICF), and appropriate 
related documents must be reviewed and approved before subjects are screened for entry by 
an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) constituted and 
functioning in accordance with International Conference on Harmonisation (ICH) E6 (Good 
Clinical Practice [GCP]1), Section 3, and any local regulations (eg, Federal Regulations, Title 
21 Code of Federal Regulations [CFR] Part 56).  Documentation of IRB/IEC compliance 
with the ICH E6 and any local regulations regarding constitution and review conduct will be 
provided to the Sponsor. 
A signed letter of study approval from the IRB/IEC chairman must be sent to the Principal 
Investigator (PI) with a copy to the Sponsor before study start and the release of any study 
drug to the site by the Sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the Investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the Sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the Investigator or 
Sponsor, depending on local regulatory obligations.  If the Investigator is required to report 
to the IRB/IEC, he/she will forward a copy to the Sponsor at the time of each periodic report.  
The Investigator(s) or the Sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the Investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required. 
5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures (SOPs) of the 
Sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following: 
• Principles of the World Medical Association Declaration of Helsinki (2013) 
• ICH E6: Guidance for Industry - E6 Good Clinical Practice: Consolidated Guidance, US 
Department of Health and Human Services, Food and Drug Administration, April 1996.  
• Title 21 of the United States CFR (US 21 CFR) regarding clinical studies, including Part 
50 and Part 56 concerning informed subject consent and IRB regulations and applicable 
sections of US 21 CFR Part 312 
 


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5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the Investigator must explain to 
each subject the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the subject, and the extent of 
maintaining confidentiality of the subject’s records.  Each subject must be informed that 
participation in the study is voluntary, that he/she may withdraw from the study at any time, 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it, and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject provides verbal consent to the subject’s participation in the 
study and has signed and personally dated the ICF, the witness should sign and personally 
date the consent form.  The subject will be asked to sign an ICF at the Screening visit and all 
authorizations required by local law (eg, Protected Health Information in North America) before 
any study-specific procedures are performed.  No subject can enter the study before his/her 
informed consent has been obtained. 
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with 
ICH E6, Section 4, and all applicable local regulations.  The original, signed ICF for each 
subject will be verified by the Sponsor and kept on file according to local procedures at the 
site. 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified Investigators under the sponsorship of Kinex 
Pharmaceuticals, Inc. at approximately 4 to 6 investigational sites in the United States (US). 
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the Sponsor and of any contract research organizations (CROs) will be listed in the 
Regulatory Binder provided to the site. 
7 
INTRODUCTION 
7.1 
Indication 
In this study, the activity, safety, and pharmacokinetics (PK) of KX2-391 Ointment 1% will 
be evaluated in adult subjects with a clinical diagnosis of stable, clinically typical actinic 
keratosis (AK) on the face or scalp. 


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7.1.1 
Mechanism of Action 
KX2-391 (also referred to as KX01) is a synthetic and highly selective inhibitor of Src 
tyrosine kinase signaling and tubulin polymerization. KX2-391 ointment is being developed 
as a topical treatment for actinic keratosis.  KX2-391 is also being developed as an oral agent 
for oncology indications.  In defining its pharmacological activity in tumor cells, both in vitro 
and in vivo, KX2-391 has been shown to have potent activity against a wide range of solid 
tumors as well as leukemia cell lines, including cell lines that are resistant to commonly used 
cancer drugs.  Clinically, the safety, tolerability and pharmacokinetics of KX2-391 have been 
studied in approximately 120 patients in both solid and liquid tumors using either once or 
twice daily dosing.  The best overall response in these early studies has been ‘stable disease’ 
in 25-30% of patients.   
KX2-391 promotes the induction of p53, G2/M arrest of proliferating cell populations and 
subsequent apoptosis via the stimulation of Caspase-3 and PARP cleavage. Data from pre-
clinical dermatology studies coupled with an understanding of the mechanism of action of 
KX2-391 suggests that this compound will have clinical activity in dermatology indications 
such as actinic keratosis.  Potent inhibition of the growth of primary human keratinocytes and 
several melanoma cell lines in vitro (50% growth inhibition [GI50 values] ≤50 nM), suggests 
that KX2-391 has the potential to inhibit the proliferative expansion and promote apoptosis 
of abnormally proliferating cells in the epidermal and dermal layers upon topical application. 
KX2-391 has also been observed to inhibit T cell migration and endothelial tubule formation 
in vitro, suggesting additional potential therapeutic benefits for conditions where pathology is 
supported by lymphocyte infiltration, inflammation, and/or angiogenesis. 
Information regarding KX2-391 nonclinical studies is provided in the Investigator’s 
Brochure. 
7.1.2 
Clinical Experience with KX2-391 
KX2-391 Ointment 1% has been administered to humans in ongoing study KX01-AK-01-
US.  Based on preliminary PK data from this study in AK lesions on the forearm, the 
systemic exposure to KX2-391 following topical administration is limited, and is 
considerably lower than observed in previous clinical studies of oral KX2-391.  Patients 
should be monitored for the occurrence of application site reactions and systemic toxicity. 
KX2-391 has been administered orally to approximately 120 patients with malignancy. 
The Kinex studies of oral KX2-391 are as follows: 
KX2-391 was evaluated in a Phase I clinical trial, Study No. KX01-01-07, entitled “A 
Combined Rising Single-Dose (RSD) and Rising Multiple-Dose (RMD) Phase I Study to 
Evaluate Safety, Tolerability, and Pharmacokinetics of KX2-391 in Patients with Advanced 
Malignancies That Are Refractory to Conventional Therapies”. 
KX2-391 has been evaluated in Study No. KX01-002-09, entitled “A Phase II, Open-Label, 
Single-Arm Study Evaluating the Safety, Efficacy and Pharmacokinetics of KX2-391 in 


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Patients with Bone-Metastatic, Castration-Resistant Prostate Cancer Who Have Not Received 
Prior Chemotherapy.”  
KX2-391 was evaluated in Study No, KX01-03-11, “A Phase 1b Rising Multiple-Dose 
Clinical Study to Evaluate Safety, Tolerability and Activity of Oral Monotherapy with KX2-
391 in Elderly Subjects with Acute Myeloid Leukemia (AML) Who Are Refractory to or 
Have Declined Standard Induction Therapy”. 
7.2 
Study Rationale 
Actinic keratoses represent the initial intra-epidermal manifestation of abnormal keratinocyte 
proliferation having the potential to progress to squamous cell carcinoma (SCC).  Squamous 
cell carcinoma is the second leading cause of skin cancer deaths in the US, with up to 65% of 
SCC arising from pre-existing actinic keratoses.2,3  The risk of progression has been 
determined to be between 0.025% and 16% per year,2,4 and the calculated lifetime risk of 
malignant transformation for a patient with AKs followed up for 10 years is between 6.1% 
and 10.2%.5  The rationale behind treating every AK is based on the difficulty in predicting 
which single AK will progress to squamous cell carcinoma.6,7  Suchniak et al8 reported 36% 
of lesions previously diagnosed clinically as AKs being in fact SCC, with 14% being in situ 
SCC.  Ehrig et al9 showed that 4% of AKs clinically diagnosed by board-certified 
dermatologists were in fact SCC and 5% were considered occult early stage of cutaneous 
malignancy.  Spontaneous regression has been reported in up to 25.9% of AKs over a 
12-month period, although 15% later reappeared.10,11,12  The goals of treatment are to 
completely eliminate AKs, minimizing their risk of progression to invasive SCC, reducing 
the potential to metastasize and cause death, while obtaining the best cosmetically acceptable 
outcomes.  Current approved/marketed treatment has shown up to approximately 60% 
efficacy, with a recurrence rate of approximately 35%. 
8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
The primary objective of the study is: 
• To evaluate the activity of KX2-391 Ointment 1% administered topically to the face or 
scalp in subjects with AK by determining complete response rate, defined as 100% 
clearance at Day 57 
8.2 
Secondary Objectives 
The secondary objectives of the study are: 
x To assess the activity of KX2-391 Ointment 1% during Days 1-57 
x To assess the safety and tolerability of KX2-391 Ointment 1% in subjects with AK on 
the face or scalp 
x To assess the PK of KX2-391 Ointment 1% in subjects with AK on the face or scalp 


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8.3 
Exploratory Objective 
The exploratory objective of the study is: 
x To determine recurrence rates to 12 months post-Day 57 for subjects who show 
response at Day 57 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This study will be an open-label, multicenter, activity, safety, tolerability, and PK study of 
KX2-391 Ointment 1% administered topically to the face or scalp of subjects with actinic 
keratosis. 
The study consists of Screening, Treatment, and Follow-up Periods. 
Eligible subjects will receive 5 consecutive days of topical treatment, to be applied at the 
study site, with 50 mg of KX2-391 Ointment 1% each day.  Blood samples for PK analysis 
will be collected on Day 1 and Day 5.  Subjects will return for Follow-up visits until Day 57.  
Thereafter, only Day 57 complete responders will continue Recurrence Follow-up Visits 
every 3 months for an additional 12 months after Day 57.  Activity (lesion counts) and safety 
evaluations will be performed. 
On Day 1 (Visit 2) and Day 5 (Visit 6), subjects will stay for approximately 5 hours at the 
investigational center until after the last PK blood sample is collected. 
9.1.1 
Screening Period 
The Screening Period may last up to 28 days. 
Subject eligibility will be established during the Screening Period.  Subjects will be screened 
within 28 days of the first dose of study drug.  All screening assessments/evaluations, as 
presented in Table 1 will be performed after the subject provides informed consent and 
eligibility criteria are met. 
Approximately 80 subjects will be enrolled to provide approximately 60 subjects in the 
Evaluable Set, defined as subjects who complete 5 days of treatment and the Day 57 Follow-
up visit. 
Treatment Area Identification 
At Screening (Visit 1), the Investigator will select a continuous treatment area affected with 
AK on the face or scalp for each subject that: 
x measures 25 cm2 
x contains 4 to 8 AK lesions that are clinically typical 


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The location and approximate shape of the treatment area will be recorded on the appropriate 
body chart. 
At Visit 1, the Investigator and an investigational center staff member will identify the 
treatment area by:  
x Examining the face or scalp and locating each AK with a dot of removable surgical 
skin marker. 
x Using an 8 x 11 acetate transparency sheet with 1x1 cm squares.  The acetate will 
have 20 squares across and 26 squares vertically. 
x Mapping at least 2 anatomical landmarks on the acetate sheet.  Example of landmarks 
could be bony prominences, scars, moles, seborrheic keratosis, and veins. 
x Indicating location of AK lesions with permanent marker dots on transparency acetate 
sheet. 
x Removing surgical skin marker dots with alcohol swabs. 
x Outlining the treatment area on the face or scalp with a fine-tipped indelible marker. 
9.1.2 
Treatment Period 
The inclusion/exclusion criteria will be reviewed again prior to treatment on Day 1, to 
re-confirm subjects’ eligibility to participate in the study. 
Subjects will be treated for 5 consecutive days (Days 1-5 [Visits 2-6]) during the Treatment 
Period.  Visits 2 through 6 should be scheduled to occur at approximately the same time each 
day. 
At Visit 2 (Day 1), prior to study drug application, the Investigator and any appropriate 
investigational staff member(s) (Investigator-trained designee) will confirm the location of 
the treatment area using the Visit 1 acetate sheet and the body charts.  The Investigator 
should re-mark the treatment area borders as needed so the study evaluations may be 
effectively completed. 
Once the treatment area has been re-identified at Visit 2, photographs will be taken 
(Section 9.5.1.5.8).  50 mg of KX2-391 Ointment 1% will be applied topically once daily to 
the 25 cm2 treatment area (2 mg/cm2; 0.5 mg KX2-391 total).  KX2-391 Ointment 1% will be 
applied for 5 consecutive days (see Section 9.4.2.4 for a detailed description of study 
medication application). 
Pharmacokinetic blood sampling, activity, safety assessments, and local skin reaction (LSR) 
assessments (see Section 9.5 for details) will be performed (Table 1).  Pigmentation and 
scarring in the treatment area also will be assessed by the Investigator (or a trained designee). 
Standardized photography will be performed at designated visits throughout the study 
(Table 1). 


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9.1.3 
Follow-up Period 
After the Treatment Period, there will be Follow-up Visits at Days 8, 15, 29, and 57 to assess 
safety, activity, LSRs, pigmentation, and scarring. 
9.1.4 
Recurrence Follow-up Period 
Only for subjects who show complete response at Day 57, there will be additional visits 
every 3 months up to 12 months post-Day 57 (ie, at 3, 6, 9, and 12 months post-Day 57) to 
assess recurrence of AK lesions.  These subjects will continue to undergo scheduled activity 
and safety assessments (Table 1). 
9.2 
Discussion of Study Design, Including Choice of Control Groups 
This is a nonrandomized, open-label study.  No control group has been included. 
9.3 
Selection of Study Population 
Eligible subjects will be adults (≥18 years of age) with a clinical diagnosis of stable, 
clinically typical AK on the face or scalp. 
9.3.1 
Inclusion Criteria 
Inclusion criteria will be reviewed at Screening (Visit 1). 
Subjects must meet all of the following criteria to be included in this study: 
1. Males and females ≥18 years old 
2. Clinical diagnosis of stable, clinically typical actinic keratosis 
3. A treatment area on the face or scalp that: 
x is a continuous area measuring 25 cm2 
x contains 4 to 8 AK lesions 
4. Females must be postmenopausal (>50 years of age with at least 18 months of 
amenorrhea), surgically sterile (by hysterectomy, bilateral oophorectomy or tubal 
ligation) or otherwise incapable of pregnancy for at least 1 year; or, if of childbearing 
potential, must be using highly effective contraception for at least 90 days prior to 
treatment with KX2-391 Ointment 1% and must agree to continue to use highly 
effective contraception for at least 90 days following their last dose of KX2-391 
Ointment 1%.  Highly effective contraception includes oral hormonal contraceptives, 
hormonal contraceptive implant or patch, or intrauterine device).  Abstinence and 
double barrier methods do not qualify as highly effective methods of contraception. 
5. Males who have not had a vasectomy must agree to use barrier contraception from 
Screening through 90 days after their last dose of KX2-391 Ointment 1%. 


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6. All subjects must agree not to donate sperm or eggs or attempt conception from 
Screening through 90 days following their last dose of KX2-391 Ointment 1%. 
7. Females of childbearing potential must have a negative serum pregnancy test at 
Screening and a negative urine pregnancy test on Day 1 prior to administration of study 
treatment. 
8. Subjects who in the judgment of the Investigator, are in good general health based on: 
x medical history 
x no physical examination (PE) findings that Principal Investigator (PI) determines 
would interfere with interpretation of study results 
x screening electrocardiogram (ECG) without clinically significant abnormalities  
x clinical chemistry, hematology, and urinalysis results that are within the reference 
ranges; clinical laboratory values outside the reference ranges that are considered by 
the PI to be clinically insignificant are also acceptable 
9. Willing to avoid excessive sun exposure 
10. Able to comprehend and are willing to sign an informed consent form 
9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Clinically atypical and/or rapidly changing AK lesions on the treatment area 
2. Malignancy within 5 years prior to Screening except basal or squamous cell carcinoma 
not on the treatment area that were treated with curative intent and are without 
recurrence 
3. Used any of the following systemic therapies within the specified period before Visit 1: 
x retinoids; 90 days 
x glucocorticosteroids; 28 days (intra-articular and inhaled steroids are allowed) 
x methotrexate or other anti-metabolites; 28 days 
4. Used any of the following topical therapies on the treatment area within the specified 
period before Visit 1: 
x retinoids; 90 days 
x glucocorticosteroids; 14 days 
x analgesic and/or anti-inflammatory medication on the face or scalp; 72 hours 
x moisturizers or emollients on the face or scalp; 12 hours 
5. Had any of the following on the treatment area within 90 days (or until the site has 
healed, whichever is longer) before Visit 1: 
x ingenol mebutate (eg, Picato) 
x 5-fluorouracil (eg, 5-FU; Efudex) 


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x imiquimod (eg, Aldara; Zyclara) 
x diclofenac with or without hyaluronic acid (eg, Solaraze) 
6. Surgical or destructive modalities on the treatment area within 30 days (or until the site 
has healed following treatment, whichever is longer) before Visit 1: 
x cryotherapy 
x electrodesiccation 
x laser, light (eg, photodynamic therapy, intense pulsed light) or any other energy-based 
therapy 
x chemical peels (eg, tricholoracetic acid) 
x dermabrasion 
x surgical removal (eg, curettage, excision) 
7. Currently, or has experienced any of the following on the treatment area within the 
specified period before Visit 1: 
x cutaneous malignancy; 180 days 
x sunburn; 28 days 
x body art (eg, tattoo, piercing); currently 
8. A history of sensitivity and/or allergy to any of the ingredients in the study medication 
9. A skin disease (eg, atopic dermatitis, psoriasis, eczema) or condition (eg, scarring, open 
wounds) that, in the opinion of the Investigator, might interfere with the study conduct 
or evaluations, or which exposes the subject to an unacceptable risk by study 
participation 
10. Other significant uncontrolled or unstable medical diseases or conditions that, in the 
opinion of the Investigator, would expose the subject to unacceptable risk by study 
participation 
11. Females who are pregnant or nursing 
12. Participated in an investigational drug trial during which an investigational study 
medication was administered within 14 days or 5 half-lives of the investigational 
product, whichever is longer, before Screening 
9.3.3 
Removal of Subjects from Therapy or Assessment 
The Investigator may discontinue treating a subject with study treatment or withdraw the 
subject from the study at any time for safety or administrative reasons.  The subject may 
decide to discontinue study treatment or withdraw from the study at any time for any reason. 


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Subjects will be removed from the study if any of the following occurs:  
x Death 
x Occurrence of serious or clinically significant AEs 
x Occurrence of pregnancy  
x Use of a prohibited concomitant medication or treatment (see Section 9.4.7.3) 
x Conditions that, in the opinion of the Investigator, would make the subject’s 
continued participation in the study inadvisable 
x Noncompliance 
x Withdrawal of consent (subject asked, but not required to give a reason) 
x Other (Investigator must describe) 
If the study is terminated by the Sponsor, the Investigator will promptly explain to the subject 
involved that the study will be discontinued and provide appropriate medical treatment and 
other necessary measures for the subject. 
9.4 
Treatments 
The investigational product in the study is KX2-391 Ointment 1%. 
9.4.1 
Treatment Administered 
Information regarding study treatment is provided in Table 2. 
Table 2 
Treatment Administered in KX01-AK-002 
Investigational Product 
Strength 
Size of 
Treatment 
Area 
Quantity 
study 
medication/
KX2-391 
Number 
Applications and 
Frequency 
Study Days 
Administered 
KX2-391 Ointment 1% 
1% 
25 cm2 
50 mg/ 
0.5 mg 
1 application daily 
for 5 consecutive 
days 
Days 1-5 
 
9.4.2 
Identity of Investigational Products 
 
Chemical Name and Structural Formula of KX2-391 
x Study drug code:  KX2-391 Ointment 1% 
x Drug Product:  KX2-391 free base ointment formulated with glyceryl 
monostearate and propylene glycol 
x Chemical name:  N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl) 
acetamide   


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x Molecular formula:  C26H29N3O3 
x Molecular weight:  431.53 g/mole 
x Structural formula:   
 
 
Labeling for Study Drug 
Investigational product will be packaged and labeled in a manner consistent with the study 
and will be designed by:  
Kinex Pharmaceuticals, Inc. 
1001 Main Street 
Suite 600 
Buffalo, NY 14203 
Labels will be nonremovable in nature. 
Labels for the investigational product will be in accordance with US regulations and will 
include (but will not be limited to) the following information: 
• 
 For clinical study use only 
• Name and address of the Sponsor 
• Chemical name/drug identifier 
• Lot number/batch number 
• Storage conditions, expiration date if necessary 
 
Storage Conditions 
Study drug will be stored in accordance with labeled storage conditions. Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The Investigator is responsible for ensuring that the 
temperature is monitored throughout the total duration of the trial and that records are 
maintained; the temperature should be monitored continuously by using either an in house 
validated data acquisition system, a mechanical recording device, such as a calibrated chart 
recorder, or by manual means, such that minimum and maximum thermometric values over a 
specific time period can be recorded and retrieved as required. 


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Administration of Investigational Products 
The study medication is for external topical use on the treatment area.  An investigational 
center staff member will perform the study medication applications.  The staff member must 
wash her/his hands before and after each study medication application. 
50 mg of KX2-391 Ointment 1% will be applied topically to a 25 cm2 treatment area.  This 
amount contains a total of 0.5 mg KX2-391 free base.  KX2-391 Ointment 1% will be 
applied once daily for 5 consecutive days (see Table 2). 
The staff member will weigh the appropriate amount of study medication into a weighing 
boat (or equivalent) using a calibrated scale.  The amount of study medication applied will be 
calculated by determining the difference of the weight of the weighing boat with study 
medication before and after application.  The amount of study medication weighed will be as 
close to the intended dose as possible. 
A study staff member will perform and document a scale accuracy check at least every day 
before weighing study medication. 
The study medication will be applied to the subject’s treatment area using a fingertip 
protected with a powder-free finger cot or examination glove.  The study medication will be 
gently and evenly rubbed over the treatment area until no visible accumulation is evident. 
The time when the study medication application is completed (Application Completion 
Time) will be recorded. 
The study medication should remain on the treatment area. Subjects must avoid touching or 
wetting the treatment area and are not allowed to apply any topical products to the treatment 
area (see Section 9.4.7.3) up until the end of Visit 7 (Day 8).  Showers may be taken in the 
morning on Days 1 through 5 in preparation for the study visit, approximately 24 hours after 
study drug application.  Instructions will be sent home with the subject clarifying on how to 
care for the treatment area on Days 1 through 8. 
9.4.3 
Method of Assigning Subjects to Treatment Groups 
This is a study with one treatment group.  All subjects will be assigned the same treatment. 
9.4.4 
Selection of Doses in the Study 
The dose of 50 mg of KX2-391 applied to a 25 cm2 area on the face or scalp for 
5 consecutive days is based on a previous study using the same dose regimen for the 
treatment of AK on the forearm (study KX01-AK-01-US).  Preliminary data show that this 
regimen had an acceptable LSR and safety profile, with efficacy outcomes considered to 
warrant further investigation. 


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9.4.5 
Selection and Timing of Dose for Each Subject 
Section 9.4.2.4 provides detailed instructions for administering KX2-391 Ointment 1% in 
this study.  Study medication should be applied at about the same time each day. 
9.4.6 
Blinding 
The study will not be blinded. 
9.4.7 
Prior and Concomitant Therapy 
 
Prior Therapy 
All medications (prescription and nonprescription including vitamins and dietary 
supplements), treatments, and therapies including radiotherapy taken 28 days before Day 1 
through the final study visit must be recorded in the case report form/electronic case report 
form (CRF/eCRF).  A complete AK treatment history will be recorded on the AK Treatment 
History CRF/eCRF (see Section 9.5.1.2.1). 
 
Concomitant Medication/Therapy 
Concomitant medication/therapies are any new or existing therapy received by the subject 
after signing the ICF until discharge from the study. 
Any medication (including nonprescription medications) or therapy administered to the 
subject during the course of the study (starting at the date of informed consent) will be 
recorded on the Concomitant Medication CRF/eCRF.  The Investigator will record any AE 
on the Adverse Events CRF/eCRF for which the concomitant medication/therapy was 
administered.  
Subjects will refrain from receipt of any therapy in accordance with the inclusion/exclusion 
criteria.  Subjects should refrain from changing the use of any concomitant therapies during 
the study. 
 
Prohibited Medication/Therapy 
Use of any non-study drug treatment for AK lesions on the face or scalp is prohibited during 
the study.  During the Recurrence Follow-up Period, isolated lesion treatment such as 
cryotherapy or biopsy is allowed for treatment of AK lesions emerging in the selected 
treatment area.  Any treated lesion will be considered as a recurrence. 
Subjects are prohibited from applying any topical products, including but not limited to, 
lotions, creams, and ointments (Note: routine cleansers are allowed) to the treatment area up 
until the end of Visit 7 (Day 8), except when those medications are prescribed by the 
Investigator for the management of local skin reactions. 


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Subjects have unrestricted use of skin products on areas outside of the treatment area during 
the study.  Lesions located outside the study treatment area may be treated topically as 
determined by the Investigator. 
Subjects are excluded from participation in this study if they:  
x Have used any of the following systemic therapies within the specified period before 
Visit 1: 
○ retinoids; 90 days 
○ glucocorticosteroids; 28 days (intra-articular and inhaled steroids are allowed) 
○ methotrexate or other anti-metabolites; 28 days 
x Have used any of the following topical therapies on the treatment area within the 
specified period before Visit 1: 
○ retinoids; 90 days 
○ glucocorticosteroids; 14 days 
○ analgesic and/or anti-inflammatory medication on the face or scalp; 72 hours 
○ moisturizers or emollients on the face or scalp; 12 hours 
x Had any of the following on the treatment area within 90 days (or until the site has 
healed, whichever is longer) before Visit 1: 
○ ingenol mebutate (eg, Picato) 
○ 5-fluorouracil (eg, 5-FU; Efudex) 
○  imiquimod (eg, Aldara; Zyclara) 
○ diclofenac with or without hyaluronic acid (eg, Solaraze) 
x Surgical or destructive modalities on the treatment area within 30 days (or until the 
site has healed following treatment, whichever is longer) before Visit 1: 
○ cryotherapy 
○ electrodesiccation 
○ laser, light (eg, photodynamic therapy, intense pulsed light) or any other 
energy-based therapy 
○ chemical peels (eg, tricholoracetic acid) 
○ dermabrasion 
○ surgical removal (eg, curettage, excision) 
Subjects should not start such medications/treatments while enrolled in this protocol. 
Any subjects who start systemic therapies for the treatment of AK will be withdrawn from 
the study. 


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Any subjects who start topical therapies for AK on the treatment area will be withdrawn from 
the study. 
The decision to administer a prohibited medication/treatment is done with the safety of the 
study subject as the primary consideration. 
9.4.8 
Prohibitions and Restrictions during Study Period 
Except for those diagnosed as having diabetes, subjects must be fasted for laboratory 
assessments (see Section 9.5.1.5.3); otherwise there are no food, water, beverage, or physical 
activity restrictions during the study. 
9.4.9 
Treatment Compliance 
Records of treatment administration for each subject will be kept during the study.  The 
clinical research associates (CRAs) will review treatment administration throughout the 
course of the study. 
9.4.10 
Drug Supplies and Accountability 
The Investigator and study staff will be responsible for the accountability of all clinical 
supplies (dispensing, inventory, and record keeping) following the Sponsor’s instructions.  In 
this matter, the Investigator and study staff must adhere to GCP guidelines, as well as 
national requirements. 
Under no circumstances will the Investigator allow the study drugs to be used other than as 
directed by this protocol.  Clinical supplies will be dispensed only by an appropriately 
qualified person and will not be dispensed to any individual who is not enrolled in the study. 
An accurate and timely record of the receipt of all clinical supplies and dispensing of study 
drug to the subject must be maintained.  This includes, but is not limited to: 
x documentation of receipt of clinical supplies 
x study drugs dispensing/return reconciliation log, including amount and date of 
dispensing 
x study drugs accountability log 
x all shipping service receipts 
x documentation of study drug returned to the Sponsor 
All forms will be provided by the Sponsor (or its designee).  Any comparable forms that the 
investigational site wishes to use must be approved by the Sponsor.  A copy of the drug 
accountability record must be provided to the Sponsor at the end of the study. 
The supplies and inventory records must be made available, on request, for inspection by the 
Sponsor (or its designee) or a representative of a health authority.  If applicable, all unused 
study drugs and empty containers, are to be returned to the Investigator by the subject and 


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ultimately to the Sponsor at the conclusion of the study unless provision is made by the 
Sponsor for destruction of supplies and containers at the investigational site.  On completion 
of drug accountability and reconciliation procedures by investigational site personnel and 
documentation procedures by Sponsor personnel, study drug that is to be returned to the 
Sponsor, if necessary must be boxed and sealed and shipped back to the Sponsor following 
all local regulatory requirements. 
The CRA(s) will review drug accountability during monitoring site visits and at the 
completion of the study. 
9.5 
Study Assessments 
9.5.1 
Assessments 
All assessments and timing of the assessments should be performed according to the 
Schedule of Procedures and Assessments (Table 1). 
 
Demography 
Subject demographic information will be collected at the Screening Visit.  Demographic 
information includes date of birth (or age), sex, race/ethnicity. 
 
Baseline Assessments 
9.5.1.2.1 MEDICAL/SURGICAL AND ACTINIC KERATOSIS HISTORY 
Medical and surgical history and current medical conditions will be recorded at Screening 
(Visit 1).  All pertinent medical history must be noted in the CRF/eCRF.  A complete AK 
medical history will also be recorded. 
Medical history will include:  
x A complete medical and surgical history; childhood diseases and common colds are 
not required unless it is ongoing at Screening 
x A complete AK history from the time of initial diagnosis 
x A complete AK treatment history including all commercial and investigational 
products, including medical therapies and surgical modalities, and other prescribed 
and nonprescription therapies dating back to the initial diagnosis.  
9.5.1.2.2 FITZPATRICK SKIN-TYPE CLASSIFICATION 
The Fitzpatrick Skin-Type is a skin classification system (Appendix 1) which measures 
2 components (genetic disposition and reaction to sun exposure).  Skin-types range from very 
fair (Type I) to very dark (Type VI). 
Subjects’ skin will be typed using this classification system at Screening (Visit 1). 


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9.5.1.2.3 PRIOR MEDICATIONS 
Prior medications taken within 28 days before Day 1, including nonprescription remedies, 
vitamins, etc, will be recorded at Screening (Visit 1). 
 
Activity Assessments 
9.5.1.3.1 ACTINIC KERATOSIS LESION COUNT 
The Investigator will perform a count of AK lesions (lesion count) for all subjects at Visits 1 
and 2, Visits 7 through 10, and for Day 57 complete responders, also at Visits 11 through 14. 
The AK lesion count is the Investigator’s assessment of the number of AK lesions in the 
treatment area.  A subject must have 4 to 8 AK lesions in the treatment area to be eligible to 
continue in the study at Visit 1. 
For this assessment, an AK lesion is considered to be on the treatment area, and should be 
counted if it is completely inside the treatment area or is touching any of the borders of the 
treatment area.  These lesions will be treated during the study medication application process. 
The Investigator must NOT refer to any other evaluation to assist with the AK lesion count.  
This is not a comparison with the AK lesion count at any other timepoint. 
 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
9.5.1.4.1 PHARMACOKINETIC ASSESSMENTS 
Blood samples (3 mL at each timepoint) for PK analysis of KX2-391 will be collected at the 
following timepoints (Table 3): 
Table 3 
Blood Sample Collection Times for Pharmacokinetic Analyses  
Application Day 
Time (hours) 
 
0 
predose 
0.5 
postdose 
1 
postdose 
4 
postdose 
Window 
 
±5 minutes 
±10 minutes 
±10 minutes 
Day 1 (Visit 2) 
X 
X 
X 
X 
Day 5 (Visit 6) 
Xa 
X 
X 
X 
a 
Prior to application of study treatment. 
Approximately 24 mL will be collected for measurement of plasma concentrations of 
KX2-391. 
The actual times of PK sampling will be recorded. 


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A description of collection, handling, and shipping procedures for PK samples will be 
provided to the sites. 
Plasma concentrations of KX2-391 will be analyzed to determine Cmax, and where applicable, 
AUCt, Cmin, and accumulation ratio R. 
Plasma concentrations of study drug will be measured using a validated liquid 
chromatography/tandem mass spectrometry (LC-MS/MS) assay. 
9.5.1.4.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS 
Not applicable 
 
Safety Assessments 
Safety assessments will include recording all AEs and serious adverse events (SAEs). 
Safety assessments also include laboratory evaluation of hematology, biochemistry, and 
urinalyses; periodic measurement of weight, vital signs, ECGs, and performance of PEs, as 
detailed in the sections below and shown in Table 1. 
Subjects will be queried for spontaneously reported AEs at each study visit, before 
assessment of local skin reactions.  AEs will be reported separately from LSRs. 
Subject-reported LSRs will not be reported as adverse events.  Treatments administered for 
LSRs will be recorded on the Concomitant Medications CRF. 
9.5.1.5.1 ADVERSE EVENTS AND OTHER EVENTS OF INTEREST 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is KX2-391 
Ointment 1%. 
Treatment-emergent AEs are defined as: 
x either those AEs with an onset after dosing or  
x those pre-existing conditions that worsen after dosing 
The criteria for identifying AEs are: 
• any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product 
• any new disease or exacerbation of an existing disease  


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• any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation from study drug 
• recurrence of an intermittent medical condition (eg, headache) not present at baseline 
All AEs, regardless of relationship to study drug or procedure, should be collected beginning 
from the time the subject signs the study ICF through the final contact in the Follow-up 
Period.  For subjects participating in the Recurrence Follow-up Period, only AEs at the 
treatment area will be collected.  Subjects who fail screening primarily due to AE(s) must 
have the AE(s) leading to screen failure reported on the Screening Disposition CRF/eCRF. 
Subjects with onset of an AE or deterioration of a pre-existing condition will be followed 
until resolution, resolved with sequelae, or under medical care.  All SAEs must be followed 
to resolution or, if resolution is unlikely, to stabilization. 
All AEs observed during the study will be reported on the CRF/eCRF. 
Laboratory Adverse Events 
A treatment-emergent abnormal laboratory test result should be considered as a treatment-
emergent AE (TEAE) if the identified laboratory abnormality leads to any type of 
intervention whether prescribed in the protocol or not. 
An abnormal laboratory result should be considered by the Investigator to be an AE if it: 
x results in the withdrawal of study drug 
x results in withholding of study drug pending some investigational outcome 
x results in the initiation of an intervention, based on medical evaluation (eg, 
potassium supplement for hypokalemia) 
x results in any out of range laboratory value that in the Investigator’s judgment 
fulfills the definitions of an AE with regard to the subject’s medical profile 
x increases in severity compared with baseline 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
Investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF/eCRF. 
ECG changes and associated clinical symptoms determined to be clinically significant by the 
Investigator will be reported as AEs.  An ECG abnormality in a subject with symptoms may 
meet the criteria for an AE as described in this protocol.  In these instances, the AE 
corresponding to the symptomatic ECG abnormality will be recorded on the Adverse Events 
CRF/eCRF. 


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For symptomatic ECG abnormalities meeting criteria as SAEs, the study site must submit an 
SAE report, including the ECG report to the Sponsor, or designee, using the SAE reporting 
procedures (Section 9.5.3.1). 
Assessing Severity of Adverse Events 
Every effort must be made by the Investigator to categorize each AE according to its severity 
and its relationship to the study treatment. 
Adverse events will be graded for severity as follows: 
Mild 
An event that is easily tolerated by the patient, causing minimal discomfort 
and not interfering with everyday activities 
Moderate 
An event that is sufficiently discomforting to interfere with everyday 
activities 
Severe 
An event that prevents normal everyday activities 
Investigators will assess severity for all AEs (for both increasing and decreasing severity).  
The criteria for assessing severity are different from those used for seriousness (see 
Section 9.5.1.5.2). 
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
x temporal relationship of the onset of the event to the initiation of the study treatment 
x the course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
x whether the event is known to be associated with the study treatment or with other 
similar treatments 
x the presence of risk factors in the study subject known to increase the occurrence of 
the event 
x the presence of nonstudy treatment-related factors that are known to be associated 
with the occurrence of the event 
Classification of Causality 
The relationship of each AE to the study drug will be recorded on the CRF/eCRF using the 
following criteria: 
Definitely Related:  A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to drug administration, and which cannot be explained by 
concurrent or underlying disease or other drugs or conditions 


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Probably Related:  A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to concurrent or 
underlying disease or other drugs or conditions  
Possibly Related:  A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, but which could also be explained by concurrent 
or underlying disease or other drugs or conditions 
Unlikely Related:  A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship improbable, and in 
which other drugs, conditions or concurrent or underlying disease provide plausible 
explanations 
9.5.1.5.2 
 SERIOUS ADVERSE EVENTS AND OTHER EVENTS OF INTEREST 
An SAE is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death) 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, other events of interest, which include pregnancy, overdose, and 
significant treatment-emergent laboratory abnormality (See Section 9.5.1.5.1), are to be 
captured using the SAE procedures but are to be considered as SAEs only if they met one of 
the above criteria. All events of these types are to be reported on the CRF/eCRF whether or 
not they meet the criteria for SAEs. 
The following hospitalization is not considered to be an SAE because there is no “AE” (ie, 
there is no untoward medical occurrence) associated with the hospitalization: 
• hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 


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All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 
9.5.1.5.3 LABORATORY MEASUREMENTS 
Blood will be collected for clinical laboratory tests at Screening (Visit 1), Day 8 (Visit 7), 
and Day 57 (Visit 10) (Table 1).  Collection of blood and urine (including samples for 
pregnancy testing, where applicable) will be conducted at the clinic site.  Approximately 
20 mL of blood will be collected for clinical laboratory testing, including pregnancy testing, 
when required.  Except for those diagnosed as having diabetes, subjects must be fasted for 
laboratory assessments.  Fasting status must be documented for all laboratory samples. 
Microscopic urinalysis will be conducted only when clinically indicated based on dipstick 
results (laboratory protocol) or as determined by the Investigator.  When conducted, 
microscopic urinalysis results will be recorded on the CRF/eCRF. 
The clinical laboratory tests to be measured during the study are provided in Table 4. 
Table 4 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
red blood cells (RBC), hemoglobin, hematocrit, platelets, and white 
blood cells (WBC) with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils), mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), RBC distribution width (RDW) 
Chemistry 
 
 Electrolytes 
chloride, potassium, sodium, bicarbonate (HCO3) 
 Liver function tests 
alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), gamma glutamyl transpeptidase (GGT), direct 
bilirubin, total bilirubin 
 Renal function tests 
blood urea/blood urea nitrogen, creatinine 
 Other 
Albumin, calcium, cholesterol, glucose, lactate dehydrogenase (LDH), 
phosphorus, total protein, triglycerides, uric acid 
Urinalysis (dipstick)a 
hydrogen ion concentration (pH), specific gravity, protein, glucose, 
ketones, leukocyte esterase, nitrite, bilirubin, urobilinogen, blood 
Pregnancy Testing 
serum pregnancy test, urine pregnancy test (where applicable) 
a 
Microscopic urinalysis will be conducted only when clinically indicated based on dipstick results 
(laboratory protocol) or as determined by the Investigator. 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1).  In these instances, the AE corresponding to the laboratory 
abnormality will be recorded on the Adverse Event CRF/eCRF. 
For laboratory abnormalities meeting the criteria of SAEs (see Section 9.5.1.5.2), the site 
must electronically transmit the SAE report including the laboratory report to the Sponsor 
using the SAE form (see Section 9.5.3.1). 


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9.5.1.5.4 VITAL SIGNS 
Vital sign (pulse rate, systolic and diastolic blood pressure, respiratory rate, and body 
temperature) measurements will be taken after the subject has been seated for at least 
5 minutes at Screening (Visit 1), Day 5 (Visit 6), Day 8 (Visit 7), Day 15 (Visit 8), Day 29 
(Visit 9), and Day 57 (Visit 10) (Table 1).  Serial vital signs may be obtained to confirm 
accurate readings.  
9.5.1.5.5 PHYSICAL EXAMINATIONS 
A complete PE will be performed at Screening (Visit 1) and Day 57 (Visit 10) (Table 1). 
A complete PE will include weight and an assessment of head, eyes, ears, nose, and throat 
(HEENT), integumentary, gastrointestinal, cardiovascular, respiratory, muscular-skeleton, 
and neurological systems. 
Documentation of the PE will be included in the source documentation at the site.  Only 
changes from screening PE findings that meet the definition of an AE will be recorded on the 
Adverse Events CRF/eCRF. 
9.5.1.5.6 ELECTROCARDIOGRAMS 
A 12-lead ECG will be completed at Screening (Visit 1), Day 8 (Visit 7), and Day 57 
(Visit 10) (Table 1).  ECGs may be performed at a convenient time during the visit.  Subjects 
must be in the recumbent position for a period of 5 minutes prior to the ECG.  The ECG data 
recorded on the CRF/eCRF must include rate, rhythm, intervals, and QTc/QTcF. 
ECG changes and associated clinical symptoms determined to be clinically significant by the 
Investigator will be reported as AEs. 
9.5.1.5.7 PREGNANCY TESTING 
Serum pregnancy tests will be obtained in females of childbearing potential at Screening 
(Visit 1), Day 8 (Visit 7), and Day 57 (Visit 10) (Table 1). 
A urine pregnancy test will be performed on females of childbearing potential before study 
medication application on Day 1 (Visit 2).  Visit 1 and Visit 2 test results must be reviewed 
before dosing. 
9.5.1.5.8 OTHER ASSESSMENTS 
Concomitant Medications 
Concomitant medications will be assessed at all clinic visits (Table 1).  Any medication 
(including nonprescription medications) or therapy administered to the subject during the 
course of the study (starting at the date of informed consent) will be recorded on the 
Concomitant Medication CRF/eCRF.  The Investigator will record any AE on the Adverse 
Events CRF/eCRF for which the concomitant medication/therapy was administered. 


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Local Skin Reactions 
At every post-Screening clinic visit through Day 57 (Visit 10), the Investigator or trained 
designee will assess any LSR on the treatment area for signs: 
x Before study medication application (on dosing days) 
x After the assessment of adverse events 
The LSR assessment is the Investigator’s (or trained designee’s) assessment of the following 
signs 
on 
the 
treatment 
area: 
 
erythema, 
flaking/scaling, 
crusting, 
swelling, 
vesiculation/pustulation, and erosion/ulceration.  These signs will be assessed using a grading 
scale ranging from 0 (not present) to 4 (worst) (Table 5). 
Table 5 
Local Skin Reaction Grading Criteria 
 
Grading Criteria 
Local Skin 
Response 
0 
1 
2 
3 
4 
Erythema 
Not present 
Slightly pink 
<50% 
Pink or light red 
>50% 
Red, restricted to 
treatment area 
Red extending 
outside treatment 
area 
Flaking / 
Scaling 
Not present 
Isolated scale, 
specific to lesion 
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 
 
Examples of LSR signs are shown in photographs in Appendix 2. 
Application site reactions not classified as LSRs (eg, pruritus, pain, infection) will be 
reported as adverse events. 
All application site reactions and LSRs will be followed to resolution, or if resolution is 
unlikely, to stabilization. 


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Treatment for any LSR or interruption/discontinuation of study treatment for an LSR will be 
recorded on the CRF/eCRF. 
LSRs will be reported separately from adverse events. 
Pigmentation and Scarring 
Hypo- and hyper- pigmentation and scarring on the treatment area will be assessed by the 
Investigator (or a trained designee) as being present or absent.   
Pigmentation will be assessed at every post-Screening clinic visit through Day 57 (Visit 10) 
(Table 1). 
Standardized Photography 
Standardized photography will be performed at Screening (Visit 1), Day 1 (Visit 2), Day 8 
(Visit 7), Day 57 (Visit 10), and during the Recurrence Follow-up (at 3, 6, 9, and 12 months 
post-Day 57).  Before study medication application on Day 1, the Investigator or a qualified 
staff member must obtain standardized photography of each subject’s treatment area before 
application of study medication. 
Care must be taken to ensure the same lighting, background, subject positioning relative to 
the camera and camera settings are used for each photograph.  Equipment, supplies and 
detailed instructions for obtaining and managing the photographs will be provided to the 
investigational center prior to the initiation of subject enrollment. 
The photographs are to document the appearance of the subjects’ treatment area and to assist 
with the identification and confirmation of the location of the treatment area throughout the 
study (Section 9.1.1). 
Equipment, supplies and detailed instructions for obtaining and managing the photographs 
will be provided to the investigational center prior to the initiation of subject enrollment. 
9.5.2 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in dermatology studies 
as well as in the routine clinical care of patients with actinic keratosis. 
9.5.3 
Reporting of Serious Adverse Events, Pregnancy, and Other Events of 
Interest 
 
Reporting of Serious Adverse Events 
All SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by electronic transmission as soon as possible but no later than 
1 business day from the date the Investigator becomes aware of the event.  Instructions 
will be provided in the Safety Management Plan.  


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All SAEs, regardless of causality assessment, must be collected through the last subject 
contact and followed to resolution or, if resolution is unlikely, to stabilization.  SAEs 
reported to the site from the time of the last subject contact up to 30 days after the last 
contact, will be collected (ie, Day 57 plus 30 days).  These SAEs will be discussed in the 
clinical study report.  Any SAE event judged by the Investigator to be related to the study 
treatment should be reported to the Sponsor regardless of the length of time that has passed 
since study completion. 
Deaths and life-threatening events should be reported immediately by telephone.  The 
immediate report should be followed up within 1 business day by electronically 
transmitting the completed SAE form. 
The detailed contact information for reporting of SAEs is provided in the Safety 
Management Plan, located in the Investigator File. 
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report. This includes the Investigator’s assessment of causality.  All 
supporting documents should be sent de-identified and should contain the assigned subject 
number. Send only supporting documents directly related to the event. 
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the Investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the Sponsor. 
 
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding 
Any pregnancy for which the estimated date of conception was either before the last visit or 
within 30 days of last study treatment must be reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same timeframe and in 
the same format as all other SAEs (see Section 9.5.3.1). 
Pregnancies must be reported by electronic transmission as soon as possible but no later than 
1 business day from the date the Investigator becomes aware of the pregnancy.  The contact 
information for the reporting of pregnancies is provided in the Investigator File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the Investigator becomes aware of the outcome. 


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A subject who becomes pregnant must be withdrawn from the study. 
 
Reporting of Other Events of Interest 
9.5.3.3.1 REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, 
MISUSE, ABUSE, OR MEDICATION ERROR 
Study drug overdose is defined as the accidental or intentional use of the drug in an amount 
higher than the dose being studied. 
Any study drug overdose should be noted on the Study Medication CRF/eCRF. 
All AEs associated with overdose, or medication error should be captured on the Adverse 
Event CRF/eCRF and also reported using the procedures detailed in Section 9.5.3.1 even if 
the AEs do not meet serious criteria.  If the AE associated with an overdose or medication 
error does not meet serious criteria, it must still be reported using the SAE form and in an 
expedited manner but should be noted as nonserious on the SAE form and the Adverse Event 
CRF/eCRF. 
 
Expedited Reporting 
The Sponsor (or its designee) must inform Investigators and regulatory authorities of 
reportable events, in compliance with applicable regulatory requirements, on an expedited 
basis (ie, within specific timeframes).  For this reason, it is imperative that sites provide 
complete SAE information in the manner described above. 
In determining what SAEs meet criteria for expedited reporting, the current version of the 
Investigator’s Brochure will be used for reference safety information. 
 
Breaking the Blind 
Not applicable 
 
Regulatory Reporting of Adverse Events 
Adverse events will be reported by the Sponsor or a third party acting on behalf of the 
Sponsor to regulatory authorities in compliance with local law and established guidance.  The 
format of these reports will be dictated by the local and regional requirements. 
9.5.4 
Completion/Discontinuation of Subjects 
A subject may elect to discontinue from the study at any time for any reason.  See 
Section 9.3.3 for reasons why Investigators may discontinue subjects from the study.  
Investigators must document the actual reason(s) why they decided to discontinue subjects, 
or why subjects withdrew consent, as applicable.  Study disposition information will be 
collected on the Disposition CRF/eCRF. 


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Subjects who withdraw from study treatment (with the exception of death or withdrawal of 
consent) will be encouraged to complete the Early Termination assessments at the time of 
withdrawal as indicated in Table 1.  A subject who has ceased to return for visits will be 
followed up by mail, phone, or other means to gather information such as the reason for 
failure to return, the status of treatment compliance, the presence or absence of AEs, and 
clinical courses of signs and symptoms.  This information will be recorded in the CRF/eCRF.  
9.5.5 
Abuse or Diversion of Study Drug 
Not applicable 
9.5.6 
Confirmation of Medical Care by another Physician 
The Investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the Investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the Investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study. 
9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
may be made periodically by the Sponsor’s or the CRO’s qualified compliance auditing 
team, which is an independent function from the study team responsible for conduct of the 
study. 
9.6.1 
Data Collection 
Data required by the protocol will be documented in the subject source documentation, 
collected on the CRF/eCRFs and entered into a validated data management system that is 
compliant with all regulatory requirements.  A CRF/eCRF or a select CRF/eCRF page may 
be used as a source document.  CRF/eCRFs used as source documents will be listed in the 
Data Management Plan.  As defined by ICH E6 guidelines (Section 1.11), the CRF is a 
printed, optical, or electronic document designed to record all of the protocol-required 
information to be reported to the Sponsor on each study subject.  In this study, the CRF may 
refer to either a paper (CRF) or electronic data collection form (eCRF), or both. 
Data collected on the CRF/eCRF must be completed following the instructions described in 
the CRF/eCRF Completion Guidelines, which will be based on the Data Management Plan.  
The Investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRF/eCRF.  The PI must sign the CRF/eCRF to 
attest to its accuracy, authenticity, and completeness. 


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Completed, original CRFs/eCRFs are the sole property of the Sponsor and should not be 
made available in any form to third parties without written permission from the Sponsor, 
except for authorized representatives of the Sponsor or appropriate regulatory authorities. 
Responsible site personnel will enter the information required by the protocol onto the 
CRF/eCRFs in accordance with the CRF/eCRF Completion Guidelines that are provided.  A 
CRA will visit each site as documented in the monitoring plan to review the CRF/eCRFs for 
completeness and accuracy against the source documents. They will identify any 
discrepancies and ensure that appropriate site personnel address the discrepancies. 
The original CRFs/eCRFs will be maintained at the site in a central document repository. If 
used, a copy of the CRF will be forwarded to the Sponsor. 
At the end of the study an electronic copy of the database along with appropriate system 
version will be archived. 
Uniform procedures will be discussed at the Investigator meetings or at site initiation and/or 
will be documented in the CRF/eCRF Completion Guidelines. 
9.6.2 
Clinical Data Management 
All data, both CRF/eCRF and external data, will be loaded into a clinical system as specified 
in the Data Management Plan. 
Quality control and data validation procedures will be applied to ensure the validity and 
accuracy of the clinical data. 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements. 
9.7 
Statistical Methods 
All statistical analyses will be performed by the Sponsor or designee after the study is 
completed and the database is locked.  Statistical analyses will be performed using Phoenix 
WinNonlin and SAS software or other validated statistical software as required. 
Statistical analyses will be reported using summary tables, graphs, and data listings. 
Continuous variables will be summarized using the mean, standard deviation (SD), median, 
minimum, and maximum.  Categorical variables will be summarized by counts and by 
percentage of subjects in corresponding categories.  All raw data obtained from the 
CRF/eCRF, as well as any derived data will be included in data listings. 
For all analyses, study Day 1 will be defined as the date of the first dose of study drug. 


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9.7.1 
Statistical and Analytical Plans 
 
Study Endpoints 
9.7.1.1.1 PRIMARY ENDPOINTS 
The primary endpoint is activity. 
Activity will be evaluated by reduction in lesion count.  Complete response rate will be 
defined as the proportion of subjects achieving 100% complete clearance of all treated AK 
lesions on the face or scalp at Day 57.  Sustained response will be defined as the proportion 
of subjects achieving 100% (complete) clearance at Day 57 without any identified AK 
lesions on the treatment area at 12 months post-Day 57.  
9.7.1.1.2 SECONDARY ENDPOINTS 
Activity 
Reduction in lesion counts at each visit during Days 1-57 will be assessed as the secondary 
endpoint for activity. 
Safety 
Safety will be evaluated primarily by assessment of AEs and clinical laboratory data.  The 
results of other safety assessments (vital signs, PEs, ECGs) will also be evaluated. 
Pharmacokinetic 
Secondary endpoints include the following PK parameters derived by noncompartmental 
analysis using the plasma concentration-time data of KX2-391:  Cmax, and where applicable, 
AUCt, Cmin, and accumulation ratio R. 
9.7.1.1.3 EXPLORATORY ENDPOINTS 
The exploratory endpoint in the study is recurrence rate. 
Recurrence rate will be defined as the proportion of subjects who achieved 100% complete 
clearance at Day 57 (Visit 10) with any identified AK lesions on the face or scalp at 3, 6, 9, 
and 12 months post-Day 57. 
 
Definitions of Analysis Sets 
The Per-Protocol Set is the group of protocol-eligible subjects who receive 5 days of study 
treatment and complete at least one scheduled post-treatment evaluation.  
The Evaluable Set is the group of subjects who receive 5 days of treatment and complete 
most evaluations including the Day 57 Follow-up Visit. 
The Safety Analysis/Full Analysis Set is the group of subjects who receive at least one dose 
of study treatment. 


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The PK Analysis Set is the group of subjects who receive study treatment and complete at 
least one scheduled post-treatment PK evaluation. 
 
Subject Disposition 
All subjects will be tabulated as to study discontinuation and the reasons for discontinuation 
as described in Section 9.3.3. 
 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized.  For continuous demographic 
variables, results will be summarized and presented as N, mean, SD, median, and minimum 
and maximum values.  For categorical (nominal or ordinal) variables, the number and 
percentage of subjects will be used.  No statistical testing will be performed. 
 
Prior and Concomitant Therapy 
All Investigator terms for medications recorded in the CRF/eCRF will be coded to an 
11-digit code using the World Health Organization Drug Dictionary drug codes. 
Prior medications will be defined as medications that stopped before the first dose of study 
drug. 
Concomitant medications will be defined as medications that (1) started before the first dose 
of study drug and were continuing at the time of the first dose of study drug, or (2) started on 
or after the date of the first dose of study drug.  Prior and concomitant medications will be 
further coded to the appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating 
therapeutic classification.  A listing of prior and concomitant medications by drug and drug 
class will be included in the clinical study report for this protocol. 
All medications will be presented in subject data listings. 
 
Activity Analyses 
AK lesion counts will be summarized at Day 1 (pretreatment) and at each subsequent 
timepoint for subjects in the Full Analysis Set and the Per-Protocol Set. 
A 95% confidence interval (CI) for the complete clearance (response rate) at Day 57 and 
12 months post-Day 57 will be estimated in the Evaluable Set. 
Recurrence rates for all subjects who achieved complete clearance at Day 57 will be 
summarized by timepoint in the Evaluable Set. 


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Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
9.7.1.7.1 PHARMACOKINETIC ANALYSES 
PK analyses will be performed on the PK Analysis Set. 
Plasma concentrations of KX2-391 will be analyzed to determine Cmax, and where applicable, 
AUCt, Cmin, and accumulation ratio R. 
Individual timepoints will be tabulated and displayed graphically and listed for all subjects.  
Summary PK parameters will be analyzed as applicable. 
9.7.1.7.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
Not applicable 
 
Safety Analyses 
All subjects in the Safety Analysis Set will be included in the safety analyses. 
Safety data will be summarized using descriptive statistics (eg, n, mean, SD, median, 
minimum, maximum for continuous variables; n [%] for categorical variables).  Safety 
variables include AEs, clinical laboratory parameters, weight, vital signs, 12-lead ECG 
results, and physical examination findings 
9.7.1.8.1 EXTENT OF EXPOSURE 
The actual number of doses for each subject will be summarized. 
9.7.1.8.2 ADVERSE EVENTS 
For AEs, verbatim terms on the CRFs/eCRFs will be mapped to preferred terms (PTs) and 
system organ classes (SOCs) using the Medical Dictionary for Regulatory Activities 
(MedDRA; version 16.0 or higher).  Subject incidence of AEs will be displayed by SOC.  
Adverse events will also be summarized by severity and relationship to study drug.  Subject 
incidence of SAEs will also be displayed. 
Only those AEs that were treatment-emergent will be included in summary tables.  
Treatment-emergent AEs are defined as: 
x either those AEs with an onset after dosing or  
x those pre-existing AEs that worsen after dosing 
All AEs, treatment emergent or otherwise, will be presented in subject data listings. 
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT.  A subject data listing of all AEs leading to death will be provided. 


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The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT.  A subject data listing of all AEs leading to 
discontinuation from study drug will be provided. 
9.7.1.8.3 LABORATORY VALUES 
Laboratory parameters will be summarized using descriptive statistics at baseline and at each 
subsequent timepoint.  Changes from baseline will also be summarized. 
In addition, shift tables (ie, low-normal-high at baseline versus low-normal-high at follow-up 
in a 3-by-3 contingency table) will be provided to assess changes in laboratory values from 
baseline to follow-up. 
9.7.1.8.4 VITAL SIGNS 
Vital sign values will be evaluated on an individual basis by subject.  Abnormal vital sign 
values will be identified as those outside (above or below) the reference range. 
9.7.1.8.5 ELECTROCARDIOGRAMS 
ECG data will be tabulated for each individual subject. 
9.7.1.8.6 PHYSICAL EXAMINATIONS 
Physical examination findings will be listed for each subject. 
9.7.1.8.7 PREGNANCY TESTS 
Results of pregnancy tests will be listed for all subjects, as applicable. 
9.7.1.8.8 OTHER ANALYSES 
Local Skin Reactions 
Local skin reactions as reported by the Investigator will be displayed and summarized by 
visit for all subjects. 
Pigmentation and Scarring 
Pigmentation and scarring as reported by the Investigator will be displayed and summarized 
by visit for all subjects. 
9.7.2 
Determination of Sample Size 
A sample size of 60 subjects is sufficient to detect a 100% complete clearance rate at Day 57 
greater than 20% with 80% power, based on a two-sided (alpha=0.05) binomial test, 
assuming a response rate of 35%, and less than a 25% dropout rate.  This corresponds to a 
two-sided 95% CI with a half-width of less than 15% (ie, lower boundary of the CI above 
20%). 


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9.7.3 
Interim Analysis 
Since this is an open-label study, after each group of 20 subjects completes Day 57 
assessments, activity data will be tabulated. 
9.7.4 
Other Statistical/Analytical Issues 
Not applicable 
9.7.5 
Procedure for Revising the Statistical Analysis Plan 
If the prespecified plans need to be revised after the study starts, the Sponsor will determine 
how the revision impacts the study and how the revision should be implemented.  The details 
of the revision will be documented and described in the clinical study report. 


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10 REFERENCE LIST 
1. ICH E6: Guidance for Industry - E6 Good Clinical Practice: Consolidated Guidance, 
US Department of Health and Human Services, Food and Drug Administration, April 
1996. 
2. Marks R, Rennie G, Selwood TS.  Malignant transformation of solar keratoses to 
squamous cell carcinoma.  Lancet 1988;1(8589):795-7. 
3. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: natural history 
and risk of malignant transformation in the Veterans Affairs Topical Tretinoin 
Chemoprevention Trial. Cancer 2009;115(11):2523-30. 
4. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol 
2000;42(1 Pt 2):23-4. 
5. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am 
Acad Dermatol 2000;42(1 Pt 2):4-7. 
6. Guidelines for the Management of Actinic Keratoses.  2004/2005 European 
Dermatology Forum.  Available from: http://www.euroderm.org  [Accessed 02 July 
2012]. 
7. Drake LA, Ceilley RI, Cornelison RL, et al. Guidelines of care for actinic keratoses. 
Committee on Guidelines of Care. J Am Acad Dermatol 1995;32(1):95-8. 
8. Suchniak JM, Baer S, Goldberg LH. High rate of malignant transformation in 
hyperkeratotic actinic keratoses. J Am Acad Dermatol 1997;37(3 Pt 1):392-4. 
9. Ehrig T, Cockerell C, Piacquadio D, et al. Actinic keratoses and the incidence of 
occult squamous cell carcinoma: a clinical-histopathologic correlation. Dermatol Surg 
2006;32(10):1261-5. 
10. Berman B, Bienstock L, Kuritzky L, et al. Primary Care Education Consortium; 
Texas Academy of Family Physicians. Actinic keratoses: sequelae and treatments. 
Recommendations from a consensus panel.  J Fam Pract 2006;55(5 Suppl):1-8. 
11. Quaedvlieg PJ, Tirsi E, Thissen MR, et al. Actinic keratosis: how to differentiate the 
good from the bad ones? Eur J Dermatol 2006;16(4):335-9. 
12. Marks R, Foley P, Goodman G, et al.  Spontaneous remission of solar keratoses:  the 
case for conservative management. Br J Dermatol 1986;115(6):649-55. 


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11 APPENDICES 
 
 


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Appendix 1 
Fitzpatrick Skin-Type Classification 
 


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Appendix 2 
Photographs of Local Skin Reactions 
 
 
Source:  (CDER) Clinical Review NDA 202833 PICATO™ (ingenol mebutate gel, PEP005 Gel) November 
30, 2011. 
 

SAP_001.pdf: 
Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN 
 
Study Protocol Number: 
KX01-AK-002 
Study Protocol Title: 
A Phase 2a, Open-Label, Multicenter, Activity and 
Safety Study of KX2-391 Ointment 1% in Subjects with 
Actinic Keratosis on the Face or Scalp 
Date: 
01 Aug 2018 
Version: 
1.0 


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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................4 
3 
INTRODUCTION .............................................................................................................5 
3.1 
Study Objectives ......................................................................................................5 
3.1.1 
Primary Objective ..........................................................................................5 
3.1.2 
Secondary Objectives.....................................................................................5 
3.1.3 
Exploratory Objectives ..................................................................................5 
3.2 
Overall Study Design and Plan ................................................................................5 
4 
DETERMINATION OF SAMPLE SIZE ..........................................................................6 
5 
STATISTICAL METHODS ..............................................................................................6 
5.1 
Study Endpoints .......................................................................................................6 
5.1.1 
Primary Endpoint ...........................................................................................6 
5.1.2 
Secondary Endpoints .....................................................................................6 
5.1.3 
Exploratory Endpoints ...................................................................................7 
5.2 
Study Subjects ..........................................................................................................7 
5.2.1 
Definitions of Analysis Sets...........................................................................7 
5.2.2 
Subject Disposition ........................................................................................7 
5.2.3 
Protocol Deviations ........................................................................................8 
5.2.4 
Demographic and Other Baseline Characteristics .........................................8 
5.2.5 
Prior and Concomitant Therapy .....................................................................8 
5.2.5.1 
Prior and Concomitant Medications ....................................................8 
5.2.5.2 
Procedures ............................................................................................9 
5.2.6 
Treatment Compliance and Extent of Exposure ............................................9 
5.2.6.1 
Extent of Exposure ...............................................................................9 
5.2.6.2 
Treatment Compliance .......................................................................10 
5.3 
Data Analysis General Considerations ..................................................................10 
5.4 
Activity Analyses ...................................................................................................10 
5.4.1 
Primary Activity Analyses ...........................................................................10 
5.4.2 
Secondary Activity Analyses .......................................................................10 
5.4.3 
Other Activity Analyses ...............................................................................10 
5.4.4 
Exploratory Analyses ...................................................................................10 
5.4.5 
Subgroup Analysis .......................................................................................11 
5.5 
Safety Analyses ......................................................................................................11 
5.5.1 
Adverse Events ............................................................................................11 
5.5.2 
Local Skin Reactions ...................................................................................13 
5.5.3 
Pigmentation and Scarring ...........................................................................13 
5.5.4 
Laboratory Data – Hematology and Blood Chemistry ................................14 


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5.5.5 
Laboratory Data – Urinalysis .......................................................................14 
5.5.6 
Vital Signs ....................................................................................................15 
5.5.7 
12-Lead Electrocardiograms ........................................................................15 
5.5.8 
Other Safety Analyses..................................................................................15 
6 
ONGOING ANALYSES .................................................................................................15 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................16 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................16 
8.1 
Baseline Values ......................................................................................................16 
8.2 
Adverse Event Relationship to Study Drug ...........................................................16 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................16 
10 STATISTICAL SOFTWARE ..........................................................................................16 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................16 
12 APPENDICES .................................................................................................................16 
12.1 
Schedule of Procedures and Assessments..............................................................16 
12.2 
Vital Sign Normal Ranges .....................................................................................21 
12.3 
List of Subjects Whose Disposition Events in the Recurrence Follow-up 
Period Are Recategorized to AK Recurrence ........................................................21 
 


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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
AK 
actinic keratosis 
ADS 
analysis data specifications 
CI 
confidence interval 
LSR 
local skin reaction 
LOCF 
last observation carried forward 
PT 
preferred term 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
 


Statistical Analysis Plan 
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3 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the protocol for study KX01-AK-002 
Amendment 2, v3.0, dated 26SEP2016.  This SAP supersedes the statistical section of the 
protocol and provides data analysis details for the activity and safety data analysis in the 
clinical study report (CSR).  It does not include information regarding the pharmacokinetic 
(PK) analysis of the study drug, KX2-391 Ointment 1.0%; that information is provided 
separately. 
3.1 
Study Objectives 
As stated above, objectives related to the PK analysis are not discussed in this document. 
3.1.1 
Primary Objective 
x To evaluate the activity of KX2-391 Ointment 1% administered topically to the face or 
scalp in subjects with actinic keratosis (AK) by determining complete response rate, 
defined as 100% clearance at Day 57 
3.1.2 
Secondary Objectives 
x To assess the activity of KX2-391 Ointment 1% during Days 1-57 
x To assess the safety and tolerability of KX2-391 Ointment 1% in subjects with AK on 
the face or scalp 
x To assess dose regimens by contrasting 5-day treatment with 3-day treatment in terms 
of the activity and safety of KX2-391 Ointment 1% in subjects with AK on the face or 
scalp 
3.1.3 
Exploratory Objectives 
x To determine recurrence rates up to 12 months post-Day 57 for subjects who show 
response at Day 57 
x To determine sustained response rates at 12 months post-Day 57 for subjects who show 
response at Day 57 
3.2 
Overall Study Design and Plan 
This is an open-label, multicenter, activity, safety, tolerability, and PK study of KX2-391 
Ointment 1% administered topically to the face or scalp of subjects with actinic keratosis in 2 
sequential cohorts: a 5-day dosing regimen (Cohort 1) and a 3-day dosing regimen (Cohort 2). 
The study consists of Screening, Treatment, Follow-up, and Recurrence Follow-up Periods. 
In Cohort 1, eligible subjects will receive 5 consecutive days of topical treatment, to be applied 
at the study site, with 50 mg of KX2-391 Ointment 1% each day. Blood samples for PK 
analysis will be collected on Day 1 and Day 5.  Subjects will return for Follow-up visits until 


Statistical Analysis Plan 
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Day 57.  Only Day 57 complete responders will continue Recurrence Follow-up Visits every 
3 months for an additional 12 months after Day 57. Activity (lesion counts) and safety 
evaluations will be performed. 
The Sponsor will review accumulating data.  If the 5-day regimen (Cohort 1) has sufficient 
activity and safety to warrant evaluating a 3-day regimen, enrollment of Cohort 2 will start 
after there are 60 evaluable subjects or up to 80 subjects are enrolled (whichever comes first) 
in Cohort 1.  For the most part, protocol procedures for Cohort 1 will be duplicated for Cohort 
2, except PK samples will be collected on Days 1 and 3, and subjects will not return for Visits 
5 and 6. 
4 
DETERMINATION OF SAMPLE SIZE 
For either cohort, a sample size of 60 subjects is sufficient to detect a 100% clearance rate at 
Day 57 greater than 20% with 80% power, based on a two-sided (alpha=0.05) binomial test, 
assuming a response rate of 35%, and less than a 25% dropout rate.  This corresponds to a two-
sided 95% confidence interval (CI) with a half-width of less than 15% (ie, lower boundary of 
the CI above 20%).  The sample size of Cohort 2 may be adjusted, depending on the results of 
Cohort 1. 
5 
STATISTICAL METHODS 
Statistical analyses will be reported using summary tables, graphs and data listings. In general, 
continuous variables will be summarized with mean, standard deviation (SD), median, 
minimum, and maximum. Categorical variables will be summarized with counts and 
percentage of subjects in corresponding categories. 
5.1 
Study Endpoints 
5.1.1 
Primary Endpoint 
x Activity will be evaluated by complete response rate, which is defined as the proportion 
of subjects achieving 100% clearance of all treated AK lesions on the face or scalp at 
Day 57. 
5.1.2 
Secondary Endpoints 
x Activity: Reduction in lesion counts during Days 1-57 
x Safety: Evaluation of adverse events (AEs), local skin reactions (LSRs) and clinical 
laboratory data; the results of other safety assessments (vital signs, physical 
examinations, ECGs) will also be evaluated 


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5.1.3 
Exploratory Endpoints  
x Recurrence rate will be estimated with a Kaplan-Meier method for subjects who 
achieved 100% clearance at Day 57 (Visit 10) with any identified AK lesions on the 
treatment area at 3, 6, 9, and 12 months post-Day 57. 
x Sustained response rate will be estimated with the same Kaplan-Meier method for 
subjects who achieved 100% clearance at Day 57 (Visit 10) without any identified AK 
lesions on the treatment area at 12 months post-Day 57. 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
x Per-Protocol Set:  the group of protocol-eligible subjects who receive 5 days (Cohort 1) 
or 3 days (Cohort 2) of study treatment and complete at least one scheduled post-
treatment AK lesion evaluation 
x Evaluable Set:  the group of protocol-eligible subjects who receive 5 days (Cohort 1) 
or 3 days (Cohort 2) of treatment and complete Day 1 and Day 57 AK lesion 
evaluations  
x Safety Analysis/Full Analysis Set:  the group of subjects who receive at least one dose 
of study treatment 
x Recurrence Follow-up Set:  the group of subjects who achieve complete clearance at 
Day 57 
5.2.2 
Subject Disposition 
For screen failure subjects, a listing will be provided to present their screen failure reasons. 
The number of subjects in each analysis set (Safety/Full Analysis, Per-Protocol, Evaluable, 
and Recurrence Follow-up) will be tabulated by cohort. 
For the Safety/Full Analysis Set, subject disposition will be summarized by cohort for:  
x Subjects dosed  
x Subjects who completed the Day 57 visit  
x Subjects who achieved 100% AK clearance at the Day 57 visit 
x Subjects who discontinued before the Day 57 visit and their primary reason for 
discontinuation  
In addition, the number of subjects dosed and the number of subjects who completed the 
Day 57 visit will be summarized by study site and cohort. 
A listing of those subjects who discontinued before the Day 57 visit and the associated reasons 
will be presented.  


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For the Recurrence Follow-up Set, the recorded discontinuation reasons will be reviewed and 
subjects who discontinued early due to AK recurrence will be assigned “AK Recurrence” as 
the new primary reason for discontinuation. 
Subject disposition will be summarized by cohort for:  
x Subjects who entered the Recurrence Follow-up Period  
x Subjects who completed the Recurrence Follow-up Period  
x Subjects who discontinued during the Recurrence Follow-up Period and their primary 
reason for discontinuation 
Subjects who discontinued during the Recurrence Follow-up Period will also be listed.  
5.2.3 
Protocol Deviations 
Any protocol deviations identified during site monitoring will be captured on the eCRF.  A 
listing with protocol deviation details will be presented. 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic data and baseline characteristics will be analyzed for the Safety/Full Analysis 
Set, the Per-Protocol Set, the Evaluable Set, the Recurrence Follow-up Set, the subjects with 
recurrence in the Recurrence Follow-up Set and the subjects without recurrence at 12 Months 
Post-Day 57 Visit in the Recurrence Follow-up Set. 
Demographic data, including age (in years), age category (65), sex, race, and ethnicity 
will be summarized by cohort. 
Baseline characteristics, including location of treatment area (face or scalp), Fitzpatrick skin 
type, baseline weight, primary diagnosis of treatment area, and baseline AK lesion count will 
be summarized by cohort. 
Demographic and baseline characteristic data mentioned above will be presented in data 
listings for the Safety/Full Analysis Set only. 
Other baseline data, including AK history, AK treatment history, medical history for non-AK 
conditions, and surgical history for non-AK conditions will be listed for the Safety/Full 
Analysis Set.  
5.2.5 
Prior and Concomitant Therapy 
5.2.5.1 
Prior and Concomitant Medications 
Non-study treatment medications will be recorded on the eCRF from 28 days before Day 1 
through the final study visit. All verbatim terms collected will be coded with the World Health 
Organization Drug Dictionary (WHO-DD) March 1, 2017.  


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Prior medications will be defined as medications that stopped before the first dose of study 
treatment. 
Concomitant medications will be defined as medications that (1) started before the first dose 
of study treatment and were continuing at the time of the first dose of study treatment, or (2) 
started on or after the date of the first dose of study treatment. Since it may not be able to 
determine medication dates relative to the first dose of study treatment due to partial or missing 
dates, if a medication cannot be determined to be ‘prior’ (ie, before the first dose of study 
treatment), it will be considered a concomitant medication. 
Furthermore, to identify medications that start before the Recurrence Follow-up Period, start 
dates will be compared with the actual Day 57 visit date for each subject.  If a medication start 
date cannot be confirmed to fall in the Recurrence Follow-up Period due to missing or partial 
dates, this medication will be considered to have started before this period. 
The number and percentage of the subjects with concomitant medications starting before the 
Recurrence Follow-up Period will be summarized for the Safety/Full Analysis Set: 
1) by anatomical therapeutic chemical class, standardized drug name, and cohort 
2) by standardized drug name and cohort 
The incidence of concomitant medications in the Recurrence Follow-up Period (i.e. those start 
after Day 57 visit) will be summarized in the same way, but separately. 
In addition, a listing of all prior and concomitant medications collected throughout the entire 
study will be provided.  
5.2.5.2 
Procedures 
All procedures collected on the eCRF will be presented in a data listing. 
5.2.6 
Treatment Compliance and Extent of Exposure 
5.2.6.1 
Extent of Exposure 
In general, subjects in each cohort at each dosing schedule received study drug in the range of 
30 to 70 mg with 50 mg being the most common dose, as planned in the protocol. However, 
one subject from Cohort 1 and two subjects from Cohort 2 received 500 mg of study drug for 
each daily dose during their treatment period. In addition, dosing amount of another two 
subjects from Cohort 1 at Day 1 is missing because the site personnel inadvertently did not 
record the amount dosed after applying the study treatment on the subjects. Compared with 
other subjects, these overdosed or dose-missing subjects showed similar safety and activity 
profiles. Thus, they are still considered as protocol-eligible subjects.  
The number of doses each subject received will be summarized as a continuous variable by 
cohort at each visit. 


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5.2.6.2 
Treatment Compliance 
Study treatment compliance will be defined as the actual number of doses a subject received 
divided by the planned number of doses, 5 (Cohort 1) or 3 (Cohort 2).  Study treatment 
compliance will be summarized by cohort.  
5.3 
Data Analysis General Considerations 
Both cohorts will be analyzed with the same statistical methods. Since this is not a dose 
regimen-randomized study, contrast between the 2 cohorts may be performed, but would 
mainly be noninferential, and consist of listings and descriptive statistics. 
5.4 
Activity Analyses 
5.4.1 
Primary Activity Analyses 
The proportion of subjects with 100% clearance of all treated AK lesions at Day 57 will be 
considered to follow a binomial distribution. Based on the number of subjects who achieved 
100% clearance at Day 57, the complete response rate and its corresponding 95% Clopper-
Pearson Exact CI will be estimated in the Evaluable Set. 
5.4.2 
Secondary Activity Analyses 
The number of AK lesions at the Screening, Day 1, Day 8, Day 15, Day 29, and Day 57 visits 
and actual/percentage lesion number change from baseline will be summarized by cohort at 
each visit in the Per-Protocol Set. Baseline values are defined as the assessments at Day 1.  
5.4.3 
Other Activity Analyses 
The number of subjects with partial clearance (75%) of treated AK lesions at Day 57 will be 
analyzed in the same way as the primary activity endpoint. 
5.4.4 
Exploratory Analyses 
Analysis visits in the Recurrence Follow-up Period will be mapped based on the actual days 
relative to the Day 57 visit of each subject: 
Actual Visit Date - Day 57 Visit Date 
Analysis Visit 
Between 1 and 136 (inclusive)  
3 MONTHS POST-DAY 57 
Between 137 and 226 (inclusive)  
6 MONTHS POST-DAY 57 
Between 227 and 316 (inclusive)  
9 MONTHS POST-DAY 57 
317 and Beyond 
12 MONTHS POST-DAY 57 
Recurrence rates and the associated 95% CIs will be evaluated with a Kaplan-Meier method at 
each post-Day 57 analysis visit:  
RRj=1 - Sj, with Sj= Sj-1*[1 - Rj/Nj] for j>0 and S0=1 


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where 
j: Visit j  
RRj: Recurrence rate at visit j  
Sj: Sustained response rate at visit j 
Rj: Number of subjects with AK lesion recurrence at visit j  
Nj: Number of subjects at risk at visit j  
Early-discontinued subjects with no AK recurrence will be considered as censored at the last 
visit with AK lesion assessment. Completed subjects with no AK recurrence will be considered 
as censored at 12 Months post-Day 57 visit. The number of subjects at risk for visit j will be 
calculated as Nj-1 - Rj-1 - Cj-1, where Nj-1 is the number of subjects at risk at the visit j-1. Rj-1 is 
the number of subjects with recurrence at the visit j-1 and Cj-1 is the number of subjects 
censored at visit j-1. 
The recurrence rates and their associated 95% CIs will be presented by analysis visit, treatment 
location, and cohort for the Recurrence Follow-up Set.   
Similarly, the sustained response rate and its 95% CI at 12 Months Post-Day 57 will be 
estimated by treatment location and cohort for the Recurrence Follow-up Set.   
A listing of subjects who is included in the Kaplan-Meier analysis will be presented to provide 
their event or censoring details. 
5.4.5 
Subgroup Analysis 
Complete clearance rate at Day 57, partial clearance rate at Day 57, sustained response rate at 
12 Months Post-Day 57 will be analyzed by cohort in the following subJURXSVDJH
sex (female, male), baseline AK lesion count (4, 5, 6, 7 and 8), baseline weight (< 200 and 
OEVVNLQW\SHJURXSHDFKVNLQW\SHVWXG\VLWHHDFKVWXG\VLWH  
5.5 
Safety Analyses 
All safety variables will be analyzed in the Safety/Full Analysis Set. 
5.5.1 
Adverse Events 
All AEs, regardless of relationship to study treatment, will be collected from the time the 
subject signs the informed consent form through the final contact in the Follow-up Period at 
Day 57. In addition, treatment-related AEs/SAEs may be followed after the Day 57 visit to 
resolution, or if resolution is unlikely, to stabilization. For subjects participating in the 
Recurrence Follow-up Period, all spontaneously reported AEs will be collected whether they 
occurred at the treatment area or not. 


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For AEs, verbatim terms on the eCRF will be mapped to system organ classes (SOCs) and 
preferred terms (PTs) using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 18.1. 
Treatment-emergent AEs (TEAEs) will be identified, and are defined as: 
x Either those AEs with an onset on or after the first dose date/time of study treatment 
x Those pre-existing AEs that worsen after the first dose date/time of study treatment 
If an AE cannot be determined to be treatment-emergent according to the definition above due 
to partial or missing dates, it will be considered as a TEAE unless it is confirmed to have 
stopped before the first dose date/time of study treatment. 
Furthermore, to identify TEAEs that start before the Recurrence Follow-up Period, AE start 
dates will be determined relative to the actual Day 57 visit date for the corresponding subject. 
In such cases, if an AE start date cannot be confirmed to fall within the Recurrence Follow-up 
Period due to partial or missing dates, that AE will be considered to have started before that 
period. 
An overall summary table of AEs will include the number of subjects with the following events 
for each cohort.  
x Any AEs 
x Any TEAEs 
x Any AEs that are at least possibly related to study treatment, including those definitely 
related, probably related and possibly related or those with missing relationship 
x Any serious AEs 
x Any severe AEs 
x Any AEs leading to study discontinuation   
x Any AEs that are associated with death 
In addition, summaries of the number of subjects with the following AEs will be displayed for 
each cohort: 
x All TEAEs by SOC and PT  
x All TEAEs by PT 
x All TEAEs by PT and maximum severity (mild, moderate, or severe)  
x All AEs that are at least possibly related to study treatment by SOC and PT 
x All AEs that are at least possibly related to study treatment by PT 
x All AEs that are at least possibly related to study treatment by PT and maximum 
severity (mild, moderate or severe) 


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Severe or serious AEs, whether treatment-emergent or not, will be presented in listings.  AEs 
leading to treatment discontinuation will also be listed.  
AEs that are collected during the Recurrence Follow-up Period (i.e. those with start dates after 
Day 57 visit) will be summarized and listed in the same way, but separately, for the Recurrence 
Follow-up Set. 
Moreover, all AEs will be reviewed manually by the study Medical Monitor to identify any 
skin cancer-related records. Those event records will be displayed in a separate listing.  
All AEs collected during the entire study including the Recurrence Follow-up Period will be 
presented in a subject data listing. 
5.5.2 
Local Skin Reactions  
LSRs will be assessed using a 5-point grading scale ranging from 0 (Not Present) to 4 (Worst) 
for such signs as Erythema, Flaking/Scaling, Crusting, Swelling, Vesiculation/Pustulation, 
Erosion/Ulceration on the treatment area at the following visits:  Day 1, Day 2, Day 3, Day 4 
(Cohort 1 only), Day 5 (Cohort 1 only), Day 8, Day 15, Day 29, and Day 57. In addition, LSRs 
may be followed after the Day 57 visit to resolution, or if resolution is unlikely, to stabilization. 
LSR baseline grades are defined as the LSR grades recorded at Day 1 (either pre-dose or post-
dose).  
The incidence of LSRs will be summarized by grade and cohort at each visit for each sign.  In 
addition, LSR grades will be regarded as continuous values and will be summarized using 
descriptive statistics by cohort at each visit for each sign.  Similarly, grades for each LSR sign 
will be visually presented in bar graphs by cohort at each visit.  
Further, the incidence of the worst post-baseline LSR grade will be summarized by LSR grade 
and cohort for each sign.  
The number of subjects with shift from baseline to the worst post-baseline grade and to the 
Day 57 grade will be summarized by cohort for each sign. 
Furthermore, a composite LSR score will be constructed by summing the individual LSR 
grades for each sign at each visit. This composite score and change from baseline will be 
summarized by cohort at each visit using descriptive statistics.  In addition, this score will be 
presented graphically by cohort in a line plot.  
All LSR grades, including the derived composite score, and any associated comments will be 
displayed in data listings. 
5.5.3 
Pigmentation and Scarring 
Presence or absence of pigmentation (including hypo-pigmentation and hyper-pigmentation) 
and scarring will be assessed on the treatment area at the following visits:  Day 1, Day 2, Day 3 


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Day 4 (Cohort 1 only), Day 5 (Cohort 1 only), Day 8, Day 15, Day 29, and Day 57. In addition, 
pigmentation and scarring may be followed after the Day 57 visit to resolution, or if resolution 
is unlikely, to stabilization. 
Results will be summarized by cohort at each visit.  The number of subjects with shift from 
baseline to Day 57 will be summarized by cohort. 
All pigmentation and scarring records with comments will be presented in data listings. 
5.5.4 
Laboratory Data – Hematology and Blood Chemistry  
Laboratory assessments for hematology and blood chemistry will be performed at Screening, 
Day 8, and Day 57.  
Actual values, changes from baseline, and percentage change from baseline for the following 
laboratory parameters will be summarized by cohort at each visit using descriptive statistics. 
x Hematology:  
Red Blood Cells, Hemoglobin, Hematocrit, Platelets, White Blood Cells, Neutrophils 
(Absolute Count), Neutrophils (%), Lymphocytes (Absolute Count), Lymphocytes (%), 
Monocytes (Absolute Count), Monocytes (%), Eosinophils (Absolute Count), Eosinophils (%), 
Basophils (Absolute Count), Basophils (%), Mean Corpuscular Volume, Mean Corpuscular 
Hemoglobin, Mean Corpuscular Hemoglobin Concentration, Red Blood Cell Distribution 
Width 
x Blood Chemistry:  
Electrolyte: Sodium, Potassium, Chloride, Carbon Dioxide 
Liver Function: Alkaline Phosphatase, Aspartate Aminotransferase (AST), Alanine 
Aminotransferase (ALT), Gamma-glutamyl Transferase (GGT), Bilirubin (Total), Bilirubin 
(Direct) 
Renal Function: Blood Urea/Blood Urea Nitrogen, Creatinine 
Other: Glucose, Calcium, Albumin, Cholesterol, Triglycerides, Phosphorus, Lactate 
Dehydrogenase (LDH), Total Protein, Uric Acid 
These laboratory parameters will also be analyzed using shift tables by post-baseline visit (Day 
8 and Day 57) and cohort.  
Listings of all hematology and blood chemistry values will be provided with abnormalities 
flagged. 
5.5.5 
Laboratory Data – Urinalysis  
Urinalysis assessment will be performed at Screening, Day 8 and Day 57.  All parameter values 
will be provided in a data listing with abnormalities flagged.  


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5.5.6 
Vital Signs 
Vital signs (systolic/diastolic blood pressures, pulse rate, respiratory rate and body 
temperature) will be assessed at the following visits:  Screening, Day 3 (Cohort 2 only), Day 5 
(Cohort 1 only), Day 8, Day 15, Day 29, and Day 57. 
Actual values, change from baseline, and percentage change from baseline for each vital sign 
parameter will be summarized using descriptive statistics by cohort at each visit.  
A listing of vital sign values will be provided with flags for those outside (above or below) the 
reference range (see Section 12.2). 
5.5.7 
12-Lead Electrocardiograms 
A 12-lead ECG will be completed at Screening, Day 1 (4 hours postdose, Cohort 2 only), Day 
3 (4 hours postdose, Cohort 2 only), Day 8, and Day 57 to assess rhythm, heart rate, and 
intervals (PR, QRS, QT, and QTcF). 
QTc will be collected.  Study sites may have applied different formulae for calculation of QTc, 
therefore, this parameter will be reported in a data listing, but will not be analyzed.  
For heart rate and ECG intervals, actual values, changes from baseline, and percentage change 
from baseline will be summarized using descriptive statistics by cohort at each visit. 
Additionally, a listing of subjects with clinically significant abnormal ECG results will be 
presented.  
All 12-lead ECG data, including details of abnormal findings from investigators, will be 
provided in a subject listing. 
5.5.8 
Other Safety Analyses 
Physical examination findings at Screening and Day 57 will be listed for each subject. 
Weight will be measured at Screening and Day 57.  Actual values, change from baseline, and 
percentage change from baseline will be summarized by cohort and visit. 
Results of pregnancy tests will be listed for subjects if applicable. 
6 
ONGOING ANALYSES 
A formal interim analysis is not planned.  Since this is an open-label study, after each group of 
approximately 20 subjects, ongoing analyses will be performed with tabulation of activity, 
LSRs, and adverse events. 


Statistical Analysis Plan 
Protocol: KX01-AK-002 
 
 
Kinex Pharmaceuticals  
v1.0_01 Aug 2018 
Confidential 
 
 
Page 16 of 23 
 
7 
CHANGES IN THE PLANNED ANALYSES 
Definition of the Evaluable Set is updated to include Day 1 and Day 57 AK lesion evaluations 
only.  
The Recurrence Follow-up Set is defined in this document to analyze data collected during the 
Recurrence Follow-up Period.  
AK recurrence is not listed as a discontinuation event on CRF. The Sponsor reviewed all 
collected disposition event details and recategorized the subjects who discontinued due to AK 
recurrence in the Recurrence Follow-up Period into a new category of primary reason for 
discontinuation - “AK recurrence” (See Section 12.3).   
The recurrence rates and the sustained response rate will be estimated with a Kaplan-Meier 
method to consider censored subjects who discontinued due to non-AK recurrence reasons. 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 
Baseline Values  
Unless stated otherwise, baseline values are defined as the last non-missing data collected 
before or on the first dose date/time, which would be either, the Screening or Day 1 visit.  
8.2 
Adverse Event Relationship to Study Drug 
If an adverse event relationship to study drug is missing, it will be considered as related to 
study drug.  
9 
PROGRAMMING SPECIFICATIONS 
Analysis dataset specifications will be provided as a stand-alone document. 
10 STATISTICAL SOFTWARE 
Statistical software SAS® v9.4 will be used for all summaries and statistical analyses. 
11 MOCK TABLES, LISTINGS, AND GRAPHS 
Mock tables, listings, and graphs will be provided as standalone documents. 
12 APPENDICES 
12.1 Schedule of Procedures and Assessments