Conditions: Graft Versus Host Disease JNS Kinase Topical Administration
Keywords: cGVHD Epidermal JAK Inhibitor Skin JAK-STAT
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
Background:

About half the people who have a hematopoietic stem cell transplant using donor cells get Chronic Graft Versus Host Disease (cGVHD). This is chronic graft versus host disease. Immune cells from the donor may see the body tissues in the person as foreign and attack, causing damage. The skin is the most commonly affected organ. Most cGVHD therapies have serious side effects. The cream ruxolitinib inhibits proteins that may play a role in cGVHD.

Objective:

To test the safety and effectiveness of topical ruxolitinib 1.5 percent cream in people with cGVHD of the skin.

Eligibility:

People ages 12 and older with epidermal skin cGVHD

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Skin sample taken (biopsy) to confirm the diagnosis.

At the baseline visit, participants will have:

Skin disease measured with rulers, photographs, and tracing the outline of skin lesions

To complete questionnaires about their symptoms

Blood and urine tests

Some participants will also have a skin biopsy, or total body photographs while they wear only underwear.

Participants will get the ruxolitinib cream and a placebo cream to apply to 2 separate areas of disease. They will do this twice a day for 6 weeks, if they do not have serious side effects. Neither the study team nor the participant will know which area will get ruxolitinib cream and the placebo cream.

Participants will write down:

* When they apply the creams
* Any side effects
* Any medications they take

Most participants will have 4 visits during the 6 weeks they use the creams. Some will have 3 visits and a phone call to see how they are doing. All participants will get a call 4-6 weeks after they stop. Visits include physical exams, blood tests, skin disease measurements, questionnaires, and photos.

Detailed description:
Background:

* Chronic graft-versus-host disease (cGVHD) develops in approximately half of individuals who undergo allogeneic hematopoietic cell transplant (HCT) and is the leading cause of non-relapse mortality.
* There are no skin-targeted therapies for cutaneous cGVHD that are directed to the pathogenesis of cGVHD.
* Many inflammatory cytokines involved in the pathogenesis of cGVHD signal through the Janus kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathway.
* Systemic JAK inhibitors have been studied in GVHD murine models and in humans with improvement at the cellular and clinical level.
* Topical JAK inhibitors have not been studied in cutaneous cGVHD but have demonstrated the ability to decrease inflammatory markers as well as improve clinical findings of psoriasis.

Objectives:

* To determine the safety and tolerability of topical ruxolitinib 1.5% cream in patients with cutaneous cGVHD with epidermal involvement (non-sclerotic form)
* To determine the efficacy of topical ruxolitinib 1.5% cream in patients with cutaneous cGVHD with epidermal involvement (non-sclerotic form)

Eligibility:

Inclusion:

* Age greater than or equal to 12 years old
* Histologically confirmed epidermal cGVHD (including lichen planus-like, papulosquamous, erythematous) involving at least 2 separate, non-ulcerated sites that can be delineated by body region (e.g., right forearm and left forearm)
* Stable systemic cGVHD treatment including immunosuppressant therapy for 4 weeks prior to enrollment
* Karnofsky or Lansky score greater than or equal to 60%

Exclusion:

* Concurrent use of JAK inhibitors (topical or systemic), fluconazole, or strong Cytochrome P450 3A4 (CYP3A4) inhibitors
* Known hypersensitivity to JAK inhibitors or their components
* Active infection including cytomegalovirus (CMV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV)
* Recurrent or progressive malignancy requiring anticancer treatment
* Patients receiving other investigational agents
* Pregnancy

Design:

* This is a Phase II, placebo-controlled, double-blinded study to determine the safety, tolerability and efficacy of topical ruxolitinib in patients with epidermal cGVHD.
* Participants with at least 2 non-ulcerated sites of epidermal cGVHD will apply topical ruxolitinib 1.5% cream to 1 prespecified site and vehicle cream to the second prespecified site twice a day for 6 weeks.
* Safety will be assessed according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. Assessments will occur during visits and/or phone follow-up every 2 weeks during treatment.
* Efficacy will be assessed at 6 weeks. The initial surface areas of the 2 target lesions will be measured at baseline, week 2, and week 6 on evaluable patients, with the option for an in-person assessment at week 4. The percent decline in the surface area of the 2 lesions will be determined, and the difference in decline between the 2 lesions will be calculated, expressed consistently as ruxolitinib decline minus placebo decline.
* A skin biopsy and peripheral blood samples will be collected prior to treatment and at week 6 to evaluate the cutaneous immune compartment cellular infiltrate, cytokine profiling, signal transducer and activator of transcription (STAT) phosphorylation, and in situ cGVHD biomarkers.
* Pharmacokinetic studies will be performed at week 2.
* Up to 15 patients will be enrolled to achieve 10 evaluable patients, defined as participants who remain active at the time of the primary endpoint. 10 evaluable patients will provide 80% power to detect whether these paired differences in the changes from baseline are equal to one standard deviation (SD) of the difference of the changes (effect size=1.0) using a two-tailed 0.05 significance level paired t-test. In practice, a Wilcoxon signed rank test may be used instead of a t-test if the differences are not consistent with a normal distribution (p\<0.05 by a Shapiro-Wilks test).

Arms:
arm 1: Investigational cream to 1 location; vehicle cream to 2nd location arm 2: Investigational cream to 1 location; vehicle cream to 2nd location

Interventions: intervention 1: Ruxolitinib 1.5% cream intervention 2: vehicle cream
Intervention descriptions: intervention 1: Topical formulation of ruxolitinib, a Janus kinases (JAK) 1/2 inhibitor. intervention 2: Matching vehicle cream applied as a thin film

Protocol document:
ICF_002.pdf: 



























Prot_SAP_000.pdf: 
Abbreviated Title: Topical ruxolitinib in cdVHD 
Version Date: 01/25/2021 
Abbreviated Title: Topical ruxolitinib in cGVHD 
CC Protocol#: 18-AR-0035 
Version Date: 01/25/2021 
NCT Number: NCT03395340 
Title: Phase II study of topical ruxolitinib for cutaneous chronic graft versus host disease 
(cGVHD) 
NIH Principal Investigator: 
1 
Investigational Agents: 
Drug Name: 
Ruxolitinib 
IND Number: 
136890 
Sponsor: 
NlAMS 
Manufacturer: 
Incyte 


2 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
PRECIS 
Background: 
• 
Chronic graft-versns-host disease ( cGVHD) develops in approximately half of 
individuals who undergo allogeneic hematopoietic cell transplant (HCT) and is the 
leading cause of non-relapse mortality. 
• 
There are no skin-targeted therapies for cutaneous cGVHD that are directed to the 
pathogenesis of cGVHD. 
• 
Many inflammatory cytokines involved in the pathogenesis of cGVHD signal through the 
Janus kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathway. 
• 
Systemic JAK inhibitors have been studied in GVHD murine models and in humans with 
improvement at the cellular and clinical level. 
• 
Topical JAK inhibitors have not been studied in cutaneous cGVHD, but have 
demonstrated the ability to decrease inflammatory markers as well as improve clinical 
findings of psoriasis. 
Objectives: 
• 
To determine the safety and tolerability of topical ruxolitinib 1.5% cream in patients with 
cutaneous cGVHD with epidermal involvement (non-sclerotic form} 
• 
To determine the efficacy of topical ruxolitinib 1.5% cream in patients with cutaneous 
cGVHD with epidermal involvement (non-sclerotic form) 
Eligibility: 
Inclusion: 
• 
Age~ 12 years old 
• 
Histologically confirmed epidermal cGVHD (including lichen planus-like, 
papulosquamous, erythematous) involving at least 2 separate, non-ulcerated sites that can 
be delineated by body region ( e.g. right forearm and left forearm) 
• 
Stable systemic cGVHD treatment including immunosuppressant therapy for 4 weeks 
prior to enrollment 
• 
Karnofsky or Lansky score 2'. 60% 
Exclusion: 
• 
Concurrent use of JAK inhibitors (topical or systemic), fluconazole, or strong CYP3A4 
inhibitors 
• 
Known hypersensitivity to JAK inhibitors or their components 
• 
Active infection including CMV, EBV, HIV, HBV, and/or HCV 
• 
Recurrent or progressive malignancy requiring anticancer treatment 
• 
Patients receiving other investigational agents 
• 
Pregnancy 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
Design: 
• 
This is a Phase II, placebo-controlled, double-blinded study to determine the safety, 
tolerability and efficacy of topical ruxolitinib in patients with epidermal cGVHD. 
3 
• 
Participants with at least 2 non-ulcerated sites of epidermal cGVHD will apply topical 
ruxolitinib 1.5% cream to 1 prespecified site and vehicle cream to the second prespecified 
site twice a day for 6 weeks. 
• 
Safety will be assessed according to CTCAE v5.0 criteria. Assessments will occur during 
visits and/or phone follow-up every 2 weeks during treatment. 
• 
Efficacy will be assessed at 6 weeks. The initial surface areas of the 2 target lesions will 
be measured at baseline, week 2, and week 6 on evaluable patients, with the option for an 
in-person assessment at week 4. The percent decline in the surface area of the 2 lesions 
will be determined, and the difference in decline between the 2 lesions will be calculated, 
expressed consistently as ruxolitinib decline minus placebo decline. 
• 
A skin biopsy and peripheral blood samples will be collected prior to treatment and at 
week 6 to evaluate the cutaneous immune compartment cellular infiltrate, cytokine 
profiling, ST AT phosphorylation, gene expression profiling, and in situ cGVHD 
biomarkers. 
• 
Pharmacokinetic studies will be performed at week 2. 
• 
Up to 15 patients will be enrolled to achieve 10 evaluable patients, defined as participants 
who remain active at the time of the primary endpoint. 10 evaluable patients will provide 
80% power to detect whether these paired differences in the changes from baseline are 
equal to one SD of the difference of the changes (effect size=l.0) using a two-tailed 0.05 
significance level paired t-test. In practice, a Wilcoxon signed rank test may be used 
instead of at-test if the differences are not consistent with a normal distribution (p<0.05 
by a Shapiro-Wilks test). 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
TABLE OF CONTENTS 
4 
PRECIS ............................................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................... .4 
LIST OF TABLES ........................................................................................................................... 7 
LIST OF FIGURES ......................................................................................................................... 8 
1 
INTRODUCTION ................................................................................................................... 9 
1.1 
Study Objectives ............................................................................................................ 9 
1.1.1 
Primary Objective: ..................................................................................................... 9 
1.1.2 
Secondary Objectives: ............................................................................................... 9 
1.1.3 
Exploratory Objective(s) ........................................................................................... 9 
1.2 
Background and Rationale ............................................................................................ 9 
1.2.1 
Chronic graft-versus-host disease .............................................................................. 9 
1.2.2 
JAK-STAT pathway in cGVHD .............................................................................. 10 
1.2.3 
Ruxolitinib ............................................................................................................... 11 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 13 
2.1 
Eligibility Criteria ........................................................................................................ 13 
· 2.1.1 
Inclusion Criteria ..................................................................................................... 13 
2.1.2 
Exclusion Criteria .................................................................................................... 14 
2.1.3 
Recruitment Strategies ............................................................................................. 14 
2.2 
Screening Evaluation ................................................................................................... 14 
2.3 
Registration Procedures ............................................................................................... 15 
2.4 
Baseline Evaluation ..................................................................................................... 15 
3 
STUDY IMPLEMENTATION ............................................................................................. 16 
3.1 
Study Design ............................................................................................................... 16 
3.1.1 
Dose Limiting Toxicity ............................................................................................ 17 
3.2 
Drug Administration .................................................................................................... 17 
3.3 
Dose Modifications ..................................................................................................... 18 
3 .4 
Questionnaires ............................................................................................................. 19 
3.5 
Follow-up .................................................................................................................... 19 
3.6 
Study Calendar ............................................................................................................ 20 
3.7 
Surgical Guidelines ..................................................................................................... 21 
3.8 
Criteria for Removal from Protocol Therapy and Off Study Criteria ......................... 21 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
5 
3.8.1 
Criteria for removal from protocol therapy ............................................................. 21 
3.8.2 
Off-Study Criteria .................................................................................................... 21 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. .22 
4.1 
Concomitant Corticosteroid Therapy .......................................................................... 22 
4.2 
Other Treatments for cGVHD ..................................................................................... 22 
5 
BIOSPECIMEN COLLECTION ........................................................................................... 22 
5.1 
Correlative Studies for Research/Pharmacokinetic Studies ........................................ 22 
5.1.1 
Skin biopsy .............................................................................................................. 22 
5.1.2 
Immunologic assays from blood .............................................................................. 22 
5.1.3 
Measurement ofruxolitinib serum levels ................................................................ 23 
5.1.4 
Machine learning imaging process ......................................................................... .24 
5.2 
Sample Storage, Tracking and Disposition ................................................................. 24 
5.2.1 
ETIB Procedures ...................................................................................................... 24 
5.2.2 
Blood Processing Core ............................................................................................ 25 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 26 
6.1 
Data Collection ............................................................................................................ 26 
6.1.1 
Adverse Events ........................................................................................................ 27 
6.2 
Data Sharing Plans ..................................................................................................... .27 
6.2.1 
Human Data Sharing Plan ...................................................................................... .27 
6.2.2 
Genomic Data Sharing Plan ..................................................................................... 28 
6.3 
Response Criteria ........................................................................................................ 28 
6.3 .1 
Definitions ............................................................................................................... 28 
6.3 .2 
Disease Parameters .................................................................................................. 28 
6.3.3 
Methods for Evaluation of Measurable Disease ...................................................... 28 
6.3.4 
Response Criteria ..................................................................................................... 29 
6.4 
Toxicity Criteria .......................................................................................................... 29 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 
29 
7 .1 
Definitions ................................................................................................................... 29 
7 .2 
Expedited Reporting to NIH Intramural IRB .............................................................. 29 
7.3 
NIH Intramural IRB Requirements for PI Reporting at Continuing Review .............. 29 
7.4 
NIAMS Clinical Director Reporting ........................................................................... 29 


6 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/202 I 
7.5 
IND Sponsor Reporting Criteria .................................................................................. 30 
7.5.1 
Reporting Pregnancy ............................................................................................... 30 
7 .6 
Safety Reporting Criteria to tbe Pharmaceutical Collaborators .................................. 31 
7.7 
Data and Safety Monitoring Plan ................................................................................ 31 
7. 7 .1 
Principal Investigator/Research Team ..................................................................... 31 
7.7.2 
Sponsor Monitoring Plan ........................................................................................ .32 
8 
STATISTICAL CONSIDERATIONS .................................................................................. 32 
8.1 
8.1.1 
8.1.2 
8.2 
8.3 
8.4 
8.4.1 
8.4.2 
8.4.3 
8.4.4 
8.4.5 
8.4.6 
8.4.7 
8.4.8 
8.4.9 
Statistical hypotheses .................................................................................................. 32 
Primary efficacy endpoints: .................................................................................... .32 
Secondary Efficacy endpoints: ............................................................................... .32 
Sample size determination: ........................................................................................ .32 
Populations for analysis .............................................................................................. .33 
Statistical analyses ...................................................................................................... .33 
General approach ..................................................................................................... 33 
Analysis of the primary efficacy endpoints ............................................................. 33 
Analysis of the secondary efficacy endpoints ........................................................ .33 
Safety Analyses ...................................................................................................... .34 
Baseline Descriptive Statistics ................................................................................ .34 
Planned interim analyses ......................................................................................... 34 
Subgroup analyses .................................................................................................. .34 
Tabulation of individual participant data ................................................................ .34 
Exploratory analyses ............................................................................................... .34 
9 
COLLABORATIVE AGREEMENTS .................................................................................. 34 
9.1 
CRADA ...................................................................................................................... .34 
9 .1.1 
A CRADA has been executed with Incyte, who will provide Ruxolitinib for use in 
this protocol. CRADA number C-0l l-2018 ............................................ : ............................. 34 
9 .2 
Material transfer agreements (MT As) ......................................................................... 34 
9.2.1 
An MTA will be executed for tbe studies noted in Section 5.1.4 ............................ 34 
10 HUMAN SUBJECTS PROTECTIONS ................................................................................ 35 
I 0.1 
Rationale For Subject Selection .................................................................................. 35 
10.2 
Participation of Children ............................................................................................ .35 
I 0.3 
Participation of Adult Subjects Unable to Consent.. ................................................... 35 


7 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
10.4 
Evaluation of Benefits and Risks/Discomforts ........................................................... 35 
10.4.1 
Related to topical ruxolitinib .................................................................................. .35 
10.4.2 Related to blood collection ..................................................................................... .35 
10.4.3 Related to skin biopsy ............................................................................................. .36 
10.5 
Risks/Benefits Analysis .............................................................................................. .36 
10.6 
Consent and Assent Process and Documentation ....................................................... .36 
10.6.1 
Consent for minors when they reach the age of majority ........................................ 37 
10.6.2 Telephone consent .................................................................................................. .37 
10.6.3 Telephone assent ...................................................................................................... 38 
10.6.4 Informed consent of non-English speaking subjects .............................................. .38 
11 
PHARMACEUTICAL AND INVESTIGA TIONAL DEVICE INFORMATION ............... 39 
11.1 
Topical ruxolitinib 1.5% cream, IND# 136890 ......................................................... .39 
11.1.1 
Source ..................................................................................................................... .39 
11.1.2 Toxicity .................................................................................................................... 39 
11.1.3 Formulation and preparation .................................................................................... 39 
11.1.4 Stability and Storage ............................................................................................... .40 
11.1.5 Administration procedures ...................................................................................... .40 
11.1.6 Incompatibilities ..................................................................................................... .40 
12 REFERENCES ..................................................................................................................... .41 
13 
Appendices ........................................................................................................................... .43 
13.l 
Appendix A - Performance Status Criteria ................................................................ .43 
13.2 
Appendix B - Strong Cyp3a4 Inhibitors ..................................................................... .44 
13 .3 
Appendix C - Organ Specific And Global Scoring Of Chronic Gvhd ...................... .45 
13.4 
Appendix D - Global Scoring Of cGVHD ............................................................... ..48 
13.5 
Appendix E- PHYSICIAN'S GLOBAL ASSESSMENT ........................................ .49 
13.6 
Appendix F-PATIENT REPORTED OUTCOME SURVEYS: PATIENT VISUAL 
ANALOG SCALES ................................................................................................................... 50 
13.7 
Appendix G-MEDICATION DIARY ..................................................................... .51 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
LIST OF TABLES 
8 
Table 1: Dose Modifications ......................................................................................................... 18 
Table 2: Study Calendar ................................................................................................................ 20 
Table 3: Research Blood ................................................................................................................ 23 
LIST OF FIGURES 
Figure 1: Administration of INCB0 18424 for one month decreased the clinical GVHD score 
compared with DMSO treated mice .............................................................................................. 10 
Figure 2: Absolute number ofTreg cells in the spleen of mice on day 8, 14, and 29 of treatment 
with vehicle or ruxolitinib ............................................................................................................. 10 
Figure 3: CD4+ lFNy+ T cells from the ileum of vehicle-treated versus ruxolitinib-treated mice 
....................................................................................................................................................... 11 
Figure 4: Patient with cutaneous, epidermal cGVHD shown before and 1.5 weeks after 
ruxolitinib. There is resolution of erytbema and scale .................................................................. 11 
Figure 5: Patient with cutaneous cGVHD with epidermal involvement shown before and 3 weeks 
after ruxolitinib demonstrating significant improvement in scale and erythema .......................... 12 
Figure 6: Individual components (erythema, thickness, scaling) of the total Lesion Scores in 
study ofINCB018424 phosphate 1.5% cream twice a day .......................................................... .12 
Figure 7: INCB018424 Phosphate structural formula ................................................................... 40 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 
Primary Objective: 
9 
• 
To determine the safety and tolerability of topical ruxolitinib 1.5% cream in patients with 
cutaneous cGVHD with epidermal involvement (non-sclerotic form) 
• 
To determine the efficacy of topical ruxolitinib 1.5% cream in patients with cutaneous 
cGVHD with epidermal involvement (non-sclerotic form) by calculating the percent 
decline in surface area involvement: ruxolitinib treated site decline minus the placebo 
treated site decline 
1.1.2 Secondary Objectives: 
• 
To determine the efficacy of topical ruxolitinib 1.5% cream on measures of disease activity 
in patients with epidermal cGVHD 
• 
To describe pharmacokinetics and pharmacodynamics of topical ruxolitinib 1.5% cream in 
patients with epidermal cGVHD 
1.1.3 Exploratory Objective(s) 
• 
To characterize and analyze the effect of topical ruxolitinib 1.5% cream on inflammatory 
pathways in the skin and peripheral blood of patients with epidermal cGVHD using 
immunohistochemistry, and cytokine and gene expression studies 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 
Chronic graft-versus-host disease 
The Center for International Blood and Marrow Transplant Research estimates that as of 2013, 
over 8,000 allogeneic HCT are performed annually in the United States.(!) It is estimated that 
approximately one-half of allogeneic HCT recipients will develop cGVHD and the incidence is 
increasing.(2) After relapse of primary malignancy, cGVHD is the next leading cause of mortality 
in allogeneic HCT recipients.(3) cGVHD is a multisystem disorder characterized by immune 
dysregulation and impaired organ function including the lungs, gastrointestinal tract, liver, 
musculoskeletal system, and skin. The skin is the most commonly affected organ. 
Cutaneous cGVHD has several manifestations which can involve the epidermis, dermis, and the 
subcutis.( 4) Epidermal manifestations include erythema, papulosquamous lesions, and lichen 
planus-like lesions. Dermal and subcutaneous cGVHD result in skin thickening and tightness.(5) 
First-line therapy for cGVHD is systemic corticosteroids.( 6) The side effects of corticosteroids are 
significant, including osteoporosis, avascularnecrosis of the joints, hyperglycemia, hypothalamus-
pituitary axis suppression, and increased risk of infection. Topical therapies that are available for 
cutaneous cGVHD include topical corticosteroids and topical calcineurin inhibitors.(?) Topical 
steroids also have significant side effects which can limit their use. The side effects include 
cutaneous atrophy, striae, infection, as well as risk of systemic side effects from absorption when 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
used over a large body surface area. There has been a paucity of targeted topical therapies for 
epidermal cGVHD. 
1.2.2 JAK-STAT pathway in cGVHD 
The JAK-STAT pathway is a signaling pathway for many cytokines, including several that are 
implicated in the pathogenesis of cGVHD such as IFNy, common y-chain cytokines, and IL-6. Of 
the four JAKs, JAK 1 and JAK2 are important in the signaling of relevant cytokines including 
IFNy, TNFa, IL-1, IL-2, IL-6, IL-12, and IL-23. Studies have provided preclinical data to support 
the importance of the JAK-STAT pathway in the management of acute and chronic GVHD.(8-12) 
Choi et al. demonstrated that INCB018424 (ruxolitinib) reduced expression of CXCR3, a 
chemokine receptor important in T-cell trafficking to cGVHD target organs, and resulted in lower 
clinical GVHD score compared to placebo treated mice (Figure 1).(10) 
Figure h Administration ofINCB018424 
for one month decreased the clinical GVHD 
score compared with DMSO treated mice. 
Spoerl et al. studied a murine model of acute GVHD in which they demonstrated that 
phosphorylation and activation of STAT3, a transcription factor activated by JAK tyrosine kinase 
phosphorylation, was inhibited by ruxolitinib.(12) They also demonstrated that Treg cells were 
increased in the spleens of mice (Figure 2) and CD4+IFNy+ cells were decreased (Figure 3) in the 
ileum of mice treated with ruxolitinib, findings that are consistent with improvement in cGVHD. 
Figure 2: Absolute number ofTreg cells in the spleen of mice on day 8, 14, and 29 of treatment 
with vehicle or ruxolitinib 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
11 
Figure 3: CD4+ IFNy+ T cells from the ileum of vehicle-treated versus ruxolitinib-treated mice 
1.2.3 
Ruxolitinib 
Ruxolitinib is a JAK inhibitor which is FDA approved in an oral formulation for treatment of 
myelofibrosis and polycythemia vera. A topical formulation has been studied in humans with 
psoriasis, alopecia areata, atopic dermatitis (AD), vitiligo and other inflammatory diseases. 
Ruxolitinib is a potent, reversible inhibitor of JAKl (ICso = 1.68 nM) and JAK2 (ICso = 0.35 nM), 
with modest to marked selectivity against TYK2 (IC5o = 2.80 nM) and JAK3 (ICso = 4.75 nM).(13) 
In cellular assays, INCB018424 inhibits JAK signaling and function in peripheral blood 
mononuclear cells and isolated T cells. Signaling of multiple inflammatory cytokines, including 
IL-6, IL-12, and IL-23, is inhibited at concentrations :5 100 nM. INCB018424 inhibits IL-2-
induced proliferation of T-cells and cytokine-induced production of inflammatory factors such as 
IL-17, IL-22, and MCP-1. INCB0l 8424 also inhibits cytokine mediated signaling in keratinocytes. 
Studies have demonstrated inhibition ofIFNy-induced upregulation of chemokines and expression 
of intercellular adhesion molecule 1 (ICAM-1) and IFNy-induced STATl phosphorylation in these 
cells. 
Oral ruxolitinib has been studied in GVHD. Spoerl et al.(12) first reported ruxolitinib in patients 
with GVHD in Blood in 2014. Six patients with GVHD, 2 with cGVHD, were treated with 
ruxolitinib. Both cGVHD patients had only skin involvement and both experienced a response 
within 1 week (Figure 4) and systemic corticosteroids were reduced in both patients. 
Figure 4: Patient with cutaneous, 
epidermal cGVHD shown before 
and 1.5 weeks after ruxolitinib. 
There is resolution of erythema and 
scale. 
Khoury et al.(14) presented a poster abstract describing oral ruxolitinib treatment of 16 patients 
with cGVHD of different organs. All 16 patients had cutaneous involvement. They described 
complete response in the patients who had nonsclerotic, erythematous cutaneous cGVHD. Median 
response time was 14 days. 10/16 patients were able to discontinue corticosteroids and 2 patients 
decreased the dose to physiologic levels. 


12 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
In the largest published report to date, Zeiser et al.(15) described 41 adult patients with cGVHD 
treated with systemic ruxolitinib. Overall response rate was 85% (35/41 ), including 32 partial 
responses and 3 complete responses (Figure 5). The median time to response was 3 weeks (range 
1-25 weeks) after initiating ruxolitinib. Responses were seen in all organ systems involved. 7% 
experienced Grade 3 or 4 cytopenia, 14 % had CMV reactivation, and 1 patient had a relapse of the 
primary malignancy. This retrospective study included patients with any organ involvement of 
moderate to severe severity. 
!! 
.. X''" 
Figure 5: Patient with cutaneous 
cGVHD with epidermal involvement 
shown before and 3 weeks after 
ruxolitinib demonstrating significant 
improvement in scale and erythema. 
Topical ruxolitinib has not been reported in GVHD, but it has been studied in psoriasis, alopecia 
areata atopic dermatitis (AD), vitiligo and other inflammatory diseases. (13, 16-19) At time of 
review, 11 clinical studies have been completed in the ruxolitinib cream clinical development 
program (5 studies in healthy participants, 3 studies in participants with psoriasis, 1 study in 
participants with alopecia aerata (AA), and 2 studies in participants with AD) and 6 studies are 
ongoing (3 studies in participants with AD, and 3 studies in participants with vitiligo ). Safety was 
demonstrated, with no serious cutaneous toxicities noted. There was minimal systemic absorption, 
suggesting a decreased risk of AEs identified with systemic use of ruxolitinib, such as cytopenias. 
In the cGVHD population, this is particularly important as patients with cGVHD may have 
cytopenias at baseline and cannot tolerate further decline in hematopoietic cell lines. Efficacy of 
topical ruxolitinib was evaluated in the 3 studies. Figure 6 demonstrates a decrease in erythema, 
thickness, and scale of psoriatic plaques during a 28-day period of treatment with 1.5% ruxolitinib 
cream.(18) 
Figure 6: Individual components 
( erythema, thickness, scaling) of 
the total Lesion Scores in study of 
INCB018424 
phosphate 
1.5% 
cream twice a day. 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 
ELIGIBILITY CRITERIA 
2.1.1 
Inclusion Criteria 
13 
• 
Patients must have histologically confirmed epidermal cGVHD including lichen planus-
like, papulosquamous, and erythematous cGVHD with clinical involvement at 2 separate 
body regions ( e.g. right forearm and left forearm). 
• 
Patients must have measurable disease, defined as at least 2 areas of cutaneous, 
nonulcerated, epidermal cGVHD involvement. Each site must involve at least 0.5% body 
surface area (1 palm equivalent) and cannot be a site of current or previous nonmelanoma 
skin cancer (NMSC). 
• 
Stable immunosuppressant or inununomodulatory systemic cGVHD treatment, including 
phototherapy and extracorporeal photopheresis, for 4 weeks prior to enrollment 
• 
Age> 12 years. There is no available safety or adverse events data available for children 
younger than 12 years of age. 
• 
Kamofsky or Lansky 2': 60, see APPENDIX A. 
• 
Patients must have normal organ and marrow function as defmed below: 
- absolute neutrophil count 
2':1,000/mcL 
- platelets 
2>:50,000/mcL 
- hemoglobin 
> 9 g/dL 
- total bilirubin 
<1.SX institutional upper limit of normal 
except if known history of Gilbert's disease 
- AST(SGOT)/ALT(SGPT) 
:<c5X institutional upper limit of normal 
- creatinine clearance 
2>:50 mL/min/1. 73 m2 for patients with 
creatinine levels above institutional normal. 


14 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
• 
Willingness to comply with twice daily application of 2 different creams to 2 separate, 
prespecified sites. 
• 
The effects of ruxolitinib on the developing human fetus are unknown. For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation. Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately. 
• 
Ability of subject or Legally Authorized Representative (LAR) to understand and the 
willingness to sign a written informed consent document. 
2.1.2 Exclusion Criteria 
• 
Patients concurrently receiving a JAK. inhibitor (topical or systemic). 
• 
Patients receiving any other investigational agents. 
• 
Patients concurrently taking oral fluconazole. 
• 
Patients concurrently taking strong CYP3A4 inhibitors (APPENDIX B) 
• 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ruxolitinib or other agents used in study. 
• 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
including EBY, CMV, HIV, HBV, and HCV, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
• 
Pregnant women are excluded from this study because ruxolitinib is an agent with the 
potential for teratogenic or abortifacient effects. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with ruxolitinib, breastfeeding should be discontinued if the mother is treated with 
ruxolitinib. These potential risks may also apply to other agents used in this study. 
• 
Recurrent or progressive malignancy requiring anticancer treatment. 
• 
Other cancer (except that for which HCT was performed) within 2 years of study entry, 
except nonmelanoma skin cancer or carcinoma in situ of the breast, uterus, or cervix. 
I 
• 
History of cutaneous malignancy at target lesion site. 
• 
Any participant who, in the investigator's opinion, would be unable to comply with study 
requirements or for whom participation may pose a greater medical risk. 
2.1.3 
Recruitment Strategies 
Participants, including under-represented minorities, will be recruited for this study through the 
well-established NIH cGVHD multidisciplinary study group and its referral network. Patients who 
undergo HCT at NIH will be eligible as well. Recruitment will also occur through professional 
societies and patient advocacy forums. 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
2.1.4 Compensation 
15 
Cost associated with screening will not be reimbursed. Once consent is obtained, this study will 
assist with air or train travel through a government approved contractor. Mileage will be 
compensated per NIH guidelines. For long distance travelers, meals will be compensated per NIH 
guidelines. Lodging maybe provided through the Children's Inn or Safra Lodge, if space permits. 
If not available, we will provide compensation toward local lodging per NIH guidelines. 
2.2 
SCREENINGEVALUATION 
Screening procedures may be performed on a screening protocol, including 04-C-0281, "Natural 
History of Chronic GVHD," or 96-AR-0102, "Evaluation and Treatment of Subjects with 
Dermatologic Diseases". 
All screening studies must be completed within 4 weeks prior to enrollment except 'Yhere stated 
otherwise: 
• 
History and physical examination including Karnofsky or Lansky performance status 
• 
Skin biopsy to confirm diagnosis of epidermal cGVHD within 3 months of enrollment 
• 
Laboratory studies: 
o CBC and differential 
o Blood urea nitrogen and serum creatinine 
o Hepatic function panel 
o Serum b-hCG in women of childbearing potential. Not required for women who are 
status-post hysterectomy or postmenopausal (no menses for> I year) 
• 
Infectious studies: 
o Anti-IDV 1/2 antibody 
o HBsAg and anti-HCV antibody 
o CMVPCR 
o EBVPCR 
For baseline evaluations, please see Section 2.4. 
2.3 
REGISTRATION PROCEDURES 
The eligibility checklist is to be completed at study entry by the PI or MAI. The protocol research 
nurse will file the checklist in the participants research study binder. 
2.4 
BASELINEEVALUATION 
The following baseline studies will be performed within one week of starting the study drug: 
• 
History and physical examination, including Kamofsky or Lansky performance status 
• 
Documentation of cGVHD diagnosis per 2014 NIH criteria, NIH organ and global score 
(APPENDIX C & APPENDIX D), date of cGVHD diagnosis, prior and current treatments 
including topical agents, prednisone or other steroid dose, and other patient, donor, and 
transplant characteristics 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
16 
• 
Clinical examination of all cutaneous cGVHD with the following for the target epidermal 
cGVHD sites: measurement with a ruler or calipers, transparency tracing, automated 
photographic measurement, clinical photography, and completion of the Physician Global 
Assessment (PGA) (APPENDIX E) 
• 
Laboratory studies: 
o CBC and differential 
o Blood urea nitrogen and serum creatinine 
o Hepatic function panel 
o Serum b-hCG in women of childbearing potential. Not required for women who are 
status-post hysterectomy or postrnenopausal (no menses for> 1 year) 
• 
Infectious studies: 
o CMVPCR 
o EBVPCR 
• 
Patient-reported outcome (PRO) surveys completed for each of the 2 target lesion sites: 
Overall disease severity visual analog scale (VAS), pruritus VAS, pain VAS (APPENDIX 
F) 
• 
Research blood samples 
• 
Total body photography performed at the investigator's discretion 
3 
STUDY IMPLEMENTATION 
3.1 
STUDYDESIGN 
This is a phase II, placebo controlled study to evaluate the safety, tolerability, and efficacy of 1.5% 
topical ruxolitinib cream, INCB018424, in patients with epidermal cGVHD. Case series and 
anecdotal reports of systemic JAK inhibitors in cGVHD have suggested a benefit for cGVHD 
involvement of the skin and other organs, warranting further study. For patients with cGVHD that 
manifests with primarily epidermal skin disease, effective topical therapy is desirable. Current 
topical therapies (corticosteroids and calcineurin inhibitors), can have significant side effects and 
are not specific to the disease pathology. 
In this study, patients with a minimum of 2 distinct areas of involvement with intact (no ulceration) 
epidermal cGVHD that has been confirmed histologically, will be eligible for participation. Each 
participant will receive active study agent and placebo. Chronic GVHD is a heterogeneous disease 
with a waxing and waning course. Given the heterogeneity and the natural history of this disease 
as well as use of concurrent systemic medications, each participant will serve as his/her own 
control to allow for better comparison of placebo and active study drug. Randomization table 
generated by Seth Steinberg, statistician, will be provided to the pharmacy, such that the labeling 
of placebo and active study drug as container A and B will be randomized at the pharmacy. All 
participants will be provided with active study drug to apply to the designated affected area 
(maximum application BSA of 10%) twice a day and a second container containing a vehicle 
cream to be applied twice a day on a second affected area. Subjects who experience dose limiting 
toxicities (DLT) will have the dose adjusted as described in Section 3.1.1. 


17 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
Participants will be evaluated in-person at baseline, at week2 (+/- 3 business days), and at week 6 
(+/- 3 business days). Clinical examination including surface area measurements, transparency 
tracing, photography for automated measurement, PGA score, clinical photographs, blood draw, 
and completion of PRO surveys will occur at the baseline visit. During the week 2 visit there will 
be an assessment for response and AEs. This visit will include surface area measurements, 
transparency tracing, photography for automated measurement, PGA score, clinical photographs, 
blood draw, and completion of PRO surveys. Pharmacokinetic studies will be conducted at this 
visit as well. Patients will either be seen in-person or receive a phone call from the study team (at 
the physician's discretion) at week 4 to assess AEs and for those seen in-person, assessment of 
response. Clinical examination including surface area measurements, transparency tracing, 
photography for automated measurement, PGA score, clinical photographs, blood draw, and 
completion of PRO surveys will occur for those who have an in-person visit at week 4. All 
participants will be evaluated in-person at week 6 ( +/- 3 business days) for primary outcome 
assessment. Clinical examination including surface area measurements, transparency tracing, 
photography for automated measurement, PGA score, clinical photographs, and blood draw will 
occur during this visit. Patient will complete the PRO surveys at this visit. Patients will receive a 
follow up call at week 12 (+/- 4 weeks). 
With the patient's or LAR's consent, at the discretion of the investigator, a skin biopsy for research 
will be taken from each treated site at week 6. The effect of ruxolitinib on the histologic findings 
of cGVHD in the epidermis, as well as the impact on the cutaneous cellular infiltrate, cytokine 
profile, STAT phosphorylation, gene expression profile (including lymphocyte receptor 
sequencing) and cGVHD biomarkers will be compared with the placebo treated site as well as the 
biopsy obtained during screening if available. Corresponding experiments may be done on 
peripheral blood mononuclear cells and serum samples to compare with the skin biopsy data when 
appropriate. 
3.1.1 
Dose Limiting Toxicity 
DLT will be defined as any grade ;::: 3 adverse event which is thought to be probably or definitely 
related to the investigational drug. Grade 3 toxicities that resolve within 72 hours to ::, grade 1 with 
supportive care (e.g. pruritus, nausea, vomiting, fatigue, diarrhea) will not be counted as DLTs. 
Study drug and placebo will be held until resolution of any grade;::: 3 adverse event. If2 subjects 
experience a grade 3 AE probably or definitely attributable to the study drug, the study will be 
stopped for safety review. In patients that have experienced disease progression, further dosing 
will cease in a patient at the occurrence of the first DLT. All patients will be evaluable for toxicity 
from the time of their first treatment with topical ruxolitinib until the end of study participation, 
regardless of inclusion in primary response evaluation. 
3.2 
DRUG ADMINISTRATION 
Topical ruxolitinib cream and vehicle cream will be supplied by Incyte in containers labeled with 
a perforated label as active study drug or placebo. The pharmacy will remove the perforated label 
and apply a label containing site of administration as well as label A or B according to the 
randomization table. Participants will be carefully instructed regarding the site of application of 
each cream. Neither the study drug nor the vehicle cream should be applied to areas of skin with 
ulceration. Participants will be provided with photographs of the body site to apply each cream as 
a guide at home for application. Application will be twice a day (12 hours apart) for 6 weeks. 


18 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
Application should occur at approximately the same time each day and at least 2 hours before 
showering/bathing. Participants should wear gloves when applying cream. A new pair of gloves 
should be used when applying cream to the second site. This will minimize the possibility of cross 
contamination. Medication and vehicle cream will be applied as a thin layer. Patients will be asked 
to complete a medication diary (APPENDIX G). 
If a dose is missed, it should be applied as soon as possible on the same day unless it is within 1 
hour of the next dose. If it is within 1 hour of the next dose, the missed dose should not be applied. 
Missed doses will not be reported to the IRB as a protocol deviation unless the patient misses > 5 
doses per month. 
During application of the study drug and the vehicle, care should be taken to avoid the eyes and 
mouth. If study drug or vehicle are ingested, study staff should be contacted immediately. If the 
cream is applied to the participant's body by a pregnant individual, that individual should use 
gloves and a wooden applicator to apply the creams on to the participant. 
3.3 
DOSE MODIFICATIONS 
Table 1: Dose Modifications 
All dose modifications will be discussed with the Pl or MAI. 
Adverse event 
CTCAE grade/attribution 
Protocol Action 
Any adverse event 
Grade 2 >7 days that is probably 
Hold study drug; *If AE 
( excluding ulceration, 
or definitely related to study 
resolves to :'S grade 1 or 
infection, treatment-related 
drug. 
baseline within 7 days: 
malignancy) 
resume dose. ** If AE does 
not resolve to :'S grade 1 or 
baseline within 7 days: 
patient comes off dru<>. 
Any adverse event 
Same grade 2 >7 days recurs 
Hold study drug; *If AE 
( excluding ulceration, 
that is probably or definitely 
resolves to :'S grade 1 or 
infection, treatment-related 
related to study drug. 
baseline within 7 days: 
malignancy) 
decrease dose to once daily. 
* *If AE does not resolve to 
:'S grade 1 or baseline within 
7 days: patient comes off 
drug. 
Any adverse event 
Same grade 2 >7 days recurs 
Patient comes off drug. 
( excluding ulceration, 
after dose reduction that is 
infection, treatment-related 
probably or definitely related 
malignancy) 
to study drug. 
Any adverse event 
Grade 3 that is probably or 
Hold study drug; *If AE 
( excluding ulceration, 
definitely related to study drug. 
resolves to :'S grade 1 or 
baseline within 7 days: 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
infection, treatment-related 
malignancy) 
Any adverse event 
Same grade 3 recurs after dose 
( excluding ulceration, 
reduction that is probably or 
infection, treatment-related 
definitely related to study drug. 
malignancy) 
Any adverse event 
Grade 4 that is probably or 
( excluding ulceration, 
definitely related to study drug. 
infection, treatment-related 
malignancy) 
Skin ulceration at treatment 
Any grade 
site 
Infection 
Grade 2 that is probably or 
definitely related to study drug. 
Infection 
Grade 2 recurs that is probably 
or definitely related to study 
drug. 
Infection 
Grade 2 recurs after dose 
reduction that is probably or 
definitely related to study drug. 
Infection 
Grade 3 that is probably or 
definitely related to study drug. 
Infection 
Grade4 
Treatment-related 
Grade 3 
malignancy 
Treatment-related 
Grade4 
malignancy 
Exceptions to the above treatment modifications: 
1. Alopecia any grade 
19 
decrease dose to once daily. 
* *If AE does not resolve to 
:; grade 1 or baseline within 
7 days: patient comes off 
drug. 
Patient comes off drug. 
Patient comes off drug. 
Patient comes off drug. 
Hold study drug until 
completion of systemic 
antibiotic course and 
resolution of infection, then 
restart at same dose level. 
Hold study drug until 
completion of systemic 
antibiotic course and 
resolution of infection, then 
decrease dose to once daily. 
Patient comes off drug. 
Patient comes off drug. 
Patient comes off drug. 
Patient comes off drug. 
Patient comes off drug. 


20 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
2. Dry skin any grade 
3. Grade 2 skin or soft tissue infection at untreated site 
4. Grade 2 paronychia 
Doses withheld while recovering from an adverse event should not be made up. 
3.4 
QUESTIONNAIRES 
The following scales will be administered twice at each indicated time point to independently 
assess the 2 treatment sites. 
1. Pruritus Visual Analog Scale (VAS) is a self-administered psychometric response 
instrument which measures subjective characteristics or attitudes that cannot be directly 
measured. It ranges from 0-10. This scale has been used for measurement in a variety of 
dermatologic settings. This questionnaire will be administered at baseline, week 2, week 4 
(for participants who come for an in-person study visit), and week 6. (1 minute) 
2. Skin Pain VAS is a self-administered psychometric response instrument which measures 
subjective characteristics or attitudes that cannot be directly measured. It ranges from 0-
10. This scale has been used for measurement in a variety of dermatologic settings. This 
questionnaire will be administered at baseline, week 2, week 4 ( for participants who come 
for an in-person study visit), and week 6. (1 minute) 
3. Overall Disease Severity VAS is a self-administered psychometric response instrument 
which measures subjective characteristics or attitudes that cannot be directly measured. It 
ranges from 0-10. This scale has been used for measurement in a variety of health settings. 
This questionnaire will be administered at baseline, week 2, week 4 ( for participants who 
come for an in-person study visit), and week 6. (1 minute) 
3.5 
FOLLOW-UP 
All persons will be followed for SAEs for 14 days after last application of topical ruxolitinib. All 
participants, including those who discontinue therapy for any reason, will receive a follow-up 
phone call 6 weeks (+/-4 weeks) after discontinuation of topical ruxolitinib (week 12). The phone 
call will focus on a) survival status and cause of death if applicable, b) ongoing topical and/or 
systemic treatment for cGVHD and date of discontinuation, c) primary malignancy progression, 
d) any second primary malignancy, e) return to work part-time or full-time. Primary and 
contributing causes of death are to be recorded in the CRF and the patient's medical record. 
3.6 
STUDY CALENDAR 
Table 2: Study Calendar 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
amBID 
PE 
X 
X 
Vital si 
s 
X 
X 
Kamofsky or Lansky 
X 
X 
erformance Score 
PGAscore 
X 
cGVHD diagnosis 
X 
assessment (2014 NIH 
Criteria 
Labs: 
CBC + differential 
X 
X 
BUN+ Creatinine 
X 
X 
Hepatic Panel 
X 
X 
Serum b-hCG1 
X 
X 
HIV 1/2 antibody 
X 
HBsAg 
X 
Anti-HCV antibody 
X 
CMV and EBV PCR 
X 
X 
Surface 
s 
X 
Clinical 
X 
Skin bio 
X 
Total body 
* 
Correlative Research 
X 
Studies 
Pharmacokinetics 
Response Evaluation: 
X 
Overall disease 
severity VAS, Pruritus 
VAS, Pain VAS 
Adverse Events 
Concomitant 
X 
X 
Medications 
Study drug 
X 
dispensation/ 
return/accountabili 
*Optional 
21 
X 
* 
X 
X 
* 
X 
X 
X 
X 
* 
X 
X 
X 
* 
X 
X 
* 
X 
X 
* 
X 
X 
* 
X 
X 
* 
X 
* 
X 
X 
* 
X 
* 
* 
* 
* 
X 
X 
X 
* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* 
X 


22 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
1Only in women of childbearing potential age. Exceptions include women status-post hysterectomy or in menopause 
> 1 year since last menstrual period. 
3.7 
SURGICAL GUIDELINES 
A skin biopsy will be obtained during screening (may be performed at an outside facility) to 
confirm epidermal cGVHD. At week 6, skin biopsies will be obtained from the 2 treated sites at 
the investigator's discretion. Skin biopsy procedure will be explained to the patient and informed 
consent will be obtained. 
The risk of infection, scarring, nerve damage, pigment change, numbness, bleeding, pain, and 
allergy to anesthesia will be reviewed. The biopsy site will be locally anesthetized. Size of punch 
biopsies will be up to 6mm. One punch biopsy will be performed from each of the 2 treatment 
sites. Sutures will be placed for hemostasis. Petrolatum and bandage will be applied to the wound 
site and wound care will be reviewed. Written wound care instructions will be given. We will 
instruct the patient regarding suture removal. 
3.8 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
3.8.1 
Criteria for removal from protocol therapy 
• 
Completion of 6-week protocol therapy 
• 
Progressive disease in skin or other organ system requiring an increase or change in 
systemic therapy 
• 
Participant requests to be withdrawn from active therapy 
• 
Unacceptable toxicity as defined in Section 11. 1.2 
• 
Investigator discretion 
• 
Pregnancy 
3.8.2 Off-Study Criteria 
• 
Completion of study follow-up period 
• 
Participant requests to be withdrawn from study 
• 
Death 
4 
CONCOMITANT MEDICATIONS/MEASURES 
All prescription and nonprescription medications, including topical agents, used during the study 
period will be recorded on the appropriate pages of the CRF. Patients will be advised to contact 
the study team prior to initiating any new medication. 
4.1 
CONCOMITANT CORTICOSTEROID THERAPY 
Participants may remain on systemic corticosteroids during the course of the 6-week study at a 
stable or tapering dose. If a pulse of corticosteroids is required for cutaneous or other organ 
cGVHD, the patient will be withdrawn from the study. Topical corticosteroids may not be used 
for the duration of this study. 


23 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
4.2 
OTHER TREATMENTS FOR cGVHD 
• 
Other systemic treatments such as calcineurin inhibitors (tacrolirnus or cyclosporine ), 
sirolimus, mycophenolate mofetil, or other immunosuppressants must be maintained at a 
stable or tapering dose. Dose adjustments based on drug interactions or maintaining 
therapeutic drug level will be permitted. 
• 
Patients cannot initiate new immunosuppressant or immunomodulatory therapeutic 
interventions, including extracorporeal photopheresis or phototherapy, during the 6 weeks 
of the study. 
• 
Patients cannot apply topical medications, prescription or nonprescription, besides the 
study drugs for the duration of this study. All topical therapies, except emollients, should 
be discontinued at least 1 week prior to start of therapy. 
S 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
5.1.1 
Skin biopsy 
A skin biopsy will be obtained during screening and 2 skin biopsies will be obtained at week 6, at 
the discretion of the investigator, one from each of the 2 treatment sites. Skin biopsies will be 
bisected and a section will be sent to the Laboratory of Pathology in formalin for histologic 
assessment with hematoxylin and eosin stain. Unstained slides will be made for 
immunohistochemical studies to evaluate the T-cell infiltrates, IFN-induced transcription markers, 
pSTAT, and myofibroblast and pericyte markers. The additional tissue will either be placed in 
OCT and processed, stored, and analyzed at the ETIB pre-clinical core and/or in John O'Shea's 
lab or will be immediately processed for single cell RNA sequencing (gene expression and 
lymphocyte receptor sequencing) in the Dermatology Branch. 
5.1.2 Immunologic assays from blood 
Peripheral blood will be obtained for immunologic assays. Heparinized plasma will be assayed for 
BAFF, CXCL9, CXCLlO, IL-6, TNFa, and other IFN-induced chemokines. Whole blood will be 
collected for flow cytometry oflymphocyte populations. Changes in CD3, CD4, CDS, B cells, and 
NK cells will be assessed at baseline compared to week 6 in the Clinical Center's CLIA certified 
immunophenotyping lab. Additional assessments ofregulatory, naive, memory and effector T cells 
will be performed in the ETIB Preclinical Core lab. Single cell RNA sequencing, including 
lymphocyte receptor sequencing, may be done from peripheral blood in the Dermatology Branch. 
5.1.3 Measurement ofruxolitinib serum levels 
Blood samples for the determination of plasma levels of ruxolitinib will be obtained from each 
patient via 6mL sodium heparin tube (BD, Franklin Lakes, NJ) collected during the first follow up 
visit, 2 weeks after commencement of twice daily topical treatment of a 1.5% cream formulation. 
A pre-dose trough sample will be collected just prior to application of the treatment on the day of 
their follow-up visit. After application in clinic, blood samples will be collected at 1hr, 2hr, and 
4hr to understand the rate and extent of systemic exposure. Bioanalytical measurements will be 


24 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
conducted on an ultra HPLC-MSMS system using an assay developed and validated by the Blood 
Processing Core. 
This data will be used to monitor ruxolitinib plasma concentrations in order to primarily 
understand the rate and extent of systemic exposure of ruxolitinib from a 1.5% strength topical 
cream applied to skin affected with epidermal cGVHD. Secondarily, these plasma measurements 
can also be used to correlate to pharmacodynamic endpoints, clinical response, and toxicity. 
The samples will be placed immediately on wet ice and refrigerated. The date and exact time of 
each blood draw should be recorded on the sample tube and the PK sheet. 
Please e-mail 
 at 
least 24 hours before transporting samples (the Friday before is preferred). 
For sample pickup, 
. 
For immediate help, 
 
). 
For questions regarding sample processing, contact 
. 
Upon arrival in the Blood Processing Core (BPC), samples will be centrifuged and the plasma 
transferred into cryovials for storage at -80°C until the time of analysis. In addition, samples will 
be barcoded as described in Section 5 .2.2. 
Table 3: Research Blood 
Test/assay 
Volume blood 
Type of 
Collection point Location of 
(approx.) 
tube 
(+/-48hrs) 
specimen analysis 
Immunemonitoring 
48 mls 
6 Sodium 
Baseline, Week 
ETIB Preclinical 
(baseline) 
heparin 
6 
Core lab 
48 mls (week 
6) 
PK (pre & post at 
12 mis (4 
Sodium 
Week2 
Dr. Figg's lab 
week2) 
draws) 
heparin 
Flow cytometry for 
3 ml 
lEDTA 
Baseline, Week 
ETIB Preclinical 
regulatory, naive, 
6 
Core lab 
memory and effector 
Tcells 
Immunophenotyping 3ml 
lEDTA 
Baseline, Week 
Clinical Center 
panel (CD3, CD4, 
6 
CLIA certified lab 
CD8, B cells, and 
NK.cells) 
RNA sequencing 
10ml 
Sodium 
Week6 
Dermatology Branch 
heparin 


25 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
5.1.4 Machine learning imaging process 
Through a collaboration with Dr. Eric Tkaczyk at Vanderbilt University Medical Center, we will 
share de-identified clinical images of cGVHD skin lesions taken with both 2D and 3D cameras 
to build a repository necessary for training a machine to identify cutaneous cGVHD. The 
images will be used to determine a set of parameters and variations on optical assessments 
which collectively assess skin optical properties at an equivalent or superior level to 
subjective dermatologic exam. 
5.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
5.2.1 
ETIB Procedures 
Blood and tissue samples, collected for the purpose ofresearch under !RB-approved protocols will 
be stored and may be archived by the ETIB Preclinical Service, with the exception of blood 
samples for ruxolitinib analysis, which will be stored separately by the Blood Processing Core 
(BPC) until analysis. Any RNA or cDNA generated during the research process may be archived 
by the ETIB Preclinical Service. All data associated with archived clinical research samples is 
entered into the ETIB Preclinical Service's Microsoft Excel databases on frozen cells and plasma. 
These databases are stored on the NCI group drive in the ETIB Preclinical Service folder. Access 
to this folder is limited to ETIB clinical staff, requiring individual login and password. All staff in 
the Preclinical Service laboratory have received annually updated NIH/CIT training and maintain 
standards of computer security. 
The data recorded for each sample includes the patient ID, name, trial name/protocol number, date 
drawn, treatment cycle/post-transplant time point, cell source ( e. g. peripheral blood or skin 
biopsy) as well as box and freezer location. Patient demographics that correlate treatment 
outcomes and therapies with the samples can be obtained only through the NCI/ETIB clinical 
records or C3D. All samples currently receive a unique bar code number, which is included in the 
Preclinical Service Stored Sample database. Only this bar code will be recorded on the sample 
vial, and the vials will not be traceable back to patients without authorized access to the Preclinical 
Service database. 
Samples are stored in locked freezers at -85°C (sera, plasma, RNA and cDNA) or under liquid 
nitrogen (cells), according to stability requirements. These freezers are located onsite at the ETIB 
Preclinical Service laboratory (12C216). Access to samples from a protocol for research purposes 
will be by permission of the Principal Investigator of that protocol or through his/her submission 
and IRB approval of the NIH IRB Authorization Form stipulating whether IRB review is not 
necessary or IRB approval is granted for the pursuit of this new research activity. All researchers 
are required to sign a form stating that the samples are only to be used for research purposes 
associated with objectives of the original protocol for which the samples were collected, or (using 
only unlinked or coded samples) for an !RB-approved protocol as stipulated on the IRB 
Authorization Form, and that any unused samples must be returned to the Preclinical Service 
laboratory. 
5.2.1.1 Protocol Completion/Sample Destruction 
Once primary research objectives for the protocol are achieved, researchers can request access to 
remaining samples, providing they have both approval of the Principal Investigator of the original 


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protocol under which the samples or data were collected and either an !RB-approved protocol and 
patient consent or the IRB Authorization Form stipulating that the activity is exempt from IRB 
review. Samples, and associated data, will be stored permanently unless the patient withdraws 
consent. If researchers have samples remaining once they have completed all studies associated 
with the protocol, they must be returned to the Preclinical Service laboratory. 
If a patient withdraws consent, the participant's data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved. The Preclinical Service staff will report to the Principal Investigators any destroyed 
samples, if samples become unsalvageable because of environmental factors ( e.g., broken freezer 
or lack of dry ice in a shipping container), lost in transit between facilities or misplaced by a 
researcher. The Principal Investigators will annually report this information to the IRB. Freezer 
problems, lost samples or other problems associated with samples will also be reported to the IRB 
and the NIAMS Clinical Director. 
5.2.2 Blood Processing Core 
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with 
access to LABrador limited to defmed Figg lab personnel, who are issued individual user accounts. 
Installation of LABrador is limited to computers specified by Dr. Figg. These computers all have 
a password restricted login screen. All Figg lab personnel with access to patient information 
annually complete the NIH online Protection of Human Subjects course. 
LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without LABrador access. The data recorded for each sample includes the patient 
ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well 
as box and freezer location. Patient demographics associated with the clinical center patient 
number are provided in the system. For each sample, there are notes associated with the processing 
method (delay in sample processing, storage conditions on the ward, etc.). 
5.2.2.1 Sample Storage and Destruction 
Barcoded samples are stored in barcoded boxes in a locked freezer at either-20 or -80°C according 
to stability requirements. These freezers are located onsite in the BPC and offsite at NCI Frederick 
Central Repository Services in Frederick, MD. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LABrador. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per IRB approved protocol) and that any unused samples 
must be returned to the BPC. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting the 
rights to use the material. 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LABrador. It is critical that the sample remains linked to patient information such as race, age, 


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dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed and reported as such to the IRB. The PI will report destroyed samples 
to the IRB if samples become unsalvageable because of environmental factors ( ex. Broken freezer 
or lack of dry ice in a shipping container) or if a patient withdraws consent. Samples will also be 
reported as lost if they are lost in transit between facilities or misplaced by a researcher. Freezer 
problems, lost samples or other problems associated with samples will also be reported to the IRB 
and the NIAMS Clinical Director. 
6 
DATA COLLECTION AND EVALUATION 
6.1 
DATA COLLECTION 
All data will be entered into C3D using predesigned CRFs. The PI will be responsible for 
overseeing entry of data into an in-house password protected electronic system and ensuring data 
accuracy, consistency and timeliness. Complete records will be maintained on each patient 
including the medical record with any supplementary information obtained from outside 
laboratories or physician's records. These records are the primary source documents that form the 
basis for the research record and will be uploaded in CRIS. The principal investigator, associate 
investigators/research nurses and/or a contracted data manager will assist with the data 
management efforts. All data obtained during the conduct of the protocol will be kept in secure 
network drives or in approved alternative sites that comply with NIH security standards. Primary 
and final analyzed data will have identifiers so that research data can be attributed to an individual 
human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for 30 days after removal from study treatment or until off-
study, whichever comes first. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms 
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization. 
• 
Is judged by the Investigator to be of significant clinical impact 
• If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient's 
outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 


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Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified. 
6.1.1 
Adverse Events 
Grade 1 adverse events will not be collected on this protocol. 
6.2 
DATA SHARING PLANS 
6.2.1 
Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
_X_ De-identified data in an NIH-funded or approved public repository. 
_X_ De-identified data in BTRIS (automatic for activities in the Clinical Center) 
_ X_ De-identified or identified data with approved outside collaborators under appropriate 
agreements. 
How and where will the data be shared? 
Data will be shared through (check all that apply): 
_X_ An NIH-funded or approved public repository, i.e., www.clinicaltrials.gov. 
_X_ BTRIS (automatic for activities in the Clinical Center) 
_ X_ Approved outside collaborators under appropriate individual agreements. 
_ X_ Publication and/or public presentations. 
When will the data be shared? (check all that apply) 
_X_ Before publication. 
_x_ At the time of publication or shortly thereafter. 
6.2.2 
Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.3 
RESPONSE CRITERIA 
For the purposes of this study, patients should be re-evaluated for response at week 2 and week 
6. 
6.3.1 
Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with topical ruxolitinib. 


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Evaluable for objective response: Patients who complete 6 weeks of treatment will be evaluable 
for the primary endpoint of efficacy. Patients who have progression of the skin disease earlier will 
also be included in the analysis of efficacy. 
6.3.2 Disease Parameters 
Measurable disease: Measurable lesions are defined as areas that are clinically consistent with 
epidermal cGVHD that are at least 8cm ( or approximately 1 pahn size for children) in shortest 
diameter, 
Target lesions. Two areas of measurable disease that are on separate body regions ( e.g. right arm 
and left arm) at least 10 cm apart, amenable to topical application of medicine will be identified as 
target lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), and be representative of the morphology of 
epidermal cGVHD present in the patient, be nonulcerated, show no evidence of cutaneous 
infection, show no evidence of current or prior NMSC, and in addition should be sites that lend 
themselves to reproducible repeated measurements. 
6.3.3 
Methods for Evaluation of Measurable Disease 
All measurements will be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 1 week before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
Clinical examination: Clinical photographs, photographs for automated measurements, and 
transparency tracing will be used at each visit for accurate measurements of the target areas of 
affected skin. Surface area of each target lesion will be calculated. An overall Physicians Global 
Assessment score will be documented at each visit. 
6.3.4 Response Criteria 
6.3.4.1 Evaluation of Target Lesions 
No definition of response exists for epidermal cGVHD. The 2014 Response Criteria Working 
Group of the NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-
versus-Host Disease recommended a scoring system (0-3) for cutaneous GVHD that takes into 
account total BSA for cutaneous cGVHD findings, depth of sclerotic cGVHD, and presence of 
ulceration.(20) This scoring system cannot be used for our purposes, as such there is no validated 
or defined scale and response criteria for epidermal cGVHD. 
This pilot study will evaluate the percent decline surface area after 6 weeks of treatment with 
topical ruxolitinib cream and vehicle cream to define a clinically relevant difference. This will 
potentially define a response criteria to be used for a subsequent, larger trial of topical ruxolitinib 
for epidermal cGVHD. 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
6.4 
TOXICITY CRITERIA 
30 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(https://ctep.cancer.gov/protocolDevelopment/electronic _ applications/docs/CTCAE _ v5 _Quick_ 
Reference_5x7.pdf). 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7 .1 
DEFINITIONS 
Please refer the Policy 801 for definitions of reportable events. 
7.2 
EXPEDITED REPORTING TO NIH INTRAMURAL IRB 
Please refer to the Policy 801 for expedited reporting requirements. 
7 .3 
NIH INTRAMURAL IRB REQUIREMENTS FOR Pl REPORTING AT CONTINUING REVIEW 
Please refer to the reporting requirements in Policy 801 
7.4 
NIAMS CLINICAL DIRECTOR REPORTING 
All serious adverse events (SAEs) that meet the definition per Policy 801, must be reported to 
NIAMS Clinical Director via colbertr@mail.nih.goV"1 
7.5 
IND SPONSOR REPORTING CRITERIA 
An investigator must innnediately report to the sponsor, using the mandatory MedWatch form 
3500a or equivalent, any serious adverse event, whether or not considered drug related, including 
those listed in the protocol or investigator brochure and must include an assessment of whether 
there is a reasonable possibility that the drug caused the event. 
• 
All Grade 5 ( fatal) events ( except death due to progressive disease) must be reported 
via email within 24 hours. A complete report must be submitted within one business 
day. 
• 
All other serious adverse events including deaths due to progressive disease must be 
reported within one business day 
Study endpoints that are serious adverse events (e.g. all-cause mortality) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between the 
drug and the event ( e.g. death from anaphylaxis ). In that case, the investigator must immediately 
report the death to the sponsor. 
Events will be submitted to PI and study coordinator. 
Events will be submitted to 
, authorized representative for the IND Sponsor 
(NIAMS)at: 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
 
 
 
 
 
 
7.5.1 
Reporting Pregnancy 
7.5.1.1 Maternal exposure 
31 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately and the pregnancy reported to the Sponsor. The potential risk of 
exposure of the fetus to the investigational agent( s) or chemotherapy agents ( s) should be 
documented in box BS of the MedWatch form "Describe Event or Problem". 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study treatment under 
study may have interfered with the effectiveness of a contraceptive medication. However, as 
patients who become pregnant on study risk intrauterine exposure of the fetus to agents which may 
be teratogenic, the CCR is requesting that pregnancy should be reported in an expedited manner 
as Grade 3 "Pregnancy, puerperium and perinatal conditions - Other (pregnancy)" under the 
Pregnancy, puerperium and perinatal conditions SOC. 
Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented. 
If any pregnancy occurs in the course of the study, then the investigator should inform the Sponsor 
within 1 day, i.e., immediately, but no later than 24 hours of when he or she becomes aware of 
it. 
The designated Sponsor representative will work with the investigator to ensure that all relevant 
information is provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days 
for all other pregnancies. 
The same timelines apply when outcome information is available, 
7 .5 .1.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 7 
days after the last dose of topical ruxolitinib. 
Pregnancy of the patient's partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 7 days after the last dose 
should, if possible, be followed up and documented. 
7.6 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
All Serious Adverse Events ("SAE") required to be reported pursuant to the Protocol shall be 
provided to Incyte and its representatives by Institution or Principal Investigator within twenty-


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four (24) hours of learning of the event as well as any additional reports (including follow-up) 
agreed upon by Institution or Principal Investigator and Incyte. SAE Reports will be sent to 
 
. By sending to this e-mail address, the Incyte Pharmacovigilance 
group will receive copies of the reports. This process will be tested and established before the 
first patient is enrolled in the Study. Notwithstanding anything to the contrary herein, Institution 
will have the primary responsibility of reporting adverse events ("AE") to regulatory authorities. 
Leidos will send all reports to the manufacturer. 
7.7 
DATAANDSAFETYMONITORINGPLAN 
7.7.1 
Principal Investigator/Research Team 
The clinical research team will meet on a biweekly basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or the 
medical advisory investigator. Adverse events will be reported as required above. Any safety 
concerns, new information that might affect either the ethical and or scientific conduct of the trial, 
or protocol deviations will be immediately reported to the IRB using iRIS and to the Sponsor. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
7. 7.2 
Sponsor Monitoring Plan 
As a sponsor for clinical trials, FDA regulations require NIAMS to maintain a monitoring program. 
The NIAMS program allows for confirmation of: study data, specifically data that could affect the 
interpretation of primary study endpoints; adherence to the protocol, regulations, and SOPs; and 
human subject's protection. This is done through independent verification of study data with 
source documentation focusing on: 
• 
Informed consent process 
• 
Eligibility confirmation 
• 
Drug administration and accountability 
• 
Adverse events monitoring 
• 
Response assessment. 
This trial will be monitored by personnel employed by Leidos, a NIAMS contractor. Monitors are 
qualified by training and experience to monitor the progress of clinical trials. Personnel monitoring 
this study will not be affiliated in any way with the trial conduct. 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
8 
STATISTICAL CONSIDERATIONS 
8.1 
STATISTICALHYPOTHESES 
8.1.1 
Primary efficacy endpoints: 
33 
The primary objectives are to determine the safety and tolerability as well as the efficacy of topical 
ruxolitinib 1.5% cream in patients with epidermal cGVHD. 
The primary safety and tolerability endpoint will be counts of the grades of adverse events noted. 
The primary efficacy endpoint will be the percent change in the surface area of the target lesions 
for ruxolitinib-treated vs. placebo-treated lesions. 
8.1.2 
Secondary Efficacy endpoints: 
The secondary endpoints are: 1) change in pain, pruritus, .and overall severity VAS scales and 2) 
the pharmacokinetics and pharmacodynamics of topical ruxolitinih 1.5% cream in patients with 
epidermal cGVHD. 
8.2 
SAMPLE SIZE DETERMINATION: 
The primary objectives are to determine the safety and tolerability as well as the efficacy of topical 
ruxolitinib 1.5% cream in patients with epidermal cGVHD. Patients who are compliant with 
protocol requirements through the primary endpoint, week 6, are considered evaluable. To analyze 
the efficacy of the treatment, we will measure surface area percent change. The initial surface area 
of each of the two target lesions will be measured at baseline and again at week 2, week 4 
( optional), and week 6 on evaluable patients after one lesion has received treatment with ruxolitinib 
1.5% cream and the other lesion has received treatment with the vehicle control. Following 6 
weeks of treatment, the percent decline in the surface area of the two lesions will be determined, 
and the difference between the two decline percentages between the two lesions will be formed, 
expressed consistently as ruxolitinib decline minus placebo decline. If there are 10 evaluable 
patients ( complete all study requirements through week 6) who have differences in decline 
percentages determined, then there will be 80% power to detect whether these paired differences 
in the changes from baseline are equal to one SD of the difference of the changes (effect size=l.0) 
using a two-tailed 0.05 significance level paired t-test. In practice, a Wilcoxon signed rank test 
may be used instead of a t-test if the differences are not consistent with a normal distribution 
(p<0.05 by a Shapiro-Wilks test). 
The anticipated accrual rate is 1 patient per month. Enrollment is open to individuals at least 12 
years of age, regardless of gender or racial/ethnic background. Given the complexity of this 
disease, which is often multiorgan in nature with intermittent flares of disease, the drop-out rate is 
expected to be high. In order to allow for a modest percentage of patients who are not able to 
comply with the proper administration of the two agents, the accrual ceiling will be set at 15 
patients. Therefore, it is anticipated that the study will last approximately 17 months to reach 10 
evaluable patients. 


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8.3 
POPULATIONS FOR ANALYSIS 
Per protocol analysis dataset: patients who receive at least 80% of scheduled doses of the agent in 
order to measure the change from baseline to 6 weeks will be included in the statistical analyses 
performed. 
8.4 
STATISTICALANALYSES 
8.4.1 
General approach 
The analysis will primarily focus on evaluatiog the difference in the surface area of the target 
lesions receiving active agent or placebo in each patient and testing whether the target lesions 
improve more with active agent compared to placebo. 
8.4.2 Analysis of the primary efficacy endpoints 
To analyze the efficacy of the treatment, the initial surface area of each of the two target lesions 
will be measured at baseline and again at week 2, week 4 ( optional), and week 6 on evaluable 
patients after one lesion received treatment with ruxolitinib 1.5% cream and the other lesion 
received treatment with the vehicle control. Following 6 weeks of treatment, the percent decline 
in the surface area of the two lesions will be determined, and the difference between the two decline 
percentages between the two lesions will be formed, expressed consistently as ruxolitinib decline 
minus placebo decline. The magnitude of the paired differences will be calculated and tested for 
whether the difference is equal to zero by a two-tailed 0.05 significance level paired t-test. In 
practice, a Wilcoxon signed rank test may be used instead of a t-test if the differences are not 
consistent with a normal distribution (p<0.05 by a Shapiro-Wilks test). 
8.4.3 
Analysis of the secondary efficacy endpoints 
The secondary objectives will be assessed using the following measures. Measures of disease 
activity in patients with epidermal cGVHD will be determined. These include the pain, pruritus, 
and overall disease severity VAS scales. 
To describe pharmacokinetics and pharmacodynamics of topical ruxolitinib 1.5% cream in patients 
with epidermal cGVHD, standard pharmacokinetic parameters such as AUC, clearance, 
concentration and half-life will be reported using descriptive statistics, along with 
pharmacodynamic parameters such as pSTAT3. 
8.4.4 
Safety Analyses 
Safety of the agent will be assessed by reporting the grade of adverse events noted in each patient, 
and reporting the fraction with grade 3 and grade 4 adverse events. Safety data will be presented 
in individual listings. Summaries will also be prepared. The safety data will consist of the reporting 
of all adverse events, vital signs, physical examination data, and appropriate laboratory safety data. 
8.4.5 
Baseline Descriptive Statistics 
Limited demographic and clinical characteristics of all patients will be reported. 


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8.4.6 Planned interim analyses 
None planned. 
8.4.7 
Subgroup analyses 
None will be performed. 
8.4.8 Tabulation of individual participant data 
Changes in affected lesion sizes may be reported on a per-patient basis or may be summarized. 
8.4.9 Exploratory analyses 
The exploratory objective is to characterize and analyze the effect of topical ruxolitirub 1.5% 
cream on inflammatory pathways in the skin and peripheral blood of patients with epidermal 
cGVHD using immunohistochemistry, and cytokine and gene expression studies. These analyses 
will be done using appropriate descriptive statistical methods with all results being considered 
exploratory and hypothesis generating. 
9 
COLLABORATIVE AGREEMENTS 
9.1 
CRADA 
9.1.1 
A CRADA has been executed with Incyte, who will provide Ruxolitinib for use in this 
protocol. CRADAnumber C-011-2018. 
9.2 
MATERIAL TRANSFER AGREEMENTS (MTAS) 
9.2.1 
An MTA will be executed for the studies noted in Section 5.1.4. 
10 HUMAN SUBJECTS PROTECTIONS 
10.1 RATIONALE FOR SUBJECT SELECTION 
No subjects will be excluded from participation based on gender, race, or ethnicity. The study will 
be open to all subjects who satisfy the inclusion criteria and provide an informed consent to the 
protocol. Recruitment strategies are listed in Section 2.1.3. 
10.2 PARTICIPATIONOFCHILDREN 
Children aged 12 to 17 are included in this study as children undergo allogeneic stem cell 
transplantation, develop chronic graft-versus-host disease, and suffer from a lack of organ-targeted 
measures to control skin GVHD without the systemic side effects associated with oral therapies. 
Furthermore, the topical formulation of administration in this study is anticipated to be of much 
lower relative risk compared to the known toxicity associated with systemic therapies employed 
forGVHD. 
Approximately 3,000 pediatric hematopoeitic cell transplants are performed in the US each year. 
These children are at significant risk of developing skin GVHD, the systemic treatments for which 
confer long-term risk of multiple severe adverse events, particularly infection and end organ 


36 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
damage ( e.g. nephrotoxicity from calcineurin inhibitor use). Therefore, skin directed interventions 
that potentially confer less long-term risk should be studied in this population in order to determine 
if they may be a safe and efficacious alternative for use in children. 
Recruitment is drawn from an existing NCI GVHD Natural History Study that recruits both 
children and adults, ongoing NCI pediatric transplant protocols, and outreach to area transplant 
programs, including Children's National Medical Center. 
10.3 PARTICIPATION OF ADULT SUBJECTS UNABLE TO CONSENT 
Adults unable to provide consent are excluded from enrolling in the protocol. However, it is 
possible that subjects enrolled in the protocol may permanently lose the capacity to consent for 
themselves during the course of this study. In the event this occurs, the subjects will remain in the 
study because for decisionally impaired subjects, it is unlikely that this trial would pose an 
equivalent or greater risk of adverse events compared to the risks of standard systemic 
immunosuppression to treat GVHD (mentioned above), and therefore, we believe it is ethically 
appropriate to allow clinical trial access to this skin-directed therapy. If subjects will remain in 
the study, an LAR will be identified consistent with Policy 403 and informed consent obtained 
from the LAR. 
For this reason and because there is a prospect of direct benefit from research participation (Section 
10.4), all subjects 2'. age 18 will be offered the opportunity to fill in their wishes for research and 
care, and assign a substitute decision maker on the ''NIH Advance Directive for Health Care and 
Medical Research Participation" form so that another person can make decisions about their 
medical care in the event that they become incapacitated or cognitively impaired during the course 
of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) 
for evaluation as needed for the following: an independent assessment of whether an individual 
has the capacity to provide consent; assistance in identifying and assessing an appropriate 
surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. For those 
subjects that become incapacitated and do not have pre-determined substitute decision maker, the 
procedures described in MAS Policy 87-4 and NIH HRPP Policy 403 for appointing a surrogate 
decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a 
legal guardian or durable power of attorney, will be followed. 
Evaluation of Benefits and Risks/Discomforts 
10.3.1 Related to topical ruxolitinib 
Subjects participating in this research protocol may benefit from an improvement in symptoms of 
cGVHD. Potential risks of topical ruxolitinib include the toxicities described in Section 11.1.2 and 
in the consent form. There is the potential for unexpected adverse events. All subjects will be 
monitored for development of side effects. 
10.3.2 Related to blood collection 
Side effects of blood draws include pain, bleeding, bruising, and hematoma formation at the site 
of the blood draw. 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
10.3.3 Related to skin biops~ 
37 
Appropriate measures will be taken to minimize the risks that can potentially be associated with 
skin biopsy. Procedure related risks including bleeding, infection, pain, and scarring will be 
explained during informed consent will all questions answered. 
10,4 RISKS/BENEFITS ANALYSIS 
Cutaneous manifestations of cGVHD represent one of the most common manifestations of this 
complex, multisystem disease. Cutaneous cGVHD has significant impact on quality of life and can 
increase the risk of infection when ulcerations develop. Based on current scientific knowledge, 
JAK inhibition modulates graft-versus-host disease. The benefit of this study includes the potential 
to treat epidermal cGVHD in subjects enrolled in the study as well as to potentially gain greater 
insight into the pathophysiology of epidermal cGVHD and the effect of ruxolitinib on the cells in 
the tissue and in circulation of patients with active epidermal cGVHD. The risks of the study of 
topical ruxolitinib are minimal compared to the potential benefits to them and compared to 
diagnostic procedures and therapeutic options that are currently used for this disease. 
Adult and Pediatric subjects entered on the trial will be treated with therapeutic intent and response 
to the therapy will be closely monitored. Therefore, this protocol involves greater than minimal 
risk, but presents the potential for direct benefit to individual for Adult subjects and meets Category 
2.45 CFR 46.405 regulations for Pediatric subjects. 
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation if an adult subject becomes decisionally impaired while on-study guidelines 
outlined in Section 10.3 will be followed. 
10.5 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
A discussion regarding the purpose of the study, alternatives to participating in the research, the 
treatment plan, research objectives, and follow-up of the trial will be reviewed with each subject, 
in-person, by an associate or principal investigator. Participation is voluntary and potential subjects 
will be made aware of alternatives to participating in the research. All participants, or legal 
guardian, must sign the !RB-approved informed consent document. The original signed consent 
will be kept by medical records and a copy will be provided to the patient and another copy will 
be placed in the research record. Documentation of the informed consent process will be placed in 
the medical record. At any time during participation if new information about risks, adverse events, 
or toxicities becomes available, the information will be shared with all enrolled and prospective 
participants. 
Where deemed appropriate by the clinician and the child's parent(s) or guardian, the child will 
also be included in all discussions about the trial and age-appropriate language will be used to 
describe the procedures and tests involved in this study, along with the risks, discomforts and 
benefits of participation. Written assent will not be obtained from children as the study holds out 
the prospect of direct benefit that is important to the health and well-being of the child and is 
available only in the context of the research. Verbal assent will be obtained as appropriate for 
children ages 12-17 and the parent or guardian will sign the designated line on the informed 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
38 
consent attesting to the fact that the child has given assent. The consent/assent process will be 
documented in the child's medical record, including the assessment of the child's ability to provide 
assent (verbal versus written) as applicable. All children will be contacted after they have reached 
the age of 18 to determine whether they wish to continue on the trial and informed consent will be 
obtained from them at that time. 
10.5.1 Consent for minors when they reach the age of majority 
When a pediatric subject reaches age 18, continued participation (including ongoing interactions 
with the subject or continued analysis ofidentifiable data) will require consenting of the now adult 
with the standard protocol consent document to ensure legally effective informed consent has been 
obtained. Given the length of time that has transpired for some of the subjects since their last visit 
for this study, we request waiver of informed consent for those individuals who have completed 
their participation in the research study or have been lost to follow up. 
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d): 
(1) The research involves no more than minimal risk to the subjects. 
a. Analysis of samples and data from this study involves no additional risks to 
subjects. 
(2) The waiver or alteration will not adversely affect the rights and welfare of the subjects. 
a. Retention of these samples or data does not affect the welfare of subjects. 
(3) The research could not practicably be carried out without the waiver or alteration. 
a. Considering the length of time between the minor's last contact with the 
research team and their age of majority, it will likely be very difficult to locate 
them again. A significant reduction in the number of samples analyzed is likely 
to impact the quality of the research. 
(4) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation. 
a. We plan to request a waiver ofreconsent for those subjects who have been lost 
to follow-up. 
10.5.2 Telephone consent 
In the event of a phone consent, the informed consent document will be sent to the subject. An 
explanation of the study will be provided over the telephone after the subject has had the 
opportunity to read the consent form. The subject will sign and date the informed consent. 
The original informed consent document will be sent back to the consenting investigator who will 
sign and date the consent form with the date the consent was received by the investigator. 
A fully executed copy will be returned via mail for the subject's records. 
The informed consent process will be documented on a progress note by the consenting 
investigator with the date the telephone consent was obtained and a copy of the informed consent 
document and note will be kept in the subject's research record. 


39 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
10.5.3 Telephone assent 
The informed consent and assent documents will be sent to the parents/guardian and child. An 
explanation of the study will be provided over the telephone after the parents/guardian and child 
have had the opportunity to read the documents. Age-appropriate language will be used to discuss 
the study with the child. The parents/guardian will sign and date the informed consent, including 
the line for verbal assent of a child if appropriate. All children will be contacted after they have 
reached the age of 18 to determine whether they wish to continue on the trial and informed consent 
will be obtained from them at that time. 
The original signed informed consent and assent documents will be sent back to the consenting 
investigator who will sign and date the consent form with the date the consent was received by the 
investigators. 
A fully executed copy will be returned via mail to the subject. 
The informed consent and assent process will be documented on a progress note by the consenting 
investigator with the date the telephone consent was obtained and a copy of the informed consent 
document and note will be kept in the subject's research record. 
10.5.4 Informed consent of non-English speaking subjects 
If there is an unexpected enrollment of a research participant for whom there is no translated extant 
IRB approved consent document, the principal investigator and/or those authorized to obtain 
informed consent will use the Short Form Oral Consent Process as described in MAS Policy M77-
2, OHSRP SOP 12, 45 CFR46.117 (b) (2), 21 CFR 50.27 (b) (2). The summary that will be used 
is the English version of the extant IRB approved consent document. Signed copies of both the 
English version of the consent and the translated short form will be given to the subject or their 
legally authorized representative and the signed original will be filed in the medical record. 
Unless the Pl is fluent in the prospective subject's language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
information and obtaining consent. Whenever possible, interpreters will be provided copies of the 
relevant consent documents well before the consent conversation with the subject (24 to 48 hours 
if possible). 
11 PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION 
11.1 TOPICAL RUXOLITINIB 1.5% CREAM, IND# 136890 
11.1.1 Source 
Topical ruxolitinib 1.5% cream and a placebo cream will be supplied by Incyte. Ruxolitinib is an 
approved oral agent, but the topical application of this drug is not approved by the FDA. The 
NIAMS will hold the IND for the study agent. 


40 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
11.1.2 Toxicity 
Topical ruxolitinib has been evaluated in over 2350 subjects in at least 17 clinical studies in healthy 
volunteers and participants with psoriasis, atopic dermatitis, alopecia aerata and vitiligo for a 
duration of 1-26 months. 
There have been no treatment related deaths. To date, only one severe, and/or life-threatening 
treatment emergent adverse event (TEAE), dermatitis atopic, has been attributed to the study drug. 
All other SAEs were considered unlikely related or unrelated to study drug. 
Other TEAEs that led to discontinuation of topical ruxolitinib include mild to moderate 
occurrences of application site irritation, a Grade 3 elevation in GGT, headache, fatigue, nausea, 
atopic dermatitis and hypertriglyceridemia. 
In an ongoing study of atopic dermatitits, a total of 67 pediatric participants (aged 2 to 17 years) 
received ruxolitinib cream 0.5%, 1.5%, or 0.75% cream BID. No participant had a fatal TEAE, 
SAE, or TEAE leading to discontinuation of ruxolitinib cream. 
Cutaneous AEs were seen with similar frequency for vehicle-treated lesions and active comparator 
treated lesions when compared with topical ruxolitinib treated lesions. 
The most common AEs that were considered possibly related to the study drug include 
transient hypoaesthesia, transient leukopenia and reticulocytosis, pruritus, upper respiratory 
infections, nasopharyngitis, headache, acne, dermatitis atopic, and transient application site 
irritation. All were considered mild to moderate and resolved with or without the need for 
concomitant medications. 
Oral ruxolitinib is FDA approved for treatment of myelofibrosis and polycythemia vera in adults. 
The most common AEs with oral administration include thrombocytopenia, anemia, neutropenia, 
infection, nonmelanoma skin cancer, elevation of AST and ALT. Systemic exposure with topical 
ruxolitinib is several fold below the doses that are associated with AEs following oral dosing. 
Phototoxicity 
Topical ruxolitinib tested positive in a photoclastogenicity assay, therefore there may be a risk of 
skin reaction with the combination of topical ruxolitinib and sunlight.(13) For this reason, subjects 
are cautioned to avoid excessive exposure to either natural or artificial sunlight. 
Potential for genotoxicity 
A potential for genotoxicity was not found when assessed by standard in vitro and in vivo 
assessments.( 13) 
11.1.3 Formulation and preparation 
Ruxolitinib (INCB018424) cream will be formulated in a 1.5% strength. All excipients in both the 
INCB018424 and placebo cream formulations are compendia! grade or are approved for use in 
topical products. The placebo cream is an identical formulation to the active product except for the 
absence of drug substance. 


41 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
11.1.4 Stability and Storage 
Topical ruxolitinib cream and placebo cream should both be stored between 15°C and 30°C (59°F 
and86°F) 
11.1.5 Administration procedures 
Study agent and placebo agent are applied topically to the desiguated areas. Application sites 
should avoid ulcerated and/or mucosa! surfaces. The maximal BSA to receive study drug is 10%. 
11.1.6 Incompatibilities 
The chemical name of INCB018424 phosphate is (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- lH-
pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate (Figure 7). INCB018424 phosphate has a 
molecular formula of C11H21N6O4P and a molecular weight of 404.36.(13) 
Figure 7: INCB018424 Phosphate structural formula 
12 REFERENCES 
I. M. Z. Pasquini, X., Current uses and outcomes of hematopoietic stem cell transplantation: 
CJBMTR Summary Slides. Available at: http://www.cibmtr.org/, (2015). 
2. S. Arai et al., Increasing incidence of chronic graft-versus-host disease in allogeneic 
transplantation: a report from the Center for International Blood and Marrow Transplant 
Research. Biol Blood Marrow Transplant 21, 266-274 (2015). 
3. S. J. Lee et al., Severity of chronic graft-versus-host disease: association with treatment-
related mortality and relapse. Blood 100, 406-414 (2002). 
4. S. R. Hymes, A. M. Alousi, E. W. Cowen, Graft-versus-host disease: part I. Pathogenesis and 
clinical manifestations of graft-versus-host disease. J Am Acad Dermatol 66, 5151e511-
5 l 8; quiz 533-514 (2012). 
5. M. H. Jagasia et al., National Institutes of Health Consensus Development Project on Criteria 
for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diaguosis and 
Staging Working Group Report. Biol Blood Marrow Transplant 21, 389-401 e381 
(2015). 
6. M. E. Flowers, P. J. Martin, How we treat chronic graft-versus-host disease. Blood 125, 606-
615 (2015). 
7. P.A. Carpenter et al., National Institutes of Health Consensus Development Project on 
Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary 


42 
Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 21, 
1167-1187 (2015). 
8. N. Okiyama et al., Reversal of CD8 T-cell-mediated mucocutaneous graft-versus-host-like 
disease by the JAK inhibitor tofacitinib. The Journal of investigative dermatology 134, 
992-1000 (2014). 
9. H.B. Park et al,, CP-690550, a Janus kinase inhibitor, suppresses CD4+ T-cell-mediated acute 
graft-versus-host disea~e by inhibiting the interferon-gamma pathway. Transplantation 
90, 825-835 (2010). 
10. J. Choi et al., Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the 
graft-versus-leukemia effect. PLoS One 9, e109799 (2014). 
11. C. Camiti et al., Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental 
Murine Acute GVHD While Preserving GVT Effects. Clinical cancer research : an 
official journal of the American Association for Cancer Research 21, 3740-3749 (2015). 
12. S. Spoerl et al., Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 
123, 3832-3842 (2014). 
13. INCB018424 Phosphate Investigator's Brochure (IB) v9. Wilmington, DE: Incyte 
Corporation (2016). 
14. H.J. Khoury et al., Ruxolitinib As Sparing Agent for Steroid-Dependent Chronic Graft-
Versus-Host Disease (cGVHD). Blood 126, 1938-1938 (2015). 
15. R. Zeiser et al., Ruxolitinib in corticosteroid-refractory graft-versus-host disease after 
allogeneic stem cell transplantation: a multicenter survey. Leukemia, (2015). 
16. B. G. Craiglow, D. Tavares, B. A. King, Topical Ruxolitinib for the Treatment of Alopecia 
Universalis. JAMA Dermatol 152, 490-491 (2016). 
17. N. Punwani et al., Downmodulation of key inflammatory cell markers with a topical Janus 
kinase 1/2 inhibitor. Br J Dermatol 173, 989-997 (2015). 
18. N. Punwani et al., Preliminary clinical activity of a topical JAKl/2 inhibitor in the treatment 
of psoriasis. J Am Acad Dermatol 67, 658-664 (2012). 
19. L. Xing et al., Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK 
inhibition. Nat Med 20, 1043-1049 (2014). 
20. S. J. Lee et al., Measuring therapeutic response in chronic graft-versus-host disease. National 
Institutes of Health consensus development project on criteria for clinical trials in chronic 
graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol 
Blood Marrow Transplant 21, 984-999 (2015). 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
13 APPENDICES 
13.1 APPENDIX A- PERFORMANCE STATUS CRITERIA 
% 
Karnofskyt 
Score Lansky Scale# 
100 
Normal; no complaints/ no 
100 
Fully Active 
evidence of disease . 
Able to carry on normal 
Minor restrictions in physically 
90 
activity; minor signs or 
90 
symptoms of disease 
strenuous play 
Normal activity with effort; 
Restricted in strenuous play, tires 
80 
some signs or symptoms of 
80 
disease 
more easily, otherwise active 
Cares for self; unable to carry 
Both greater restrictions of and 
70 
on normal activity or do active 
70 
work 
less time spent in active play 
Requires occasional assistance 
Ambulatory up to 50% of time, 
60 
but is able to care for most of 
60 
limited active play with assistance 
his needs 
/ supervision 
Requires considerable 
Considerable assistance required 
50 
assistance and frequent medical 50 
for any active play; fully able to 
care 
engage in quiet play 
40 
Disabled, requires special care 
40 
Able to initiate quiet activities 
and assistance 
Severely disabled; 
Needs considerable assistance for 
30 
hospitalization is indicated 
30 
quiet activity 
though death not imminent 
20 
Very sick; hospitalization is 
20 
Limited to very passive activity 
necessary 
initiated by others e.g. TV 
10 
Moribund; fatal process 
10 
Completely disabled, not even 
progressing rapidly 
passive play 
0 
Unresponsive, coma 
t 
Karnofsky = D.A., et al., Cancer 1: 634-656, 1948 
• Lansky Scale= Lansky, et. al., Cancer Oct 1; 60(7): 1651-1656, 1987 
43 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
13.2 .APPENDIX B - STRONG CYP3A4 INHIBITORS 
Clarithromycin 
Nelinavir 
Itraconazole 
Ritonavir 
Ketoconazole 
Saquinavir 
Atazanavir 
Tipranavir 
Darunavir 
Nefazodone 
Indinavir 
44 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
13.3 APPENDIX C - ORGAN SPECIFIC AND GLOBAL SCORING OF CHRONIC GVHD 
sc9~0. 
l'ERFORMANCE 
SCORE: 
I 
KPS ECOG LPS 
Asymptomatic and 
fully active (ECQG 
0;KPSorLPS 
100%) 
SKINt 
SCORE%BSA D 
GVHD. features to be scored 
bJ,J}&j; 
Check all that apply: 
Maculopapular rasb/erytbema 
Licheo planus-Jlke features 
Sclerotic teatures 
Papulosquamous lesions or 
icbthyosis 
Keratosis pilarls-Jlke GVHD 
SKIN FEATURES 
SCORE: 
No BSA 
involved 
No sclerotic 
teatures 
Other skin GVHD features fNOTscored by HSA) 
Check all that apply: 
Hypmpigmentation 
Hypopigmentation 
Poikiloderma 
Severe or generalized pruritus 
Nail involvement 
Symptomatic, 
Symptomatic, 
Symptomatic, 
fully ambulatory, 
ambulatory, capabl, 
limited self'.care, 
restricl<:d only in 
of self-care, >SO% 
>SO% t>f waking 
physically 
ofwelring hours oo 
hours in bed (ECOG 
sJreonous activity 
of bed (ECOO 2, 
3-4, KPS or LPS 
(ECOG 1, KPS 
KPS or LPS 60-
<60%) 
. orLPS8Q-J0%) ..... 70%) 
l-18%BSA 
D 19-50%BSA 
Superficial 
sclerotic features 
4'not hidebound" 
(able to pinch) 
>50%BSA 
Check all that apply: 
D Deep sclerotic 
teatures 
0 "Hidebound" 
(unsble to pinch) 
Impaired mobility 
Ulceration 
45 
Abnormaiity present but "/Plained entirely by non-GVHD Mcumented cause (spec!fj,) .. • ___________ _ 
MOUTH 
No symptoms 
Mild symptoms 
Moderate 
Lichen planus-11/re 
with disuse sigos 
symptoms with 
features present: 
but not limiting 
disease signs with 
Ye• 
oral intake 
partial limitation 
No 
significantly 
of oral intelre 
Severe symptoms with 
disease slgos on 
examination with major 
limitation of ore! intake 
b111on-GVHD.dtJ.cu"!e11tedcause_{,SJ?•~ilji).,: ____________ _ 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
EYJ<S 
Keratoconjuncti-yitis 
sicc:a (KCS) c01ifirmed 
by ophthalmologist: 
D Ye• 
D Not OJ<amlned 
SCORE0 
D No symptoms 
SCORE! 
Mild dry eye 
symptoms not 
affecting AOL 
(requitement of 
lubricant eye 
drops :, 3 x per 
day) 
SCORE2 
Moderate dry eye 
symptoms partially 
affecting AOL 
(requiring lubricant 
eye drops > 3 x per 
~Y or punctal 
plugs), 
WITROUTnew 
vmion impainnent 
dnetoKCS 
46 
SCORE3 
Sovero dry eye 
symptoms significantly 
affecting AOL (special 
eyeware to relieve pain) 
OR unable to work 
beclltlse of ocular 
symptoms OR loss of 
vision dne to KCS 
Abnormality present but rocplained entjrely by non-<JVHD documented cause (specify) .. · ___________ _ 
GlTract 
Checl< all thut 11pply: 
Esophageal web/ 
proxlmal stric~ 
or ring 
Dyophagia 
Weight loss~%• 
to tlnive 
D No symptoms 
without 
significant wdght 
loss• (<5%) 
Symptoms 
associa\ed with 
mlld to moderste 
weight loss• 
(S-15%)OR 
moderste diarrhea 
without 
significant 
interference with 
dally living 
P SymptQDJB a~sociated 
with. sigoiflcant weight 
loss• > 15%~ requires 
notritiona1 supplement for 
most caloric rieeds OR 
esophageal .dilation OR 
severe diarrhea with: 
significant interference 
with daily Jiving 
Abnormality present but explained entire/)! by non-GVHD documented cause (specify): __________ _ 
LIVER 
D Normal total 
Normal total 
Elevated total 
bilirubin and 
bilirobin with ALT 
bilirubin but 
ALTorAP 
~to5xULNor 
:,:lmg/dLor 
<3xULN 
AP,::3xULN 
ALT>5ULN 
D Abnormality present but explained entire/), by n~n,GVHD docurnented cauae (fpec/fy): 
LtJNos•• 
Symptom score: 
Lung score: 
%FEVILJ 
Pulmonary fimctlon tests 
Notp¢ormed 
D No symptoms 
D FEVl,::80% 
Mild symptoms 
( Shortness of 
breath after 
climbing one flight 
ofs!ep$) 
D FEVi 60-79% 
Moderate 
symptoms 
(shortness ofbrellth 
after walking on 
fiat ground) 
FEVl 40-59% 
D Elevsted total 
bilimbin > 3 mg/dL 
Severo symptoms 
(shortness ofbreath at 
rest; requiring 0,) 
FEVI :,39% 
Abnormality present but exJ>lained entirel,y bynon0GVHD_docwnented c<luse(specifj,):_~~~--~-~-~ 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
JOINTS AND FASCIA 
P-ROMscore 
(see below) 
Shoulder (1-7):_ 
Elbow(l-7):_ 
Wrist/finger (1-7):_ 
Ankle (1-4):_ 
SCORE0 
No 
symptoms 
SCORE1 
Mild tightness of 
anns or legs, 
normal or mild 
decreased range of 
motion (ROM) 
AND not affecting 
ADL 
SCORE2 
Tightness of arms or 
legs OR joint 
contractures, 
erythema thought 
due lo lasciitis, 
moderate decrease 
ROM AND mild to 
moderate limitation 
ofADL 
47 
SCORE3 
Contractures WITH 
significant decrease of 
ROM AND significant 
limitation of ADL 
(wiable to tie shoes, 
button shirts, dress self 
etc.) 
but explained entirely by non-GVHD documented cause (specify).· ___________ _ 
GENITAL TRACT 
No signs 
Mild s!gns1 and 
Moderate signiand 
{See Supplemental figure1) 
females with or 
may have 
Not examined 
without disCQmfort 
symptoms with 
Currently sexually active 
on exam 
discomfort on exam 
D Yes 
0 No 
Abnormality present but e:q,lained entirely by non-GVHD documented cause (spec[{r): 
Severe signs1 with 
or without 
symptoms 
Other indicators, clinical fea'tures or complications related to chronic GVHD (check all that apply and assign a 
score to severity (Ow3) based on functional impact where applicable none 0,mlld -1, moderate .. 2, severe-3) 
D Ascites (serositis)_ 
Myasthenia Gravis_ 
0 Pericardia! Effusion_ 
Peripheral Neuropathy_ 
Pleural Effusion(s)_ 
Polymyositis_ 
D Wei tloss>5%* without GI s 
toms 
Eosinophilia > 500/µl_ 
0 Platelets <100,000/µ1 _ 
Others 
l;J NoGVBD 
l;J Mlld 
0 Moderate 
0 Severe 
Pluitoll!'~Phicllange ofl\[olil)n (P-ROM) 
'"'"'"' a an a 11 • 
"
00
• ii,tBli Ii i 
w"'"''" f;~~ ~r:i l\lfj 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
13.4 APPENDIX D- GLOBAL SCORING OF cGVHD 
STAGE 
DEFINITION 
Mild 
1 or 2 organs involved with no more than score 1 
p/us 
Lung score O 
Moderate 
At least 1 organ (not Lung) with a score of 2 
OR 
Lung score 1 
OR 
3 or more organs involved with no more than score 1 
Severe 
At least 1 organ with a score of 3 
OR 
Lung score of 2 or 3 
In skin: higher of the 2 scores to be used for calculating global severity 
In lung: FEV1 is used instead of clinical score for calculating global severity 
If the entire abnormality in an organ is noted to be unequivocally explained by a non-GVHD documented 
cause, that organ is not included for calculation of the global severity. 
If the abnormality in an organ is attributed to multifactorial causes (GVHD plus other causes), the scored 
organ will be used for calculation of the global severity regardless of the contributing cause (no 
downgrading of organ severity). 
48 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
13.S APPENDIX E-PHYSICIAN'S GLOBAL ASSESSMENT 
Physician's Global Assessment of epidermal cGVHD 
0 
Clear 
Residual hyperpigmentation may be present 
49 
E:ight ecythema, papulos and/or scale involving 0-20% of • /,· 
target area 
· 
' 
· · 
2 
Mild 
4 
Severe 
Erythema, fine scale and/or papules involving >20% of 
target area 
Confluent erythema and scale and/or papules covering 
>80% of target area 
.) 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
13.6 APPENDIX F-PATIENT REPORTED OUTCOME SURVEYS: PATIENT VISUAL 
ANALOG SCALES 
Patient Visual Analog Scales 
50 
Definitions: Pain due to skin disease from zero (no pain) to 10 (worst Imaginable pain) 
Pruritus Is level of discomfort from Itching from zero (no Itching) to 10 (worst 
Imaginable Itching) 
SITE 1: 
Skin Pain 
0 
Pruritus 
0 
Overall 
Disease 0 
SITE 2: 
Skin Pain 
0 
Pruritus 
0 
Overall 
Disease 0 
Overall disease Is patient's assessment of degree of disease activity on the 
skin 
10 
10 
10 
10 
10 
10 
COMPLETED BY INVESTIGATOR: 
SKIN PAIN (0-10) 
PRURITUS (0-10) 
OVERALL DISEASE SEVERITY 
(0-10) 
Site 1 
----------
--
Site2 
. 


Abbreviated Title: Topical ruxolitinib in cGVHD 
Version Date: 01/25/2021 
13,7 APPENDIX G-MEDICATION DIARY 
MEDICATION DIARY FOR TOPICAL RUXOLITINIB 
18-AR-0035 
SUBJECT ID.: ___ _ 
SITE# __ 
LOCATION~: _______ _ 
Study 
Date 
Medication 
Reason if not administered 
Observations (i.e. irritation, itching, pain, 
Day 
administered/rime 
(i.e. forgot/held) 
improvement) 
1 
YIN 
__ 
AM 
YIN 
__ 
PM 
2 
YIN 
__ AM 
YIN 
__ 
PM 
3 
YIN 
__ 
AM 
YIN 
__ 
PM 
4 
YIN 
__ AM 
YIN 
__ 
PM 
5 
YIN 
__ AM 
YIN 
__ 
PM 
. 
6 
YIN 
__ 
AM 
YIN 
__ 
PM 
7 
YIN 
__ AM 
YIN 
__ 
PM 
8 
YIN 
__ 
AM 
YIN 
__ 
PM 
9 
YIN 
__ AM 
YIN 
__ 
PM 
10 
YIN 
AM 
YIN 
__ 
PM 
11 
YIN 
__ AM 
YIN 
__ 
PM 
12 
YIN 
__ AM 
YIN 
__ 
PM 
13 
YIN 
AM 
YIN 
__ 
PM 
14 
YIN 
~-AM 
YIN 
__ 
PM 
Diary completed by: ___________ Relationsbip to patient: _________ _ 
Signature: 
Date: ___ _ 
Study Team Review 
Name: ________________ ~Reviewer Signature. ___________ _ 
Date Reviewed: ___ _ 
SI 

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