Clinical trial NCT02759731
Conditions: Chronic Graft vs Host Disease Chronic Graft-Versus-Host Disease
Keywords: Murine Models Rheumatoid Arthritis Corticosteroids Systemic Therapy Inflammatory Cytokines
Sponsor: National Cancer Institute (NCI)
Start date: 2016-11-01; Completion date: 2024-05-30
Enrollment: 24 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
Background:

Chronic graft versus host disease (cGVHD) can affect people who had a hematopoietic stem cell transplant using donor cells. It is often fatal. It is usually treated with high doses of steroids. But that helps only about half the people in the long term. Researchers want to see if a drug called baricitinib can help people with cGVHD that has not responded to therapy. The drug inhibits the proteins involved in communication in the immune system. These proteins may play a role in cGVHD and other inflammatory diseases.

Objectives:

To test the safety and effectiveness of baricitinib in people with cGVHD that has not responded to therapy.

Eligibility:

Adults 18 and older with cGVHD that has not responded to therapy.

Design:

Participants will be screened with a medical history, physical exam, and blood and urine tests. They will have lung and heart tests and chest scans.

Baseline visit: Participants will have:

Medical history

Physical exam

Blood tests

Tests for infectious diseases

Skin, eye, and teeth evaluations

Rehabilitation and occupational medicine evaluations

Photos of any lesions

Gynecology evaluation (females)

The study will occur in 28-day cycles. Participants will take the study drug by mouth every day for 3 cycles. Some will take it for 3 or 6 more cycles.

Participants will have a few visits during each cycle. They will repeat some previous tests. They may also have scans and questionnaires.

Participants will have a visit when they stop taking the drug and another 3 months later. They will repeat a few study tests. They will have follow-up calls for 2 years.

Detailed description:
* Background:

  * Chronic graft-versus-host disease (cGVHD) is the leading cause of non-relapse morbidity and mortality in persons after allogeneic hematopoietic stem cell transplantation (SCT).
  * Approximately 50% of patients with cGVHD have disease refractory to systemic corticosteroids; currently, there is no standard second-line therapy.
  * The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway relays the signaling function of several inflammatory cytokines that have a role in GVHD (interferon (IFN)-gamma, Interleukin-2 (IL-2), Interleukin-6 (IL-6), Interleukin-12 (IL-12)).
  * Murine models have demonstrated activity of JAK inhibitors in graft-versus-host disease.
  * Baricitinib is a potent and selective inhibitor of Janus kinase 1 (JAK1) and Janus kinase 1 (JAK2) that has demonstrated anti-inflammatory effects and a good safety profile in patients with rheumatoid arthritis but has not been evaluated in GVHD.
* Objectives:

  * To determine the safety and tolerability of baricitinib in patients with cGVHD that is refractory to steroids
  * To determine the efficacy of baricitinib in patients with cGVHD that is refractory to steroids
* Eligibility:

  * Inclusion:

    * Age greater than or equal to 18 years
    * Moderate or severe cGVHD per NIH consensus criteria
    * Karnofsky performance status greater than or equal to 50%
    * cGVHD that did not respond to high-dose corticosteroids (prednisone at 1.0 mg/kg/day for at least 1 week or prednisone at 0.5 mg/kg/day or 1 mg/kg every other day for at least 4 weeks), or second-line therapy (any)
    * Receiving stable or tapering doses of systemic therapy in the preceding 4 weeks if taking systemic therapy for cGVHD
  * Exclusion:

    * Neutrophils \<1.0x10\^9/L, platelets \<50X10\^9/L, creatinine greater than or equal to 1.5 times the upper limit of normal or estimated creatinine clearance \<50mL/min/1.73m\^2 (Cockroft-Gault formula), serum aspartate aminotransferase or alanine aminotransferase concentration \>3x upper limit of normal (ULN) or total bilirubin greater than or equal to 1.5x ULN
    * Progressive malignancy, uncontrolled infection or any major organ dysfunction as defined by the protocol
* Design:

  * This is a Phase 1/2 trial to determine the safety and efficacy of baricitinib in patients with cGVHD that is refractory to steroids.
  * Patients will initially be treated with baricitinib at 2mg daily for 12 weeks. If the response at 12 weeks is a complete response (CR) and there has not been a dose-limiting toxicity (DLT), the dose will remain at 2mg daily for an additional 12 weeks, with the primary response assessment at 24 weeks of total treatment. If the response is a partial response (PR) or stable disease, the dose will be increased to 4mg daily for an additional 12 weeks, with the primary response assessment at 24 weeks of total treatment. If there is progression of disease at any time within the first 12 weeks, the dose can be increased to 4mg daily at that time, and patients will continue for a total of 24 weeks of treatment. Patients will have the option to continue baricitinib for an additional 6 months as tolerated if they have stable or responding disease.
  * The co-primary endpoint of safety will be determined by rate, severity, and duration of adverse events based on Common Terminology Criteria for Adverse Events (CTCAE) v4 criteria. Assessment for DLTs will occur every 2 weeks during the first 4 weeks of each dose level. Safety monitoring will occur every 4 weeks thereafter.
  * The co-primary endpoint of efficacy will be defined as rate of overall response at 24 weeks per National Institutes of Health (NIH) consensus criteria (CR or PR).
  * Peripheral blood samples will be collected prior to treatment, at 2 weeks, at 12 weeks and every 12 weeks thereafter to evaluate cytokine and cellular profiles, STAT phosphorylation, candidate chronic GVHD biomarkers. Pharmacokinetic studies will also be performed at each dose level.
  * In an initial futility analysis, if 0 of the first 7 patients enrolled in cohort 1 have responded at 12 weeks, then a 2nd cohort of patients will be accrued to start treatment at the higher dose (4mg daily). Otherwise, if 1 or more of the first 7 patients respond in cohort 1, then 21 evaluable patients will be treated in cohort 1. Similarly, if the second cohort is used, and if 0 of the 7 patients enrolled in this second cohort have responded at 12 weeks, then no further patients will be accrued. Otherwise, if 1 or more of the first 7 patients respond in cohort 2, then 21 evaluable patients will be treated in cohort 2.
  * A total of 21 evaluable patients will be enrolled in either cohort 1 or 2 as appropriate, in order to have 80% power to detect a response rate consistent with 30% and ruling out 10%, with a one-sided significance level of 0.10 for the cohort. As an early stopping rule for safety, if 2/3 or greater patients at any given dose level experiences a dose limiting toxicity requiring dose reduction or discontinuation, that dose will not be subsequently used, and no further dose escalation will take place.

Arms: arm 1: Single arm, intra-patient dose escalation. Arm 1 (starting dose) -Baricitinib starting at a dose of 2mg daily for 12 weeks. If the response at 12 weeks is a complete response (CR) and there has not been a dose-limiting toxicity (DLT), the dose will remain at 2mg daily for an additional 12 weeks. Arm 2 (dose escalation) - If the response is a partial response (PR) or stable disease (from cohort 1), the dose will be increased to 4mg daily for an additional 12 weeks. If there has been a DLT within the first 4 weeks will have a dose reduction back to 2mg daily.

Each participant is exposed to both dose levels (with the exception of participants who developed toxicity or progressive disease that caused them to discontinue study early before they were able to undergo the per-protocol dose escalation at 12 weeks).
Interventions: intervention 1: Baricitinib
Intervention descriptions: intervention 1: Cycle=28 days: Baricitinib: 1mg-4mg by mouth (PO) every day (QD)

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title: Baricitinib in cGVHD
Version Date: 10/19/2022
1
Abbreviated Title: Baricitinib in cGVHD
NIH Protocol #: 16C0094 
NCT #:  NCT02759731
Version Date: 10/19/2022
Title: A Phase 1/2 study of baricitinib, a JAK1/2 inhibitor, in chronic graft-versus-host disease 
(cGVHD) after allogeneic hematopoietic stem cell transplantation (SCT)
NCI Principal Investigator:
Steven Z. Pavletic, MD, MS, 
Immune Deficiency Cellular Therapy Program (IDCTP)
National Cancer Institute
Building 10, Room 4-3130
10 Center Drive
Bethesda, MD 20892
Phone: 240-760-6174
E-mail: pavletis@mail.nih.gov 
Drug Name:
Baricitinib
IND Number:
129360
Sponsor:
Center for Cancer Research
Manufacturer:
Eli Lilly and Company
Supplier:
Eli Lilly and Company
Commercial Agents: None


Abbreviated Title: Baricitinib in cGVHD
Version Date: 10/19/2022
2
PRÉCIS 
Background:
Chronic graft-versus-host disease (cGVHD) is the leading cause of non-relapse morbidity and 
mortality in persons after allogeneic hematopoietic stem cell transplantation (SCT). 
Approximately 50% of patients with cGVHD have disease refractory to systemic corticosteroids; 
currently, there is no standard second-line therapy.
The JAK-STAT pathway relays the signaling function of several inflammatory cytokines that 
have a role in GVHD (IFN-γ, IL-2, IL-6, IL-12).
Murine models have demonstrated activity of JAK inhibitors in graft-versus-host disease.
Baricitinib is a potent and selective inhibitor of JAK1 and JAK2 that has demonstrated anti-
inflammatory effects and a good safety profile in patients with rheumatoid arthritis, but has not 
been evaluated in GVHD.
Objectives:
To determine the safety and tolerability of baricitinib in patients with cGVHD that is refractory 
to steroids
To determine the efficacy of baricitinib in patients with cGVHD that is refractory to steroids
Eligibility:
Inclusion:
Age ≥18 years
Moderate or severe cGVHD per NIH consensus criteria
Karnofsky performance status ≥ 50%
cGVHD that did not respond to high-dose corticosteroids (prednisone at 1.0 mg/kg/day for at 
least 1 week or prednisone at 0.5 mg/kg/day or 1 mg/kg every other day for at least 4 weeks), or 
second-line therapy (any)
Receiving stable or tapering doses of systemic therapy in the preceding 4 weeks if taking 
systemic therapy for cGVHD
Exclusion:
Neutrophils <1.0x109/L, platelets <50X109/L, creatinine  ≥ 1.5 times the upper limit of normal or 
estimated creatinine clearance <50mL/min/1.73m2 (Cockroft-Gault formula), serum aspartate 
aminotransferase or alanine aminotransferase concentration >3x ULN or total bilirubin ≥1.5x 
ULN
Progressive malignancy, uncontrolled infection or any major organ dysfunction as defined by the 
protocol
Design:
This is a Phase 1/2 trial to determine the safety and efficacy of baricitinib in patients with 
cGVHD that is refractory to steroids. 


Abbreviated Title: Baricitinib in cGVHD
Version Date: 10/19/2022
3
Patients will initially be treated with baricitinib at 2mg daily for 12 weeks.  If the response at 12 
weeks is a CR and there has not been a DLT, the dose will remain at 2mg daily for an additional 
12 weeks, with the primary response assessment at 24 weeks of total treatment.  If the response 
is a PR or stable disease, the dose will be increased to 4mg daily for an additional 12 weeks, with 
the primary response assessment at 24 weeks of total treatment.  If there is progression of disease 
at any time within the first 12 weeks, the dose can be increased to 4mg daily at that time, and 
patients will continue for a total of 24 weeks of treatment.  Patients will have the option to 
continue baricitinib for an additional 6 months as tolerated if they have stable or responding 
disease.  
The co-primary endpoint of safety will be determined by rate, severity, and duration of adverse 
events based on CTCAE v4 criteria.  Assessment for DLTs will occur every 2 weeks during the 
first 4 weeks of each dose level.  Safety monitoring will occur every 4 weeks thereafter.
The co-primary endpoint of efficacy will be defined as rate of overall response at 24 weeks per 
NIH consensus criteria (CR or PR).
Peripheral blood samples will be collected prior to treatment, at 2 weeks, at 12 weeks and every 
12 weeks thereafter to evaluate cytokine and cellular profiles, STAT phosphorylation, candidate 
chronic GVHD biomarkers.  Pharmacokinetic studies will also be performed at each dose level. 
In an initial futility analysis, if 0 of the first 7 patients enrolled in cohort 1 have responded at 12 
weeks, then a 2nd cohort of patients will be accrued to start treatment at the higher dose (4mg 
daily).  Otherwise, if 1 or more of the first 7 patients respond in cohort 1, then 21 evaluable 
patients will be treated in cohort 1.  Similarly, if the second cohort is used, and if 0 of the 7 
patients enrolled in this second cohort have responded at 12 weeks, then no further patients will 
be accrued.  Otherwise, if 1 or more of the first 7 patients respond in cohort 2, then 21 evaluable 
patients will be treated in cohort 2.
A total of 21 evaluable patients will be enrolled in either cohort 1 or 2 as appropriate, in order to 
have 80% power to detect a response rate consistent with 30% and ruling out 10%, with a one-
sided significance level of 0.10 for the cohort.  As an early stopping rule for safety, if 2/3 or 
greater patients at any given dose level experiences a dose limiting toxicity requiring dose 
reduction or discontinuation, that dose will not be subsequently used and no further dose 
escalation will take place.  


Abbreviated Title: Baricitinib in cGVHD
Version Date: 10/19/2022
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TABLE OF CONTENTS
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................7
1
INTRODUCTION ..................................................................................................................7
1.1
Study Objectives............................................................................................................7
1.2
Background and Rationale.............................................................................................7
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT ......................................................12
2.1
Eligibility Criteria........................................................................................................12
2.2
Screening Evaluation...................................................................................................14
2.3
Participant Registration and Status Update Procedures...............................................14
2.4
Baseline Evaluation .....................................................................................................15
3
STUDY IMPLEMENTATION ............................................................................................16
3.1
Study Design................................................................................................................16
3.2
Drug Administration....................................................................................................19
3.3
Dose Modifications......................................................................................................19
3.4
Questionnaires .............................................................................................................20
3.5
Follow-up.....................................................................................................................20
3.6
Telehealth ....................................................................................................................21
3.7
Study Calendar.............................................................................................................22
3.8
Cost and Compensation ...............................................................................................26
3.9
Criteria for Removal from Protocol Therapy and Off Study Criteria .........................26
4
CONCOMITANT MEDICATIONS/MEASURES..............................................................27
4.1
Concomitant Corticosteroid Therapy and Tapering Guideline ...................................27
4.2
Other Treatments for cGVHD .....................................................................................27
4.3
Other Allowed Concomitant Therapy .........................................................................28
4.4
Prohibited Concomitant Therapy.................................................................................28
5
CORRELATIVE STUDIES FOR RESEARCH ..................................................................28
5.1
Biospecimen Collection...............................................................................................28
5.2
Sample Storage, Tracking and Disposition .................................................................30
6
DATA COLLECTION AND EVALUATION ....................................................................32
6.1
Data Collection ............................................................................................................32
6.2
Data sharing plans........................................................................................................33


Abbreviated Title: Baricitinib in cGVHD
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6.3
Response Criteria.........................................................................................................33
6.4
Toxicity Criteria...........................................................................................................36
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN....36
7.1
Definitions ...................................................................................................................36
7.2
OHSRP Office of Compliance and Training...............................................................36
7.3
NCI Clinical Director Reporting .................................................................................37
7.4
NIH Required Data and Safety Monitoring Plan.........................................................37
8
SPONSOR SAFETY REPORTING.....................................................................................37
8.1
Definitions ...................................................................................................................37
8.2
Assessment of Safety Events.......................................................................................38
8.3
Reporting of Serious Adverse Events..........................................................................39
8.4
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................39
8.5
Reporting Pregnancy ...................................................................................................39
8.6
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND ...............40
9
CLINICAL MONITORING.................................................................................................40
10
STATISTICAL CONSIDERATIONS .................................................................................41
11
COLLABORATIVE AGREEMENTS.................................................................................41
11.1
Cooperative Research and Development Agreement (CRADA) ................................41
12
HUMAN SUBJECTS PROTECTIONS...............................................................................41
12.1
Rationale For Subject Selection...................................................................................41
12.2
Participation of Children..............................................................................................42
12.3
Participation of NIH Subjects Unable to Give Consent ..............................................42
12.4
Evaluation of Benefits and Risks/Discomforts............................................................42
12.5
Risks/Benefits Analysis...............................................................................................43
12.6
Consent Process and Documentation...........................................................................43
13
REGULATORY AND OPERATIONAL CONSIDERATIONS.........................................44
13.1
Study Discontinuation and Closure .............................................................................44
13.2
Quality Assurance and Quality Control.......................................................................44
13.3
Conflict of Interest Policy............................................................................................45
13.4
Confidentiality and Privacy .........................................................................................45
14
PHARMACEUTICAL INFORMATION ............................................................................46
14.1
Baricitinib (IND # 129360) .........................................................................................46
15
REFERENCES .....................................................................................................................51


Abbreviated Title: Baricitinib in cGVHD
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16
PPENDICES.........................................................................................................................55
Appendix A: Performance Status Criteria .................................................................................55
Appendix B: Diagnostic Criteria of Chronic GVHD ................................................................56
Appendix C: Clinical Differentiation of Acute and Chronic GVHD ........................................60
Appendix D: Organ Specific and Global Scoring of Chronic GVHD.......................................61
Appendix E: Global Scoring of cGVHD...................................................................................64
Appendix F: Chronic GVHD Assessment (Clinician) Form.....................................................65
Appendix G: Chronic GVHD Assessment (Patient) Form........................................................68
Appendix H: Data Collection Elements ....................................................................................69
Appendix I: Patient Reported Outcomes Questionnaires ..........................................................71
Appendix J: Medication Diary...................................................................................................80
Appendix K: Response Determination for Chronic GVHD Trials Based on Clinician 
Assessments.................................................................................................................82
Appendix L: Occupational therapy evaluation for functional assessment, fatigue assessment, 
and upper extremity use...............................................................................................84
Appendix M: cGVHD New Patient Data Form.........................................................................96


Abbreviated Title: Baricitinib in cGVHD
Version Date: 10/19/2022
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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objectives:

To determine the safety and tolerability of baricitinib in patients with cGVHD that is 
refractory to steroids

To determine the efficacy of baricitinib in patients with cGVHD that is refractory to 
steroids
1.1.2
Secondary Objectives:

To determine the efficacy of baricitinib on patient reported outcomes in patients with 
steroid-refractory cGVHD

To determine impact of baricitinib on the immune system and inflammatory markers

To describe pharmacokinetics and pharmacodynamics of baricitinib in patients with 
cGVHD
1.2
BACKGROUND AND RATIONALE
1.2.1
Chronic graft-versus-host disease
Chronic graft-versus-host disease (cGVHD) is an important late complication of allogeneic 
hematopoietic cell transplantation.  It is a leading cause of mortality in patients who are more 
than 2 years after allogeneic hematopoietic stem cell transplantation (SCT).1,2  Symptoms of 
cGVHD usually appear within 2 years post-SCT.  Reported incidences have been in the range of 
36% in recent years, and has been significantly rising compared to previous time periods,3 and 
can depend on recipient age, donor type, graft type, graft manipulation or donor lymphocyte 
infusions.4  Chronic GVHD is strongly associated with prior acute GVHD (aGVHD).5,6  
Traditionally, the cutoff point between aGVHD and cGVHD was day 100 post-SCT.  In 2005, an 
NIH consensus project proposed two main GVHD categories, each with two subcategories: (1) 


Abbreviated Title: Baricitinib in cGVHD
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“classic” aGVHD occurring within 100 days after SCT and (2) “persistent, recurrent or late” 
aGVHD.  The broad category of cGVHD includes: (1) “classic” cGVHD (without features or 
characteristics of aGVHD), and (2) an “overlap syndrome” with concordant features of cGVHD 
and aGVHD.4  Chronic GVHD is a multi-organ alloimmune and autoimmune disorder 
characterized by immune dysregulation, immunodeficiency, impaired organ function and 
decreased survival.  It requires prolonged ongoing immunosuppression and inter-disciplinary 
management.  Moreover, studies of long term survivors of SCT have shown the chronic GVHD 
is a key risk factor for mortality and leading cause of death in patients who survive 2-5 years 
after SCT.7,8 
Pathophysiology
The pathophysiology of cGVHD is poorly understood.  T- (Th1, Th17, Thf) and B-cells play a 
role in the pathogenesis of cGVHD, suggesting a general loss of tolerance, including 
abnormalities in the function of regulatory T-cells (Tregs) 9,10.  Natural Tregs 
(CD4+,CD25+,FoxP3+) maintain self-tolerance.10,11  Studies in mice indicate Tregs can suppress 
GVHD and that a deficiency of Tregs worsens GVHD.12  There are conflicting data in humans 
concerning role of Tregs in the development of cGVHD.13  A recent study suggested in vivo 
administration of low-dose IL-2 as a potential Treg-mediated therapeutic approach for severe 
cGVHD.14 
Chronic GVHD is associated with T-cell dysregulation, which consequently leads to cytokine 
dysregulation.  In persons with cGVHD, higher levels of tumor necrosis factor-α, IL- 6, 
transforming growth factor-β, and IL-1β are reported.15-19 
Autoimmunity and autoreactive T-cells have an important role in cGVHD. Some studies have 
shown that host thymus is not required for induction of cGVHD and that quiescent autoreactive 
T- and B-cells in transplants from non-autoimmune donors may be activated and expanded to 
cause cGVHD.20  In contrast, involvement of thymus-dependent pathways in cGVHD 
development begins with injury to the thymus from a chemotherapy-conditioning regimen or 
aGVHD.  Loss of B-cells with the ability to produce antibodies and to present antigen is also 
involved in the pathophysiology and may enhance development of cGVHD.  Autoantibodies like 
anti-nuclear, anti-mitochondrial, anti-parietal, anti–smooth muscle and anti–parotid are present in 
persons with cGVHD.21,22  Also, persons with autoantibodies had more cGVHD-associated 
symptoms than persons without autoantibodies.22  Autoantibodies against platelet-derived growth 
factor receptor (PDGFR) may play a role in cGVHD.23  These PDGFR-α autoantibodies 
stimulate thyrosine phosphorylation in a cascade of events contributing inflammation and 
fibrosis. 
There are studies that also report elevated levels of BAFF (B-cell activating factor of the TNF 
family), which is produced by T-cells and granulocytes.  BAFF supports differentiation and 
survival of normal B-cells in persons with cGVHD and autoimmune diseases.12,24  Fujii et al. 
showed that in early-onset cGVHD, there are elevated sBAFF, sIL-2Rα, sCD13, and anti-
dsDNA levels.  In late-onset cGVHD, sBAFF, anti-dsDNA and ANA are higher, suggesting that 
the B-cell activation is predominant.25  These observations create rationale for treatments with 
anti-CD20 antibodies in cGVHD.26  All of these pathways are potential targets for cGVHD 
therapy.  However, to date, no laboratory parameter is considered a reliable biomarker for the 
diagnosis, measurement of severity, prognosis or therapeutic effect in cGVHD.27  
Clinical manifestations


Abbreviated Title: Baricitinib in cGVHD
Version Date: 10/19/2022
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The usually affected organs in cGVHD are the skin, eyes, mouth, gut, liver, lungs, joints and 
genitourinary tract. Examples of diagnostic skin manifestations are sclerotic features and 
poikiloderma, lichen-type and hyperkeratotic plaques in the mouth or bronchiolitis obliterans in 
lung biopsy.4  The clinical manifestations of the disease are reminiscent of the autoimmune 
diseases such as systemic sclerosis, systemic lupus erythematosus or Sjögren syndrome.  
According to the NIH consensus global scoring system, cGVHD is categorized as mild, 
moderate or severe.  Systemic immune-suppressive therapy is usually indicated in persons with 
cGVHD involving 3 or more organs or with a severity score of 2 or higher in any organ.  
Systemic therapy is also to be considered in persons with thrombocytopenia (platelets 
<100x109/L) or progressive onset during prednisone treatment.5  Chronic GVHD eventually 
leads to impaired functional performance, deteriorating quality of life, increased risk of 
infections and death.28-31 
Treatment
Initial therapy for cGVHD is well established consisting of prednisone with or without a 
calcineurin inhibitor.  However, only about 50% of persons have a durable response.11,32  There 
are no standard recommendations for second-line treatment of cGVHD and about 75% of 
patients fail treatment.33  There are no FDA approved agents in the treatment of cGVHD.  
Recommendations for therapy are based on a long list of poorly standardized phase 2 trials or 
retrospective case analyses.32  Diverse drugs (about 40 are described) are used, including 
sirolimus, tacrolimus, mycophenolate, methotrexate, extracorporeal photopheresis, monoclonal 
antibodies, pentostatin, imatinib, low dose IL-2, and others. The decision for which drug to use is 
based on logistics, cost, failed prior treatments, toxicity profile and subject or clinician 
preferences.
For many years, cGVHD has been difficult to address because of the lack of standardized criteria 
for diagnosis, staging and response to therapy.  In 2004, as an effort of the NIH-sponsored 
Consensus Development Project, a series of guidelines were published to address diagnosis and 
staging, histopathology, biomarkers, assessment of response to therapy, ancillary therapy, 
supportive care and the design of clinical trials.(2005 NIH consensus papers).34  These were 
recently updated based on evidence from prospective validations (2014 NIH consensus papers).35  
Typically, cGVHD usually lasts 2 to 5 years, and approximately 85% of survivors are able to 
discontinue systemic immune suppression.  Five-year survival rates for patients with cGVHD 
ranged from 72%, 52%, and 25% in patients with low, intermediate, and high risk, respectively, 
using a Center for Blood and Marrow Transplant Research (CIBMTR) risk score.36  Treatment 
goals in management of cGVHD include both alleviation of symptoms and the control and 
reversion of the destructive immunological process.  Therapy for cGVHD is largely 
unsatisfactory and persons should be treated on investigational clinical protocols whenever 
possible.29
1.2.2
JAK inhibition in cGVHD
JAK inhibitors are agents that block the JAK-signal transducer and activator of transcriptional 
factor (STAT) pathways, which are involved in the signaling function of many inflammatory 
cytokines and ultimately impact T-cell differentiation.  In particular, JAK1/2 relays signaling of 
IFN-γ, IL-2, IL-6, IL-12, and IL-23.  Given the efficacy of JAK inhibition in relieving symptoms 
in patients with myelofibrosis related to an excess of proinflammatory cytokines, even in patients 
who are JAK2 mutation-negative,37 there has been interest to evaluate JAK inhibition in GVHD.  


Abbreviated Title: Baricitinib in cGVHD
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10
In addition to the direct impact on T-cell differentiation, there is also evidence that JAK1/2 
inhibition impairs the differentiation, maturation, and cytokine production of dendritic cells,38 
thus impacting antigen presentation.  JAK1/2 also mediates IFN-γ receptor signaling, which is 
essential for CXCR3 expression that is involved in T-cell trafficking to target organs.  Moreover, 
murine models of aGVHD have shown that STAT1 and STAT3, which serve as transcription 
factors after being phosphorylated by activated JAK kinases, are activated in an early stage of 
aGVHD, and lead to further proinflammatory cytokine production.39  These data further support 
the potential role of JAK inhibition in the treatment of GVHD.  Ruxolitinib, a selective JAK1/2 
inhibitor, has been extensively studied and is approved for patients with myelofibrosis and 
polycythemia vera, and has recently been evaluated in the setting of GVHD.  Of note, STAT 
phosphorylation has not been studied in animal models or human subjects with cGVHD, and this 
will be addressed in the current study.
Several studies have demonstrated that treatment with ruxolitinib in murine models of aGVHD 
has led to significantly improved survival, less weight loss, and less histopathologic evidence of 
GVHD in target organs.40-42  In addition, donor T-cells in the ruxolitinib treated mice have 
maintained alloreactivity and anti-tumor activity.  Carniti et al demonstrated that treatment with 
ruxolitinib led to dose-dependent reduction in IL-6 and IL-12 levels; moreover, CXCR3 
expression was decreased on donor T-cells, which led to differential migration of T-cells to 
target organs compared to control mice.  They also showed some evidence of hepatotoxicity 
from ruxolitinib but no impact on hematologic parameters.  Spoerl et al showed that ruxolitinib 
led to decreased expansion of alloreactive T-cells compared to controls.  In addition, T-cell 
phenotypes differed, where the ruxolitinib treated mice had higher frequencies of Tregs, and 
lower CD4+ IFN-γ+ cells and T-central memory cells, which are known to maintain GVHD42.  
There was also evidence of direct suppression of STAT3 phosphorylation.  Choi et al, showed 
that ruxolitinib reduced T-cell CXCR3 expression, and reduced GVHD and survival by 
modulating T-cell trafficking26,41.  
Broad JAK inhibition was evaluated by Park et al 43using tofacitinib, a JAK1/2/3 inhibitor, in a 
semi-allogeneic murine model, which led to reduction of GVHD pathology and suppression of 
donor CD4+ T-cell proliferation and IFN-γ production.  It also reduced mucocutaneous GVHD 
in a skin-specific model.  However, the JAK3 pathway is involved in Treg proliferation and 
survival, as well as hematopoiesis, and response to infectious pathogens.  Tofacitinib has not 
been tested clinically in patients with GVHD, and in general, there is theoretical concern that 
broad JAK1/2/3 inhibition would lead to toxicities in SCT patients who are at higher risk for 
cytopenias and infection.  Thus, agents with selective JAK1/2 inhibition are preferable in this 
setting.
Based on the promising preclinical results of ruxolitinib in GVHD, there has been some early 
clinical experience in patients with GVHD.  Spoerl et al reported on their experience treating 6 
patients with steroid-refractory aGVHD (n=4) and cGVHD (n=2).42  The 2 patients with cGVHD 
had skin involvement and multiple prior therapies, and had a response after 1 week of treatment.  
These findings were concomitant with decrease in serum IL-6 and IL-2R (soluble IL2 receptor).  
At a low dose of ruxolitinib, cytopenias were not observed.  In a study from Germany, 
ruxolitinib was used and retrospectively analyzed in 54 patients with steroid-refractory aGVHD 
and 41 patients with steroid-refractory cGVHD (median 3 prior lines of therapy) across 13 
transplant centers.44  In patients with cGVHD, the overall response rate (defined as 50% decrease 
of immunosuppression for at least 4 weeks) was 85% with a median time to response of 3 weeks 


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(range 1-25).  Toxicities included cytopenias (17%) and CMV reactivation (15%).  There was no 
increase in malignancy relapse.  In addition, responses were not restricted to specific organs.  
Ruxolitinib off label use for advanced chronic GVHD has also been reported in an abstract of a 
case series from Emory, with similar results as in the German study (Khoury et al, American 
Society of Hematology Annual Meeting 2015).  These reports support further study of JAK 
inhibition in patients with steroid-refractory cGVHD.
1.2.3
Baricitinib
Baricitinib (LY3009104, formerly INCB028050, Eli Lilly and Company) is a selective JAK1/2 
inhibitor that has been studied in patients with inflammatory conditions such as rheumatoid 
arthritis, psoriasis, and diabetic nephropathy.  It is an oral, potent, and reversible inhibitor of 
JAK1 (IC50=5.9 nM) and JAK2 (IC50=5.7 nM), with less potency for JAK3, tyrosine kinase 2 
(TYK2), or other kinases.45  In addition, it has demonstrated excellent potency for inhibition of 
IL-2-, IL-6-, and IL-23- stimulated phosphorylation of JAKs and STATs, and IL-2 induced 
proliferation of T-cells.  In preclinical models of arthritis, it has demonstrated anti-inflammatory 
effects while preserving humoral immunity and had no hematologic effects.45  It has been tested 
in doses of 0.5mg-20mg in over 3000 patients and healthy volunteers, and the safety profile is 
well understood.46,47  Phase 1, 2, and 3 studies in RA have been completed, and several studies in 
patients with psoriasis and diabetic nephropathy are ongoing.  Common toxicities seen across 
studies include decreases in hemoglobin and neutrophils (mean values usually remaining within 
the normal range), increases in platelets (mean values usually remaining within the normal 
range), increases in creatinine (mean values usually remaining within the normal range) and 
increases in exposure in patients with renal impairment, increases in total cholesterol, high-
density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides, increases in hepatic 
enzymes, increases in creatine phosphokinase (CPK), and increased incidence of infections 
(mostly respiratory).  Decreases in neutrophils and hemoglobin and other lab abnormalities have 
been reversible upon discontinuation of the drug.  
The efficacy of baricitinib in the treatment of RA has been demonstrated.  A Phase 2a study in 
patients with RA refractory to disease-modifying anti-rheumatic drugs (DMARDs) showed 
improvements in signs and symptoms of RA after treatment with baricitinib for 12 weeks, with a 
flat dose-response curve at 4mg, 7mg, and 10mg daily doses.48  This study did show an increased 
incidence of mild to moderate herpes zoster infections.  A randomized controlled Phase 2b study 
using baricitinib for RA with inadequate response to methotrexate at doses of 1, 2, 4, and 8mg 
showed that patients treated at 4mg and 8mg had significantly better response compared to 
placebo at 12 weeks.49  There was no difference between the 4mg and 8mg groups in regards to 
efficacy.  However, there were more hematologic toxicities with the 8mg dose (decreases in 
neutrophil count and hemoglobin).  Other common adverse events included upper respiratory 
tract infections, and increases in LDL, HDL, creatinine, and CPK.  Importantly, there were no 
cases of opportunistic infections.  Based on these results, the 4mg dose was the dose chosen to 
evaluate in the Phase 3 studies in RA.50  There is some experience at the NIH using baricitinib in 
patients with rare autoinflammatory conditions, and per personal communication (data 
unpublished), there have been cases of BK virus infection.  The final results of this study are 
pending, and infection will be monitored closely on the current protocol.  
In regards to pharmacodynamics, baricitinib maximally inhibits cytokine-induced STAT 
phosphorylation at 2 hours after the dose.  A dose of 10mg has shown 70% reduction in IL-6 
induced phosphorylation of STAT3, which returns to baseline at 24 to 48 hours without 


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subsequent dosing45.  In the Phase 2a study in patients with DMARDs-refractory RA, significant 
reductions in plasma levels of IL-6, IL-1β, TNF-α were observed after 12 weeks of treatment at 
both 7mg and 10mg doses.  
Baricitinib has not been previously evaluated in the treatment of patients with GVHD.  Based on 
the efficacy of baricitinib in RA through the mechanism of selective JAK1 and JAK2 inhibition, 
the growing data supporting the use of JAK inhibitors in the treatment of aGVHD and cGVHD, 
and the dire need for effective second line therapeutic options in cGVHD, we aim to evaluate the 
safety and efficacy of baricitinib in patients with cGVHD that is refractory to steroids.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
 ELIGIBILITY CRITERIA
2.1.1
 Inclusion Criteria
2.1.1.1
Moderate or severe cGVHD (after allogeneic hematopoietic stem cell transplantation) 
diagnosed and staged per NIH criteria,4 Appendix B and Appendix C.  Responses to 
JAK inhibitors have not been restricted to specific organs, so any organ involvement is 
eligible.
2.1.1.2
Age ≥18 years of age. Because inadequate dosing or adverse event data are currently 
available on the use of baricitinib in patients <18 years of age, children are excluded 
from this study.
2.1.1.3
Karnofsky performance score >50% (Appendix A)
2.1.1.4
Chronic GVHD that did not respond to high-dose corticosteroids (prednisone at 1.0 
mg/kg/day for at least 1 week or prednisone at 0.5 mg/kg/day or 1 mg/kg every other 
day for at least 4 weeks), or second-line therapy (any)
2.1.1.5
If patient is taking systemic therapy for cGVHD at the time of enrollment, they must be 
on a stable or tapering doses in the preceding 4 weeks. 
2.1.1.6
Patients must have normal organ and marrow function as defined below: 

absolute neutrophil count
>1,000/mcL

absolute lymphocyte count
≥500/mcL

platelets
>50,000/mcL

hemoglobin
>9 g/dL

total bilirubin
<1.5 X institutional upper limit of normal, unless 
there is a known history of Gilbert’s disease 

AST(SGOT)/ALT(SGPT)
<3 X institutional upper limit of normal

Creatinine
< 1.5 times the upper limit of normal, or:

creatinine clearance
>50 mL/min/1.73 m2.  Creatinine clearance should 
be calculated per institutional standard.
2.1.1.7
Primary malignancy for which the patient received transplant has been stable for 3 
months prior to enrollment on study
2.1.1.8
The effects of baricitinib on human fetal development are unknown.  Women of child-
bearing potential and men must agree to use 2 effective forms of contraception 
(hormonal or barrier method of birth control; abstinence) for the duration of study 
participation and for at least 7 days after study drug exposure. Should a woman become 


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pregnant or suspect she is pregnant while she or her partner is participating in this study, 
or if a man’s partner becomes pregnant or suspects she is pregnant while he is 
participating in this study, she or he should inform their treating physician immediately.
2.1.1.9
Ability of subject to understand and the willingness to sign a written informed consent 
document.
2.1.2
 Exclusion Criteria
2.1.2.1
Systemic immune suppression or systemic therapy for cGVHD started within preceding 
4 weeks. 
2.1.2.2
Hypersensitivity to JAK inhibitors
2.1.2.3
Any serious medical condition within the previous 4 weeks which places the subject at 
an unacceptable risk if he or she were to participate in the study or confounds the ability 
to interpret data from the study, including, but not limited to, symptomatic congestive 
heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmias, acute kidney 
injury, or psychiatric illness/social situations that would limit compliance with study 
requirements.
2.1.2.4
Uncontrolled infection, including active HIV-1, Hepatitis B (HBV) and/or Hepatitis C 
(HCV) infection (positive HBV or HCV viral load in the setting of positive HBV core 
antibody or surface antibody or HCV antibody). History of HBV or HCV is allowed if 
there is no uncontrolled viral infection.  Because the study agent may impact response 
to infections, patients with any active viral infection are excluded.
2.1.2.5
Recurrent or progressive malignancy requiring anticancer treatment
2.1.2.6
Other cancer except that for which the transplant was done <2 years before study entry, 
except non-melanoma skin cancer or carcinoma in situ of the uterine cervix or breast
2.1.2.7
Patients who are receiving any other investigational agents
2.1.2.8
NIH lung score 3 (Appendix D)
2.1.2.9
Pregnant women are excluded from this study because the teratogenic effects of 
baricitinib are unknown.  Because there is an unknown but potential risk for adverse 
events in nursing infants secondary to treatment of the mother with baricitinib, 
breastfeeding should be discontinued if the mother is treated with this agent. 
2.1.3
Recruitment Strategies
This protocol may be abstracted into a plain language announcement posted on NIH websites 
and on NIH social media platforms. In addition, patients will be directly referred to the NIH for 
this clinical trial through the well-developed NIH chronic GVHD study group referral base.  In 
addition, patients who are referred for the CCR protocol “Natural History Study of Clinical and 
Biological Factors Determining Outcomes in Chronic Graft-Versus-Host Disease” study (04-C-
0281) will be screened for this trial.  Also, patients who undergo SCT at the NIH will be eligible 
for enrollment on this trial, which will provide another mechanism for screening patients.  
Finally, physicians and patients will be made aware of the study through our patient advocacy 
groups (National Marrow Donor Program, National Bone Marrow Transplant Link, Blood & 
Marrow Transplant Information Network, Meredith Cowden Foundation) and other professional 
forums. 


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2.2
SCREENING EVALUATION
Screening procedures will be performed on a CCR screening protocol (01C0129), or most 
commonly on 04C0281 “Natural History of Chronic GVHD.” All studies must be completed 
within 4 weeks prior to enrollment:

History and physical exam, Karnofsky performance score

Documentation of cGVHD diagnosis, NIH organ and global severity stage 

Laboratory studies: CBC, platelets, differential, PT/PTT, serum chemistries (including 
sodium, potassium, chloride, CO2, calcium, magnesium, phosphorus, blood urea nitrogen 
[BUN], creatinine/creatinine clearance, glucose, albumin, total protein, alkaline 
phosphatase, total bilirubin, AST [SGOT], ALT [SGPT], lactate dehydrogenase [LDH], 
and uric acid), creatine kinase (CK), urinalysis, pregnancy testing (in women of 
childbearing potential), thyroid-stimulating hormone (TSH), free T4 

Additional screening studies: Serologies for HIV, HBV, HCV; CMV PCR; blood and 
urine cultures, respiratory viral panel. Cultures with no growth present at 48 hours will be 
deemed negative. 

Pulmonary function tests (PFTs): FEV1, FEV1/FVC ratio, RV, RV/TLC, FEF25-75, 
DLCO; this will include pre- and post-bronchodilator evaluation

Chest CT scan in inspiration and end-expiration

Electrocardiogram (ECG) and echocardiogram
For baseline evaluations, please see Section 2.4.
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
2.3.1
Treatment Assignment and Randomization Procedures
Cohorts
Number
Name
Description
1
Phase I cohort
Patients who have undergone hematopoietic allogeneic transplant 
and  have moderate to severe cGVHD that is refractory to 
treatment with steroids up to 21 patients, for response assessment 
at 2-4 mg
2
Phase II cohort
Patients who have undergone hematopoietic allogeneic transplant 
and  have moderate to severe cGVHD that is refractory to 
treatment with steroids after response determination in cohort 1.
Arms


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Number
Name
Description
1
Phase 1 Arm
Baricitinib 2 mg per day, increasing to 4 mg per day in patients 
who have a partial response or unchanged disease at 12 weeks
2
Phase II Arm
Baricitinib  4 mg per day
Arm Assignment
Patients in Cohort I will be directly assigned to Arm I.  Patients in Cohort II will be directly 
assigned to Arm II.
2.4
BASELINE EVALUATION
The following studies will be performed at baseline after consent and enrollment on this protocol 
and within 10 days prior to starting the study drug, unless otherwise indicated below. Tests done 
at screening that fall within the appropriate timeframe for baseline testing need not be repeated.

History and physical exam, Karnofsky performance status

Documentation of cGVHD diagnosis per NIH criteria (ref), NIH organ and global stage 
(Appendix D and Appendix E), baseline assessments (clinician assessment form A and 
patient assessment form B) (Appendix F and Appendix G) per NIH response criteria,51 
date of cGVHD diagnosis, prior and current treatments, prednisone or other steroid dose, 
and other patient, donor, and transplant characteristics (Appendix H)

Laboratory studies: CBC with differential, serum chemistries (including sodium, 
potassium, chloride, CO2, calcium, magnesium, phosphorus, blood urea nitrogen (BUN), 
creatinine, glucose, albumin, total protein, alkaline phosphatase, total bilirubin, AST 
(SGOT), ALT (SGPT), lactate dehydrogenase (LDH), uric acid), CK, urinalysis, 
pregnancy test, TBNK, drug levels if pertinent (tacrolimus, cyclosporine, sirolimus), 
CRP, C3 and C4, immunoglobulin levels, CMV PCR, BK virus PCR (blood and urine), 
fasting lipid panel

Pregnancy test in women that can have children

MRI of the involved extremity if clinically indicated (acceptable if done within 4 weeks)    

Specialty evaluations of cGVHD (acceptable within 4 weeks): dermatology, 
ophthalmology, dental, rehabilitation and occupational therapy, gynecology for females 

Occupational therapy evaluation: functional assessment (ACS and HAQ), fatigue 
assessment (MDFI), and upper extremity use (DASH/MAM) (See Appendix L)

Patient-reported outcome surveys: Lee cGVHD symptom scale, human activity profile, 
FACT-BMT (See Appendix I)

Optional diagnostic and research biopsies of the skin and mouth, and other organs (only 
if clinically indicated).  Biopsies performed within 3 months prior to enrollment (e.g. on 
04-C-0281 “Natural History of Chronic GVHD” protocol) are acceptable.  Patients may 
opt out of research and diagnostic biopsies and these will not be required for initiating 
study drug.


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
Research samples (blood, saliva, oral microbiome swabs) (see Section 5.1) Saliva and 
oral microbiome swabs will be collected at the time of the oral biopsy, if performed

Documentation of concurrent medications
Of note:  Patients who have already been enrolled, but who have symptoms suggestive of 
infection (fever, productive cough, radiologic findings) at the baseline evaluation will have 
further workup as standard of care to rule out active infection. Patients with active infection will 
be treated until the infection is under control or antibiotic therapy is completed.  Baseline 
procedures that have exceeded the desired timeframe will be repeated before the patient may 
begin study therapy.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is a phase 1/2 single arm study to evaluate the safety and efficacy of baricitinib at doses of 
2mg-4mg in patients with cGVHD after SCT.  Doses of 0.5mg-20mg have been studied in 
patients with autoimmune diseases and have demonstrated a good safety profile (Baricitinib 
Investigator’s Brochure, Eli Lilly and Company).  Based on studies in patients with RA, there 
seems to be a plateau efficacy response at doses above 4mg daily, and it is the 4mg daily dose 
that was taken to the Phase 3 studies.  In addition, in anecdotal experience with JAK inhibitors in 
patients with GVHD, low doses appear to be sufficient for response.  
Patients will be enrolled in up to 2 sequential cohorts of up to 21 patients.
The first cohort of patients will be treated with baricitinib starting at a dose of 2mg daily for 12 
weeks.  For safety purposes, patients who experience a DLT within the first 4 weeks will be able 
to restart at 1mg daily, and will continue at this dose as tolerated (see Section 3.1.1).  If they 
experience a DLT at this dose, they will be taken off treatment.  Regarding efficacy, patients 
who have a complete response (CR) on 2mg daily at 12 weeks will continue the same dose until 
the 24 week time point for the primary efficacy endpoint.  For patients who have a partial 
response (PR) or unchanged disease at 12 weeks, the dose will be increased to 4mg daily until 
the primary efficacy endpoint response assessment at 24 weeks.  Following any dose increase to 
4mg, patients who experience a DLT within the first 4 weeks will have a dose reduction back to 
2mg daily.  For patients who experience cGVHD progression at any time within the first 12 
weeks on 2mg daily, the dose can be increased to 4mg daily up until the primary efficacy 
endpoint response assessment at 24 weeks, unless they experience a DLT.  Prior to the 12 week 
response assessment, an initial response assessment will occur at 6 weeks, but there will be no 
dose changes unless there has been progression or toxicities, as outlined.  If at least 1 patient in 
the first cohort has a PR or CR, the remainder of the study will follow the initial schema as 
above, and 21 evaluable patients will be treated as part of cohort 1.  After the primary response 
assessment, patients who have unchanged or responding disease will have the option to continue 
baricitinib for an additional 6 months as tolerated.
If no patients among the first 7 achieve a CR or PR on 2mg daily at the 12 week response 
assessment in the first cohort of patients, the second cohort will be enrolled starting at 4mg daily 
if no safety issues have arisen, with the same parameters for DLT monitoring.   Similarly, if 0 of 
the first 7 treated in cohort 2 have a response, then no further patients will be treated in cohort 2. 


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If there is at least one patient with a response in the first 7 patients treated on cohort 2, then 21 
evaluable patients will be treated in cohort 2.
Concurrent topical and ancillary treatments for cGVHD are allowed per standards of care and 
will be recorded (see Section 4). Other systemic immune suppression must stay stable or be 
tapered (systemic immunosuppression taper should be attempted no earlier than after 4 weeks on 
study), throughout the treatment with baricitinib (with up to 2 steroid pulses allowed for disease 
stabilization per Section 4.1). 
Patients who discontinue therapy for any reason will be followed for up to 24 months after 
discontinuing baricitinib as indicated in section 3.5.
Peripheral blood samples will be collected prior to treatment, at 2 weeks, at 12 weeks and every 
12 weeks thereafter to evaluate cytokine and cellular profiles, STAT phosphorylation, candidate 
chronic GVHD biomarkers.  Pharmacokinetic studies will also be performed at each dose level 
on day 1 and after 15 days of treatment (Section 5.1.3).


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3.1.1
Dose Limiting Toxicity
DLT will be defined as any grade ≥3 non-hematologic or grade ≥4 hematologic adverse event, or 
hemoglobin <6.5 g/dL, within 4 weeks of starting any dose level (1mg, 2mg or 4mg) except 
those that are clearly and incontrovertibly due to extraneous causes.   One intrapatient dose de-
escalation after a DLT will be permitted in patients who have not experienced cGVHD 
progression.  In patients that have experienced disease progression, further dosing will cease in a 
patient at the occurrence of the first DLT.    


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3.1.1.1
Dose Escalation
This study will include an intra-patient dose escalation.  The starting dose of baricitinib will be 
2mg PO daily, a dose that has been well tolerated in previous studies of patients with 
autoimmune diseases.  The first 7 subjects will be treated for a total of 12 weeks at this dose, 
unless they demonstrate cGVHD progression prior to this, at which time they will increase the 
dose to 4mg.  If patients have a CR, they will continue at this dose until the primary efficacy 
endpoint.  If patients have a PR or unchanged disease (see Section 6.3), the dose will increase to 
4mg until the primary efficacy endpoint evaluation takes place at 24 weeks, unless they 
experience a DLT.  If at least 1 patient of the first 7 in cohort 1 has a response, subjects will 
follow the original dose escalation schema.  If 0 of these first 7 patients have a response, then 
patients will begin to be enrolled onto cohort 2, and will be started at the 4mg PO daily dose 
initially, unless they experience a DLT, at which time they will decrease the dose to 2mg.  
As an early stopping rule for safety, if 2/3 or greater patients at any given dose level experiences 
a dose limiting toxicity requiring dose reduction or discontinuation, that dose will not be 
subsequently used.  
3.2
DRUG ADMINISTRATION
Baricitinib will be given as 1 mg, 2mg or 4mg tablets to be taken orally once a day on days 1-28 
of a 28 day cycle.  Each daily dose should be taken at approximately the same time of day.  
There is no restriction in regards to taking the drug in relation to meals.  Patients will be asked to 
complete a medication diary (see Appendix J).  
Baricitinib tablets should be swallowed whole and not broken or chewed.
If a dose of baricitinib is missed, it should be taken as soon as possible on the same day, unless it 
is within 1 hour of the next dose, at which time the dose should not be made up.
Patients who take more than the prescribed dose of baricitinib should be instructed to seek 
medical care if needed and contact study staff immediately.
3.3
DOSE MODIFICATIONS
Patients who develop grade 2 toxicity (not including comorbidities that are present at baseline 
prior to treatment) for >7 days should hold baricitinib until the toxicity resolves (≤grade 1) and 
then restart at the same dose level.  Toxicities will be monitored at each study visit.  If grade 2 
toxicity recurs or worsens, the patient should be reduced to the next lower dose level, unless they 
are at dose level -1, at which time they should discontinue study drug.  Should the toxicity recur 
Intra-patient Dose Escalation Schedule
Dose Level
Dose of IND Agent
Level -1
1mg
Level 1
2mg
Level 2
4mg


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after dose reduction, the patient should be taken off treatment.  In the case of multiple 
simultaneous grade 2 toxicities, these instructions will apply to each individual toxicity 
separately.  
After the 4 week DLT assessment period for any dose level, patients who develop grade 3 non-
hematologic or grade 4 hematologic toxicity (not including comorbidities that are present at 
baseline prior to treatment), or hemoglobin <6.5 g/dL, should hold baricitinib until the toxicity 
resolves (≤grade 1 or baseline).  If the toxicity resolves within 28 days, patients may restart at the 
next lower dose level, unless they are at dose level -1, at which time they should discontinue the 
study drug.  Should the toxicity recur at grade 3 non-hematologic or grade 4 hematologic toxicity 
(not including comorbidities that are present at baseline prior to treatment), or hemoglobin <6.5 
g/dL, after dose reduction, the patient should be taken off treatment.
Patients who develop grade 4 non-hematologic toxicity should discontinue and be taken off 
treatment.
Study drug may be held up to 28 days for resolution of grade 2 or grade 3 toxicity.  Otherwise, if 
no resolution within 28 days, patients will be taken off treatment, 
For infection related toxicities only: study drug should be held for any infectious toxicity of 
≥grade 3.  Infection will need to be controlled with appropriate management prior to restarting 
study drug for grade 3.  If the infection occurs at the time of a study evaluation, all of the 
assessments at that time point will need to be postponed until the infection is controlled.  Study 
drug can be restarted at the same dose level for grade 3 unless other criteria are met for dose 
reduction as above.  Study drug may be held up to 28 days in the setting of uncontrolled 
infection; otherwise, if no resolution within 28 days, patients will be taken off treatment.  
Patients who develop grade 4 toxicity related to infection should discontinue and be taken off 
treatment.
Toxicities are defined as those events that are possible, probably, or definitely related to 
baricitinib. 
3.4
QUESTIONNAIRES
Patient self-report questionnaires administered in this study are part of the standard NIH chronic 
consensus recommended criteria for the evaluation of cGVHD in clinical trials.  Questionnaires 
will be completed by patients with each cGVHD assessment and response evaluation (see section 
3.7,  Study Calendar).  These standardized assessments are designed to evaluate patient quality 
of life (FACT-BMT), functional performance (HAP) and symptoms (Lee cGVHD symptom 
scale). The purpose of these evaluations is to assess the potential benefit of the administered 
therapy as compared to the baseline. These forms have been extensively used, published and 
validated. These forms are also standard part of many NCI CCR cGVHD protocols (Appendix 
I). Patient questionnaires are only offered in English and are therefore not required in non-
English speaking subjects that may unexpectedly be enrolled on the protocol.
3.5
FOLLOW-UP
All persons will be followed for adverse events for whichever is longer, 30 days after last dose of 
baricitinib or until return to baseline or stabilization of AE per section 6.1 0 by phone call.  
Patients who discontinue therapy before completion of the 24 or 48 weeks will be asked to return 
for a follow up visit to complete their off treatment assessments within 30 days after the last dose 


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of study drug.  Patients who discontinue therapy at the completion of 24 or 48 weeks will 
complete the off treatment assessments at the last scheduled visit.  Following this, patients will 
be invited for a follow up visit at 3 months after last dose, then followed up by a phone call to the 
patient and/or the primary physician’s office at 12, 18 and 24 months after completing 
baricitinib.  If they choose not to follow up at 3 months, they will be followed up by phone call.  
The phone call will focus on a) survival status and cause of death if pertinent, b) ongoing 
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
TELEHEALTH
Telemedicine is the use of interactive audio, video, audio-visual, or other telecommunications or 
electronic technology by a licensed health care practitioner to deliver clinical services. This 
protocol will allow the team to practice telemedicine to communicate with patients in real time, 
to be able to monitor and collect data, as well as the ability to share the patients’ health 
information with other health professionals. Providers may include primary providers, 
specialists/consultants and nurses. Other members of the healthcare team may also be present to 
aid with the communication devices, scheduling or records management. These visits may 
include the following: patient history, verbal exam, symptom reporting, education, and 
questionnaires.
The patient or patient’s legal representative will be informed prior to the use of a telemedicine 
encounter and consent will be obtained as outlined in the Consent Process and Documentation 
(section 12.6). 
Telemedicine visits will be arranged through our NIH Clinical Center Health Information 
Management Department and will be scheduled using NIH-approved remote platforms. 
Telemedicine visits may be used for follow-up visits if deemed appropriate by the PI. All 
telemedicine visits must be documented in CRIS like a normal onsite visit and the note should 
indicate that this visit was performed virtually. Remote visits will be conducted in compliance 
with NIH guidelines and FDA regulations. 
Local Evaluations
A patient may be asked to come to the NIH CC for an in-person assessment or be referred to 
their local provider or outside lab, at the discretion of the investigator. All physical exams, 
assessments, and labs used for follow-up visits may also be performed with the patient’s local 
physician or completed at outside labs. For laboratory evaluations conducted with local 
providers, interlaboratory variability is not a concern. In the case of any visits with participants’ 
local providers or outside labs, records will be obtained. 


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22
3.7
 STUDY CALENDAR
Assessments1
Screen (D -28 to -1)
BL
BL /  C1 D1
C1 D15
C2 D1
C2 D15
C3  D1
C3  D15
12 weeks
C4 D1
C4D15
C5,6 D1
24 weeks
C7 D1
C8,9 D1
36 weeks
C10 D1
C11,
12 D1
48 weeks
C12
D28
Off Treatment13 
Optional 3 month 
follow up13
Visit Window
±5 days
±5 days
±5 days
±5 days
±5 days
±5 days
+/-5 days
± 7 days
± 7 days
± 7 days
± 7 days
± 7 days
± 7 days
± 7 days
± 7 days
Informed Consent
X
--
--
--
--
--
--
--
--
--
--
--
--
--
  --
--
NIH Advanced Directives 
Form17
X
Baricitinib po qd2
--
X
X
X
X
X
X
X
X
X2
X2
X2
X2
X2
  --
--
History and Physical Exam 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
  X
X
Confirmation of cGVHD3
X
--
--
--
--
--
--
--
--
--
--
--
--
  --
--
Body Photography 
X
--
--
--
--
--
--
--
X
--
--
--
  X
--
Pulmonary Function Testing
X
--
--
--
--
--
--
X
--
X
--
X
--
X
  X
--
Imaging4
X
--
Pregnancy Test5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
  
--
cGVHD Therapies Recording
X
Throughout the study
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
--
X
  X
X
Height
X
--
--
--
--
--
--
--
--
--
--
--
--
  --
--
Weight
X
X
X
X
X
X
X
X
X
X
X
X
--
X
  X
X
ECHO
X
--
--
--
--
--
--
--
--
--
--
--
--
  --
--
ECG6
X
--
--
X
--
X
--
X
--
X
--
--
--   
  --
--
cGVHD New Patient Data Form
X
Karnofsky Performance Status
X
X
--
--
--
--
--
X
--
X
--
X
--
X
  X
X
Additional screening studies7
X
--
--
--
--
--
--
--
--
--
--
--
  --
--
BK virus PCR (blood & urine)
X
X
X
X
X


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Version Date: 10/19/2022
23
Assessments1
Screen (D -28 to -1)
BL
BL /  C1 D1
C1 D15
C2 D1
C2 D15
C3  D1
C3  D15
12 weeks
C4 D1
C4D15
C5,6 D1
24 weeks
C7 D1
C8,9 D1
36 weeks
C10 D1
C11,
12 D1
48 weeks
C12
D28
Off Treatment13 
Optional 3 month 
follow up13
Visit Window
±5 days
±5 days
±5 days
±5 days
±5 days
±5 days
+/-5 days
± 7 days
± 7 days
± 7 days
± 7 days
± 7 days
± 7 days
± 7 days
± 7 days
CBC w/ differential, platelets 
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
X 
  X
X
PT, PTT
X
Serum Chemistry8
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
X
  X
X
CRP, C3, C418
--
X
--
X
--
X
--
X
--
X
--
X
--
X
  X
--
Urinalysis, fasting lipid panel
X
--X
--
--
--
--
--
X
--
X
--
X
--
X
  X
--
TSH, free T4
X
--
--
--
--
--
--
--
--
--
--
--
--
  --
--
cGVHD Assessment and 
Response Calculation9
X
--
--
X
--
--
X
--
X
--
X
--
X
  X
--
Lee scale, HAP, FACT-BMT
X
X
X
X
X
X
X
X
AE Monitoring
--
Throughout the study 
Concurrent Drugs
X
Throughout the study  
Dermatology, ophthalmology, 
dental, gynecology
X
X14
X14
Occupational therapy 
evaluation15 
X
X14
 X14
Skin and Oral Biopsies, saliva 
collection and oral microbiome 
swabs10
--
X
--
--
--
--
--
--
--
X
--
--
--
--
  --
--
TBNK
--
X
X
--
--
X
X
--
X
--
X
  X16
X16
Blood for Immunologic Studies 
(includes PD)11
--
X
X
--
--
--
--
X
X
--
X
--
X
  X
Blood for PK
Studies12
--
X
C1D
1
X
C1D
15
--
--
--
--X12 
C4D1
X
--
--
--
--
--
--
 --
--


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Assessments1
Screen (D -28 to -1)
BL
BL /  C1 D1
C1 D15
C2 D1
C2 D15
C3  D1
C3  D15
12 weeks
C4 D1
C4D15
C5,6 D1
24 weeks
C7 D1
C8,9 D1
36 weeks
C10 D1
C11,
12 D1
48 weeks
C12
D28
Off Treatment13 
Optional 3 month 
follow up13
Visit Window
±5 days
±5 days
±5 days
±5 days
±5 days
±5 days
+/-5 days
± 7 days
± 7 days
± 7 days
± 7 days
± 7 days
± 7 days
± 7 days
± 7 days
Study drug dispensation/ 
return/accountability
--
X
--
X
X
X
X
X
X
X
X
X
  X
--
1
Clinic visits can occur ± 5 days. All procedures at protocol-driven time points are performed at the NIH Clinical Center, but if circumstances make this 
impossible, these data points will be collected in collaboration with referring physicians.   
2
Baricitinib at assigned doses for 6 months; another 6-month course of treatment will be allowed for patients with response. Only patients who continue 
therapy beyond 6 months will be required to have clinical monitoring tests during cycles 7 through 12.
3
Use NIH diagnostic criteria for cGVHD (Appendix B and Appendix M: cGVHD New Patient Data Form. In addition, use Appendix C for 
clinical differentiation of acute versus cGVHD.
4
Chest CT done at screening; a chest CT may be done at response assessments if clinically indicated; a MRI may be done at baseline if clinically 
indicated
5
Pregnancy tests for females of childbearing potential. A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone 
a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any 
time in the preceding 24 consecutive months).
6
ECG at indicated intervals screening and as clinically indicated. Prolongation of QTc > 0.5 s or QTc interval increases from baseline > 0.06 s is 
considered as a safety concern.
7
Serologies for HIV, HBV, HCV, CMV PCR, blood and urine cultures, respiratory viral panel, CMV PCR. Cultures with no growth present at 48 hours 
will be deemed negative.  BK virus PCR (urine) will be performed at baseline.
8
Including at screening: sodium, potassium, chloride, CO2, calcium, magnesium, phosphorus, blood urea nitrogen (BUN), creatinine, glucose, albumin, 
total protein, alkaline phosphatase, total bilirubin, AST (SGOT), ALT (SGPT), lactate dehydrogenase (LDH), and uric acid), creatine kinase (CK); at 
baseline and on study assessments (30-mL) include all screening studies as well as: drug levels if pertinent (tacrolimus, cyclosporine, sirolimus), 
immunoglobulin levels, CMV PCR at least every other week the first 12 weeks, then every 4 weeks until 24 weeks. CMV PCR will not be performed at 
remote visits unless clinically indicated. Note: Baseline studies performed within the appropriate timeframe at screening need not be repeated. (See 
section 2.4)
9
Includes primary and secondary measurement of response, performance scale, global rating (Appendix D, Appendix E, Appendix F, Appendix G, 
Appendix I).  Note:  The response assessment in Appendix H is not performed at baseline.
10
Skin and oral biopsies, saliva and microbiome swab collection will be performed at baseline and after 6 months of treatment, with intent to sample as 
close to the same area as possible.  At baseline, the saliva and oral microbiome swabs will be collected at the time of the oral biopsy, if performed.  


Abbreviated Title: Baricitinib in cGVHD
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25
11
Blood (48 mL in 6 CPT tubes) for immunologic studies will be drawn prior to first drug at all timepoints. PD baseline assay will be performed using 
some of the blood for immunologic studies.  PD studies at the peak blood level of baricitinib will be performed on a 6ml (green topped heparin) tube 
collected at 2 hours post drug at Cycle 1 Day 1. PD studies will be repeated at any increase in drug dose. 
12
For determining serum baricitinib levels (PK), on the first day of each dose level a 3-mL blood (EDTA) sample will be taken pre-dose, then at 1, 2, and 
4 hours after the dose. A sample will be collected at 24 hours after the first dose in up to 10 patients as feasible, but is not required on protocol. A trough 
level blood sample will be collected at the next scheduled visit at 15 (+/-1) days of continuous treatment at the initial dose. The sample will always be 
collected immediately before the next baricitinib dose to measure a 24 hour PK time point. This collection will also occur following 15 (+/-1) days of 
continuous treatment after an increase in dose level.  The PK sample at week 12 is not collected if no change in dose level occurred. In the event of a 
serious adverse event or at the end of study, an additional sample may be collected within 24 hours of the last dose at the discretion of the investigator 
(See Section 5.1). Every effort will be made to collect samples as prescribed in the timeline.  Samples that are collected ± 15 minutes of collection time 
will not be considered a protocol deviation.
13
Patients who discontinue study drug before completion will be asked to return to complete off treatment assessments within 30 days after the last dose 
of study drug.  Patients who complete therapy (24 or 48 weeks) will complete the off treatment assessments at the last scheduled visit.  All patients, 
regardless of reason for study drug discontinuation will be followed for adverse events by phone call for at least 30 days for adverse events and invited 
for an optional follow up visit a 3 months after study drug discontinuation followed by phone calls to the patient or patient’s primary physician at 12, 18 
and 24 months (if patients choose not to follow up at 3 months, they will be followed up by phone call) (see Section 3.5)
14
Subspecialty evaluations are required at baseline. Subsequent evaluations at 6 months and off treatment will be arranged based on organ involvement 
and medical need of individual patients.  All response assessments will be performed by the transplant clinical team.
15
Functional assessment (ACS and HAQ), fatigue assessment (MDFI), and upper extremity use (DASH/MAM) (See Appendix L)
16
If PI deems TBNK is necessary at this visit.
17
As indicated in section 12.3, all subjects will be offered the opportunity to complete an NIH advanced directives form.  This should be done preferably 
at baseline but can be done at any time during the study as long as the capacity to do so is retained.  The completion of the form is strongly 
recommended, but is not required.
18
CRP, C3, C4 will not be performed at remote visits unless clinically indicated.


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3.8
COST AND COMPENSATION 
3.8.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they 
are not covered by an insurance company.  Medicines that are not part of the study treatment will 
not be provided or paid for by the NIH Clinical Center.    
3.8.2
Compensation
Participants will not be compensated on this study.
3.8.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.   
3.9
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy.
3.9.1
Criteria for removal from protocol therapy

Completion of 12-month course of protocol therapy 

Progressive cGVHD or malignancy requiring new line of systemic therapy

Participant requests to be withdrawn from active therapy

Positive pregnancy test

Unacceptable toxicity as defined in Sections 3.1.1 and 3.3

Dose interruption longer than 28 days

Investigator discretion
The PI is to be notified of all discontinuations from study drug. The reason for dose 
modification/discontinuation should be recorded in the CRF and in the patient’s medical records.
3.9.2
Off-Study Criteria

Completed 2 year follow up period

Subject withdrawal from follow-up period

Patient lost to follow-up

Investigator discretion

Death


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3.9.3
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site will attempt to contact the participant and reschedule the missed visit within one 
month and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, an IRB approved certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in 
the participant’s medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
All medications (prescription and non-prescription), treatments and therapies taken throughout 
the study must be recorded on the appropriate page of the CRF. Patients will be advised to 
contact the study team before starting any new medications.
4.1
CONCOMITANT CORTICOSTEROID THERAPY AND TAPERING GUIDELINE
During the study, patients may remain on corticosteroids with intent to taper.  A steroid taper 
will be allowed to begin earliest at 4 weeks after starting on the Phase 1b continuation phase or 
Phase 2 study, with a 10% (of starting dose) decrease per week.  The study allows maximum two 
total pulses of steroids with subsequent rapid taper for cGVHD flares associated with the study 
drug initiation and/or one time later for any flares or worsening of cGVHD symptoms during 
steroid or other immunosuppression taper or treatment interruptions.  Typical corticosteroid 
pulse is defined as up to 2 mg/kg/day prednisone or equivalent tapered to the pre-pulse baseline 
within 3 weeks.  Steroid pulses require the PI’s approval.  Administration steroid pulses will be 
carefully recorded in the protocol case report forms. 
4.2
OTHER TREATMENTS FOR CGVHD
Patients who are taking concomitant systemic agents for control of cGVHD, such as calcineurin 
inhibitors (e.g., tacrolimus or cyclosporine) or other immunosuppressants (e.g., mycophenolate 
or sirolimus) must be on a stable or tapering dose in the preceding 4 weeks with an intent to stop 
if possible after corticosteroids are at stable or supplementation doses (maximum 7.5 mg 
prednisone/day) or discontinued.  Patient should not receive any investigational drugs or initiate 
any systemic therapy for cGVHD once started on baricitinib.  Patients should not be undergoing 
extracorporeal photopheresis (ECP) concomitantly with study drug.


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4.3
OTHER ALLOWED CONCOMITANT THERAPY
Ancillary therapy and supportive care considered necessary for the patient’s wellbeing may be 
administered at the discretion of the PI and will follow the NIH Blood and Marrow Transplant 
Consortium guidelines for supportive care: 
http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml.  Any ancillary or supportive care 
which may have some effect on efficacy analysis including topical cGVHD treatments will be 
carefully recorded in the CRF.  
4.4
PROHIBITED CONCOMITANT THERAPY
Given risk of concurrent NSAID use to decrease potential of the kidney to respond to 
hemodynamic changes and subsequent renal dysfunction, NSAID use will not be allowed during 
the course of baricitinib treatment.
Baricitinib does not have significant impact on CYP enzymes, and thus the potential to cause 
clinically significant interaction via CYP are low.  There is no specific contraindication on this 
study for CYP-metabolized agents.
In addition, radiation therapy, cancer chemotherapy, biologic or immunotherapy is prohibited 
during participation in this study. Concomitant use of other investigational agents is not 
permitted while persons are receiving study drug. 
5
CORRELATIVE STUDIES FOR RESEARCH 
5.1
BIOSPECIMEN COLLECTION
Please note that tubes and media may be substituted based on availability with the permission of 
the PI or laboratory investigator.
5.1.1
Skin and oral biopsy, saliva collection, oral microbiome swabs 
Skin and oral research biopsies will be performed before treatment and after 6 months of 
baricitinib treatment (with intent to sample as close to the same area as possible).  
Immunohistochemistry methods will be applied to look for T-cell infiltrates, and IFN-induced 
factors in the oral mucosa and erythematous skin.  The advantage of histology is the greater 
amount of information on cell populations and functional changes in situ of the disease.  These 
biopsies will be obtained by one of the study investigators and processed, stored and analyzed at 
the Blood Processing Core (Dr. Figg’s Lab).  A biopsy sample will be also sent to the NCI 
pathology laboratory.  Patients will have an option to decline any of these research biopsies.  
Biopsy samples collected on the 04-C-0281 cGVHD natural history study can be also used for 
these studies if obtained in the timeframe as part of the screening evaluations for this study.        
Whole saliva and oral swabs of the buccal mucosa, tongue and gingiva will be collected at the 
same time that the buccal mucosal biopsies are performed to evaluate the salivary proteome, 
microbiome and cytokine profile at baseline and after 6 months of baricitinib treatment. The 
samples may be analyzed using a variety of methods including immunohistochemistry, 
microscopy, gene expression profiling, microbial sequencing, and protein-based assays in order 
to assess oral tissues for immune changes and for local specific markers of response or lack 
thereof to baricitinib therapy. 


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5.1.2
Immunologic Analyses Using Plasma and PBMCs
1. Blood: Blood will be collected, and PBMC and plasma will be cryopreserved for later 
batch analyses of markers relevant to cGVHD activity.  Cellular markers of active 
cGVHD have been proposed, although not verified at multiple institutions or validated in 
prospective trials27.  Heparinized plasma will be assayed for potential markers of cGVHD 
activity (including but not limited to BAFF, IFN-induced chemokines).  
Pharmacodynamic of baricitinib (inhibition of cytokine-induced STAT phosphorylation) 
will be assayed prior to drug administration and 2 hours post administration on the first 
day of cycle 1 and at any later increase in drug dosage.  Monocyte transcriptome 
assessments of IFN-inducible genes should be noted to be an experimental endpoint with 
potential relevance to cGVHD pathogenesis.  PBMC will be cryopreserved for 
subsequent flow cytometry of cell populations and sorting of monocytes for 
transcriptional analysis of genes upregulated in active cGVHD.  The primary collection 
of blood for these analyses of baricitinib effect on cGVHD will be collected prior to dose 
and 2 hours after dose at the following timepoints: baseline, at the time of any increase in 
dose level. Each aliquot contains 10 x 106 cells—with no more than cells in a single vial. 
All samples collected will be cryopreserved and frozen for future analyses as detailed in 
Section 5.2.1.
2. Plasma will be assayed for BAFF, CXCL9/CXCL10, IL-6, TNFα, and other IFN-induced 
chemokines. Take one 1 mL aliquot of plasma from each of the CPTs, without disturbing 
the cell interface, and place into standard cryovials. Barcode as buffy plasma and store at 
-80°C. All samples collected will be cryopreserved and frozen for future analyses as 
detailed in Section 5.2.1. 
1. Additionally, ELISA assays may include but not be limited to the following 
proposed biomarkers of cGVHD: CXCL9, MMP3, DKK3, ST2, CD163
2. Additional or alternative plasma factors will be considered based upon relevant 
cGVHD biomarkers identified by the end of biospecimen accrual.
3. Monocyte transcriptome: Monocytes will be sorted from PBMC for Nanostring 
evaluation of the monocyte transcriptome.  This would be done on cryopreserved cells at 
the end of the study.  Monocytes circulate throughout the body, are responsive to a 
variety of cytokines in tissues affected by cGVHD and may therefore serve as a reporter 
for changes in cGVHD-affected tissues.
4. Lymphocyte populations. Assays characterizing lymphocyte populations will be 
performed to include, but not be limited to, assessments of %CXCR3+ T-cells, %T-reg 
cells and %CD21 B-cells.  Furthermore, multilineage lymphocyte immune reconstitution 
after transplant will be investigated to examine the impact of JAK1/2 inhibition on 
lymphopoiesis (CD3, CD4, CD8, B and NK populations).  At baseline prior to dose, 2 
weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks and if PI deems necessary at end of 
treatment and followup visits, one 3mL lavender (EDTA) tube will be drawn and 
lymphophenotyping will be performed using Clinical Center’s CLIA certified 
Immunophenotyping panel and reported in the CRIS.  Further research assessments of the 
percentages of regulatory T cells, of naïve, memory and effector T cells and of B cell 
transitional, naïve and memory populations will be done in the Blood Processing Core 
(Dr. Figg’s Lab). Active cGVHD has been associated with decreases in Treg populations, 


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30
reduced thymopoiesis (fewer naïve T cells) and increases in CD21- transitional B cell 
populations. 
The assays indicated are designed to assess the alterations in skin, oral mucosa and in circulating 
lymphocytes and plasma that may result from baricitinib.  If there is an increase in Th1 cells or a 
shift in Treg populations, this may be reflected in circulating T cell populations, plasma 
cytokines and tissue infiltrates. 
5.1.3
Measurement of Baricitinib Serum Levels  
For each dose level of baricitinib administered, one plasma sample will be collected per patient 
for measurement of baricitinib concentration after at least 7 days of continuous treatment (on day 
15 of that cycle).  This testing is performed to ensure that drug concentrations do not exceed 
baricitinib exposures previously studied.  Each time the baricitinib dose is increased or decreased 
an additional single sample will be collected after at least 7 days of continuous treatment on the 
new dose (on day 15 of that cycle). The sample will always be collected immediately before 
taking the next baricitinib dose.  In addition, on the first day of each dose level, blood will be 
taken pre-dose, then at 1, 2, and 4 hours after the dose.  A sample will be collected at 24 hours 
after the dose in up to 10 patients as feasible, but is not required on protocol.  The sample at 
week 12 is not collected if no change in dose level occurred.  In the event of a serious adverse 
event or at the end of study, an additional sample may be collected within 2 hours of the last dose 
at the discretion of the investigator.  A 3-mL blood sample will be collected immediately before 
taking the daily baricitinib dose.  Actual dosing dates and times will be recorded.  These sample 
collections will occur at the protocol scheduled evaluation visits at the NIH Clinical Center. 
Every effort will be made to collect samples as prescribed in the timeline.  Samples that are 
collected ± 15 minutes of collection time will not be considered a protocol deviation.
In the event of a serious adverse event (SAE) or at the end of the study, an additional sample 
may be collected within 24 hours of the last dose, at the discretion of the investigator.  If this 
sample is collected, it will be as soon as possible after identification of the event and the time of 
the last dose and the time of sample collection will be recorded.
All samples for measurement of baricitinib will be collected, processed, stored, documented and 
the Blood Processing Core (Dr. Figg’s Lab). Plasma samples will be batch tested for baricitinib 
concentration not more than two years after collection using a validated liquid chromatography 
with tandem mass spectrometry method, with a limit of quantification of 0.5 ng/mL, by the 
Clinical Pharmacology Program of the NCI, directed by William Figg.
5.1.4 Sample processing 
Please email Clinical Pharmacology Blood Processing Core (BPC) at 
NCIBloodcore@mail.nih.gov at least 24 hours before the scheduled research blood draw time 
and before patient treatment start times (the Friday before is preferred).
For sample pickup, page 102-11964. 
For immediate help, call the main line for the BPC at (240) 760-6180. If no answer, call the main 
clinical pharmacology lab phone number at (240) 760-6190.
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.


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31
The samples will be processed, barcoded, and stored in Dr. Figg’s lab until requested by the 
investigator.
5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. 
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required. 
5.2.1
Sample Procedures
Blood and tissue samples, collected for the purpose of research under IRB-approved protocols of 
the Experimental Transplantation and Immunology Branch and the Immune Deficiency Cellular 
Therapy Program will be stored and may be archived by the Blood Processing Core (BPC) will 
be barcoded, with data entered and stored in the Labmatrix utilized by the BPC. This is a secure 
program, with access to Labmatrix limited to defined Figg lab personnel, who are issued 
individual user accounts. Installation of Labmatrix is limited to computers specified by Dr. Figg. 
These computers all have a password restricted login screen. 
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without Labmatrix 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.).
Samples are stored in locked freezers at -85°C (sera and plasma) or under liquid nitrogen (cells), 
according to stability requirements. These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times. Access to stored clinical samples is 
restricted. Samples will be stored until requested by a researcher named on the protocol. All 
requests are monitored and tracked in Labmatrix. 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 
the IRB approved protocol) and that any unused samples must be returned to the BPC. It is the 
responsibility of the NCI Principal Investigator to ensure that the samples requested are being 
used in a manner consistent with IRB approval.
5.2.1.1
Protocol Completion/Sample Destruction 
Once primary research objectives for the protocol are achieved, researchers can request access to 
remaining samples for human subjects research, providing they have both approval of the 
Principal Investigator of the original protocol under which the samples or data were collected 
and either an IRB-approved protocol and patient consent or an OHSRP determination that the 
activity is exempt from IRB review. 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. 
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. The PI will record any loss or 


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unanticipated destruction of samples as a deviation. Reporting will be per the requirements of 
section 7.2 Error! Reference source not found..
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 
Labmatrix. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
Data will be prospectively collected and entered into an NCI 21 CFR Part 11-compliant data 
capture system using pre-designed CRFs. All persons must have signed an Informed Consent and 
have an on-study confirmation of eligibility form completed before entering on the study. 
Complete records will be maintained on each patient including the hospital chart with any 
supplementary information obtained from outside laboratories, radiology reports, or physician’s 
records. These records will be the primary source documents that form the basis for the research 
record. The primary source documentation will assure the availability of the following: on-study 
information, including patient eligibility data and patient history; flow sheets, specialty forms for 
pathology, radiation, or surgery; and off-study summary sheet, including a final assessment by 
the treating physician.
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts. 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.  
Document AEs from the first study intervention, Study Day 1, through 30. Beyond 30 days after 
the last intervention, only adverse events which are serious and related to the study intervention 
need to be recorded.
An abnormal laboratory value will be considered an AE 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, this will be reported expeditiously per 
requirements in section 7.2.1. 
6.1.1
Eligibility Checklist
The eligibility checklist is to be completed at study entry by the protocol research nurse who will 
forward the checklist to the Central Registration Office. 
6.1.2
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 (check all that 
apply):
_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.  Insert name or names: 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
Not applicable. No genomic data, large scale or otherwise, is generated on this study.
6.3
RESPONSE CRITERIA
6.3.1
Definitions
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with baricitinib.
Evaluable for efficacy: Patients who complete 6 months of therapy will be evaluable for the 
primary endpoint of efficacy assessment. Patients who progress earlier will be also included in 


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the analysis of efficacy. Patients should have received at minimum of 75% of planned baricitinib 
doses to be evaluable for the primary efficacy 6 month endpoint.     
6.3.2
Efficacy Analysis
The primary evaluation point is overall response at 24 weeks using the NIH cGVHD response 
criteria measures51.  The overall response score will be assessed as CR, PR, or lack of response 
as per NIH guidelines.  The organ-specific and other subcomponents of the overall response 
score will be analyzed individually and absolute values recorded.
Up to 2 corticosteroid pulses will be allowed, one for initial flares and one for late flares as 
described in Section 4.1.  
Response will be assessed every 12 weeks from the start of baricitinib.  To ensure comparability, 
baseline and on-study methods for response assessment will be performed using identical 
grading, scale or techniques.  The Chronic GVHD Assessment (Clinician) Form will be 
completed at each 12 week evaluation visit (Appendix F). Included in that form are both organ-
specific primary measurements and clinician-assessed secondary measurements. The response of 
each affected organ will be evaluated and an overall response will be determined. 
6.3.2.1
Response Criteria
Efficacy will be assessed using NIH consensus criteria measuring for therapeutic response in 
clinical trials for cGVHD.

CR is defined as resolution of all manifestations in each organ or site

PR is defined as improvement at least 1 organ or site without progression in any other 
organ or site.  The criteria for PR and progression are provided in Appendix K

Lack of Response: including unchanged, mixed response, and disease progression: 

Mixed response: CR or PR in at least 1 organ accompanied by progression in another 
organ

Disease progression: see Appendix K for organ criteria

Unchanged: Outcomes that do not meet the criteria for CR, PR, disease progression, or 
mixed response
As outlined in Section 3.7, type of involved organ, location and its measurements will be 
recorded at scheduled evaluations and reported on the appropriate CRF, equal to “Chronic 
GVHD Assessment (Clinician) Form,” (Appendix F).  All other measurements not being 
included in primary assessment but clinically related to cGVHD (e.g., change of pigmentation) 
will be reported in the source documents. 
Skin and skin appendages:  Skin assessment will be based on the NIH 0-3 Skin Score, which 
correlates with cGVHD severity, symptoms, and survival (Appendix D).  Clinician-perceived 
severity of sclerosis will also be captured on a 0-10 scale.  Patient-reported symptoms will be 
captured on a 0-10 scale and on the Lee symptom scale.
Musculoskeletal connective tissue:  Assessment of joint range of motion will be performed by 
the photographic range of motion (P-ROM) scale and the NIH 0-3 Joint Score, which correlate 
with changes in joint involvement.  In a prior study, both scales performed well but the 
Joint/Fascia scale better reflected clinical perception of improvement, and the P-ROM better 
reflected the clinical perception of worsening33.  If these measurements are discrepant, priority 


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will be given to the NIH 0-3 scale when improvement is detected, and to P-ROM when 
worsening is detected.  If the resolution cannot be achieved then the priority will be given to the 
NIH 0-3 Joint/Fascia scale, as the P-ROM is of more recent origin and still deemed exploratory 
in the 2014 NIH cGVHD organ staging recommendations4.    
Eyes:  The NIH Eye Score uses a scale of 0-3 based on symptoms, need for eye drops, and use of 
therapeutic procedures or devices.  This has been shown to detect improvement of worsening in 
ocular cGVHD.  Patient-reported symptoms will be captured on a 0-10 scale and on the Lee 
symptom scale.
Mouth:  Mouth assessments on the NIH-modified Oral Mucosa Rating Scale (OMRS) include: 
(1) mucosal erythema by 0-3 grading based on the color intensity, (2) lichen-type 
hyperkeratosis by 0-3 grading based on the percentage of oral surface area,(3) ulceration 
by 0-6 based on percentage of oral surface area
Gastrointestinal tract:  Gastrointestinal (GI) symptoms will be graded through interview by the 
investigator according to 0-3 severity scales, and weight will be measured at each visit.
Liver:  Involvement of liver is graded according to the levels of total serum bilirubin, alkaline 
phosphatase, and alanine aminotransferase (ALT). 
Lung:  Absolute percent predicted of the forced expiratory volume in the first second (FEV1), 
forced vital capacity (FVC), single breath diffusion lung capacity for carbon monoxide (DLCO), 
total lung capacity (TLC), and residual volume (RV) will be measured on pulmonary function 
testing (post-bronchodilator response values, as cGVHD of the lungs is not a bronchodilator-
responsive process).  The %FEV1 will be used for response assessment.  Symptoms will be 
graded through interview by the investigator according to the NIH Symptom Scale 0-3.  Slope of 
%FEV1 will also be measured. 
Genitals:  Patient-reported symptoms will be captured on a 0-10 scale.Global chronic GVHD 
Rating:  The overall clinical impression of patient’s cGVHD will be recorded on a 4-point (0-3) 
scale on the Chronic GVHD Assessment (Clinician) Form.  
Chronic GVHD Improvement Scale:  The overall changes of patient’s cGVHD symptoms 
during previous 3 months will be recorded on a 7-point (-3 to +3) scale on the Chronic GVHD 
Assessment (Clinician) Form.
Chronic GVHD Symptom Severity Scale:  The overall severity of patient’s cGVHD symptoms 
will be recorded on an 11-point (0-10) numeric scale on the Chronic GVHD Assessment 
(Clinician) Form.
Lee symptom scale was developed as a 30-item symptom scale with 7 subscales to capture the 
cGVHD-specific symptom burden (Appendix I). This symptom scale showed to correlate with 
persons’ self-assessed mild, moderate, and severe cGVHD manifestations in cross-sectional 
validation analysis.  Evidence supports the validity, reliability, and sensitivity to chronic GVHD 
severity.
NIH organ 0-3 scoring (Appendix D) will be collected at the evaluation endpoints.  
6.3.2.2
Summary of Response Measures
i. Primary response measures
1. Skin: NIH 0-3 Skin Score


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2. Joints: P-ROM (1-7 and 1-4) and NIH Joints Fascia Score
3. Eye: NIH 0-3 Eye Score
4. Mouth: NIH-modified 0-12 OMRS
5. GI: GI 0-3 clinician symptom severity scale
6. Liver: bilirubin, alkaline phosphatase, ALT 
7. Lung: %FEV1     
8. Clinician global assessment scale (3-point, 7-point change, 11-
point)
ii.     Secondary assessments 
1. Overall response rate at 12 weeks of therapy
2. NIH organ scoring 
3. Rate of >50% reduction of immunosuppressive therapy at 24 
weeks and 48 weeks (steroid pulses on study per section 4.1 will 
not count towards this assessment)
4. Overall survival
5. Platelet count, CRP, C3, C4, albumin
6. Lee symptom scale, HAP, FACT-BMT
7. Skin and oral biopsies (if positive at baseline)
8. MRI (if positive baseline)
9. Pharmacokinetics
10. Pharmacodynamic/correlative studies
6.3.2.3
Other endpoints to be recorded at the evaluation time points: Need for secondary 
systemic therapy for GVHD, malignancy progression, discontinuation of immune 
suppression, steroid doses, other immunosuppressive drug doses, new topical treatments 
introduced, intensity of immunosuppression scale, NIH global severity (Appendix E), 
survival, progression-free/malignancy-free survival, disability-free survival.   
6.4
TOXICITY CRITERIA
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 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 


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7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety 
Reports that meet the definition of an unanticipated problem will need to be reported per these 
policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a weekly 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 a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines.
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. 


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8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:

Death,

A life-threatening adverse event (see section 8.1.3)

Inpatient hospitalization or prolongation of existing hospitalization
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.

Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions

A congenital anomaly/birth defect.

Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)


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8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 4.0.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  

Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.

Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution.
SAEs will be:

Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator.

Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.

Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.4.
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited 
reporting requirements are found in section 8.4.
All SAE reporting must include the elements described in section 8.2.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 


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and instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible.
8.4
WAIVER OF EXPEDITED REPORTING TO CCR 
As death/hospitalization due to disease progression are part of the study objectives (efficacy-
response rate), and captured as an endpoint in this study, they will not be reported in expedited 
manner to the sponsor. However, if there is evidence suggesting a causal relationship between 
the study drug and the event, report the event in an expedited manner according to section 8.3.
8.5
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described below. 
The PI or designee will report all Serious Adverse Events to the IND Manufacturer within 3 days of 
the Investigator(s) becoming aware of them. 
Fax all SAE forms to: Lilly Global Patient Safety at 866-644-1697 
Additionally, the IND manufacturer will be provided with copies of all investigational product-
related reports submitted to regulatory authorities.
8.6
REPORTING PREGNANCY 
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions 
can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 
8.6.1
Maternal exposure
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 no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy become known,
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as 
SAEs. 
The outcome of all pregnancies should be followed up and documented.
8.6.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for at 
least 7 days after the last dose of baricitinib.
Pregnancy of the patient’s partner is not considered to be an AE. The outcome of all pregnancies 
occurring from the date of the first dose until 28 days after the last dose should, if possible, be 
followed up and documented. Pregnant partners may be offered the opportunity to participate in 
an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry study) to 
provide data about the outcome of the pregnancy for safety reporting purposes.


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8.7
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event.  CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
8.8
SPONSOR PROTOCOL DEVIATION REPORTING
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual 
of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by the 
Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online 
application. The entries into the PDTS online application should be timely, complete, and 
maintained per CCR PDTS user requirements. 
In addition, any deviation to the protocol should be documented in the participant’s source 
records and reported to the reviewing IRB per their guidelines. OSRO required protocol 
deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 
Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol 
deviations.
9
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure:

that the rights of the participants are protected; 

that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and, 

the quality and integrity of study data and data collection methods are maintained.  
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable 
regulatory requirements.
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 


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to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the study site(s). 
Monitoring visit reports will describe visit activities, observations, and associated action items or 
follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring reports 
will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, coordinating 
center (if applicable), and the Sponsor regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol 
Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per 
institutional and IRB guidance.
10 STATISTICAL CONSIDERATIONS  
The primary objectives of the study are to determine the tolerability and efficacy of baricitinib in 
patients with steroid-refractory cGVHD.  The primary efficacy objective is to treat a total of 21 
patients in either cohort 1 or cohort 2 in order to have 80% power to detect a response rate 
consistent with 30% and ruling out 10%, with a one-sided significance level of 0.10.  
Patients will first be enrolled onto cohort 1, and in an initial futility analysis, if 0 of the first 7 
patients enrolled in cohort 1 have responded, then subsequent patients will be accrued to cohort 
2, starting treatment at the higher dose (4mg daily).  If 1 or more of the initial 7 patients treated 
in cohort 1 has a response, then a total of 21 evaluable patients will be treated in cohort 1.
If patients are enrolled onto cohort 2, and if 0 of the first 7 patients enrolled in cohort 2 have 
responded, then no further patients will be accrued onto the trial. On the other hand, if 1 or more 
of the initial 7 evaluable patients enrolled in cohort 2 have responded then a total of 21 evaluable 
patients will be treated in cohort 2.  
As an early stopping rule for safety, if 2/3 or greater patients at any given dose level experiences 
a dose limiting toxicity requiring dose reduction or discontinuation, that dose will not be 
subsequently used.  Accrual will continue at a lower dose level with no further dose escalation, 
unless this occurs at the lowest dose level, at which time accrual to the study will be stopped.
If patients are enrolled in both cohort 1 and cohort 2, then up to 28 evaluable patients may be 
required (either 21 in cohort 1 or 7 in cohort 1 and 21 in cohort 2). In order to allow for a small 
number of inevaluable patients, the accrual ceiling will be set at 31. It is anticipated that 8-12 
patients may be enrolled onto this protocol per year; thus, 2 to 4 years may be required to accrue 
up to 31 patients.


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11 COLLABORATIVE AGREEMENTS 
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)
Baricitinib is provided by Eli Lilly and Company under a CRADA (# 34604). 
12 HUMAN SUBJECTS PROTECTIONS 
12.1 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. 
12.2 PARTICIPATION OF CHILDREN
As there is inadequate published data on baricitinib in children, this study will be limited to 
subjects age 18 years or older.
12.3 PARTICIPATION OF NIH SUBJECTS UNABLE TO GIVE CONSENT
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 (section 12.5), all subjects 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) to assess ongoing capacity of the subjects and to 
identify an LAR, as needed.
Please see section 12.6.1 for consent procedure.
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
12.4.1 Related to baricitinib
Potential risks of baricitinib include the range of toxicities described in Section 14.1.2 and the 
consent form.  There may also be unexpected side effects.  All subjects will be carefully 
monitored for side effects. 
12.4.2 Related to Blood Collection
Minor complications including bleeding, pain, and hematoma formation at the site of blood 
draws, or infections may rarely occur.
12.4.3 Related to Tissue Biopsy
Skin and oral punch biopsy is a minor surgical procedure that may be associated with temporary 
bleeding, hematoma at the site, local infection and postoperative discomfort.  These risks are small 
(generally <5%) and transient.


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12.4.4 Related to Pulmonary Function Tests
PFTs are safe for most participants; however, some may experience dizziness, shortness of breath 
and fainting. In rare PFTs may lead to a collapsed lung. In participants with asthma, PFTs may 
precipitate an asthma attack. 
12.4.5 Related to ECG and echocardiogram 
Other than possibly experiencing some minor skin irritation from the electrodes there are no 
anticipated risks related to complete the electrocardiogram and/or the echocardiogram.
12.4.6 Related to Questionnaires
The potential risk of questionnaires include questions that may be sensitive in nature.
12.4.7 Related to Radiation Exposure
A CT scan is done at screening; however, all screening is performed on a separate study. 
Therefore, radiation risks are assessed to the screening protocols.
12.5 RISKS/BENEFITS ANALYSIS
The benefits of the study include the potential to improve knowledge of the biology of cGVHD 
and impact of JAK inhibition in the treatment of this disease.  In addition, if shown to be 
effective, the study drug may improve overall outcomes after SCT, a curative therapy for many 
hematologic malignancies, as well as have implications for prevention.  Individual patients may 
benefit from participation in this protocol if treatment stabilizes or improves their cGVHD.  
Patients may also benefit by knowing they are participating in a study aimed at improving 
treatment of cGVHD, which we ultimately hope will benefit future patients.  The risks of the 
study to participants are minimal compared to the potential benefits to them or to the overall 
knowledge and future study of JAK inhibition in cGVHD.
12.6 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) as applicable for review prior to consenting. A designated 
study investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee.  Whether in person or remote, the privacy of 
the subject will be maintained. Consenting investigators (and participant/consent designee, when 
in person) will be located in a private area (e.g., clinic consult room). When consent is conducted 
remotely, the participant/consent designee will be informed of the private nature of the 
discussion and will be encouraged to relocate to a more private setting if needed.
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 


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(non-electronic) signature on the electronic document.  When required, witness signature will be 
obtained similarly as described for the investigator and participant.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures:

Adobe platform (which is not 21 CFR Part 11 compliant); or,  

iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when in the same location, but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) 
found 
at:   
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
For the optional biopsy, the patient will consent at the time of the procedure.  If the patient 
refuses the optional biopsy at that time, the refusal will be documented in the medical record and 
in the research record.
12.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research 
Participation
For participants addressed in section 12.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 12.6. 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met


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
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the National Cancer 
Institute has established policies and procedures for all study group members to disclose all 
conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest.
13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
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The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by the clinical site(s) and by NCI CCR research staff will be secured and password 
protected. At the end of the study, all study databases will be archived at the NCI CCR.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
14 PHARMACEUTICAL INFORMATION  
14.1 BARICITINIB (IND # 129360)
14.1.1 Source 
Baricitinib will be provided by the manufacturer Eli Lilly and Company under a clinical trials 
agreement.
14.1.2 Toxicity 
As of August 2021, approximately 13,800 subjects have received baricitinib since the start of 
clinical development program.  
A large, randomized trial of tofacitinib (a JAK 1/2/3 inhibitor) in patients with rheumatoid 
arthritis detected higher risk of heart attack, stroke, cancer and blood clots and death when 
compared to standard therapy with anti-TNF drugs. Based on these studies in September 2021, 
FDA extended this warning to baricitinib (JAK 1/2 ) and another JAK inhibitor drug used in 
arthritis. This warning has not been extended to similar drugs used for cancer (or GVHD).
The following potential treatment related side effects have been identified:
Increased Adverse Events Due to Increased Exposures in Patients with Renal Impairment: 
Data from completed studies indicate that subjects with renal impairment have increased 
exposures to baricitinib. Increased exposure could place a person at increased risk for any other 
risk that is related to exposure. Therefore, adjustment in dose has been implemented in clinical 
studies to compensate for these observed differences. Investigators should follow dosing 
guidelines specified in the protocol, and monitor creatinine in study subjects and follow protocol 
drug interruption and discontinuation criteria.


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Blood Clots in the Blood Vessels
Increased incidence of pulmonary embolism, venous and arterial thrombosis with another JAK 
inhibitor vs. TNF blockers. Events of deep venous thrombosis (DVT) and pulmonary embolism 
(PE) have been reported in patients receiving baricitinib. 
Data from the placebo-controlled time period from the integrated safety analysis of Phase 2/3 RA 
studies showed a numerical imbalance in the reports of DVT/PE, with more events reported in 
the baricitinib 4-mg group compared to the placebo group. The exposure-adjusted incidence rate 
(EAIR) of DVT/PE for baricitinib-treated RA patients over long-term exposures [0.45] was 
similar to the background rates published in the literature. There was no pattern of increased or 
decreased risk in any given 48-week time period including long-term exposures. Risk factors 
found more commonly in patients with these events included prior history of DVT/PE, obesity, 
and older age. In a retrospective observational study of baricitinib in RA patients, a higher 
incidence rate of venous thromboembolic events was observed compared to patients treated with 
TNF blockers.
Baricitinib should be used with caution in patients with risk factors for deep vein thrombosis or 
pulmonary embolism (DVT/PE) and enrollment of patients with multiple risk factors should be 
carefully considered in clinical trials. If clinical features of DVT/PE occur, interrupt baricitinib, 
evaluate promptly, and institute appropriate treatment. 
Myelosuppression: Baricitinib is anticipated to down-regulate the JAK pathway and result in 
changes to WBC counts. Although dose-related decreases in neutrophils and other phagocytic 
cell lines have been observed, neutropenia and lymphocytopenia have been observed 
infrequently. Investigators should monitor leukocyte parameters in study subjects and follow 
protocol drug interruption and discontinuation criteria.
Increased Infections (including opportunistic infections and herpes zoster): In addition to 
the observed decreases in phagocytic cells, JAK inhibition down-regulates cytokines related to 
the immune system. Although infections and infestations were the most frequently reported SOC 
of TEAEs, an excess occurrence of infections typically considered to be opportunistic has not 
been observed in clinical studies with baricitinib. The incidence rate of herpes zoster observed in 
baricitinib studies is within the range reported in observational studies and clinical trials of 
patients with RA, including the rate observed in placebo recipients. Investigators should monitor 
subjects for clinical signs and symptoms of infectious events, including herpes zoster. If a subject 
is clinically diagnosed with herpes zoster, the investigator should interrupt investigational 
product, initiate standard of care (including antiviral therapy and relevant supportive care as 
appropriate), monitor for multi-dermatomal involvement or other evidence of dissemination, and 
follow subjects until clinical recovery of skin lesions (vesicles). For study subjects at risk for 
herpes zoster, investigators should encourage, and offer to provide, vaccination against 
varicella/zoster prior to starting investigational product in clinical trials (at least 4 weeks before 
randomization).
Increased Cardiovascular Events: Higher rate of MACE (defined as cardiovascular death, 
myocardial infarction, and stroke) with another JAK inhibitor vs. TNF blockers in RA patients. 
Higher rate of all-cause mortality, including sudden cardiovascular death with another Janus 
kinase inhibitor (JAK) vs. TNF blockers in rheumatoid arthritis (RA) patients. Increases in mean 
total cholesterol, LDL, HDL, and triglycerides have been noted in studies with baricitinib. 
Nuclear magnetic resonance data indicate that the changes in cholesterol are due primarily to 


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increases in the number of HDL particles without a change in HDL particle size; an increase in 
the number of large LDL particles with no significant increases in small, medium-small or very 
small LDL particles; and an increase in the number of total, as well as medium and small, very 
low density lipoprotein (VLDL) particles. The mean values for the HDL/LDL ratio did not 
change. These changes in lipid particles, particularly in view of the observed increase in large 
LDL particles, suggest that the overall effect on the vasculature may not be atherogenic52-54. Data 
from A Randomized, Double-Blind, Placebo- Controlled, Dose-Ranging, Parallel-Group, Phase 
2b Study of LY3009104 in Patients with Active Rheumatoid Arthritis on Background 
Methotrexate Therapy (Study JADA) 46 suggest that concomitant use of statins can ameliorate the 
effect on lipids. Any increase in cholesterol carries a potential risk of cardiovascular events. Data 
from patients with RA given 4 to 15 mg baricitinib QD or 5 mg baricitinib BID have shown no 
clinically meaningful changes in vital signs or ECG parameters for baricitinib versus placebo. 
Investigators should monitor vital signs and carefully review ECGs for findings that may be 
associated with cardiovascular events. Investigational product should be interrupted or 
discontinued if major adverse cardiovascular events occur.
Fetal Malformations: Reproductive toxicity was observed in rat and rabbit toxicology studies, 
including maternal toxicity and skeletal malformations in the rat fetus. A decrease in mating 
performance (fertility and copulation indices) was observed in the male rat fertility study. This 
change occurred without effects on spermatogenesis as assessed by histopathology and 
semen/sperm endpoints. Pregnant women should not participate in clinical studies of baricitinib.
To manage any potential risks, women and men of reproductive potential should avoid becoming 
pregnant or fathering a child by using 2 forms of highly effective contraceptives while 
participating in clinical studies and for at least 7 days following exposure to baricitinib. If the 
patient becomes pregnant, study drug should be discontinued for the duration of the pregnancy 
and any subsequent period of breastfeeding.
Malignancies: Baricitinib has immunomodulatory effects on the immune system. Effects on the 
immune system may permit emergence of malignancies previously contained by the immune 
system. No signals concerning effects of baricitinib on malignancy have emerged from clinical 
studies. Long-term safety evaluations for baricitinib are ongoing. Patients should be monitored 
closely for evidence of neoplasia or malignancy, and study drug should be discontinued if such 
events occur.
Higher rate of lymphomas and lung cancers with another JAK inhibitor vs. TNF blockers in RA 
patients.
Pharmacologic Interaction between NSAIDs and Baricitinib to Decrease the Capacity of 
the Kidney to Respond to Hemodynamic Changes: Among patients in Study JADA46, with at 
least 1 creatinine value ≥ 1.3 mg/dL, two-thirds of them had other data to suggest that an 
intercurrent illness with transient hemodynamic effects had occurred preceding or coincident 
with the increased creatinine value and that concomitant use of a NSAID may be associated with 
an increased risk of increased creatinine and decreased GFR in this circumstance.
14.1.3 Formulation and preparation 
The drug product is supplied for clinical study use as tablets and is composed of baricitinib and 
the inactive ingredients microcrystalline cellulose, mannitol, croscarmellose sodium, and 


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magnesium stearate.  Each tablet contains baricitinib equivalent to 1 mg, 2 mg, or 4 mg of the 
free base compound. 
14.1.4 Stability and Storage 
Please refer to label for storage information.
The drug substance is stable at room temperature.
14.1.5 Administration procedures
Please see section 3.2.
14.1.6 Incompatibilities  
Molecular Formula: C16H17N7O2S
Molecular Weight: 371.42
Molecular Structure:
Interactions:
The potential for an effect of baricitinib on the PK of oral contraceptives (OC) was evaluated 
in Study JAGD46, conducted in healthy female subjects. Oral doses of 10 mg baricitinib QD 
had no clinically significant effect on AUC or Cmax of the ethinyl estradiol or levonorgestrel 
components of Microgynon 30®, a commonly used estrogen progestogen combination OC.
Because in vitro data suggested that baricitinib was a P-gp substrate, the potential for 
baricitinib to interact with digoxin, a commonly used P-gp probe substrate, was evaluated in 
healthy male subjects (Study JAGL)46. Coadministered of 10 mg baricitinib with digoxin did 


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not have a clinically significant effect on the systemic exposure to, or renal excretion of, 
digoxin. Baricitinib is, therefore, unlikely to act as a P-gp inhibitor.
An open-label drug-drug interaction study (Study JADB)46 was conducted in patients with 
RA to evaluate the effects of coadministration of baricitinib (5 mg BID or 10-15 mg QD) and 
methotrexate (7.5-25 mg weekly) on the PK profiles of each drug, as well as methotrexate’s 
metabolite, 7-OH-methotrexate. Baricitinib coadministration did not significantly affect dose 
normalized Cmax or AUC of methotrexate or 7-OH-methotrexate. Methotrexate co-
administration had no significant effect on the geometric mean Cmax or AUC of baricitinib. 
Thus, dosing regimens of baricitinib and methotrexate need not be altered when these 2 drugs 
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39.Ma H, Lu C, Ziegler J, et al. Absence of Stat1 in donor CD4(+) T cells promotes the 
expansion of Tregs and reduces graft-versus-host disease in mice. The Journal of clinical 
investigation 2011;121:2554-69.
40.Carniti C, Gimondi S, Vendramin A, 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 
2015;21:3740-9.
41.Choi J, Cooper ML, Alahmari B, et al. Pharmacologic blockade of JAK1/JAK2 reduces 
GvHD and preserves the graft-versus-leukemia effect. PloS one 2014;9:e109799.
42.Spoerl S, Mathew NR, Bscheider M, et al. Activity of therapeutic JAK 1/2 blockade in graft-
versus-host disease. Blood 2014;123:3832-42.
43.Park HB, Oh K, Garmaa N, et al. CP-690550, a Janus kinase inhibitor, suppresses CD4+ T-
cell-mediated acute graft-versus-host disease by inhibiting the interferon-gamma pathway. 
Transplantation 2010;90:825-35.
44.Zeiser R, Burchert A, Lengerke C, et al. Ruxolitinib in corticosteroid-refractory graft-versus-
host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia 
2015;29:2062-8.


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45.Fridman JS, Scherle PA, Collins R, et al. Selective inhibition of JAK1 and JAK2 is 
efficacious in rodent models of arthritis: preclinical characterization of INCB028050. Journal of 
immunology 2010;184:5298-307.
46.Laboratories LR. Barcitinib (LY3009104) Investigator's Brochure. Indianaoplis, Indiana: Eli 
Lily adn Company; 2014.
47.Shi JG, Chen X, Lee F, et al. The pharmacokinetics, pharmacodynamics, and safety of 
baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers. Journal of clinical pharmacology 
2014;54:1354-61.
48.Greenwald MW, Fidelus-Gort R, Levy R, et al. A randomized dose-ranging, placebo-
controlled study of INCB028050, a selective JAK1 and JAK2 inhibitor in subjects with active 
rheumatoid arthritis [abstract]. Arthritis & Rheumatology 2010;62:2172.
49.Keystone EC, Taylor PC, Drescher E, et al. Safety and efficacy of baricitinib at 24 weeks in 
patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Annals 
of the rheumatic diseases 2015;74:333-40.
50.Jabbari A, Dai Z, Xing L, et al. Reversal of Alopecia Areata Following Treatment With the 
JAK1/2 Inhibitor Baricitinib. EBioMedicine 2015;2:351-5.
51.Lee SJ, Wolff D, Kitko C, et al. Measuring therapeutic response in chronic graft-versus-host 
disease. National Institutes of Health consensus development project on criteria for clinical trials 
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Biology of blood and marrow transplantation : journal of the American Society for Blood and 
Marrow Transplantation 2015;21:984-99.
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in the MRC/BHF Heart Protection Study. Circulation 2012;125:2469-78.
53.Mora S, Otvos JD, Rifai N, Rosenson RS, Buring JE, Ridker PM. Lipoprotein particle 
profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in 
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16  PPENDICES
APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some signs or symptoms of 
disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours.
30
Severely disabled, 
hospitalization indicated.  Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


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APPENDIX B: DIAGNOSTIC CRITERIA OF CHRONIC GVHD
Screening/Baseline
Organ or Site
Diagnostic 
Features1
Distinctive 
Features2
Others3
Common 
Features4
Skin
□ Poilkiloderma
□ Lichen planus-     
    like features
□ Sclerotic       
    features
□ Morphea-like   
   features
□ Lichen  
   sclerosus-like    
   features
□ Depigmentation
□ Sweat 
    impairment
□ Ichthyosis
□ Keratosis pilaris
□Hypopigmentation
□Hyperpigmentation
□ Erythema
□ Maculopapular 
   rash
□ Pruritus
Nails
□ Dystrophy
□ Longitudinal 
   ridging,   
   splitting, or   
   brittle features
□ Onycholysis
□ Pterygium 
    unguis
□ Nail loss 5,6
Scalp and body 
hair
□ New onset of 
   scarring or   
   nonscarring   
   scalp alopecia7
□ Scaling, 
   papulosquamous   
   lesion
□ Thinning scalp 
    hair, typically   
    patchy, coarse,   
    or dull 8
□ Premature grey   
    hair


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Organ or Site
Diagnostic 
Features1
Distinctive 
Features2
Others3
Common 
Features4
Organ or Site
Diagnostic 
Features1
Distinctive 
Features2
Others3
Common 
Features4
Mouth
□ Lichen-type 
   features
□ Hyperkeratotic 
    plaques
□ Restriction of 
   mouth opening       
   from sclerosis
□ Xerostomia
□ Mucocele
□ Mucosal   
    atrophy
□ Pseudomembranes 6
□ Ulcers6 
□ Gingivitis
□ Mucositis
□ Erythema
□ Pain
Eyes
□ New onset dry, 
    gritty, or   
    painful eyes 9
□ Cicatricial 
    conjunctivitis
□ Keratoconjunctivitis 
   sicca 9
□ Confluent areas 
    of punctuate 
    keratopathy
□ Photophobia
□ Periorbital  
   hyperpigmentation  
□ Blepharitis 10
Genitalia
□ Lichen planus-
    like features
□ Vaginal 
    scarring or 
    stenosis
□ Erosions 6
□ Fissures 6
□ Ulcers 6
Lung
□ Bronchiolitis  
    obliterans     
    diagnosed with 
    lung biopsy
□ Bronchiolitis 
    obliterans 
    diagnosed with 
    PFTs 12 and 
    radiology 9
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Organ or Site
Diagnostic 
Features1
Distinctive 
Features2
Others3
Common 
Features4
Hematopoietic 
and immune
□Thrombocytopenia
□ Eosinophilia
□ Lymphopenia
□ Hypo- or 
   hypergamma-
   globulinemia
□ Autoantibodies 
(AIHA and ITP)14
Muscle, Fascia, 
joints
□ Fasciitis
□ Joint stiffness or
    contractures
    secondary to 
    sclerosis
□ Myositis or 
   polymyositis
□ Edema
□ Muscle cramps
□ Arthralgia or 
   arthritis
Other
□ Pericardial or 
    pleural 
    effusions
□ Ascites
□ Peripheral 
    neuropathy
□ Nephrotic 
   syndrome
□ Myasthenia   
    gravis
□ Cardiac   
   conduction   
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   cardiomyopathy


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1.
Sufficient to establish the diagnosis of cGVHD
2.
Seen in cGvHD, but insufficient alone to establish a diagnosis of cGvHD
3.
Can be acknowledged as part of the cGVHD symptomatology if the diagnosis is confirmed
4.
Seen with both acute and cGVHD
5.
Usually symmetric—affects most nails
6.
In all cases, infection, drug effects, malignancy, or other causes must be excluded
7.
After recovery from chemoradiation therapy
8.
Not explained by endocrine or other causes


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APPENDIX C: CLINICAL DIFFERENTIATION OF ACUTE AND CHRONIC GVHD
Category
Time of 
Symptoms After 
HCT or DLI
Presence of 
Acute 
GVHD 
Features
Presence of 
Chronic 
GVHD 
Features2
Acute GVHD
   Classic acute GVHD
≤ 100 days
Yes
No
   Persistent, recurrent, or late-onset acute 
GVHD
> 100 days
Yes
No
Chronic GVHD
   Classic cGVHD
No time limit
No
Yes
   Overlap cGVHD
No time limit
Yes
Yes
1. Abbreviations: HCT: hematopoietic cell transplantation; DLI: donor lymphocyte infusion 
2. See Appendix B for features


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APPENDIX D: ORGAN SPECIFIC AND GLOBAL SCORING OF CHRONIC GVHD


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APPENDIX E: GLOBAL SCORING OF CGVHD
Stage
Definition
Mild
1 or 2 organs involved with no more than score 1 plus Lung score 0
Moderate
At least 1 organ (not lung) with a score of 2 
                   or
3 or more organs involved with no more than score 1
                   or
Lung 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-cGVHD 
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 
score organ will be used for calculation of the global severity regardless of the contributing causes 
(no downgrading of organ severity score).


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APPENDIX F: CHRONIC GVHD ASSESSMENT (CLINICIAN) FORM


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APPENDIX G: CHRONIC GVHD ASSESSMENT (PATIENT) FORM


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APPENDIX H: DATA COLLECTION ELEMENTS
A. PATIENT ENROLLMENT 
Recipient

Date of birth, age, gender, race, ethnicity

Height

Weight

Karnofsky Performance Status

Date of original diagnosis of the underlying disease (month/year)

Diagnosis for which transplant was performed

Date and type of transplant

Myeloablative or non-myeloablative conditioning regimen

Stem cell source (marrow, blood, cord)

Acute GVHD yes/no (classic, late) 

Chronic GVHD date of diagnosis

Chronic GVHD classification (classic, overlap)

Prior systemic therapy for cGVHD

Baseline cGVHD manifestations (Appendix B, NIH scores (Appendix D), Forms A 
and B (Appendix F & Appendix G) and cGVHD New Patient Data form 
(Appendix M: cGVHD New Patient Data Form) 

Intensity of current immunosuppression: None, Mild (single agent prednisone <0.5 
mg/kg/day), Moderate (prednisone >0.5 mg/kg/day and or any single 
agent/modality), High (2 or more agents/modalities +prednisone >0.5 mg/kg/day)

Clinician’s impression of activity: Inactive, off systemic therapy or topical 
immunosuppression; Inactive, on systemic therapy or topical immunosuppression; 
Active, irrespective of the level of current therapy; Highly Active, irrespective of the 
level of current therapy

Findings of consultations done at screening
Donor

Related or Unrelated 

HLA matched or mismatched 

Haploidentcal (yes-no)


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B.  STUDY DRUG ADMINISTRATION AND RESPONSE FOR EACH COURSE OF 
THERAPY GIVEN

Dates and times study drug given

Actual dose given

Response assessment at timepoints (CR, PR, unchanged- SD, progression - PD, mixed - 
MR) 
C.   LABORATORY AND DIAGNOSTIC TEST DATA

All Clinical laboratory and diagnostic test results done at screening and timepoints, 
except diagnostic tests which are not specified in the protocol, and if the results are not 
needed to document the start or end of an adverse event that requires reporting.

All tests done to document resolution of adverse events
D.  ADVERSE EVENTS

Baseline AEs 

All grade ≥ 2 events per cycle

All deaths, to include cause of death 
E.  CONCOMITANT TREATMENTS

Systemic therapy for chronic GVHD

Prednisone dose (or prednisone equivalent)  

New topical therapy and organ site

Steroid pulses (date and starting dose)

Therapy for AEs 
F. OFF STUDY

Date and reason for off treatment

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APPENDIX I: PATIENT REPORTED OUTCOMES QUESTIONNAIRES
Lee Chronic GVHD Symptom Scale
Not at 
all
Slightly
Moderately
Quite a 
bit
Extremely
SKIN:
a. Abnormal skin color
0
1
2
3
4
b. Rashes
0
1
2
3
4
c. Thickened skin
0
1
2
3
4
d. Sores on skin
0
1
2
3
4
e. Itchy skin
0
1
2
3
4
EYES AND MOUTH:
f. Dry eyes
0
1
2
3
4
g. Need to use eye drops frequently
0
1
2
3
4
h. Difficulty seeing clearly
0
1
2
3
4
i. Need to avoid certain foods due to 
mouth pain
0
1
2
3
4
j. Ulcers in mouth
0
1
2
3
4
k. Receiving nutrition from an 
intravenous line or feeding tube
0
1
2
3
4
BREATHING:
l. Frequent cough
0
1
2
3
4
m. Colored sputum
0
1
2
3
4
n. Shortness of breath with exercise
0
1
2
3
4
o. Shortness of breath at rest
0
1
2
3
4
p. Need to use oxygen
0
1
2
3
4
EATING AND DIGESTION:


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q. Difficulty swallowing solid foods
0
1
2
3
4
r. Difficulty swallowing liquids
0
1
2
3
4
s. Vomiting
0
1
2
3
4
t. Weight loss
0
1
2
3
4
MUSCLES AND JOINTS:
u. Joint and muscle aches
0
1
2
3
4
v. Limited joint movement
0
1
2
3
4
w. Muscle cramps
0
1
2
3
4
x. Weak muscles
0
1
2
3
4
ENERGY:
y. Loss of energy
0
1
2
3
4
z. Need to sleep more/take naps
0
1
2
3
4
aa. Fevers
0
1
2
3
4
MENTAL AND EMOTIONAL:
bb. Depression
0
1
2
3
4
cc. Anxiety
0
1
2
3
4
dd. Difficulty sleeping
0
1
2
3
4


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APPENDIX J: MEDICATION DIARY
Today’s date ___________________________Page 1
Patient Name____________________________ Patient Study ID________________________
(initials acceptable)
INSTRUCTIONS TO THE PATIENT:
1.
Complete one form for each cycle.
2.
You will take your dose baricitinib each day at approximately the same time.  Baricitinib tablets should be swallowed 
whole, and should not be broken, chewed or opened.  You will take ____  ____mg tablets each day.
3.
Record the date, the number of capsules of each size you took, and when you took them.  
4.
If you have any comments or notice any side effects, please record them in the Comments column.
5.
Please bring your pill bottle and this form to your physician when you go for your next appointment.
# of tablets taken
Date
Day
Time 
of 
daily dose
1 mg
2 mg
4 mg
Comments
1
2
3
4
5
6
7
8
9
10
11
12
13
14


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Page 2
Patient Name____________________________ Patient Study ID________________________
(initials acceptable)
INSTRUCTIONS TO THE PATIENT:
1.
Complete one form for each cycle.
2.
You will take your dose baricitinib each day at approximately the same time.  Baricitinib tablets should be swallowed 
whole, and should not be broken, chewed or opened.  You will take ___  ___mg tablets each day.
3.
Record the date, the number of capsules of each size you took, and when you took them.  
4.
If you have any comments or notice any side effects, please record them in the Comments column.
5.
Please bring your pill bottle and this form to your physician when you go for your next appointment.
# of tablets taken
Date
Day
Time of daily
dose
1 mg
2 mg
4 mg
Comments
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Patient’s Signature: __________________________________________ Date: _________________________
Physician’s Office will complete this section:
1.
Date patient started protocol treatment___________ Date patient was removed from study ____________
2.
Patient’s planned daily dose______________   Total number of pills taken this month _________________
Physician/Nurse/Data Manager’s Signature _____________________________________________________


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APPENDIX K: RESPONSE DETERMINATION FOR CHRONIC GVHD TRIALS BASED ON 
CLINICIAN ASSESSMENTS
Organ
Complete Response
Partial Response
Progression
Skin
NIH Skin Score 0 
after previous 
involvement
Decrease NIH Skin 
Score by 1 or more 
points
Increase in NIH Skin 
Score by 1 or more 
points, except 0 to 1
Eyes
NIH Eye Score 0 
after previous 
involvement
Decrease in NIH Eye 
Score by 1 or more 
points
Increase in NIH Eye 
Score by 1 or more 
points, except 0 to 1
Mouth
NIH Modified OMRS 
0 after previous 
involvement 
Decrease in NIH 
Modified OMRS of 2 
or more points
Increase in NIH 
Modified OMRS of 2 
or more points
Esophagus
NIH Esophagus 
Score 0 after previous 
involvement 
Decrease in NIH 
Esophagus Score by 
1 or more points
Increase in NIH 
Esophagus Score by 
1 or more points, 
except 0 to 1
Upper GI
NIH Upper GI Score 
0 after previous 
involvement 
Decrease in NIH 
Upper GI Score or 
more points
Increase in NIH 
Upper GI Score by 1 
or more points, 
except 0 to 1
Lower GI
NIH Lower GI Score 
0 after previous 
involvement
Decrease in NIH 
Lower GI Score by 1 
or more points
Increase in NIH 
Lower GI Score by 1 
or more points, 
except from 0 to 1
Liver
Normal ALT, 
alkaline phosphatase, 
and Total bilirubin 
after previous 
elevation of 1 or 
more
Decrease by 50%
Increase by 2 x ULN
Lungs
-Normal %FEV1, 
alkaline phosphatase, 
and Total bilirubin 
after previous 
elevation of 1 or 
more
-If PFTs not 
available, NIH Lung 
-Increase by 10% 
predicted absolute 
value of %FEV1
-If PFTs not 
available, decrease in 
NIH Lung Symptom 
-Decrease by 10% 
predicted absolute 
value of %FEV1
-If PFTs not 
available, increase in 
NIH Lung Symptom 


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Organ
Complete Response
Partial Response
Progression
Symptom Score 0 
after previous 
involvement
Score by 1 or more 
points
Score by 1 or more 
points, except 0 to 1
Joints and fascia
Both NIH Joint and 
Fascia Score 0 and P-
ROM score 25 after 
previous involvement 
by at least 1 measure
Decrease in NIH 
Joint and Fascia 
Score by 1 or more 
points or increase in 
P-ROM score by 1 
point for any site
Increase in NIH Joint 
and Fascia Score by 1 
or more points or 
decrease in P-ROM 
score by 1 point for 
any site
Global
Clinician overall 
severity score 0
Clinician overall 
severity score 
decreases by 2 or 
more points on a 0-10 
scale
Clinician overall 
severity score 
increases by 2 or 
more points on a 0-10 
scale


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APPENDIX L: OCCUPATIONAL THERAPY EVALUATION FOR FUNCTIONAL ASSESSMENT, FATIGUE 
ASSESSMENT, AND UPPER EXTREMITY USE


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APPENDIX M: CGVHD NEW PATIENT DATA FORM
Baricitinib for cGVHD (16-C-0094)
New Patient Data Form (Baseline) 
Karnofsky Score: 
Date on Study:_______________
Disease Characteristic  
Diagnosis
 
Transplant information:
Date of transplant
                                                                      
Type of transplant
□ Bone marrow   □Bone marrow & PBSC    □Cord Blood  □Other
□ Peripheral blood stem cell (PBSC)    □ Donor Mobilized
Haploidentical Transplant
□ yes  □ no
Donor relationship
 ____________________________     
Degree of HLA match:
□  8/8, 10/10 or 
12/12 
□   HLA Mismatch
2nd transplant  (allo or auto)
□Y   □N    
Early post transplant events
 
Acute GVHD
 □Y   □N    
DLI
□Y   □N    
cGVHD 
history
                       
Date of cGVHD Diagnosis:  _________          GVHD Classification □ Classic □ Overlap


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Prior Systemic therapy for cGVHD (list all 
medications/therapies)
  
□ Tacrolimus     □ Sirolimus     □ Cyclosporine    □ Cellcept       □ Imatinib      □ Rituximab     □ 
Prednisone    
□ ECP   □ Anti-thymocyte globulin     □ Methotrexate    □ Dacluzimab    □ Ruxolitinib    □ Pomalidomide   
Please list all other therapy previously taken for cGVHD: 
Current Systemic therapy for cGVHD (list all 
medications/therapies, and add dose just for 
steroids)
 □Y   □N   
□ Tacrolimus     □ Sirolimus     □ Cyclosporine    □ Cellcept   □ Imatinib  □ Rituximab □ ECP  
□ Ruxolitinib  □ Methotrexate □ Ibrutinib □ Pomalidomide        
□ Prednisone (dose) __________________________________
Please list all others: 
Current topical therapy for cGVHD 
 □Y   □N   
If yes, list all topical therapy:
 Intensity of current immunosuppression:*see note on bottom of page 3
□ None
□ Mild (single agent prednisone<0.5 mg/kg/day)
□ Moderate (prednisone≥0.5 mg/kg/day and/or any single agent/modality)
□ High (2 or more agents/modalities ± prednisone≥0.5 mg/kg/day)


Abbreviated Title: Baricitinib in cGVHD
Version Date: 10/19/2022
99
Clinician’s impression of activity 
□ Inactive, off systemic therapy or topical immunosuppression
□ Inactive, on systemic therapy or topical immunosuppression
□ Active, irrespective of the level of current therapy
□ Highly active, irrespective of the level of current therapy
BOS
□ Y (1. FEV1<75% and FEV1/FVC ratio <0.7or 2. 
FEV1<75% and ratio >_0.7 must have RV or 
RV/TLC >120% PLUS CT c/w air trapping)
□ N
LIP Print Name:__________________________________ LIP 
Signature:_____________________________
Date of Evaluation:__________
Timepoint: Baseline______ 
* - for “Intensity of current immunosuppression” scale on page 2 just systemic 
immunosuppression should be considered (PUVA and ursodiol are not systemic 
immunosuppressive agents, and ECP can be considered as systemic immunosuppressive 
agent/modality for that scale) 

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/15/2022
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: Steven Pavletic, MD
STUDY TITLE: A Phase 1/2 Study of Baricitinib, a JAK1/2 Inhibitor, in Chronic Graft-
Versus-Host Disease (cGVHD) after Allogeneic Hematopoietic Stem Cell 
Transplantation (SCT)
STUDY SITE:  NIH Clinical Center
Cohort: 
Affected Patient
Consent Version:  
02/15/2022
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator: Steven Pavletic, MD
240-760-6174
pavletis@mail.nih.gov
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
The remaining document will now describe the research study in more detail. This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research interventions in which they would want to 
participate. Take the time you need to ask any questions and discuss this study with NIH staff, and 
with your family, friends, and personal health care providers.
If the individual being asked to participate in this research study is not able to give consent for 
themselves, you, as the Legally Authorized Representative, will be their decision-maker and you 
are being asked to give permission for this person to be in this study. For the remainder of this 
document, the term “you” refers to you as the decision-maker and/or the individual being asked to 
participate in this research.  
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
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PATIENT IDENTIFICATION
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WHY IS THIS STUDY BEING DONE?
Chronic graft versus host disease (cGVHD) is reported to occur in about 36% of patients that have 
had a hematopoietic stem cell transplant using donor cells. It is the leading cause of death in 
patients who survive 2 – 5 years after transplant. There are no FDA approved agents in the 
treatment of cGVHD, but patients are generally treated with high doses of steroids. Unfortunately, 
only half of the patients receiving steroids have any long-term benefit and there is no generally 
accepted treatment once steroids have not worked.
Baricitinib is an investigational drug that specifically inhibits the proteins (JAK 1 and JAK 2) 
which are involved in communication in the immune system and which are thought to play a role 
in cGVHD and other inflammatory diseases. JAK has been tested in other JAK related 
inflammatory diseases such as rheumatoid arthritis with promising results. In this trial, we plan to 
test the safety and effectiveness of baricitinib in patients with cGVHD that has not responded to 
therapy.
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You are being asked to participate in this study because you have been diagnosed with moderate 
to severe chronic graft versus host disease that has not responded to therapy.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Up to 31 patients will be enrolled in this study.
DESCRIPTION OF RESEARCH STUDY
We plan to study two doses of baricitinib on this study. The drug will be tested at a lower dose 
level initially, but if there is not sufficient response, we will test at a higher dose level. If at any 
given dose level, more than one third of patients develop intolerable side effects, no further patients 
will be enrolled at that dose level. Individual patients that experience intolerable side effects will 
be given a lower dose.
The study therapy period will be divided into cycles, each lasting 28 days. On this study, you will 
take the drug every day, by mouth, at the approximately the same time each day for 12 weeks (3 
cycles). Depending on your response to the drug, you may take it an additional 12 weeks (6 cycles 
total).
Baricitinib tablets should be swallowed whole and not broken or chewed. If you miss a dose, it 
should be taken as soon as possible the same day, unless it is within 1 hour of the next dose, at 
which time the dose should not be made up.
Patients whose disease does not worsen will have the option of taking baricitinib for an additional 
6 months, making the maximum length of treatment ~ 1 year.
Before you begin the study
You will need certain tests before you begin the study to determine if you are eligible. Most of 
these tests would be performed as part of your usual medical care for your disease and may include: 
medical history and physical exam, routine blood and urine tests, pregnancy test (if you are a 
woman that can become pregnant), tests to measure your lung function, tests for certain viruses 
IRB NUMBER: 16C0094
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and other infections, EKG and echocardiogram to test heart function and a chest CT scan. These 
tests were performed on a separate protocol.
During the Study
If it is determined that you are eligible for the study and you chose to sign the consent, you will 
begin study therapy as described above and undergo the tests listed below. You may not have to 
repeat some of the tests performed at baseline (before you begin taking baricitinib) if you have 
already done them as a part of screening.
Performed at baseline only:

Tests for certain viruses

Pregnancy test in women that can have children

Evaluations by the following groups:
o
Dermatology (skin)
o
Ophthalmology (eyes)
o
Dental
o
Gynecology (female patients only)
o
Occupational therapy (questionnaires are only required if you are able to read 
English)
Performed at baseline and every 2 weeks for the first 3 cycles and on the first day of subsequent 
cycles:

History and physical exam including weight and vital signs

Routine blood tests
Performed at every visit

Pregnancy test in women that can have children
Performed every 3 cycles

Tests to measure your lung function

cGVHD assessment and questionnaires. The questionnaires will take about 15 minutes and 
will only be required if you are able to read English.

Routine urine tests
Performed at baseline and after 6 cycles

Photographs to document any lesions you may have

Occupational therapy evaluation, with questionnaires you will be asked to complete during 
your visit about how you feel
Performed before every cycle for first 4 cycles and before cycle 7

Electrocardiogram to monitor your heart function
Additional Research tests
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Research testing will be performed on your blood, saliva and on tissue samples (biopsies) from 
your skin and your mouth. They will be used to study how your immune system responds to the 
study drug and to measure the levels of drug in your body.

Research blood will be collected on day 1 of each cycle for the first 4 cycles, then every 3 
cycles until the end of treatment. A research blood sample to measure the level of 
baricitinib in your blood will be performed on the first day you receive medication, at the 
following times—before your dose, and then 1, 2 and 4 hours after the dose. We will also 
measure the level of baricitinib in your blood after you have taken the drug for 7 continuous 
days (on day 15 of the cycle). These research bloods make be repeated if we change the 
dose of baricitinib.

Saliva, oral swabs, and optional skin and oral biopsies will be collected at baseline and 
after you have completed 6 cycles of study therapy. You will be asked to sign a separate 
consent for the biopsies at the time of the procedures.
When you are finished taking the drugs
When you complete your study therapy you will have the following tests performed at your last 
study visit:

History and physical exam

Tests to measure your lung function

Disease assessments including: CT scans or MRIs (if your physician thinks necessary); 
body photography; cGVHD questionnaires

Routine blood (about 5 tablespoons) and urine tests

Research blood tests (about 8 tablespoons)

We may ask you to complete the occupational therapy forms again at this time
If you discontinue the study therapy at any other time, you will be asked to return to the clinic 
within 30 days after your last dose to complete the above assessments.
Regardless of the reason for stopping study therapy, all patients will be contacted by phone ~ 30 
days after your last dose of study therapy. We will ask you about any side effects that you might 
experience. We may follow you for side effects for longer if they are still present at the 30-day 
phone call.
You will also be invited for an optional follow up visit at 3 months after your last dose. If you are 
able to come to clinic, we will perform the following tests; otherwise, you will be assessed by 
phone at this time:

History and physical exam

Routine blood tests (about 5 tablespoons)

cGVHD symptom assessment

Research blood tests (about 8 tablespoons)
We will continue to follow you with phone calls to you or to your primary physician and 12, 18 
and 24 months after your last dose to determine your survival status, to ask about medications you 
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PATIENT IDENTIFICATION
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are taking for your cGVHD, to ask about your cancer status and to determine whether or not you 
have returned to work.
Birth Control
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. Women who are 
pregnant or breastfeeding should not take baricitinib. Studies of baricitinib in animals have shown 
harmful effects in both the mother and unborn babies, including abnormal formation of the bones. 
It is not known whether baricitinib passes into the breast milk of humans, or if it is harmful to a 
child who is breastfeeding.  If you are a woman who can become pregnant, or are the partner of a 
woman who can become pregnant, you will need to practice abstinence or two effective forms of 
birth control before starting study treatment, during study treatment, and for at least one week after 
you finish study treatment. If you think that you or your partner is pregnant, you should tell your 
study doctor or nurse at once.
In addition, if you are a male, you should not donate sperm during the study, and for at least one 
week after you finish study treatment.
Effective forms of birth control include:

intrauterine device (IUD)

hormonal [birth control pills, injections, or implants]

tubal ligation

vasectomy
Risks or Discomforts of Participation
The baricitinib used in this study may affect how different parts of your body work such as your 
liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you know 
if changes occur that may affect your health.
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, or some may never go 
away.

Some side effects may interfere with your ability to have children.

Some side effects may be serious.
Here are important points about how you and the study doctor can make side effects less of a 
problem:

Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect.

The study doctor may be able to treat some side effects.

The study doctor may adjust the study drugs to try to reduce side effects.
IRB NUMBER: 16C0094
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PATIENT IDENTIFICATION
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Risks of baricitinib
Baricitinib is a molecule that blocks the effects of proteins in the body called Janus kinases. 
Blocking these proteins can affect the immune system. One effect may be an improvement in 
inflammatory and autoimmune diseases such as rheumatoid arthritis, psoriasis, systemic lupus 
erythematous (lupus), atopic dermatitis, or diabetic kidney disease. Drugs that affect the immune 
system can increase the risk of infection and cancer. Baricitinib may also increase these risks.
This section describes possible risks seen with baricitinib. It also describes other notable events 
associated with baricitinib. Event rates for bad effects are based on safety data from 1,142 people 
with RA who took baricitinib. Not enough safety data are available from people with other diseases 
to calculate reliable event rates. However, the type and severity of their events were similar to 
those seen in the people with rheumatoid arthritis.
Baricitinib is removed from the body by the kidneys. People with reduced kidney function do not 
remove baricitinib as quickly as those with normal kidney function. People with reduced kidney 
function may require a lower dose of baricitinib.
The bad effects we know about so far are listed below. You could have some, all, or none.
Very Common
(10% or greater)
Common
(1 to less than 10%)
Uncommon
(0.1 to less than 1%)
Cough, stuffy or runny 
nose, scratchy or sore 
throat, sneezing
Higher amounts of 
cholesterol in the blood
Upper respiratory tract 
infections
Small changes in blood 
tests related to the liver
Higher number of blood 
platelets (parts of the blood 
that aid in clotting)
Cold sores and shingles
Nausea, abdominal pain
Headache
Acne
Urinary tract infection
Viral infection
Cancers of the skin, blood 
cells, lung, prostate, breast, 
uterus, ovary, kidney, and 
colon
Changes in blood test 
related to muscle
Clots in the blood vessels 
of the legs, which may 
dislodge and travel to the 
lungs
Lower number of white 
blood cells, including 
special types of white 
blood cells (blood cells that 
fight infections)
Higher amounts of fat in 
the blood
Weight gain
Heart attack
Stroke
Death
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Additional study drug risks:
A large, randomized trial of tofacitinib (a drug similar to baricitinib) in patients with rheumatoid 
arthritis detected a higher risk of heart attack, stroke, cancer and blood clots and death when 
compared to standard therapy with anti-inflammation drugs. Based on these studies, in September 
2021 the FDA extended this warning to baricitinib and another protein inhibitor drug used in 
arthritis. This warning has not been extended to similar drugs used for cancer (or GVHD).
Risks of blood collection
Taking blood may cause some discomfort, bleeding or bruising where the needle enters the body, 
and in rare cases, it may result in fainting. There is a small risk of infection. Some people have not 
felt well when having their blood taken. Some people have felt dizzy while having their blood 
drawn or after. Let the nurse know if you would prefer to lie down while you have your blood 
drawn.
Risks of skin and oral biopsies
Skin and oral punch biopsies may be associated with temporary bleeding, bruising and/or infection 
at the collection site and discomfort. Local anesthesia will be used to decrease the risk of 
discomfort.
Risks of Pulmonary Function Tests (PFTs)
PFTs are safe for most participants; however, some may experience dizziness, shortness of breath 
and fainting. In rare PFTs may lead to a collapsed lung. In participants with asthma, PFTs may 
precipitate an asthma attack. 
Risks of ECG and echocardiogram 
Other than possibly experiencing some minor skin irritation from the electrodes there are no 
anticipated risks related to complete the electrocardiogram and/or the echocardiogram.
Risks of Questionnaires
The potential risk of questionnaires include questions that may be sensitive in nature. 
Potential Benefits of Participation
The aim of this study is to see if this experimental treatment will cause your cGVHD symptoms to 
improve. We do not know if you will receive personal medical benefits from taking part in this 
study. Ptential benefits could include the lessening of your symptoms that are caused by the 
cGVHD. Because there is not much information about the drug’s effect on your cGVHD, we do 
not know if you will benefit from taking part in this study, although the knowledge gained from 
this study may help others in the future who have cancer.
REMOTE ASSESSMENTS
In the first quarter of 2020, a pandemic was announced for COVID-19 (Coronavirus Disease 2019) 
which is caused by the virus SARS-CoV-2. In light of the pandemic, tele-medicine has been used 
as an alternative way to perform assessments without having participants in clinical trials come to 
the clinic. Your study doctor may determine that the risks associated with you visiting the clinic 
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PATIENT IDENTIFICATION
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
during the COVID-19 pandemic may outweigh the benefit from seeing you in person at the clinic. 
Remote assessments may be performed at the discretion of your study doctor via phone, email, or 
video chat to speak with you directly about the following: patient history, verbal exam, symptom 
reporting, education, and questionnaires. 
ALTERNATIVE APPROACHES OR TREATMENTS
What other choices do I have if I do not take part in this study?
Instead of being in this study, you have these options:

Getting treatment or care for your cGVHD without being in a study

Taking part in another study

Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cGVHD. It does not treat 
the cGVHD directly. Instead, it tries to improve how you feel. Comfort care tries to keep 
you as active and comfortable as possible.
Please talk to your doctor about these and other options.
STOPPING THERAPY
Your doctor may decide to stop your therapy for the following reasons:

You complete study therapy as outlined above (6 months or 12 months total)

if he/she believes that it is in your best interest

if your cGVHD gets worse during treatment even at the highest study dose that you can 
tolerate

if you have side effects from the treatment that your doctor thinks are too severe

if your treatment is interrupted for more than 28 days

if you become pregnant

if new information shows that another treatment would be better for you
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Eli Lily and Company or 
designated representatives. If you withdraw your consent and leave the trial, any samples of yours 
that have been obtained for the study and stored at the NCI can be destroyed upon request. 
However, any samples and data generated from the samples that have already been distributed to 
other researchers or placed in the research databases cannot be recalled and destroyed.
CONFLICT OF INTEREST
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a Protocol Review Guide.  You may ask your research team 
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
for a copy of the Protocol Review Guide or for more information. Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study. This is allowed under federal rules and is not a 
conflict of interest.
The National Institutes of Health and the research team for this study are using a drug developed 
by Eli Lily and Company through a joint study with your researchers and the company. The 
company also provides financial support for this study.
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying human 
samples. They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved. Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses. These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for research 
purposes. Your specimens and data will be used for research purposes only and will not benefit 
you. It is also possible that the stored specimens and data may never be used.
Results of research done on your specimens and data will not be available to you or your doctor. 
It might help people who have cancer and other diseases in the future.
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data. Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
PAYMENT
Will you receive any type of payment for taking part in this study?
You will not receive any payment for taking part in this study. 
REIMBURSEMENT
Will you receive reimbursement or direct payment by NIH as part of your participation?
On this study, the NCI will reimburse the cost for some of your expenses such as those for hotel, 
travel, meals.  Some of these costs may be paid directly by the NIH and some may be reimbursed 
after you have paid. The amount and form of these payments are determined by the NCI Travel 
and Lodging Reimbursement Policy.  You will be given a summary of the policy which provides 
more information.
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
If your travel to the NIH Clinical Center (e.g. flight, hotel) is arranged and paid for by the NIH, 
the agency making the reservations and their representatives will have access to your identifiable 
information.
COSTS
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the NIH Clinical Center, you may have 
to pay for these costs if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be provided 
by the NIH Clinical Center.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private?
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor (Center for Cancer Research) or their agent(s)

Qualified representatives from Eli Lilly and Compant, the pharmaceutical company who 
produces Baricitinib.
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.    
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
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IRB APPROVAL DATE: 02/18/2022


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File in Section 4: Protocol Consent (1)
Version Date: 02/15/2022
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
IRB NUMBER: 16C0094
IRB APPROVAL DATE: 02/18/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Steven 
Pavletic, MD, 240-760-6174, pavletis@mail.nih.gov. You may also call the NIH Clinical Center 
Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if 
you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 16C0094
IRB APPROVAL DATE: 02/18/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/15/2022
Page 13 of 13
CC pre rCR ICF template v. 12.01.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either:
1. A short form consent process has been used to enroll a non-English speaking subject or
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Signature of Witness
Print Name of Witness
Date
NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 16C0094
IRB APPROVAL DATE: 02/18/2022