Clinical trial NCT03616184
Conditions: Graft-versus-host-disease (GVHD)
Sponsor: University of Nebraska
Start date: 2018-09-05; Completion date: 2023-06-12
Enrollment: 49 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study is to examine the efficacy of ruxolitinib in patients with sclerotic chronic graft-versus-host disease (GVHD).

Detailed description:
Chronic graft-versus-host-disease (GVHD) is a major complication of allogeneic hematopoietic cell transplant that impairs quality of life, and is associated with significant morbidity and mortality. Management of chronic GVHD with prednisone is associated with an overall response rate of approximately 60%, and a complete response rate of approximately 30% but sclerotic features do not respond as well. Based on the biology of chronic GVHD and available preliminary evidence, the investigators hypothesize that ruxolitinib will be effective in the management of sclerotic chronic GVHD. The study is an open label, phase II multicenter trial designed to evaluate the efficacy of ruxolitinib as a salvage treatment for patients with sclerotic GVHD (sclerosis or fasciitis). The primary objective is to determine the proportion of patients with response rate (complete and partial responses) in skin and/or joint, as determined by 2014 NIH (National Institutes of Health) consensus criteria, at 6 months of therapy with ruxolitinib. Eligibility criteria includes adult patients with chronic GVHD and skin, joint and/or fascia sclerosis, who have received systemic corticosteroids for \>12 months and at least one additional line of therapy OR systemic corticosteroids and at least two additional lines of therapy for chronic GVHD. A sample size of 47 patients (43 evaluable patients and estimated 10% dropout) will allow an α of 0.044 and a power of 84% to test the null hypothesis response rate of 25% compared to an alternative of 45%. Subjects will receive ruxolitinib for 6 months for the treatment of sclerotic chronic GVHD. Subjects will be evaluated for GVHD status as well as non-relapse mortality, relapse of underlying malignancy and quality of life/functional status. Plasma cytokine levels and T/Natural Killer (NK) cell subset in peripheral blood will be measured at various time points. The response rate will be reported as a proportion and 95% exact confidence interval. If positive, the trial results will support other ongoing studies to establish the role of ruxolitinib in chronic GVHD in general and specifically in sclerotic chronic GVHD.

Arms: arm 1: Patients will receive oral ruxolitinib at a dose of 10 mg twice daily.
Interventions: intervention 1: Ruxolitinib
Intervention descriptions: intervention 1: Patients with sclerotic chronic graft-versus-host disease (GVHD) will receive oral ruxolitinib at a dose of 10 mg twice daily. Doses may not exceed 10 mg twice daily. Ruxolitinib will be continued for 6 months. Patients who continue to have stable disease, mixed responses or partial/complete responses at the end of 6 months may continue the drug for a total of 12 months.

Protocol documents:
Prot_SAP_001.pdf: 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Title: A Single Arm, Open Label, Phase II Study of Ruxolitinib in Sclerotic Chronic Graft-
Versus-Host Disease after Failure of Systemic Glucocorticoids   
Principal Investigator:  
 
Vijaya Raj Bhatt, MBBS 
 
 
 
 
 
Associate Professor of Medicine 
 
 
 
 
 
986840 Nebraska Medical Center 
 
 
 
 
  
Omaha, Ne 68198-6840 
 
 
Co-Principal Investigator: 
 
Stephanie J. Lee, MD, MPH 
 
Clinical Research Division,  
 
Fred Hutchinson Cancer Research Center 
 
Seattle, Washington 
 
 
UNMC Secondary Investigators: 
 
Lori Maness-Harris, MD 
 
 
 
 
 
 
Krishna Gundabolu, MBBS 
 
Zaid Al-Kadhimi, MD 
 
 
 
 
 
 
 
Multi-site Participation: 
 
 
Fred Hutchinson Cancer Research Center 
 
Moffitt Cancer Center 
 
Ohio State University Comprehensive Cancer Center 
 
Cleveland Clinic Cancer Center 
 
 
IND Number: 
138661 
Clinical Trials.gov # 
NCT03616184 
NCI-CTRP #: 
NCI-2018-01299 
 
 
BioStatistician: 
 
 
 
Lynette M. Smith, PhD 
 
 
Study Drug: 
 
 
 
 
Incyte Protocol Reference Number: 
Ruxolitinib 
 
I-RUX-17-69 
 
 
Protocol Version: 
 
 
Version 1.3, Dated 15 June 2018 
Version 1.4, Dated 20 March 2019 
Version 1.5, Dated 06 March 2020 
Version 1.6, Dated 25 January 2021 
 
 
 


UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Abstract ......................................................................................................................................................... 3 
Study Schema................................................................................................................................................ 4 
Section 1.0 Objectives .................................................................................................................................. 5 
Section 2.0 Introduction ................................................................................................................................ 6 
Section 3.0 Eligibility Criteria .................................................................................................................... 12 
Section 4.0 Registration Procedure ............................................................................................................. 14 
Section 5.0 Treatment Plan ......................................................................................................................... 15 
Section 6.0 Measurement of Effect ............................................................................................................. 24 
Section 7.0 Study Parameters (also see section 5.5) ................................................................................... 25 
Section 8.0 Drug Formulation and Procurement......................................................................................... 26 
Section 9.0 Toxicity and Adverse Event Reporting Guidelines ................................................................. 30 
Section 10.0 Statistical Considerations ....................................................................................................... 35 
Section 11.0 Records to be Kept ................................................................................................................. 39 
Section 12.0 Subject Consent...................................................................................................................... 40 
Section 13.0 References .............................................................................................................................. 42 
Section 14.0 Data Collection Forms ........................................................................................................... 45 
Appendix A: Manifestations of chronic graft-versus-host disease ............................................................. 46 
Appendix B: Organ scoring of chronic graft-versus-host disease per 2014 NIH consensus ...................... 48 
Appendix C: NIH Global Severity of chronic GVHD ................................................................................ 51 
Appendix D: Lee Symptom Scale ............................................................................................................... 52 
Appendix E: Modified Scleroderma Health Assessment Questionnaire (SHAQ) ...................................... 54 
Appendix F: Eligibility Checklist ............................................................................................................... 56 
Appendix G: Response Determination for Chronic GVHD Clinical Trials based on Clinician Assessments
 .................................................................................................................................................................... 59 
Appendix H: NCI Common Toxicity Criteria Version 4.03 (CTCAE), Active Date: June 14, 2010 ......... 60 
Appendix I: Tool for Body Mapping .......................................................................................................... 61 
Appendix J:  Dosing Diary ......................................................................................................................... 62 


UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Abstract  
Title: A Single Arm, Open Label, Phase II Study of Ruxolitinib in Sclerotic Chronic Graft-
Versus-Host Disease after Failure of Systemic Glucocorticoids 
Chronic graft-versus-host-disease (GVHD) is a major complication of allogeneic hematopoietic 
cell transplant that impairs quality of life, and is associated with significant morbidity and 
mortality. Management of chronic GVHD with prednisone is associated with an overall response 
rate of approximately 60%, and a complete response rate of approximately 30% but sclerotic 
features do not respond as well. Based on the biology of chronic GVHD and available 
preliminary evidence, we hypothesize that ruxolitinib will be effective in the management of 
sclerotic chronic GVHD. The study is an open label, phase II multicenter trial designed to 
evaluate the efficacy of ruxolitinib as a salvage treatment for subjects with sclerotic GVHD 
(sclerosis or fasciitis). The primary objective is to determine the proportion of subjects with 
response rate (complete and partial responses) in skin and/or joint, as determined by 2014 NIH 
consensus criteria, at 6 months of therapy with ruxolitinib.  Eligibility criteria includes adult 
subjects with chronic GVHD and skin, joint and/or fascia sclerosis, who have received systemic 
corticosteroids for >12 months and at least one additional line of therapy OR systemic 
corticosteroids and at least two additional lines of therapy for chronic GVHD. A sample size of 
47 subjects dosed (42 evaluable subjects and estimated 10% dropout) will allow an α of 0.044 
and a power of 84% to test the null hypothesis response rate of 25% compared to an alternative 
of 45%. Subjects will receive ruxolitinib for 6 months for the treatment of sclerotic chronic 
GVHD. Subjects will be evaluated for GVHD status as well as non-relapse mortality, relapse of 
underlying malignancy and quality of life/functional status. Plasma cytokine levels and T/NK 
cell subset in peripheral blood will be measured at various time points. The response rate will be 
reported as a proportion and 95% exact confidence interval. If positive, the trial results will 
support other ongoing studies to establish the role of ruxolitinib in chronic GVHD in general and 
specifically in sclerotic chronic GVHD. 
 
 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
Ruxolitinib therapy for 6 months 
Assess for graft-versus-host-disease status, non-relapse mortality, relapse of 
underlying malignancy and quality of life/functional status 
Patients with chronic graft-versus-host-disease and skin, joint and/or fascia sclerosis, 
who have received systemic corticosteroids for >12 months and at least one additional 
line of therapy OR systemic corticosteroids and at least two additional lines of therapy 
Informed consent and registration 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Section 1.0 Objectives  
1.1 
Primary Objective 
The primary objective of the study is to examine the efficacy of ruxolitinib in subjects with 
sclerotic chronic graft-versus-host disease (GVHD).   
Efficacy will be assessed by: 
• Determining the proportion of subjects with complete and partial responses in skin and/or 
joint, as determined by 2014 NIH Criteria (1), at 6 months of therapy.  
1.2 
Secondary Objective 
To determine the proportion of subjects with complete or partial responses overall, as determined 
by 2014 NIH Criteria (1), at 6 months of therapy. 
1.3 
Exploratory Objectives  
The exploratory objectives are to assess the following: 
1. Treatment failure (treatment failure defined as: administration of additional systemic 
therapy for chronic GVHD, malignancy relapse or mortality) by 6 months from study 
enrollment 
2. Non-relapse mortality  by 6 months 
3. Change in patient-reported outcomes: skin subscale and summary score of the Lee 
Chronic GVHD Symptom Scale, and Scleroderma Health Assessment Questionnaire 
between enrollment and 6 months  
4. Response rate in skin/joint and overall at 12 months, for subjects treated on the extension 
study  
5. Proportion who reduce prednisone (or prednisone equivalent) dose by 50% from baseline 
to 6 months 
1.4 
Correlative Objectives 
1. Determine the association between responses at 6 months and the changes in the plasma 
levels of various proteins and cytokines (ST2, SPON1, CXCR3, CXCL10, IFN gamma, 
soluble IL-2R, IL-2, IL-4, IL-5, IL-6, IL-12, TNF-α, TRAIL/TNSFSF10/7; profibrotic 
cytokines such as IL-1β and TGF-β) from baseline to 3 and 6 months.   
2. Determine the correlation between responses at 6 months and changes in the percentage 
of peripheral blood T/NK-cell population (CD3-CD56+) [Treg(FoxP3+), effector T cell 
(CD8+T cell, CD4+ TH1, TH2 and TH17 cells), CD3+, CD4-CD25+, Gr-1, Ter-119, and 
Antigen presenting cells (APC) APC-CD80+] from baseline to 3 and 6 months.  
 
 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Section 2.0 Introduction  
Chronic graft versus host disease 
Chronic graft-versus-host disease (GVHD) is a major late complication of allogeneic 
hematopoietic cell transplantation (HCT) that affects up to 70% of HCT survivors. The 
syndrome is associated with major transplant-related morbidity, mortality, infectious 
complications, prolonged duration of immune suppression, and impaired patient-reported quality 
of life (2-9). Thus, it represents a major obstacle to recovery and survival following HCT, and its 
prevention and treatment are of significant importance. The syndrome is characterized by diverse 
clinical manifestations, but the most commonly affected organs are the skin, eyes, mouth, and 
liver.  
Sclerotic GVHD is a distinctive phenotype of chronic GVHD that usually begins in superficial 
layers of the skin and then extends to deeper layers. Sclerotic GVHD can severely affect 
patients’ mobility and quality of life, and it is often refractory to standard and secondary 
therapies. The presence of sclerosis after allogeneic HCT is considered diagnostic for chronic 
GVHD (10). Progressive or poorly controlled sclerotic GVHD results in joint contractures, 
chronic skin ulcers and pulmonary restriction causing major disability. In a large study from Fred 
Hutchinson Cancer Research Center and Seattle Cancer Care Alliance, the cumulative incidence 
of sclerosis was 20% at 3 years. Of the patients who developed sclerosis, 13% had only skin 
sclerosis, 33% had only joint contracture or fasciitis, and 53% had both clinical manifestations. 
The development of sclerosis was associated with a reduced rate of withdrawal of 
immunosuppressive treatment (11). These findings as well as our own experience indicate that 
patients with sclerotic chronic GVHD have poor quality of life, often require multiple sequential 
therapies and frequently exhaust available treatment options (12-15).  
Diagnosis and staging of chronic GVHD  
Diagnosis, classification and staging of chronic GVHD are based on the 2014 NIH Consensus 
Conference on Chronic GVHD (10). According to the historical classification, acute and chronic 
GVHD were distinguished by the occurrence of manifestations before or following day 100 post-
HCT. According to the 2014 NIH Consensus definitions, the diagnosis of chronic GVHD is 
based on the presence of diagnostic manifestations of the syndrome, rather than the time of onset 
following HCT. Two subtypes of chronic GVHD exist, namely classic chronic GVHD and 
overlap syndrome. Classic chronic GVHD is defined by the definitive manifestations of the 
syndrome in the absence of concurrent acute GVHD manifestations (Appendix A). Presence of 
both chronic and acute GVHD manifestations defines the overlap subtype of chronic GVHD 
(10). Chronic GVHD severity is scored according to objective criteria for each organ involved 
(Appendix B), which is summarized for an overall global severity score of mild, moderate, or 
severe (Appendix C) (10).  
Therapy of established chronic GVHD 
Accepted standard primary therapy for chronic GVHD includes 1 mg/kg or greater of prednisone 
(or prednisone equivalent) with or without a calcineurin inhibitor (3, 16). The addition of other 
systemic immune-suppressive agents to initial therapy has not provided benefit, as evidenced by 
trials adding azathioprine, thalidomide, hydroxychloroquine or mycophenolate mofetil to initial 
treatment with steroids(17). Published primary chronic GVHD therapy trials demonstrate that on 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
average 30% will achieve complete response, and 60% will achieve overall response (complete + 
partial response) by 6-9 months after starting initial therapy(16-21). However, sclerotic features 
do not respond as well. Consequently, most patients with chronic GVHD require salvage 
therapies, which are frequently ineffective in sclerotic chronic GVHD (12-15).  
Based on insufficient response to primary therapy or a flare of chronic GVHD after tapering of 
initial therapy, many will go on to require additional immune-suppressive agents for chronic 
GVHD control.  
Steroid-refractory chronic GVHD (22) is defined when: 
“Manifestations progress despite the use of a regimen containing prednisone at ≥1 mg/kg/day for 
at least 1 week or persist without improvement despite continued treatment with prednisone 
at ≥0.5 mg/kg/day or 1 mg/kg every other day for at least 4 weeks.” 
Such a definition is less relevant to eligibility criteria for trials beyond second-line treatment, 
because the decision to start second-line treatment has already been made (22).  
In addition to steroid-refractoriness, other clinical indications for additional lines of systemic 
immune suppressive therapy include steroid dependence and steroid intolerance. Patients with 
steroid-dependent chronic GVHD cannot tolerate tapering prednisone due to recurrent chronic 
GVHD manifestations. Steroid-dependent chronic GVHD (22) is defined when: 
“Prednisone doses >0.25 mg/kg/day or >0.5 mg/kg every other day are needed to prevent 
recurrence or progression of manifestations as demonstrated by unsuccessful attempts to taper 
the dose to lower levels on at least 2 occasions, separated by at least 8 weeks.” 
Steroid intolerant patients have medical complications of steroid therapy (e.g., hyperglycemia, 
psychosis, osteoporosis), and thus require additional immune-suppressive agents to control 
GVHD and facilitate taper of prednisone. Multiple immune-suppressive therapies, including 
pharmacologic agents, monoclonal antibodies, and strategies such as extracorporeal 
photopheresis have demonstrated moderate activity in this setting, both ameliorating objective 
chronic GVHD manifestations, as well as facilitating taper of systemic steroids (reviewed in 
detail in the report of the Consensus Conference on Clinical Practice in Chronic GVHD) (23). 
Their effectiveness is suboptimal, however, and many patients will require multiple agents to 
achieve disease control or stabilization. For example, imatinib and rituximab are two commonly 
utilized therapies for sclerotic chronic GVHD. A randomized phase II trial of imatinib versus 
rituximab for steroid refractory cutaneous sclerosis conducted at 11 institutions within the 
Chronic GVHD Consortium demonstrated a significant clinical response rate of 26-27% (15). 
The overall burden of chronic GVHD despite routine pharmacologic GVHD prophylaxis, limited 
response to primary and secondary therapies, and the attendant morbidity and mortality all 
support the need for novel approaches in chronic GVHD treatment. 
In August 2017, the Food and Drug Administration approved ibrutinib for management of 
chronic GVHD after failure of one or more treatments. Ibrutinib is the first therapy to receive 
FDA approval for the treatment of chronic GVHD. The approval was based on a multicenter 
single-arm trial of 42 patients with chronic GVHD with inadequate response to corticosteroid 
(24). The best overall response was 67% at a median follow-up of 13.9 months. A total of 34 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
patients had skin involvement, and 88% of these patients had a response. Details regarding the 
number of patients with skin sclerosis, fasciitis or joint contractures, and responses in these 
patients are unavailable. Adverse events including infectious complications (69%, grade ≥3 
events 36%) were common and led to treatment discontinuation in 33% of patients. No major 
hemorrhage event was observed, and grade 3 atrial fibrillation was reported in 1 patient in this 
study (24). Nonetheless, the use of ibrutinib can be associated with a significant risk of 
complications in some patients including but not limited to those with cardiac arrhythmias, 
history of major bleeding, or those requiring anticoagulation or antiplatelet agents (25). Hence, 
the use of ibrutinib may not be appropriate in some patients. 
Patient-Reported Outcomes 
Chronic GVHD can severely affect patients’ quality of life (1). Progressive or poorly controlled 
sclerotic GVHD can also result in joint contractures, chronic skin ulcers and pulmonary 
restriction causing major disability (11). Sclerotic GVHD is difficult to assess; responses are 
slow, and potentially reversible active sclerotic manifestations are not easily distinguished from 
fixed, irreversible deficits. Hence, patient-reported quality of life measures can provide valuable 
insight regarding the impact of chronic GVHD, and changes in quality of life in response to 
therapy. Such patient-reported outcome measures can augment but not replace objective changes 
in chronic GVHD activity (1). 
Lee Chronic GVHD Symptom Scale (26) (Appendix D), recommended by the 2014 NIH 
Consensus conference (1), will be utilized as measures of patient-reported outcomes in this 
study. The Lee Chronic GVHD Symptom Scale (26) provides a global assessment of the burden 
of a symptom resulting from varying intensity of the symptom, its frequency, and its emotional 
and functional impact. Additionally, Scleroderma Health Assessment Questionnaire (Appendix 
E) will be used (27, 28). There are no validated functional or quality of life measures specifically 
for patients with sclerotic GVHD. The Scleroderma Health Assessment Questionnaire, a 
validated self-reported functional status measure in scleroderma, will therefore be utilized given 
the similarity between sclerotic GVHD and scleroderma. An improvement (decrease) in the 
SHAQ score by ≥0.2 is considered clinically meaningful (15, 27, 29). 
Biomarkers in chronic GVHD 
The 2014 NIH Biomarker Working Group Report states that the development of diagnostic and 
predictive biomarkers is critically necessary and represents the areas of high priority in chronic 
GVHD (30). In this study, we will measure the percentage of peripheral blood T/NK-cell 
population and the plasma levels of various proteins and cytokines (ST2, SPON1, CXCL10, IFN 
gamma, soluble IL-2R, IL-2, IL-6, TNF-α; profibrotic cytokines such as IL-1β and TGF-β) at 
various time points. Such assessments may allow identification of predictive biomarkers and 
provide insights into the biology of sclerotic chronic GVHD, and the pharmacodynamic effect of 
ruxolitinib in sclerotic chronic GVHD.  
In a murine model, ruxolitinib reduced proliferation of effector T cells and suppression of 
proinflammatory cytokine production (such as TNF-alpha and IL-12p70). Further, differentiation 
of CD4+T cells into IFN-gamma and IL17A-producing T-cells (implicated in GVHD) was 
impaired (31). In patients with steroid refractory acute and chronic GVHD, responses correlated 
with an increase in FoxP3+ regulatory T cells, as well as a reduction in the serum levels of IL-6 
and soluble IL-2 receptor (31). Zeiser et al demonstrated a decline in CD3+HLA-DR+ cells, IL-6 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
and soluble IL-2R in peripheral blood after ruxolitinib treatment (32). In myelofibrosis, the use 
of ruxolitinib was associated with suppression of proinflammatory cytokines such as IL-6, and 
TNF-alpha (33). Hence, the changes in T-cell subsets and cytokine levels correlate with GVHD 
activity and are associated with responses to ruxolitinib. 
Although the pathogenesis of chronic GVHD is complex and still incompletely understood, 
various T/NK-cell subsets play an important role in various phases of the development of chronic 
GVHD (34). T/NK-cell subsets such as CD8+T cells and NK-cells are the main effector 
populations in the adaptive immune system responsible for chronic GVHD. Regulatory 
populations such as Tregs provide compensatory inhibition to limit chronic inflammation and 
tissue injury. The relative predominance of effector or regulatory cells determine whether 
chronic GVHD is active or absent. Other T-cell subsets such as TH2 and TH17 cells are 
considered pro-fibrotic and may contribute to fibrosis (34). Whereas many cytokines are 
implicated in sclerosis and dampened by ruxolitinib (31), two-protein biomarkers (Spondin-1, 
ST2) may correlate with longitudinal changes in sclerosis (35). CXCL10 is elevated in sclerosis, 
and levels may correlate with clinical worsening or responses (36). This molecular underpinning 
provides the rationale for the proposed tests in this trial. 
Ruxolitinib 
Detailed information is available in the attached investigator brochure.  
Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) represents a novel, potent, 
and selective inhibitor of JAK1 (Janus kinase 1) (inhibition concentration 50% 
[IC50]=3.3 ± 1.2 nM) and JAK2 (IC50=2.8 ± 1.2 nM) with modest to marked selectivity against 
TYK2 (tyrosine kinase 2) (IC50=19 ± 3.2 nM) and JAK3 (IC50=428 ± 243 nM), respectively. 
Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are 
important for hematopoiesis and immune function. 
JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) 
to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to 
modulation of gene expression. Dysregulation of the JAK/STAT pathway has been associated 
with several types of cancer and increased proliferation and survival of malignant cells. In 
particular, this pathway may be dysregulated in the majority of patients with Philadelphia 
chromosome-negative myeloproliferative neoplasms (MPNs, including myelofibrosis (MF) and 
polycythemia vera (PV), suggesting that JAK inhibition may be efficacious in these diseases. 
Ruxolitinib is currently under development for the treatment of MF, PV, essential 
thrombocytopenia (ET), GVHD and other hematologic malignancies and has been granted 
Marketing Authorization Approval for the treatment of MF and PV. 
Summary of clinical efficacy data 
The results from two Phase III studies in myelofibrosis (COMFORT-I, COMFORT-II) 
demonstrate the effectiveness of ruxolitinib in patients with primary myelofibrosis (PMF), post-
polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis 
(PET-MF). The results of these two studies were consistent, demonstrating statistically 
significant (p<0.0001) improvement in rates of ≥35% spleen volume reduction compared with 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
either placebo or an investigator’s selection of best available therapy (BAT). Ruxolitinib was 
associated with prolonged survival compared with placebo (COMFORT-I) and best available 
therapy (COMFORT-II). 
Consistent with its activity in myelofibrosis, ruxolitinib demonstrated efficacy in a related 
myeloproliferative neoplasm, polycythemia vera in the RESPONSE and RESPONSE-2 studies. 
A significantly greater proportion of patients who were randomized to ruxolitinib met the 
primary endpoint of the RESPONSE study, which was a composite endpoint of hematocrit 
control in the absence of phlebotomy and spleen volume reduction ≥35% when compared to 
patients randomized to BAT (22.7% vs. 0.9%, p<0.0001). Of the patients meeting the primary 
endpoint at Week 32, 88% maintained their response at Week 48, and 80% maintained their 
response for at least 48 weeks from initial response. The efficacy analyses at Week 80 data 
cutoff (03-Sept 2014) for the RESPONSE study confirmed the durability of the responses in the 
patients randomized to ruxolitinib arm. The RESPONSE-2 study met its primary endpoint and 
the findings of this study indicate that ruxolitinib could be considered a standard of care for 
second-line therapy in this post-hydroxyurea patient population. 
Summary of clinical safety data 
In the randomized period of the two pivotal studies in MF, COMFORT-I and COMFORT-II 
(cut-off 01-Mar-2011, median duration of exposure = 10.8 months) discontinuation due to 
adverse events, regardless of causality was observed in 11.3% of patients. The most frequently 
reported adverse drug reactions were thrombocytopenia and anemia. Hematological adverse 
reactions (any CTCAE Grade) included anemia (82.4%), thrombocytopenia (69.8%) and 
neutropenia (16.6%). Anemia, thrombocytopenia and neutropenia are dose-related effects. The 
three most frequent non-hematological adverse reactions were bruising (21.6%), dizziness 
(15.3%) and headache (14.0%). The three most frequent non-hematological laboratory 
abnormalities were raised alanine aminotransferase (ALT) (27.2%), raised aspartate 
aminotransferase (AST) (18.6%) and hypercholesterolemia (16.9%). 
Long-term follow-up in patients with MF (including 615 patients treated with ruxolitinib during 
the controlled and extension phases of studies INCB 18424-251: cut-off 01-Oct-2012. 
COMFORT-I: 15-Oct-2015; COMFORT-II: 20-Apr-2015) has shown that as expected, the 
numbers and proportions of AEs and SAEs has increased. However, no new safety signals have 
emerged (median duration of exposure for this population is 28.78 months, with 1578.45 patient-
years of exposure). 
Study INCB 18424-258 established 5 mg b.i.d. as a safe starting dose in patients with PMF, 
PPVMF, and PET-MF, with a platelet count between 50 and 100 × 109/L. 
Study INCB 18424-261 showed that 10 mg b.i.d was an effective starting dose by providing 
symptomatic benefit and reducing palpable spleen length in the majority of subjects while having 
less of an impact on hematologic parameters than seen in the pivotal Phase III studies. 
Up to Week 32 of the randomized phase in the RESPONSE trial (median duration of exposure 
was 7.8 months), ruxolitinib was generally well tolerated in patients with PV and only a small 
proportion of patients discontinued ruxolitinib due to AEs (6.4%). Most of the AEs have been 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
managed by dose adjustments and/or supportive care. Hematological toxicities were less frequent 
and less severe in patients with PV as compared to those observed in patients with MF. Analysis 
of Week 80 data did not identify any new safety findings.  
The AE profile of the compound has been assessed in more than 370 healthy volunteers, subjects 
with various degrees of renal (n=32) or hepatic (n=24) impairment, and in patients with RA 
(n=59) receiving ruxolitinib: AEs were, in general, mild and resolved without interventions. 
A thorough QT study was conducted in 50 healthy subjects. There was no indication of a 
QT/QTc prolonging effect of ruxolitinib in single doses up to a supra-therapeutic dose of 200 mg 
indicating that ruxolitinib has no effect on cardiac repolarization. 
Rationale for using ruxolitinib in graft-versus-host disease 
A study in MHC-mismatched mouse transplant model has demonstrated that interferon (IFN)-
gamma receptor signaling via induction of chemokine receptor CXCR3 alters alloreactive T-cell 
trafficking to GVHD target organs and reduces GVHD (37). The same study also highlighted 
that pharmacologic inhibition of IFN-gamma receptor signaling with ruxolitinib reduces GVHD 
and improves survival after allogeneic HCT (37). Subsequent studies in murine models 
confirmed that the use of ruxolitinib mitigated GVHD (31, 38, 39) while preserving graft-versus-
leukemia effect (38, 39). In a murine model, ruxolitinib also reduced proliferation of effector T 
cells and suppression of proinflammatory cytokine production (such as TNF-alpha and IL-
12p70). Further, differentiation of CD4+T cells into IFN-gamma and IL17A-producing T-cells 
(implicated in GVHD) was impaired (31). 
Subsequent studies have provided evidence of clinical efficacy and safety of ruxolitinib in 
patients with steroid refractory acute and chronic GVHD including patients with cutaneous and 
musculoskeletal chronic GVHD (31, 32, 40). Spoerl et al. demonstrated responses in 6 patients 
with steroid refractory acute and chronic GVHD (31). In a retrospective multicenter study (n=95) 
(32), ruxolitinib at a dose of 5–10 mg orally twice daily was studied as a salvage therapy for 
steroid refractory grade III/IV acute (n=54) or moderate or severe chronic (n=41) GVHD. 
Patients with chronic GVHD were heavily pre-treated with a median of 3 (range 1-10) prior 
therapies. Patients were followed for a median of 22 (3–135) weeks. Ruxolitinib resulted in an 
overall response rate of 85% with a rate of GVHD-relapse of 5.7% in responding patients, and 6-
month survival of 97%. The median time from initiation of ruxolitinib to response was 3 (1–25) 
weeks. Cytopenia and CMV reactivation was observed in 17% and 15% of patients. Cytopenias 
preceded the use of ruxolitinib in most of the patients (15%). CMV reactivation responded to 
antiviral therapy. Relapse of underlying malignancy was reported in 2.4% of patients (32). 
Additional follow-up of these patients have demonstrated a one-year survival of 92.7%. 
Approximately, 24% of patients have an ongoing response and are free of any 
immunosuppression, whereas 86% of patients (n=13) with GVHD relapse or progression 
responded to retreatment with ruxolitinib or any immunosuppressive therapy (41). These results 
provide preliminary evidence of the safety and efficacy of ruxolitinib in chronic GVHD patients. 
Study Design and Rationale 
The study is an open label, phase II multicenter trial designed to evaluate ruxolitinib as a salvage 
treatment for patients with sclerotic GVHD (sclerosis or fasciitis). Previous trials (12-15) and our 
own experiences have demonstrated that patients with sclerotic chronic GVHD have poor quality 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
of life, often require multiple sequential therapies and are among the most likely group of 
patients to be enrolled in clinical trials because they have exhausted other treatment options. 
Preliminary evidence indicates that ruxolitinib may be effective in previously treated patients 
with sclerotic chronic GVHD (31, 32). In this context, the overarching goal of the study is to 
assess the role of ruxolitinib in the management of steroid refractory sclerotic chronic GVHD. 
Section 3.0 Eligibility Criteria 
3.1 
Inclusion Criteria 
1. Sclerotic chronic GVHD (classic chronic or overlap syndrome) that meets 2014 NIH 
Consensus Criteria. Eligible patients will have superficial or deep skin sclerosis, fasciitis or 
joint contractures.  
2. The subject must have received the following therapy for chronic GVHD (not necessarily for 
sclerotic manifestations): 
a) Systemic corticosteroids for >12 months and at least one additional line of systemic 
therapy OR  
b) Systemic corticosteroids and at least two additional lines of systemic therapy.  
For the purpose of this study, intra-oral narrow-band UVB phototherapy and “FAM” 
(fluticasone, azithromycin and montelukast) therapy for lung GVHD will be considered a topical 
therapy. Investigators are encouraged but not mandated to use ibrutinib for appropriate patients 
prior to enrollment in this trial.  
3. Adults, Age ≥18 years (state of Nebraska, Age ≥19 years) 
4. Karnofsky performance status ≥60% at the time of enrollment  
5. All allogeneic donor sources and all conditioning regimens are allowed.  
6. Absolute neutrophil count (ANC) greater than 1000/µL, and platelet count ≥50,000/µL 
without the use of growth factors or platelet transfusion. 
7. Able to take orally-administered medication.  
8. Female patient of reproductive potential must have a negative serum or urine pregnancy test 
≤7 days prior to starting the study drug. Women are considered NOT to have reproductive 
potential if they have had 12 months of amenorrhea with an appropriate clinical profile (i.e. 
≥51 years, history of vasomotor symptoms, OR supportive hormone levels such as low 
estrogen and high follicle-stimulating hormone levels), OR surgical sterilization.  
9. Male and female subjects of reproductive potential must be willing to avoid pregnancy or 
fathering children from enrollment to one month after the end of study treatment. This will 
require either a total abstinence, OR exclusively non-heterosexual activity (when this is in 
line with the preferred and usual lifestyle of the subject), OR two methods of contraception 
(male or female condom with or without a spermicidal agent, diaphragm or cervical cap with 
spermicide, or hormonal based contraception including intrauterine device).  
10. Life expectancy greater than 6 months 
11. Written informed consent to participate in the study.  
 
 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
3.2 
Exclusion Criteria 
1. Fibrosis of internal organs such as gut, liver or lung as the sole manifestation of sclerosis.  
2. Fluconazole at a dose more than 200 mg daily. Subjects should stop fluconazole or lower 
dose to less than or equal to 200 mg daily before starting ruxolitinib.  
3. Current evidence of malignancy after allogeneic transplant. 
4. History of progressive multifocal leuko-encephalopathy (PML) 
5. Active uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are 
considered controlled if appropriate therapy has been instituted and, at the time of 
screening, no signs of infection progression are present. Progression of infection is 
defined as hemodynamic instability attributable to sepsis, new symptoms, worsening 
physical signs or radiographic findings attributable to infection. Persisting fever without 
other signs or symptoms will not be interpreted as progressing infection 
6. Presence of known HIV infection, active hepatitis B or C infection.  
7. Active tuberculosis infection that developed after allogeneic HCT 
8. Total bilirubin 1.5 × the upper limit of the normal range   
9. Creatinine clearance <30 mL/min 
10. Presence of uncontrolled cardiopulmonary conditions such as ongoing cardiac 
arrhythmias, unstable angina or myocardial infarction, uncontrolled hypertension (e.g. 
blood pressure higher than 150/90), New York Heart Association class III/IV congestive 
heart failure, or requirement of supplemental oxygen at rest or having a resting O2 
saturation <90% by pulse oximetry  
11. Any other condition that is judged by the physician to potentially interfere with 
compliance to the study protocol or pose a significant risk to the patient.  
12. Pregnancy, breastfeeding or planning to be pregnant.  
13. Exposure to JAK inhibitor therapy for any indication after allogeneic transplant 
14. Initiation of a new systemic immunosuppressant for management of chronic GVHD 
within 8 weeks prior to enrollment. However, subjects who develop disease progression 
can enroll as early as 4 weeks after initiation of a new systemic immunosuppressant. 
Also, subjects who are unable to tolerate current therapy can enroll any time after 
initiation of a new systemic immunosuppressant, as long as the “new” 
immunosuppressant is stopped in these cases prior to initiation of ruxolitinib. Initiation of 
any new topical therapy (including FAM or intra-oral narrow-band UVB phototherapy) 
and changes in dose of existing immunosuppressive agents such as corticosteroids, 
sirolimus, calcineurin inhibitors or other agents are acceptable at any time prior to 
enrollment. The use of immunosuppressants for short term period, for example 7 days, 
for indications other than GVHD will be acceptable. 
15. Treatment with any other investigational agent, device, or procedure, within 21 days (or 5 
half-lives, whichever is greater) 
16. Known allergies, hypersensitivity, or intolerance to any of the study medications, 
excipients, or similar compounds.  
 
 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
3.3 
Inclusion of Women and Minorities  
Both men and women and members of all races and ethnic groups are eligible for this trial. 
Section 4.0 Registration Procedure 
4.1  
Recruitment 
Subjects who are referred to the UNMC/Nebraska Medicine or other IRB approved participating 
sites with sclerotic chronic GVHD may be eligible for this trial.  
Screening eligibility is based on standard clinical care performed by the transplant physician. 
The subject’s treating physician will determine eligibility based on the criteria listed in Section 
3.0 prior to offering consent.  All study personnel from UNMC and non-UNMC IRB approved 
sites will contact the UNMC IIT Office if a subject appears to meet the eligibility criteria 
(pending further screening tests) to confirm that target accrual has not been met. 
Some insurance carriers may decline to cover the costs of usual medical care if the subject is 
participating in a clinical trial. The potential subject will be provided assistance by the research 
nurse coordinator or designated staff in determining if the insurance carrier will decline 
coverage. Insurance carriers may or may not pay for study related expenses. The potential 
subject can then decide if he/she wishes to participate.  
If the subject is screened as potentially eligible, he/she will then be offered the option to 
participate. An informed consent will be signed by the subject after thorough review of the study 
is completed with the physician and his/her designee.  
4.2 
Eligibility Verification/Registration  
Before subjects are registered into the study, the Eligibility Checklist form (Appendix F) must be 
completed to confirm whether the subject meets the eligibility criteria. The Eligibility Checklist 
form will be maintained in the study file as source documentation only if it has been reviewed, 
signed and dated prior to registration by the treating physician.  
 
• Date of enrollment is defined as the date of informed consent. 
 
All subjects will be registered through the sponsor site (UNMC).  Study personnel from UNMC 
and non-UNMC IRB approved sites will contact the UNMC Project Coordinator if a potential 
subject appears to meet eligibility criteria. The site study coordinator will email the following 
information: 
• Registration request with demographics form (located in the Study Site Manual), 
• Copy of the signed/dated consent form with at least one viewable unique subject 
identifier, 
• Completed Eligibility Checklist signed/dated by the PI or sub-I. 
Once the UNMC Research Project Coordinator confirms that the subject meets criteria, and 
target accrual has not been met, approval for the subject will be given and study subject number 
assigned. The UNMC Research Project Coordinator will send a confirmation of registration 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
email to the site.  The Project coordinator can assign a subject study number prior to final 
registration confirmation of a subject.  
In the event of an after-hours potential enrollment (i.e., clinic coast time differences), or an 
immediate need for convenience for the subject, please contact the sponsor PI or Research 
Project Coordinator.   
An electronic copy of the signed and dated consent form for each subject registered from all sites 
to the protocol is uploaded to the Clinical Trial Management System (CTMS) within 7 days that 
includes the required demographic information as noted in the UNMC SRC policies and 
procedures. 
 
Section 5.0 Treatment Plan 
The study is an open label, phase II multicenter trial designed to evaluate ruxolitinib as a salvage 
treatment for subjects with sclerotic GVHD (sclerosis or fasciitis).   
5.1 
Treatment Schedule and Administration: Ruxolitinib   
Drug 
Dose/Frequency 
Duration 
Administration  
Ruxolitinib 
10 mg BID 
6 months, may extend up 
to 12 months 
Oral 
 
Subjects will receive oral ruxolitinib at a dose of 10 mg twice daily.  Doses may not exceed 10 
mg twice daily.  Subjects will record their intake on a medication diary provided to them.  
Ruxolitinib will be continued for 6 months, unless there is intolerable toxicity, chronic GVHD 
progression requiring additional systemic treatment or relapse of the underlying malignancy.  
Subjects with mixed responses or chronic GVHD progression prior to 6 months of therapy that 
does not require initiation of additional agent are allowed to continue ruxolitinib for the complete 
6 month duration.  Therapy duration of 6 months will ensure adequate exposure to ruxolitinib, 
and is important because of the limited options for therapy in the study population and 
limitations of the current response assessment.  
Extended treatment 
Subjects who continue to have stable disease, mixed responses or partial/complete responses at 
the end of 6 months may continue the drug for a total of 12 months. Subjects with chronic 
GVHD progression (not including stable disease or mixed responses) at the end of 6 months will 
stop ruxolitinib, regardless of whether or not a new systemic therapy has been added. 
Ruxolitinib taper prior to discontinuation 
At the end of 6 months, or 12 months for subjects treated on extension study, ruxolitinib will be 
tapered over a month before discontinuation, for example, a dose reduction by 5 mg every 1-2 
weeks. Ruxolitinib may be stopped without a taper in cases of unacceptable toxicities. If an 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
abrupt cessation of ruxolitinib is required, investigators are strongly encouraged to consider 
starting or dose-escalating systemic glucocorticoid (prednisone dose ≥0.5 mg/kg/day or 
equivalent dose) for at least a week to avoid rebound symptoms. While coming off ruxolitinib, 
subjects should be carefully monitored for worsening of GVHD symptoms or any other 
withdrawal symptoms.  
5.1.1 Other immunosuppressive and topical therapies for GVHD  
Investigators are strongly encouraged but not mandated to continue other immunosuppressive 
therapies such as tacrolimus until at least a partial response is achieved; dose adjustment to 
achieve a desired drug level is allowed. However, subjects on prednisone may continue to taper 
prednisone at the discretion of the treating physician. Increase in prednisone dose (or prednisone 
equivalent dose) to a dose lower than or up to the prednisone dose at enrollment is acceptable to 
control disease symptoms, however, an increase in the dose of prednisone higher than the dose at 
enrollment will be considered a new systemic treatment and thus, therapy failure (1).  
Subjects who start a new systemic immunosuppressive agent to control chronic GVHD (1) are 
considered therapy failures for which ruxolitinib will be discontinued.  A short course of an 
immunosuppressive agent (<2 weeks) for a clearly documented non-chronic GVHD indication 
(e.g., stress dose steroids in someone on chronic steroids, a short pulse of steroids for an allergic 
reaction) will not be considered treatment failure unless it extends longer than 2 weeks.  Topical 
therapies (including FAM or intra-oral narrow-band UVB phototherapy) can be initiated or 
stopped at the discretion of the treating physician while ruxolitinib is continued and are not 
considered treatment failures. For the purpose of this study, “FAM” (fluticasone, azithromycin 
and montelukast) therapy for lung GVHD will be considered a topical therapy. 
5.2 
Ruxolitinib dose modifications for toxicities  
Ruxolitinib doses may be reduced in the event of toxicities. The lowest permissive dose of 
ruxolitinib is 5 mg daily. 
Subjects with sclerotic GVHD have limited therapy options and may be willing to accept certain 
degree of toxicities.  As such, this trial will allow treating physicians to use discretion regarding 
dose modifications of ruxolitinib but only under certain situations as specified in this section. 
For subjects with grade 2 or lower hematologic or non-hematologic toxicities, ruxolitinib may be 
continued at the current dose or dose reduced by 50% at the discretion of the treating physician. 
Dose reduction by 50% (i.e. reduction to 5 mg BID in subjects receiving 10 mg BID) or 
temporary drug cessation is allowed in subjects with certain grade ≥3 hematologic or non-
hematologic toxicities (see table below). Subjects who require drug cessation will resume 
ruxolitinib at a dose no higher than 5 mg BID for at least 2 weeks before resuming their previous 
dose. Subjects with grade 3-4 toxicities are required to undergo close monitoring with repeat 
testing of any abnormal laboratory or clinical parameter(s) within 2-7 days depending on specific 
circumstances. 
Ruxolitinib dose modifications for toxicities 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Toxicity (CTCAE Version 4.03) 
possibly, probably or definitely 
related to ruxolitinib 
Dose modification 
Subsequent starting dose 
Hematologic toxicities  
Grade 4 hematologic  toxicities:   
(platelet count <25,000/µL, 
neutrophil count <500/µL, grade 4 
febrile neutropenia with life-
threatening consequences or 
requiring urgent interventions, life 
threatening anemia) 
Temporary drug cessation until 
resolution to grade ≤2 or 
baselinea (mandatory) 
5 mg BID for at least 2 
weeks before considering 
dose escalationb 
Grade 3 hematologic toxicities: 
(platelet count <50,000-25,000/µL, 
neutrophil count <1000-500/µL with 
or without fever [single episode of 
>38.3ºC or ≥38ºC for more than 1 
hour] without serious consequences) 
Dose reduction by 50%, or 
temporary drug cessation until 
resolution to grade ≤2 or 
baselinea (at the discretion of 
investigator) 
5 mg BID for at least 2 
weeks before considering 
dose escalationb  
Grade 2 or lower neutropenia or 
thrombocytopenia; and grade 3 or 
lower anemia (hemoglobin <8 g/dl) 
Maintain dose or dose reduction 
by 50% (at the discretion of 
investigator) 
If dose reduced, dose 
escalation at the discretion 
of the treating physician   
Non-hematologic toxicities  
Grade 4 renal, hepatic or other non-
hematologic toxicities 
(e.g. creatinine >6.0 x ULN, total 
bilirubin >10.0 x ULN, AST/ALT 
>20.0 x ULN, grade 4 hypertensionc) 
Temporary drug cessation until 
resolution to grade ≤2 or 
baselinea (mandatory) 
5 mg BID for at least 2 
weeks before considering 
dose escalationb 
Grade 3 renal and hepatic toxicities 
(creatinine >3.0 - 6.0 x ULN, total 
bilirubin >3.0 - 10.0 x ULN, 
AST/ALT >5.0 - 20.0 x ULN) 
 
Temporary drug cessation until 
resolution to grade ≤2 or 
baselinea (mandatory) 
5 mg BID for at least 2 
weeks before considering 
dose escalationb 
Grade 4 increase in serum amylase 
or lipase (>5.0 x ULN) 
Temporary drug cessation until 
resolution to grade ≤2 or 
baselinea (mandatory) 
5 mg BID for at least 2 
weeks before considering 
dose escalationb 
Grade 3 or lower increase in serum 
amylase or lipase (≤5.0 x ULN) 
Maintain dose or dose reduction 
by 50% (at the discretion of 
investigator) 
If dose reduced, dose 
escalation at the discretion 
of the treating physician   
Other grade 3 non-hematologic 
toxicities 
(e.g. grade 3 hypertensiond) 
Dose reduction by 50%, or 
temporary drug cessation until 
resolution to grade ≤2 or 
baselinea (at the discretion of 
investigator) 
5 mg BID for at least 2 
weeks before considering 
dose escalationb  
Any grade 2 or lower non-
hematologic toxicities 
Maintain dose or dose reduction 
by 50% (at the discretion of 
investigator) 
If dose reduced, dose 
escalation at the discretion 
of the treating physician   
Criteria for permanent cessation of the study drug  
Subjects who cannot tolerate the lowest permissive ruxolitinib dose of 5 mg daily AND require 
cessation of drug for ≥4 weeks will be permanently removed from the study.  
Subjects who do not recover from grade 4 hematologic or non-hematologic toxicities possibly, 
probably or definitely related to ruxolitinib within 2 weeks of drug cessation will be permanently 
removed from the study. Recovery will be defined as resolution to grade ≤2 or baseline. 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
 
aRuxolitinib may be stopped without a taper in cases of unacceptable toxicities.  If an abrupt 
cessation of ruxolitinib is required, investigators are strongly encouraged to consider starting or 
dose-escalating systemic glucocorticoid for at least a week (see Section 5.1 “Ruxolitinib taper 
prior to discontinuation”). 
bIf the drug is tolerated at a lower dose for at least two weeks, doses of ruxolitinib may be further 
increased to a maximum of 10 mg BID.  
cDefinition of grade 4 hypertension: Life-threatening consequences (e.g., malignant 
hypertension, transient or permanent neurologic deficit, hypertensive crisis); urgent intervention 
indicated. 
dDefinition of grade 3 hypertension: Stage 2 hypertension (systolic BP >=160 mm Hg or 
diastolic BP >=100 mm Hg); medical intervention indicated; more than one drug or more 
intensive therapy than previously used indicated. 
 
5.2.1 Dose reduction for Concomitant Medications  
50% dose reduction should be considered when using medicinal products which are dual 
inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole). Avoid the concomitant use of 
ruxolitinib with fluconazole doses greater than 200 mg daily. 
When administering ruxolitinib with strong CYP3A4 inhibitors, the total daily dose should be 
reduced by approximately 50%.  Strong CYP3A4 inhibitors include boceprevir, clarithromycin, 
cobicistat, conivaptan, danoprevir/ritonavir,eltegravir/ritonavir, grapefruit juice, idelalisib, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, LCL161, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, sequinavir/ritonavir, telaprevir, telithromycin, 
voriconazole, indinavir/ritonavir, tipranoavir/ritonavir, and troleandomycin.  
No dose adjustment is necessary when co-administering ruxolitinib with strong CYP3A4 
inducers. 
No dose adjustment is necessary when co-administering ruxolitinib with CYP3A4 substrates. 
Ruxolitinib did not decrease the exposure of a fixed dose oral contraceptive metabolized via the 
CYP3A4 pathway, thus demonstrating lack of CYP3A4 induction potential. 
5.3 
Supportive Care  
Supportive care will follow the institutional practice of prophylactic antimicrobials, antiemetics, 
blood product transfusions and other supportive care.  
 
 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
5.4 
Duration of Study and Follow-up 
We estimate that there will be 47 subjects dosed over a 2.5-year period.  After accrual is met, we 
plan to follow the subjects for up to 2 years; the follow-up duration is discussed in detail in the 
table below. 
GVHD response 
evaluation every 
3 months 
Therapy 
duration 
End of therapy 
safety evaluation 
(30-40 days after 
the last dose of the 
study drug) 
Last follow-up 
for GVHD 
evaluation  
Data collection 
Stable disease or 
mixed responses at 
the end of 6 months 
6 to 12 
months 
followed by 
taper over 1 
month1 
8 months;  
If therapy continued 
till 12 months and 
tapered over the next 
month,14 months2 
At the end of 6 
months;  
If therapy 
continued until 12 
months, up to 24 
months from the 
study enrollment3 
Data on survival, 
relapse of 
malignancy, 
subsequent GVHD 
treatment will be 
collected till 
subjects are 
removed from the 
study, death or up 
to a total of 2 
years. For subjects 
who have 
completed last 
follow-up for 
GVHD evaluation, 
further data may be 
collected via 
review of medical 
records or 
telephone 
interview. 
Partial/complete 
responses at the end 
of 6 months 
6 to 12 
months 
followed by 
taper over 1 
month1 
8 months4;  
If therapy continued 
till 12 months and 
tapered over the next 
month,14 months2 
Up to 24 months 
from the study 
enrollment3 
GVHD progression, 
toxicity or relapse5 
<6 months 
(may stop 
without a 
taper) 
About 30 days after 
the last dose 
At the end of 6 
months  
1If no intolerable toxicity, chronic GVHD progression requiring initiation of an additional 
systemic agent, or relapse of underlying malignancy within the 6 months of the study 
participation, ruxolitinib may be continued till 12 months 
2 If no toxicity concerns were raised at 12-month follow-up, this evaluation may be performed 
over the phone with a plan to see the subject in a follow-up at 15 months. 
3 The subject will be followed every 3 months until progression of chronic GVHD requiring 
initiation of an additional systemic agent, relapse of underlying malignancy or for a total of 2 
years  
4For subjects with partial or complete responses at 6 months, if no toxicity concerns were raised 
at 6-month follow-up, this evaluation may be performed over the phone with a plan to see the 
subject in a follow-up at 9 months. 
5If the subject develops intolerable toxicity, chronic GVHD progression requiring initiation of an 
additional systemic agent, or relapse of underlying malignancy before the 6 months of the study 
participation. If the subject has GVHD progression that is not considered significant enough to 
necessitate additional systemic GVHD therapy, and the subject is tolerating ruxolitinib, 
ruxolitinib may be continued till the end of 6 months at the discretion of the treating physician. 
In such cases, GVHD status will be reassessed at the end of 6 months of therapy.  At 6 months, if 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
the subject continues to have GVHD progression without any responses in any organ, ruxolitinib 
will be discontinued.  
5.5 
Assessment Schedule 
Subjects should be evaluated for GVHD activity at the time of consenting, at the end of 3 months 
(+/-14 days) after starting ruxolitinib, and at the end of 6 months of therapy (+/-14 days) (see 
section 5.4 for duration of follow-up).  
Subjects, who maintain complete or partial response at the end of 6 months, will be followed 
every 3 months until start of another systemic treatment for chronic GVHD, relapse of 
underlying malignancy or for a total of 2 years to determine the duration of response.  
Subjects should also be evaluated if they develop grade 3 or higher toxicities. In an event that the 
subject cannot travel to the transplant center, the subject may be evaluated by a local physician 
until the subject is able to travel.  Subjects may have to be seen more frequently, as clinically 
indicated.  
5.5.1 Baseline assessment (-28 days) 
Assessments at the time of enrollment will include: 
• History and physical exam including Karnofsky performance status 
• Clinical laboratory parameters (hematology, serum chemistry, lipid levels, pancreatic 
enzymes, Hepatitis B and C), and pregnancy testing in women with reproductive 
potential. 
• Electrocardiogram (EKG) 
• Comprehensive GVHD assessment including digital pictures of range of motion (if 
abnormal) and any visible skin lesions, mapping of sclerotic areas (Appendix I) 
• Patient reported outcomes  
• Research blood collection for correlative studies 
5.5.2 Safety Monitoring (Study Days 14 and 28, End of Month 2, 4, and 5) 
Subjects will undergo hematology and serum chemistry testing in 2 and 4 weeks +/- 4 days, then 
monthly +/- 14 days while receiving ruxolitinib.  Lipid levels will be checked at the end of 2 
months +/- 14 days.  Pancreatic enzymes should be checked if triglyceride level ≥500 mg/dl.  
These laboratories may be tested locally if more convenient for the subject.  When tests are done 
locally, and not at the study center, the subject will receive a phone call from the study personnel 
if there are abnormal results.  All observed grade 3 or above treatment-emergent adverse events 
(new or worsening from baseline) and all serious adverse events will be collected.  CTCAE 
version 4.03 (Appendix H) will be utilized to grade the severity of adverse events.  Please also 
see sections 5.5.6 and 7.0.  
 
 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
5.5.3 End of Month 3 Visit (+/-14 days) 
Assessments at the end of month 3 visit will include: 
• History and physical exam 
• Clinical laboratory parameters (hematology and serum chemistry)   
• Comprehensive GVHD assessment including digital pictures of range of motion (if 
abnormal) and any visible skin lesions, mapping of sclerotic areas (Appendix I) 
• Patient reported outcomes  
• Research blood collection for correlative studies 
• Adverse event monitoring 
Data on relapse of the underlying malignancy, survival, chronic GVHD flares, prednisone dose 
and use of other immunosuppressive agents will be captured at scheduled time points, and 
verified at each visit.  
5.5.4 End of Month 6 Visit (+/-14 days) 
Assessments at the end of month 6 visit will include: 
• History and physical exam 
• Clinical laboratory parameters (hematology and serum chemistry)   
• Comprehensive GVHD assessment including digital pictures of range of motion (if 
abnormal) and any visible skin lesions, mapping of sclerotic areas (Appendix I) 
• Patient reported outcomes  
• Research blood collection for correlative studies 
• Adverse event monitoring 
Data on relapse of the underlying malignancy, survival, chronic GVHD flares, prednisone dose 
and use of other immunosuppressive agents will be captured at scheduled time points, and 
verified at each visit. 
5.5.5 End of Month 9, 12, 15, 18, 21 and 24 Visit (+/-30 days) (Extended Treatment) 
Subjects who maintain complete or partial response at the end of 6 months, OR receive extended 
therapy (see section 5.4 for details) will be followed every 3 months (+/-30 days) until start of 
another systemic treatment for chronic GVHD, relapse of underlying malignancy or for a total of 
2 years to determine the duration of response.  
Assessments at these visits will include: 
• History and physical exam 
• Clinical laboratory parameters (hematology and serum chemistry)   
• Comprehensive GVHD assessment including digital pictures of range of motion (if 
abnormal) and any visible skin lesions, mapping of sclerotic areas (Appendix I) 
• Patient reported outcomes  
• Adverse event monitoring if receiving ruxolitinib within the past 30 days 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Data on relapse of the underlying malignancy, survival, chronic GVHD flares, prednisone dose 
and use of other immunosuppressive agents will be captured at scheduled time points, and 
verified at each visit. 
5.5.6 End-of-therapy or Safety Follow-up Visit (30-40 days after the last dose of 
ruxolitinib) 
Subjects will undergo this visit 30-40 days after the last dose of ruxolitinib (see section 5.4 for 
details).  
Assessments at safety follow-up visit will include: 
• History and physical examinations 
• Clinical laboratory parameters (hematology and serum chemistry)  
• Comprehensive GVHD assessment (if a subject withdraws from study treatment prior to 
3 or 6 month assessment time points)  
• Adverse event monitoring   
Subjects with grade 3-4 toxicities are required to undergo close monitoring with repeat testing of 
any abnormal laboratory or clinical parameter(s) within 2-7 days depending on specific 
circumstances. 
5.6 
Criteria for Discontinuation of the Study Drug and Removal from Study  
Subjects will discontinue the study drug for any of the following reasons:  
• Progression of GVHD resulting in initiation of a new systemic immunosuppressive agent 
(also see Section 5.1.1) 
• Development of an adverse reaction that necessitates discontinuation of the study drug, 
including any unresolved serious adverse event.  Please see section 5.2 for further details. 
• Development of a serious systemic allergic response or severe degree of intolerance to 
the study medication.  
• Development of intercurrent medical problems that would make continued protocol 
therapy detrimental to the subject's safety. 
• The subject chooses to discontinue treatment.  
Subjects who stop study medication for GVHD progression or relapse of underlying malignancy 
will stop research visits except for the safety follow-up visit. Data may continue to be collected 
via chart review. 
Subjects will be removed from the study (study withdrawal) for any of the following reasons:  
• If at any time the requirements of this protocol are detrimental to the subject's wellbeing, 
the subject will be removed from the study. In this event, the reason(s) for withdrawal 
will be documented.  
• The subject requests removal from the study.  
The reason(s) for study withdrawal will be documented and no further information may be 
collected on the subject. The reason(s) for stopping study medication will be documented in the 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
case report form.  If available, the following information will be recorded in the case report form: 
GVHD status, date of relapse of underlying malignancy, date of death, cause of death, and 
autopsy report.  Subjects who stop the study drug but do not withdraw from the study may 
remain in the study. 
 5.7 
Correlative Studies 
The correlative objectives for this trial are to: 
1. Determine the correlation between response at 6 months and change in the 
expression level of various cytokines (ST2, SPON1, , CXCR3, CXCL10, IFN 
gamma, soluble IL-2R, IL-2, IL-4, IL-5, IL-6, IL-12, TNF-α, 
TRAIL/TNSFSF10/7; profibrotic cytokines such as IL-1β and TGF-β). 
2. Determine the correlation between response at 6 months and change in the 
percentage of peripheral blood T/NK-cell population (CD3-CD56+) [Treg 
(FoxP3+), effector T cell (CD8+T cell, CD4+ TH1, TH2 and TH17 cells), CD3+, 
CD4-CD25+, Gr-1, Ter-119,  and Antigen presenting cells (APC) APC-CD80+] 
These studies aim to determine the correlation and to quantitate the changes of the above from 
plasma and peripheral blood samples obtained at baseline (pre-treatment), and at 3 and 6 month 
time points.  Collection and handling instructions are provided in Study Site Manual.  For each 
time point, 2x10 mL whole blood will be collected in EDTA treated tubes for quantitation of the 
various cytokines by various commercially available ELISA assays. Additionally, 8 mL blood 
will be collected in sodium heparin treated tubes and processed for peripheral blood 
mononuclear cells (PBMCs) prior to shipping to UNMC Central lab in order to perform flow 
cytometry to determine T/NK/APC population.  If any samples remain after analysis for this 
study, these samples will be maintained at UNMC central lab for future unspecified use. 
Please see study lab manual for additional information regarding processing before shipping to 
UNMC central lab for isolation and analysis of samples. 
5.8  
Patient Reported Outcomes (PROs) 
5.8.1 Lee Chronic GVHD Symptom Scale 
Lee Chronic GVHD Symptom Scale (26) measures the degree of “bother” that subjects have 
experienced due to symptoms in 7 domains. These domains potentially affected by chronic 
GVHD include skin, eyes and mouth, breathing, eating and digestion, muscles and joints, energy, 
emotional distress.  This can be found in Appendix D and the Study Site Manual.  
5.8.2 Modified Scleroderma Health Assessment Questionnaire 
The Scleroderma Health Assessment Questionnaire is based on the Health Assessment 
Questionnaire, an instrument initially developed for rheumatoid arthritis patients.  Both 
instruments contain 20 items measuring activities of daily living on a 4 point scale (0-3) from 
“without any difficulty” to “unable to do.” The Scleroderma modification added 5 visual analog 
scales specific for scleroderma disease activity (pain, Raynaud’s phenomenon, finger ulcers, 
intestinal problems, breathing problems, overall severity) (27, 28). Three of these problems 
(Raynaud’s, finger ulcers and intestinal problems) are unlikely in sclerotic GVHD, and will not 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
be retained for the purpose of this study.  This can be found in Appendix E and the Study Site 
Manual.  
Section 6.0 Measurement of Effect 
6.1 
Assessment of therapeutic response in chronic GVHD 
The established method for response determination in the majority of chronic GVHD therapy 
trials is clinician-determined response based on organ scoring. The Response Criteria Working 
Group Report from the 2014 NIH Consensus Conference on chronic GVHD has recommended 
three general categories of overall response: complete response (CR), partial response (PR), and 
lack of response (unchanged, mixed response, progression) (1). Further details are provided in 
the Appendix B and G. 
The primary endpoint of this study is to determine the proportion of subjects with complete and 
partial responses in skin and/or joint, which are defined by 2014 NIH Criteria (1) as follow:  
Complete response (CR) in skin and/or joint requires NIH skin and joint score 0, and P-ROM 
score of 25. 
Partial response in skin and/or joint requires decrease in NIH skin score OR joint score by 1 or 
more points, or increase in P-ROM score by 1 point for any site. 
 
 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Section 7.0 Study Parameters (also see section 5.5) 
 
 
 
Treatment 
Follow-Up 
Procedures 
Baseline 
(-28 
days) 
Study 
Day 1 
Study 
Day 
14  
and 
28 
(±4 
days)7 
End of 
Month 
2, 4, 5  
(±14 
days)7 
End of 
Month 
3, 6 
(±14 
days) 
Visits every 
3  months 
(end of 
month 9,  
12, 15, 18, 
21, 24) 
 (±30 days) 
End of 
Treatment 
Safety 
Follow-Up 
(30-40 
days after 
last dose) 
Informed consent 
X 
 
 
 
 
 
 
Eligibility Verification 
X 
 
 
 
 
 
 
History and Physical Exam 
X 
 
 
 
X 
X 
X 
Karnofsky Performance Status 
X 
 
 
 
 
 
 
Comprehensive GVHD 
assessment including digital 
pictures and body mapping4 
X 
 
 
 
X 
X 
X2 
Hematology (CBC) 
X 
 
X 
X 
X 
X 
X 
Serum creatinine, total bilirubin, 
AST, ALT, Albumin, Alkaline 
Phosphatase, Calcium, Sodium, 
Potassium, Blood Urea Nitrogen 
(BUN), Glucose 
X 
 
X 
X 
X 
X 
X 
Total Cholesterol, LDL, HDL, 
Triglycerides 
X 
 
 
X (check at the end of 2 months+/-14 days, then 
as clinically indicated) 
Amylase, lipase 
X 
 
 
Check if triglyceride level ≥500 mg/dl 
Urine Pregnancy 
X 
 
 
 
 
 
 
Hepatitis B Surface Antigen1 
X 
 
 
 
 
 
 
Hepatitis C antibody1 
X 
 
 
 
 
 
 
CMV DNA 
Monthly for the first 3 months and as clinically indicated 
HIV testing1 
X 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
Other Laboratory tests 
As clinically indicated 
Radiology Tests 
As clinically indicated 
Patient Reported Outcomes 
Lee Chronic GVHD Symptom 
Scale 
Scleroderma Health Assessment 
Questionnaire 
X 
 
 
 
X 
X 
 
Correlative study samples3 
X 
 
 
 
X 
 
 
Ruxolitinib 
 
X 
X 
X 
X 
X8 
 
Adverse event monitoring 
 
Monitor until 30 days after treatment 
Concomitant medications 
including systemic 
glucocorticoid5 
X 
 
 
 
X 
X6 
X6 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
1. 
Testing for Hepatitis B, C and HIV completed prior to transplant will be acceptable.  No 
additional testing is required for study eligibility. 
2. 
If a subject withdraws from study treatment prior to the end of 3 or 6 month assessment time 
points, the comprehensive GVHD assessment should be completed at the End of 
Treatment/Safety follow up visit,.  
3. 
The correlative sample can be collected at any time during the scheduled visit. 
4. 
Body mapping and digital pictures will be uploaded in the eCRF.  The instructions are listed 
the CRF Completion Guidelines 
5. 
For all subjects enrolled in this study including those enrolled in the past, data on only 
concomitant medications of interest (i.e. glucocorticoid, and other immunosuppressive 
agents including narrow band UVB phototherapy and extracorporeal photopheresis) should 
be collected at baseline, at each 3-monthly visit until the subject stops ruxolitinib and end of 
treatment/safety follow-up.  
6. 
After the subjects stop ruxolitinib, if a new immunosuppressive agent is started for treatment 
of GVHD, only data on the new immunosuppressive medicine should be collected. 
7. 
The subject should be called to check on dose compliance and lab results. 
8. 
If the subject has stable disease, mixed responses or partial/complete response, the subject 
can continue to take ruxolitinib for a total of 12 months before tapering off the study drug.  
Please review section 5.1 for further details. 
 
Section 8.0 Drug Formulation and Procurement 
8.1 
Ruxolitinib  
Details available in the investigator brochure.  
8.1.1 Mechanism of Action  
Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) represents a novel, potent, 
and selective inhibitor of JAK1 (Janus kinase 1) (inhibition concentration 50%[IC50]=3.3 ± 1.2 
nM) and JAK2 (IC50=2.8 ± 1.2 nM) with modest to marked selectivity against TYK2 (tyrosine 
kinase 2) (IC50=19 ± 3.2 nM) and JAK3 (IC50=428 ± 243 nM), respectively. Ruxolitinib 
interferes with the signaling of a number of cytokines and growth factors that are important for 
hematopoiesis and immune function. 
8.1.2 Clinical Formulation 
Available for oral administration as 5 mg tablet. Ruxolitinib tablets are round and white to off-
white in color. 
8.1.3 Drug procurement 
Open label ruxolitinib will be supplied by Incyte Corporation.  Ruxolitinib tablets (5 mg) will be 
administered as oral doses without regard to food in an outpatient setting.   
 
 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
8.1.4 Packaging and Labeling 
Ruxolitinib 5 mg tablets are packaged as 60-count in high-density polyethylene (HDPE) bottles. 
The bottles will include labeling “New Drug - Limited by Federal (USA) Law to Investigational 
Use”.  
8.1.5 Storage/Stability  
The bottles of tablets should be stored at room temperature, 15°C to 30°C (59°F to 86°F). 
Stability studies will be conducted on all clinical batches to support the clinical trial. 
8.1.6 Administration 
Subjects will receive oral ruxolitinib at a dose of 10 mg twice daily Doses may not exceed 10 mg 
twice daily.  Any missed dose can be taken up to 8 hours after the scheduled time. 
8.1.7 Instruction to Subjects for Handling Ruxolitinib 
The subject should be instructed in the handling of study drug as follows: 
• 
•To store the study drug at room temperature. 
• 
•To only remove from the study drug bottle/kit the number of tablets needed at the time 
of administration. 
• 
•Not to remove doses in advance of the next scheduled administration. 
• 
•To make every effort to take doses on schedule. However, doses can be taken up to 8 
hours after scheduled time. 
• 
•To report any missed doses. 
• 
•To take study drug without regard to food with a glass of water. 
• 
•Not to take another dose if vomiting occurs after taking study drug. 
• 
•To keep study drug in a safe place and out of reach of children. 
• 
•To bring all used and unused study drug kits to the site at each visit. 
8.1.8 Clinical Pharmacology 
Fifteen Phase I, nine Phase II and three Phase III clinical studies (two in MF, one in PV) 
provided clinical pharmacology data on ruxolitinib in healthy volunteers and in patients with 
MF, ET, PV, subjects with renal or hepatic impairment, prostate cancer, pancreatic cancer, 
multiple myeloma (MM) or rheumatoid arthritis (RA). Oral absorption of ruxolitinib is rapid and 
nearly complete, with ≥95% absorption indicating high in vivo permeability in the human 
gastrointestinal tract, consistent with a Biopharmaceutical 
Classification System (BCS) Class I compound. Mean peak plasma concentration (Cmax) is 
achieved 1-2 hour post-dose. 
• The effect of food on ruxolitinib exposure is minimal and is not expected to be clinically 
significant; as a result, the drug may be administered either with or without food. 
• Dose proportional exposure is observed between 5 and 200 mg dose range with linear 
pharmacokinetics (PK). 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
• Plasma protein binding is approximately 97% ex vivo. There is moderate distribution to 
organs and tissues with no long-term retention of drug-related material in preclinical 
species and limited drug penetration into the central nervous system (CNS) or across the 
blood-brain barrier. 
• There is >95% [14C]-ruxolitinib recovery in a mass balance study with 74% and 22% of 
the dose excreted in urine and feces of healthy subjects, respectively. Less than 1% of the 
administered dose is recovered in urine and feces as unchanged parent drug. 
• The mean terminal elimination half-life is ~3 hour with no appreciable accumulation of 
either parent or metabolites with twice daily dosing. 
• Metabolism is predominantly via the cytochrome P450 isozyme CYP3A4 to yield 
oxygenated and subsequent conjugated metabolites. 
• Oxidative metabolites of ruxolitinib retain pharmacological activity albeit with one half 
to one fifth of the activity of the parent compound. Ex vivo 
pharmacokinetic/pharmacodynamic (PK/PD) analysis indicates that the total of 8 active 
metabolites contribute to 18% of the overall PD activity of ruxolitinib. 
• Ruxolitinib PK in healthy volunteers was largely comparable between Japanese, Chinese 
and Western subjects and did not lead to a conclusion of meaningful ethnic differences. 
• Baseline elevations in inflammatory markers such as tumor necrosis factor alpha (TNFα), 
interleukin (IL)-6, and C-reactive protein (CRP) noted in patients with MF was 
associated with constitutional symptoms such as fatigue, pruritus, and night sweats. 
Decreases were observed in these markers over the 24 weeks of treatment with 
ruxolitinib, with no evidence that patients became refractory to the effects of ruxolitinib 
treatment. 
8.1.9 Potential Drug Interactions 
50% dose reduction should be considered when using medicinal products which are dual 
inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole). Avoid the concomitant use of 
ruxolitinib with fluconazole doses greater than 200 mg daily. 
• When administering ruxolitinib with strong CYP3A4 inhibitors, the total daily dose 
should be reduced by approximately 50%. 
• No dose adjustment is necessary when co-administering ruxolitinib with strong CYP3A4 
inducers. 
• No dose adjustment is necessary when co-administering ruxolitinib with CYP3A4 
substrates. 
• Ruxolitinib did not decrease the exposure of a fixed dose oral contraceptive metabolized 
via the CYP3A4 pathway, thus demonstrating lack of CYP3A4 induction potential. 
8.1.10 Drug toxicities 
The following drug toxicities were noted in trials mostly involving patients with myelofibrosis 
and polycythemia vera.  


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Blood and lymphatic system disorders: 
Anemia (40.8-82.4%), thrombocytopenia (16.8-69.8%), neutropenia (16.6%). Also includes 
febrile neutropenia. Cytopenias are dose dependent and reversible with dose reduction/ 
interruption. 
Infections and infestations:  
Urinary tract infections (6-12.6%) Including urosepsis, Cystitis, Kidney infection, Urinary tract 
infection bacterial, Nitrite urine present, and pyuria.  Pneumonia (8.3%)  Herpes zoster (4.0-
4.3%)  Tuberculosis (0.3%) 
Gastrointestinal disorders:  
Flatulence (3.3%) and Constipation (8.7%). 
Hepatic dysfunction: 
Raised alanine aminotransferase (22.3-27.2%) and aspartate aminotransferase (19.9-26.1%) 
Metabolism and nutrition disorders: 
Weight gain (7.6-12.3%),  Hypercholesterolemia (16.9-20.7%),  Hypertriglyceridemia (9.8%) 
Nervous system disorders: 
Dizziness (12.0-15.3%%),  Headache (14.0%) 
Skin and subcutaneous tissue disorders: 
Bruising (21.6%) including hematoma, petechiae and purpura   
Vascular disorders: 
Hypertension (6.5%) 
General disorders and administration site conditions:  
In clinical studies in myelofibrosis, fatigue, bone pain, pyrexia, pruritus, night sweats, 
splenomegaly and weight loss noted in 60.4% after discontinuation of ruxolitinib. 
In a retrospective study of ruxolitinib in patients with chronic GVHD, cytopenia and CMV 
reactivation was observed in 17% and 15% of patients. Cytopenias preceded the use of 
ruxolitinib in most of the patients (15%). 
Progressive Multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment. 
Physicians should be alert for neuropsychiatric symptoms suggestive of PML. If PML is 
suspected, further dosing must be suspended until PML has been excluded. 
Non-melanoma skin cancers (NMSCs), including basal cell, squamous cell, and Merkel cell 
carcinoma have been reported in patients treated with ruxolitinib. Most of these patients had 
histories of extended treatment with hydroxyurea and prior histories of NMSC or pre -malignant 
skin lesions. A causal relationship to ruxolitinib has not been established. Periodic skin 
examination is recommended for patients who are at increased risk for skin cancer. 
8.1.11    Drug Accountability 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Responsibility for drug accountability at the study site rests with the investigator; however, the 
investigator may assign some of the drug accountability duties to an appropriate pharmacist or 
designee.  Inventory and accountability records must be maintained and readily available for 
inspection by the study monitor and are open to inspection at any time by any applicable 
regulatory authorities. 
The investigator or designee will be expected to collect and retain all used, unused, and partially 
used containers of study medication until the end of the study.  The Investigator or designee must 
maintain records that document: 
• 
investigational product delivery to the study site 
• 
the inventory at the site 
• 
use by each subject including pill/unit counts from each supply dispensed 
• 
product returned to the investigator or designee.   
These records should include dates, quantities, batch/serial numbers (if available), and the unique 
code numbers (if available) assigned to the investigational product and study subjects.   
The investigational product must be used only in accordance with the protocol.  The investigator 
will also maintain records adequately documenting that the subjects were provided the study 
medication specified. 
Completed accountability records will be archived by the site. If any unused ruxolitinib bottles 
remain at the end of the study, they will be accounted for by the site prior to study closure. If a 
site is able to destroy ruxolitinib at their premises, or through a certified vendor, they may do so 
upon authorization by the sponsor, provided their destruction policy is made available to the 
sponsor. 
Section 9.0 Toxicity and Adverse Event Reporting Guidelines 
This protocol will comply with monitoring and adverse event reporting requirements of the 
UNMC Fred & Pamela Buffett Cancer Center Data Monitoring plan. The protocol will adhere to 
the institutional and FDA guidelines for the toxicity reporting.  
All subjects will be closely followed for toxicity from the time of informed consent until 30 days 
after last administration of study medication. The reporting is only for “study medication,” until 
30 days after last administration of study medication.  
Adverse events (AEs) will be assessed by reports from subjects to their physician/Investigator 
and by physical examinations. Per NCI guidelines, serious adverse events (SAEs) and AEs will 
be graded and toxicity will be assessed using the revised NCI CTCAE version 4.03 (Appendix 
H). Adverse event will be followed until resolution, baseline or ≤ grade 1 levels. 
Serious adverse events should be followed until resolution, baseline or ≤ grade 1 levels, death, or 
until no further improvement is reasonably expected. Deaths occurring within 30 days of study 
treatment regardless of relationship will be reported to the Fred & Pamela Buffett Cancer Center 
Data and Safety Monitoring Committee (DSMC).  
9.1 Definitions 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Adverse Event  
An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not the event is 
considered causally related to the use of the product.  
An elective surgery or procedure that is scheduled to occur during a study will not be considered 
an adverse event if the surgery or procedure is being performed for a pre-existing condition and 
the surgery or procedure has been planned before study entry. However, if the pre-existing 
condition deteriorates unexpectedly during the study (e.g., the surgery is performed earlier than 
planned), then the deterioration of the condition for which the elective surgery or procedure is 
being done will be considered an adverse event.  
Any worsening of a pre-existing condition or illness is considered an adverse event. Laboratory 
abnormalities and changes in vital signs are considered to be adverse events if they result in 
discontinuation from the study, necessitate therapeutic medical intervention, require dose 
modifications and/or if the investigator considers them to be adverse events.  
Unexpected Adverse Event  
An unexpected adverse event is any adverse drug event that is not listed in the current 
labeling/Investigator’s Brochure. “Unexpected,” as used in this definition, refers to an adverse 
drug experience that has not been previously observed (i.e., included in the labeling) rather than 
from the perspective of such experience not being anticipated from the pharmacological 
properties of the pharmaceutical product.  
Serious Adverse Event  
A serious adverse event is one that at any dose (including overdose) and regardless of causality:  
• Results in death  
• Is a serious threat to life, health, safety or welfare-fare of subject 1  
• Requires inpatient hospitalization or prolongation of existing hospitalization  
• Requires intervention to prevent permanent impairment or damage 
• Results in persistent or significant disability or incapacity2  
• Is a congenital anomaly or birth defect  
• Is another serious important medical event3  
• Is any medical event in an investigational drug study that requires treatment to 
prevent one of the outcomes listed above 
• Seriously jeopardizes the rights, safety, or welfare of subjects  
1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious 
adverse event; it does not refer to a serious adverse event that hypothetically might have caused death if it 
were more severe.  
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a 
person’s ability to carry out normal life functions.  
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred. Important medical events that 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
may not be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the definition above 
should also usually be considered serious. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. A new 
diagnosis of cancer during the course of a treatment should be considered as medically important.  
9.2 
Adverse Event Reporting and Definitions Per University of Nebraska Medical 
Center, IRB and Fred & Pamela Buffett Cancer Center Data and Safety Monitoring 
Committee (DSMC) and Incyte Corporation 
This protocol will adhere to all institutional guidelines for adverse event reporting. Adverse 
events will be evaluated using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 (Appendix H).  
9.2.1 IRB Reporting  
All internal serious adverse events (AE) must be reported to the local IRB promptly per 
institutional policy and in no case later than two (2) business days following PI notification that 
the event occurred if the principal investigator determines that conditions A, and B, are met:  
a. The AE is unexpected, AND  
b. The AE is related to, or possibly related to, the drug, biologic, device, or other research 
intervention  
 
All unexpected, internal, fatal AEs must be reported promptly to the local IRB per institutional 
policy, but no later than 24 hours following PI notification that the event occurred. If 
documentation is still pending, the IRB office must be notified by a telephone call or e-mail.  
All expected, internal, fatal AEs (i.e., due to progressive disease or which reflect a risk currently 
found in the consent form) must be reported to the local IRB per institutional policy no later than 
ten (10) business days following PI notification that the event occurred.  
9.2.2 Fred & Pamela Buffett Cancer Center Data and Safety Monitoring Committee 
(DSMC) Reporting  
In its initial review, the DSMC will make a recommendation for the frequency of DSMC 
monitoring based on an assessment of risk associated with study-associated therapy, per the 
DSMC policy. Reporting of the following will be done in accordance with DSMC guidelines: 
• All Serious adverse events (SAEs) and toxicity reporting will be reported to the DSMC.  
• All adverse events grade 3 or higher (expected or unexpected, regardless of attribution) 
will be reported to the DSMC.  
Attribution of AE: The likelihood of relationship of the AE to the study drugs will be determined 
by the investigator based on the following definitions:  
Not related: The subject was not exposed to the study treatment or another cause is obvious.  


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Probably not related: The AE is most likely explained by another cause, and the time of 
occurrence of the AE is not reasonably related to the study treatment.  
Possibly related: Study treatment administration and AE occurrence reasonably related in time, 
and the AE is explained equally well by causes other than study treatment, or treatment 
administration and AE occurrence are not reasonably related in time, but the AE is not obviously 
a result of other causes.  
Probably related: Study treatment administration and AE occurrence are reasonably related in 
time, and the AE is more likely explained by study treatment than by other mechanisms.  
Definitely related: The occurrence and timing of the AE are clearly attributable to the study 
treatment.  
AEs will be collected from the time the subject signs the consent form and ending 30 days 
following the final dose of study drug. All AEs will be followed until resolution, a cause is 
identified, or until no further improvement is expected. AEs judged by the investigator as not 
related or probably not related to the treatment will NOT be followed beyond the 30 days after 
the final dose of study drug. 
All SAEs and AE reporting will be completed using DSMC approved forms.  Detailed policy 
and procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html 
9.2.3 Incyte Reporting 
To ensure subject safety, every Serious Adverse Event (SAE), occurring after the subject has 
consented and until at least 30 days after the subject has stopped taking the Incyte study product 
(ruxolitinib) must be reported to Incyte within twenty four (24) hours of learning of the event.  
If a subject experiences a SAE after signing informed consent, but prior to receiving ruxolitinib, 
the event will NOT be collected unless the investigator feels the event may have been caused by 
a protocol procedure.  Previously planned (prior to signing the informed consent document) 
surgeries should not be reported as SAEs unless the underlying medical condition has worsened 
during the course of the study. 
All SAEs are to be captured on Incyte’s Adverse Event Report Form.  
The study sites will submit the SAEs to Incyte via IncyteSafety@Telerx.com. If critical or 
outstanding information is missing from the Adverse Event Report Form or additional 
clarification is needed, the Incyte representative will submit a Data Clarification Form (DCF) to 
the Sponsor-Investigator. The Sponsor will be required to complete all queries listed on the DCF 
and return the completed DCF to Incyte. 
The Sponsor-Investigator must report to Incyte all Serious Adverse Events regardless of the 
causality assessment. 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Follow- up Reporting 
When new information regarding an SAE becomes available, this information must be reported 
to Incyte on a new or updated Adverse Event Report Form twenty four (24) hours of becoming 
aware of the information. 
Reconciliation 
On a periodic basis (quarterly at minimum), the Sponsor-Investigator will provide a listing of all 
Safety Information recorded for the study to Incyte for reconciliation purposes.  The Sponsor-
Investigator will forward the listing via email to IncytePhVOpsIST@incyte.com  
Interventional Investigator Initiated Trials 
The Sponsor-Investigator reports all Suspect Unexpected Serious Adverse Reactions (SUSARs) 
to the relevant Health Authority where the Investigational New Drug (IND) was approved for the 
Sponsor-Investigator and distributes Investigator Notifications (IN) as required by local 
regulations.  
Incyte will submit to the relevant Health Authorities outside of Sponsor-Investigator’s approved 
countries and distributes Investigator Notifications to other Investigators as applicable. 
• The Sponsor-Investigator will author the Development Safety Update Report (DSUR) 
and share the completed DSUR with Incyte for comment prior to submission to the health 
authority. 
Pregnancies 
Pregnancy, in and of itself, is not regarded as an adverse event, unless there is suspicion that 
study medication may have interfered with the effectiveness of a contraceptive medication or 
method.  The procedures to be followed based on a confirmed pregnancy by a positive serum test 
result are listed below: 
• Investigator and subject must notify each other immediately 
• Investigator must notify the Investigator –Sponsor and Incyte immediately  
• Discontinue study medication immediately 
• Perform the required End-of-treatment visit study evaluations 
• Investigator must complete and submit the Pregnancy Initial and Follow-up report forms 
to the Sponsor 
To ensure subject safety, each pregnancy in a subject during maternal or paternal exposures to 
study drug must be reported within 24 hours of learning of its occurrence.  
Any SAE experienced during pregnancy must be reported on the SAE Report Form and needs to 
be reported to the Investigator-Sponsor and Incyte. 
9.3 
Monitoring  
Various methods will be implemented by the sponsor (UNMC) to exchange information with 
participating sites:  
• Site Initiation/Orientation  


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
• Regular Teleconferences including group wide progress within the agenda  
• Investigator meetings as feasible (remote or on an as needed basis, possibly in 
conjunction with larger meetings)  
• Email distributions/reports as needed  
9.3.1 Data Monitoring 
For this study, data monitoring is the act of overseeing the progress of a clinical trial, and of 
ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard 
operating procedures (SOPs), Good Clinical Practice (GCP), and applicable regulatory 
requirement(s).  Monitoring is a Quality Control, continuous process during the entire trial. 
All participating sites will perform routine data monitoring for this study by each site’s 
institution according to the institution’s internal guidelines and policies.  A copy of the site’s 
monitoring report will be submitted to UNMC.  
9.4 
Auditing  
Auditing is a systematic and independent examination of trial-related activities and documents to 
determine: 
• whether the evaluated trial-related activities were conducted 
•  the data were recorded, analyzed, and accurately reported, according to the protocol, to 
the sponsor's SOPs, GCP, and applicable regulatory requirement(s).  
Auditing is a Quality Assurance, one point process during the trial. 
The UNMC Fred & Pamela Buffett Cancer Center Scientific Review Committee (SRC) will 
review this protocol on at least an annual basis.  
This study will undergo audit on at least a semi-annual basis by the UNMC Fred & Pamela 
Buffett Cancer Center Audit Committee.  
Detailed policy and procedures for this section may be reviewed at: 
https://www.unmc.edu/cancercenter/clinical/prms.html. 
Section 10.0 Statistical Considerations 
10.1   Study Design and Sample Size Description 
The study is an open label, phase II, multicenter trial designed to evaluate ruxolitinib as a salvage 
treatment for subjects with sclerotic GVHD (sclerosis or fasciitis).   
If a subject receives one dose of ruxolitinib then the subject will be included in the safety 
analysis set.  
The full analysis set will include all subjects that are evaluable at 6 months as well as subjects 
who are considered a treatment failure (including deaths) prior to 6 months. Subjects who drop 
out of the study prior to 6 months for reasons unrelated to treatment will be excluded from the 
full analysis set. 


Page 36 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
The primary endpoint is complete and partial responses in skin and/or joint, as determined by 
2014 NIH Criteria (1) at 6 months from initiation of ruxolitinib without addition of any other 
systemic chronic GVHD treatment, relapse of the underlying disease, or death. The historical 
benchmark for overall response for steroid refractory sclerotic chronic GVHD is 25% in a 
randomized phase II trial by Arai et al., comparing imatinib and rituximab (15). In the trial by 
Arai et al., a significant clinical response was defined as “2 or more point improvement on the 
Vienna Skin Score without worsening elsewhere or at least a 1-point improvement in the 4-level 
P-ROM scale or a 2-point improvement in the 7-level scale without worsening elsewhere.” The 
Vienna Skin Score is different from the 2014 NIH criteria (1) for responses in skin and/or joint. 
According to the 2014 NIH guidelines (1), “because the NIH 0 to 3 Skin Score is now 
recommended for response assessment, even substantial improvement in sclerotic features will 
not be considered responses unless the NIH Skin Score improves.” For this reason, for the 
purpose of the stopping rules, responses will include complete and partial responses in skin 
and/or joint, at least a 2-point improvement on 0-10 semiquantitative scale for capturing 
clinician-perceived severity of sclerosis, or clinically significant improvement (improvement by 
≥6 point) on the skin subscale of the Lee symptom scale, consistent with the recommendations of 
the 2014 NIH Criteria (1). Additionally, improvement in percentage of BSA involved with deep 
sclerosis/fasciitis will also be taken into consideration as a marker of responses. 
A two-stage design is planned to test the null hypothesis that the overall response rate p≤0.250 
versus the alternative that p≥0.450. The first stage will occur once 18 subjects have completed 6 
months of treatment. If only 4 or fewer out of the 18 subjects respond at the end of 6 months of 
treatment, the trial will be stopped for futility. At stage two, an additional 24 subjects will be 
enrolled for a combined total of 42 from both stages. If only 15 or fewer respond out of 42 
subjects at the end of stage two, then no further investigation is warranted. If 16 or more respond 
then further investigation is warranted. This design achieves 84% power with a significance level 
of 0.044. Retrospective studies (31, 32, 40) have demonstrated that ruxolitinib is well tolerated 
and effective in patients with steroid-refractory chronic graft-versus-host disease (GVHD) in 
general and sclerotic GVHD. Therefore, the accrual will not be put on hold for interim analysis. 
To meet our statistical endpoints, a sample size of 42 is required; however, to account for 
dropout rate of approximately 10%, the study will dose 47 subjects.  
10.2 
Analysis plan 
Descriptive statistics will be computed for subject characteristics. Mean, standard deviation 
(SD), median and range will be reported for continuous variables and frequencies and 
percentages will be used to describe categorical variables.  
 
 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
10.2.1 Efficacy Endpoints 
Primary and secondary objectives 
The primary objective of the study is to determine the complete and partial responses in skin 
and/or joint after 6 months of therapy. The response rate will be reported as a proportion and 
95% exact confidence interval. This analysis will be conducted on the full analysis set. 
The secondary objective is to determine the overall complete and partial responses after 6 
months of therapy. The response rate will be reported as a proportion and 95% exact confidence 
interval. 
Exploratory Objectives 
Treatment failure (treatment failure defined as: administration of additional systemic therapy for 
chronic GVHD, malignancy relapse or mortality) by 6 months from study enrollment.  
Time to treatment failure will be defined as study enrollment to failure event. Kaplan-Meier 
methods will be used to estimate the distribution for time to treatment failure. The failure rate at 
6 months will be estimated from the Kaplan-Meier curve, and the rate and 95% confidence 
interval will be reported.  
Time to non-relapse mortality will be computed as study enrollment to non-relapse death. 
Cumulative incidence methods will be used to estimate the distribution with relapses and relapse 
related deaths as competing events. The rate at 6 months will be estimated from the curve along 
with 95% confidence intervals. 
For subjects treated on the extension study, the response rate at 12 months will be reported as a 
proportion and 95% exact confidence interval. 
For subjects on steroids at baseline, we will explore the change in dose of steroids at 6 months. 
We will calculate the average percent change in dose for each subject along with a 95% CI. We 
will also determine the number and proportion of subjects that had a dose reduction greater than 
50% as well as an exact 95% confidence interval. 
10.2.3  Safety endpoint 
Safety endpoints will be assessed on the safety analysis set. All adverse events recorded during 
the study will be summarized by each subject.  The incidence of treatment-emergent adverse 
events (new or worsening from baseline) will be summarized by severity and type of adverse 
event. Listings of deaths, severe adverse events, and adverse events leading to early termination 
of study treatment or premature withdrawal from study will also be provided. 
10.2.4 Analysis of patient reported outcomes and Correlative data 
Descriptive statistics will be computed for patient reported outcomes Lee Chronic GVHD 
Symptom Scale, and Scleroderma Health Assessment Questionnaire at study enrollment and 6 
months.  Changes in patient reported outcomes from study enrollment to 3 and 6 months will be 
assessed with paired t-tests or Wilcoxon sign rank test depending on whether test assumptions 
are met. 


Page 38 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
For correlative studies, changes in measured parameters from baseline to defined time points 
after therapy initiation will be measured. We will graphically display biomarker levels over time 
for each subject individually as well as averages at each time point for responders and non-
responders separately. Univariate and multiple logistic regression will be used to determine if the 
change in biomarker level from baseline to 3 and 6 months is predictive of responder status at 6 
months, looking at the biomarkers individually as well as in combination. 
10.3 
Accrual goal 
It is expected that 20 subjects will be enrolled in the trial each year.  To meet the accrual goals of 
47, we require approximately 2.5 years of enrollment with 2 years of follow up.  
10.4 
Stopping rule 
Serious adverse events and deaths will be reviewed by the study team and principal investigators 
on an ongoing basis.  
The risk of treatment-related mortality is 10-20% in patients with steroid refractory chronic 
GVHD (15, 42). The study will have continuous mortality monitoring, and if ≥20% have 
treatment-related mortality that is possibly, probably or definitely related to the study drug, 
accrual will be halted (see stopping rules below). Subjects, who are already enrolled in the study, 
and are tolerating the study drug may continue the drug at the discretion of the treating 
physician.  
Continuous monitoring (43) will be performed after each subject has received the first dose of 
ruxolitinib, beginning when the 2nd subject has received the first dose of ruxolitinib, with K=47 
interim analyses, a null hypothesis mortality rate of 0.10, an alternative hypothesis of 0.20, and 
power of 0.80. The sample size is too small to control alpha and power simultaneously, so alpha 
is 0.19 to allow for 80% power (see below table for operating characteristics). The table below 
displays the boundaries bk for each interim analysis k. If the observed number of treatment-
related mortality is greater than bk, accrual will be terminated. Stopping boundaries were 
calculated with the R package “clinfun” based on Ivanova (41), using this code: toxbdry(0.1 ,0.2, 
3:47, cP0=0.1, cP1=0.8, priority="alt"). 
Continuous monitoring boundaries for K=47 when the true mortality rate is 0.10 and the 
alternative hypothesis is 0.20 and alpha=0.05, 80% power  
Stop if treatment-related mortality is greater than or equal to the boundary (>=bk) 
K 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 
bk - 2 2 2 2 2 2 2 2 
3 
3 
3 
3 
3 
3 
4 
4 
4 
4 
4 
4 
4 
5 
  
K 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 
bk 
5 
5 
5 
5 
5 
5 
6 
6 
6 
6 
6 
6 
6 
6 
7 
7 
7 
7 
7 
7 
 


Page 39 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
K 44 45 46 
47 
bk 
7 
8 
8 
9 
 
Operating characteristics of the stopping rule 
P(death) 
P(stopping) 
Expected sample size 
0.10 
0.192 
41.1 
0.12 
0.309 
37.8 
0.14 
0.443 
34.1 
0.16 
0.577 
30.2 
0.18 
0.697 
26.4 
0.20 
0.795 
22.9 
 
All grade 3 and above or serious adverse events recorded during the study will be summarized. 
Listings of deaths, serious adverse events, and adverse events leading to early termination of 
study treatment or premature withdrawal from study will also be provided to the DSMC. 
Section 11.0 Records to be Kept  
Information regarding the actual treatments, adverse events, and laboratory tests are to be 
recorded on appropriate forms. See attached Data forms. Serious adverse events, when noted, 
will be recorded on site via the standard serious adverse effects form. 
11.1 
Quality Assurance  
Complete records must be maintained in a research chart on each subject treated on the protocol. 
Research chart can be maintained either as an electronic record, paper chart or a combination of 
both. These records should include primary documentation (e.g., laboratory report slips, 
physician notes, etc.) which confirm that:  
- 
The subject met the eligibility criteria.  
- 
Signed informed consent was obtained prior to treatment.  
- 
Treatment was given according to protocol (dated notes about doses given and reasons 
for any dose modifications).  
- 
Toxicity was assessed according to protocol (laboratory report slips, etc.).  
- 
Response was assessed according to protocol (dated notes on clinical assessment, 
laboratory reports as appropriate).  


Page 40 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
11.2 
Advarra Electronic Data Capturing (EDC) System  
Data will be stored electronically for this study on the Advarra secure server. Data forms will not 
differ from the paper versions with the exception of an electronic format containing the UNMC 
Fred & Pamela Buffett Cancer Center and Advarra logo.  
Advarra EDC provides for remote data collection that meets FDA 21 CFR Part 11 requirements 
as well as HIPAA and other regulatory requirements designed to enhance data security and 
protect patient confidentiality. Authorized users log into Advarra through a secure connection 
and must provide a valid username, password, and database ID. This data may be made available 
to the public at large.  
Section 12.0 Subject Consent  
12.1 
Human Subjects Research Protection Training  
All personnel involved in this research project will have completed the OHRP-approved 
computer based training course on the Protection of Human Research Subjects. All clinical and 
correlative research included in this protocol will have approval by the institutional review 
board.  
12.2 
Study Population  
Subjects are from all socio-economic groups and will be entered into the study without bias with 
respect to gender or race. Attempts will be made to recruit minorities. No vulnerable subjects 
will be included in the study.  
12.3 
Sources of Material 
Only material collected for this trial is the blood specimen for the correlative studies. No other 
pathology material is necessary. 
12.4 
Recruitment and Informed Consent  
Subjects with the diagnosis of sclerotic GVHD seen and evaluated at UNMC/Nebraska Medicine 
or other IRB-approved sites will be available for recruitment. These patients will be informed of 
the nature of this study, and will be asked to participate on a voluntary basis after informing them 
of the possible risks and benefits of the study.  A number of public registries may be accessible 
to health care providers and prospective subjects as listed on the title page of this protocol.  
12.5 
Subject Competency  
Subjects will be eligible to participate in the study only if they are competent to give informed 
consent. A subject that the investigators judges to be incompetent will not be enrolled.  
 
 


Page 41 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
12.6 
Process of Informed Consent  
If the patient chooses to be a participant in this study, informed consent will be obtained by the 
investigators. The study and procedures involved including the risks will be explained in detail to 
each subject. It will be clearly explained to the subject that this is a research study and that 
participation is entirely on a voluntary basis. Subjects will be given the option to discuss the 
study with a family member, friend, counselor or, another physician. The participating 
investigators will be available to discuss the study with them.  
12.7 
Subject/Representative Comprehension  
When the process of informed consent is completed, the subject will be asked to state in his/her 
own words, the purpose of the study, the procedures that will be carried out, potential risk, 
potential benefits to the subject, the alternatives and the right to withdraw from the study. If there 
is any indication that a given subject's comprehension is anything less than accurate, the points 
of confusion will be discussed and clarified.  
12.8 
Information Purposely Withheld 
The results of the tests done solely for research purposes will not be disclosed to the subject. No 
other information will be purposely withheld from the subject. 
12.9 
Potential Benefits of the Proposed Research to the Subjects  
It is hoped that the use of ruxolitinib may result in improvement in GVHD. 
12.10 Potential Benefits to Society 
Information obtained from this study may help other GVHD patients by establishing the role of 
ruxolitinib. 
12.11 Potential Risks  
The use of ruxolitinib is associated with numerous potential risks as described in section 8.1.10 
under drug toxicities.  
12.12 Therapeutic Alternatives  
If patients choose not to participate in this study, they may elect to receive other therapy as per 
their treating physician.  
12.13 Risk/Benefit Relationship  
Although there are inherent risks involved because of the use of ruxolitinib, the risk is considered 
to be acceptable in this setting.  
 
 


Page 42 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
12.14 Consent Form Documents  
The results of the tests done solely for research purposes will not be disclosed to the subject. No 
other information will be purposely withheld from the subject. The consent document used in 
this study will include the adult consent document.  
Section 13.0 References   
1. 
Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M, et al. Measuring therapeutic 
response in chronic graft-versus-host disease. National Institutes of Health consensus 
development project on criteria for clinical trials in chronic graft-versus-host disease: IV. 
The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant. 2015 
Jun;21(6):984-99. 
2. 
Flowers ME, Parker PM, Johnston LJ, Matos AV, Storer B, Bensinger WI, et al. 
Comparison of chronic graft-versus-host disease after transplantation of peripheral blood 
stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a 
randomized trial. Blood. 2002 Jul 15;100(2):415-9. 
3. 
Lee SJ, Flowers ME. Recognizing and managing chronic graft-versus-host disease. 
Hematology Am Soc Hematol Educ Program. 2008:134-41. 
4. 
Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow 
Transplant. 2003 Apr;9(4):215-33. 
5. 
Lee SJ, Klein JP, Barrett AJ, Ringden O, Antin JH, Cahn JY, et al. Severity of chronic 
graft-versus-host disease: association with treatment-related mortality and relapse. Blood. 
2002 Jul 15;100(2):406-14. 
6. 
Socie G, Stone JV, Wingard JR, Weisdorf D, Henslee-Downey PJ, Bredeson C, et al. 
Long-term survival and late deaths after allogeneic bone marrow transplantation. Late 
Effects Working Committee of the International Bone Marrow Transplant Registry. N 
Engl J Med. 1999 Jul 1;341(1):14-21. 
7. 
Fraser CJ, Bhatia S, Ness K, Carter A, Francisco L, Arora M, et al. Impact of chronic 
graft-versus-host disease on the health status of hematopoietic cell transplantation 
survivors: a report from the Bone Marrow Transplant Survivor Study. Blood. 2006 Oct 
15;108(8):2867-73. 
8. 
Pidala J, Anasetti C, Jim H. Quality of life after allogeneic hematopoietic cell 
transplantation. Blood. 2009 Jul 2;114(1):7-19. 
9. 
Pidala J, Kurland B, Chai X, Majhail N, Weisdorf DJ, Pavletic S, et al. Patient-reported 
quality of life is associated with severity of chronic graft-versus-host disease as measured 
by NIH criteria: report on baseline data from the Chronic GVHD Consortium. Blood.  Apr 
28;117(17):4651-7. 
10. 
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National 
Institutes of Health Consensus Development Project on Criteria for Clinical Trials in 
Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group 
report. Biol Blood Marrow Transplant. 2015 Mar;21(3):389-401 e1. 
11. 
Inamoto Y, Storer BE, Petersdorf EW, Nelson JL, Lee SJ, Carpenter PA, et al. Incidence, 
risk factors, and outcomes of sclerosis in patients with chronic graft-versus-host disease. 
Blood. 2013 Jun 20;121(25):5098-103. 
12. 
Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015 Jan 
22;125(4):606-15. 


Page 43 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
13. 
Baird K, Comis LE, Joe GO, Steinberg SM, Hakim FT, Rose JJ, et al. Imatinib mesylate 
for the treatment of steroid-refractory sclerotic-type cutaneous chronic graft-versus-host 
disease. Biol Blood Marrow Transplant. 2015 Jun;21(6):1083-90. 
14. 
Magro L, Mohty M, Catteau B, Coiteux V, Chevallier P, Terriou L, et al. Imatinib 
mesylate as salvage therapy for refractory sclerotic chronic graft-versus-host disease. 
Blood. 2009 Jul 16;114(3):719-22. 
15. 
Arai S, Pidala J, Pusic I, Chai X, Jaglowski S, Khera N, et al. A Randomized Phase II 
Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic 
Cell Transplantation. Clin Cancer Res. 2016 Jan 15;22(2):319-27. 
16. 
Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA, et al. Therapy for 
chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus 
prednisone versus prednisone alone. Blood. 2002 Jul 1;100(1):48-51. 
17. 
Martin PJ, Storer BE, Rowley SD, Flowers ME, Lee SJ, Carpenter PA, et al. Evaluation of 
mycophenolate mofetil for initial treatment of chronic graft-versus-host disease. Blood. 
2009 May 21;113(21):5074-82. 
18. 
Arora M, Wagner JE, Davies SM, Blazar BR, Defor T, Enright H, et al. Randomized 
clinical trial of thalidomide, cyclosporine, and prednisone versus cyclosporine and 
prednisone as initial therapy for chronic graft-versus-host disease. Biol Blood Marrow 
Transplant. 2001;7(5):265-73. 
19. 
Gilman AL, Schultz KR, Goldman FD, Sale GE, Krailo MD, Chen Z, et al. Randomized 
Trial of Hydroxychloroquine for Newly Diagnosed Chronic Graft-versus-Host Disease in 
Children: A Children's Oncology Group Study. Biol Blood Marrow Transplant.  May 30. 
20. 
Sullivan KM, Witherspoon RP, Storb R, Weiden P, Flournoy N, Dahlberg S, et al. 
Prednisone and azathioprine compared with prednisone and placebo for treatment of 
chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia after 
allogeneic marrow transplantation. Blood. 1988 Aug;72(2):546-54. 
21. 
Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA, et al. Thalidomide for 
treatment of patients with chronic graft-versus-host disease. Blood. 2000 Dec 
1;96(12):3995-6. 
22. 
Martin PJ, Lee SJ, Przepiorka D, Horowitz MM, Koreth J, Vogelsang GB, et al. National 
Institutes of Health Consensus Development Project on Criteria for Clinical Trials in 
Chronic Graft-versus-Host Disease: VI. The 2014 Clinical Trial Design Working Group 
Report. Biol Blood Marrow Transplant. 2015 Aug;21(8):1343-59. 
23. 
Wolff D, Schleuning M, von Harsdorf S, Bacher U, Gerbitz A, Stadler M, et al. Consensus 
Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic 
Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2011 Jan;17(1):1-17. 
24. 
Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, et al. Ibrutinib for chronic 
graft-versus-host disease after failure of prior therapy. Blood. 2017 Nov 23;130(21):2243-
50. 
25. 
Brown JR. How I treat CLL patients with ibrutinib. Blood. 2018 Jan 25;131(4):379-86. 
26. 
Lee S, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to measure 
symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 
2002;8(8):444-52. 
27. 
Steen VD, Medsger TA, Jr. The value of the Health Assessment Questionnaire and special 
patient-generated scales to demonstrate change in systemic sclerosis patients over time. 
Arthritis Rheum. 1997 Nov;40(11):1984-91. 


Page 44 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
28. 
Johnson SR, Hawker GA, Davis AM. The health assessment questionnaire disability index 
and scleroderma health assessment questionnaire in scleroderma trials: an evaluation of 
their measurement properties. Arthritis Rheum. 2005 Apr 15;53(2):256-62. 
29. 
Pope J. Measures of systemic sclerosis (scleroderma): Health Assessment Questionnaire 
(HAQ) and Scleroderma HAQ (SHAQ), physician- and patient-rated global assessments, 
Symptom Burden Index (SBI), University of California, Los Angeles, Scleroderma 
Clinical Trials Consortium Gastrointestinal Scale (UCLA SCTC GIT) 2.0, Baseline 
Dyspnea Index (BDI) and Transition Dyspnea Index (TDI) (Mahler's Index), Cambridge 
Pulmonary Hypertension Outcome Review (CAMPHOR), and Raynaud's Condition Score 
(RCS). Arthritis Care Res (Hoboken). 2011 Nov;63 Suppl 11:S98-111. 
30. 
Paczesny S, Hakim FT, Pidala J, Cooke KR, Lathrop J, Griffith LM, et al. National 
Institutes of Health Consensus Development Project on Criteria for Clinical Trials in 
Chronic Graft-versus-Host Disease: III. The 2014 Biomarker Working Group Report. Biol 
Blood Marrow Transplant. 2015 May;21(5):780-92. 
31. 
Spoerl S, Mathew NR, Bscheider M, Schmitt-Graeff A, Chen S, Mueller T, et al. Activity 
of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood. 2014 Jun 
12;123(24):3832-42. 
32. 
Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, et al. 
Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell 
transplantation: a multicenter survey. Leukemia. 2015 Oct;29(10):2062-8. 
33. 
Verstovsek  S, Kantarjian  H, Mesa  RA, Pardanani  AD, Cortes-Franco  J, Thomas  DA, 
et al. Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis. 
New England Journal of Medicine. 2010;363(12):1117-27. 
34. 
Cooke KR, Luznik L, Sarantopoulos S, Hakim FT, Jagasia M, Fowler DH, et al. The 
Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National 
Institutes of Health Consensus Development Project on Criteria for Clinical Trials in 
Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2017 Feb;23(2):211-
34. 
35. 
Rice LM, Mantero JC, Stifano G, Ziemek J, Simms RW, Gordon J, et al. A Proteome-
Derived Longitudinal Pharmacodynamic Biomarker for Diffuse Systemic Sclerosis Skin. J 
Invest Dermatol. 2017 Jan;137(1):62-70. 
36. 
Hakim FT, Memon S, Jin P, Imanguli MM, Wang H, Rehman N, et al. Upregulation of 
IFN-Inducible and Damage-Response Pathways in Chronic Graft-versus-Host Disease. J 
Immunol. 2016 Nov 01;197(9):3490-503. 
37. 
Choi J, Ziga ED, Ritchey J, Collins L, Prior JL, Cooper ML, et al. IFNγR signaling 
mediates alloreactive T-cell trafficking and GVHD. Blood. 2012;120(19):4093-103. 
38. 
Choi J, Cooper ML, Alahmari B, Ritchey J, Collins L, Holt M, et al. Pharmacologic 
Blockade of JAK1/JAK2 Reduces GvHD and Preserves the Graft-Versus-Leukemia 
Effect. PLoS One. 2014;9(10):e109799. 
39. 
Carniti C, Gimondi S, Vendramin A, Recordati C, Confalonieri D, Bermema A, et al. 
Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute 
GVHD While Preserving GVT Effects. Clinical Cancer Research. 2015;21(16):3740-9. 
40. 
Khoury HJ, Kota VK, Arellano M, Bauer S, Jillella AP, Langston AA, et al. Ruxolitinib 
As Sparing Agent for Steroid-Dependent Chronic Graft-Versus-Host Disease (cGVHD). 
Biology of Blood and Marrow Transplantation. 2017;23(3):S373. 
41. 
Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder S, et al. Long-
Term Follow-up of Patients with Corticosteroid-Refractory Graft-Versus-Host Disease 
Treated with Ruxolitinib. Blood. 2016;128(22):4561. 


Page 45 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
42. 
Zaja F, Bacigalupo A, Patriarca F, Stanzani M, Van Lint MT, Fili C, et al. Treatment of 
refractory chronic GVHD with rituximab: a GITMO study. Bone Marrow Transplant. 
2007 Aug;40(3):273-7. 
43. 
Jagasia M, Giglia J, Chinratanalab W, Dixon S, Chen H, Frangoul H, et al. Incidence and 
outcome of chronic graft-versus-host disease using National Institutes of Health consensus 
criteria. Biol Blood Marrow Transplant. 2007 Oct;13(10):1207-15. 
 
Section 14.0 Data Collection Forms 
Please refer to the Study Site Manual for the forms. 
 
 


Page 46 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Appendix A: Manifestations of chronic graft-versus-host disease  
 
 


Page 47 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
ALT indicates alanine aminotransferase; AIHA, autoimmune hemolytic anemia; ITP, idiopathic 
thrombocytopenic purpura. 
* In all cases, infection, drug effect, malignancy, or other causes must be excluded. 
† Can be acknowledged as part of the chronic GVHD manifestations if diagnosis is confirmed. 
‡ Common refers to shared features by both acute and chronic GVHD. 
§BOS can be diagnostic for lung chronic GVHD only if distinctive sign or symptom present in 
another organ (see text). 
|| Pulmonary entities under investigation or unclassified. 
¶ Diagnosis of chronic GVHD requires biopsy. 
 
 
 
 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Appendix B: Organ scoring of chronic graft-versus-host disease per 2014 NIH consensus 
 
 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
 
 
 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Appendix C: NIH Global Severity of chronic GVHD 
 
 
 
 


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UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Appendix D: Lee Symptom Scale 
 
By circling one (1) number per line, please indicate how much you have been bothered by the 
following problems in the past 7 days: 
SKIN: 
Not at 
all 
Slightly 
Moderately 
Quite a 
bit 
Extremely 
1.  
Abnormal skin color……………….. 
0 
1 
2 
3 
4 
2.  
Rashes……………………………… 
0 
1 
2 
3 
4 
3.  
Thickened skin…………...………... 
0 
1 
2 
3 
4 
4.  
Sores on skin………………………. 
0 
1 
2 
3 
4 
5. 
Itchy skin…………………...………. 
0 
1 
2 
3 
4 
EYES AND MOUTH: 
Not at 
all 
Slightly 
Moderately 
Quite a 
bit 
Extremely 
6.  
Dry eyes……………………………. 
0 
1 
2 
3 
4 
7.  
Need to use eye drops frequently.. 
0 
1 
2 
3 
4 
8.  
Difficulty seeing clearly…………… 
0 
1 
2 
3 
4 
9.  
Need to avoid certain foods due to 
mouth pain…………………………. 
0 
1 
2 
3 
4 
10.  Ulcers in mouth……………………. 
0 
1 
2 
3 
4 
11.  Receiving nutrition from an 
intravenous line or feeding tube.... 
0 
1 
2 
3 
4 
BREATHING: 
Not at 
all 
Slightly 
Moderately 
Quite a 
bit 
Extremely 
12.  Frequent cough……………………. 
0 
1 
2 
3 
4 
13.  Colored sputum……………………. 
0 
1 
2 
3 
4 
14.  Shortness of breath with exercise.. 
0 
1 
2 
3 
4 
15.  Shortness of breath at rest……... 
0 
1 
2 
3 
4 
16.  Need to use oxygen…………….. 
0 
1 
2 
3 
4 
 


Page 53 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
 
 
 
EATING AND DIGESTION: 
Not at 
all 
Slightly 
Moderately 
Quite a 
bit 
Extremely 
17.  Difficulty swallowing solid foods…. 
0 
1 
2 
3 
4 
18. 
Difficulty swallowing liquids………. 
0 
1 
2 
3 
4 
19.  Vomiting……………………………. 
0 
1 
2 
3 
4 
20.  Weight loss………………………… 
0 
1 
2 
3 
4 
MUSCLES AND JOINTS: 
Not at 
all 
Slightly 
Moderately 
Quite a 
bit 
Extremely 
21. 
Joint and muscle aches…………... 
0 
1 
2 
3 
4 
22. 
Limited joint movement…………… 
0 
1 
2 
3 
4 
23. 
Muscle cramps…………………….. 
0 
1 
2 
3 
4 
24. 
Weak muscles……………………... 
0 
1 
2 
3 
4 
ENERGY: 
Not at 
all 
Slightly 
Moderately 
Quite a 
bit 
Extremely 
25.  
Loss of energy……………………. 
0 
1 
2 
3 
4 
26.  
Need to sleep more/take naps….. 
0 
1 
2 
3 
4 
27.  
Fevers……………………………… 
0 
1 
2 
3 
4 
MENTAL AND EMOTIONAL: 
Not at 
all 
Slightly 
Moderately 
Quite a 
bit 
Extremely 
28.  
Depression………………………… 
0 
1 
2 
3 
4 
29.  
Anxiety……………………………... 
0 
1 
2 
3 
4 
30.  
Difficulty sleeping…………………. 
0 
1 
2 
3 
4 


Page 54 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Appendix E: Modified Scleroderma Health Assessment Questionnaire (SHAQ)  
In the past seven (7) days,  
Without any 
difficulty 
With some 
difficulty 
With much 
difficulty 
Unable 
to do 
Are you able to: 
Dress yourself, including tying shoelaces and doing buttons? 
 
 
 
 
Shampoo your hair? 
 
 
 
 
Are you able to: 
Stand up from an armless straight chair? 
 
 
 
 
Get in and out of bed? 
 
 
 
 
Are you able to: 
Cut your meat? 
 
 
 
 
Lift a full cup or glass to your mouth? 
 
 
 
 
Open a new carton of milk? 
 
 
 
 
Are you able to: 
Walk outdoors on flat ground? 
 
 
 
 
Climb up 5 steps? 
 
 
 
 
Are you able to: 
Wash and dry your entire body? 
 
 
 
 
Take a tub bath? 
 
 
 
 
Get on and off the toilet? 
 
 
 
 
Are you able to: 
Reach and get down a 5 pound object (such as a bag of sugar) 
from just above your head? 
 
 
 
 
Bend down and pick up clothing from the floor? 
 
 
 
 
Are you able to: 
Open car doors? 
 
 
 
 
Open jars which have previously opened? 
 
 
 
 
Turn regular taps on and off? 
 
 
 
 
Are you able to: 
Run errands and shop? 
 
 
 
 
Get in and out of a car? 
 
 
 
 
Do chores such as vacuuming or yard work? 
 
 
 
 
 
Please check any Aids or Devices that you usually use: 
 
Please check any categories for which you usually need help from another person: 
Hygiene 
 
Gripping and Opening Things 
 
Reach 
 
Errands and Chores 
 
Arising 
 
Dressing and Grooming 
 
Eating 
 
Walking 
 
 
 
Cane 
 
Dressing Devices (button hook, long shoe horn, etc.) 
 
Walker 
 
Built up or Special Utensils 
 
Bathtub seat 
 
Long Handled Appliances for reach  
 
Bathtub Bar 
 
Long Handled Appliances for Bathroom 
 
Jar Opener 
 
Raised Toilet seat 
 
Crutches 
 
Special or Built-up Chair 
 
Wheelchair 
 
        Other (Specify) 


Page 55 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Place a mark on the line to indicate the severity of the pain. 
 
How much pain have you had because of your illness in the past week? 
 
No Pain 
Very Severe Pain 
 
 
0 100 
 
 
1. In the past week, how much have your breathing problems interfered with your activities? 
 
 
 
does not interfere 
very severe limitation 
 
2. Overall, considering how much pain, discomfort, limitations in your daily life and other 
changes in your body and life, how severe would you rate your disease today? 
 
 
 
no disease 
very severe 
 
 
 
 


Page 56 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Appendix F: Eligibility Checklist 
Date Completed:      
Site #:      
Subject ID#:      
 
IRB # 333-18  
Title: A Single Arm, Open Label, Phase II Study of Ruxolitinib in 
Sclerotic Chronic Graft-Versus-Host Disease after Failure of 
Systemic Glucocorticoids 
Waiver #:      
Incyte Ref #:      
Investigator:      
Inclusion criteria: 
Yes 
No 
NA 
1. Sclerotic chronic GVHD (classic chronic or overlap syndrome) that meets 2014 
NIH Consensus Criteria. Eligible patients will have superficial or deep skin 
sclerosis, fasciitis or joint contractures.  
☐ 
☐ 
☐ 
2. The subject must have received the following therapy for chronic GVHD (not 
necessarily for sclerotic manifestations): 
a. Systemic corticosteroids for >12 months and at least one additional line of 
systemic therapy OR  
b. Systemic corticosteroids and at least two additional lines of systemic therapy for 
chronic GVHD (not necessarily for sclerotic manifestations).  
For the purpose of this study, intra-oral narrow-band UVB phototherapy and “FAM” 
(fluticasone, azithromycin and montelukast) therapy for lung GVHD will be considered a topical 
therapy. Investigators are encouraged but not mandated to use ibrutinib for appropriate patients 
prior to enrollment in this trial. 
☐ 
☐ 
☐ 
3. Adults, Age ≥18 years. (state of Nebraska, Age ≥19 years)  
☐ 
☐ 
☐ 
4. Karnofsky performance status ≥60% at the time of enrollment  
☐ 
☐ 
☐ 
5. All allogeneic donor sources and all conditioning regimens are allowed.  
☐ 
☐ 
☐ 
6. Absolute neutrophil count (ANC) greater than 1000/µL, and platelet count ≥50,000/µL 
without the use of growth factors or platelet transfusion. 
☐ 
☐ 
☐ 
7. Able to take orally-administered medication.  
☐ 
☐ 
☐ 
8. Female subject of reproductive potential must have a negative serum or urine pregnancy 
test ≤7 days prior to starting the study drug. Women are considered NOT to have 
reproductive potential if they have had 12 months of amenorrhea with an appropriate 
clinical profile (i.e. ≥51 years, history of vasomotor symptoms, OR supportive hormone 
levels such as low estrogen and high follicle-stimulating hormone levels), OR surgical 
sterilization.  
☐ 
☐ 
☐ 


Page 57 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
9. Male and female patients of reproductive potential must be willing to avoid pregnancy or 
fathering children from enrollment to one month after the end of study treatment. This 
will require either a total abstinence, OR exclusively non-heterosexual activity (when 
this is in line with the preferred and usual lifestyle of the subject), OR two methods of 
contraception (male or female condom with or without a spermicidal agent, diaphragm or 
cervical cap with spermicide, or hormonal based contraception including intrauterine 
device).  
☐ 
☐ 
☐ 
10. Life expectancy greater than 6 months 
☐ 
☐ 
☐ 
11. Written informed consent to participate in the study.  
☐ 
☐ 
☐ 
All of the above must be yes to be eligible.  
Exclusion criteria    
Yes 
No 
NA 
1. Fibrosis of internal organs such as gut, liver or lung as the sole manifestation of sclerosis.  ☐ 
☐ 
☐ 
2. Fluconazole at a dose more than 200 mg daily. Subjects should stop fluconazole or lower 
dose to less than or equal to 200 mg daily before starting ruxolitinib.  
☐ 
☐ 
☐ 
3. Current evidence of malignancy after allogeneic transplant. 
☐ 
☐ 
☐ 
4. History of progressive multifocal leuko-encephalopathy (PML) 
☐ 
☐ 
☐ 
5. Active uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are 
considered controlled if appropriate therapy has been instituted and, at the time of 
screening, no signs of infection progression are present. Progression of infection is 
defined as hemodynamic instability attributable to sepsis, new symptoms, worsening 
physical signs or radiographic findings attributable to infection. Persisting fever without 
other signs or symptoms will not be interpreted as progressing infection 
☐ 
☐ 
☐ 
6. Presence of known HIV infection, active hepatitis B or C infection.  
☐ 
☐ 
☐ 
7. Active tuberculosis infection that developed after allogeneic HCT 
☐ 
☐ 
☐ 
8. Total bilirubin 1.5 x the upper limit of the normal range 
☐ 
☐ 
☐ 
9. Creatinine clearance <30 mL/min 
☐ 
☐ 
☐ 
10. Presence of uncontrolled cardiopulmonary conditions such as ongoing cardiac 
arrhythmias, unstable angina or myocardial infarction, uncontrolled hypertension (e.g. 
blood pressure higher than 150/90), New York Heart Association class III/IV congestive 
heart failure, or requirement of supplemental oxygen at rest or having a resting O2 
saturation <90% by pulse oximetry 
☐ 
☐ 
☐ 
11. Any other condition that is judged by the physician to potentially interfere with 
compliance to the study protocol or pose a significant risk to the subject.  
☐ 
☐ 
☐ 
12. Pregnancy, breastfeeding or planning to be pregnant.  
☐ 
☐ 
☐ 


Page 58 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
13. Exposure to JAK inhibitor therapy for any indication after allogeneic transplant 
☐ 
☐ 
☐ 
14. Initiation of a new systemic immunosuppressant for management of chronic GVHD 
within 8 weeks prior to enrollment. However, patients who develop disease progression 
can enroll as early as 4 weeks after initiation of a new systemic immunosuppressant. 
Also, patients who are unable to tolerate current therapy can enroll any time after 
initiation of a new systemic immunosuppressant, as long as the “new” 
immunosuppressant is stopped in these cases prior to initiation of ruxolitinib. Initiation 
of any new topical therapy (including FAM or intra-oral narrow-band UVB 
phototherapy) and changes in dose of existing immunosuppressive agents such as 
corticosteroids, sirolimus, calcineurin inhibitors or other agents are acceptable at any 
time prior to enrollment. The use of immunosuppressants for short term period, for 
example 7 days, for indications other than GVHD will be acceptable. 
☐ 
☐ 
☐ 
15. Treatment with any other investigational agent, device, or procedure, within 21 days (or 
5 half-lives, whichever is greater) 
☐ 
☐ 
☐ 
16. Known allergies, hypersensitivity, or intolerance to any of the study medications, 
excipients, or similar compounds.  
☐ 
☐ 
☐ 
All of the above must be no to be eligible. 
Eligibility:   ☐  Subject satisfies all criteria.  
                    ☐  Subject not formally eligible, but admitted to study because (state reason)       
  
 
Subject Initials:  ______________MR #______________DOB ______________ 
ELIGIBILITY Reviewed and Confirmed By: 
Site Investigator Signature _______________________                     Date_____________        


Page 59 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Appendix G: Response Determination for Chronic GVHD Clinical Trials based on 
Clinician Assessments  
 
 
 
 


Page 60 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Appendix H: NCI Common Toxicity Criteria Version 4.03 (CTCAE), Active Date: June 14, 
2010 
 
Toxicity will be scored using NCI CTC Version 4.03 for toxicity and adverse event reporting. A 
copy of the NCI CTC Version 4.03 can be downloaded from the CTEP homepage: 
(https://ctep.cancer.gov/). All appropriate treatment areas have access to a copy of the CTC 
Version 4.03. 
 
 


Page 61 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Appendix I: Tool for Body Mapping 
 
 
 
 
Source: https://www.qxmd.com/calculate/file_source_15/rule-of-nines 
 


Page 62 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Appendix J:  Dosing Diary 
Ruxolitinib Dosing Diary 
IRB#:  333-18   
Subject ID: 
    
Subject Initials: 
    
Study Drug Storage:  
Store the drug at room temperature in a safe place that is out of reach of children.  
 
Subject Instructions: 
1. Complete one form for each month of treatment 
2. Take Ruxolitinib tablets by mouth at the same time each day with a glass of water.  It can be taken 
with or without food. 
3. Wash hands thoroughly before and after handling Ruxolitinib.  Only remove the number of tablets 
needed at the time of dosing AND do not remove extra tablets in advance of the next scheduled dose.  
4. Record the date and the number of tablets you took each time.  
5. DO NOT retake another dose if vomiting occurs after you have taken study drug.  
6. If you have any side effects or other comments, please record them in the Comments section.  
7. Bring this form and all used and unused medication to your doctor's visit.  
8. DO NOT consume Grapefruit Juice while on this study drug. 
9. Please talk to the study staff PRIOR to taking any new medications, including any supplements. 
Total Daily Dose:      mg 
Take #      of tablet(s) in AM 
Take #      of tablet(s) in PM 
Date 
# Tablets Taken 
Comments 
AM Dose 
PM Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 63 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Date 
# Tablets Taken 
Comments 
AM Dose 
PM Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 64 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Date 
# Tablets Taken 
Comments 
AM Dose 
PM Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 65 of 65 
UNMC IRB # 333-18, Protocol Version 1.6 dated 25Jan2021 
Date 
# Tablets Taken 
Comments 
AM Dose 
PM Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ICF_000.pdf: 
Title: A Single Arm, Open Label, Phase II Study of Ruxolitinib in Sclerotic Chronic Graft-Versus-Host 
Disease after Failure of Systemic Glucocorticoids   
NCT Number:   NCT03616184 
Date of the document: 04/07/2022 


CONSENT FORM
IRB PROTOCOL # 0333-18-FB
  Page 1 of 14
ADULT CONSENT - CLINICAL BIOMEDICAL
Title of this Research Study
Invitation
You are invited to take part in this research study. You have a copy of the following,
which is meant to help you decide whether or not to take part:
Informed consent form
"What Do I need to Know Before Being in a Research Study?"
The Rights of Research Subjects
Why are you being asked to be in this research study?
Your doctor invited you to take part in this study because you have sclerotic chronic
graft-versus-host disease (GVHD) after hematopoietic cell transplantation that is not
responding to treatment.
Up to 47 people will participate in this trial at many centers across the United States.
Up to 18 will be enrolled in this study at the University of Nebraska Medical Center.
If you are pregnant, nursing an infant, or plan to come to become pregnant during
this study, you may not be in this study.
What is the reason for doing this research study?
Sclerotic chronic GVHD is an important complication of transplant that can cause
unwanted symptoms and disability in many different parts of your body. Many times,
sclerotic chronic GVHD do not respond well to initial treatments, and therefore will
need to go on to additional types of chronic GVHD treatment. This research study will
investigate whether a drug called ruxolitinib can effectively treat sclerotic chronic
GVHD.
The study drug, ruxolitinib, has been approved by the Food and Drug Administration
(FDA) to treat other blood disorders, but not sclerotic chronic GVHD. The use of
ruxolitinib in patients with chronic GVHD is investigational.
What will be done during this research study?
You may be in this study for up to 24 months after study enrollment. If you decide to
participate in this study, you will come to clinic for the following study visits:
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Baseline Assessments:
The investigator will discuss the study with you, and ensure that you are eligible to
take part. If you choose to take part in this study, you will be invited to signed this
form. You will be assigned a study number which will be used to identify you
throughout the study. Your medical history will be reviewed. As part of your baseline
visit:
1. You will have a physical exam
2. Standard clinical laboratory blood tests will be performed. Additional tests will
be performed to check your blood lipid levels and pancreatic enzymes. We
will confirm that you do not have serious infectious problems including
hepatitis and HIV; tests will be performed if they have not been previously
done.
3. You will have an electrocardiogram (EKG) to check how your heart is doing.
4. If you are a woman of child-bearing potential, a pregnancy test will be
performed.
5. Blood will be collected from you for a research blood sample for this study
during this visit. These samples will be used to study how ruxolitinib affects
the immune system. You will not have more than 30ml (about 2 tablespoons)
of blood drawn for this research study at a single visit.
6. You will complete 2 questionnaires about your chronic GVHD and your quality
of life. It will take you about 30-45 minutes to complete the questionnaires.
7. The investigator will assess your GVHD using physical examination, and
digital pictures.
8. You will receive study drug
This visit will take about 2 -3 hours to complete.
Study Treatment:
Ruxolitinib (the study drug) is an oral therapy (tablet) that you will take twice a day for
up to 7 months. If the drug is helping you at 6 months, you will take it up to 13
months in total. You will fill out a medication diary to track your doses.
Day 14 & Day 28 ±4 days:
The following will be performed at this visit:
Standard clinical laboratory blood tests
This visit will take about 30-60 minutes to complete. If you complete the clinical lab
tests with your primary care provider and not at the research center, you will receive
a phone call from study personnel if there are abnormal results.
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Month 2, 4, and 5 ±14 days:
The following will be performed at this visit:
Standard clinical laboratory blood tests.
This visit will take about 30-60 minutes to complete. If you complete the clinical lab
tests with your primary care provider and not at the research center, you will receive
a phone call from study personnel if there are abnormal results.
Month 3 and 6 ±14 days:
The following will be performed at this visit:
A history and physical exam including GVHD evaluation and digital pictures,
Standard clinical laboratory blood, including tests for blood lipid levels and
pancreatic enzymes, if needed (at month 3 visit).
Research blood samples collected for the study
Picking up your supply of study drug
Filling out questionnaires about your GVHD
These visits will take about 1-2 hours to complete.
Extended Treatment:
At 6 months, if the drug is helping you, you will be followed for up to a total of 2 years
(9, 12, 15, 18, 21 and 24 months ±30 days). If the drug is helping you at 6 months
(that is GVHD is stable or responding), you will receive ruxolitinib for 7 to 13 months.
You will come to clinic for:
A history and physical exam including GVHD evaluation and digital pictures
Standard clinical laboratory blood tests
Picking up your supply of study drug (until you stop taking the study drug)
Filling out questionnaires about your GVHD
These visits will take about 1-2 hours to complete.
Safety follow-up:
After you finish taking the study drug, you will enter the safety follow-up part of the
study. This will occur 30-40 days after your last dose. You will have a history and
physical exam, and standard clinical laboratory blood tests This visit will take about
30-60 minutes to complete.
Data collection from review of your medical record may continue even when you are
off the study drug.
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What are the possible risks of being in this research study?
While on this study, you are at risk for side effects. These side effects will vary from
person to person. Many side effects go away shortly after treatment is stopped, but in
some cases side effects may be serious, long-lasting or permanent, and may even
result in hospitalization and/or death. Tell the study staff about any side effects you
may have, even if you do not think they are related to the study drugs.
Ruxolitinib: The following side effects have been observed in patients who have
been treated with ruxolitinib.
Common Risks (10% or more of people taking this drug report these side
effects):
Anemia (low red blood cells)
Neutropenia (low white blood cells)
Thrombocytopenia (low platelets)
Bruising
Raised ALT and AST (blood proteins that may indicate mild liver damage)
Hypercholesterolemia (increase in cholesterol)
Hypertriglyceridemia (increase in triglycerides)
Dizziness
Headache
Urinary tract infections
Weight Gain
Less Common Risks (1-10% of people taking this drug report these side
effects):
Gas
Constipation
Herpes zoster (shingles)
Hypertension (high blood pressure)
Ruxolitinib may cause low blood cell counts (white blood cells, red blood cells and
platelets). If your white blood cell count becomes low while you take the drug, this
means that there may be more of a chance of getting an infection, including urinary
tract infections and viral infections. You will be checked for any signs of infection
before starting ruxolitinib and any serious infections should be treated before you
start ruxolitinib; your physician will check you carefully for signs of infection while you
are being treated.
You also may become anemic (low red blood cell count) while you take the drug, and
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that may cause you to feel fatigued or short of breath. If your platelet count becomes
low while you take the drug, it may lead to bleeding and/or bruising. In some people
taking ruxolitinib, the decreases in blood cell counts have been severe. In most
cases, low blood cell counts can be reversed by stopping the study drug temporarily
or reducing the dose; you will be checked often for this side effect while on study. If
your blood cell counts do not recover quickly, your study drug dose may be stopped
for a longer duration to allow the blood cell counts to recover.
Uncommon Risks (1% or less of people taking this drug report these side
effects):
These events are events that were uncommon, but have occurred in patient during
ruxolitinib treatment are potentially serious.
Tuberculosis has occurred in a small number of patients (less than 1%) who were
treated with ruxolitinib, but it is not known whether this was due to ruxolitinib, or other
factors that are known to increase the risk of tuberculosis (such as diabetes,
bronchitis, asthma, smoking, emphysema, or steroid use). Tell your study doctor if
you have been treated for TB in the past, or have ever had a positive skin test for TB.
Additionally, you should tell your study doctor immediately if you have any of the
following symptoms while on the study: chronic cough with blood-tinged sputum,
fever, night sweats, weight loss.
About one week following interruption or discontinuation of ruxolitinib, some patients
may experience a return of symptoms (such as fatigue, bone pain, fever, itching,
night sweats, weight loss, or an enlarged spleen). There have been cases of patients
stopping ruxolitinib during another ongoing illness who became more severely ill, but
it was not clear whether stopping therapy contributed to the patients conditions
worsening.
A rare disease called progressive multifocal leukoencephalopathy (PML) has been
reported during ruxolitinib treatment. PML comes from a viral infection that causes
brain damage and can be fatal. It is unknown whether this was due to ruxolitinib
treatment since PML has occurred in patients with blood cancers who were not
treated with ruxolitinib. Tell your study doctor immediately if you have any of the
following symptoms or if anyone close to you notices that you have any of these
symptoms: confusion or problems thinking, loss of balance or problems walking,
clumsiness, difficulty speaking, decreased strength or weakness on one side of your
body, blurred and/or loss of vision.
Questionnaires: Some questions about the impact of chronic GVHD may upset you.
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You may skip any question for any reason.
Blood Draw: The risks of blood draws are pain, bruising, infection, redness, and
swelling at the site of the needle entry. There is a chance you may feel dizzy while
your blood is being drawn. If you have severe anemia, blood collection for research
may be delayed or canceled.
Reproductive Risks: It is possible that the medicines used in this study could injure
a fetus if you, or your partner, becomes pregnant while taking them. You have
already been told what is known about this possibility, and you are encouraged to
ask further questions.
You may want to discuss this with others before you agree to take part in this study.
If you wish, we will arrange for a doctor, nurse, or counselor who is not part of this
study to discuss the potential risks and benefits with you and anyone else you want
to have present.
Because of the potential risks, you, or your partner, must not become pregnant while
you are participating in this study. Women must have a negative pregnancy test
before entering the study.
If you are sexually active and can get pregnant, or can get your partner pregnant, you
must use two appropriate method(s) of birth control every time you have sex, or you
must not have sex.
Condoms (male or female) with or without a spermicidal agent
Diaphragm or cervical cap with spermicide
IUD
Hormonal based contraception
Because of the nature of this research, methods of natural family planning are not, by
themselves, sufficiently reliable to avoid pregnancy.
You can get additional information about methods to avoid pregnancy by calling the
UNMC Research Subject Advocate's Office at (402) 559-6941.
You will need to continue to avoid pregnancy for 3 months after the last dose of
ruxolitinib.
By signing this and being in the study, you are agreeing to not get pregnant while you
are on the study and for 3 months after. Should you become pregnant while on this
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study, you should immediately notify the study personnel. The investigator will assist
you in finding appropriate medical care. The investigator also may ask to be allowed
to continue getting information about your pregnancy. You can refuse to provide this
information.
Risks to breast-fed children: It is possible that the study medication could be
present in breast milk and injure a breastfed baby. Women should not breast-feed a
baby while on this study. Breast-feeding mothers must stop breast-feeding to take
part in this study.
What are the possible benefits to you?
The major potential benefit is that this study treatment could improve your sclerotic
chronic GVHD. You may not get any benefit from being in this research study. We do
not know if this study will help patients directly.
What are the possible benefits to other people?
The information learned from this study will help physicians learn more about
ruxolitinib as a treatment for GVHD. The research blood tests may also provide
information regarding the effect of GVHD and ruxolitinib on immune system. This
information may someday be of benefit to future patients.
What are the alternatives to being in this research study?
Instead of being in this research study, you can choose not to participate. If you do
not join this study, you have other choices for treatment. One FDA approved
treatment for your condition is ibrutinib.
Before you decide to take part in this study, your study doctor will talk with you about
other options available to you, which may include other medications, treatments, or
dose changes in your current medications. The investigators will discuss with you the
risks and benefits of each of the alternatives described above.
What will being in this research study cost you?
You or your insurance company will not be billed for tests and procedures done
specifically for this study (i.e., extra blood drawn for research, pregnancy tests,
questionnaires). Ruxolitinib will be provided free of charge from Incyte Corporation.
There are some extra costs for being in this study. You or your insurer will have to
pay these costs. Some insurers will not pay for research. Check with your insurer
before you join this study.
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Whether you are in the study or not, you or your insurance company will be
responsible for medications, tests, clinic and hospital visits as part of your routine
care as a transplant recipient.
You will be responsible for any applicable insurance deductibles and co-payments. If
you wish to speak with a financial counselor about your insurance coverage and
benefits, let the investigator or other study personnel know. A contact for personal
assistance will be made available for you.
Will you be paid for being in this research study?
You will not be paid to be in this research study.
Who is paying for this research?
This research is being paid for by grant funds from Incyte Corporation. The Institution
receives money from Incyte Corporation to conduct this study.
Dr. Vijaya Bhatt, the Principal Investigator of this study, receives money providing
consulting services to Incyte Corporation.
What should you do if you are injured or have a medical problem during this
research study?
Your welfare is the main concern of every member of the research team. If you are
injured or have a medical problem as a direct result of being in this study, you should
immediately contact one of the people listed at the end of this consent form.
Emergency medical treatment for this injury or problem will be available at the
Nebraska Medical Center. If there is not sufficient time, you should seek care from a
local health care provider.
The Institution has no plans to pay for any required treatment or provide other
compensation. If you have insurance, your insurance company may or may not pay
the costs of medical treatment. If you do not have insurance, or if your insurance
company refuses to pay, you will be expected to pay for the medical treatment.
Agreeing to this does not mean you have given up any of your legal rights.
How will information about you be protected?
You have rights regarding the protection and privacy of your medical information
collected before and during this research. This medical information is called
"protected health information" (PHI). PHI used in this study may include your medical
record number, address, birth date, medical history, the results of physical exams,
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blood tests, x-rays as well as the results of other diagnostic medical or research
procedures. Only the minimum amount of PHI will be collected for this research. Your
research and medical records will be maintained in a secure manner.
Who will have access to information about you?
By signing this consent form, you are allowing the research team to have access to
your PHI. The research team includes the investigators listed on this consent form
and other personnel involved in this specific study at the Institution.
Your PHI will be used only for the purpose(s) described in the section "What is the
reason for doing this research study?"
You are also allowing the research team to share your PHI, as necessary, with other
people or groups listed below:
The UNMC Institutional Review Board (IRB)
Institutional officials designated by the UNMC IRB
Federal law requires that your information may be shared with these groups:
The HHS Office of Human Research Protections (OHRP)
The Food and Drug Administration (FDA)
National Institutes of Health (NIH)
The HIPAA Privacy Rule requires the following groups to protect your PHI
Your health insurance company
The Fred & Pamela Buffett Cancer Center Scientific Review
Committee (SRC).
Your PHI may also be shared with the following groups. However, these
organization(s) do not have the same obligation to protect your PHI:
Incyte Corporation and Novartis International Pharmaceutical Ltd., provides
funds the Institution to conduct this research
Data and Safety Monitoring Committee (DSMC)
The National Cancer Institute's (NCI) Clinical Trial Reporting Program
Your information may be kept and used indefinitely.
You may cancel your authorization for further collection of PHI for use in this
research at any time by contacting the principal investigator in writing. However, the
PHI which is included in the research data obtained to date may still be used. If you
cancel this authorization, you will no longer be able to participate in this research.
How will results of the research be made available to you during and after the
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study is finished?
In most cases, the results of the research can be made available to you when the
study is completed, and all the results are analyzed by the investigator or the sponsor
of the research. The information from this study may be published in scientific
journals or presented at scientific meetings, but your identity will be kept strictly
confidential.
If you want the results of the study, contact the Principal Investigator at the phone
number given at the end of this form or by writing to the Principal Investigator at the
following address:
Vijaya Bhatt, MBBS
9876840 Nebraska Medical Center, Omaha, NE 68198-6840
A description of this clinical trial will be available on www.ClinicalTrials.gov, as
required by U.S. law. This website will not include information that can identify you. At
most, the website will include a summary of the results. You can search this website
at any time.
What will happen if you decide not to be in this research study?
You can decide not to be in this research study. Deciding not to be in this research
will not affect your medical care or your relationship with the investigator or the
Institution. Your doctor will still take care of you and you will not lose any benefits to
which you are entitled.
What will happen if you decide to stop participating once you start?
You can stop participating in this research (withdraw) at any time by contacting the
Principal Investigator or any of the research staff.
Deciding to withdraw will otherwise not affect your care or your relationship with the
investigator or this institution. You will not lose any benefits to which you are entitled.
For your safety, please talk to the research team before you stop taking any study
drugs or stop other related procedures. They will advise you how to withdraw safely.
If you withdraw you may be asked to undergo some additional tests. You do NOT
have to agree to do these tests.
You may be taken off the study if you do not follow instructions of the investigator or
the research team.
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You may also be taken off the study if
your GVHD progresses, resulting in starting of a new systemic
immunosuppressive medication
you develop an adverse reaction that requires you to discontinue the study
drug
you develop an allergic reaction or sever intolerance to the study drug
you develop other medical problems that make continuing the study could
cause you harm
you choose to discontinue the study drug
Any research data obtained to date may still be used in the research.
Will you be given any important information during the study?
You will be informed promptly if the research team gets any new information during
this research study that may affect whether you would want to continue being in the
study.
What should you do if you have any questions about the study?
You have been given a copy of "What Do I Need to Know Before Being in a
Research Study?" If you have any questions at any time about this study, you should
contact the Principal Investigator or any of the study personnel listed on this consent
form or any other documents that you have been given.
What are your rights as a research participant?
You have rights as a research subject. These rights have been explained in this
consent form and in The Rights of Research Subjects that you have been given. If
you have any questions concerning your rights, or want to discuss problems,
concerns, obtain information or offer input, or make a complaint about the research,
you can contact any of the following:
The investigator or other study personnel
Institutional Review Board (IRB)
Telephone: (402) 559-6463.
Email: IRBORA@unmc.edu
Mail: UNMC Institutional Review Board, 987830 Nebraska Medical
Center, Omaha, NE 68198-7830
Research Subject Advocate
Telephone: (402) 559-6941
Email: unmcrsa@unmc.edu
Optional Long-term Storage of Leftover Blood Samples
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You may take part in these additional studies if you want to. You can say "yes" or
"no" to this option. You can still be a part of the main study even if you say 'no' to
taking part in this additional study. Please mark your choice with your initials.
The researchers doing this study are interested in doing additional research now or in
the future on the samples collected from you to better understand the nature of
GVHD and how patients respond to treatment. Rapid advances in technology make it
impossible to predict what new tests or studies may be possible in the future.
The required collection of these research blood samples will be before you begin
treatment and at months 3 and 6. The samples will not be sold. If you allow, we will
store leftover samples for future use.
The samples will be kept until they are used up or destroyed.
Reports about any research tests done with your samples will not be given to you or
your oncologist, or family doctor. These reports will not be put in your medical
records.
Confidentiality of Samples
To protect your identity, the information that will be on your blood samples will be
limited to the participant code. The samples may possibly be traced back to you, but
we will take steps to protect your confidentiality.
Withdrawal of Required Samples
If you no longer want your samples to be used in this research, you should tell the
investigator. The investigator will ensure the samples are destroyed. If tests have
already been done on your sample(s) it will not be possible to withdraw those results.
However, no further testing will be done.
This research may not benefit you, but may help people in the future who have the
same kind of cancer as you have. You can indicate your wish to participate in this
additional research, and have your samples stored by the University of Nebraska
Medicine designated central for future extended research purposes when signing this
consent form. You may decide not to participate in the "optional" study and still
participate in this main study.
_____ You agree to allow storage and use of blood samples taken from you for
extended research (optional).
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_____ You do not agree to storage and use of blood samples to be stored for
extended research (optional).
Documentation of informed consent
You are freely making a decision whether to be in this research study. Signing this
form means that:
You have read and understood this consent form.
You have had the consent form explained to you.
You have been given a copy of The Rights of Research Subjects
You have had your questions answered.
You have decided to be in the research study.
If you have any questions during the study, you have been directed to talk to
one of the investigators listed below on this consent form.
You will be given a signed and dated copy of this consent form to keep.
Name of Subject _________________________________
Signature of Subject ______________________________
Date ___________________
My signature certifies that all the elements of informed consent described on this
consent form have been explained fully to the subject. In my judgment, the subject
possesses the legal capacity to give informed consent to participate in this research
and is voluntarily and knowingly giving informed consent to participate.
Name of Person Obtaining Consent _________________________________
Signature of Person Obtaining Consent ______________________________
Date ___________________
Authorized Study Personnel
Principal
* Bhatt, Vijaya
phone: 402-559-8008
alt #: 402-559-5174
degree: MBBS
 
 
Secondary
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* Al-Kadhimi, Zaid
alt #: 402-559-5520
degree: M.D.
* Gundabolu, Krishna
phone: 402-559-8052
alt #: 402-559-8052
degree: MBBS
 
* Maness Harris, Lori
phone: 402-559-3742
alt #: 402-559-5520
degree: MD
 
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