Clinical trial NCT03689894
Conditions: Chronic Graft-versus-host-disease
Sponsor: Dartmouth-Hitchcock Medical Center
Start date: 2019-04-11; Completion date: 2021-09-20
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Allogeneic stem cell transplant is used to treat a variety of blood cancers. However, graft-versus-host disease (GVHD) is a common condition that may occur after transplant. GVHD happens when the donor cells attack and damage the recipients' tissue.

The standard medication to treat chronic graft-versus-host-disease (cGVHD) is corticosteroids. However, there are long-term side effects of steroid therapy, including risk of infection, bone loss and other health problems. In addition, some patients with cGVHD do not respond to standard steroid therapy. In these cases, medications to suppress the immune system may be used.

The purpose of this study is to learn about the effects, both good and bad, of combining the drugs ibrutinib and rituximab for the treatment of cGVHD.

Ibrutinib is Food and Drug Administration (FDA)-approved for the treatment of cGVHD which has not responded to steroid therapy.

Rituximab is an investigational drug, which means it is not FDA approved for this particular use. Rituximab is currently approved for treatment of Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), and other conditions, but is not FDA approved for the treatment of cGVHD.

However, rituximab has been used in a clinic setting for the treatment of cGVHD in a number of patients over the past few years, and has generally been well tolerated and shown some benefit.

The combination of ibrutinib and rituximab is being studied in the treatment of certain types of lymphoma and chronic leukemia, but it has not yet been combined for patients with cGVHD. Because ibrutinib is not approved for this use when combined with rituximab, it is considered investigational in this study.

In this form, the term "study drug" refers to ibrutinib and rituximab.

This study will involve people who have chronic GVHD, have previously taken corticosteroids, and have either not benefited from treatment with corticosteroids or have been unable to successfully taper off steroids.

Detailed description:

Arms: arm 1: Rituximab

\*375 milligrams (mg) per meter squared intravenous infusion weekly for 4 (may repeat 8 weeks after initial therapy, if suboptimal response)

Ibrutinib

* 420 mg (140 mg capsule x3) by mouth daily
* May be given beyond 3-6 months (for maintenance).
Interventions: intervention 1: Ibrutinib intervention 2: Rituximab
Intervention descriptions: intervention 1: Subjects will receive oral (PO) Ibrutinib 140 mg once daily with Rituximab 375 mg per meter squared IV weekly x4 (with pre-medications and infusion procedure as per standard protocol) Rituximab Pre-medications:Acetaminophen 650 mg PO; Diphenhydramine 25 mg PO/IV; Dexamethasone 20 mg IV.

If no adverse events \>Grade 3+ are noted after 1 week, the Ibrutinib dose schedule will be increased to 280 mg daily. If no adverse events \>Gr3+ are noted after an additional 1 week, the Ibrutinib dose will be increased to 420 mg daily. intervention 2: Subject will receive an intravenous infusion of 375mg per meter squared weekly for 4 weeks, which may be repeated 8 weeks after initial therapy if only a suboptimal response is achieved.

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
Combination Ibrutinib and Rituximab for Treatment of Chronic Graft-Versus-Host 
Disease Following Allogeneic Stem Cell Transplant 
 
 
Principal Investigator: 
John M. Hill, Jr., M.D. 
 
Co - Investigators:  
Kenneth R. Meehan, M.D.  
Christi Anne Hayes, M.D. 
Christopher H. Lowrey, M.D.  
Lynn Root, R.N 
Kate Wilcox, R.N. 
 
Division of Biostatistics: 
Tor D. Tosteson, Ph.D. 
 
Clinical Research Associate: 
Darcie Findley, C.C.R.C. 
 
Data Management: 
Dorie McKenna, M.S. 
 
 
Blood and Marrow Transplant Program  
Division of Hematology/Oncology  
Department of General Internal Medicine  
Dartmouth-Hitchcock Medical Center  
Norris Cotton Cancer Center 
1 Medical Center Drive  
Lebanon, NH, 03756-0001 
Phone: 603-650-4628 
Fax: 603-650-7791 
 
 
 
 
 
 
 
 
 
 
 
 
Version Date: June 13, 2017 
Amended: March 20, 2018 
Amended: September 12th, 2018 
Amended: November 28th, 2018 


 
 
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Table of Contents 
 
Table of Contents ...................................................................................................................................................... 2 
List of Abbreviations ................................................................................................................................................ 4 
Study Summary .............................................................................................................................................................. 5 
1 
Introduction .......................................................................................................................................................... 7 
1.1 
Background ................................................................................................................................................. 7 
1.2 
Pharmaceutical agent data from clinical pharmacology .......................................................................... 8 
1.3 
Preclinical Data ........................................................................................................................................... 8 
1.4 
Clinical Data, to Date ................................................................................................................................. 8 
1.5    Dose Rationale and Risk/Benefits ................................................................................................................... 8 
2 
Study Objectives ................................................................................................................................................... 9 
3 
Study Design ......................................................................................................................................................... 9 
3.1 
General Design ............................................................................................................................................ 9 
3.2 
Primary Study Endpoints .......................................................................................................................... 9 
3.3 
Secondary Study Endpoints ....................................................................................................................... 9 
4 
Subject Selection and Withdrawal ..................................................................................................................... 10 
4.1 
Inclusion Criteria ...................................................................................................................................... 10 
4.2 
Exclusion Criteria ..................................................................................................................................... 10 
4.3 
Subject Recruitment and Screening ........................................................................................................ 10 
4.4 
Early Withdrawal of Subjects.................................................................................................................. 11 
4.4.1 
When and How to Withdraw Subjects ............................................................................................................................................ 11 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ............................................................................................................... 11 
5 
Study Drug .......................................................................................................................................................... 11 
5.1 
Treatment Regimen .................................................................................................................................. 11 
5.1.1 
Details of the Treatment Regimen ................................................................................................................................................... 12 
5.1.2 
Baseline Assessment and Follow-Up Determination of Therapeutic Response ............................................................................. 12 
5.2 
Supportive Care Recommendations ................................................................................................................................................ 13 
5.3 
Method for Assigning Subjects to Treatment Groups ........................................................................... 13 
5.4 
Preparation and Administration of Study Drug ..................................................................................... 13 
5.5 
Subject Compliance Monitoring ............................................................................................................. 13 
5.6 
Prior and Concomitant Therapy ............................................................................................................. 13 
5.7 
Treatment Discontinuation and Subsequent Therapy ........................................................................... 14 
5.8 
Packaging .................................................................................................................................................. 14 
5.9 
Blinding of Study Drug ............................................................................................................................. 14 
5.10 
Receiving, Storage, Dispensing and Return ........................................................................................... 14 
5.10.1 
Receipt of Drug Supplies.................................................................................................................................................................. 14 
5.10.2 
Return or Destruction of Study Drug ............................................................................................................................................. 14 
6 
Study Procedures ................................................................................................................................................ 14 
7 
Statistical Plan .................................................................................................................................................... 16 
7.2 
Subject Population(s) for Analysis .......................................................................................................... 17 
8 
Safety and Adverse Events ................................................................................................................................. 17 
8.1 
Definitions .................................................................................................................................................. 17 
8.2 
Recording of Adverse Events ................................................................................................................... 18 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems .................................................... 19 
8.3.1 
Investigator reporting: notifying the study sponsor ....................................................................................................................... 20 
8.3.2 
Investigator reporting: notifying the Dartmouth IRB .................................................................................................................... 20 
8.3.3 
Investigator reporting: Notifying a another IRB ............................................................................................................................ 21 
8.3.4 
Sponsor reporting: Notifying the FDA ............................................................................................................................................ 21 
8.4 
Unblinding Procedures ............................................................................................................................. 22 
8.5 
Stopping Rules .......................................................................................................................................... 22 
9 
Data Handling and Record Keeping ................................................................................................................. 23 


 
 
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9.1 
Confidentiality ........................................................................................................................................... 23 
9.2 
Source Documents .................................................................................................................................... 23 
9.3 
Case Report Forms ................................................................................................................................... 23 
9.4 
Records Retention .................................................................................................................................... 23 
10 
Study Monitoring, Auditing, and Inspecting .................................................................................................... 23 
10.1 
Medical Monitoring .................................................................................................................................. 23 
10.2 
Safety and Data Monitoring .................................................................................................................... 24 
10.3 
On-Site Monitoring................................................................................................................................... 24 
10.4 
Auditing and Inspecting ........................................................................................................................... 24 
11 
Ethical Considerations ....................................................................................................................................... 24 
12 
Study Finances .................................................................................................................................................... 24 
12.1 
Funding Source ......................................................................................................................................... 24 
13 
References ........................................................................................................................................................... 25 
14 
Attachments ........................................................................................................................................................ 26 
 
 
 
 
 
 


Ibrutinib/Rituximab cGVHD Trial 
 
 
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List of Abbreviations 
 
  *AE: Adverse event   
  *aGVHD: Acute Graft Versus Host Disease 
*Allo-SCT: Allogeneic stem cell transplant 
*BTK: Bruton’s tyrosine kinase 
*cGVHD: Chronic Graft versus Host Disease 
*CLL: Chronic lymphocytic leukemia 
*CTCAE: Common terminology criteria for adverse events 
* DSMAC: Data Safety Monitoring and Accrual Committee 
*EMR: Electronic medical record 
  *GVHD: Graft Versus Host Disease 
*ITK: IL-2 inducible T cell kinase 
*NHL: Non-Hodgkin’s lymphoma 
*SAE: Serious adverse event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Ibrutinib/Rituximab cGVHD Trial 
 
 
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Study Summary 
 
Title 
Combination Ibrutinib and Rituximab for Treatment of Chronic Graft-Versus-Host 
Disease Following Allogeneic Stem Cell Transplant 
Short Title 
Ibrutinib and Rituximab for Steroid-Refractory or Dependent Chronic GVHD 
Protocol Number 
D17120 
Phase 
Phase 1/2 
Methodology 
Open label, Within-Subject Dose-Escalation Study 
Study Duration 
2 years (patients will be followed after 6 months for survival only) 
Study Center(s) 
Single center 
Objectives 
To determine the safety and efficacy of Ibrutinib and Rituximab combination therapy 
for steroid-refractory or -dependent chronic GVHD following allogeneic stem cell 
transplant. 
Number of Subjects 
15 
Diagnosis and Main 
Inclusion Criteria 
Steroid refractory or dependent chronic graft-versus-host disease (diagnosis to be 
based on histologic sampling and/or via clinical criteria; see Attachments) 
> 18 years old  
Karnofsky Performance Status 60 or greater 
 
Study Product, Dose, 
Route, Regimen 
Within-Subject Dose-Escalation Format: 
 
-The first 5 subjects will receive treatment as follows: 
-Ibrutinib 140 mg po once daily 
-Rituximab 375 mg/m2 IV weekly x4 
-Adverse events will be defined as per the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) 
-if no adverse events >/= non-hematologic grade 3 or >/= hematologic grade 4 are noted 
after 1 week at 140 mg daily, the Ibrutinib dose schedule will be increased to 280 mg 
daily 
-if no adverse events >/= non-hematologic grade 3 or >/= to hematologic grade 4 are 
noted after 1 week at 280 mg daily, the Ibrutinib dose schedule will be increased to 420 
mg daily 
- the potential exists for a 2nd weekly x4 Rituximab course 8 weeks after initial 
Rituximab therapy, if no response or an incomplete response is noted 
Expansion cohort: 
 - following accrual of the 5 initial subjects, an additional 10 subjects will be 
accrued, with dosing to be informed by the results of the within-subject dose escalation 
cohort 
Duration of 
administration 
Ibrutinib: ongoing (indefinite), with re-assessment of patient tolerance and response at 
6 weeks, 3 months and 6 months 
Rituximab: weekly x4, with or without a repeat 8 weeks after the initial therapy, 
depending on the patient’s initial clinical response 
Reference therapy 
Patients may have received steroids or other alternative GVHD regimens (with no new 
therapy for at least two weeks prior to the start of this protocol), without benefit,  
 
OR 
Patients may have shown an initial steroid benefit, but demonstrate an inability to 
undergo steroid taper due to persistent GVHD upon attempted steroid dose reduction. 


Ibrutinib/Rituximab cGVHD Trial 
 
 
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Statistical Methodology 
 
GVHD response rates at 6 weeks, 3 months and 6 months will be assessed using exact 
binomial methods combining the initial dose escalation and expansion cohorts.  
 
Univariate and multivariate analyses will be used to identify independent correlates of 
both safety and efficacy. 


 
 
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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted according to US and 
international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional research policies and procedures. 
 
1.1 
Background 
Allogeneic stem cell transplant (allo-SCT) remains a potentially curative treatment modality for a variety of 
hematologic malignancies. Development of graft-versus-host disease (GVHD) following transplant poses clinical 
challenges and contributes significantly to post-transplant morbidity and mortality (1,2,3). GVHD is an 
immunologic condition caused by a reaction of donor T lymphocytes against host tissues after allogeneic transplant. 
The pathophysiology of GVHD is dependent on the presence of T-cells in the donor graft, allo-antigenicity between 
donor and recipient and an immunologically incompetent host. GVHD can manifest as either  acute disease, 
generally affecting the skin, GI tract and liver, or chronic, with the latter being the primary cause of late morbidity 
and mortality following allo-SCT (1,2). Traditional distinctions between acute and chronic GVHD, based on time of 
onset following transplant, have largely given way to qualitative clinical differences, as the temporal onset has 
varied in the era of non-ablative allo-SCT and the National Institutes of Health (NIH) consensus development 
project has better defined diagnostic and staging criteria for chronic GVHD (2). 
 
Acute GVHD (aGVHD) is known to be mediated almost exclusively by donor T cells, whereas the pathophysiology 
of chronic GVHD (cGVHD) is less well defined, though both CD4+ T-cells and B cells have been implicated. Thus, 
treatment of cGVHD remains challenging, with only 30-50% of patients responding to first-line (steroid) therapy. 
Those patients who develop steroid-refractory disease carry a poor prognosis, owing to the lack of any clear 
consensus on second-line therapy. Even those who initially respond to steroid therapy warrant second-line 
intervention to minimize the significant morbidity and mortality risks of longstanding steroid use (1,2,3). Since 
donor B cells have been shown to play an increasing role in the pathophysiology of cGVHD, the prospect of B-cell 
depletion has been raised as an effective modality for chronic GVHD management (4). Cutler et al. demonstrated the 
benefit of rituximab in the treatment of steroid-refractory cGVHD (5), and follow-up studies have confirmed the 
prophylactic efficacy of this agent in minimizing development of steroid-requiring cGVHD (6,7). Notably, although 
the overall clinical response rate of established cGVHD to rituximab was high (70%), complete responses were 
rare, emphasizing the need for additional agents in this area (5). 
 
In light of data indicating a role of Th2 cells in the development of cGVHD (8), studies have suggested the potential 
utility of ibrutinib in cGVHD treatment (9). Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) 
and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells (9). It has been used as mono- or 
combination therapy in various hematologic malignancies (10,11), including mantle cell lymphoma (MCL;12) and 
chronic lymphocytic leukemia (CLL;13). Various murine studies have supported ibrutinib as a potential agent to 
treat GVHD, including demonstration of efficacy in two complementary murine models (14). One involved T-cell 
driven sclerodermatous cGVHD and another demonstrated allo-antibody driven multi-organ system cGVHD, with 
manifestation of bronchiolitis obliterans chronic pulmonary GVHD. These data suggest a promising therapeutic role 
for ibrutinib in the management of (B-/T-cell driven) cGVHD, and this has been borne out by human studies, 
including a multi-center, open-label, phase II trial showing efficacy in steroid-refractory GVHD (15). This study, 
consisting of 42 patients with cGVHD who had failed 1-3 prior therapies, demonstrated an overall response rate 
(ORR) of 67%, with over 70% sustained responses (at least 20 weeks), leading to ibrutinib having recently been 
granted FDA approval for the treatment of cGVHD after failure of at least one line of systemic therapy.  
 
While identification of uniquely correlative plasma biomarkers in the cGVHD setting remains incomplete, two 
potential biomarkers of interest include suppression of tumorigenicity 2 (ST2) (16) and CD4CD25FOXp3 
Tregs (17), with potential relevance of these to both cGVHD development and therapeutic response. In 
addition, an activated Th17-prone T-cell subset expressing both CD146 and CCR5 has been shown to play a role in 
cGVHD, with potential sensitivity to pharmacologic inhibition (18, 19). Further, in a subset of 42 patients with 
cGVHD receiving ibrutinib following resistance to prior intervention, those responding were found to manifest 
decreased levels of sIL-2Ra, CX3CL1, CXCL9, CXCL10, CCL22 and CCL4 (18, 20).       
 
Another development on the clinical front has been the use of combination ibrutinib/rituximab therapy for patients 
with CLL, shown to be a well-tolerated, effective regimen, with minimal toxicity (21). To that end, we recently 


 
 
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managed a patient with high-risk CLL at our center with post-transplant relapse and concurrent cGVHD, treating 
successfully with combination ibrutinib/rituximab therapy. Given existing data supporting the efficacy of both 
ibrutinib and rituximab in human cGVHD, as well as the demonstrated tolerability of combination 
ibrutinib/rituximab in CLL, we propose a study to evaluate the tolerability and efficacy of combination 
ibrutinib/rituximab in patients with steroid-resistant or -dependent cGVHD. 
 
1.2 
Pharmaceutical agent data from clinical pharmacology 
Rituximab 
 
Rituximab is a genetically engineered chimeric murine/human monoclonal antibody, directed against the CD20 antigen 
expressed on B-lymphocytes. It has IgG-1 kappa immunoglobulin containing murine light- and heavy-chain variable 
regions and human constant regions. Rituximab is routinely used for B-cell non-Hodgkin’s lymphoma (NHL) and other 
CD20 expressing B-cell hematologic malignancies and is FDA approved for diffuse large B-cell, CD20 positive NHL 
in combination with CHOP or other lymphoma-specific cytotoxic chemotherapy regimens. It is also FDA approved in 
combination with cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy as first-line treatment for 
untreated CD20 positive follicular non-Hodgkin’s lymphoma, as well as in combination with fludarabine and 
cyclophosphamide for CD20 positive chronic lymphocytic leukemia (CLL). Ritxumab is FDA approved as single-
agent maintenance therapy for patients with CD20 positive follicular NHL.  
 
Ibrutinib 
 
Ibrutinib is a potent and irreversible Bruton’s tyrosine kinase (BTK) inhibitor (9). BTK is responsible for the 
proliferation, differentiation, apoptosis, and cell migration of B cells (9). A Phase II study showed benefit for relapsed 
or refractory mantle cell lymphoma (MCL) in median progression-free survival (PFS) and median overall survival 
(OS). (12)  A Phase III trial (MCL3001) demonstrated benefit in PFS with single-agent ibrutinib as compared with 
single-agent temsirolimus for patients who had received at least one prior rituximab-containing regimen for relapsed or 
refractory MCL (22) Another Phase III trial, RESONATE, showed significantly improved response rate (RR), PFS and 
OS with ibrutinib versus ofatumumab for patients with CLL or small lymphocytic lymphoma (SLL). (23) In addition, 
results of the Phase III RESONATE-2 trial showed that ibrutinib was superior to chlorambucil as assessed by RR, PFS, 
OS and improved hematologic variables for patients with previously untreated CLL or SLL (24). 
 
1.3 
Preclinical Data 
Available data on ibrutinib as an irreversible inhibitor of BTK and IL-2 inducible kinase targeting Th2 cells and B 
cells (30). 
Murine study data support prophylactic benefit of ibrutinib in chronic GVHD (25). 
 
1.4 
Clinical Data, to Date 
Phase 2 data for ibrutinib in human cGVHD, specifically, a multi-center, open-label trial showing efficacy in steroid-
refractory GVHD. This study, consisting of 42 patients with cGVHD who had failed 1-3 prior therapies, 
demonstrated an overall response rate (ORR) of 67%, with over 70% sustained responses, leading to ibrutinib being 
granted FDA approval for the treatment of cGVHD after failure of at least one line of systemic therapy (15). 
 
* Single arm phase 2 study showing well-tolerated ibrutinib and rituximab combination regimen for patients with 
CLL. This study assessed the safety and efficacy of the ibrutinib/rituximab combination in 40 high-risk CLL patients, 
with the 18-month PFS being 78% and toxicity mainly mild-to-moderate, including gastro-intestinal, bleeding, 
infection and fatigue (21).      
 
* Recent DHMC case demonstrating successful treatment of a patient with relapsed CLL and concurrent cGVHD. 
* No study has thus far assessed the efficacy of ibrutinib and rituximab combination therapy for cGVHD. 
 
1.5    Dose Rationale and Risk/Benefits 


 
 
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There are multiple studies supporting the tolerability and efficacy of rituximab in patients with cGVHD after 
allogeneic stem cell transplant, primarily patients with sclerodermatous and/or lichenoid cutaneous disease (3). 
Several prospective studies have used rituximab 375 mg/m2 weekly x4, with the option for a second course at 8 
weeks following initial therapy, based on the adequacy of response. There are also phase 1b/2 data supporting 420 
mg daily as a safe and effective dose schedule for ibrutinib in post-transplant human cGVHD (15). 
 
A single-arm phase II study assessing the safety and activity of ibrutinib and rituximab for patients with high risk 
CLL supports the tolerability of this combination at respective dose schedules of 420 mg daily (indefinite) and 375 
mg/m2 weekly x4, then monthly x5, with the total duration of rituximab being 6 months. However, since those 
patients were not allogeneic stem cell transplant recipients, a within-subject dose-escalation format will be 
utilized in this current study to optimize risk assessment in the post-transplant setting (see Study Summary, pages 1-
2). 
 
2 
Study Objectives 
Primary objective: to assess the safety and tolerability of ibrutinib/rituximab combined therapy in patients with 
steroid dependent or refractory GVHD. 
Secondary Objectives: 1) to assess the clinical efficacy of ibrutinib/rituximab combined therapy in patients with 
steroid dependent or refractory GVHD. 
2) To determine relevant laboratory correlates underlying clinical response, or lack thereof. 
 
 
3 
Study Design 
3.1 
General Design 
This is a non-randomized, open label, within-subject study to assess safety and preliminary efficacy for combination 
ibrutinib and rituximab in an allogeneic stem cell transplant recipient population, using a within-subject dose-escalation 
format.   
Duration: 6 months, depending on response to therapy and ongoing clinical status.  
3.2 
Primary Study Endpoints 
1. Safety of combination Ibrutinib and Rituximab therapy for steroid refractory or dependent chronic 
GVHD, based on review of dose-limiting toxicities and results of the within-subject dose-escalation 
format. 
 
 
3.3 
Secondary Study Endpoints 
1. Response rate of clinically significant GVHD based on NIH criteria (from 2014 NIH Consensus 
Development Project, see Attachment 1) at the following time points: six weeks, three months, and 
six months after initiation of therapy.   
 
2. Laboratory correlates: The following serum biomarkers will be checked at the specified time points:  
pre-treatment; six weeks; three months; six months. 
 
Elisa/Luminex                     Flow Cytometry 
sIL2Ra                                        CD146  
CX3CLI                                       CCR5 
CXCL9                      
CXCL10 
CCL22 
CCL4 
 
ST2                                               FOXp3  
 
 


 
 
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4 
Subject Selection and Withdrawal 
4.1 
Inclusion Criteria 
Patients fulfilling the following criteria will be eligible for registration onto this study: 
1. Men and women ≥18 years old who are recipients of an allogeneic bone marrow, cord blood or peripheral blood 
stem cell transplant. 
(There will be no restrictions based upon underlying disease, donor source, degree of HLA match, intensity  
 
of pre-transplant conditioning regimen or use of prior donor lymphocyte infusion(s).) 
2. Chronic GVHD that is confirmed by clinical assessment and/or biopsy. 
3 . Either steroid-refractory or steroid-dependent cGVHD. 
4. Karnofsky performance status ≥ 60. 
 
 
4.2 
Exclusion Criteria 
Patients with the following will be ineligible for registration onto this study: 
1. History of treatment with a tyrosine kinase inhibitor (eg, imatinib) or other moderate-to-significant CYPA4 
inhibitor within 2 weeks of enrollment. 
2. Renal insufficiency as follows: creatinine > 2.5 mg/dL or CrCl < 30 ml/min. 
3. Hepatic insufficiency as follows: serum bilirubin >3 mg/dL or grade 3 or greater transaminitis at baseline (even if 
deemed due to GVHD) or cirrhosis (any Childs Pugh class).  
4. History of cardiac dysrhythmias or known cardiovascular disease without formal Cardiology clearance.  
5 . History of cerebro-vascular accident or intracranial hemorrhage within 6 months prior to enrollment. 
6. History of non-intracranial hemorrhage and/or coagulopathy without formal Coagulation clearance. 
7. Uncontrolled infections not responsive to antibiotics, anti-viral medicines, or anti-fungal medicines; or infection 
requiring systemic treatment that was completed ≤14 days before enrollment. 
8. History of other hematologic malignancy. 
9. History of human immunodeficiency virus (HIV). 
10. History of active hepatitis B virus (HBV) or hepatitis C virus (HCV) without formal Infectious Disease clearance. 
1 1 Patients incapable of complying with routine follow up schedule or unable to be compliant with study therapy. 
12. Active or within 3 months use of prohibited medications or substances (e.g., illicit drugs). 
 
 
4.3 
Subject Recruitment and Screening 
 
 
Patients will be recruited from the Norris Cotton Cancer Center. Subjects will have demonstrated active 
cGVHD and either primary refractoriness to a trial of steroids (Methyl-prednisolone or 
predniso ne at a dose range of 0.5-2 mg/kg/day) or intolerance to a steroid taper prior to being 
enrolled in this study and beginning ibrutinib and rituximab therapy. 
 
The study will be introduced to patients during clinical appointments if they meet eligibility criteria. Informed 
consent, including purpose of the study, risks and benefits of participation, and rights of participants, will be 
discussed e i t h e r  a t  t h a t  t i m e  o r  separately by available study staff in an individual session. 
 
In order to confirm and assess the extent of GVHD and meet inclusion criteria, this study may require evaluation of 
participants by utilizing various diagnostic measures (within one week of enrollment): 
 
Medical history 


 
 
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Physical examination, including height and weight 
Blood studies (baseline CBC/diff, CMP, PT/PTT) 
Urinalysis, culture, urine for CrCl, as indicated 
Additional studies, as clinically indicated  
 
Studies pertinent to the organ system under 
consideration for the diagnosis of chronic GVHD 
 
-biopsy proven or strong clinical suspicion of a 
chronic GVHD diagnosis will be required  
 
  New pregnancy test  
New comprehensive infectious work-up with negative findings in the appropriate clinical setting (eg, Pulmonary 
cGVHD) will be required 
 
The decision to obtain tests and procedures noted above will depend on the individual clinical scenario.  
The guidelines for standard cGVHD intervention will be followed. 
 
 
4.4 
Early Withdrawal of Subjects 
 
4.4.1 
When and How to Withdraw Subjects 
A subject may choose to not be in this study at any time. Leaving the study will not affect regular medical care in 
any way. Participants will be asked to contact study staff if they are thinking about leaving the study. In addition, 
a follow-up visit will be utilized to ensure the safety of any participant who chooses to discontinue enrollment on 
this study. Any subject withdrawing from the study prematurely due to toxicity will be evaluable for toxicity and 
will not be replaced. Subjects withdrawing from the study for reasons other than toxicity (eg, due to relapse of 
malignancy) will be replaced.  All subjects remaining on the study for at least 6 weeks will be evaluable for efficacy.  
 
Any protocol physician may stop the study at any time. In addition, participants may be asked to leave the study. 
Possible reasons to terminate participation may include: 
1. Serious side effect (>/= grade 4 adverse event) 
2. Inability to tolerate dose of medication. 
3. No longer meeting criteria for this study. 
4. Development of new conditions needing other treatments. 
5. Emergence of new therapy or studies. 
6. Progression of disease. 
7. Personal choice of the subject to stop study participation. 
 
 
 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects 
 
If a subject withdraws consent to participate in the study, attempts will be made to obtain permission to record data 
(including survival data) up to the protocol-described end of the subject’s follow-up period. In such an instance, the 
patient will be contacted by phone.  
 
 
5 
Study Drug 
 
5.1 
Treatment Regimen 
Rituximab 
*375 mg/m2 IV infusion weekly for 4 (may repeat 8 weeks after initial therapy, if suboptimal response) 
 
Ibrutinib 
*420 mg (140 mg capsule x3) by mouth daily 


 
 
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* May be given beyond 3-6 months (for maintenance). 
 
 
5.1.1 
Details of the Treatment Regimen 
Initial cohort (first 5 patients accrued) will be treated as follows: 
Ibrutinib 140 mg po once daily with 
Rituximab 375 mg/m2 IV weekly x4 (with pre-medications and infusion procedure as per standard protocol) 
Rituximab Pre-medications: Acetaminophen 650 mg po; Diphenhydramine 25 mg po/IV; Dexamethasone 20 mg IV 
 
If no adverse events >/=  nonhematologic grade 3 or >/= hematologic grade 4 are noted after 1 week at 140 mg daily, 
the Ibrutinib dose schedule will be increased to 280 mg daily  
If no adverse events >/=  nonhematologic grade 3 or >/= hematologic grade 4 are noted after 1 week at 280 mg daily, 
the Ibrutinib dose schedule will be increased to 420 mg daily. 
If grade >/= 3 non-hematologic toxicity and/or grade 4 hematologic toxicity are noted, a dose de-escalation to the prior 
dose level will be made. Resumption of treatment at this dose level may begin once Ibrutinib toxicity has improved to 
the grade 1 (or baseline) level.       
 
If a >/= nonhematologic grade 3 or >=hematologic grade 4 adverse event is noted in any one of the 5 subjects at the 
140 mg dose level, a thorough review of this AE will be undertaken, and if deemed causative, treatment for that 
subject will be discontinued. 
If a >/= nonhematologic grade 3 or >=hematologic grade 4 adverse event is noted in >2 of the 5 subjects at the 140 
mg dose level, the study will be discontinued. 
 
If a >/= nonhematologic grade 3 or >=hematologic grade 4 adverse event is noted in a subject at the 280 mg dose 
level, the subject will then be dropped back to the prior dose level or treatment for that subject will be discontinued. 
If a >/= nonhematologic grade 3 or >=hematologic grade 4 adverse event is noted in a subject at the 420 mg dose 
level, the subject will then be dropped back to the prior dose level or treatment for that subject will be discontinued. 
 
If therapy for 2 or more subjects at either the 280 mg or 420 mg dose level requires discontinuation, per the above 
parameters, no further escalation to those dose levels will be attempted for future patients. 
 
Expansion cohort (additional 10 patients accrued) will be treated as follows: 
 
Ibrutinib 420 mg po once daily with 
Rituximab 375 mg/m2 IV weekly x4 
 
If, based on above toxicity criteria, the Ibrutinib 420 mg daily dose schedule has been discontinued, then 280 mg po 
once daily will be the expansion cohort dose schedule 
If, based on above toxicity criteria, the Ibrutinib 280 mg daily dose schedule has been discontinued, then 140 mg po 
once daily will be the expansion cohort dose schedule 
 
Duration of therapy: 
Ibrutinib  ->  420  mg  daily  (or  adjusted  dose)  will  continue  until  progression  of  cGVHD  or  development  of 
significant side effects. 
Rituximab -> there is the potential for a 2nd weekly x4 Rituximab course 8 weeks after initial therapy, if no response 
or an incomplete response is noted. 
 
 
5.1.2 
Baseline Assessment and Follow-Up Determination of Therapeutic Response 
The baseline and follow-up assessments of protocol participants will be done utilizing NIH criteria, as outlined in 
the 2014 NIH Consensus Development Project Report on Criteria for Clinical Trials in Chronic Graft-
versus-Host Disease (26) and Measuring Therapeutic Response in Chronic Graft-versus-Host Disease (27).  
 
See Attachments:  
Attachment 1:  Chronic GVHD Scoring Assessment – Clinician (26) 
Attachment 2:  Response Determination Table for Chronic GVHD Clinical Trials (27) 
  


 
 
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The timeframe for assessments will be as follows: baseline (pre-treatment); 6 weeks, 3 months and 6 months after 
initiation of therapy. 
 
The mode of assessment will include the following (to be undertaken by a limited number of team members who will 
do these assessments, so as to ensure consistency and minimize subjectivity). 
 
 
5.2 
Supportive Care Recommendations 
 
5.2.1 Infectious prophylaxis will include fluconazole, acyclovir and both PJP and encapsulated organism 
prophylaxis (recommendations from DHMC SOP addressing antimicrobial prophylaxis following 
hematopoietic transplantation, and adapted from BBMT 2009; 15: 1143). The following are recommended: 
Fluconazole 400 mg po daily 
Acyclovir 800 mg po bid 
TMP-SMX or alternative PJP prophylaxis 
TMP-SMX or alternative encapsulated organism prophylaxis (during steroid and other GVHD therapy). 
 
5.2.2 CMV PCR monitoring - using standard guidelines and the DHMC SOP addressing monitoring of post- 
transplant CMV status, it is recommended that CMV PCR be tested during active cGVHD therapy, weekly 
if prior to post-transplant day +100 and prior to 1 year post-transplant timeframe if previous CMV 
activation was documented. If after day +100 in the absence of previous CMV reactivation, then CMV 
PCR monitoring should be done at two-week intervals. Monitoring will continue while the patient remains 
on immune suppression, as clinically indicated. Treatment for a positive result will be done according to 
standard guidelines, as outlined in the DHMC SOP regarding pre- emptive CMV therapy. 
 
5.2.3 EBV monitoring - using standard guidelines and the DHMC SOP addressing monitoring of post-transplant 
EBV status, it is recommended that EBV PCR testing after transplant be considered between days +30 to 
100, as clinically indicated, based on the presence of fever, adenopathy or other signs or symptoms of 
infection or post-transplant lymphoproliferative disorder (PTLD). PCR monitoring should be done 
periodically after this timeframe, following evidence of reactivation, including during active cGVHD 
treatment with steroids and/or other immunosuppressive agents. Treatment for a positive result will be done 
according to standard guidelines as outlined in the DHMC SOP for Management of Viral Infections after 
Hematopoietic Stem Cell Transplant. 
 
 
5.3 
Method for Assigning Subjects to Treatment Groups 
Open label single arm study. 
 
5.4 
Preparation and Administration of Study Drug 
Ibrutinib will be mailed to a participant’s address. 
Rituximab will be administered weekly in the infusion suite at the Hematology Outpatient Clinic, Norris Cotton Cancer 
Center (NCCC), Dartmouth-Hitchcock Medical Center (DHMC). 
Rituximab will be prepared and dispensed through the Investigational Pharmacy, DHMC. 
 
For more information: 
Investigational Pharmacy, NCCC, DHMC 
Contact phone number: 603-650-7890 
 
5.5 
Subject Compliance Monitoring 
Each study subject will be assessed weekly from initiation of the study. A drug administration log for Ibrutinib 
will be utilized (including date, time and dose taken) and maintained, and patients will be queried about 
regular administration of Ibrunitib, as recorded in this log. Rituximab administration will be monitored through 
the electronic medical record (EMR) system. 
 
 
5.6 
Prior and Concomitant Therapy 
 


 
 
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5.6.1 Restricted and Allowable Concomitant Medications 
 
1. History of treatment with a tyrosine kinase inhibitor (eg, imatinib) or other significant CYPA4 inhibitor within 2 
weeks of enrollment is NOT allowed. 
2. History of standard-dose Rituximab therapy within 6 months of study enrollment is NOT allowed.  
3. Pre-transplant use of Ibrutinib for indications other than cGVHD (eg, lymphoma therapy) IS permitted.  
4. Concomitant use of corticosteroids for cGVHD after transplant, prior to and during this study, IS permitted and 
anticipated (with no dose change allowed for a period of at least 14 days prior to enrollment). 
5. Concomitant use of other immunosuppressive therapies prior to and during this study IS also permitted (with no dose 
change allowed for a period of at least 14 days prior to enrollment).  
6. Doses of concomitant steroids and other immunosuppressants may be tapered during the study, as clinically feasible.  
 
7. Study subjects may receive prophylactic antimicrobials, based on post-transplant status.    
  
 
5.7 
Treatment Discontinuation and Subsequent Therapy 
If there is progression of disease on evaluation at 6 weeks, 3 months or 6 months, the patient will be considered 
for other secondary therapies, depending on the severity of the cGVHD and his/her overall clinical status. Other 
commonly used secondary therapies include Tacrolimus/sirolimus, Mycophenolate 
mofetil, extracorporeal 
photophoresis (ECP), JAK1/2 inhibitors and other monoclonal antibodies. Pulsed steroid therapy may also need to be 
considered in an effort to control the degree of GVHD as a purely temporary measure (ie, “bridge” to secondary 
therapy).   
 
 
5.8 
Packaging 
Ibrutinib will be prescribed via patient’s preferred pharmacy, as per the appropriate dose schedule. 
 
5.9 
Blinding of Study Drug 
N/A 
 
5.10 Receiving, Storage, Dispensing and Return 
 
5.10.1 Receipt of Drug Supplies 
Rituximab will be prescribed and dispensed at the infusion clinic at Dartmouth-Hitchcock Norris Cancer Center. 
Ibrutinib will be prescribed and filled at patient’s preferred pharmacy. 
 
5.10.2 Return or Destruction of Ibrutinib 
At the completion of the study, there will be a final reconciliation of drug received, consumed, and remaining, since 
our pharmacy may not be shipping drug. Each subject will be asked to bring remaining medications back to our clinic 
or to dispose of them. 
 
6 Study Procedures 
 
Visit 1 (prior to or at the start of therapy) 
Initial visit 
1. Initiation of therapy as described above 
A subject will be reviewed for: 
In order to confirm and assess the extent of GVHD and meet inclusion criteria, this study may require 
evaluation of participants by utilizing various diagnostic measures (within one week of enrollment): 
Medical history 
Physical examination, including ht and weight 


 
 
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2. The subject will sign an informed consent 
3. Blood Studies  
-baseline CBC/diff, CMP, PT/PTT  
-biomarker assays will be drawn 
Elisa/Luminex                     Flow Cytometry 
sIL2Ra                                        CD146  
CX3CLI                                       CCR5 
CXCL9                      
CXCL10 
CCL22 
CCL4 
ST2                                               FOXp3  
 
4. Urine studies 
-urinalysis, culture 
-urine for CrCl, as indicated 
5. Additional studies, as clinically indicated 
6. Studies pertinent to the organ system 
under consideration for the diagnosis of 
cGVHD 
 
-biopsy proven or strong clinical suspicion 
of a cGVHD diagnosis will be required 
 
7. New pregnancy test 
8. New comprehensive infectious work-up 
with negative findings in the 
appropriate clinical setting (eg, 
Pulmonary cGVHD) will be required 
 
The decision to obtain tests and procedures noted above will depend on the individual clinical 
scenario.  
 
The guidelines for standard cGVHD intervention will be followed  
 
1. Establishment of baseline 
The degree of cGVHD will be assessed (baseline) prior to initiation of protocol treatment by using chronic 
graft-versus-host disease assessment and scoring criteria, as referenced in the NIH Consensus Development 
Project (see Attachments). 
 
2. Treatment initiation 
Treatment will start once the subject has the ibrutinib pills, on the first day of Rituximab. 
 


 
 
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Visit 2 at 1-2 weeks from initiation of the combination therapy (sooner as clinically indicated) 
i. A subject will be assessed for: 
a. 
Medical history 
b. Physical examination, including height and weight 
c. 
Blood and urine tests, as clinically indicated 
d. Additional organ function, as clinically indicated 
ii. Patients will be followed at no longer than two-week intervals over the first six weeks on 
trial, more frequently as clinically indicated. Note: participants in the dose escalation 
portion of the protocol will be followed via weekly visits, more frequently as indicated.  
 
 
Visit 3 at 2-4 weeks from initiation of the combination therapy (sooner as clinically indicated) 
i. 
A subject will be assessed for: 
a. 
Medical history 
b. Physical examination, including height and weight 
c. 
Blood and urine tests, as clinically indicated 
d. Additional organ function, as clinically indicated 
ii. Patients will be followed at no longer than two-week intervals over the first six weeks on 
trial, more frequently as clinically indicated. Note: participants in the dose escalation 
portion of the protocol will be followed via weekly visits, more frequently as indicated.  
 
 
Visit 4 at 4-6 weeks from initiation of the combination therapy (sooner as clinically indicated) 
i. A subject will be assessed for: 
a. 
Medical history 
b. 
Physical examination, including height and weight 
c. 
Blood and urine tests, as clinically indicated 
d. 
Additional organ function, as clinically indicated 
ii. Patients will be followed at no longer than two-week intervals over the first six weeks on 
trial, more frequently as clinically indicated. Note: participants in the dose escalation 
portion of the protocol will be followed via weekly visits, more frequently as indicated.  
 
2. Assessment 
a. 
At the 6 week (+/- 3 days) follow up visit, the degree of cGvHD will be formally re-assessed, 
again using NIH assessment and scoring forms (Attachment 1) 
b.   After the 6 week follow up visit, patients may be followed at 2-4 week intervals, if clinically 
appropriate 
c. 
Subjects may undergo repeat Rituximab weekly x4 therapy at 8 weeks after the initial therapy, 
depending on their prior clinical response 
d. Formal re-assessment of cGvHD response via NIH criteria (Attachment 1 forms) will again 
be undertaken at the 3 month (+/- 7 days) and 6 month (+/- 7 days) follow up visits, to 
determine updated cGvHD status 
e. 
If the subject shows progression of  cGvHD, alternative treatment options will be discussed, 
including the appropriateness for removal from the study 
f. 
If the subject shows improvement (at least a partial response, by NIH response criteria), he/she 
will be continued on Ibrutinib for maintenance 
g. After 6 months, subjects will be followed for survival only.  
 
Subsequent visits between the 6 week post-initiation period and 6 month follow-up timeframe will be at 2-4 week 
intervals, more frequently if clinically indicated (as outlined above). Serum biomarkers will be drawn at the 6 week, 3 
month and 6 month post-initiation visits. 
 
7 
Statistical Plan 


 
 
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7.1 
Statistical Methods 
 
 
GVHD response rates based on the GVHD Global Severity Score and Clinical Assessment ( Attachment 1)  
at 6 weeks, 3 months and 6 months will be assessed using exact binomial methods combining the initial 
dose escalation and expansion cohorts. With the expansion cohort after the safety dose escalation phase, a 
total of 15 patients will be available for evaluation. An exact test for proportions with a null hypothesis of a 15% 
response rate, an alternative hypothesis of a 50% response rate, and a one-sided significance level of 0.10, 
would have a power of 85% using 15 subjects, including a Bonferroni correction for looking at the 6 week, 3 
month and 6 month response rates. This test rejects the null hypothesis if 6 out of 15 subjects respond. If only the 
10 subjects from the expansion cohort are used, the null is rejected if 4 out of 10 respond, and the power is reduced 
to 0.83. Calculations were done in the PASS 2008 package. 
 
Two-sample t-tests for continuous data and Fisher’s exact test for binary data will be used to compare responders and 
non-responders for the purpose of identifying independent biomarker correlates of treatment response.  The power and 
precision of these comparisons will depend on the number of responders and non-responders compared. 
 
 
7.2 
Subject Population(s) for Analysis 
Any subject withdrawing from the study prematurely due to toxicity will be evaluable for toxicity and will not be 
replaced. Subjects withdrawing from the study for reasons other than toxicity (eg, due to relapse of malignancy) will 
be replaced.  All subjects remaining on the study for at least 6 weeks will be evaluable for efficacy. 
 
 
8 
Safety and Adverse Events 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria: 
 Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such as the IRB- 
approved protocol or consent form, the investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related means there is a reasonable 
possibility that the incident experience, or outcome may have been caused by the procedures involved in the 
research) 
 Suggests  that  the  research  places  subjects  or  others  at  greater  risk  of  harm  (including  physical, 
psychological, economic, or social harm). 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity during the 
course of the study. Intercurrent illnesses or injuries should be regarded as adverse events. Abnormal results of 
diagnostic procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that is: 
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 


 
 
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Important medical events are those that may not be immediately life threatening, but are clearly of major clinical 
significance. They may jeopardize the subject, and may require intervention to prevent one of the other serious 
outcomes noted above. For example, drug overdose or abuse, a seizure that did not result in in-patient 
hospitalization, or intensive treatment of bronchospasm in an emergency department would typically be considered 
serious. 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious adverse events. 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from the initiation 
of any study procedures to the end of the study treatment follow-up. For this study, the study treatment follow-up is 
defined as 30 days following the last administration of study treatment. 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition should be recorded as 
an adverse event if the frequency, intensity, or the character of the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition. At the end of the 
study, any new clinically significant findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event. 
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the subject is lost 
to follow-up, or the adverse event is otherwise explained. At the last scheduled visit, the investigator should instruct 
each subject to report any subsequent event(s) that the subject, or the subject’s personal physician, believes might 
reasonably be related to participation in this study. The investigator should notify the study sponsor of any death or 
adverse event occurring at any time after a subject has discontinued or terminated study participation that may 
reasonably be related to this study. The sponsor should also be notified if the investigator should become aware of 
the development of cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has 
participated in this study. 
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following conditions 
is met: 
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a dgree that requires active management; e.g. change of dose, discontinuation of the 
drug, more frequent follow-up assessments, further diagnostic investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and reported as 
a serious adverse event unless specifically instructed otherwise in this protocol. Any condition responsible for 
surgery should be documented as an adverse event if the condition meets the criteria for and adverse event. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse event in the 
following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a preexisting 
condition. Surgery should not be reported as an outcome of an adverse event if the purpose of the surgery 
was elective or diagnostic and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it is a 
worsening or increase in frequency of hospital admissions as judged by the clinical investigator. 
 
 
8.2 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by specific questioning 
and, as appropriate, by examination. Information on all adverse events should be recorded immediately in the 
source document, and also in the appropriate adverse event module of the case report form (CRF). All clearly 


 
 
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related signs, symptoms, and abnormal diagnostic procedures results should recorded in the source document, 
though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded. The clinical course of each event should be 
followed until resolution, stabilization, or until it has been determined that the study treatment or participation is not 
the cause. Serious adverse events that are still ongoing at the end of the study period must be followed up to 
determine the final outcome. Any serious adverse event that occurs after the study period and is considered to be 
possibly related to the study treatment or study participation should be recorded and reported immediately. 
 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
Investigators must conform to the adverse event reporting timelines, formats and requirements of the various 
entities to which they are responsible.  At  a minimum, serious adverse events ( S AEs )  that must be reported 
to the principal investigator (PI), or the covering BMT Attending on the Transplant Service, are those that are: 
 
 related to study participation, 
 unexpected, and 
 serious or involve risks to subjects or others 
(see definitions, section 8.1). 
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of the initial 
report includes: 
 
Study identifier 
 
Study Center 
(if multi-center study) 
 
Subject number 
 
A description of the event 
 
Date of onset 
 
Current status 
 
Whether study treatment was discontinued 
 
The reason why the event is classified as serious 
 
Investigator assessment of the association between the 
event and study treatment 


 
 
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8.3.1 
Investigator reporting: notifying the PI 
Any study-related unanticipated problem posing risk of harm to subjects or others, and any type of serious adverse 
event, must be reported to the PI by telephone within 24 hours of the event. To report such events, a Serious 
Adverse Event (SAE) form must be completed by the investigator and faxed to the study sponsor within 24 hours. 
The investigator will keep a copy of this SAE form on file at the study site. Report serious adverse events by phone 
and facsimile to: 
 
John M. Hill, Jr, MD 
Section of Hematology/Oncology 
Norris Cotton Cancer Center 
Dartmouth-Hitchcock Medical Center 
1 Medical Center Drive 
Lebanon, NH, 03756 
603-650-4628 
 
 
Within the following 48 hours, the investigator must provide further information on the serious adverse event or the 
unanticipated problem in the form of a written narrative. This should include a copy of the completed Serious 
Adverse Event form, and any other diagnostic information that will assist the understanding of the event. 
Significant new information on ongoing serious adverse events should be provided promptly to the study sponsor 
 
 
8.3.2 
Investigator reporting: notifying the Dartmouth IRB 
This section describes the requirements for safety reporting by investigators who are Dartmouth faculty, affiliated 
with a Dartmouth research site, or otherwise responsible for safety reporting to the Dartmouth IRB. The Dartmouth 
College IRB (CPHS) requires expedited reporting of those events related to study participation that are unforeseen 
and indicate that participants or others are at increased risk of harm. The Dartmouth IRB will not acknowledge 
safety reports or bulk adverse event submissions that do not meet the criteria outlined below. The Dartmouth IRB 
requires researchers to submit reports of the following problems, once the investigator becomes aware of the event: 
1. Unanticipated problems that are serious adverse events should be reported to the IRB within 1 week of the 
investigator becoming aware of the event. 
2. Any other unanticipated problem should be reported to the IRB within 2 weeks of the investigator becoming 
aware of the problem. 
 
Unanticipated Problem Involving Risks to Subjects or Others (UPRs) Any incident, experience or outcome that 
meets ALL 3 of the following criteria: 
1.Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the research procedures 
described in the protocol-related documents, such as the IRB-approved protocol and informed consent document 
and (b) the characteristics of the subject population being studied; AND 
2. Is related or possibly related to participation in the research (possibly related means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in the 
research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including physical, psychological, 
economic, legal, or social harm) than was previously known or recognized. 
Unanticipated Problems Involving Risks to Subjects or Others (UPRs) may be medical or non-medical in nature, 
and include – but are not limited to – serious, unexpected, and related adverse events and unanticipated adverse 
device effects (see below). Please note that adverse events (as defined below) are reportable to the IRB as UPRs 
only if they meet all 3 criteria listed above. 
 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the Dartmouth IRB 
via the RAPPORT format. using the form: “Unanticipated Problems Posing Risks to Subjects or Others Including 
Reportable Adverse Events” or as a written report of the event (including a description of the event with 


 
 
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information regarding its fulfillment of the above criteria, follow-up/resolution and need for revision to consent form 
and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical Investigator’s 
study file. 
 
 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the Dartmouth IRB: 
 Any adverse experience that, even without detailed analysis, represents a serious unexpected adverse event 
that is rare in the absence of drug exposure (such as agranulocytosis, hepatic necrosis, Stevens-Johnson 
syndrome). 
 Any adverse event that would cause the PI to modify the protocol or informed consent form, or would 
prompt other action by the IRB to assure protection of human subjects Information that indicates a change 
to the risks or potential benefits of the research, in terms of severity or frequency. For example: 
– An interim analysis indicates that participants have a lower rate of response to treatment than initially 
expected. 
– Safety monitoring indicates that a particular side effect is more severe, or more frequent than initially 
expected 
– A paper is published from another study that shows that an arm of your research study is of no 
therapeutic value. 
 Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in a 
research protocol. 
 Breach of confidentiality 
 Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a research 
participant. 
 Incarceration of a participant when the research was not previously approved under Subpart C and the 
investigator believes it is in the best interest of the subject to remain on the study. 
 Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot be 
resolved by the research team. 
 Protocol violation (meaning an accidental or unintentional deviation from the IRB approved protocol) that in 
the opinion of the investigator placed one or more participants at increased risk, or affects the rights or 
welfare of subjects. 
 
8.3.3 
Investigator reporting: Notifying a another IRB 
N/A 
 
8.3.4 
Sponsor reporting: Notifying the FDA 
 Within 7 calendar days 
Any study event that is: 
– associated with the use of the study drug 
– unexpected, 
– fatal or life-threatening, and 
 
 Within 15 calendar days 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the criteria for 
reporting (reporting within 15 calendar days from when event was deemed reportable). 
Any finding from tests in laboratory animals that: 
– suggests a significant risk for human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 


 
 
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Reporting Process 
Adverse events may be submitted on FDA Form 3500A or in a narrative format. If supplied as in a narrative format, 
the minimum information to be supplied is noted above at the beginning of section 8.3. 
 
 
8.4 
Unblinding Procedures 
 N/A 
 
8.5 
Stopping Rules 
Within-Subject Dose-Escalation Study stopping rules-  
Initial cohort (first 5 patients accrued) will be treated as follows: 
Ibrutinib 140 mg po once daily with 
Rituximab 375 mg/m2 IV weekly x4 (with pre-medications and infusion procedure as per standard protocol) 
Rituximab Pre-medications: Acetaminophen 650 mg po; Diphenhydramine 25 mg po/IV; Dexamethasone 20 mg IV 
 
If no adverse events >/=  nonhematologic grade 3 or >/= hematologic grade 4 are noted after 1 week at 140 mg daily, 
the Ibrutinib dose schedule will be increased to 280 mg daily  
If no adverse events >/=  nonhematologic grade 3 or >/= hematologic grade 4 are noted after 1 week at 280 mg daily, 
the Ibrutinib dose schedule will be increased to 420 mg daily. 
If grade >/= 3 non-hematologic toxicity and/or grade 4 hematologic toxicity are noted, a dose de-escalation to the prior 
dose level will be made. Resumption of treatment at this dose level may begin once Ibrutinib toxicity has improved to 
the grade 1 (or baseline) level.       
 
If a >/= nonhematologic grade 3 or >=hematologic grade 4 adverse event is noted in any one of the 5 subjects at the 
140 mg dose level, a thorough review of this AE will be undertaken, and if deemed causative, treatment for that 
subject will be discontinued. 
If a >/= nonhematologic grade 3 or >=hematologic grade 4 adverse event is noted in >2 of the 5 subjects at the 140 
mg dose level, the study will be discontinued. 
 
If a >/= nonhematologic grade 3 or >=hematologic grade 4 adverse event is noted in a subject at the 280 mg dose 
level, the subject will then be dropped back to the prior dose level or treatment for that subject will be discontinued. 
If a >/= nonhematologic grade 3 or >=hematologic grade 4 adverse event is noted in a subject at the 420 mg dose 
level, the subject will then be dropped back to the prior dose level or treatment for that subject will be discontinued. 
 
If therapy for 2 or more subjects at either the 280 mg or 420 mg dose level requires discontinuation, per the above 
parameters, no further escalation to those dose levels will be attempted for future patients. 
 
Expansion cohort (additional 10 patients accrued) will be treated as follows: 
 
Ibrutinib 420 mg po once daily with 
Rituximab 375 mg/m2 IV weekly x4 
 
If, based on above toxicity criteria, the Ibrutinib 420 mg daily dose schedule has been discontinued, then 280 mg po 
once daily will be the expansion cohort dose schedule 
If, based on above toxicity criteria, the Ibrutinib 280 mg daily dose schedule has been discontinued, then 140 mg po 
once daily will be the expansion cohort dose schedule 
 
Duration of therapy: 
Ibrutinib  ->  420  mg  daily  (or  adjusted  dose)  will  continue  until  progression  of  cGVHD  or  development  of 
significant side effects. 
Rituximab -> there is the potential for a 2nd weekly x4 Rituximab course 8 weeks after initial therapy, if no response 
or an incomplete response is noted. 
If, based on above toxicity criteria, the Ibrutinib 280 mg daily dose schedule has been discontinued, then 140 mg po 
once daily will be the expansion cohort dose schedule 
 
Duration of therapy: 


 
 
D17120 Protocol 
 
Page 23 of 30 
pv. 11.28.18 
 
Ibrutinib  ->  420  mg  daily  (or  adjusted  dose)  will  continue  until  progression  of  cGVHD  or  development  of 
significant side effects. 
Rituximab -> there is the potential for a 2nd weekly x4 Rituximab course 8 weeks after initial therapy, if no response 
or an incomplete response is noted. 
 
 
9 
Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a signed subject 
authorization informing the subject of the following: 
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the 
ability to use all information collected prior to the revocation of subject authorization. For subjects that have 
revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at least vital 
status (i.e. that the subject is alive) at the end of their scheduled study period. 
 
9.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents. 
Examples of these original documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
 
9.3 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. All data requested on the 
CRF must be recorded. All missing data must be explained. If a space on the CRF is left blank because the 
procedure was not done or the question was not asked, write “N/D”. If the item is not applicable to the individual 
case, write “N/A”. All entries should be printed legibly in black ink. If any entry error has been made, to correct 
such an error, draw a single straight line through the incorrect entry and enter the correct data above it. All such 
changes must be initialed and dated. DO NOT ERASE OR WHITE OUT ERRORS. For clarification of illegible or 
uncertain entries, print the clarification above the item, then initial and date it. 
 
 
9.4 
Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last approval of 
a marketing application in their country and until there are no pending or contemplated marketing applications in 
their country or at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  
 
 
10 
Study Monitoring, Auditing, and Inspecting 
 
10.1 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site. This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, as well as 
the construction and implementation of a site data and safety-monitoring plan (see Section 10.2). Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 


 
 
D17120 Protocol 
 
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pv. 11.28.18 
 
10.2 Safety and Data Monitoring 
This study will be monitored by the Data Safety Monitoring and Accrual Committee (DSMAC) of the Norris Cotton 
Cancer Center.  The Committee meets quarterly to review accrual rates and information for studies that have accrued 
participants.  The Clinical Cancer Review Committee (CCRC) determines the frequency of DSMAC review. The 
DSMAC has the authority to suspend or to recommend termination to the CCRC of all research activities that fall 
within its jurisdiction.  In the event that a study is suspended or terminated, that information will be forwarded to the 
CPHS (Dartmouth IRB) office. 
 
10.3 On-Site Monitoring 
Clinical research monitoring for regulatory compliance and data integrity will be conducted according to the NCI-
approved NCCC Data and Safety Monitoring Plan.  Internal monitoring is conducted by appropriately trained staff of 
the NCCC Office of Clinical Research and Dartmouth-Hitchcock Medical Center Clinical Trials Office who are not 
involved in the study.  This monitoring will include periodic assessment of the regulatory compliance, data quality, 
and study integrity.  Study records will be reviewed and directly compared to source documents, and the conduct of 
the study will be discussed with the investigator. Monitors may request access to all regulatory documents, source 
documents, CRFs, and other study documentation for on-site inspection.  Direct access to these documents is 
guaranteed by the investigator, who must provide support at all times for these activities. 
 
10.4 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, government 
regulatory bodies, and Dartmouth compliance and quality assurance groups of all study related documents (e.g. 
source documents, regulatory documents, data collection instruments, study data etc.). The investigator will ensure 
the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
Participation as an investigator in this study implies acceptance of potential inspection by government regulatory 
authorities and applicable Dartmouth compliance and quality assurance offices. 
 
 
11 
Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 21 
part 312 and International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics Committee (EC) 
or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study 
conduct. The decision of the EC/IRB concerning the conduct of the study will be made in writing to the investigator 
and a copy of this decision will be provided to the sponsor before commencement of this study. The investigator 
should provide a list of EC/IRB members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. This consent form will 
be submitted with the protocol for review and approval by the EC/IRB for the study. The formal consent of a 
subject, using the EC/IRB- approved consent form, must be obtained before that subject undergoes any study 
procedure. The consent form must be signed by the subject or legally acceptable surrogate and the investigator-
designated research professional obtaining the consent. 
 
 
12 
Study Finances 
12.1 Funding Source 
This research protocol is not currently sponsored, though funding is being requested in the form of a 2018 NCCC Pilot 
(PROUTY) Grant.   


 
 
D17120 Protocol 
 
Page 25 of 30 
pv. 11.28.18 
 
 
13 
References 
1. Jaglowski SM and Devine SM. Graft-versus-Host Disease: Why Haven’t We Made More Progress? Curr Opin 
Hematol. 2014; 21 (2): 141-147. 
2. Filipovich AH, Weisdorf, D, Pavletic S, et al. National Institutes of Health Consensus Development Project on 
Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: 1. Diagnosis and Staging Working Group 
Report. Biology of Blood and Marrow Transplantation. 2005; 11: 945-955. 
3. Wolff D, Schleuning M, von Harsdorf S, et al. Consensus Conference on Clinical Practice and Chronic GVHD: 
Second-Line Treatment of Chronic Graft-versus-Host Disease. Biology of Blood and Marrow Transplantation. 
2011; 17: 1–17. 
4. Sarantopoulos S, Blazar BR, Cutler C and Ritz J. B Cells in Chronic Graft-versus-Host Disease. Biology of 
Blood and Marrow Transplantation. 2015; 21: 16-23. 
5. Cutler C, Miklos D, Kim HT, et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood 
2006; 108(2): 756-762. 
6. Arai S, Sahaf B, Narasimhan B, et al. Prophylactic rituximab after allogeneic transplantation decreases B-cell 
alloimmunity with low chronic GVHD incidence. Blood. 2012;119:6145-6154. 
7. Cutler C, Kim, HT, Bindra B, et al. Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD 
after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial. Blood. 2013; 122(8): 1510- 
1517. 
8. Krenger W and Ferrara JL. Graft-versus-host disease and the Th1/Th2 paradigm. Immunol Res. 1996; 15(1): 
50-73. 
9. Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a 
Th1-selective pressure in T lymphocytes Blood. 2013; 122(15): 2539-2549. 
10. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant 
activity in patients with relapsed/refractory B cell malignancies. J Clin Oncol 2013; 31:88-94. 
11. Wang Y, Zhang L, Champlin R, Wang M. Targeting Bruton's tyrosine kinase with ibrutinib in B‐cell 
malignancies. Clinical Pharmacology & Therapeutics. 2015;97:455-468. 
12. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell 
lymphoma. N Engl J Med 2013; 369: 507-16. 
13. Byrd J, Furman R, Coutre S, et al. Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia. 
NEJM. 2013;369:32-42. 
14. Schutt SD, Fu J, Nguyen H, et al. Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of 
Chronic Graft-versus-Host Disease in Mice. PloS one. 2015;10:e0137641-e0137641. 
15. Miklos D, et al. Multicenter Open-Label Phase 2 Study of Ibrutinib in Chronic Graft Versus Host Disease 
(cGVHD) after Failure of Corticosteroids. Blood 2016; 128: LBA-3. 
16. Vander Lugt MT, et al. ST2 as a Marker for Risk of Therapy-Resistant Graft-versus-Host Disease and Death. 
NEJM. 2013; 369 (6): 529-539. 
17. Rozmus J and Schultz KR. Biomarkers in chronic graft-versus-host disease. Expert Rev Hematol. 2011; 4(3): 
329-342. 
18. Paczesny S. Biomarkers for posttransplantation outcomes. Blood 2018; 131: 2193-2204.  
19. Forcade E, Paz K, Flynn R, et al. An activated Th17-prone T cell subset involved in chronic graft-versus-host 
disease sensitive to pharmacologic inhibition. JCI Insight. 2017; 2(12).   
20. Miklos D, Cutler CS, Arora M, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. 
Blood 2017; 130(21): 2243-2250.  
21. Burger J, Keating M, Wierda W, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk 
chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014;15:1090-1099. 
22. Rule S, et al. Ibrutinib versus Temsirolimus: Results from a phase III, international, randomized, open-label, 
multicenter study in patients with previously treated mantle cell lymphoma. ASH Ann Mtg Abstracts 2015: 469.  
23. Byrd JC, et al. Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia. NEJM 
2014; 371: 213-223.  
24. Burger J, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. NEJM 2015; 373: 
2425-2437.  
25. Schutt SD, et al. Inhibition of BTK and ITK with Ibrutinib is Effective in the Prevention of Chronic Graft-
Versus- Host Disease in Mice. PLOS ONE/DOI: 10.1371/journal.pone.0137641 Sept. 8, 2015; 1-17.   
26. Jagasia MH et al. NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-
Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. BBMT 2015; 21: 389-401.  
27. Lee SJ, 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: 


 
 
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IV. The 2014 Response Criteria Working Group Report. BBMT 2015; 21: 984-999. 
 
 
14 
Attachments 
 
Attachment 1:  Chronic GVHD Assessment (26) 
Attachment 2:  Response Determination Table for Chronic GVHD Clinical Trials (27) 
  
 
 
 


CHRONIC GVHD ASSESSMENT 
Patient: 
 Date of Visit: 
 
MRN: 
 Completed by: 
 
Form adapted from Jagasia, MH, BBMT 21 (2015) 389-401. 
 
D17120 Protocol 
 
Page 27 of 30 
pv. 11.28.18 
 
 
Karnofsky Performance Score 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
□ Asymptomatic 
and fully active 
(KPS 100%) 
□ Symptomatic, fully 
ambulatory, restricted 
only in physically 
strenuous activity 
(KPS 80-90%) 
□ Symptomatic, 
ambulatory, capable 
of self-care, >50% of 
waking hours out of 
bed (KPS 60-70%) 
□ Symptomatic, limited 
self-care, >50% of 
waking hours in bed 
(KPS <60%) 
Skin 
None 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
Score by % BSA 
Check all that apply: 
□ Maculopapular rash/Erythema 
□ Lichen-planus features 
□ Sclerotic features 
□ Papulosquamous lesions or 
icthyosis 
□ Keratosis pilaris-like GVHD 
□  
□ No BSA 
Involved 
□ 1-18% BSA 
□ 19-50% BSA 
□ >50% BSA 
Cutaneous features score 
□  
□ No Sclerotic 
Features 
 
□ Superficial sclerotic 
features, “not 
hidebound” 
Check all that apply 
□ Deep sclerotic 
features 
□ “Hidebound”, 
impaired mobility 
□ Ulceration 
Other skin features not 
scored by BSA 
Check all that apply: 
□ 
Hyperpigmentation 
□ 
Hypopigmentation 
 
□ Poikiloderma  
□ Severe or generalized pruritus 
□ Hair or nail involvement 
Skin scoring should use both percentage of BSA involved by disease signs and 
cutaneous features score.  When a discrepancy exists between the percentage o
total body surface area score and the skin features score, OR if superficial 
sclerotic features are present (score 2), but there is impaired mobility or 
ulceration (score 3), the higher level should be used for final skin scoring. 
□ Abnormality present, but explained entirely by documented non-GVHD cause (specify): ____________________________________________ 
Mouth 
None 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
Lichen planus-like 
features present?   
□ 
Yes 
□ 
No 
 
□  
□ No Symptoms □ Mild symptoms with 
disease signs but not 
limiting oral intake 
significantly 
□ Moderate symptoms 
with disease signs 
with partial 
limitation of oral 
intake 
□ Severe symptoms with 
disease signs on 
examination with 
major limitation of 
oral intake 
□ Abnormality present, but explained entirely by documented non-GVHD cause (specify): ____________________________________________ 
Eyes 
None 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
 
 
 
Keratoconjuntivitis sicca (KCS) 
confirmed by Ophthalmologist? 
□ 
Yes 
□ 
No 
□ 
Not examined 
□  
□ No Symptoms □ Mild dry eye not 
affecting ADL; 
requiring lubricant 
drops ≤3 x per day 
□ Moderate dry eye sxs 
partially affecting 
ADL (requiring 
lubricant eye drops 
>3 x per day or 
punctal plugs), 
WITHOUT new 
vision impairment 
due to KCS 
□ Severe dry eye 
symptoms 
significantly affecting 
ADL (eyeware to 
relieve pain) OR 
unable to work 
because of ocular sxs 
OR loss of vision due 
to KCS 
□ Abnormality present, but explained entirely by documented non-GVHD cause (specify): ____________________________________________ 
Liver 
None 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
 
□  
□ Normal total 
bilirubin and 
ALT or AP < 3 
x ULN 
□ Normal total  
bilirubin with ALT >3 
to 5 x ULN or  AP > 
3 x ULN 
□ Elevated total 
bilirubin but <3 
mg/dL or ALT > 5 x 
ULN 
□ Elevated total         
bilirubin > 3 mg/dL 
□ Abnormality present, but explained entirely by documented non-GVHD cause (specify): ____________________________________________ 
Lungs 
None 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
Symptom score* 
□  
□ No Symptoms □ Mild symptoms (SOB 
after one flight of 
steps) 
□ Moderate symptoms 
(SOB after walking 
on flat ground) 
□ Severe symptoms 
(SOB  at rest; 
requiring oxygen) 
FEV1 score* 
□ PFT not Done 
□  
□ FEV1≥80% 
□ FEV1 60-79% 
□ FEV1 40-59% 
□ FEV1 <39% 
* Lung scoring should be performed using both the symptom and FEV1 scores when possible.  FEV1 should be used in the final lung scoring where 
there is a discrepancy between symptoms and FEV1 scores.   
□ Abnormality present, but explained entirely by documented non-GVHD cause (specify): ____________________________________________ 


CHRONIC GVHD ASSESSMENT 
Patient: 
 Date of Visit: 
 
MRN: 
 Completed by: 
 
Form adapted from Jagasia, MH, BBMT 21 (2015) 389-401. 
 
D17120 Protocol 
 
Page 28 of 30 
pv. 11.28.18 
 
 
 
 
 
 
 
 
 
 
GI Tract 
None 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
 
Check all that apply: 
□ Esophageal web/proximal 
stricture or ring 
□ Dysphagia 
□ Anorexia 
□ Nausea 
□ Vomiting 
□ Diarrhea 
□ Weight loss >5% within 3 
months 
□ Failure to thrive  
□  
□ No 
Symptoms 
□ Symptoms 
without 
significant 
weight loss 
(<5%) 
□ Symptoms 
associated with 
mild to moderate 
weight loss within 
3 months (5-15%) 
OR moderate 
diarrhea without 
significant 
interference with 
daily living 
□ Symptoms associated with >15% 
weight loss within 3 months, 
requires nutritional supplement for 
most calorie needs OR esophageal 
dilation OR severe diarrhea with 
significant interference with daily 
living 
□ Abnormality present, but explained entirely by documented non-GVHD cause (specify): ____________________________________________ 
Genital Tract  § 
None 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
□ Not examined 
Currently sexually active 
□ Yes 
□ No 
□  
□ No signs 
□ Mild signs‡ and females 
with or without discomfort  
on exam 
□ Moderate signs‡ 
and may have  
symptoms with 
discomfort on 
exam 
□ Severe signs‡ with  or 
without symptoms 
§ To be completed by a specialist or trained medical providers. 
□ Abnormality present, but explained entirely by documented non-GVHD cause (specify): ____________________________________________ 
JOINTS AND FACIA NEXT PAGE 
Other GVHD Manifestations 
□ Other indicators, clinical features or complications related to chronic GVHD (check all that apply and assign a score to severity (0-3) 
based on functional impact where applicable none – 0,mild -1, moderate -2, severe – 3) 
□ Ascites (serositis)______________ 
□ Myasthenia Gravis____________ 
□ Eosinophilia > 500/μl____________ 
□ Pericardial Effusion____________ 
□ Peripheral Neuropathy_______ 
□ Platelets <100,000/μl ____________ 
□ Pleural Effusion(s)_____________ 
□ Polymyositis_______________ 
□  
□ Nephrotic syndrome_______ 
□ Weight loss >5% without GI symptoms __________ 
□  
 
Global Severity Score – Please check one. 
 
Mild 
1 or 2 organs involved with no more than score 1 PLUS lung score 0 
 
Moderate 
3 or more organs involved with no more than score 1 
OR 
At least 1 organ with a score of 2 (not lung) 
OR 
Lung score 1 
 
Severe 
At least one organ with a score of 3 
OR  
Lung score 2 or 3 
 
In Skin: higher of the 2 scores is used for global severity. 
 
In Lung: FEV1 is used instead of clinical score for global severity. 
 
If the entire abnormality in an organ is noted to be unequivocally explain by a non-GVHD cause, that organ is not included 
in the global severity score.   
 
If the abnormality in an organ is attributed to multifactorial causes (GVHD plus other causes), the scored organ will be used 
for calculation of the global severity score, regardless of the contributing causes.  (No downgrading of the organ severity 
score.) 
 
CLINICIAN ASSESSMENT - Since the last evaluation, this patient’s cGVHD is: 


CHRONIC GVHD ASSESSMENT 
Patient: 
 Date of Visit: 
 
MRN: 
 Completed by: 
 
Form adapted from Jagasia, MH, BBMT 21 (2015) 389-401. 
 
D17120 Protocol 
 
Page 29 of 30 
pv. 11.28.18 
 
+3 
Very much 
better 
+2 
Moderately 
better 
+1 
A little better 
0 
About the same 
-1 
A little worse 
-2 
Moderately 
worse 
-3 
Very much 
worse 
Since the last evaluation, have immunosuppression and/or steroid therapy dosages been changed? 
Comments: 
 
 
 
 
 
 
 
JOINTS AND FASCIA 
 
 
P-ROM score  (see below) 
 
Shoulder (1-7):_________ 
Elbow (1-7): ___________ 
Wrist/finger (1-7):______ 
Ankle (1-4):____________ 
None 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
□  
□ No 
symptoms 
□ Mild tightness of 
arms or legs, 
normal or mild 
decreased range 
of motion (ROM) 
AND not affecting 
ADL 
□ Tightness of arms or 
legs OR joint 
contractures, erythema 
thought due to fasciitis, 
moderate decrease 
ROM AND mild to 
moderate limitation of 
ADL 
□ Contractures WITH 
significant decrease 
of ROM AND 
significant limitation 
of ADL (unable to tie 
shoes, button shirts, 
dress self, etc.)  
□ Abnormality present but explained entirely by non-GVHD documented cause (specify):_____________________________________________________ 
 
 
 


 
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S.J. Lee et al. / Biol Blood Marrow Transplant 21 (2015) 984-999 
Response Determination for Chronic GVHD Clinical Trials based on Clinician Assessments