Clinical trial NCT02491359
Conditions: Chronic Graft Versus Host Disease
Sponsor: Fred Hutchinson Cancer Center
Start date: 2015-11-12; Completion date: 2018-09-12
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot phase II trial studies how well carfilzomib works in treating patients with chronic graft-versus-host disease. Chronic graft-versus-host disease is a complication of a donor bone marrow or blood cell transplant, usually occurring more than three months after transplant, in which donor cells damage the host tissue. Carfilzomib may be an effective treatment for chronic graft-versus-host disease.

Detailed description:
PRIMARY OBJECTIVE:

I. Determine proportion of subjects with treatment failure by 6 months of carfilzomib therapy for chronic graft-versus-host disease (GVHD).

SECONDARY OBJECTIVES:

I. Determine 3 month overall (complete + partial), and complete response rate.

II. Determine 6 month overall (complete + partial), and complete response rate.

III. Report overall survival, non-relapse mortality, primary malignancy relapse, failure-free survival, treatment success, and discontinuation of immune suppression at 6 months and 1 year.

IV. Examine functional outcome (2-minute walk test) and patient-reported outcomes (Lee Chronic GVHD Symptom Scale, quality of life \[Short Form Health Survey (SF)-36, Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT) Questionnaire\], Human Activity Profile \[HAP\]) at study enrollment, 6 months, and 1 year.

V. Study biologic effects of proteasome inhibition.

OUTLINE:

Patients receive carfilzomib intravenously (IV) over approximately 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, and 12 months.

Arms: arm 1: Patients receive carfilzomib IV over approximately 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Carfilzomib intervention 2: Laboratory Biomarker Analysis intervention 3: Quality-of-Life Assessment intervention 4: Questionnaire Administration
Intervention descriptions: intervention 1: Given IV intervention 2: Correlative studies intervention 3: Ancillary studies intervention 4: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
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Investigator-Sponsored Trial 
Chronic Graft Versus Host Disease Consortium 
Carfilzomib for Treatment of Chronic Graft vs. Host Disease 
Version 2.0/ February 9, 2016 
IND # 124248 
Industry Sponsor: 
IND Sponsor: 
Study Drug: 
Study #: 
Onyx Pharmaceuticals 
Stephanie Lee, MD, MPH 
Carfilzomib (KYPROLIS®) 
9228 
Investigators Information 
Name: 
Address: 
 
 
 
Phone:            
Fax:                         
Email Address:     
Stephanie Lee, MD, MPH 
Fred Hutchinson Cancer Research Center 
1100 Fairview Ave 
PO Box 19024, D5-290 
Seattle, WA 98109 
206-667-5160 
206-667-1034 
sjlee@fredhutch.org 
 
Name: 
Address: 
 
 
Phone:            
Fax:                         
Joseph Pidala, MD, MS  
Moffitt Cancer Center 
12902 Magnolia Drive 
Tampa, FL 33612 
813-745-2556 
813-449-8248 


 
 
 
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Email Address:     
joseph.pidala@moffitt.org  
Statistician:  Barry Storer, PhD 
Research Coordinator: Tam Nguyen 
 
Data Manager: TBD 
 
Contracting Contact 
Name 
Address: 
 
 
 
Phone: 
Fax: 
Email Address: 
Tara Ohrazda 
Fred Hutchinson Cancer Research Center 
1100 Fairview Ave N 
PO Box 19024, D5-310 
Seattle, WA 98109 
206-667-4639 
206-667-6936 
tohrazda@fredhutch.org 
 
 
 


 
 
 
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PROTOCOL SYNOPSIS 
 
TITLE:    
 
Carfilzomib for Treatment of Chronic Graft vs. Host Disease 
OBJECTIVES: 
Primary Objective:  
Determine the proportion of subjects with treatment failure by 6 months 
after carfilzomib treatment for chronic GVHD. 
Secondary Objectives:  
1. Determine 3 month overall (complete + partial), and complete 
response rate 
2. Determine 6 month overall (complete + partial), and complete 
response rate 
3. Report overall survival, non-relapse mortality, primary 
malignancy relapse, failure-free survival, treatment success, and 
discontinuation of immune-suppressive therapy at 6 months and 
1 year  
4. Examine functional outcome (2-minute walk test) and patient-
reported outcomes (Lee Chronic GVHD Symptom Scale, quality 
of life (SF-36, FACT-BMT), Human Activity Profile (HAP)) at 
study enrollment, 6 months and 1 year 
5. Study biologic effects of proteasome inhibition 
 
STUDY DESIGN: 
Phase II, single-arm, open-label, multi-center trial. 
STUDY 
POPULATION: 
Patients with chronic GVHD (diagnosed according to NIH Consensus 
Criteria) who have failed at least one prior line of systemic immune-
suppressive therapy.  
 
INCLUSION 
CRITERIA: 
 
Disease-related: 
1. Diagnosis of chronic GVHD according to NIH Consensus 
Criteria 
a. May have either classic chronic GVHD or overlap 
subtype of chronic GVHD 
 
2. Failure of at least one prior line of systemic immune suppressive 
therapy for management of chronic GVHD 


 
 
 
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3. Subject underwent transplantation at least 3 months prior to 
enrollment 
 
Demographic:   
1. Age ≥ 18 years 
2. Anticipated life expectancy ≥ 6 months 
 
Laboratory: 
1.  ALT ≤ 3.5 times the upper limit of normal and  bilirubin ≤ 2 mg/dL , 
unless due to chronic GVHD 
2. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L  
3. Hemoglobin ≥ 8 g/dL  
4. Platelet count ≥ 50 × 109/L  
5. Creatinine clearance (CrCl) ≥ 15 mL/minute, either measured or 
calculated  
 
Other: 
1. Signed informed consent in accordance with federal, local, and 
institutional guidelines.  
2. Females of childbearing potential (FCBP) must agree to a 
pregnancy test at study enrollment and to practice contraception 
during the study.  
3. Male subjects must agree to practice contraception during the study.  
 
EXCLUSION 
CRITERIA:     
 
 
 
 
Concurrent Conditions: 
1. Evidence of recurrent or progressive underlying malignant disease 
2. Pregnant or lactating females 
3. Surgery within 21 days prior to enrollment 
a. Does not include placement of venous access device, 
bone marrow biopsy, GVHD diagnostic biopsy, or other 
routine procedures in chronic GVHD or post-
transplantation care 
4. Uncontrolled infection within 14 days prior to enrollment  
a. Infection treated with appropriate antimicrobial therapy 


 
 
 
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and without signs of progression/treatment failure does 
not constitute an exclusion criterion 
5. Documented human immunodeficiency virus (HIV) infection 
6. Active hepatitis B or C infection 
7. Unstable angina or myocardial infarction within 6 months prior to 
enrollment, NYHA Class III or IV heart failure, uncontrolled angina, 
severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or 
electrocardiographic evidence of acute ischemia or Grade 3 
conduction system abnormalities (unless subject has a pacemaker), 
LVEF < 40, history of torsade de pointe,  
8. Uncontrolled hypertension or uncontrolled diabetes within 14 days 
prior to enrollment 
a. Sustained systolic blood pressure > 160 or diastolic 
blood pressure > 100 despite medical therapy; 
sustained blood sugar > 300 despite medical therapy 
b. Chronic hypertension or diabetes on appropriate 
medical therapy does not constitute an exclusion 
criterion 
9. Non-hematologic malignancy within the past 3 years with the 
exception of: 
a. adequately treated basal cell carcinoma, squamous cell 
skin cancer, or thyroid cancer 
b. carcinoma in situ of the cervix or breast 
c. prostate cancer of Gleason Grade 6 or less with stable 
prostate-specific antigen levels 
d. cancer considered cured by surgical resection or 
unlikely to impact survival during the duration of the 
study 
10. Significant neuropathy per CTCAE ver. 4.03 or current version 
(Grade 3 and above, or Grade 2 with pain)  
11. History of allergy to Captisol® (a cyclodextrin derivative used to 
solubilize carfilzomib) 
12. Contraindication to all available HSV/varicella prophylactic antiviral 
drugs 
13. Pleural effusions requiring thoracentesis, or ascites requiring 
paracentesis, within 14 days prior to enrollment 
14. Any other clinically significant medical or psychological disease or 
condition that, in the investigator’s opinion, may interfere with 
protocol adherence or a subject’s ability to give informed consent  


 
 
 
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15. New systemic immune suppressive agent added for the treatment of 
chronic GVHD within 2 weeks prior to enrollment 
16. Treatment with a non-FDA approved drug in the previous 4 weeks 
PROCEDURES: 
Eligible patients will be treated with carfilzomib for up to 6 cycles per the 
described treatment schedule, and will be followed for clinical efficacy, 
patient-reported outcomes and functional measures. Total study follow 
up will be one year. 
STUDY 
TREATMENT: 
Cycle 1:  
Carfilzomib will be administered at 20 mg/m2 on day 1, and then 
36mg/m2 on days 8 and 15 of a 28-day treatment cycle. 
Cycle 2 and subsequent cycles:  
Carfilzomib will be administered at 36 mg/m2 on days 1, 8, and 15 of a 
28-day treatment cycle.  
PRIMARY 
ENDPOINT 
 
6 month treatment failure: 
Defined by requirement for an additional line of systemic immune-
suppressive therapy, recurrent malignancy, or death.  
 
SECONDARY 
ENDPOINTS: 
Failure-free survival 
This time-to-event outcome will be estimated with the composite event 
of death from any cause, relapse or addition of secondary immune 
suppressive agents. This will be estimated at 6 months and 1 year. 
Overall response rate 
Overall response rate (ORR) at 3 and 6 months following initiation of 
carfilzomib represents the composite outcome of complete and partial 
response (CR + PR). ORR will be determined by clinician-defined 
categories of CR and PR, and separately calculated according to the 
proposed response definitions of the NIH Consensus Conference.1 
Complete response rate 
Complete response (CR) at 3 and 6 months following initiation of 
therapy will be determined by clinician-defined CR, and separately 
calculated according to the proposed response definitions of the NIH 
Consensus Conference.1 
Cumulative incidence of non-relapse mortality and primary 


 
 
 
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malignancy relapse 
The cumulative incidence of non-relapse mortality (defined as death in 
the absence of primary malignancy relapse after transplant) and relapse 
(defined as hematologic relapse or any unplanned intervention to 
prevent progression of disease in patients with evidence (molecular, 
cytogenetic, flow cytometric, radiographic) of malignant disease after 
transplantation) will be estimated from time of carfilzomib initiation. 
These will be treated as competing-risk events, and estimated at 6 
months and 1 year. 
Overall survival 
Overall survival will be determined from date of carfilzomib initiation, with 
death from any cause as the event of interest, and censoring at last 
follow up date for those with incomplete observations. This will be 
determined at 6 months and 1 year. 
Use of additional systemic immune suppressive therapies 
The use of additional systemic immune suppressive agents will be 
captured at each study visit, as this constitutes treatment failure.  
Discontinuation of all systemic immune suppressive therapies 
The incidence of complete discontinuation of all systemic immune-
suppressive therapies will be determined at 6 months and 1 year.  
Treatment success 
This endpoint will be estimated at 6 months and 1 year with a composite 
outcome of complete resolution of all reversible chronic GVHD 
manifestations, discontinuation of all systemic immune-suppressive 
agents, and freedom from death or primary malignancy relapse after 
transplant.  
Patient-reported outcomes and functional measures 
Patients will provide assessments of their functional ability (2-minute 
walk test), symptom burden, and quality of life using validated 
instruments recommended by the NIH Consensus Development Project 
on Chronic GVHD (Lee Chronic GVHD Symptom Scale,2 HAP functional 
scale,3 SF-364, and FACT-BMT5). These will be studied at baseline, 6 
months, and 1 year. 
Biologic studies 
These studies aim to discern the biologic impact of proteasome 
inhibition in the treatment of chronic GVHD. Peripheral blood samples 
will be obtained at baseline (study enrollment pre-treatment), and then at 


 
 
 
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the 3 and 6 month time points. An additional event-driven blood sample 
will be obtained when a new systemic immune suppressive therapy is 
added (treatment failure of carfilzomib). 
STATISTICAL 
METHODS: 
 
The primary endpoint is overall treatment failure at 6 months from study 
enrollment. Treatment failure represents the composite of addition of a 
new line of systemic immune-suppressive therapy beyond carfilzomib 
(objective signal of failure to control GVHD with carfilzomib), non-relapse 
death, and primary malignancy relapse.6 The historical benchmark for 
this outcome based on the analysis of 312 chronic GVHD patients is a 6 
month treatment failure rate of 44%. With 20 patients, the standard error 
of the estimated failure rate will be approximately 10 percentage points.  
In the analysis of secondary objectives, we will study the 3 and 6 month 
overall (complete + partial) response and complete response rates, 
other efficacy measures listed above, patient reported outcomes, and 
biologic outcome measures. We will study association between biologic 
outcome measures and clinical parameters (response, treatment failure, 
mortality).  
 


 
 
 
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STUDY THERAPY SCHEMA 
 
 
 
 
 
Cycle 1:  
day 1:  
20mg/m2 
day  8, 15: 
36mg/m2 
Subsequent cycles:  
day 1, 8, 15:  36mg/m2 
Cycle 1 
      2                   3               4                      5                      6 
(28d)             (28d)          (28d)          (28d)             (28d)           (28d) 


 
 
 
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Table of Contents 
INVESTIGATOR-SPONSORED TRIAL .......................................................................................... 1 
PROTOCOL SYNOPSIS ..................................................................................................................... 3 
STUDY THERAPY SCHEMA ............................................................................................................ 9 
TABLE OF CONTENTS................................................................................................................... 10 
1 
INTRODUCTION ................................................................................................................ 13 
1.1 
Disease Specific Background ......................................................................................13 
1.1.1 
Chronic graft vs. host disease ...................................................................13 
1.1.2 
Chronic GVHD diagnosis and classification .........................................13 
1.1.3 
Therapy of established chronic GVHD ..................................................13 
1.1.4 
Assessment of therapeutic response in chronic GVHD ...................14 
1.1.5 
Immune modulation following proteasome inhibition ..................16 
1.1.6 
Effect of proteasome inhibition on chronic GVHD in the 
clinical setting .................................................................................................16 
1.2 
Summary of trial rationale ...........................................................................................17 
1.2.1 
Proteasome Background ............................................................................17 
1.2.2 
Carfilzomib Background .............................................................................18 
1.2.3 
Carfilzomib clinical pharmacology .........................................................18 
1.2.4 
Summary of Safety and efficacy experience from human 
phase I and II trials .......................................................................................20 
1.3 
Dose and schedule Rationale ......................................................................................23 
2 
OBJECTIVES ........................................................................................................................ 25 
2.1 
Primary Objective ...........................................................................................................25 
2.2 
Secondary Objectives .....................................................................................................25 


 
 
 
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3 
EXPERIMENTAL PLAN .................................................................................................... 26 
3.1 
Study Design ......................................................................................................................26 
3.2 
Number of Subjects ........................................................................................................26 
3.3 
Estimated Study Duration ............................................................................................26 
3.4 
Treatment Schema ..........................................................................................................26 
4 
SUBJECT SELECTION ....................................................................................................... 27 
4.1 
Inclusion Criteria .............................................................................................................27 
4.2 
Exclusion Criteria ............................................................................................................28 
5 
SUBJECT ENROLLMENT .................................................................................................. 29 
6 
TREATMENT PROCEDURES .......................................................................................... 29 
6.1 
Drug Preparation and Administration. ...................................................................29 
6.2 
Dose Reductions/Adjustments ..................................................................................31 
6.2.1 
Missed Doses ...................................................................................................36 
6.2.2 
Changes in Body Surface Area (BSA) .....................................................36 
6.3 
Concomitant medications ............................................................................................36 
6.3.1 
Required Concomitant Medications and contraceptive 
practices ............................................................................................................36 
6.3.2 
Management of prednisone and other immune suppression ......37 
7 
STUDY OUTCOMES ........................................................................................................... 38 
8 
STUDY DISCONTINUATION ........................................................................................... 40 
8.1 
Criteria for study discontinuation ............................................................................40 
8.2 
Discontinuation of carfilzomib therapy ..................................................................40 
9 
ADVERSE EVENTS ............................................................................................................ 41 
9.1 
Definitions ..........................................................................................................................41 


 
 
 
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9.2 
Recording of Adverse Events ......................................................................................43 
9.3 
IND Safety Reporting .....................................................................................................44 
9.4 
Reporting to Onyx ...........................................................................................................45 
9.5 
Pregnancy ...........................................................................................................................46 
9.6 
Notifying Institutional Review Boards ....................................................................47 
10 
STATISTICAL ANALYSIS ................................................................................................. 47 
10.1 
Study Design ......................................................................................................................47 
10.2 
Study Endpoints ...............................................................................................................47 
10.2.1 
Safety Endpoints ............................................................................................47 
10.3 
Sample Size Considerations and Planned Methods of Analysis ....................47 
10.4 
Study Stopping Rules .....................................................................................................48 
11 
INVESTIGATIONAL PRODUCT ...................................................................................... 49 
11.1 
Carfilzomib Description ................................................................................................49 
11.2 
Formulation .......................................................................................................................49 
11.3 
Storage .................................................................................................................................49 
11.4 
Accountability ...................................................................................................................50 
12 
REGULATORY OBLIGATIONS ....................................................................................... 50 
12.1 
Informed Consent ............................................................................................................50 
12.2 
Compliance with Laws and Regulations .................................................................50 
12.3 
Subject Confidentiality ..................................................................................................52 
13 
REFERENCES ...................................................................................................................... 53 
APPENDIX A:  NCI-CTCAE VERSION 4.03 ............................................................................... 57 
APPENDIX B:  STUDY CALENDAR............................................................................................. 58 
 


 
 
 
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1 INTRODUCTION   
1.1 Disease Specific Background 
1.1.1 Chronic graft vs. host disease 
Chronic graft vs. host disease (chronic GVHD) is a major late complication of allogeneic 
hematopoietic cell transplantation (HCT) that affects up to 70% of HCT survivors. The 
syndrome is associated with major transplant-related morbidity, mortality, infectious 
complications, prolonged duration of immune suppression, and impaired patient-reported 
quality of life.7-14  Thus, it represents a major obstacle to recovery and survival following 
HCT, and its prevention and treatment are of significant importance. The syndrome is 
characterized by diverse clinical manifestations, but the most commonly affected organs are 
the skin, eyes, mouth, and liver. However, most organs can be involved, with parallels to 
other systemic immune-mediated disorders.  
  
1.1.2 Chronic GVHD diagnosis and classification 
Diagnosis and classification of the syndrome has undergone major revision following the 
2005 NIH Consensus Conference on Chronic GVHD.  According to the historical 
classification, acute and chronic GVHD were distinguished by the occurrence of 
manifestations before or following day 100 post-HCT.15  According to the proposed NIH 
Consensus definitions, the diagnosis of chronic GVHD is based on the presence of 
diagnostic manifestations of the syndrome, rather than the time of onset following HCT. 
Classic chronic GVHD is defined by the definitive manifestations of the syndrome in the 
absence of concurrent acute GVHD manifestations. Presence of both chronic and acute 
GVHD manifestations defines the overlap subtype of chronic GVHD. Chronic GVHD severity 
is scored according to objective criteria for each organ involved, which is summarized for an 
overall global severity score of mild, moderate, or severe.16  
 
1.1.3 Therapy of established chronic GVHD 
Accepted standard primary therapy for chronic GVHD includes 1 mg/kg or greater of 
prednisone or equivalent with or without a calcineurin inhibitor.8,17 The addition of other 
systemic immune-suppressive agents to initial therapy has not provided benefit, as 


 
 
 
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evidenced by trials adding azathioprine, thalidomide, or hydroxychloroquine to initial 
treatment with steroids,18-20 or the more recent randomized trial evaluating the combination 
of steroids and mycophenolate mofetil.21  Published primary chronic GVHD therapy trials 
demonstrate that on average 27% will achieve complete response, and 60% will achieve 
overall response (complete + partial response) by 6-9 months after starting initial therapy.17-
22  
 
Based on insufficient response to primary therapy or a flare of chronic GVHD after tapering 
of initial therapy, many will go on to require additional immune-suppressive agents for 
chronic GVHD control. “Steroid-refractory” chronic GVHD has most commonly been defined 
as either progressive manifestations despite one month of treatment, or incomplete 
response despite two months of 1-2mg/kg of prednisone or equivalent.8 In addition to 
steroid-refractoriness, other clinical indications for additional lines of systemic immune 
suppressive therapy include steroid dependence and steroid intolerance. Patients with 
steroid-dependent chronic GVHD can’t tolerate tapering prednisone due to recurrent chronic 
GVHD manifestations. Steroid intolerant patients have medical complications of steroid 
therapy (e.g. hyperglycemia, edema, psychosis, osteoporosis), and thus require additional 
immune-suppressive agents to control GVHD and facilitate taper of prednisone. Multiple 
immune-suppressive therapies, including pharmacologic agents, monoclonal antibodies, 
and strategies such as extracorporeal photopheresis have demonstrated moderate activity 
in this setting, both ameliorating objective chronic GVHD manifestations, as well as 
facilitating taper of systemic steroids.23 Their effectiveness is suboptimal, however, and 
many patients will require multiple agents to achieve disease control.  
 
The overall burden of chronic GVHD despite routine pharmacologic GVHD prophylaxis, 
limited response to primary and secondary therapy, and the attendant morbidity and 
mortality all support the need for novel approaches in chronic GVHD treatment. 
 
1.1.4 Assessment of therapeutic response in chronic GVHD 
The established method for response determination in the majority of chronic GVHD therapy 
trials is clinician-determined response. This method relies on the treating clinician’s 


 
 
 
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integration of dynamic chronic GVHD manifestations for a summary response categorization 
of complete response (CR), partial response (PR), stable disease (SD), or progressive 
disease (PD). CR indicates complete resolution of all chronic GVHD manifestations; PR 
signifies reduction in disease activity compared with pre-treatment levels, but without 
complete resolution; SD indicates no response and no progression; and PD indicates 
progressive chronic GVHD manifestations from baseline.  
 
Following a 2005 NIH Consensus Conference for Chronic GVHD, several additional means 
of response assessment in chronic GVHD therapeutic trials have been proposed. These 
include change in overall NIH severity categories, proposed NIH response criteria, 0-4 and 
0-10 ordinal scales that rely on clinician assessment, organ-specific tools such as the 
Vienna skin scale, as well as patient-determined change in chronic GVHD activity, chronic 
GVHD-associated symptom burden, functional limitations, and change in quality of life. The 
Chronic GVHD Consortium is currently assessing these competing measures of disease 
activity and their relationship to longer-reaching outcomes indicating clinical benefit, such as 
failure-free survival, discontinuation of all immune suppression, overall survival, or patient-
reported benefit. 
Interpretation of previously published trials for secondary chronic GVHD treatment is limited 
by a number of factors, most notably heterogeneity in response determination. A recently 
published large analysis has examined failure-free survival (FFS) as a proposed outcome 
among chronic GVHD patients treated with second-line systemic treatment. It included  312 
patients who met the following criteria: (1) Had already received systemic steroid treatment 
for chronic GVHD at a prednisone-equivalent dose of at least 0.5 mg/kg/day, (2) also on an 
additional systemic immunosuppressive treatment when second-line treatment was started, 
and (3) received second-line treatment because of progressive GVHD manifestations after 
at least 1 week of initial treatment or because of lack of improvement after at least 2 weeks 
of initial treatment. Commonly used second-line treatments included mycophenolate mofetil, 
tacrolimus, sirolimus, extracorporeal photopheresis, cyclosporine, methotrexate, or other 
agents. By 6 months of second-line therapy, 44% had experienced treatment failure 
(composite of requirement of additional systemic immune suppression beyond second-line 
therapy, death, and malignancy relapse),6 and thus 6 month failure-free survival (FFS) was 
56%. In multivariate analysis, three factors were significant determinants of treatment failure: 


 
 
 
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high-risk disease at transplantation (defined as diseases other than low risk; low-risk 
disease categories included chronic myeloid leukemia in chronic phase, acute leukemia in 
first complete remission, myelodysplastic syndrome without excess blasts, and non-
malignant diseases), lower gastrointestinal involvement  as second-line treatment was 
added, and severe NIH global score as second-line treatment was added.  These three 
factors were used to define risk groups: low-risk had no risk factors, intermediate-risk 
included those with 1 risk factor, and high-risk included those with 2-3 risk factors. The 
cumulative incidence of 6 month treatment failure was 33% for low-risk, 41% for 
intermediate risk, and 56% for high risk.  
1.1.5 Immune modulation following proteasome inhibition 
Proteasome inhibition exerts powerful effects on immune cells implicated in GVHD 
pathogenesis. Pre-clinical and clinical data provide robust support for this concept.24,25 
Proteasome inhibitors interfere with antigen processing and presentation, as well as 
signaling cascades involved in immune cell function and survival: In dendritic cells (DC), 
there is impaired maturation, co-stimulatory molecule expression, and reduction of pro-
inflammatory cytokines. T lymphocytes demonstrate apoptosis, reduced proliferation, 
impaired pro-inflammatory cytokine production, as well as expansion of regulatory T cells 
(Treg). B cell proliferation is decreased, and reduced antibody production is observed 
among plasma cells. Thus, proteasome inhibition targets key mediators established to be 
relevant in GVHD pathogenesis. In a murine GVHD model, bortezomib inhibited alloreactive 
T cells and protected from GVHD, did not adversely affect donor reconstitution, and did not 
impair cytotoxic T cell killing of tumor.26  
 
1.1.6 Effect of proteasome inhibition on chronic GVHD in the clinical setting 
While published clinical trials demonstrate the activity of proteasome inhibition in the primary 
prevention of GVHD,27,28 less is known in the setting of chronic GVHD treatment. Emerging 
clinical data suggest that proteasome inhibition may control chronic GVHD: In a case report, 
a patient with relapsed multiple myeloma after HCT was successfully treated with 
bortezomib for oral lichen planus and biopsy-confirmed hepatic chronic GVHD.29 In a case 
series (n=8), multiple myeloma patients were treated with bortezomib for relapsed disease 
after HCT, and those with chronic GVHD (n=4) experienced improvement.30  Three had 
remission of chronic GVHD at a median of 150 days after bortezomib discontinuation, and 


 
 
 
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one had recurrent ocular manifestations of chronic GVHD.  Finally, in a larger series, 37 
multiple myeloma patients with progressive or residual disease after HCT were treated with 
bortezomib. Of these, 8 patients had limited chronic GVHD, and 3 had extensive chronic 
GVHD. Patients were treated with a median of 6 cycles of bortezomib, and this was 
tolerated well. Common adverse events included peripheral neuropathy, mild 
thrombocytopenia not requiring transfusion, and fatigue, and there were no treatment 
related deaths. Of the 3 extensive chronic GVHD cases, 2 responded and were down-
graded to limited disease at last evaluation. Of the 8 with limited chronic GVHD, none 
required additional immune suppressive therapy, and one had resolution of chronic GVHD.31 
Because these limited data are of interest but difficult to interpret in the setting of myeloma 
relapse or persistence, additional insight should arise from an existing chronic GVHD 
primary therapy trial (NCT00815919) testing the combination of prednisone and bortezomib.  
 
1.2 Summary of trial rationale 
The majority of patients with chronic GVHD will require therapy beyond first-line treatment, 
and novel therapies are needed in this setting to improve outcomes. Pre-clinical and clinical 
data demonstrate that proteasome inhibition produces an immunomodulatory effect relevant 
to GVHD control. Carfilzomib is proteasome inhibitor that has been proven safe and 
effective in clinical trials of multiple myeloma therapy. We propose a phase II trial of 
carfilzomib to examine its clinical and biologic activity in the treatment of advanced chronic 
GVHD.  
1.2.1 Proteasome Background 
The proteasome is a multi-catalytic proteinase complex that is responsible for degradation of 
a wide variety of protein substrates within normal and transformed cells.  Intracellular 
proteins targeted for degradation by the proteasome are first ubiquitinated via the ubiquitin 
conjugation system.  Ubiquitinated proteins are cleaved within the proteasome by one or 
more of three separate threonine protease activities: a chymotrypsin-like activity (CT-L), a 
trypsin-like activity (T-L), and a caspase-like (C-L) activity.  Proteasome inhibition leads to 
the accumulation of poly-ubiquitinated protein substrates within cells, with multiple effects 
including ER stress, alteration of important cellular signaling events, growth arrest, and 
apoptosis. 


 
 
 
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1.2.2 Carfilzomib Background 
Carfilzomib (PR-171) is a tetrapeptide epoxyketone protease inhibitor specific for the 
chymotrypsin-like (CT-L) active site of the 20S proteasome.  Carfilzomib induces a dose-
dependent suppression of proteasome CT-L activity in a wide range of tissues, with the 
exception of the brain. In human studies, carfilzomib at doses of 15-36mg/m2 lead to 77-
86% proteasome inhibition in whole blood and peripheral blood mononuclear cells (PBMC) 
at 1 hour after dosing. Carfilzomib is structurally and mechanistically distinct from the 
dipeptide boronic acid proteasome inhibitor bortezomib (Velcade).  In addition, when 
measured against a broad panel of proteases including metallo, aspartyl, and serine 
proteases, carfilzomib demonstrated less reactivity against non-proteasomal proteases 
when compared to bortezomib.1,2 
1.2.3 Carfilzomib clinical pharmacology 
Mechanism of Action 
Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the 
N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core 
particle within the 26S proteasome. Carfilzomib has anti-proliferative and pro-apoptotic 
activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibits 
proteasome activity in blood and tissue and delays tumor growth in models of multiple 
myeloma, hematologic, and solid tumors. 
Pharmacodynamics 
Intravenous carfilzomib administration results in suppression of proteasome chymotrypsin-
like activity when measured in blood 1 hour after the first dose. On Day 1 of Cycle 1, 
proteasome inhibition in peripheral blood mononuclear cells (PBMCs) ranged from 79% to 
89% at 15 mg/m2, and from 82% to 83% at 20 mg/m2. In addition, carfilzomib administration 
results in inhibition of the LMP2 and MECL1 subunits of the immunoproteasome ranging 
from 26% to 32% and 41% to 49%, respectively, at 20 mg/m2. On day 1 of cycle 2, CT-L 
inhibition in PBMC following a dose of 27mg/m2 was 76% to 92%.  
Pharmacokinetics 


 
 
 
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Absorption: The Cmax and AUC following a single intravenous dose of 27 mg/m2 is 
4232 ng/mL and 379 ng•hr/mL, respectively. Repeated doses do not lead to systemic 
accumulation of carfilzomib. Increased doses are associated with dose-dependent 
increased exposure. 
 
Distribution: The mean steady-state volume of distribution of a 20 mg/m2 dose of 
carfilzomib is 28 L. When tested in vitro, the binding of carfilzomib to human plasma 
proteins averaged 97% over the concentration range of 0.4 to 4 micromolar. 
 
Metabolism: Carfilzomib is rapidly and extensively metabolized. The predominant 
metabolites measured in human plasma and urine, and generated in vitro by human 
hepatocytes, are peptide fragments and the diol of carfilzomib, suggesting that peptidase 
cleavage and epoxide hydrolysis are the principal pathways of metabolism. Cytochrome 
P450-mediated mechanisms play a minor role in overall carfilzomib metabolism. The 
metabolites have no known biologic activity, and none of the metabolites inhibit the 20S 
proteasome activity.  
 
Elimination: Following intravenous administration of doses ≥ 15 mg/m2, carfilzomib is 
rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on Day 1 of Cycle 1. 
The systemic clearance ranged from 151 to 263 L/hour, and exceeded hepatic blood flow, 
suggesting that carfilzomib was largely cleared extra-hepatically. The pathways of 
carfilzomib elimination have not been characterized in humans. 
 
Age: Analysis of population pharmacokinetics data after the first dose of Cycle 1 (Day 1) in 
154 patients who had received an IV dose of 20 mg/m2 showed no clinically significant 
difference in exposure between patients < 65 years and ≥ 65 years of age. 
Gender: Mean dose-normalized AUC and Cmax values are comparable between male and 
female patients in a population pharmacokinetics study. 
Hepatic Impairment: No pharmacokinetic studies were performed with carfilzomib in 
patients with hepatic impairment. 
 


 
 
 
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Renal Impairment: A pharmacokinetic study was conducted in which 43 multiple myeloma 
patients who had various degrees of renal impairment and who were classified according to 
their creatinine clearances (CrCl) into the following groups: normal function (CrCl > 80 
mL/min, n = 8), mild impairment (CrCl 50–80 mL/min, n = 12), moderate impairment (CrCl 
30–49 mL/min, n = 8), severe impairment (CrCl < 30 mL/min, n = 7), and chronic dialysis (n 
= 8). Carfilzomib was administered intravenously over 2 to 10 minutes, on two consecutive 
days, weekly for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period 
every 28 days. Patients received an initial dose of 15 mg/m2, which could be escalated to 
20 mg/m2 starting in Cycle 2 if 15 mg/m2 was well tolerated in Cycle 1. In this study, renal 
function status had no effect on the clearance or exposure of carfilzomib following a single 
or repeat-dose administration. 
 
Cytochrome P450: In an in vitro study using human liver microsomes, carfilzomib showed 
modest direct and time-dependent inhibitory effect on human cytochrome CYP3A4/5. In vitro 
studies indicated that carfilzomib did not induce human CYP1A2 and CYP3A4 in cultured 
fresh human hepatocytes. Cytochrome P450-mediated mechanisms play a minor role in the 
overall metabolism of carfilzomib. A clinical trial of 17 patients using oral midazolam as a 
CYP3A probe demonstrated that the pharmacokinetics of midazolam were unaffected by 
concomitant carfilzomib administration. Carfilzomib is not expected to inhibit CYP3A4/5 
activities and/or affect the exposure to CYP3A4/5 substrates. 
P-gp: Carfilzomib is a P-glycoprotein (P-gp) substrate and showed marginal inhibitory 
effects on P-gp in a Caco-2 monolayer system. Given that Carfilzomib is administrated 
intravenously and is extensively metabolized, the pharmacokinetic profile of carfilzomib is 
unlikely to be affected by P-gp inhibitors or inducers. 
1.2.4 Summary of Safety and efficacy experience from human phase I and II 
trials 
Phase I, I-II, and II trials have been conducted in humans with carfilzomib as a single agent, 
largely focused in relapsed/refractory multiple myeloma. In the first phase I trial, carfilzomib 
was given at escalating doses for five consecutive days, followed by nine days off therapy 
for a total 14 day cycle. The 15mg/m2 dose was determined to be the maximal tolerated 
dose (MTD) due to dose-limiting toxicity (DLT) of thrombocytopenia and febrile neutropenia. 


 
 
 
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In a second phase I trial, carfilzomib was delivered days 1, 2, 8, 9, 15 and 16 on a four week 
cycle. No MTD was reached at the maximal dose of 27mg/m2. Three patients had serious 
adverse events (SAEs) during phase one (sepsis, elevated liver enzymes, and chemical 
pancreatitis), possibly related to carfilzomib.  
Phase II studies have largely examined the regimen of 20mg/m2 for cycle 1, followed by 
27mg/m2 for subsequent cycles. The primary trial used for registration (PX 171-003) tested 
this regimen as single-agent therapy in 266 pre-treated myeloma patients. Related AE (of 
any grade) most frequently included fatigue (37%), nausea (34%), and thrombocytopenia. 
Grade 3/4 hematologic AE included anemia (24%), thrombocytopenia (29%), lymphopenia 
(20%), and neutropenia (11%). Nonhematologic AEs grade 3/4 included pneumonia (9%), 
hyponatremia (8.3%), fatigue (7.5%), and hypophosphatemia (6.0%). One-third of the 
patients experienced mild to moderate dyspnea without detectable lung injury. Peripheral 
neuropathy was uncommon (12.4%), and was considered related in only 8.3% of patients. 
Acute renal failure qualifying for a severe AE occurred in 5 of 266 patients. Additional phase 
II trials have demonstrated activity of carfilzomib in relapsed bortezomib-naïve myeloma 
patients, safety of standard dose therapy in those with renal insufficiency, and safety of long 
term therapy.  
Additionally, extended infusion time – from 2-10 minutes to 30 minutes – facilitated delivery 
of higher dose carfilzomib: In a phase I-II trial (PX-171-007), carfilzomib was given as a 30 
minute IV infusion on days 1, 2, 8, 9, 15, and 16 of a 28 day cycle. The cycle 1/day 1 and 
cycle 1/day 2 doses were given at 20mg/m2, and subsequent doses were given at 
escalating dose cohorts (36, 45, 56, or 70mg/m2). 33 patients were enrolled: 4 at 36 mg/m2 , 
3 at 45 mg/m2, 24 at 56 mg/m2, and 2 at 70 mg/m2. Patients received carfilzomib at stepped-
up doses from 36 to 70 mg/m2: Median number of cycles received was 4 (range 1–17). No 
DLTs reported in the 36 mg/m2, 45 mg/m2, or 56 mg/m2 dose cohorts. Reversible DLTs were 
recorded in 2 patients in the 70 mg/m2 cohort: Grade 3 acute renal failure within 24 hours 
after the 1st dose (C1D8), and G3 fatigue with fever 4 days after the 4th dose (C1D20). Both 
patients were successfully re-challenged and continued on treatment at reduced doses. The 
majority of the AEs in this cohort were Grade 1/2 in severity. The most common grade 3-4 
AEs in the 20/56 mg/m2 cohort were thrombocytopenia (38%), anemia (21%), hypertension 
(13%), and pneumonia (13%). PK analysis demonstrated a proportional increase in Cmax and 
AUC with increasing dose, without affecting t1/2 or clearance of carfilzomib.  


 
 
 
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20mg/m2 (n=26) 
36mg/m2 (n=9) 
45mg/m2 (n=9) 
56mg/m2 (n=10) 
Cmax (ng/mL) 
985 +/- 641 
1795 +/- 957 
1902 +/- 884 
2513 +/- 1527 
AUC last (hr*ng/mL) 
385 +/- 253 
690 +/- 365 
862 +/- 363 
1018 +/- 416 
AUC inf (hr*ng/mL) 
387 +/- 255 
691 +/- 368 
864 +/- 366 
1025 +/- 424 
T ½ (hr) 
1.0 +/- 0.5  
1.2 +/- 0.8 
1.1 +/- 0.2 
1.2 +/- 1.0 
CL (L/hr) 
146 +/- 87 
123 +/- 54 
129 +/- 54 
124 +/- 43 
 
Pharmacodynamic analysis demonstrated an increased inhibition of proteasome 
chymotrypsin-like activity (CT-L) and all 3 subunits of immunoproteasome (LMP7, MECL1, 
LMP2) with higher doses of carfilzomib compared to the 20mg/m2 dose.  
Summarizing current evidence from phase Ib and II trials with carfilzomib, the following are 
the most commonly reported AE (among those occurring in ≥ 20% of patients): fatigue 
(55.9%), nausea (43.2%), anemia (42.2%), dyspnea (35.1%), diarrhea (33.8%), 
thrombocytopenia (32.7%), pyrexia (32.1%), cough (26.8%), headache (26.4%), upper 
respiratory tract infection (25.4%), vomiting (23.4%), peripheral edema (22.8%), 
lymphopenia (22.4%), back pain (21.5%), constipation (21.1%), and increased creatinine 
(20.7%).   
Summarizing current evidence from phase Ib and II trials with carfilzomib, the following are 
the most commonly reported SAE (among those occurring in ≥ 1% of patients), regardless 
of causality: pneumonia (8.1%), disease progression (5.9%), acute renal failure (3.4%), 
pyrexia (3.4%), congestive heart failure (2.8%), dyspnea (2.7%), pathological fracture 
(1.6%), hypercalcemia (1.5%), spinal cord compression (1.3%), anemia (1.1%), dehydration 
(1.1%), sepsis (1.1%), mental status changes (1.0%), and pulmonary embolism (1.0%).  
 


 
 
 
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1.3 Dose and schedule Rationale 
Dose   
Available data supports that proteasome inhibition is augmented with higher dose 
carfilzomib therapy. In the pre-clinical setting, murine experiments have demonstrated – with 
selectivity of PR-171 for the chymotrypsin-like (CT-L) proteasome activity – a dose-
dependent inhibition of proteasome activity in multiple organ sites (blood, bone marrow, 
spleen, adrenal, heart, liver, and lung).32 This therapy leads to accumulation of proteasome 
substrates, and induction of cell cycle arrest and apoptosis. In the clinical setting, escalated 
dose is associated with proportional increased Cmax and AUC, without affecting t ½ or 
clearance of carfilzomib. Doses up to 56mg/m2 have been well tolerated, and 56mg/m2 was 
defined as the MTD in a phase Ib-II study (PX-171-007) that tested 20mg/m2 in cycle 1 days 
1-2, and then escalated dose (36, 45, 56, and 70mg/m2 cohorts) in subsequent 
doses/cycles. 
Human PBMC were tested for the effect of increased dose of carfilzomib in the PX-171-007 
trial: In comparison to pre-treatment levels, post-carfilzomib treatment levels of proteasome 
activity (including CT-L, chymotrypsin-like activity of the constitutive proteasome, LMP7, CT-
L activity of the immunoproteasome, LMP2, caspase-like activity of the immunoproteasome, 
and MECL1, trypsin-like activity of the immunoproteasome) were significantly reduced. 
Greater inhibition of proteasome and immunoproteasome activity was observed with 
increased dose carfilzomib. CT-L activity returned to baseline by start of cycle 2 (expected, 
given the week off therapy at the end of each cycle), but comparable inhibition was then 
achieved following subsequent therapy in cycle 2. Following the 36mg/m2 dose in cycle 2, 
potent inhibition (> 80% inhibition of pre-treatment levels) of CT-L (β5 and LMP7) activity 
was observed. Alongside these pharmacodynamic measures, there was also an association 
between increasing carfilzomib dose and subsequent clinical response and progression-free 
survival in this trial. Of note, there were no grade 3/4 treatment-emergent adverse events 
among those treated in the 36mg/m2 cohort, while a greater proportion of hematologic 
(anemia, neutropenia, thrombocytopenia) and non-hematologic (dyspnea, fatigue, 
hypertension, hypoxia, pneumonia) grade 3/4 adverse events were observed in the higher 
dose cohorts. Taken together, these pre-clinical and clinical data support dose-dependent 
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Schedule 
The following data support once-weekly dosing of  carfilzomib in this trial: 
Pre-clinical data support prolonged inhibition of CT-L proteasome activity in murine models: 
Single dose PR-171 treatment was associated with prolonged inhibition of CT-L activity to 
20-25% of control levels through 72 hours in whole blood. By 168 hours (7 days), CT-L 
activity was < 50% of control levels.32 Notably, this same trend was not observed following 
single dose bortezomib therapy, wherein CT-L activity was greater than 50% of control 
levels by 24 hours and nearly 100% by 72 hours. Single dose PR-171 treatment was also 
directly compared to two consecutive day (i.e. day 1, day 2) PR-171 treatment. Recovery of 
CT-L activity in the bone marrow was comparable at 48 and 72 hours. In erythrocyte 
depleted whole blood, both approaches produced significant inhibition of CT-L activity (< 
20% of control) that was sustained for 48-72 hours. These data demonstrate that prolonged 
inhibition is achieved with a single dose of this irreversible proteasome inhibitor, as recovery 
of activity is dependent upon production of new functional proteasomes.  
Clinical evidence is also supportive of once-weekly dosing of carfilzomib. A single arm, 
phase I-II study (NCT01677858) has been designed to test the safety and efficacy of once 
weekly carfilzomib in patients with relapsed/refractory multiple myeloma. Results from the 
phase I trial have been presented (Berenson, et al. ASH 2013, abstract 1934). 
Relapsed/refractory multiple myeloma patients who had received 1-3 prior treatment 
regimens were treated with a 30-minute IV infusion on days 1, 8, and 15 of a 28 day cycle in 
a phase I trial 3+3 dose escalation design. All received 20mg/m2 carfilzomib on day 1 of 
cycle 1; subsequent doses tested were 45 mg/m2, 56 mg/m2, 70 mg/m2, and 88 mg/m2. 
Once MTD was determined, an expansion cohort of 9 additional patients was studied. 
Pharmacokinetic studies were performed in the 70 mg/m2 and 88 mg/m2 cohorts using 
peripheral blood samples on days 1 and 15 of cycle 1 at the following time points: pre-dose, 
5, 15, and 30 minutes following start of infusion, and 5, 15, and 30 minutes, and 1, 2, and 4 
hours after end of infusion. A total of 27 patients were enrolled on the phase I component of 
the study. The 45 mg/m2 and 56 mg/m2 cohorts enrolled 3 patients each, and no DLT events 
were observed. The 70 mg/m2 and 88 mg/m2 cohorts each enrolled 6 patients, and the 70 
mg/m2 dose level was identified as the maximally tolerated dose: At the 88mg/m2 dose, 2 
DLT events (grade 3 dyspnea and grade 3 vomiting) were observed. At the 70mg/m2  dose 
level, 1 DLT was observed (grade 3 dyspnea).  An additional 9 patients were studied in the 


 
 
 
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expansion, thus totalling 15 patients at the 70mg/m2 dose. In the 45 mg/m2, 56 mg/m2, and 
70 mg/m2 dose cohorts, no patients required dose reduction for toxicity. PK analysis 
demonstrated dose-proportional increase in mean Cmax and AUC from the 20mg/m2 to 
88mg/m2 dose, and a mean terminal half-life of weekly carfilzomib of 0.8 hours. Treatment 
with 70mg/m2  weekly resulted in similar total AUC per cycle (2373h*ng/mL) as the 
traditional 20/27mg/m2 twice weekly regimen (2274h*ng/mL), and achieved lower Cmax 
levels (2640ng/mL vs. 4232ng/mL, respectively). The phase II component of the trial is 
ongoing, with planned enrollment of 127 patients.  
Infusion time:  In clinical studies, 27mg/m2 of carfilzomib (bolus administration over 2-10’) 
is well tolerated in MM patients overall and can be tolerated for >12 cycles in late stage MM 
patients with comorbidities. In the PX-171-007 trial, more recently patients have been 
treated with carfilzomib given as a 30-minute infusion in order to minimize Cmax-related 
infusion events. All protocols using ≥36mg/m2 carfilzomib are now administering the drug as 
a 30-minute infusion. For consistency, all doses of this agent will be delivered over a 30 
minute infusion in this trial. 
2 OBJECTIVES 
2.1 Primary Objective 
1. Determine proportion of subjects with treatment failure by 6 months of carfilzomib 
therapy for chronic GVHD 
 
2.2 
Secondary Objectives 
1. Determine 3 month overall (complete + partial), and complete response rate 
2. Determine 6 month overall (complete + partial), and complete response rate 
3. Report overall survival, non-relapse mortality, primary malignancy relapse, failure-
free survival, treatment success, and discontinuation of immune suppression at 6 
months and 1 year. 
4. Examine functional outcome (2-minute walk test) and patient-reported outcomes 
(Lee Chronic GVHD Symptom Scale, quality of life (SF-36, FACT-BMT), Human 
Activity Profile (HAP)) at study enrollment, 6 months, and 1 year 
5. Study biologic effects of proteasome inhibition 


 
 
 
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3 EXPERIMENTAL PLAN 
3.1 Study Design 
In this open-label, phase II, multi-center trial, patients with chronic GVHD who have failed at 
least one line of systemic immune-suppressive therapy will be treated with intravenous 
carfilzomib to discern clinical efficacy and biologic activity of this novel therapeutic approach.  
3.2 Number of Subjects 
Twenty patients will be enrolled in this study. 
3.3 Estimated Study Duration 
Enrolled patients will have up to 6 cycles of treatment, and the primary endpoint will be 
measured at 6 months. An additional study follow-up for late outcomes will occur at 1 year. 
Thus, the total duration of time on study for each patient will be one year.  
3.4 Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1:  
day 1:  
20mg/m2 
day  8, 15: 
36mg/m2 
Subsequent cycles:  
day 1, 8, 15:  36mg/m2 
Cycle 1 
      2                   3               4                      5                
6 
(28d)             (28d)          (28d)          (28d)             (28d)           


 
 
 
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Cycle 1:  
Carfilzomib will be administered at 20 mg/m2 on day 1, and then 36mg/m2 on days 8 and 15 
of a 28-day treatment cycle. 
Cycles 2 through 6:  
Carfilzomib will be administered at 36 mg/m2 on days 1, 8, and 15 of a 28-day treatment 
cycle. 
*The acceptable window for each dose of carfilzomib is +/- 3 days. 
*See section 6.2 for guidelines on toxicity management and dose reduction. 
4 SUBJECT SELECTION 
4.1 Inclusion Criteria   
Disease-related: 
1. Diagnosis of chronic GVHD according to NIH Consensus Criteria 
a. May have either classic chronic GVHD or overlap subtype of chronic GVHD 
 
2. Failure of at least one prior line of systemic immune suppressive therapy for 
management of chronic GVHD 
 
3. Subject underwent transplantation at least 3 months prior to enrollment 
 
Demographic:   
1. Age ≥ 18 years 
2. Anticipated life expectancy ≥ 6 months 
 
Laboratory: 
1.  ALT ≤ 3.5 times the upper limit of normal and  bilirubin ≤ 2 mg/dL, unless due to chronic 
GVHD 
2. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L  
3. Hemoglobin ≥ 8 g/dL  
4. Platelet count ≥ 50 × 109/L  


 
 
 
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5. Creatinine clearance (CrCl) ≥ 15 mL/minute, either measured or calculated  
 
Other: 
1. Signed informed consent in accordance with federal, local, and institutional guidelines.  
2. Females of childbearing potential (FCBP) must agree to a pregnancy test at study 
enrollment and to practice contraception during the study.  
3. Male subjects must agree to practice contraception during the study. 
 
4.2 Exclusion Criteria 
Concurrent Conditions: 
1. Evidence of recurrent or progressive underlying malignant disease 
2. Pregnant or lactating females 
3. Surgery within 21 days prior to enrollment 
a. Does not include placement of venous access device, bone marrow biopsy, 
GVHD diagnostic biopsy, or other routine procedures in chronic GVHD or 
post-transplantation care 
4. Uncontrolled infection within 14 days prior to enrollment  
a. Infection treated with appropriate antimicrobial therapy and without signs of 
progression/treatment failure does not constitute an exclusion criterion 
5. Documented human immunodeficiency virus (HIV) infection 
6. Active hepatitis B or C infection 
7. Documented unstable angina or myocardial infarction within 6 months prior to 
enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled 
ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute 
ischemia or Grade 3 conduction system abnormalities (unless subject has a 
pacemaker), LVEF < 40%, history of torsade de pointe,  
8. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment 
a. Sustained systolic blood pressure > 160 or diastolic blood pressure > 100 
despite medical therapy; sustained blood sugar > 300 despite medical 
therapy 
b. Chronic hypertension or diabetes on appropriate medical therapy does not 
constitute an exclusion criterion 
9. Non-hematologic malignancy within the past 3 years with the exception of: 


 
 
 
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a. adequately treated basal cell carcinoma, squamous cell skin cancer, or 
thyroid cancer 
b. carcinoma in situ of the cervix or breast 
c. prostate cancer of Gleason Grade 6 or less with stable prostate-specific 
antigen levels 
d. cancer considered cured by surgical resection or unlikely to impact survival 
during the duration of the study 
10. Significant neuropathy per CTCAE ver. 4.03 or current version (Grade 3 and above, or 
Grade 2 with pain) within 14 days prior to enrollment 
11. History of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib) 
12. Contraindication to all available HSV/varicella prophylactic antiviral drugs 
13. Pleural effusions requiring thoracentesis, or ascites requiring paracentesis, within 14 
days prior to enrollment 
14. Any other clinically significant medical or psychological disease or condition that, in the 
investigator’s opinion, may interfere with protocol adherence or a subject’s ability to give 
informed consent 
15. New systemic immune suppressive agent added for the treatment of chronic GVHD 
within 2 weeks prior to enrollment 
16. Treatment with a non-FDA approved drug in the previous 4 weeks 
 
5 SUBJECT ENROLLMENT 
Potentially eligible patients will be approached at participating study centers. The treating 
clinician will review the informed consent document with them, and eligibility will be 
confirmed. Eligible patients interested in participating will sign consent and initiate study 
procedures. Subjects will be registered through the online database system. 
6 TREATMENT PROCEDURES 
6.1 Drug Preparation and Administration.   
Carfilzomib preparation 
 
Carfilzomib for Injection is supplied as a lyophilized parenteral product in single-use 
vials.  


 
 
 
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 
The lyophilized product is reconstituted with Water for Injection to a final carfilzomib 
concentration of 2.0 mg/mL prior to administration.   
 
The dose will be calculated using the subject’s BSA at baseline.  BSA will be 
calculated and updated (if required) according to institutional standards. 
 
Subjects with a BSA > 2.2 m2 will receive a dose based upon a 2.2 m2 BSA. 
 
Doses may be rounded per institutional standards   
Pre-treatment dexamethasone 
 
Dexamethasone will be administered prior to all carfilzomib doses during the first 
cycle. For the 20mg/m2 initial carfilzomib dose, the required PO/IV dexamethasone 
dose is 4mg. For the subsequent 36mg/m2 doses, the required PO/IV dexamethasone 
dose is 8mg. The timing of dexamethasone administration before carfilzomib and 
selection of PO or IV dexamethasone will adhere to institutional standards.  
 
If treatment-related fever, rigors, chills, and/or dyspnea are observed during or after 
any dose of carfilzomib after dexamethasone pre-medication has been discontinued, 
dexamethasone (8 mg PO/IV) should be re-started and administered prior to 
subsequent doses.  
IV hydration  
 
IV hydration will be given immediately prior to carfilzomib during Cycle 1.  This will 
consist of 250mL normal saline or other appropriate IV fluid.  Pre-treatment IV 
hydration is only required before therapy in cycle 1. In all subsequent cycles, 
hydration may be given before or after carfilzomib according to the treating clinician’s 
judgment, however IV hydration is only required by this protocol before therapy in 
cycle 1. 
 
Subjects should be monitored for evidence of fluid overload.  
 
Carfilzomib infusion time 
 
Carfilzomib should be infused over approximately 30 minutes.   


 
 
 
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 
The dose will be administered at a facility capable of managing hypersensitivity 
reactions.   
 
Subjects will remain at the clinic under observation for at least 1 hour following the 
completion of each dose of carfilzomib in Cycle 1 and following the first dose of Cycle 2.   
 
6.2 Dose Reductions/Adjustments  
The dose of carfilzomib should be held and/or reduced according to the following guidelines: 
Toxicity 
Condition 
Action 
Toxicity 
resolution 
definition 
Action post-
resolution 
Thrombocytopenia 
platelets < 30 × 
109/L 
Subsequent drop 
to < 30 × 109/L 
 
 
- Interrupt CFZ 
- follow CBC*  
- Interrupt CFZ 
- follow CBC*  
 
Return to ≥ 30 × 
109/L 
Return to ≥ 30 × 
109/L 
Resume at full 
dose 
Resume at 1 dose 
decrement 
Neutropenia 
 
 
ANC < 1.0 × 109/L 
 
 
 
 
 
 
 
 
 
 
 
 
- Interrupt CFZ   
- Add filgrastim 
- follow CBC* 
 
 
 
 
 
 
 
 
 
 
Return to > 1.0 × 
109/L 
(if neutropenia was 
the only toxicity 
noted)Returns to > 
1.0 × 109/L 
(if other toxicity 
noted) 
 
 
 
Returns to > 1.0 × 
109/L  
 
 
 
Resume at full 
dose 
 
 
 
 
 
Resume at 1 dose 
decrement 
 
 
 
 


 
 
 
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Subsequent ANC < 
1.0× 109/L 
 
- Interrupt CFZ   
- Add filgrastim  
- follow CBC* 
 
 
 
Resume at 1 dose 
decrement 
 
 
 
 
Allergic reaction, 
Hypersensitivity 
Grade 2 or 3 
 
 
 
Recurrent Grade 2-
3 reaction 
 
 
Any Grade 4 
Hold CFZ 
 
 
 
Hold CFZ 
 
 
 
Discontinue CFZ 
Decrease to ≤ 
Grade 1  
 
 
Decrease to ≤ 
Grade 1  
 
 
n/a 
Resume at full 
dose 
 
 
Resume at 1 dose 
decrement 
 
 
n/a 
Infection 
Grade 3 or 4 
 
Hold CFZ until 
infection controlled 
Infection controlled 
per treating 
clinician  
Resume CFZ at full 
dose 
 
*If neutropenic, 
follow above 
neutropenic dosing 
guidelines 
Herpes zoster or 
simplex 
reactivation 
Any grade 
Hold CFZ until 
lesions are 
improved and dry 
Lesions dry 
Resume CFZ at full 
dose 
Neuropathy 
Grade 2 treatment-
emergent 
neuropathy with 
pain or Grade 3 
neuropathy (not 
persistent for > 2 
weeks) 
 
Continue CFZ  
 
 
 
 
n/a 
 
 
 
 
n/a 
 
 
 
 


 
 
 
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Grade 2 
neuropathy with 
pain or grade 3 
neuropathy 
(persistent for > 2 
weeks) 
 
 
Recurrent Grade 2 
neuropathy with 
pain or grade 3 
neuropathy 
(persistent for > 2 
weeks) 
 
 
 
 
Grade 4 
neuropathy 
 
 
 
 
 
Hold CFZ until ≤ 
Grade 2 without 
pain 
 
 
 
 
 
Hold CFZ until ≤ 
Grade 2 without 
pain 
 
 
 
 
 
 
 
 
Discontinue 
 
 
 
 
 
Neuropathy 
improved to ≤ 
Grade 2 without 
pain 
 
 
 
 
Neuropathy 
improved to ≤ 
Grade 2 without 
pain 
 
 
 
 
 
 
 
n/a 
 
 
 
 
 
Resume CFZ at 
one dose 
decrement 
 
 
 
 
 
Resume CFZ at 
one dose 
decrement 
 
 
 
 
 
 
 
 
n/a 
Renal dysfunction 
 Creatinine > 2 x 
baseline 
Hold CFZ 
Creatinine ≥ 2 x 
baseline 
Resume CFZ at 
one dose 
decrement 
Congestive heart 
failure 
Clinical evidence of 
CHF AND either 
LVEF < 40% or 
reduction in LVEF 
below 55% with a 
drop in LVEF from 
Hold CFZ 
 Control of clinical 
CHF, and return of 
LVEF to ≥ 40% or 
(if held due to drop 
below LVEF of 
55% with > 20% 
Resume CFZ at 
one dose 
decrement 
 


 
 
 
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prior baseline by > 
20%  
drop from baseline) 
return of LVEF to 
within 15% of 
baseline value 
If improvement 
defined above is 
not met 
 
 
 
 
 
 
 
 
 
 
Discontinue CFZ 
therapy 
Other non-
hematologic 
toxicity  > Grade 3 
Other non-
hematologic CFZ-
related > Grade 3 
toxicity not listed 
individually 
elsewhere 
 
 
Hold CFZ 
 
 
 
 
 
 
 
 
Resolved or back 
to baseline 
 
 
 
 
 
Resume CFZ at 
one dose 
decrement 
 
 
 
 
 
 
Pulmonary 
Hypertension 
Grade 3 or 4 
Hold CFZ 
 
Resolved or 
returned to 
baseline 
Resume CFZ at 
one dose 
decrement 
Pulmonary 
Complications 
Grade 3 or 4 
Hold CFZ 
Resolved or 
returned to 
baseline 
Resume CFZ at 
one dose 
decrement 
Hepatic toxicity 
Grade 3 or 4 
elevation of 
transaminases, 
bilirubin, or other 
liver abnormalities 
Hold CFZ 
Follow LFT 
Resolved or 
returned to 
baseline 
 
Resume CFZ at 
one dose 
decrement 
 


 
 
 
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*CBC – Frequency of CBC monitoring after holding dose for toxicity is directed by treating clinician’s 
judgment, and not mandated by this protocol. A recommended guideline is weekly until return to 
baseline. 
*LFT – Frequency of LFT monitoring is directed by treating clinician’s judgment, in keeping with note above 
regarding CBC monitoring. 
   
Permissible dose decrements:  
 
36mg/m2  27mg/m2 
 
27mg/m2  20mg/m2 
 
20mg/m2  15mg/m2 
 
If toxicity persists or reoccurs requiring dose reduction below 15mg/m2, then 
carfilzomib therapy should be discontinued. No more than three dose reductions 
will be permitted in an individual subject on study.  If toxicity continues or recurs 
after three dose reductions, carfilzomib therapy should be discontinued. 
 
If toxicity requiring dose reduction occurs on the first dose (i.e. 20mg/m2), only 
one dose decrement will be possible to 15mg/m2. If toxicity persists or recurs on 
the 15mg/m2 dose, carfilzomib therapy should be discontinued. 
 
Conditions not requiring dose reduction: 
 
Grade 3 nausea, vomiting or diarrhea (unless persisting > 3 days despite 
treatment with anti-emetics or anti-diarrheals)  
 
Grade 3 fatigue (unless persisting continuously for >14 days) 
 
Alopecia 
 
Hyperglycemia attributed to steroids 
 
Persistent toxicity for 3 weeks after withholding CFZ therapy: 
 
If the patient has toxicity attributable to carfilzomib that does not return to 
baseline or reach < grade 1 in severity by 3 weeks, carfilzomib therapy will be 
discontinued 
 
Patient tolerates decreased dose following dose reduction for toxicity: 
 
If the patient tolerates the decreased dose x 2 cycles, full-dose CFZ (i.e. 
36mg/m2) should be resumed on subsequent cycles. 


 
 
 
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 
If subsequent toxicity occurs as defined above, the stated rules for dose 
reduction apply, but a second attempt to resume full-dose therapy should not be 
made. 
 
6.2.1 Missed Doses 
Missed doses will not be replaced. If a subject misses doses of planned therapy due to 
toxicity, they will resume treatment according to planned schedule once the toxicity is 
resolved (see above guidelines). If toxicity resolves within the acceptable (+3 day) window 
surrounding planned therapy, that dose may be administered. 
6.2.2 Changes in Body Surface Area (BSA)  
Dose adjustments do not need to be made for weight gains/losses of ≤ 20%. Subjects with a 
Body Surface Area (BSA) of greater than 2.2 m2 will receive a capped dose for a BSA of 2.2 
m2. Frequency of weight measurement and subsequent recurring calculation of BSA will be 
done according to institutional guidelines. 
 
6.3 Concomitant medications 
6.3.1 Required Concomitant Medications and contraceptive practices 
Contraception: 
Female subjects of child-bearing potential must agree to use contraception (barrier, 
hormonal, or intrauterine) for the duration of the study.  Male subjects must agree to use a 
barrier method of contraception for the duration of the study if sexually active with a female 
of child-bearing potential. Men who have had a prior vasectomy do not need to use a barrier 
method for contraception. 
Antimicrobial prophylaxis: 
Subjects should receive antimicrobial prophylaxis according to institutional treatment 
standards. 


 
 
 
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6.3.2 Management of prednisone and other immune suppression 
Prednisone: 
The management of prednisone will be directed by the treating clinician, and dose/duration 
of prednisone therapy is not mandated by this protocol. 
Additional systemic immune-suppressive agents: 
It is expected that patients will be on additional systemic immune-suppressive agents at the 
time of enrollment, and management of those agents is not mandated by this protocol. Other 
agents can be tapered or discontinued as directed by the treating clinician.  
Addition of new systemic immune-suppressive agents while on trial constitutes treatment 
failure, regardless of the indication for the agent. Systemic immune-suppressive agents 
include orally or intravenously administered systemically active immune-suppressive drugs, 
as well as procedures including extra-corporeal photopheresis (ECP).  
Treatment failure does not include the following: 
1. Adjustment of dosing of existing immune suppressive agents to maintain therapeutic 
drug levels (e.g. tacrolimus, cyclosporine, sirolimus), as this is standard practice. 
2. Adjustment of prednisone dose up or down according to clinical judgment based on 
clinical manifestations of chronic GVHD and patient tolerance of steroid treatment. 
3. Use of topical therapies, including: 
a. ocular drops or physical interventions (e.g. moisturizing eye drops, ocular 
cyclosporine drops, punctal plugs, scleral lenses, etc) 
b. oral rinses or agents (e.g. oral steroid rinse, oral topical immune suppressive 
agents) 
c. non-absorbable gastrointestinal steroid agents (e.g. beclomethasone, 
budesonide) 
d. topical agents applied to the skin (e.g. topical steroid creams, moisturizing 
lotion, topical immune suppressive agents such as tacrolimus) 
e. topical agents applied to the vaginal mucosa (e.g. topical steroid creams or 
topical immune suppressive agents such as tacrolimus) 
4. PUVA 
5. Fluticasone, azithromycin, or monteleukast 


 
 
 
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7 STUDY OUTCOMES 
Primary endpoint: 
Treatment failure 
Treatment failure is the cumulative incidence of addition of systemic immune suppressive 
therapy, recurrent malignancy, and death. The primary endpoint is 6-month treatment 
failure.  
 
See above definitions of systemic immune-suppressive therapy (section 6.3.2) 
 
Recurrent malignancy – This is defined as hematologic relapse or any unplanned 
intervention (including withdrawal of immune suppression) to prevent progression of 
disease in patients with evidence (molecular, cytogenetic, flow cytometric, 
radiographic) of malignant disease after transplantation. 
 
The date of this event will be the earlier date of the following: 
a. Evidence of relapse 
b. Initiation date of intervention for treatment or prevention of relapse 
 
Secondary endpoints: 
Failure-free survival 
This time-to-event outcome will be estimated with the composite event of death from any 
cause, relapse and addition of secondary immune suppressive agents. This will be 
estimated at 6 months and 1 year. 
Overall response rate 
Overall response rate (ORR) at 3 and 6 months following initiation of therapy represents the 
composite outcome of complete and partial response (CR + PR). ORR will be determined by 
both clinician-defined categories of CR and PR, as well as separately calculated according 
to the proposed response definitions of the NIH Consensus Conference.1 
Complete response rate 
Complete response (CR) at 3 and 6 months following initiation of therapy. CR will be 
determined by both clinician-defined CR, as well as separately calculated according to the 
proposed response definitions of the NIH Consensus Conference.1 
Cumulative incidence of non-relapse mortality and primary malignancy relapse 
The cumulative incidence of non-relapse mortality (defined as death in the absence of 
primary malignancy relapse after transplant) and relapse (defined as hematologic relapse or 


 
 
 
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any unplanned intervention to prevent progression of disease in patients with evidence 
(molecular, cytogenetic, flow cytometric, radiographic) of malignant disease after 
transplantation) will be estimated from time of study therapy initiation. These will be treated 
as competing-risk events, and estimated at 6 months and 1 year. 
Overall survival 
Overall survival will be determined from date of study therapy initiation, with death from any 
cause as the event of interest, and censoring at last follow up date for those with incomplete 
observations. This will be determined at 6 months and 1 year. 
Use of additional systemic immune-suppressive therapies 
The use of additional systemic immune-suppressive agents will be captured at each study 
visit, as this constitutes treatment failure. See above clarification (section 6.3.2) for 
definitions of systemic immune-suppressive therapies. 
Discontinuation of all systemic immune-suppressive therapies 
The incidence of complete discontinuation of all systemic immune-suppressive therapies will 
be determined at 6 months and 1 year.  
Treatment success 
This endpoint will be estimated at 6 months and 1 year with a composite outcome of 
complete resolution of all reversible chronic GVHD manifestations, discontinuation of all 
systemic immune suppressive agents, and freedom from death or primary malignancy 
relapse after transplant.  
Patient-reported outcomes and functional measures 
Patients will provide assessment of their functional ability, symptom burden, and quality of 
life using validated instruments recommended by the NIH Consensus Development Project 
on Chronic GVHD (2 minute walk test, Lee Chronic GVHD Symptom Scale,2 HAP functional 
scale,3 QOL instruments SF-364 and FACT-BMT5). These will be studied at baseline, 6 
months, and 1 year. 
Biologic studies 
These studies aim to discern the biologic impact of proteasome inhibition in the treatment of 
chronic GVHD. Peripheral blood samples will be obtained at baseline (study enrollment pre-
treatment), and then at the 3 and 6 month time points. An additional event-driven blood 
sample will be obtained when a new systemic immune suppressive therapy is added 
(treatment failure of carfilzomib). 
A total of 15 mL of blood will be drawn at each timepoint, labeled with a study ID and date of 
draw, and shipped to Moffitt Cancer Center. Samples will be used to confirm effective 


 
 
 
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proteasome inhibition. In addition, these samples will be used to perform RNA-sequencing 
discovery studies for therapeutic response vs. nonresponse, and NanoString nCounter 
validation of any identified targets. Plasma will be used to conduct ELISAs or other tests to 
validate potential targets.  
8 STUDY DISCONTINUATION 
8.1 Criteria for study discontinuation 
The following conditions require discontinuation of carfilzomib therapy and termination of 
study follow up: 
1. Patient decision to withdraw from study 
2. Death 
3. Completion of all study follow up 
8.2 Discontinuation of carfilzomib therapy  
In the following circumstances, carfilzomib therapy will be discontinued, however study 
follow up will continue: 
1. The treating clinician determines that the patient has responded to therapy and does 
not require any additional carfilzomib treatment 
2. Carfilzomib therapy is discontinued due to unresolved toxicity 
3. Carfilzomib therapy is discontinued due to patient non-adherence 
4. Carfilzomib therapy is discontinued due to the addition of another line of systemic 
immune suppressive therapy  
5. The patient has relapse of their hematologic disorder or malignancy after transplant 
 
*As described below (section 9.2), AE will be collected until 30 days after the last dose of 
carfilzomib. 


 
 
 
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9 ADVERSE EVENTS 
For more information about reporting and monitoring adverse events, see the DSMB Charter 
and the Data Safety Monitoring Plan. 
9.1 Definitions 
Adverse Event 
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. It can be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease, temporally associated with 
the use of a drug. 
AE Grading Criteria: 
The study site will grade the severity of adverse events experienced by study participants on 
a scale from 1 to 5 according to NCI CTCAE v4.03 or current version. Grade 1 and grade 2 
adverse events do not require reporting. Adverse events not included in the NCI CTCAE 
should be recorded and graded according to the General Grade Definition provided below: 
ADVERSE EVENT GENERAL GRADE DEFINITIONS 
 
*Instrumental ADL: Preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
Grade 1 
Mild 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated 
Grade 2 
Moderate 
Minimal, local or non-invasive intervention indicated; 
limiting age-appropriate instrumental ADL* 
Grade 3 
Severe 
Severe or medically significant, but not immediately 
life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care 
ADL** 
Grade 4 
Life-threatening 
Life-threatening consequences; urgent intervention 
indicated 
Grade 5 
Death related to AE 
Death related to AE 


 
 
 
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**Self-care ADL: Bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.  
Suspected Adverse Reactions – a subset of Adverse Events based on causality 
       
 A suspected adverse reaction is any adverse event for which there is a reasonable 
possibility that the drug caused the event. Reasonable possibility means there is evidence to 
suggest a causal relationship between the drug and the event.  Some examples are: 
 
A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure.  
 
One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug. If 
the event occurs in association with other factors strongly suggesting causation 
(e.g., strong temporal association, event recurs on re-challenge), a single case 
may be sufficiently persuasive.  Often, more than one occurrence is needed 
before the sponsor-investigator can determine that there is a reasonable 
possibility that the drug caused the event.  
 
An aggregate analysis of events observed in a clinical trial that indicates those 
events occur more frequently in the drug treatment group than in a similar 
population not receiving the study drug. 
If there is reason to conclude with certainty that the drug caused the event, the event is                  
classified as an Adverse Reaction. 
Unexpected  
An adverse event is considered unexpected if it is not listed in the investigator brochure, or 
is not listed at the specificity or severity that has been observed in the event.  “Unexpected” 
also refers to adverse events that are mentioned in the investigator brochure as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, but 
are not specifically mentioned as occurring with the particular drug under investigation.  
Serious 
An adverse event is considered “serious” if, in the view of either the investigator or the 
sponsor, it results in any of the following outcomes: 
1. Death 
2. A life-threatening adverse event (places the subject at an immediate risk of 
death) 
3. Inpatient hospitalization or prolongation of existing hospitalization 


 
 
 
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4. A persistent or significant disability or incapacitation 
5. A congenital anomaly or birth defect 
Additionally, events that jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes above may also be considered serious based 
on appropriate medical judgment.  
 
9.2 Recording of Adverse Events 
The study will collect all Grade 3 and above adverse events, regardless of relationship to 
study therapy or study procedures.  Severity grading will be based on the current version of 
the Common Terminology Criteria for Adverse Events (CTCAE).  Grade 1 and 2 events will 
not be collected. 
Adverse events will be collected from the time of first study procedure or first dose of 
carfilzomib until 30 days after the last dose of carfilzomib.  Events that occur after this time 
will be recorded only if there is a reasonable possibility that the event was caused by a study 
procedure or carfilzomib.  All recordable adverse events will be followed until resolution. 
Reporting procedures: 
All Grade 3 and above adverse events will be reported through case report forms and must 
be recorded in the database within 7 calendar days of becoming aware of the event. All AEs 
are documented and reported as applicable from the time of ICF signature through 30 days 
after the last dose of study drug. 
Exceptions:  
The following are frequent events in the chronic GVHD population and will not be recorded 
as adverse events as long as they are not serious: 
 
Abnormalities present at study enrollment: Will not be considered adverse events, 
unless such abnormalities worsen (i.e. increase in frequency, intensity, or present 
new complications or untoward events) during study follow up 
 
Electrolyte abnormalities: Increase or decrease in sodium, potassium, chloride, 
bicarbonate, phosphorus, magnesium, calcium, hyperglycemia following steroid 
therapy 
 
Ocular: GVHD related eye dryness, discomfort, requirement for moisturizing eye 
drops or other topical GVHD ocular therapies or interventions (e.g. punctal plugs, 
scleral lenses), changes in visual acuity. 


 
 
 
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 
Dermatology: Nail changes, GVHD rash (to include erythema, scleroderma, 
ulceration, lichenoid changes, hyper- or hypo-pigmentation, dry skin and alopecia) or 
cushingoid appearance due to steroid therapy. 
 
Gastrointestinal: Xerostomia, oral ulcers or other GVHD associated lesions, oral pain 
or sensitivity, anorexia, difficulty swallowing due to esophageal stricture or narrowing, 
nausea/vomiting, salivary gland changes, GVHD associated abdominal pain, 
bloating, diarrhea, weight loss 
 
Respiratory: shortness of breath, cough, or oxygen requirement associated with 
pulmonary chronic GVHD involvement 
 
Growth and Development: Reduced growth velocity, delayed puberty. 
 
Musculoskeletal changes: Avascular necrosis, fracture, arthritis, osteoporosis, 
decrease in range of motion associated with joint or fascial GVHD involvement 
 
Sexual Function: Erectile dysfunction, infertility, amenorrhea, vaginal stenosis, 
vaginal dryness or discomfort. 
 
Events secondary to routine procedures performed for chronic GVHD therapies: 
Extracorporeal photopheresis, PUVA therapy. 
Non-serious adverse events collected in the database will be compiled by the coordinating 
center and reported to the DSMB approximately every 6 months.  
All serious adverse events must be reported in the database within 24 hours of becoming 
aware of the event.  Significant and relevant follow-up information should also be reported 
immediately within 24 hours of awareness. 
Exception: 
 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an SAE. 
The site Principal Investigator must notify the coordinating center and sponsor-investigator 
when a serious adverse event has been entered. The sponsor-investigator will then 
determine whether the event meets the criteria for expedited reporting (see below) and will 
work with the coordinating center to prepare the IND Safety Report. 
 
9.3 IND Safety Reporting 
An event must meet all three of the following criteria in order to qualify for expedited 
reporting to the FDA in an IND Safety Report: 
1) Serious 


 
 
 
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2) Unexpected 
3) Suspected adverse reaction (i.e. there is a reasonable possibility that the drug 
caused the event) 
The sponsor-investigator is ultimately responsible for determining whether all criteria are 
met. Details are as follows: 
 
Seriousness: If either the sponsor-investigator or local investigator believes that an 
event is serious, it must be considered serious and evaluated by the sponsor-
investigator for expedited reporting. Similarly, if either the sponsor-investigator or local 
investigator believes that an event is life threatening, it must be considered life 
threatening for reporting purposes. 
 
 
Expectedness: The sponsor-investigator is responsible for determining whether an 
event is unexpected. 
 
 
Causality: Although local investigators are required to provide a causality assessment 
for each serious adverse event originating from their sites, it is ultimately the sponsor-
investigator who decides whether the event meets the definition of a suspected adverse 
reaction.  
IND Safety reports will be submitted on a MedWatch3500A form to the FDA and all 
participating investigators no later than 15 days after the sponsor-investigator determines 
that the event qualifies for reporting.  
Exception: Fatal or life-threatening events will be reported within 7 days of when the 
sponsor-investigator receives notification of the event.  
Relevant additional information should be submitted in a follow-up report as soon as 
possible, but no later than 15 days after the sponsor-investigator receives the information.  
All other adverse events that are collected by the study but do not meet the criteria for 
expedited reporting will be reported to the FDA in the IND Annual Report. 
Notification of SAE that meet requirement for expedited reporting will also be provided to 
individual site principal investigators of this trial. 
9.4 Reporting to Onyx 
The coordinating center is responsible for all communication with Onyx. The sponsor-
investigator will submit IND Safety Reports (per above guidelines, namely serious, 
unexpected, suspected adverse reactions) to Onyx in an expedited manner (same criteria 


 
 
 
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as above, namely within 24 hours of awareness. This notification will be documented on a 
MedWatch3500A form.  
The initial report will be as complete as possible, at a minimum including the serious 
adverse event term (s), patient identifier, date of awareness of the event, an assessment of 
the causal relationship between the event and the investigational product(s), and name of 
the reporter (investigator).  Information not available at the time of the initial report (e.g., an 
end date for the adverse event or laboratory values received after the report) must be 
documented on a follow-up MEDWATCH form.  The Onyx protocol number and the 
institutional protocol number will be included on all reports to Onyx.   
All other SAEs (i.e. those not meeting above criteria for expedited reporting) will be sent to 
Onyx within 30 days of awareness, and include the following: Patient identifier, SAE onset 
and stop dates, event name (term), outcome, dates of study drug exposure, action taken 
with study drug, assessment of causality and expectedness.  
To report a Serious Adverse Event or other safety related information to Onyx Drug Safety 
please use: 
Drug Safety Hotline:      
650.266.2501 
Drug Safety Fax:            
650.266.0501 or 800-783-7954 
Drug Safety Email:  
AdverseEvents@onyx.com 
 
9.5 Pregnancy 
Female participants of child-bearing potential must have a negative pregnancy test prior to 
treatment and agree to use dual methods of contraception for the duration of the study and 
for 30 days following completion of study. Male participants must also agree to use a barrier 
method of contraception for the duration of the study and for 30 days following completion of 
study if sexually active with a female of child-bearing potential. 
 
If a subject or partner of a subject becomes pregnant during or up to 30 days following 
administration of the last dose of carfilzomib, Onyx Drug Safety must be notified by the 
study-investigator within 24 hours of research personnel becoming aware of it. Carfilzomib 
must be stopped if a subject becomes pregnant. Subjects or pregnant partners will be 
followed through the outcome of the pregnancy. The outcome must be reported to Onyx 
Drug Safety.  If the outcome qualifies as a serious adverse event, the serious adverse event 
reporting procedures should be followed. 
 


 
 
 
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9.6 Notifying Institutional Review Boards 
Study sites are responsible for adhering to their local IRB guidelines.  In general, all 
investigators are required to promptly report to their IRB all unanticipated problems involving 
risk to human subjects or others. IND Safety Reports, which will be distributed to all 
investigators, will usually require reporting under this category.  
10 STATISTICAL ANALYSIS 
10.1 Study Design 
This is a single arm, pilot phase II trial examining the efficacy of carfilzomib for treatment of 
chronic GVHD. 
10.2 Study Endpoints 
The major study endpoints are listed in section 7, ‘study outcomes’.  
10.2.1 Safety Endpoints 
Patients will be monitored for adverse events through 30 days following their last therapy 
with carfilzomib on trial.  
10.3 Sample Size Considerations and Planned Methods of Analysis 
The primary endpoint is overall treatment failure at 6 months from study enrollment. 
Treatment failure represents the composite including addition of new line of systemic 
immune suppressive therapy beyond carfilzomib (objective signal of failure to control GVHD 
with carfilzomib), non-relapse death, and primary malignancy relapse.6 The historical 
benchmark for this outcome based on this analysis of 312 chronic GVHD patients is a 6 
month treatment failure rate of 44%. With 20 patients, the standard error of the estimated 
failure rate will be approximately 10 percentage points.   
The major contribution to the observed treatment failure rate was 34% requiring additional 
immune suppressive therapy beyond second-line therapy. Assuming effective therapy with 
ongoing carfilzomib over the treatment period could reduce this risk by 50% (i.e. to 17%) 
with little or no increased risk for relapse (3% in this published analysis) or non-relapse 
death (7% in this analysis), the overall improvement in the 6 month treatment failure rate 
could be 15%. Given the feasible sample size of 20 patients, we do not expect to be able to 
demonstrate statistically significant differences relative to the historical rate; however, an 


 
 
 
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observed failure rate in the 30-35% range or better would be considered promising for future 
study of carfilzomib. Patients who are lost to follow up or otherwise not evaluable will not be 
replaced. 
Although the overall 6 month failure rate in the historical benchmark study was 44%, this 
varied from 33% to 41% to 56% for patients that were classified as low, intermediate and 
high risk, respectively.  Thus the relative proportions of patients in the different risk 
categories will need to be considered in order to interpret the possible benefit of carfilzomib 
therapy. 
In the analysis of secondary objectives, we will study the 3 and 6 month overall (complete + 
partial) response and complete response rates, other efficacy measures listed above, 
patient reported outcomes, and biologic outcome measures. We will study association 
between biologic outcome measures and clinical parameters (response, treatment failure, 
mortality).  
10.4 Study Stopping Rules 
The principal investigators and the Data and Safety Monitoring Board (DSMB) will review 
safety data on an ongoing basis and formally every 6 months.  If any of these reviews 
conclude that there are significant safety concerns, then the trial could be permanently 
terminated.  The criteria described below provide additional guidance for suspending trial 
enrollment, analyzing safety data in detail, and deciding whether to continue.   
While Carfilzomib has demonstrated safety as a single agent and in combination therapy in 
multiple myeloma, it has not been previously studied in chronic GVHD therapy after 
allogeneic hematopoietic cell transplantation. Current evidence suggests that approximately 
7% of patients will experience non-relapse mortality during the initial 6 months of therapy.33 
In our current trial, if reasonable evidence exists that non-relapse mortality during the initial 
6 months exceeds this threshold, then enrollment to the trial will be halted while data are 
reviewed. Reasonable evidence indicates that the lower bound of an exact 1-sided 80% 
confidence interval for the true non-relapse mortality rate exceeds 7%. The data will be 
evaluated at least every 5 patients, and will be triggered if 2 or more of 5, 2 or more of 10, 3 
or more of 15, or 3 or more of 20 patients experience non-relapse mortality within the first 6 
months.  


 
 
 
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The operating characteristics of this stopping rule are provided below: 
True rate of event 
Probability of stopping* 
Average N at stopping* 
0.12 
51% 
16 
0.17 
73% 
13 
0.22 
88% 
11 
*Based on 10,000 Monte Carlo simulations 
11 INVESTIGATIONAL PRODUCT 
11.1 Carfilzomib Description 
Carfilzomib is a synthetic small molecule peptide bearing the chemical name (2S)-N-((S)-1-
((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-
2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide.  The molecular 
formula is C40H57N5O7 and the molecular weight is 719.91.  It specifically functions as an 
inhibitor of the chymotrypsin-like activity of the 20S proteasome which leads to the 
accumulation of protein substrates within the cell and induction of apoptosis.   
11.2 Formulation 
Carfilzomib for Injection will be provided as a lyophilized powder which, when reconstituted, 
contains 2 mg/mL isotonic solution of carfilzomib Free Base in 10 mM sodium citrate buffer 
(pH 3.5) containing 10% (w/v) sulfobutylether--cyclodextrin (SBE--CD, Captisol®).   
11.3 Storage 
Lyophilized Carfilzomib for Injection must be stored at 2–8ºC under the conditions outlined in 
the separate Pharmacy Manual, in a securely locked area to which access is limited to 
appropriate study personnel. 


 
 
 
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11.4 Accountability 
Onyx, Inc. and the Investigator’s pharmacy will maintain records of each shipment of 
investigational product.  The records will document shipment dates, method of shipment, 
batch numbers, and quantity of vials contained in the shipment.  Upon receipt of the 
investigational product, the designated recipient at the study site will inspect the shipment, 
verify the number and condition of the vials, and prepare an inventory or drug accountability 
record.  
Drug accountability records must be readily available for inspection by representatives of 
Onyx, by regulatory authorities, and by the Sponsor-Investigator or her designates.  
Empty and partially used vials should be accounted for and destroyed at the study site in 
accordance with the internal standard operating procedures.  Drug destruction records must 
be readily available for inspection by representatives of Onyx, by regulatory authorities, and 
by the Sponsor-Investigator or her designates.  
Only sites that cannot destroy unused drug on-site will be required to return their unused 
supply of investigational product. 
12 REGULATORY OBLIGATIONS 
12.1 Informed Consent 
All patients will provide informed consent following review of the informed consent form and 
discussion with their treating clinician, in keeping with standards at each participating study 
site. 
12.2 Compliance with Laws and Regulations 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) 
and International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice 
(GCP), the Declaration of Helsinki, Health Canada, any applicable local health authority, and 
Institutional Review Board (IRB) or Ethics Committee requirements. 
This study must have the approval of a properly constituted IRB.  Before the investigational 
drug is shipped to the Investigator, the Investigator or designee will provide Onyx with a 


 
 
 
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copy of the IRB approval letter stating that the study protocol and any subsequent 
amendments and informed consent form have been reviewed and approved. 
The Investigator or designee will be responsible for obtaining annual IRB reapproval 
throughout the duration of the study.  Copies of the Investigator’s annual report to the IRB 
and copies of the IRB continuance of approval must be provided to both Onyx and the 
Sponsor-Investigator as follows: 
Onyx Pharmaceuticals, Inc. 
Regulatory Department 
249 East Grand Ave 
South San Francisco, CA 94080 
 
Stephanie Lee, MD, MPH 
Fred Hutchinson Cancer Research Center 
1100 Fairview Ave 
PO Box 19024, D5-290 
Seattle, WA 98109 
chronicGVHDstudies@fredhutch.org 
 
Onyx will provide study sites with any expedited safety reports generated from any ongoing 
studies with carfilzomib, changes to the Investigator’s Brochure, and any other safety 
information which changes the risk/benefit profile of carfilzomib during the conduct of the 
study, to allow him/her to fulfill his/her obligation for timely reporting to the IRB and other 
Investigators participating in the study. 
Upon completion of the trial, the Investigator must provide the IRB and Onyx with a 
summary of the trial’s outcome. 


 
 
 
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12.3 Subject Confidentiality 
Subject medical information obtained as part of this study is confidential, and must not be 
disclosed to third parties, except as noted below.  The subject may request in writing that 
medical information be given to his/her personal physician. 
The Investigator/Institution will permit direct access to source data and documents by Onyx, 
its designee, the FDA and/or other applicable regulatory authority.  The access may consist 
of trial-related monitoring, audits, IRB reviews, and FDA inspections. 
Release of research results should preserve the privacy of medical information and must be 
carried out in accordance with Department of Health and Human Services Standards for 
Privacy of Individually Identifiable Health Information, 45 CFR 164.508. 
 


 
 
 
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Lee S, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to measure 
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6. 
Inamoto Y, Storer BE, Lee SJ, Carpenter PA, Sandmaier BM, Flowers ME, Martin PJ. 
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Flowers ME, Parker PM, Johnston LJ, Matos AV, Storer B, Bensinger WI, Storb R, 
Appelbaum FR, Forman SJ, Blume KG, Martin PJ. Comparison of chronic graft-versus-host 
disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic 
recipients: long-term follow-up of a randomized trial. Blood. 2002;100:415-419. 
8. 
Lee SJ, Flowers ME. Recognizing and managing chronic graft-versus-host disease. 
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Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow 
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Lee SJ, Klein JP, Barrett AJ, Ringden O, Antin JH, Cahn JY, Carabasi MH, Gale RP, Giralt S, 
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Socie G, Stone JV, Wingard JR, Weisdorf D, Henslee-Downey PJ, Bredeson C, Cahn JY, 
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Fraser CJ, Bhatia S, Ness K, Carter A, Francisco L, Arora M, Parker P, Forman S, Weisdorf 
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Palmer J, Arai S, Jagasia M, Lee SJ. Patient-reported quality of life is associated with severity of 
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15. 
Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, Hackman R, 
Tsoi MS, Storb R, Thomas ED. Chronic graft-versus-host syndrome in man. A long-term 
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Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, 
Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, 
Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman 
H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development 
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working group report. Biol Blood Marrow Transplant. 2005;11:945-956. 
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Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA, Sanders JE, Witherspoon 
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18. 
Sullivan KM, Witherspoon RP, Storb R, Weiden P, Flournoy N, Dahlberg S, Deeg HJ, 
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prednisone and placebo for treatment of chronic graft-v-host disease: prognostic influence of 
prolonged thrombocytopenia after allogeneic marrow transplantation. Blood. 1988;72:546-
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19. 
Arora M, Wagner JE, Davies SM, Blazar BR, Defor T, Enright H, Miller WJ, Weisdorf DF. 
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Transplant. 2001;7:265-273. 
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Gilman AL, Schultz KR, Goldman FD, Sale GE, Krailo MD, Chen Z, Langholz B, Jacobsohn 
DA, Chan KW, Ryan RE, Kellick M, Neudorf SM, Godder K, Sandler ES, Sahdev I, Grupp SA, 
Sanders JE, Wall DA. Randomized Trial of Hydroxychloroquine for Newly Diagnosed Chronic 


 
 
 
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Graft-versus-Host Disease in Children: A Children's Oncology Group Study. Biol Blood Marrow 
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Martin PJ, Storer BE, Rowley SD, Flowers ME, Lee SJ, Carpenter PA, Wingard JR, 
Shaughnessy PJ, DeVetten MP, Jagasia M, Fay JW, van Besien K, Gupta V, Kitko C, Johnston LJ, 
Maziarz RT, Arora M, Jacobson PA, Weisdorf D. Evaluation of mycophenolate mofetil for initial 
treatment of chronic graft-versus-host disease. Blood. 2009;113:5074-5082. 
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Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA, Sanders JE, Witherspoon 
RP, Appelbaum FR, Storb R, Martin PJ. Thalidomide for treatment of patients with chronic graft-
versus-host disease. Blood. 2000;96:3995-3996. 
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Wolff D, Schleuning M, von Harsdorf S, Bacher U, Gerbitz A, Stadler M, Ayuk F, Kiani A, 
Schwerdtfeger R, Vogelsang GB, Kobbe G, Gramatzki M, Lawitschka A, Mohty M, Pavletic SZ, 
Greinix H, Holler E. Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line 
Treatment of Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2011;17:1-17. 
24. 
Moran E, Carbone F, Augusti V, Patrone F, Ballestrero A, Nencioni A. Proteasome 
inhibitors as immunosuppressants: biological rationale and clinical experience. Semin 
Hematol;49:270-276. 
25. 
Koreth J, Alyea EP, Murphy WJ, Welniak LA. Proteasome inhibition and allogeneic 
hematopoietic stem cell transplantation: a review. Biol Blood Marrow Transplant. 
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26. 
Sun K, Welniak LA, Panoskaltsis-Mortari A, O'Shaughnessy MJ, Liu H, Barao I, Riordan W, 
Sitcheran R, Wysocki C, Serody JS, Blazar BR, Sayers TJ, Murphy WJ. Inhibition of acute graft-
versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor 
bortezomib. Proc Natl Acad Sci U S A. 2004;101:8120-8125. 
27. 
Koreth J, Stevenson KE, Kim HT, Garcia M, Ho VT, Armand P, Cutler C, Ritz J, Antin JH, 
Soiffer RJ, Alyea EP, 3rd. Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-
versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation 
from HLA-mismatched unrelated donors. Blood. 2009;114:3956-3959. 
28. 
Koreth J, Stevenson KE, Kim HT, McDonough SM, Bindra B, Armand P, Ho VT, Cutler C, 
Blazar BR, Antin JH, Soiffer RJ, Ritz J, Alyea EP, 3rd. Bortezomib-based graft-versus-host disease 
prophylaxis in HLA-mismatched unrelated donor transplantation. J Clin Oncol. 2012;30:3202-
3208. 
29. 
Todisco E, Sarina B, Castagna L, Mazza R, Rahal D, Nozza A, Santoro A. Inhibition of 
chronic graft-vs-host disease with retention of anti-myeloma effects by the proteasome 
inhibitor bortezomib. Leuk Lymphoma. 2007;48:1015-1018. 
30. 
Mateos-Mazon J, Perez-Simon JA, Lopez O, Hernandez E, Etxebarria J, San Miguel JF. Use 
of bortezomib in the management of chronic graft-versus-host disease among multiple 
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31. 
El-Cheikh J, Michallet M, Nagler A, de Lavallade H, Nicolini FE, Shimoni A, Faucher C, 
Sobh M, Revesz D, Hardan I, Furst S, Blaise D, Mohty M. High response rate and improved graft-
versus-host disease following bortezomib as salvage therapy after reduced intensity 
conditioning allogeneic stem cell transplantation for multiple myeloma. Haematologica. 
2008;93:455-458. 
32. 
Demo SD, Kirk CJ, Aujay MA, Buchholz TJ, Dajee M, Ho MN, Jiang J, Laidig GJ, Lewis ER, 
Parlati F, Shenk KD, Smyth MS, Sun CM, Vallone MK, Woo TM, Molineaux CJ, Bennett MK. 
Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 
2007;67:6383-6391. 
33. 
Inamoto Y, Storer BE, Lee SJ, Carpenter PA, Sandmaier BM, Flowers ME, Martin PJ. 
Failure-free survival after second-line systemic treatment of chronic graft-versus-host disease. 
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Appendix A:  NCI-CTCAE Version 4.03 
Common Terminology Criteria for Adverse Events (CTCAE)  
National Cancer Institute (NCI) v4.03 
Publish Date:  June 14, 2010 
http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Appendix B:  Study Calendar 
 
Procedure 
Screening 
Baseline 
 
Follow Up**** 
 
 
 
 
3 
months 
6 
months 
12 
months 
Carfilzomib administration* 
 
X 
X 
X 
 
 
 
 
 
 
 
Screening Procedures 
 
 
 
 
 
Eligibility criteria** 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessments 
 
 
 
 
 
Chronic GVHD activity 
- NIH score  
- clinician severity assessments 
- clinician response assessments 
- patient-reported severity 
 
 
X 
X 
X 
X 
Patient- reported outcomes 
- QOL 
- HAP 
- Lee symptom scale 
 
X 
 
X 
X 
 Functional measures 
- 2 minute walk test  
 
X 
 
X 
X 
Record systemic immune 
suppressive agents 
 
X 
X 
X 
X 
Biologic samples 
 
X 
X 
X 
 


 
 
 
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Survival and malignancy relapse 
 
 
X 
X 
X 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
Physical exam 
 
X 
X 
X 
X 
Adverse events*** 
 
X 
X 
X 
 
 
*Carfilzomib administration: Weekly for 3 weeks (day 1, 8, 15) out of each 28 day cycle for total of 6 
cycles of therapy. Acceptable window for each planned carfilzomib administration date is +/- 3 days.  
Monitoring of routine laboratory tests (CBC, chemistry, LFT) are per institutional standards. 
 
**Eligibility includes the following: 
- 
Review of patient records for compliance with all listed inclusion and exclusion criteria 
- 
Laboratory studies required to meet laboratory criteria (obtained within 14 days of study 
enrollment) 
 
CBC, chemistry, liver function tests 
- 
EKG to demonstrate no active ischemic changes; other listed cardiac conditions can be 
addressed by review of patient medical records (EKG should be performed within 14 days of 
study enrollment) 
- 
Confirmation of no history of HIV or hepatitis B/C 
 
If HIV and hepatitis B/C testing has been previously done and documented in the patient 
record, new testing at time of eligibility screening for this study is not necessary 
 
If HIV+, the patient is excluded 
 
If Hepatitis B serology indicates prior infection (i.e. core Ab positive, or surface antigen 
positive), hepatitis B PCR testing on peripheral blood should be done.  
 
If PCR negative, the patient is eligible, but if positive, ineligible. 
 
If hepatitis C antibody testing is positive, hepatitis C PCR should be tested in peripheral 
blood.  
 
If PCR negative, the patient is eligible, but if positive, ineligible. 
 


 
 
 
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***AE/SAE are monitored for duration of therapy through 30 days following the final dose of study 
therapy  
 
****Acceptable window for study visits at 3 and 6 months is +/- 14 days, and acceptable window for the 12 month 
study visit is +/- 1 month.