Carfilzomib in Treating Patients With Chronic Graft-Versus-Host Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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Carfilzomib for Treatment of Chronic Graft vs. Host Disease

Conditions
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Chronic Graft Versus Host Disease

Intervention / Treatment
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* Drug: Carfilzomib
* Other: Laboratory Biomarker Analysis
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of chronic GVHD according to National Institutes of Health (NIH) Consensus Criteria May have either classic chronic GVHD or overlap subtype of chronic GVHD Failure of at least one prior line of systemic immune suppressive therapy for management of chronic GVHD Subject underwent transplantation at least 3 months prior to enrollment Anticipated life expectancy >= 6 months Alanine aminotransferase (ALT) =< 3.5 times the upper limit of normal, unless due to chronic GVHD Bilirubin =< 2 mg/dL, unless due to chronic GVHD Absolute neutrophil count (ANC) >= 1.0 × 10^9/L Hemoglobin >= 8 g/dL Platelet count >= 50 × 10^9/L Creatinine clearance (CrCl) >= 15 mL/minute, either measured or calculated Signed informed consent in accordance with federal, local, and institutional guidelines Females of childbearing potential (FCBP) must agree to a pregnancy test at study enrollment and to practice contraception during the study Male subjects must agree to practice contraception during the study Exclusion Criteria: Evidence of recurrent or progressive underlying malignant disease Pregnant or lactating females Surgery within 21 days prior to enrollment 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 Uncontrolled infection within 14 days prior to enrollment Infection treated with appropriate antimicrobial therapy and without signs of progression/treatment failure does not constitute an exclusion criterion Documented human immunodeficiency virus (HIV) infection Active hepatitis B or C infection Documented unstable angina or myocardial infarction within 6 months prior to enrollment, New York Heart Association (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), left ventricular ejection fraction (LVEF) < 40%, history of torsade de pointe Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment Sustained systolic blood pressure > 160 or diastolic blood pressure > 100 despite medical therapy; sustained blood sugar > 300 despite medical therapy Chronic hypertension or diabetes on appropriate medical therapy does not constitute an exclusion criterion Non-hematologic malignancy within the past 3 years with the exception of: Adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer Carcinoma in situ of the cervix or breast Prostate cancer of Gleason grade 6 or less with stable prostate-specific antigen levels Cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study Significant neuropathy per Common Terminology Criteria for Adverse Events (CTCAE) version (ver.) 4.03 or current version (grade 3 and above, or grade 2 with pain) within 14 days prior to enrollment History of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib) Contraindication to all available herpes simplex virus (HSV)/varicella prophylactic antiviral drugs Pleural effusions requiring thoracentesis, or ascites requiring paracentesis, within 14 days prior to enrollment 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 New systemic immune suppressive agent added for the treatment of chronic GVHD within 2 weeks prior to enrollment Treatment with a non-Food and Drug Administration (FDA) approved drug in the previous 4 weeks

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (carfilzomib)<br>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. | Drug: Carfilzomib<br>* Given IV<br>* Other names: PR-171;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | according to National Cancer Institute CTCAE, version 4.03 | Up to 30 days following completion of study treatment | 
| Probability of Treatment Failure at 6mo | Kaplan-Meier estimate assessed at 6 months for treatment failure, defined as requirement of an additional line of systemic immune-suppressive therapy, recurrent malignancy, or death. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate | Complete response (CR) at 6 months will be determined by both clinician-defined CR, as well as separately calculated according to the proposed response definitions of the NIH Consensus Conference. | Up to 6 months | 
| 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 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 1 year. | 1 year | 
| Probability of Failure-free Survival at 1 Year | Kaplain-Meier estimate assessed at 1 year for failure-free survival, defined as absence of death from any cause, relapse, or addition of secondary immune-suppressive agents. | 1 year | 
| Impact of Proteasome Inhibition | The biologic impact of proteasome inhibition in the treatment of chronic GVHD will be assessed at baseline, 3 and 6 months. The association between biologic outcome measures and clinical parameters (response, treatment failure, mortality) will be studied. | Up to 6 months | 
| Incidence of Discontinuation of All Systemic Immune-suppressive Therapies | The incidence of complete discontinuation of all systemic immune-suppressive therapies will be determined at 1 year. | 1 year | 
| Overall Response Rate | Overall response rate (ORR) (complete response + partial response) at 6 months will be determined by both clinician-defined categories of complete response and partial response, as well as separately calculated according to the proposed response definitions of the NIH Consensus Conference. | 6 months | 
| Probability of Overall Survival at 1 Year | Kaplan-Meier estimate assessed at 1 year for overall survival, defined as absence of death from any cause. | 1 year | 
| Treatment Success | Treatment success will be estimated at 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. | 1 year | 
| Use of Additional Systemic Immune-suppressive Therapies | Addition of therapy after carfilzomib constitutes failure, could occur at any time from baseline to 12mo. | 1 year | 
| Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | SF-36 subscales have min=0 and max=100; results given are actual scores at 12mo, with higher scores indicating higher quality of life. | baseline | 
| Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | FACT-BMT subscales have various min/max, see below; results given are actual 12mo scores, with higher scores indicating better functioning. FACT physical well-being (0-28) FACT social/family well-being (0-28) FACT emotional well-being (0-24) FACT functional well-being (0-28) FACT Bone Marrow Transplant (BMT) subscale (0-40) FACT trial outcome index (0-96) FACT-General (G) (0-108) FACT-BMT total (0-148) | baseline | 
| Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP) | HAP subscales have min=0 and max=94; results given are actual 12mo scores, with higher scores indicating better functioning. Maximum Activity Score (MAS) is highest item number answered still doing. Represents highest oxygen demanding activity that respondent still performs. Adjusted Activity Score (AAS) is MAS minus total number of stopped doing responses below MAS. A measure of usual daily activities. Modified AAS is MAS minus total number of stopped doing responses below MAS but not penalized for not doing activities not permitted post transplant. The following items are not counted against the score:11,15,19,20,22,25,34,41,42,47,49,50,52,53,54,57,72,73,77,78. | baseline | 
| Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | Lee symptom scale (LSS) has subscales with min=0, max=100; results given are 12mo scores, with higher numbers indicating higher symptom burden. | baseline |