- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02491359
Carfilzomib in Treating Patients With Chronic Graft-Versus-Host Disease
Carfilzomib for Treatment of Chronic Graft vs. Host Disease
Study Overview
Status
Conditions
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Florida
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Tampa, Florida, United States, 33612
- Moffitt Cancer Center
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New York
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Buffalo, New York, United States, 14263
- Roswell Park Cancer Institute
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Ohio
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Columbus, Ohio, United States, 43210
- Ohio State University Comprehensive Cancer Center
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Pennsylvania
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Pittsburgh, Pennsylvania, United States, 15232
- University of Pittsburgh Cancer Institute (UPCI)
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Washington
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Seattle, Washington, United States, 98109
- Fred Hutch/University of Washington Cancer Consortium
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (carfilzomib)
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.
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Correlative studies
Ancillary studies
Other Names:
Ancillary studies
Given IV
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of Adverse Events
Time Frame: Up to 30 days following completion of study treatment
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according to National Cancer Institute CTCAE, version 4.03
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Up to 30 days following completion of study treatment
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Probability of Treatment Failure at 6mo
Time Frame: 6 months
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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.
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6 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Probability of Overall Survival at 1 Year
Time Frame: 1 year
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Kaplan-Meier estimate assessed at 1 year for overall survival, defined as absence of death from any cause.
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1 year
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Complete Response Rate
Time Frame: Up to 6 months
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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.
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Up to 6 months
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Cumulative Incidence of Non-relapse Mortality and Primary Malignancy Relapse
Time Frame: 1 year
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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.
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1 year
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Probability of Failure-free Survival at 1 Year
Time Frame: 1 year
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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.
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1 year
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Impact of Proteasome Inhibition
Time Frame: Up to 6 months
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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.
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Up to 6 months
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Incidence of Discontinuation of All Systemic Immune-suppressive Therapies
Time Frame: 1 year
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The incidence of complete discontinuation of all systemic immune-suppressive therapies will be determined at 1 year.
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1 year
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Overall Response Rate
Time Frame: 6 months
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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.
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6 months
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Treatment Success
Time Frame: 1 year
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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.
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1 year
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Use of Additional Systemic Immune-suppressive Therapies
Time Frame: 1 year
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Addition of therapy after carfilzomib constitutes failure, could occur at any time from baseline to 12mo.
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1 year
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Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36)
Time Frame: baseline
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SF-36 subscales have min=0 and max=100; results given are actual scores at 12mo, with higher scores indicating higher quality of life.
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baseline
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Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT)
Time Frame: baseline
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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
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Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP)
Time Frame: baseline
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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
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Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale
Time Frame: baseline
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Lee symptom scale (LSS) has subscales with min=0, max=100; results given are 12mo scores, with higher numbers indicating higher symptom burden.
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baseline
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Collaborators and Investigators
Sponsor
Collaborators
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 9228 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)
- P30CA015704 (U.S. NIH Grant/Contract)
- NCI-2015-00809 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- 9228.00
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