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

Chronic Graft Versus Host Disease Clinical Trial

Official title:

Carfilzomib for Treatment of Chronic Graft vs. Host Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02491359
• Other study ID #: 9228
• Secondary ID: NCI-2015-0080992
• Status: Completed
• Phase: Phase 2
• Start date: November 12, 2015
• Est. completion date: September 12, 2018

Study information

• Verified date: January 2019
• Source: Fred Hutchinson Cancer Research Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: September 12, 2018
• Est. primary completion date: February 19, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chronic Graft Versus Host Disease
• Graft vs Host Disease

Intervention

Drug:
• Carfilzomib
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Locations

Country	Name	City	State
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Research Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Adverse Events	according to National Cancer Institute CTCAE, version 4.03	Up to 30 days following completion of study treatment
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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