Chronic Graft Versus Host Disease
Conditions
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.
Interventions
DRUGCarfilzomib
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events | Up to 30 days following completion of study treatment | according to National Cancer Institute CTCAE, version 4.03 |
| Probability of Treatment Failure at 6mo | 6 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Probability of Failure-free Survival at 1 Year | 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. |
| Impact of Proteasome Inhibition | Up to 6 months | 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. |
| Incidence of Discontinuation of All Systemic Immune-suppressive Therapies | 1 year | The incidence of complete discontinuation of all systemic immune-suppressive therapies will be determined at 1 year. |
| Overall Response Rate | 6 months | 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. |
| Probability of Overall Survival at 1 Year | 1 year | Kaplan-Meier estimate assessed at 1 year for overall survival, defined as absence of death from any cause. |
| Complete Response Rate | Up to 6 months | 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. |
| Use of Additional Systemic Immune-suppressive Therapies | 1 year | Addition of therapy after carfilzomib constitutes failure, could occur at any time from baseline to 12mo. |
| Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | baseline | SF-36 subscales have min=0 and max=100; results given are actual scores at 12mo, with higher scores indicating higher quality of life. |
| Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | baseline | 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) |
| Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP) | baseline | 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. |
| Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | baseline | Lee symptom scale (LSS) has subscales with min=0, max=100; results given are 12mo scores, with higher numbers indicating higher symptom burden. |
| Treatment Success | 1 year | 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. |
| Cumulative Incidence of Non-relapse Mortality and Primary Malignancy Relapse | 1 year | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Treatment (Carfilzomib) |
|---|---|
| Age, Continuous | 53 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Primary Disease Acute leukemia (ALL/AML) | 12 Participants |
| Primary Disease Chronic leukemia (CML/CLL) | 4 Participants |
| Primary Disease Lymphoma (NHL/HD) | 2 Participants |
| Primary Disease Myeloma | 1 Participants |
| Primary Disease Myeloproliferative neoplasm | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 20 |
| other Total, other adverse events | 7 / 20 |
| serious Total, serious adverse events | 8 / 20 |
Outcome results
Primary
Incidence of Adverse Events
according to National Cancer Institute CTCAE, version 4.03
Time frame: Up to 30 days following completion of study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Carfilzomib) | Incidence of Adverse Events | Serious Adverse Events | 8 participants |
| Treatment (Carfilzomib) | Incidence of Adverse Events | Non-Serious Adverse Events | 7 participants |
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.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Carfilzomib) | Probability of Treatment Failure at 6mo | 0.4 probability of treatment failure |
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.
Time frame: Up to 6 months
Population: Participants who could be evaluated for response (not missing data)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Carfilzomib) | Complete Response Rate | mixed response | 0 participants |
| Treatment (Carfilzomib) | Complete Response Rate | progressive | 2 participants |
| Treatment (Carfilzomib) | Complete Response Rate | unchanged | 2 participants |
| Treatment (Carfilzomib) | Complete Response Rate | failed | 7 participants |
| Treatment (Carfilzomib) | Complete Response Rate | partial response | 5 participants |
| Response Evaluated by NIH | Complete Response Rate | failed | 7 participants |
| Response Evaluated by NIH | Complete Response Rate | partial response | 4 participants |
| Response Evaluated by NIH | Complete Response Rate | mixed response | 4 participants |
| Response Evaluated by NIH | Complete Response Rate | unchanged | 1 participants |
| Response Evaluated by NIH | Complete Response Rate | progressive | 0 participants |
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.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Carfilzomib) | Cumulative Incidence of Non-relapse Mortality and Primary Malignancy Relapse | 7 Participants |
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.
Time frame: Up to 6 months
Population: Data were not collected because biologic studies were not performed. Response to study drug too minimal to justify time and expense.
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.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Carfilzomib) | Incidence of Discontinuation of All Systemic Immune-suppressive Therapies | 2 Participants |
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.
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Carfilzomib) | Overall Response Rate | Physician impression ORR | 4 participants |
| Treatment (Carfilzomib) | Overall Response Rate | NIH ORR | 3 participants |
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.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Carfilzomib) | Probability of Failure-free Survival at 1 Year | .32 probability of failure-free survival |
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.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Carfilzomib) | Probability of Overall Survival at 1 Year | .65 probability of overall survival |
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)
Time frame: baseline
Population: Only baseline surveys analyzed. Only 7 patients completed surveys at 6mo, not analyzed due to low number.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | physical well-being | 21.5 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | social/family well-being | 21.5 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | emotional well-being | 18.5 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | functional well-being | 16.5 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | BMT subscale | 28 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | FACT-G | 72.8 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | trial outcome index | 65 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | FACT-BMT total | 101.3 units on a scale |
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.
Time frame: baseline
Population: Only baseline surveys analyzed. Only 7 patients completed surveys at 6mo, not analyzed due to low number.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP) | maximum activity score | 66 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP) | adjusted activity score | 57 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP) | modified adjusted activity score | 60 units on a scale |
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.
Time frame: baseline
Population: Only baseline surveys analyzed. Only 7 patients completed surveys at 6mo, not analyzed due to low number.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | skin scale | 32.5 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | energy scale | 42.9 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | lung scale | 5 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | eye scale | 62.5 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | nutrition scale | 5 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | psychological scale | 25 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | mouth scale | 0 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | overall summary score | 21.6 units on a scale |
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.
Time frame: baseline
Population: Only baseline surveys analyzed. Only 7 patients completed surveys at 6mo, not analyzed due to low number.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | Norm-based physical functioning | 36 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | norm-based role-physical score | 33.6 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | norm-based bodily pain score | 41.4 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | norm-based general health score | 32.9 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | norm-based vitality score | 42.7 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | norm-based social functioning | 40.5 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | norm-based role-emotional score | 40.3 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | norm-based mental health score | 50 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | standardized physical component score | 37 units on a scale |
| Treatment (Carfilzomib) | Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | standardized mental component score | 49 units on a scale |
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.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Carfilzomib) | Treatment Success | 0 participants |
Secondary
Use of Additional Systemic Immune-suppressive Therapies
Addition of therapy after carfilzomib constitutes failure, could occur at any time from baseline to 12mo.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Carfilzomib) | Use of Additional Systemic Immune-suppressive Therapies | 13 participants |