Lung Transplant Rejection
Conditions
Keywords
antibody-mediated rejection, lung transplant, Carfilzomib
Brief summary
The clinical trial is a Phase II open label, single-arm pilot study to evaluate the safety and efficacy of combination therapy with carfilzomib, plasma exchange and intravenous immunoglobulins for AMR after lung transplantation and elucidate important clinical and immunologic phenotypes and mechanisms associated with these outcomes.
Detailed description
The main objective of the proposed clinical investigation is to evaluate the effects of carfilzomib in addition to conventional therapy on short-term outcomes after the diagnosis of antibody-mediated rejection in lung transplant recipients. In this study, Carfilzomib will be administered at a dose of 20 mg/m2 on two consecutive days, each week for three weeks (Days 1 2, 8, 9, 15, and 16) to constitute one therapeutic cycle. Carfilzomib may be administered for 1-2 complete cycles in the study. Patients will be followed for the duration of their hospital admission after enrollment. Post treatment follow-up will also occur on Days 42 and 90.
Interventions
DRUGCarfilzomib
Carfilzomib will be used in combination with the conventional therapy (plasma exchange and intravenous immunoglobulins)
Sponsors
John F. McDyer, MD
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
* Adult lung transplant recipients ≥ 18 years of age who meet the diagnostic criteria for AMR and who have underwent PFT testing unless intubated and transbronchial biopsy prior to enrollment.
Exclusion criteria
* Direct contraindications or previous intolerances to any component of the standard of care regimen including PLEX, 5% human albumin, 5% gammagard S/D or 10% gammagard liquid * Leukopenia * Neutropenia * Thrombocytopenia * Known Child-Pugh B/C cirrhosis * Total bilirubin \> 4 * ALT \> 90 * Known systolic heart failure with LVEF \< 40% * Known pulmonary hypertension * Any uncontrolled comorbid condition * Pregnant women * Breastfeeding women * Ongoing bacterial or fungal or viral infection that is life-threatening * Active cytomegalovirus disease * Active varicella zoster infection * Previous intolerance to carfilzomib * Concurrent use of another proteasome inhibitor (e.g., bortezomib)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Decrease in Titer of One or More DSA (Either Reduced MFI or Absence of DSA on Same Dilution) | Day 1 to Day 42 | Number of Participants with a Decrease in titer of one or more DSA (either reduced MFI or absence of DSA on same dilution). |
| Number of Participants With an Absence of One or More Previously Positive DSA on Cq1 Assay | Day 1 to Day 42 | Number of Participants with an Absence of one or more previously positive DSA on Cq1 assay. |
| Number of Participants With a Decrease in DSA Titer | Day 1 to Day 42 | Number of Participants with a Decrease in DSA Titer. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Decrease in Titer of One or More DSA (Either Reduced MFI or Absence of DSA on Same Dilution) | Day 1 to Day 90 | Number of Participants with a Decrease in titer of one or more DSA (either reduced MFI or absence of DSA on same dilution). |
| Patient Death Attributable to AMR | Day 1 to Day 90 | Patient death attributable to AMR |
| Number of Participants With a Decrease in DSA Titer | Day 1 to Day 90 | Number of Participants with a Decrease in DSA Titer. |
| Number of Participants With an Absence of One or More Previously Positive DSA on Cq1 Assay | Day 1 to Day 90 | Number of Participants with an Absence of one or more previously positive DSA on Cq1 assay. |
| Absolute Change in Forced Expiratory Volume in 1 Second (FEV1) | Day 1 to Day 42 | Absolute change in forced expiratory volume in 1 second (FEV1) |
| Presence or Absence of Pathologic Changes Consistent With AMR on Transbronchial Biopsy | Day 1 to Day 42 | Presence or absence of pathologic changes consistent with AMR on transbronchial biopsy |
Other
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Effects (AE) | Day 1 to Day 16 | Incidence of adverse effects (AE) |
| Incidence of Hypogammaglobulinemia | Day 1 to Day 16 | Incidence of hypogammaglobulinemia |
| Incidence of Culture-proven de Novo Infection | Day 1 to Day 42 | Incidence of culture-proven de novo infection |
| Diagnosis of Systemic Inflammatory Response Syndrome | Day 1 to Day 16 | Diagnosis of systemic inflammatory response syndrome |
| Patient Death | Day 1 to Day 90 | Patient death |
| Incidence of Adverse Effects (AE) Requiring Dose-modification | Day 1 to Day 16 | Incidence of adverse effects (AE) requiring dose-modification |
| Non-lung Irreversible End-organ Failure | Day 1 to Day 16 | Non-lung irreversible end-organ failure |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Carfilzomib Treatment Arm Carfilzomib will be administered at a dose of 20 mg/m2 on two consecutive days, each week for three weeks (Days 1 2, 8, 9, 15, and 16) to constitute one therapeutic cycle. Carfilzomib may be administered for 1-2 complete cycles in the study.
Carfilzomib: Carfilzomib will be used in combination with the conventional therapy (plasma exchange and intravenous immunoglobulins) | 22 |
| Total | 22 |
Baseline characteristics
| Characteristic | Carfilzomib Treatment Arm |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Age, Continuous | 48 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 22 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 22 |
| other Total, other adverse events | 22 / 22 |
| serious Total, serious adverse events | 4 / 22 |
Outcome results
Primary
Number of Participants With a Decrease in DSA Titer
Number of Participants with a Decrease in DSA Titer.
Time frame: Day 1 to Day 42
Population: Change in DSA Titer (Titer Decreased) \[6 not evaluable\]
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib Treatment Arm | Number of Participants With a Decrease in DSA Titer | 13 Participants |
Primary
Number of Participants With a Decrease in Titer of One or More DSA (Either Reduced MFI or Absence of DSA on Same Dilution)
Number of Participants with a Decrease in titer of one or more DSA (either reduced MFI or absence of DSA on same dilution).
Time frame: Day 1 to Day 42
Population: Decrease in titer of one or more DSA (either reduced MFI or absence of DSA on same dilution)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib Treatment Arm | Number of Participants With a Decrease in Titer of One or More DSA (Either Reduced MFI or Absence of DSA on Same Dilution) | 17 Participants |
Primary
Number of Participants With an Absence of One or More Previously Positive DSA on Cq1 Assay
Number of Participants with an Absence of one or more previously positive DSA on Cq1 assay.
Time frame: Day 1 to Day 42
Population: Absence of one or more previously positive DSA on Cq1 assay \[14 not evaluable\]
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib Treatment Arm | Number of Participants With an Absence of One or More Previously Positive DSA on Cq1 Assay | 5 Participants |
Secondary
Absolute Change in Forced Expiratory Volume in 1 Second (FEV1)
Absolute change in forced expiratory volume in 1 second (FEV1)
Time frame: Day 1 to Day 42
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Carfilzomib Treatment Arm | Absolute Change in Forced Expiratory Volume in 1 Second (FEV1) | Baseline | 1.77 FEV1% |
| Carfilzomib Treatment Arm | Absolute Change in Forced Expiratory Volume in 1 Second (FEV1) | Day 42 | 1.93 FEV1% |
p-value: 0.36Wilcoxon Signed Rank
Secondary
Absolute Change in Forced Expiratory Volume in 1 Second (FEV1)
Absolute Change in Forced Expiratory Volume in 1 Second (FEV1)
Time frame: Day 1 to Day 90
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Carfilzomib Treatment Arm | Absolute Change in Forced Expiratory Volume in 1 Second (FEV1) | Baseline | 1.77 Median FEV1 value |
| Carfilzomib Treatment Arm | Absolute Change in Forced Expiratory Volume in 1 Second (FEV1) | Day 90 | 2.09 Median FEV1 value |
p-value: 0.16Wilcoxon Signed Rank
Secondary
Number of Participants With a Decrease in DSA Titer
Number of Participants with a Decrease in DSA Titer.
Time frame: Day 1 to Day 90
Population: Change in DSA Titer (Titer Decreased) \[9 not evaluable\]
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib Treatment Arm | Number of Participants With a Decrease in DSA Titer | 10 Participants |
Secondary
Number of Participants With a Decrease in Titer of One or More DSA (Either Reduced MFI or Absence of DSA on Same Dilution)
Number of Participants with a Decrease in titer of one or more DSA (either reduced MFI or absence of DSA on same dilution).
Time frame: Day 1 to Day 90
Population: Decrease in titer of one or more DSA (either reduced MFI or absence of DSA on same dilution)\[2 not evaluable\]
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib Treatment Arm | Number of Participants With a Decrease in Titer of One or More DSA (Either Reduced MFI or Absence of DSA on Same Dilution) | 17 Participants |
Secondary
Number of Participants With an Absence of One or More Previously Positive DSA on Cq1 Assay
Number of Participants with an Absence of one or more previously positive DSA on Cq1 assay.
Time frame: Day 1 to Day 90
Population: Absence of one or more previously positive DSA on Cq1 assay \[12 not evaluable\]
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib Treatment Arm | Number of Participants With an Absence of One or More Previously Positive DSA on Cq1 Assay | 6 Participants |
Secondary
Patient Death Attributable to AMR
Patient death attributable to AMR
Time frame: Day 1 to Day 90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib Treatment Arm | Patient Death Attributable to AMR | 1 Participants |
Secondary
Presence or Absence of Pathologic Changes Consistent With AMR on Transbronchial Biopsy
Presence or absence of pathologic changes consistent with AMR on transbronchial biopsy
Time frame: Day 1 to Day 42
Population: Unable to calculate at dates specified at this time. Re-biopsy of patients is not routinely completed. Research biopsy was not part of the protocol.
Other Pre-specified
Diagnosis of Systemic Inflammatory Response Syndrome
Diagnosis of systemic inflammatory response syndrome
Time frame: Day 1 to Day 16
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib Treatment Arm | Diagnosis of Systemic Inflammatory Response Syndrome | 0 Participants |
Other Pre-specified
Incidence of Adverse Effects (AE)
Incidence of adverse effects (AE)
Time frame: Day 1 to Day 16
Population: Incidence of adverse effects (AE)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib Treatment Arm | Incidence of Adverse Effects (AE) | 22 Participants |
Other Pre-specified
Incidence of Adverse Effects (AE) Requiring Dose-modification
Incidence of adverse effects (AE) requiring dose-modification
Time frame: Day 1 to Day 16
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib Treatment Arm | Incidence of Adverse Effects (AE) Requiring Dose-modification | 5 Participants |
Other Pre-specified
Incidence of Culture-proven de Novo Infection
Incidence of culture-proven de novo infection
Time frame: Day 1 to Day 42
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib Treatment Arm | Incidence of Culture-proven de Novo Infection | 6 Participants |
Other Pre-specified
Incidence of Hypogammaglobulinemia
Incidence of hypogammaglobulinemia
Time frame: Day 1 to Day 16
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib Treatment Arm | Incidence of Hypogammaglobulinemia | 0 Participants |
Other Pre-specified
Non-lung Irreversible End-organ Failure
Non-lung irreversible end-organ failure
Time frame: Day 1 to Day 16
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib Treatment Arm | Non-lung Irreversible End-organ Failure | 1 Participants |
Other Pre-specified
Patient Death
Patient death
Time frame: Day 1 to Day 90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib Treatment Arm | Patient Death | 3 Participants |