Combination Therapy With Carfilzomib for the Antibody-Mediated Rejection Diagnosis in Lung Transplantation

Study Overview
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Brief Summary
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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
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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.

Official Title
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Combination Therapy With the Proteasome Inhibitor Carfilzomib for the Antibody-Mediated Rejection Diagnosis in Lung Transplantation Trial (PICARD-Lung)

Conditions
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Lung Transplant Rejection

Intervention / Treatment
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* Drug: Carfilzomib


Participation Criteria
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Eligibility Criteria
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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)

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: Carfilzomib Treatment Arm<br>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. | Drug: Carfilzomib<br>* Carfilzomib will be used in combination with the conventional therapy (plasma exchange and intravenous immunoglobulins)<br>* Other names: Kyprolis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Day 1 to Day 42 | 
| Number of Participants With a Decrease in DSA Titer | Number of Participants with a Decrease in DSA Titer. | 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 an Absence of one or more previously positive DSA on Cq1 assay. | Day 1 to Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Day 1 to Day 90 | 
| Number of Participants With a Decrease in DSA Titer | Number of Participants with a Decrease in DSA Titer. | Day 1 to Day 90 | 
| 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. | Day 1 to Day 90 | 
| Absolute Change in Forced Expiratory Volume in 1 Second (FEV1) | 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) | Absolute Change in Forced Expiratory Volume in 1 Second (FEV1) | Day 1 to Day 90 | 
| Presence or Absence of Pathologic Changes Consistent With AMR on Transbronchial Biopsy | Presence or absence of pathologic changes consistent with AMR on transbronchial biopsy | Day 1 to Day 42 | 
| Patient Death Attributable to AMR | Patient death attributable to AMR | Day 1 to Day 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antibody-mediated rejection, lung transplant, Carfilzomib