Clinical trial NCT03805178: Lung Transplant Plasmapheresis/Belatacept/Carfilzomib for Antibody Mediated Rejection and Desensitization
Official title: Lung Transplant Plasmapheresis (PLEX)/Belatacept/Carfilzomib Protocol for Treatment of Antibody Mediated Rejection (AMR) and Desensitization
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Lung Transplant Rejection
Antibody-mediated Rejection
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2019-01-15
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Antibody mediated rejection (AMR) post transplant contributes to poor long term outcomes after lung transplantation. Additionally, high antibodies detected pre transplant in candidates limit donor availability for lung transplant. This proposal would include belatacept in a multi-therapy regimen. Open label study with two patient cohorts for safety and efficacy of belatacept in a multi-modal protocol. The two patient cohorts are an AMR post-transplant cohort and pre-transplant desensitization cohort. A total of 10 patients will be enrolled.The primary objection is drug tolerability and secondary objectives are antibody measurements and allograft function.

Detailed description: Antibody mediated rejection (AMR) post transplant contributes to poor long term outcomes after lung transplantation. Additionally, high antibodies detected pre transplant in candidates limit donor availability for lung transplant. Multimodal therapies with rituximab, intravenous immunoglobulin, plasmapheresis and proteasome inhibitors have not significantly altered the antibodies in these patients. Belatacept targets the T and B cell interaction such that it represents a novel therapeutic strategy. This proposal would include belatacept in a multi-therapy regimen.

This is an open label study with two patient cohorts for safety and efficacy of belatacept in a multi-modal protocol. The two patient cohorts are an AMR post-transplant cohort and pre-transplant desensitization cohort. A total of 10 patients will be enrolled.The primary objection is drug tolerability and secondary objectives are antibody measurements and allograft function.

Eligibility criteria: Inclusion Criteria:

Inclusion criteria for the AMR post-transplant cohort

* Positive DSAs and allograft dysfunction defined by changes in pulmonary physiology, gas exchange, radiological features or deteriorating functional performance that is highly suspicious for AMR
* Recipient is Epstein-Barr virus positive (EBV+) by serology
* Ability to provide signed and dated IRB approved written consent in accordance with regulatory and institutional guidelines prior to any protocol-related procedure

Inclusion criteria for the pre-transplant desensitization cohort

* Elevated HLA antibodies (defined as MFI \>1000) such that the calculated panel reactive antibodies are \>60%
* At least 2 HLA antibodies with Mean Fluorescent Intensity (MFI) \<10,000 and at least 2 HLA antibodies with MFI \<5,000 on undiluted serum that do not demonstrate an increase in MFI with dilution at 1:16 (no evidence of a prozone effect).
* EBV+ by serology
* Clinically stable defined by not on invasive mechanical ventilation, extracorporeal membrane oxygenation support or other invasive life support requiring ICU level of care
* Ability to provide signed and dated IRB approved written consent in accordance with regulatory and institutional guidelines prior to any protocol-related procedure

Exclusion criteria for both AMR post-transplant cohort and pre-transplant cohort

* Active systemic infection
* Allergy to carfilzomib or belatacept
* Known malignancy in the previous 2 years except for non-melanomatous skin cancer
* Pregnancy
* Inability to commit to complete treatment protocol at Duke as all procedures must be completed at Duke
* Prisoners or those who are compulsory detained

Primary outcomes:
measure: Occurrence of drug side effects
timeFrame: Within 28 days of last administration of study drugs
measure: Occurrence of infection
timeFrame: Within 28 days of last administration of study drugs
measure: Occurrence of malignancy
timeFrame: Within 28 days of last administration of study drugs
Secondary outcomes:
measure: Number of subjects in the AMR cohort with resolution of at least one donor specific human leukocyte antigen (HLA) antibody (DSA)
timeFrame: Within 4 weeks of completion of treatment
measure: Number of subjects in the AMR cohort with improvement or stabilization of lung function as measured by spirometry data
timeFrame: Within 4 weeks of completion of treatment
measure: Number of subjects in the AMR cohort with improvement in oxygenation as measured by Liters/min oxygen at rest
timeFrame: Within 4 weeks of completion of treatment
measure: Number of subjects in the AMR cohort with decrease in DSA by one log
timeFrame: Within 4 weeks of completion of treatment
measure: Number of subjects in the AMR cohort with elimination of DSA at 1:16 dilution
timeFrame: Within 4 weeks of completion of treatment
measure: Number of subjects in the transplant desensitization cohort with decrease in non-DSA HLA antibodies by one log
timeFrame: Within 4 weeks of completion of treatment
measure: Number of subjects in the transplant desensitization cohort with elimination of non-DSA HLA antibodies at 1:16 dilution
timeFrame: Within 4 weeks of completion of treatment
Other outcomes:
Locations:
Study officials:
affiliation: Duke University
name: Laurie Snyder
role: PRINCIPAL_INVESTIGATOR
References: