Study of Daratumumab for Decreasing Circulating Antibodies in Sensitized Patients Awaiting Heart Transplantation

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to test whether daratumumab, a drug that eliminates antibody-producing plasma cells, can effectively lower the level of preformed antibodies in patients awaiting heart transplantation. These preformed antibodies limit the number of donor hearts that are compatible for the patients. If daratumumab can effectively remove preformed, donor-specific antibodies, then highly allosensitized patients will have more compatible hearts available to them, potentially decreasing transplant waitlist time and reducing mortality.

Official Title
-----------------
A Phase 1 Study of Daratumumab for Reduction of Circulating Antibodies in Patients With High Allosensitization Awaiting Heart Transplantation

Conditions
-----------------
Allosensitization, Heart Transplant Failure and Rejection

Intervention / Treatment
-----------------
* Drug: Daratumumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant is on an active list for a heart transplant. Participant has a high level of allosensitization, defined as a calculated PRA (panel of reactive antibodies) of 50%, based on their antibody status at the time of entry into the study. Ability to understand and willingness to sign an informed consent form prior to any study-related procedures. Women of childbearing potential must have a negative pregnancy test at screening. Both male and female patients must use effective methods of birth control, must not donate eggs or sperm during the course of the study and for 3 months after stopping daratumumab. Exclusion Criteria: History of allergy or intolerance to daratumumab. Prior diagnosis of myeloma or light chain amyloidosis. Active infection. Women who are pregnant or breastfeeding. Ongoing desensitization treatment with another agent. Subjects are excluded if they have received: a. IVIG within 30 days of enrollment. b. Proteasome inhibitor within 60 days of enrollment. c. Rituximab within 180 days of enrollment. Any condition which could interfere with, or the treatment for which might interfere with, the conduct of the study or which would, in the opinion of the Investigator, unacceptably increase the subject's risk by participating in the study. Contraindication to herpes zoster prophylaxis. Known to be seropositive for human immunodeficiency virus (HIV). Known to be seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response (SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy). Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is <50% of predicted normal. Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daratumumab infusion<br>Participants will receive an intravenous infusion of daratumumab weekly for 8 doses and then every other week for 2 doses. For this dose-escalation study, the initial patients will receive a 2 mg/kg dose of daratumumab. In subsequent patients, the dose will be uptitrated to 16 mg/kg as tolerated. Participants will undergo laboratory testing, including for circulating antibodies, at baseline, prior to each infusion session, and at the end of the study. | Drug: Daratumumab<br>* >Daratumumab 16 mg/kg intravenous weekly for 8 weeks and then every other week for 2 doses.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the number of individual preformed HLA antibodies before and after daratumumab treatment. | Will compare the number of individual circulating preformed human leukocyte antigen (HLA) antibodies (i.e., those HLA antibodies that have a mean fluorescence intensity [MFI] >3000) at baseline with the number of preformed antibodies after daratumumab treatment. | Baseline and Week 12 (or the last measurement prior to heart transplantation, whichever is earlier). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent MFI change for each individual preformed HLA antibody after 4 weeks of daratumumab treatment. | Percent change in the MFI of each circulating preformed HLA antibody from baseline to 4 weeks or the time of heart transplantation (whichever is earlier). | Baseline and Week 4 (or the last measurement prior to heart transplantation, whichever is earlier). | 
| Percent MFI change for each individual preformed HLA antibody at 8 weeks of daratumumab treatment. | Percent change in the MFI of each circulating preformed HLA antibody from baseline to 8 weeks or the time of heart transplantation (whichever is earlier). | Baseline and Week 8 (or the last measurement prior to heart transplantation, whichever is earlier). | 
| Change in the number of individual preformed HLA antibodies after 6 weeks of daratumumab. | Will compare the number of individual circulating preformed HLA antibodies at baseline with the number of preformed antibodies after 6 weeks of daratumumab treatment. | Baseline and Week 6 (or the last measurement prior to heart transplantation, whichever is earlier). | 
| Change in the percentage of calculated panel of reactive antibodies before and after daratumumab treatment. | Will compare the serum panel of reactive antibodies (PRA) percentage at baseline with the PRA percentage after 12 weeks of treatment with daratumumab. | Baseline and Week 12 (or the last measurement prior to heart transplantation, whichever is earlier). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Immunotherapy, anti-CD38 antibody