Daratumumab in Cardiac Allograft AMR & HLA Desensitization Prior to Transplantation

Study Overview
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Brief Summary
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The purpose of this study is to learn about how well the drug daratumumab/hyaluronidase-fihj (DARZALEX Faspro™) helps to lower high levels of HLA (Human Leukocyte Antigen) antibodies in a person waiting for a heart transplant, and helps to lower HLA antibodies in heart transplant recipients who have developed antibody mediated rejection (AMR) due to a high number of HLA antibodies .

Detailed Description
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Daratumumab is an IgG1k, CD38-targeting monoclonal antibody, and the IV formulation was United States Food and Drug Administration (FDA) approved in 2015 for the treatment of multiple myeloma. Daratumumab has not been approved for the indication being studied in this current trial and has been granted investigational new drug (IND) approval by the FDA (IND 157466) for use in this research. Subjects treated for AMR will be in the study for 40 weeks, and subjects treated for HLA desensitization will be in the study for 16 weeks. Each subject will receive daratumumab/hyaluronidase-fihj 1800mg/30000u subcutaneously once a week for 8 weeks. Subjects will have close follow-up for several weeks afterwards with usual testing to monitor for rejection after transplantation. This includes echocardiograms, heart biopsy or MRI and blood tests. Janssen Biotech, Inc. is providing the daratumumab/hyaluronidase-fihj (DARZALEX Faspro™) for the study.

Official Title
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A Phase II Prospective Study Evaluating the Role of Daratumumab in Resistant Antibody Mediated Cardiac Allograft Rejection and HLA Desensitization Prior to Transplantation

Conditions
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Antibody-mediated Rejection, Cardiac Transplant

Intervention / Treatment
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* Biological: Daratumumab and hyaluronidase-fihj


Participation Criteria
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Eligibility Criteria
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General Inclusion Criteria: Absolute neutrophil count > 1,500 Total bilirubin < 1.5x institutional upper limit normal (ULN) AST/ALT < 2. 5 - 3x ULN (Options for patients with liver dysfunction may be available) Creatinine clearance > 20 ml/min Specific Inclusion Criteria [AMR Treatment Group] Elevated DSA with biopsy proven AMR, or active inflammation on MRI and LV ejection fraction <45% and Previous treatment with plasmapheresis and rituximab and without improvement. Negative pregnancy test (if woman of childbearing potential) If able to become pregnant or father a child, agreement to use one of the birth control methods described in this protocol Able to provide informed consent Specific Inclusion Criteria [HLA Desensitization Group] Calculated PRA (cPRA) greater than 50%. Currently actively listed for heart or combined heart and kidney transplantation. Negative pregnancy test (if woman of childbearing potential) If able to become pregnant or father a child, agreement to use one of the birth control methods described in this protocol Able to provide informed consent General Exclusion Criteria: Prior or current exposure to any of the following: daratumumab or other anti-CD-38 therapies, exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic half-lives, whichever is longer. 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 participants suspected of having COPD and participants must be excluded if FEV1 is < 50% of predicted normal. Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate. Woman who is pregnant or breastfeeding. Participant is: known history of human immunodeficiency virus (HIV); Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg negative with antibodies to total hepatitis B core antigen [anti-HBc] with or without the presence of hepatitis B surface antibody [anti-HBs]) must be screed 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 HBV vaccination, do not need to be testing for HBV DNA by PCR; 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). Clinically significant cardiac disease, including: myocardial infarction within 6 months before randomization, or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV); Uncontrolled cardiac arrhythmia Specific Exclusion Criteria [AMR Treatment Group] Patients with biopsy evidence of grade 2R or 3R acute cell mediated rejection (CMR) Inability to give informed consent Specific Exclusion Criteria [HLA Desensitization Group] Patients listed for combined heart and liver transplantation will be excluded, as our unique experience with combined heart liver transplant (liver placed first), has demonstrated that in those cases high levels of circulating HLA antibodies may not increase the risk of hyperacute rejection. Seropositivity for human immunodeficiency virus (HIV) Seropositivity 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. Seropositivity 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). Patients unable to give informed consent will also be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMR Treatment Group<br>Subjects with antibody mediated cardiac allograft rejection (AMR) and cardiac allograft dysfunction will receive daratumumab/hyaluronidase-fihj. | Biological: Daratumumab and hyaluronidase-fihj<br>* Daratumumab and hyaluronidase-fihj for subcutaneous (under the skin) injection has different dosing and administration instructions compared to daratumumab for intravenous (in the vein) infusion. Daratumumab and hyaluronidase-fihj contains recombinant hyaluronidase, which mimics hyaluronidase, a naturally occurring substance that increases permeability of subcutaneous tissue. This makes it possible for 15 mL containing 1,800 mg of daratumumab to be administered in approximately 3 to 5 minutes. Subjects will receive a 1800mg/30000u injection subcutaneously weekly for a total of 8 doses<br>* Other names: DARZALEX FASPRO®;|
| Experimental: HLA Desensitization Group<br>Subjects awaiting cardiac transplantation with high levels of circulating Human Leukocyte Antigen (HLA) antibodies will receive daratumumab/hyaluronidase-fihj. | Biological: Daratumumab and hyaluronidase-fihj<br>* Daratumumab and hyaluronidase-fihj for subcutaneous (under the skin) injection has different dosing and administration instructions compared to daratumumab for intravenous (in the vein) infusion. Daratumumab and hyaluronidase-fihj contains recombinant hyaluronidase, which mimics hyaluronidase, a naturally occurring substance that increases permeability of subcutaneous tissue. This makes it possible for 15 mL containing 1,800 mg of daratumumab to be administered in approximately 3 to 5 minutes. Subjects will receive a 1800mg/30000u injection subcutaneously weekly for a total of 8 doses<br>* Other names: DARZALEX FASPRO®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of daratumumab therapy on human leukocyte antibody (HLA) titers in resistant antibody mediated rejection (AMR) | Levels of HLA titers by measure of fluorescence intensity levels (MFI) of donor specific antibodies (DSA). | Sixteen weeks | 
| Effect of daratumumab therapy on HLA antibody titers in sensitization (pre-transplant) | Assessed as calculated panel of reactive antibodies (cPRA) and absolute HLA antibody levels (MFI) | Sixteen weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of daratumumab on cardiac contractility in AMR | As measured by a change in left ventricle (LV) ejection fraction percentage. | One month post completion | 
| Effect of daratumumab on Cardiac Systolic Strain in AMR | Assessed by echocardiogram and measured by a change in Global LV Longitudinal Peak Systolic Strain percentage, which is the measure of the degree of change in cardiac shape that occurs during systole and diastole. | One month post completion | 
| Effect of daratumumab on Left Ventricular Filling Pressure Ratio in AMR | Assessed by echocardiogram and measured as a change in the ratio (E/e') between early mitral inflow velocity and mitral annual diastolic velocity. | One month post completion | 
| Effect of daratumumab on Right Ventricular Systolic Pressure (RVSP) in AMR | Assessed by echocardiogram as a change in approximate pulmonary arterial systolic pressure. Units are mmHg (millimeters of mercury). | One month post completion | 
| Effect of daratumumab on cardiac contractility in HLA sensitized patients | As measured by a change in left ventricle (LV) ejection fraction percentage. | One month post completion | 
| Effect of daratumumab on Cardiac Systolic Strain in HLA sensitized patients | Assessed by echocardiogram and measured by a change in Global LV Longitudinal Peak Systolic Strain percentage, which is the measure of the degree of change in cardiac shape that occurs during systole and diastole. | One month post completion | 
| Effect of daratumumab on Left Ventricular Filling Pressure Ratio in HLA sensitized patients | Assessed by echocardiogram and measured as a change in the ratio (E/e') between early mitral inflow velocity and mitral annual diastolic velocity. | One month post completion | 
| Effect of daratumumab on Right Ventricular Systolic Pressure (RVSP) in HLA sensitized patients | Assessed by echocardiogram as a change in approximate pulmonary arterial systolic pressure. Units are mmHg (millimeters of mercury). | One month post completion | 
| Effect of daratumumab on histological evidence of AMR | Based on evidence of changes on current biopsy when previous biopsy findings have been suggestive of AMR. AMR is defined in terms of histological features such as endothelial cell swelling and cellular infiltrates, and/or immunopathological features with C4d (complement) staining on immunohistochemistry or immunofluorescence. Histological scoring is as follows: pAMR 0 : Negative for histological and immunopathological features pAMR 1, H+ or I+: Histological features present and immunopathological absent (H+), or vice versa (I+) pAMR 2: Histological and immunopathological findings both present pAMR 3: AMR2 plus interstitial hemorrhage, endothelial cell pyknosis, edema | Measured every 2 weeks while on treatment and than at one month post completion | 
| Effect of daratumumab on MRI evidence of AMR | Based on changes on current magnetic resonance imaging (MRI) when previous MRI findings have been suggestive of AMR (late gadolinium [GAD] enhancement) For MRI evidence of AMR, there are two parameters: A qualitative measure as to whether late gadolinium enhancement (LGE) is present or absent. T2 weighted imaging which is a quantitative measure of tissue texture. Units are msec (milliseconds). | Measured every 2 weeks while on treatment and than at one month post completion | 
| Effect of daratumumab on incidence of acute AMR post-transplant in sensitized patients | Evidence of AMR (antibody mediated rejection) based on post-transplant biopsy findings. AMR is defined in terms of histological features such as endothelial cell swelling and cellular infiltrates, and/or immunopathological features with C4d (complement) staining on immunohistochemistry or immunofluorescence. Histological scoring is as follows: pAMR 0 : Negative for histological and immunopathological features pAMR 1, H+ or I+: Histological features present and immunopathological absent (H+), or vice versa (I+) pAMR 2: Histological and immunopathological findings both present pAMR 3: AMR2 plus interstitial hemorrhage, endothelial cell pyknosis, edema | Time Frame: Weeks 2, 3 and 4 post-transplant | 
| Effect of daratumumab on incidence of acute CMR post-transplant in sensitized patients | Evidence of CMR (cellular mediated rejection) based on post-transplant biopsy findings. CMR is scored as follows: Grade 0R: no rejection. Grade 1R, mild: interstitial or perivascular infiltrate (or both) with £1 focus of myocyte damage. Grade 2R, moderate: ³2 foci of infiltrate with associated myocyte damage. Grade 3R, severe: diffuse infiltrate with multifocal myocyte damage, with or without edema, hemorrhage, or vasculitis. | Time Frame: Weeks 2, 3 and 4 post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AMR, Heart Transplant Rejection, Sensitisation, Transplant; Complication, Rejection