Daratumumab in HLA Desensitization Prior to Transplantation

Cardiac Transplant Clinical Trial

Official title:

A Phase II Prospective Study Evaluating the Role of Daratumumab in HLA Desensitization Prior to Transplantation

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT05300451
• Other study ID #: 20-012885
• Status: Enrolling by invitation
• Phase: Phase 2
• Start date: March 31, 2022
• Est. completion date: August 2024

Study information

• Verified date: April 2024
• Source: Mayo Clinic
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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 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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 6
• Est. completion date: August 2024
• Est. primary completion date: August 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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 [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 [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.

Related Conditions & MeSH terms

• Cardiac Transplant

Intervention

Biological:
• Daratumumab and hyaluronidase-fihj
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

Locations

Country	Name	City	State
United States	Mayo Clinic Rochester	Rochester	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Barry A. Boilson	Janssen Biotech, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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