Using daratumumab to treat Primary Antiphospholipid Syndrome

Targeting CD38 With Daratumumab in Primary Antiphospholipid Syndrome: A Phase 1b Dose Escalation Safety Trial (ITN093AI)

This study is testing if daratumumab can safely help people with Primary Antiphospholipid Syndrome feel better.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 22 (estimated)
• Ages: 18 Years to 65 Years
• Sex: All
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Drugs / interventions: daratumumab, isatuximab, belimumab, rituximab, methotrexate, Cyclophosphamide, prednisone
• Locations: 8 sites (Baltimore, Maryland and 7 other locations)
• Trial ID: NCT05671757 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the safety of daratumumab in treating individuals with Primary Antiphospholipid Syndrome (APS). It involves a phase 1b open-label design with three dosing cohorts (4 mg/kg, 8 mg/kg, and 16 mg/kg) administered intravenously over eight weeks. The study will monitor participants for dose-limiting toxicities and efficacy, with follow-up visits scheduled for up to 48 weeks post-treatment. An independent safety committee will oversee dose escalation based on safety and efficacy criteria.

Who should consider this trial

Good fit: Ideal candidates for this study are adults aged 18 to 70 with a confirmed history of Primary Antiphospholipid Syndrome.

Not a fit: Patients with conditions that contraindicate the use of daratumumab or those outside the specified age range may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients suffering from APS.

How similar studies have performed: While this approach is novel for APS, similar studies using daratumumab for other autoimmune disorders have shown promising results.

Eligibility criteria

Inclusion Criteria:

1. Adults 18 to 70 years of age, inclusive.
2. The completion of the following vaccinations at least 14 days prior to Visit 0:

   1. At least one dose of the most recently updated COVID-19 vaccine, and
   2. At least one dose of the herpes zoster vaccination series, and
   3. Current seasonal influenza vaccine, if available.
3. History of APS according to the updated 2006 Sapporo classification criteria, including at least one of the following:

   a. Arterial thrombosis, except transient ischemic attack, confirmed by objective validated criteria such as imaging, or b. Venous thrombosis, except superficial thrombophlebitis, confirmed by objective validated criteria such as imaging, or c. Pregnancy morbidity, based on the updated 2006 Sapporo APS classification criteria, or d. Microvascular APS, with at least one of the following: i. Renal biopsy documentation of aPL-associated nephropathy, or ii. Lung biopsy or bronchoalveolar lavage documentation of diffuse alveolar hemorrhage (DAH), or iii. Skin biopsy documentation of livedoid vasculopathy.
4. History of triple positive aPL within the prior 5 years and at least 12 weeks prior to enrollment, including all of the following:

   1. aCL IgG level \> Upper Limit of Normal (ULN), and
   2. aβ2GPI IgG level \> ULN, and
   3. Positive LA test.
5. Confirmation of triple positive aPL at screening, including all of the following:

   1. aCL IgG level ≥ 40 GPL, and
   2. aβ2GPI IgG level ≥ 40 SGU, and
   3. Positive LA test.
6. Undergoing anticoagulation with warfarin or low molecular weight heparin (LMWH), if there is a history of arterial or venous thrombosis.

Exclusion Criteria:

1. Inability or unwillingness to give written informed consent.
2. Inability or unwillingness to comply with study protocol.
3. Systemic autoimmune diseases other than APS, including but not limited to:

   1. Systemic lupus erythematosus (SLE) meeting the EULAR/ACR classification criteria.
   2. Rheumatoid arthritis meeting the ACR/EULAR classification criteria.
   3. Small, medium, and large vessel vasculitis meeting ACR classification criteria.
4. Catastrophic APS classification within the prior 90 days.
5. Acute arterial or venous thrombosis within the prior 30 days.
6. Use of the following medications:

   1. Any prior treatment with CD38 targeting monoclonal antibodies, including daratumumab or isatuximab-irfc.
   2. The following within the prior 30 days:

   i. Corticosteroids \> 10 mg/day prednisone or equivalent. ii. Direct oral anticoagulants (DOACs). iii. Live attenuated vaccines. iv. IVIG or other supplemental immunoglobulin. c. Azathioprine, methotrexate, mycophenolate mofetil, mycophenolate sodium, lefluonomide, or calcineurin inhibitors within the prior 90 days.

   d. Cyclophosphamide within the prior 90 days. e. Immunomodulatory or immunosuppressive biologic agents, including belimumab, within the prior 90 days or 5 half-lives, whichever is greater.

   f. Investigational agents within the prior 90 days or 5 half-lives, whichever is greater, except for COVID-19 vaccines and medications for prevention or treatment of COVID-19 per FDA Emergency Use Authorization (EUA).

   g. Biologic B cell depleting agents including rituximab with any of the following: i. Treatment within the prior 180 days, or ii. CD19+ absolute count \< 40/ μl, or iii. Serum IgG \<500 mg/dL.
7. Plasma exchange within the prior 90 days.
8. Hemodialysis within the prior 90 days.
9. Major surgical procedure within the prior 60 days.
10. Known allergy, hypersensitivity, or intolerance to boron, malitol, sorbitol, corticosteroids, monoclonal antibodies including daratumumab, human proteins, or their excipients.
11. Allergy, intolerance, or contraindication to acyclovir, valacyclovir, and famciclovir.
12. Active or chronic infection, including the following:

    1. Active bacterial, viral, fungal, or opportunistic infection.
    2. Chronic infection requiring suppressive antibiotic treatment.
    3. Intravenous antibiotics or hospitalization for infection within the prior 30 days.
    4. Evidence of current or prior Mycobacterium tuberculosis infection.
    5. Human immunodeficiency virus (HIV).
    6. Current or prior infection with hepatitis B virus (HBV).
    7. Current or prior infection with hepatitis C virus (HCV), except adequately treated HCV with sustained virologic response ≥ 12 weeks.
    8. History of recurrent herpes zoster, or history of herpes zoster ophthalmicus, disseminated herpes zoster, or disseminated herpes simplex.
13. The following laboratory abnormalities:

    ITN093AI: DARE-APS Version 3.0 September 12, 2023 Daratumumab in Primary Antiphospholipid Syndrome
    1. Absolute neutrophil count \< 1500/mm3.
    2. Platelets \< 100,000/mm3.
    3. Hemoglobin (Hgb) \< 10 g/dL.
    4. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase \> 2x the Upper Limit of Normal (ULN).
    5. Total bilirubin \> 2x ULN, except in the case of congenital bilirubinemia then direct bilirubin \> 2x ULN.
    6. eGFR \< 45 ml/min/1.73 m2.
14. History of primary immunodeficiency.
15. History of solid organ or hematopoietic stem cell transplantation.
16. Comorbidities requiring systemic corticosteroid therapy, including those which have required three or more courses of systemic corticosteroids within the 12 months prior to Visit 0.
17. Any of the following conditions with FEV1 \< 70% predicted within the prior 90 days:

    1. Asthma.
    2. Chronic obstructive pulmonary disease (COPD).
    3. DAH.
18. Pulmonary hypertension.
19. Adrenal insufficiency.
20. Poorly controlled diabetes mellitus defined as hemoglobin A1c (HbA1c) ≥ 8.0%.
21. Concomitant malignancy or history of malignancy, except adequately treated or excised nonmetastatic squamous cell carcinoma, basal cell skin carcinoma, or cervical carcinoma in situ.
22. Clinically significant cardiac disease, including but not limited to:

    1. Myocardial infarction within the prior 6 months, or
    2. Unstable or uncontrolled disease or condition related to or affecting cardiac function, including but not limited to:

    i. Unstable angina, or ii. Congestive heart failure, New York Heart Association Class II-IV, or iii. Uncontrolled cardiac arrhythmia.
23. Current diagnosed mental illness or current diagnosed or self-reported drug or alcohol abuse which, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements.
24. Severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, or neurological disease.
25. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements, or may impact the quality or interpretation of the data obtained from the study.
26. Lack of peripheral venous access.
27. Pregnancy, or planning a pregnancy during the 48 week study duration.
28. Breast-feeding.
29. Unwillingness to use medically acceptable non-prothrombotic contraception if of reproductive potential and engaging in sexual activity that could lead to pregnancy.

Where this trial is running

Baltimore, Maryland and 7 other locations

• Johns Hopkins University — Baltimore, Maryland, United States (Recruiting)
• University of Michigan — Ann Arbor, Michigan, United States (Recruiting)
• Mayo Clinic Rochester — Rochester, Minnesota, United States (Completed)
• Northwell Health — Great Neck, New York, United States (Recruiting)
• NYU Langone — New York, New York, United States (Recruiting)
• Hospital for Special Surgery — New York, New York, United States (Recruiting)
• Weill Cornell — New York, New York, United States (Recruiting)
• Duke University — Durham, North Carolina, United States (Recruiting)

Conditions Autoimmune Disorders; Daratumumab; Anti-Phospholipid Syndrome