Daratumumab in Primary Antiphospholipid Syndrome

The purpose of this study is to see if the study medication, daratumumab, is safe to treat individuals with Anti-Phospholipid Syndrome (APS).Three daratumumab dosing cohorts are planned with up to six participants in each dosing cohort with the potential to enroll an additional 4 subjects in the highest safe dose (HSD) cohort, for a total of up to 22 participants. The dosing cohorts are: 4 mg/kg, 8 mg/kg, and 16 mg/kg. Each cohort will receive intravenous (IV) administration of daratumumab according to the following schedule, for a total of 8 doses.The primary objective is to determine the safety of daratumumab in APS defined as Dose Limiting Toxicities (DLTs) occurring during the dose escalation phase.

Inclusion Criteria:Adults 18 to 65 years of age, inclusive.The completion of the following vaccinations at least 14 days prior to Visit 0:COVID-19 vaccination series according to the current Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommendations, andAt least one dose of the herpes zoster vaccination series, andCurrent seasonal influenza vaccine, if available.History of APS according to the updated 2006 Sapporo classification criteria, including at least one of the following within the prior 5 years: a. Arterial thrombosis, except transient ischemic attack, or b. Venous thrombosis, except superficial thrombophlebitis, 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.History of triple positive aPL within the prior 5 years and at least 12 weeks prior to enrollment, including all of the following: a. aCL IgG level > upper limit of normal (ULN), and b. aβ2GPI IgG level > ULN, and c. Positive LA test.Confirmation of triple positive aPL at screening, including all of the following:aCL IgG level ≥ 40 GPL, andaβ2GPI IgG level ≥ 40 SGU, andPositive LA test.Willing and able to undergo anticoagulation with warfarin or low molecular weight heparin (LMWH), if there is a history of arterial or venous thrombosis.Willing and able to discontinue direct oral anticoagulants, including factor Xa inhibitors and direct thrombin inhibitors, if applicable.Exclusion Criteria:Inability or unwillingness to give written informed consentInability or unwillingness to comply with study protocolSystemic autoimmune diseases other than Anti-Phospholipid Syndrome (APS), including but not limited to:a. Systemic lupus erythematosus (SLE) meeting the EULAR/ACR criteria American College of Rheumatology (ACR) classification criteriab. Rheumatoid arthritis meeting the ACR/EULAR classification criteriac. Small, medium, or large vessel vasculitis meeting ACR classification criteriaCatastrophic APS classification within the prior 90 daysAcute arterial or venous thrombosis within the prior 30 daysUse of the following medications:Any prior treatment with CD38 targeting monoclonal antibodies, including daratumumab or isatuximabAdministration of the Janssen COVID-19 vaccine within the prior 14 daysThe following within the prior 30 days:i. Corticosteroids > 10 mg/day prednisone or equivalent ii. Direct oral anticoagulants (DOACs) iii. Live attenuated vaccines iv. Intravenous Immunoglobulin (IVIG) d. Azathioprine, methotrexate, mycophenolate mofetil, mycophenolate sodium, lefluonomide, or calcineurin inhibitors within the prior 90 days e. Cyclophosphamide within the prior 90 days f. Immunomodulatory or immunosuppressive biologic agents, including belimumab, within the prior 90 days or 5 half-lives, whichever is greater g. Investigational agents within the prior 90 days or 5 half-lives, whichever is greater, except for vaccines and medications for prevention and treatment of COVID-19 per FDA Emergency Use Authorization (EUA) h. Biologic B cell depleting agents including rituximab with either of the following: i. Treatment within the prior 180 days, or ii. CD19+ absolute count < Lower Limit of Normal (LLN)8. Plasma exchange within the prior 90 days 9. Hemodialysis within the prior 90 days 10. Major surgical procedure within the prior 60 days 11. Known allergy, hypersensitivity, or intolerance to boron, malitol, sorbitol, corticosteroids, monoclonal antibodies including daratumumab, human proteins, or their excipients 12. Allergy or intolerance to acyclovir, valacyclovir, and famciclovir 13. Active or chronic infection, including the following:a. Active bacterial, viral, fungal, or opportunistic infectionb. Chronic infection requiring suppressive antibiotic treatmentc. Intravenous antibiotics or hospitalization for infection within the prior 30 daysd. Evidence of current or prior Mycobacterium tuberculosis infectione. Human immunodeficiency virus (HIV)f. Current or prior infection with hepatitis B virus (HBV)g. Current or prior infection with hepatitis C virus (HCV), except adequately treated HCV with sustained virologic response >= 12 weeksh. Positive SARS-CoV-2 nucleic acid amplification test (NAAT) within the prior 14 daysi. History of recurrent herpes zoster, herpes zoster ophthalimicus, disseminated herpes zoster, or disseminated herpes simplex14. The following laboratory abnormalities:Absolute neutrophil count < 1500/mm^3Platelets < 100,000/mm^3Hemoglobin (Hgb) < 10 g/dLAspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase > 2x the upper limit of normal (ULN)Total bilirubin > 2x ULN, except in the case of congenital bilirubinemia then direct bilirubin > 2x ULNeGFR < 45 ml/min/1.73 m^215. History of primary immunodeficiency16. History of solid organ or hematopoietic stem cell transplantation17. Comorbidities requiring corticosteroid therapy, including those which have required three or more courses of systemic corticosteroids within the 12 months prior to Visit 018. Any of the following conditions with Forced exploratory volume in 1 second (FEV1) < 70% predicted within the prior 90 days:a. Asthmab. Chronic obstructive pulmonary disease (COPD)c. DAH19. Pulmonary hypertension20. 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 situ22. Clinically significant cardiac disease, including but not limited to:Myocardial infarction within the prior 6 months, orUnstable or uncontrolled disease or condition related to or affecting cardiac function, including but not limited to:i. Unstable angina, orii. Congestive heart failure, New York Heart Association Class II-IV, oriii. Uncontrolled cardiac arrhythmia23. 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 requirements24. Severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, or neurological disease25. 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 study26. Lack of peripheral venous access27. Pregnancy, or planning a pregnancy during the 48 week study duration28. Breast-feeding29. Unwillingness to use medically acceptable non-prothrombotic contraception if of reproductive potential and engaging in sexual activity that could lead to pregnancy