Starting soon
Phase EARLY_PHASE1
Daratumumab for Familial Cerebral Cavernous Malformations: A Single-Arm Safety and Efficacy Study
Condition(s) studied
Cavernous Malformation, Cerebral
Investigational drug(s) / intervention(s)
Daratumumab: Participants receive intravenous daratumumab (16 mg/kg weekly for 8 weeks), diluted in 1000 mL (first dose) or 500 mL (subsequent doses) of saline, with infusion rates escalated stepwise from 50 to 200 mL/h under vital sign monitoring. Premedication (antihistamines/analgesics) is administered 30 minutes prior to each infusion to mitigate reactions.
Study summary
Cerebral cavernous malformation (CCM) is a common vascular abnormality of the brain, affecting 0.1%-0.5% of people. It often causes recurrent brain hemorrhages, epilepsy, and neurological impairments, with surgery being the main treatment. However, surgery carries high risks for patients with multiple lesions or lesions in critical areas, and no effective pharmacological treatment is available. CCM is linked to mutations in genes like CCM1, CCM2, CCM3, or MAP3K3, which activate the MEK5-ERK5-KLF2/4 pathway, disrupting endothelial function. Immune cell infiltration, particularly plasma cells with high CD38 expression, suggests a role for humoral immunity in CCM. Depleting B cells in mouse models reduced lesions and hemorrhages, but broad B cell depletion is risky.
To find a safer treatment, researchers tested anti-CD38 monoclonal antibodies in mice, showing that targeting CD38 reduced CCM lesion formation. Given the success of CD38-targeted therapies like daratumumab in treating multiple myeloma, this study proposes evaluating daratumumab for CCM in a single-center trial with 10 adult patients to assess its safety and efficacy.
Eligibility
Inclusion Criteria:
* Age ≥ 18 years;
* Diagnosed with familial cerebral cavernous malformation (familial CCM) (diagnosis requires at least one of the following: multiple CCMs or ≥2 family members with CCM);
* Presence of clinical symptoms or history of symptomatic events: intracerebral hemorrhage, stroke, permanent or transient neurological deficits, seizures, disability, or any other neurological symptoms associated with cavernous malformations;
* Deemed unsuitable for surgical resection by a physician;
* Able to provide written informed consent;
* Participant is willing and able to attend outpatient follow-up visits.
Exclusion Criteria:
* Stable familial CCM lesions not requiring intervention;
* Presence of metal implants or other contraindications to MRI;
* History of statin therapy within the past 6 months;
* History of beta-blocker therapy within the past 6 months;
* Laboratory abnormalities: absolute neutrophil count \<1 × 10⁹/L, platelet count \<100 × 10⁹/L, ALT \>2.5× upper limit of normal (ULN), ALP \>2.5× ULN, bilirubin \>1.5× ULN, serum creatinine \>2× ULN;
* Known HIV positivity, hepatitis B virus seropositivity (excluding passive immunity from vaccination or immunoglobulin therapy), defined as HBsAg-positive and/or anti-HBs and anti-HBc positive, or known hepatitis C virus positivity;
* Chronic or ongoing active infections requiring systemic treatment (e.g., chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis);
* Poorly controlled comorbidities, including chronic obstructive pulmonary disease (COPD), severe asthma, poorly controlled diabetes, renal and/or hepatic failure;
* Cardiovascular diseases, including unstable angina, acute myocardial infarction (within 6 months prior to screening), congestive heart failure (NYHA Class II), arrhythmias requiring treatment (excluding premature beats or minor conduction abnormalities), deep vein thrombosis (excluding stable muscular vein thrombosis as judged by the investigator), pulmonary embolism, or other severe thromboembolic events, or history of deep vein thrombosis, pulmonary embolism, or severe thromboembolic events within 6 months prior to enrollment with a risk of recurrence as assessed by the investigator;
* Participation in other interventional medical research or clinical trials within 4 weeks prior to screening (observational, natural history, or epidemiological studies without interventions are allowed);
* Known allergic reactions to infused protein products;
* Pregnancy (positive urine or serum pregnancy test in premenopausal women without documented surgical sterilization) or lactation;
* Any condition (e.g., substance abuse, alcohol dependence) that, in the investigator's opinion, may compromise the participant's compliance with study requirements;
* Participant or legal guardian unable to provide informed consent for the study.
Primary outcome measure(s)
- Incidence of severe infusion-related reactions (IRRs) — Up to 2 month
Incidence of severe infusion-related reactions (IRRs) (defined as any adverse reaction directly caused by the injection procedure or drug administration, including fever, chills, hyperhidrosis, headache, bronchospasm, myalgia, arthralgia, hypotension, hypertension, etc., where the reaction persists without rapid resolution after symptomatic treatment and/or infusion interruption, recurs after initial improvement, or results in clinical consequences requiring hospitalization).
- Change in total lesion volume on MRI during treatment — Up to 2 month
Change in total lesion volume on MRI during treatment (specifically comparing post-treatment SWI \[Susceptibility Weighted Imaging\] sequence imaging with baseline imaging).
Trial sites (1)
| Facility | City | Region | Status |
|---|
| Beijing Tiantan Hospital |
Beijing |
China |
|
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