Daratumumab for Familial Cerebral Cavernous Malformations: A Single-Arm Safety and Efficacy Study

NCT07026604 | Not Yet Recruiting Early Phase 1 DMC

• 1 other identifier: CCM-DS01
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Cavernous Malformation, Cerebral

Keywords

cavernous malformation; CD38; Daratumumab; immunotherapy

Outcome Measures

Primary Outcomes (2)

• Incidence of severe infusion-related reactions (IRRs)

  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).

  Up to 2 month

• Change in total lesion volume on MRI during treatment

  Change in total lesion volume on MRI during treatment (specifically comparing post-treatment SWI \[Susceptibility Weighted Imaging\] sequence imaging with baseline imaging).

  Up to 2 month

Secondary Outcomes (8)

• Incidence of neutropenia during treatment

  Up to 2 month

• Incidence of anemia during treatment

  Up to 2 month

• Incidence of cytokine release syndrome (CRS) during treatment

  Up to 2 month

• Incidence of moderate IRRs

  Up to 2 month

• Incidence of mild IRRs

  Up to 2 month

Study Arms (1)

intervention

EXPERIMENTAL

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. Weekly laboratory tests (hematology, liver/kidney function) and post-treatment MRI (3-month follow-up) assess safety and efficacy.

Drug: Daratumumab

Interventions

Daratumumab DRUG

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.

intervention

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Beijing Tiantan Hospital: lead

Study Sites (1)

Beijing Tiantan Hospital

Beijing, China

Location

MeSH Terms

Conditions

Hemangioma, Cavernous, Central Nervous System

Interventions

daratumumab

Condition Hierarchy (Ancestors)

Hemangioma, Cavernous; Hemangioma; Neoplasms, Vascular Tissue; Neoplasms by Histologic Type; Neoplasms; Cavernous Sinus Syndromes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Central Nervous System Vascular Malformations; Nervous System Malformations; Vascular Malformations; Cardiovascular Abnormalities; Cardiovascular Diseases; Hemostatic Disorders; Vascular Diseases; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Central Study Contacts

Yingfan Sun, Master of Clinical Medicine

CONTACT

+86 15140437077; yingfansun@hotmail.com

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 10, 2025
• First Posted: June 18, 2025
• Study Start: July 1, 2025
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): November 1, 2026
• Last Updated: June 18, 2025

Record last verified: 2025-06

Locations

CN (1)