Daratumumab for Antiphospholipid Syndrome

(DARE-APS Trial)

Recruiting at 7 trial locations

Overseen By Shruti Chaturvedi

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Warfarin, LMWH

Must not be taking: Corticosteroids, DOACs, Biologics, others

Disqualifiers: Systemic autoimmune diseases, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 22

22 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of a medication called daratumumab for individuals with Antiphospholipid Syndrome (APS), a condition where the immune system mistakenly attacks normal blood proteins, leading to blood clots. Participants will receive varying doses of daratumumab to determine the safest dose and identify any side effects. Suitable candidates have confirmed APS through blood tests and have experienced blood clots or specific pregnancy issues related to APS. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive it.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before participating. Specifically, you must not have used corticosteroids over 10 mg/day, direct oral anticoagulants, certain immunosuppressive drugs, or biologic agents within specified time frames before joining the study. If you are on warfarin or low molecular weight heparin due to a history of thrombosis, you may continue these medications.

Is there any evidence suggesting that daratumumab is likely to be safe for humans?

Research shows that patients generally tolerate daratumumab well. In studies involving patients with relapsed or hard-to-treat multiple myeloma, daratumumab was tolerated equally well whether administered as an injection under the skin or through an IV, resulting in similar side effects regardless of the method.

However, some serious reactions have been reported. In certain cases, daratumumab treatments have caused severe reactions, including a few fatal ones. Therefore, participants must be closely monitored during treatment.

Daratumumab is already approved for other conditions, indicating that its safety has been thoroughly studied. This trial will specifically examine its safety for treating Anti-Phospholipid Syndrome (APS). Participants will receive varying doses to assess their tolerance. The goal is to identify the highest safe dose without causing major side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Antiphospholipid Syndrome?

Daratumumab is unique because it targets CD38, a protein commonly found on the surface of certain immune cells. This is different from the standard treatments for Antiphospholipid Syndrome, which typically include blood thinners like warfarin or aspirin. Researchers are excited about daratumumab because it offers a novel mechanism of action, potentially reducing the risk of blood clots by modulating immune cell activity rather than just thinning the blood. Additionally, daratumumab is administered intravenously, which may provide more consistent dosing compared to oral medications.

What evidence suggests that daratumumab might be an effective treatment for Antiphospholipid Syndrome?

Research has shown that daratumumab holds promise for treating multiple myeloma, a type of blood cancer. One study found that many patients responded positively to the treatment. Specifically, 63.4% of patients responded well to DARZALEX FASPRO®, a form of daratumumab, compared to only 2% with other treatments, indicating its potential effectiveness. In this trial, researchers are studying daratumumab for antiphospholipid syndrome (APS) across different dosage cohorts. While these early results from other conditions are encouraging, the current study will evaluate its effectiveness specifically for APS. The treatment works by attaching to a specific protein on certain cells, aiding the immune system in attacking those cells. ^{1 2 3 6 7}

Who Is on the Research Team?

Jason Knight, M.D., Ph.D.

Principal Investigator

University of Michigan Health System: Department of Internal Medicine, Division of Rheumatology

Doruk Erkan, M.D., M.P.H.

Principal Investigator

Hospital for Special Surgery, New York: Division of Rheumatology

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with Anti-Phospholipid Syndrome (APS), who meet specific criteria including a history of certain types of thrombosis or pregnancy complications related to APS. Participants must have completed recommended vaccinations, be willing to use warfarin or LMWH for anticoagulation, and not have other autoimmune disorders like rheumatoid arthritis or systemic lupus erythematosus.

Inclusion Criteria

History of triple positive aPL within the prior 5 years and at least 12 weeks prior to enrollment

Willing and able to discontinue direct oral anticoagulants if applicable

I am willing to take blood thinners if I have a history of blood clots.

Exclusion Criteria

Inability or unwillingness to give written informed consent

Inability or unwillingness to comply with study protocol

I have an ongoing infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive weekly intravenous administration of daratumumab for 8 doses to determine the highest safe dose

8 weeks

8 visits (in-person)

Expansion Phase

Four additional participants are treated at the highest safe dose weekly for 8 doses

8 weeks

8 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

48 weeks

6 visits (in-person) at weeks 9, 12, 18, 24, 36, and 48

What Are the Treatments Tested in This Trial?

Interventions

• Daratumumab

Trial Overview The study tests the safety of daratumumab at different doses (4 mg/kg, 8 mg/kg, and 16 mg/kg) in treating APS. Up to 22 participants will receive intravenous doses on a set schedule to identify any dose-limiting toxicities during this phase.

How Is the Trial Designed?

Group I: 8 mg/kg Cohort Experimental Treatment 1 Intervention

This cohort will receive intravenous (IV) administration of 8 mg/kg daratumumab administered weekly for 8 doses (weeks 0 through 7). Post-treatment follow-up visits will occur at weeks 9, 12, 18, 24, 36, and 48

Group II: 4 mg/kg Cohort Experimental Treatment 1 Intervention

This cohort will receive intravenous (IV) administration of 4 mg/kg daratumumab administered weekly for 8 doses (weeks 0 through 7). Post-treatment follow-up visits will occur at weeks 9, 12, 18, 24, 36, and 48

Group III: 16 mg/kg Cohort Experimental Treatment 1 Intervention

This cohort will receive intravenous (IV) administration of 16 mg/kg daratumumab administered weekly for 8 doses (weeks 0 through 7). Post-treatment follow-up visits will occur at weeks 9, 12, 18, 24, 36, and 48

Daratumumab is already approved in European Union, United States for the following indications:

Approved in European Union as Darzalex for:

• Relapsed and refractory multiple myeloma
• Newly diagnosed multiple myeloma in combination with bortezomib, melphalan, and prednisone

Approved in United States as Darzalex for:

• Multiple myeloma in patients who have received at least three prior therapies
• Newly diagnosed multiple myeloma in combination with bortezomib, melphalan, and prednisone
• Relapsed or refractory multiple myeloma in combination with lenalidomide and dexamethasone

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

PPD DEVELOPMENT, LP

Industry Sponsor

Trials

167

Recruited

38,000+

David Simmons

PPD DEVELOPMENT, LP

Chief Executive Officer since 2012

BSc in Applied Science from Georgia Institute of Technology

Martina Flammer

PPD DEVELOPMENT, LP

Chief Medical Officer since 2024

MD

PPD Development, LP

Industry Sponsor

Immune Tolerance Network (ITN)

Collaborator

Trials

68

Recruited

7,900+

PPD

Industry Sponsor

Trials

162

Recruited

36,600+

Dr. Austin Smith

PPD

Chief Medical Officer since 2020

Doctor of Medicine from the Royal College of Surgeons in Ireland

David Simmons

PPD

Chief Executive Officer since 2012

Bachelor’s degree in Applied Mathematics and Industrial Management from Carnegie Mellon University

Rho Federal Systems Division, Inc.

Industry Sponsor

Trials

44

Recruited

15,000+

Published Research Related to This Trial

Intravenous daratumumab, when combined with bortezomib, thalidomide, and dexamethasone, significantly improves treatment outcomes for adults with newly diagnosed multiple myeloma, leading to higher rates of stringent complete response and prolonged progression-free survival, as shown in the phase III CASSIOPEIA trial.

The addition of daratumumab has a minimal impact on overall toxicity, with the most common serious side effects being blood-related issues, indicating it is a relatively safe option for patients undergoing treatment for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Combination Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma. Lamb, YN.[2021]

Daratumumab, a monoclonal antibody targeting CD38, has shown significant efficacy as a monotherapy in relapsed/refractory multiple myeloma, achieving an overall response in about one-third of patients, with rapid and durable effects.

In combination with other treatments like bortezomib or lenalidomide, daratumumab significantly prolonged progression-free survival, although the overall survival benefit is still being evaluated, and it was generally well tolerated with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Relapsed and/or Refractory Multiple Myeloma. Blair, HA.[2018]

In a 6-month trial involving 107 patients with various rheumatic diseases, treatment with biological agents like rituximab and infliximab led to significant improvements, with 57.9% achieving complete remission and 39.3% achieving partial remission.

The incidence of severe adverse events (AEs) was relatively low, with only 5.6% of patients experiencing serious AEs, including severe infusion reactions and systemic infections, indicating that while risks exist, the benefits of using biological agents in managing rheumatic diseases are notable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Severe adverse events from treatment with genetically engineered biological agents in patients with rheumatic diseases]. Moiseev, SV., Novikov, PI., Semenkova, EN., et al.[2015]

Daratumumab, a monoclonal antibody for treating refractory multiple myeloma, can be detected in serum protein electrophoresis, appearing as an additional band in the slow gamma region.

It is crucial for diagnostic laboratories to recognize daratumumab in test results to avoid misinterpretation as a new monoclonal protein, ensuring accurate patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Electrophoretic patterns post daratumumab. Sheldon, J., Wheeler, RD., Powles, R.[2018]

Direct-acting oral anticoagulants (DOACs), such as rivaroxaban, are emerging as first-line therapy for antiphospholipid syndrome (APS) due to their effectiveness in preventing thrombosis without the need for regular monitoring, unlike warfarin.

Clinical studies indicate that DOACs are non-inferior to warfarin in various anticoagulation scenarios, making them a promising option for managing APS and its associated thrombotic risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of Direct Oral Anticoagulation Agents as Thromboprophylaxis in Antiphospholipid Syndrome. Arora, S., Nair, S., Prabhu, R., et al.[2021]

Daratumumab, an anti-CD38 monoclonal antibody, was used off-label to treat two adult patients with primary immune thrombocytopenia (ITP) after standard therapies failed, showing promising results in one patient with rapid and lasting improvement in platelet counts.

The treatment appears to effectively target long-lived plasma cells that produce antiplatelet autoantibodies, suggesting that daratumumab could be a valuable option for ITP and warrants further clinical evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab as a novel treatment option in refractory ITP. Vernava, I., Schmitt, CA.[2023]

In a study of 22 patients with antiphospholipid syndrome (APS), both low-dose and standard-dose rituximab (RTX) were found to be effective, with 42.1% of patients achieving complete remission after 6 months of treatment.

The study indicated that low-dose RTX (<1000mg) had similar efficacy to standard-dose RTX (≥1000mg) in reducing anticardiolipin antibody levels and improving patient outcomes, suggesting that lower doses may be a safe and effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose versus standard dose rituximab for the treatment of antiphospholipid syndrome: A pilot study from a tertiary medical center. Gan, Y., Zhong, X., Zhao, Y., et al.[2022]

Patients with triple-positive antiphospholipid syndrome (APS) are at the highest risk for thrombotic events, even with anticoagulation, leading to recommendations against using direct-acting oral anticoagulants (DOACs) for secondary prevention in all APS patients.

The review highlights a lack of evidence for the safety and efficacy of DOACs in patients with single- or dual-positive APS, suggesting that the current guidelines may be overly cautious and warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What is the appropriate anticoagulation strategy for thrombotic antiphospholipid syndrome? Arachchillage, DRJ., Laffan, M.[2020]

Direct-acting oral anticoagulants (DOACs) like rivaroxaban and apixaban are significantly less effective than vitamin K antagonists (VKAs) in preventing thrombosis recurrence in patients with antiphospholipid syndrome (APS), especially those with prior arterial thrombosis or multiple antiphospholipid antibodies.

The risk of severe bleeding as a side effect is similar for both DOAC and VKA treatments, suggesting that DOACs may not be a safe or effective option for managing thrombotic APS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Direct-acting oral anticoagulants in antiphospholipid syndrome: A systematic review]. Girón-Ortega, JA., Girón-González, JA.[2023]

Daratumumab, a monoclonal antibody targeting CD38, has been approved in the USA for treating multiple myeloma in patients who have undergone at least three prior therapies, demonstrating its role as a treatment option for difficult-to-treat cases.

In a phase II trial, daratumumab monotherapy showed an overall response rate of about 30% in patients with relapsed or refractory multiple myeloma, indicating its efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: First Global Approval. McKeage, K.[2018]

Antiphospholipid syndrome (APS) is a serious autoimmune disorder that leads to recurrent blood clots and pregnancy complications, and traditional anticoagulation treatments often fail to prevent these issues in many patients.

While direct oral anticoagulants are a promising alternative to standard treatments, they may not be effective for high-risk APS patients, prompting research into other therapies like immunomodulators and novel agents to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the management of antiphospholipid syndrome. Rodziewicz, M., D'Cruz, DP.[2020]

The BIOBADASER III registry, initiated in December 2015, includes data from 2,664 patients with rheumatic diseases treated with biological or synthetic drugs, focusing on tracking adverse events and treatment effectiveness.

In the first year, the most common adverse events reported were infections and infestations, highlighting the need for ongoing monitoring of safety in patients undergoing long-term treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Objectives and methodology of BIOBADASER phase iii. Sanchez-Piedra, C., Hernández Miguel, MV., Manero, J., et al.[2021]

The establishment of European biologics registers for rheumatic diseases is crucial for improving drug safety assessments, and a set of seven key considerations has been identified to guide the creation of these registers.

To enhance the quality and interpretability of safety data, nine additional points for analysis and reporting have been proposed, emphasizing the importance of thoughtful design and harmonization in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EULAR points to consider when establishing, analysing and reporting safety data of biologics registers in rheumatology. Dixon, WG., Carmona, L., Finckh, A., et al.[2022]

This erratum corrects information from a previous study that evaluated the risk of major adverse cardiovascular events in psoriasis patients undergoing biologic therapy.

The original study aimed to assess the safety of biologic treatments in terms of cardiovascular health, but specific details on the number of subjects or findings are not provided in the erratum.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Risk of Major Adverse Cardiovascular Events with Biologic Therapy in Patients with Psoriasis (Errata). Bissonnette, R., Langholff, W.[2021]

BIOBADASER, the Safety Register of the Spanish Society of Rheumatology, has successfully served as a template for creating other safety registers, such as BIOBADAMERICA and BIOBADADERM, highlighting its influence in standardizing data collection in rheumatology and beyond.

While template registers like BIOBADASER improve data collection and communication of safety concerns, they also face challenges in merging rare data and making comparisons across different registers due to their varied structures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BIOBADASER, BIOBADAMERICA, and BIOBADADERM: safety registers sharing commonalities across diseases and countries. Carmona, L., de la Vega, M., Ranza, R., et al.[2017]

Citations

1. jnj.com jnj.com/media-center/press-releases/darzalex-faspro-daratumumab-and-hyaluronidase-fihj-shows-51-percent-reduction-in-risk-of-progression-to-active-multiple-myeloma-for-patients-with-high-risk-smoldering-multiple-myeloma

DARZALEX FASPRO® (daratumumab and hyaluronidase ... Additionally, patients who received DARZALEX FASPRO® saw a higher overall response rate of 63.4 percent compared to 2.0 percent with active ...

2. darzalexhcp.com darzalexhcp.com/

DARZALEX® (daratumumab) & DARZALEX FASPRO ... You can see from the results presented that more patients achieved a complete response or better with DRd by 18 months vs Rd alone. Forty-nine point eight ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10758190/

Safety and Efficacy of Subcutaneous Daratumumab in ... At median follow-up of 7.5 months, progression of disease had been observed in 51% of patients in each arm. Median progression-free survival was ...

4. prnewswire.com prnewswire.com/news-releases/tecvayli-plus-darzalex-faspro-combination-regimen-significantly-improves-progression-free-survival-and-overall-survival-versus-standard-of-care-302585407.html

TECVAYLI® plus DARZALEX FASPRO® combination ... At almost three years follow-up, the combination of TECVAYLI and DARZALEX FASPRO met the primary endpoint of progression-free survival (PFS) ( ...

5. jnjmedicalconnect.com jnjmedicalconnect.com/products/darzalex-faspro/medical-content/darzalex-darzalex-faspro-adverse-event-hematologic-events-in-patients-with-relapsed-and-refractor

DARZALEX + DARZALEX FASPRO - Adverse Event The most common grade 3/4 (≥20%) hematologic TEAEs were neutropenia (41.5%), anemia (27.7%), and thrombocytopenia (24.6%).

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/761145s009lbl.pdf

Darzalex Faspro - accessdata.fda.gov Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO [see. Adverse Reactions (6.3)]. Systemic Reactions. In a ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05671757

Study Details | NCT05671757 | Daratumumab in Primary ... The purpose of this study is to see if the study medication, daratumumab, is safe to treat individuals with Anti-Phospholipid Syndrome (APS).