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Daratumumab

Daratumumab SC (daratumumab and hyaluronidase) is administered subcutaneously (SC) as 1800 mg/30,000 units weekly for a total of 8 weeks (8 doses) followed by every 2 weeks for a total of 16 weeks (8 doses) followed by every 4 weeks for up to 96 weeks (24 doses)

Daratumumab SC

Anaida Widell

Kathryn A Lurain, M.D.

National Cancer Institute Referral Office

Background:

Primary effusion lymphoma (PEL) is an aggressive form of cancer that affects cells in the immune system and lymph nodes. How PEL develops is not well understood, and this disease does not respond well to standard treatments for other types of lymphomas.

Objective:

To test a drug treatment (daratumumab SC) in people with PEL.

Eligibility:

People aged 18 and older with PEL. Their PEL must have failed to respond to therapy or they must be unable to receive standard treatment for the disease.

Design:

Participants will be screened. They will have a physical exam with blood tests. They will have imaging scans and tests of their heart and lung function. They may need to have a biopsy: tissue or fluid will be collected. They will have an eye exam.

Daratumumab SC is given as an injection into the fat under the skin in the abdomen. This takes 3 to 5 minutes. Participants will receive the treatment once a week for 8 weeks; then every 2 weeks for 16 weeks; then every 4 weeks for up to 24 months.

Participants will have other tests during the study period. These may include lumbar punctures: A needle will be inserted between the bones of the spine to draw some fluid from the area around the spinal cord. Participants may also have a thoracentesis: A needle or plastic tube will be inserted into the space around the lungs to withdraw fluid. Participants will have more imaging scans and blood tests.

Follow-up visits will continue after treatment ends. Participants will be in the study for up to 5 years.

Background

* Primary effusion lymphoma (PEL) is an aggressive B cell lymphoma caused by the Kaposi sarcoma herpesvirus (KSHV) with clinicopathologic and molecular profiles distinct from other HIV-related lymphomas.
* Immunophenotypically, PEL is a post-germinal center B cell neoplasm expressing surface markers consistent with plasmacytic differentiation, such as CD45, CD38, CD138, MUM-1, and IRF4, similar to that of multiple myeloma.
* Outcomes for PEL treated with front-line combination chemotherapy are inferior to those of other HIV-associated lymphomas, and second-line cytotoxic chemotherapy is often ineffective and profound immunosuppression often prevents this approach.
* In the second-line setting, chemotherapy-sparing treatments that do not contribute to further immune suppression may be more effective. In addition, patients with PEL often have concurrent KS, which can be severely exacerbated by immune suppression and contributes to mortality in PEL.
* Kaposi sarcoma herpesvirus-associated multicentric Castleman disease (KSHV-MCD) is a rare lymphoproliferative disorder that develops predominantly in people with HIV with inflammatory symptoms associated with high levels of interleukin-6 (IL-6), KSHV-encoded viral IL-6 (vIL-6), and other cytokines.
* The pathologic hallmark of KSHV-MCD is the presence of KSHV-infected Lambda-restricted plasmablasts in the mantle zones of lymph nodes which stain brightly for CD45 and CD38 and negative for CD20.
* KSHV-MCD is generally treated with the anti-CD20 monoclonal antibody, rituximab, with the goal to rapidly improve symptoms and eliminate of reservoirs of KSHV-infected plasmablasts.
* Concurrent Kaposi sarcoma is often exacerbated by or develops during rituximab therapy and contributes to morbidity in KSHV-MCD.
* Daratumumab is a human monoclonal antibody that binds to a unique region on CD38 and induces killing of CD38-expressing cells via antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis.
* Daratumumab also depletes immunosuppressive non-plasma cells that express CD38 thereby reducing local immunosuppression and stimulating an increase in T-helper cells, cytotoxic T cells, T cell functional response, and TCR clonality in the tumor microenvironment.

Objective

-To evaluate the partial response (PR) plus complete response (CR) rate (further referred to as the overall response rate \[ORR\]) of daratumumab SC in participants with relapsed/refractory PEL and/or symptomatic KSHV-MCD or who are ineligible for frontline chemotherapy

Eligibility

* Age \>=18 years
* Pathologically confirmed relapsed and/or refractory primary effusion lymphoma (PEL), including extracavitary variant and KSHV-associated large cell lymphoma or ineligible for front line chemotherapy
* Participants with PEL must have:

  * Measurable or assessable disease
  * ECOG Performance Status (PS) 0-3
  * Received first-line curative-intent therapy for PEL, unless such therapy is contraindicated
* Participants with KSHV-MCD must have:

  * ECOG Performance Status (PS) 0-3
  * At least one clinical symptom and at least one laboratory abnormality attributable to KSHV-MCD

Design

* This is a Phase 2 study to evaluate the response rate of daratumumab SC in participants with relapsed/refractory PEL and/or symptomatic KSHV-MCD.
* The study will accrue up to 12 evaluable participants with PEL and up to 12 evaluable participants with KSHV-MCD.
* For participants with relapsed/refractory PEL, daratumumab SC will be administered subcutaneously (SC) as 1800 mg/30,000 units weekly for a total of 8 weeks (8 doses) followed by every 2 weeks for a total of 16 weeks (8 doses) followed by every 4 weeks for up to 96 weeks (24 doses) in the absence of off-treatment criteria.
* For participants with symptomatic KSHV-MCD, daratumumab SC will be administered SC as 1800 mg/30,000 units weekly for 8 weeks. If response assessment indicates progressive or stable disease, daratumumab SC will be given every 2 weeks for 8 additional doses for up to 24 weeks (6 months).

Daratumumab for Relapsed/Refractory Primary Effusion Lymphoma

A Phase II Study of Daratumumab for Relapsed/Refractory Primary Effusion Lymphoma and Multicentric Castleman Disease

Percentage of participants with the best overall response of CR or PR to therapy

Adverse events (AEs) will be reported by type and grade of toxicity

National Cancer Institute (NCI)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Daratumumab for Relapsed/Refractory Primary Effusion Lymphoma	NCT05907759	Lymphoma, Prima...	Daratumumab SC	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Daratumumab for Relapsed/Refractory Primary Effusion Lymphoma	NCT05907759	Lymphoma, Prima...	Daratumumab SC	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for kaposi sarcoma herpesvirus