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.
- Plasmablastic lymphoma (PBL) is an aggressive B-cell lymphoma frequently caused by
Epstein-Barr virus (EBV) with frequent extranodal presentations involving the bones
and gastrointestinal tract.
- Immunophenotypically, PEL and PBL are post-germinal center B cell neoplasms
expressing surface markers consistent with plasmacytic differentiation, such as
CD45, CD38, CD138, MUM-1, and IRF4, similar to that of multiple myeloma (MM).
- Outcomes for PEL and PBL 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 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 T-cell receptor (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 or PBL and/or symptomatic KSHV-MCD or who are ineligible for
front-line chemotherapy
Eligibility
- Age >=18 years
- Participants with pathologically confirmed relapsed and/or refractory PEL, including
extracavitary variant and KSHV-associated large cell lymphoma, PBL, or ineligible
for front line chemotherapy
- Participants with PEL or PBL must have:
- Measurable or assessable disease
- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-3
- Received first-line curative-intent therapy for PEL or PBL, unless such therapy
is contraindicated
- Participants with KSHV-MCD must have:
- ECOG PS (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 or PBL, and/or symptomatic KSHV-MCD.
- The study will accrue up to 12 evaluable participants with PEL or PBL and up to 12
evaluable participants with KSHV-MCD.
- For participants with relapsed/refractory PEL or PBL, 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).