Linvoseltamab for Amyloidosis
(LINKER-AL2 Trial)
Recruiting in Palo Alto (17 mi)
+15 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Regeneron Pharmaceuticals
Disqualifiers: Non-AL amyloidosis, Plasmacytosis, Myocardial infarction, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This study is researching an experimental drug called linvoseltamab ("study drug").
This study is focused on patients who have AL amyloidosis that has returned or have failed other therapies and need to be treated again.
The study consists of 2 phases (Phase 1 and Phase 2):
* In Phase 1, linvoseltamab will be given to a small number of participants to study the side effects of the study drug and to determine the recommended doses of the study drug to be given to participants in Phase 2.
* In Phase 2, linvoseltamab will be given to more participants to continue to assess the side effects of the study drug and to evaluate the ability of linvoseltamab to treat AL amyloidosis.
The study is looking at several other research questions, including:
* How many participants treated with linvoseltamab have improvement in the abnormal proteins that cause organ problems and for how long
* How many participants treated with linvoseltamab have improvement in the heart or kidney and for how long
* What the right dosing regimen is for linvoseltamab
* What side effects may happen from taking linvoseltamab
* How much linvoseltamab is in the blood at different times
* Whether the body makes antibodies against linvoseltamab (which could make the drug less effective or could lead to side effects)
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.
What data supports the effectiveness of the drug Linvoseltamab for treating amyloidosis?
The research suggests that targeting long-lived plasma cells, which are involved in antibody responses, can be effective in certain conditions. Although not directly related to Linvoseltamab, similar strategies using proteasome inhibitors like bortezomib have shown success in reversing harmful antibody responses in other diseases, indicating potential for plasma cell-targeting treatments.
12345How is the drug Linvoseltamab different from other treatments for amyloidosis?
Linvoseltamab is unique because it is a bispecific antibody that targets both BCMA (B-cell maturation antigen) and CD3, potentially offering a novel mechanism of action compared to existing treatments like daratumumab, which targets CD38. This dual targeting approach may provide a new way to treat amyloidosis by engaging the immune system more directly.
678910Eligibility Criteria
This trial is for adults with AL amyloidosis who have tried at least one but no more than four treatments and need more therapy. They should have a certain level of abnormal proteins in their blood, be able to perform daily activities with ease or some difficulty (ECOG score ≤2), and have good heart, liver, kidney, and blood function.Inclusion Criteria
Key
I have been diagnosed with AL amyloidosis.
My liver, blood, kidney, and heart are functioning well.
+3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Phase 1 Treatment
Linvoseltamab is given to a small number of participants to study side effects and determine recommended doses
4 weeks
Phase 2 Treatment
Linvoseltamab is given to more participants to assess side effects and evaluate treatment efficacy
39 months
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study tests linvoseltamab in two phases: Phase 1 determines safe dosages through a small group; Phase 2 expands the testing for effectiveness against AL amyloidosis symptoms. It also examines how long improvements last, optimal dosing schedules, potential side effects, drug levels in the blood over time, and if the body resists the drug.
4Treatment groups
Experimental Treatment
Group I: Phase 2: Low DoseExperimental Treatment1 Intervention
Dose Expansion: Participants will be randomized in a 1:1 ratio
Group II: Phase 2: High DoseExperimental Treatment1 Intervention
Dose Expansion: Participants will be randomized in a 1:1 ratio
Group III: Phase 1: Cohort 2: High DoseExperimental Treatment1 Intervention
Dose Escalation: Non-Randomized
Group IV: Phase 1: Cohort 1: Low DoseExperimental Treatment1 Intervention
Dose Escalation: Non-Randomized
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Karmanos Cancer InstituteDetroit, MI
City of HopeDuarte, CA
MD Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
Regeneron PharmaceuticalsLead Sponsor
References
Monoclonal antibody therapy of inflammatory rheumatic diseases. [2019]The recognition that certain monoclonal antibodies have immunosuppressive properties led to the therapeutic application in autoimmune rheumatic diseases, rheumatoid arthritis in particular. The therapeutic potential of monoclonal antibodies directed against cell surface antigens mainly present on T-cells has been suggested by open trials in rheumatoid arthritis but the results of controlled studies are disappointing. Open intervention studies with monoclonal antibodies directed at other antigens relevant for the rheumatoid inflammation such as the intercellular adhesion molecule ICAM-1 or the cytokines IL-6 and TNF alpha provided encouraging clinical improvements. The impressive potential of anti-TNF alpha which was already illustrated by the immediate suppression of the acute phase response in open studies could be confirmed by a recently completed controlled trial. The present overview summarizes the available information on the results of these treatment modalities and discusses the possibilities of monoclonal antibodies as a long term treatment for rheumatic diseases.
Rituximab in the treatment of dermatomyositis and other inflammatory myopathies. A report of 4 cases and review of the literature. [2017]Rituximab is an anti-CD20 monoclonal antibody targeting B cells, which has been used with success in a wide variety of autoimmune diseases. The experience with this drug in patients with inflammatory myopathies (IM), nonetheless, is still limited. We review the literature and highlight several aspects in relation to therapy with rituximab in IM.
A role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins. [2016]Antibody responses to life saving therapeutic protein products, such as enzyme replacement therapies (ERT) in the setting of lysosomal storage diseases, have nullified product efficacy and caused clinical deterioration and death despite treatment with immune-suppressive therapies. Moreover, in some autoimmune diseases, pathology is mediated by a robust antibody response to endogenous proteins such as is the case in pulmonary alveolar proteinosis, mediated by antibodies to Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). In this work, we make the case that in such settings, when the antibody response is high titered, sustained, and refractory to immune suppressive treatments, the antibody response is mediated by long-lived plasma cells which are relatively unperturbed by immune suppressants including rituximab. However, long-lived plasma cells can be targeted by proteasome inhibitors such as bortezomib. Recent reports of successful reversal of antibody responses with bortezomib in the settings of ERT and Thrombotic Thrombocytopenic Purpura (TTP) argue that the safety and efficacy of such plasma cell targeting agents should be evaluated in larger scale clinical trials to delineate the risks and benefits of such therapies in the settings of antibody-mediated adverse effects to therapeutic proteins and autoantibody mediated pathology.
[Therapy of refractory chronic polyarthritis with tumor necrosis factor alpha receptor fusion proteins (TNFR55-IgG1)--results of double-blind placebo-controlled studies over 3 months]. [2019]AIM OF STUDIES: To determine the optimal dose regimen for i.v. TNFR55-IgG1 in refractory rheumatoid arthritis.
[Rituximab treatment of rheumatoid arthritis: new evidence]. [2018]New evidence is reviewed on efficacy and safety of chimeric monoclonal antibodies to B-cell CD20 molecule (rituximab) in the treatment of rheumatoid arthritis.
Daratumumab in the Treatment of Light-Chain (AL) Amyloidosis. [2021]Systemic light-chain (AL) amyloidosis is caused by a small B cell, most commonly a plasma cell (PC), clone that produces toxic light chains (LC) that cause organ dysfunction and deposits in tissues. Due to the production of amyloidogenic, misfolded LC, AL PCs display peculiar biologic features. The small, indolent plasma cell clone is an ideal target for anti-CD38 immunotherapy. A recent phase III randomized study showed that in newly diagnosed patients, the addition of daratumumab to the standard of care increased the rate and depth of the hematologic response and granted more frequent organ responses. In the relapsed/refractory setting, daratumumab alone or as part of combination regimens gave very promising results. It is likely that daratumumab-based regimens will become new standards of care in AL amyloidosis. Another anti-CD38 monoclonal antibody, isatuximab, is at an earlier stage of development as a treatment for AL amyloidosis. The ability to target CD38 on the amyloid PC offers new powerful tools to treat AL amyloidosis. Future studies should define the preferable agents to combine with daratumumab upfront and in the rescue setting and assess the role of maintenance. In this review, we summarize the rationale for using anti-CD38 antibodies in the treatment of AL amyloidosis.
[Interest of daratumumab in refractory AL amyloidosis in a 96-year-old patient]. [2022]Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+plasma cells, resulting in organ dysfunction. Cardiac involvement has a major prognostic value. Antiplasma cell chemotherapy reduces the synthesis of immunoglobulin light chains (precursors of amyloid deposits). We describe a case of AL amyloidosis in a 95-year-old patient. Our patient responded poorly to treatment with rituximab, cyclophosphamide-bortezomib-dexamethasone, and rituximab-bendamustine. Finally, the anti-CD38 antibody daratumumab was associated with the best hematologic responsiveness without significant adverse effects. In conclusion, our case suggests that daratumumab is an effective and well-tolerated alternative to chemotherapy in the treatment af AL amyloidosis in very elderly patients.
Monoclonal Antibody Therapies in Systemic Light-Chain Amyloidosis. [2021]In systemic light-chain amyloidosis, monoclonal antibodies target antigens that are either membrane-bound or circulating or deposited in the organs. CD38 holds high promise as a target against clonal plasma cells. Multiple anti-CD38 antibodies are either approved for use or being investigated in clinical trials. Daratumumab has been investigated and has clinical efficacy in upfront or refractory settings. High rates of hematologic response are seen with daratumumab, which translates to high organ response rates. Rituximab is usually integrated into the treatment regimen for IgM amyloidosis. Anti-amyloid therapies have shown preclinical proof of principle, but lack confirmation of improvement.
CD32B is highly expressed on clonal plasma cells from patients with systemic light-chain amyloidosis and provides a target for monoclonal antibody-based therapy. [2021]Despite advances in therapy, many patients with systemic light-chain amyloidosis (AL) die within 3 years from diagnosis. The humanized 2B6 monoclonal antibody (MoAb) is specific for the low-affinity IgG Fc receptor CD32B and effective in a human CD32B+ B-cell lymphoma murine xenograft model. Because MoAb therapy could improve outcomes in AL, we studied CD32B expression by clonal plasma cells obtained from 48 patients with AL. Transcript profiling showed that expression of CD32B was significantly higher than expression of all other Fc receptor family members. Reverse-transcriptase polymerase chain reaction (RT-PCR) using double-enriched CD138+ plasma cells showed uniform expression of the stable cell surface CD32B1 isoform at diagnosis and relapse, and flow cytometry showed intense CD32B cell surface staining on 99% of CD138+ plasma cells at diagnosis and relapse. These data provide a rationale for the novel therapeutic targeting of CD32B using the humanized 2B6 MoAb in patients with systemic AL-amyloidosis.
Daratumumab: A Review in Newly Diagnosed Systemic Light Chain Amyloidosis. [2022]Subcutaneous daratumumab (DARZALEX®) co-formulated with recombinant human hyaluronidase (DARZALEX FASPRO®) is approved in several countries, including the USA and those of the EU, for use in combination with bortezomib, cyclophosphamide and dexamethasone for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis. Daratumumab is a CD38-targeting, human IgG1κ monoclonal antibody. In the pivotal phase III ANDROMEDA trial in adults with newly diagnosed systemic AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide and dexamethasone significantly increased the proportion of patients achieving a haematological complete response relative to bortezomib, cyclophosphamide and dexamethasone alone (primary endpoint). Daratumumab combination therapy produced rapid and deep haematological responses which were associated with improved major organ deterioration progression-free survival (PFS). The addition of daratumumab also led to higher cardiac and renal response rates at 6 and 12 months. Daratumumab had an acceptable tolerability profile when used as combination therapy. Therefore, daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone represents an important emerging first-line treatment option for patients with systemic AL amyloidosis.