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Clinical Trial Summary

This study is a phase II trial of belimumab in combination with rituximab/venetoclax in patients with refractory or relapsed chronic lymphocytic leukemia (CLL). Treatment of CLL has drastically changed in the past years as new therapeutic agents have gained clinical approval. The combination rituximab/venetoclax over a course of two years is approved as second line therapy especially in patients with high risk CLL (del17p), showing high remission rates and achievement of MRD (minimal residual disease) negativity. The next goals in CLL therapy are now to increase the rate of MRD negativity and to achieve an earlier MRD negativity during the course of treatment to allow for a reduction of treatment time and therefore treatment-induced toxicities. In line with other hematologic diseases, progression free survival depends on remission status, especially MRD negativity, after last treatment as MRD positivity after therapy indicates the persistence of treatment resistant CLL cells. One mechanism of therapy resistance has been described as reduced sensitivity to rituximab-induced antibody dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cell production of B-lymphocyte stimulator (BlyS, also called BAFF), which can be bound by belimumab, a human anti-BAFF antibody. Moreover, recombinant human (rh)BAFF can dose dependently reverse cytotoxic effects of venetoclax, which could also be restored by the application of belimumab. This led to the conceptualization of this clinical trial, in which belimumab is applied as a weekly subcutaneous injection in combination with standardrituximab/venetoclax treatment for up to 24 months in relapsed and refractory CLL patients. By removing BAFF from the CLL microenvironment we aim to increase the efficacy of rituximab/venetoclax treatment to achieve higher and earlier MRD negativity rates and allow for an abbreviated treatment.


Clinical Trial Description

The treatment landscape for relapsed/refractory CLL has faced profound changes and new developments in the past years. Conventional chemoimmunotherapies show only limited efficacy in the relapsed setting and are associated with side effects caused by rather unspecific mode of action of chemotherapy. Therefore, several targeted agents have become available for the treatment of CLL in recent years. However, beside the combination of rituximab and venetoclax all of these substances require continuous treatment bearing the risk of developing therapy resistance and accumulation of side effects. The combination of rituximab and venetoclax shows high response rates in the relapsed setting with MRD negativity rates of 83%, however still requiring a 2-year period of continuous treatment. Future efforts have now to focus on the further and earlier elimination of MRD in all treated patients to allow for a reduced treatment time and therefore lower risks of side effects and development of resistance as well as the achievement of long-lasting remission and potential cure in the future. The available data on the sensitizing effect of belimumab for venetoclax treatment, together with the published results showing a belimumab-induced sensitization of CLL cells to NK cell antitumor immunity as mediated by rituximab, provide a clear rationale for the evaluation of a combinatorial treatment with belimumab to increase sensitivity and response to the established CLL treatment regimen venetoclax/rituximab. Thus, we here propose an open-label, randomized, controlled, multicenter Phase II study analyzing safety and efficacy of belimumab in combination with venetoclax and rituximab in patients with refractory or relapsed CLL. Justification of combinational treatment The published and preclinical data on the sensitizing effect of belimumab on CLL cells to venetoclax and rituximab provides a clear rationale for combinational treatment of rituximab/venetoclax with belimumab. Although high MRD negativity rates are achieved withrituximab/venetoclax some patients still present with persisting MRD and suffer from early disease relapse. This phase II trial is designed to investigate the efficacy of belimumab in addition to rituximab/venetoclax in relapsed/refractory CLL. The primary endpoint is achievement of MRD negativity at end of induction treatment (EOI). Furthermore, the following secondary objectives will be assessed: - Safety of belimumab and rituximab/venetoclax in patients with relapsed or refractory CLL - Overall response rate (ORR) - Progression free survival (PFS) - Overall survival (OS) - Duration of response (DOR) - Assessment of further efficacy markers of belimumab in combination with rituximab/venetoclax in CLL compared to control - Pharmacokinetics of belimumab in CLL patients ;


Study Design


Related Conditions & MeSH terms


NCT number NCT05069051
Study type Interventional
Source University Hospital Tuebingen
Contact Juliane Walz, Prof.Dr.
Phone +49 (0)7071 29-83275
Email [email protected]
Status Not yet recruiting
Phase Phase 2
Start date October 15, 2021
Completion date July 14, 2027

See also
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