Trial in Progress: A Phase II Trial to Investigate Venetoclax in Combination with Ibrutinib and Rituximab or Conventional Chemoimmunotherapy (Bendamustine and Rituximab) and Ibrutinib in Patients with Treatment-Naive Mantle Cell Lymphoma Not Eligible for High-Dose Therapy – MCL Elderly III

Mantle cell lymphoma (MCL) is a rare but challenging B-cell-lymphoma affecting predominantly elderly patients. While fit patients traditionally receive an intensive first-line treatment followed by autologous stem cell transplantation, elderly or unfit patients are often treated by chemo-immunotherapy alone followed by anti-CD20-antibody maintenance. In recent years, potential long-term sequelae of chemotherapy have become a concern. At the same time, the advent of effective targeted agents has opened new therapeutic opportunities. Venetoclax, a bcl-2 inhibitor, has shown substantial efficacy in relapsed MCL. In order to prolong duration of remission, the combination with the Bruton tyrosinkinase inhibitor (BTKi) Ibrutinib has successfully been investigated in various clinical trials in the relapsed setting. We initiated a trial to determine the feasibility of a chemo-free combination therapy in elderly patients with newly diagnosed MCL.

MCL-Elderly III is an international, randomized phase II trial assessing efficacy and safety of the combination Venetoclax, Ibrutinib and Rituximab for 6 cycles followed by 24-months maintenance treatment of Venetoclax, Ibrutinib and Rituximab (EU CT registration number 2022-501808-96-00). As a comparative arm serves the combination Bendamustine, Rituximab and Ibrutinib for 6 cycles followed by 24-months maintenance of Rituximab and Ibrutinib, as adopted from the SHINE trial. In the maintenance period in both arms, Rituximab is administered every second cycle. A total of 150 adult patients (≥60 years, ECOG ≤ 2) with previously untreated stage II-IV MCL and at least 1 measurable tumor lesion (>1.5 cm x >1.0 cm) will be enrolled and allocated at a 1:1 ratio. Main inclusion criteria are an adequate hematopoietic reserve as well as sufficient liver and renal function. Patients with serious cardiovascular disease or bleeding disorders are excluded.

Patients will be recruited in 40 sites in Germany and Italy. The duration of this study is estimated to be 66 months (5.5 years). The primary endpoint is efficacy as measured by failure-free survival (FFS) at 30 months. FFS will be reported separately for the two trial arms. For each treatment arm, a separate exact binomial hypothesis test will be performed using the null hypothesis 30-month FFS ≤ 60%. The significance level will be set to 10%, accounting for the phase 2 design with a limited sample size. Secondary endpoints comprise other efficacy endpoints such as overall survival (OS) and overall response rate (ORR) as well as safety endpoints such as the rate of adverse events. Notably, a geriatric assessment will be performed within the screening period. Quality of life during induction and maintenance therapy will be assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life core questionnaire (EORTC QLQ-C30) along with its module for high-grade non-Hodgkin lymphoma (EORTC QLQ-NHL-HG29). Importantly, the accompanying scientific program will evaluate genetic subclassification, minimal residual disease (MRD) based on next-generation sequencing (NGS), and immune-reconstitution.

The first patient was included in May 2023. As of July 18th, 34 German trial sites are activated and 32 patients were enrolled. The activation of Italian sites is planned for September 2024.