Safety and Efficacy of the New Drug LY4584180 in Patients with Previously Treated B-Cell Lymphoma (NOVA-BCL6-1)

B-cell non-Hodgkin lymphomas (B-NHL) are a group of malignant diseases of B lymphocytes, a subtype of white blood cells that are part of the immune system. There are various subtypes of B-NHL, including follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). There are also other, rarer forms. The clinical presentation of these diseases varies widely. Symptoms may sometimes be nonspecific, such as swollen lymph nodes, fever, increased night sweats, weight loss, or an increased susceptibility to infections. The standard treatment for NHL often involves a combination of chemotherapy and immunotherapy. Although patients often respond well to treatment, the disease may not respond to therapy (refractory) or may return after initial success (relapse). The drug LY4584180, which has not yet been approved, could represent a new treatment option in this context. It is a novel medication that specifically promotes the degradation of a molecule known as BCL6, which promotes the growth of B-cell lymphomas.

The goal of this Phase 1a/1b study is to investigate the efficacy, safety, and optimal dose of LY4584180 in humans for the first time (“first-in-human”). The study consists of two phases: In the Phase 1a dose-escalation phase, small groups of patients will receive progressively higher doses of LY4584180 as monotherapy to determine the maximum tolerated dose. This will be determined after 28 days. Phase 1b, known as the dose-expansion phase, is designed to further test the previously determined safe dose. For this purpose, the study drug will be administered either as monotherapy or in combination with the antibody rituximab. Rituximab is a well-established drug for the treatment of lymphomas. It is a CD20 antibody that binds to malignant B lymphocytes and triggers cell death. Assignment to the groups is not random (non-randomized) and is open-label, meaning that both patients and medical staff are aware of the treatment. LY4584180 is taken as a tablet, while rituximab is administered as an infusion through a venous line. Patients will be closely monitored to detect side effects early on. At the same time, researchers will examine how the body absorbs and metabolizes the drug (pharmacokinetics) and whether the tumor responds to treatment. Overall, the study will evaluate the treatment’s efficacy and side effects for up to 3 years.

Eligible participants include women and men aged 18 and older with B-cell lymphoma who have already received at least two prior treatments or for whom no further standard therapies are an option. Patients with additional involvement of the central nervous system, an infection with cytomegalovirus or HIV, hepatitis B or hepatitis C, or severe heart disease are not eligible to participate in the study.