A Study of Nemtabrutinib Plus Venetoclax vs. Venetoclax + Rituximab (VR) in Second-Line (2L) and Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) is a malignant disease of the hematopoietic system in which the bone marrow produces too many B lymphocytes and releases them into the blood. Lymphocytes are a subtype of white blood cells that are part of the body’s immune system. If the lymphocytes are instead found primarily in the lymph nodes and the spleen, the condition is referred to as small-cell lymphocytic lymphoma (SLL), which is grouped together with CLL under a single clinical entity. CLL/SLL is a type of non-Hodgkin lymphoma and typically progresses slowly. It occurs primarily in older adults, and while the causes of CLL are not yet fully understood, genetic factors play a role. Treatment is usually necessary when symptoms arise, such as rapid enlargement of the lymph nodes, fever, night sweats, or weight loss. The treatment depends on the severity of the symptoms and the patient’s overall physical condition. If patients are asymptomatic or very frail, no treatment is administered, and they are subsequently monitored regularly. If symptoms develop after the initial diagnosis, standard therapy depends on the results of a genetic analysis of the malignant cells for known characteristic mutations. Immunotherapy is usually initiated, for example, with an antibody such as rituximab or a Bruton’s tyrosine kinase inhibitor (BTK inhibitor) such as ibrutinib. In many cases, immunotherapy is combined with another active ingredient, such as venetoclax. If the disease progresses again (relapse) or is uncontrollable (refractory), immunotherapy is administered once more.

The goal of this Phase 3 study is to investigate the efficacy and safety of combination therapy with nemtabrutinib and venetoclax compared to combination therapy with venetoclax and rituximab in a larger number of patients. Nemtabrutinib is a new drug and belongs to the class of BTK inhibitors, which are designed to stop cancer cell growth by binding to the cancer cells. The drug has not yet been approved for the treatment of CLL/SLL. Venetoclax also inhibits the growth of cancer cells by binding to their surface protein Bcl-2. Venetoclax is already approved for the treatment of CLL. Both drugs are administered in tablet form.

The study is divided into two parts: Part 1 for dose confirmation and Part 2 for an expanded investigation of efficacy. In the first part, participants will be assigned to different dosages of nemtabrutinib and venetoclax to determine the safest and most effective dose. In the second part, participants will be randomly assigned to two groups. Group 1 will receive the combination of nemtabrutinib and venetoclax in 28-day cycles for up to 2 years. The medication is administered daily, although only nemtabrutinib is given during the first cycle. Group 2 will receive venetoclax and rituximab in 28-day cycles for up to 2 years. Venetoclax is administered daily, and rituximab is given as an infusion via a venous line during cycles 2–6 (on day 1 of each cycle). The study is open-label, meaning that both the medical staff and the patient know which medications are being administered. Treatments and follow-up examinations as part of the study will continue for up to 9 years, during which the effectiveness of the therapy and the occurrence of side effects from the various medications will be evaluated. A key factor is whether or when the disease progresses again during treatment.

Patients aged 18 and older with CLL or SLL are eligible to participate in this study. The disease must have been previously treated and must either have recurred or be uncontrollable (refractory) despite therapy.