New combination therapy using the already approved drug tazemetostat for follicular lymphoma with recurrent disease activity

Follicular lymphoma (FL) is a malignant disease of the lymphatic system and is classified as a type of non-Hodgkin lymphoma. It is characterized by the uncontrolled proliferation of B lymphocytes. Lymphocytes are a type of white blood cell that is part of the immune system. Symptoms of the disease may include fatigue, anemia, weight loss, fever, night sweats, and swollen lymph nodes. The causes of this disease are not fully understood, but genetic and immunological factors play a role.

FL with disease recurrence or uncontrollable (refractory) FL is often treated with a combination of immunotherapy and chemotherapy or other targeted therapies when symptoms are present and the patient’s general condition is good. The combination of rituximab and lenalidomide (R²) is an established treatment option. Rituximab is an antibody that targets a surface protein (CD20) on cancer cells. Lenalidomide is an immunomodulator with various effects on cancer cells and the body’s immune system. A drug that was relatively recently approved for this indication (in 2020 in the U.S., in 2022 in Europe) is tazemetostat. It inhibits the activity of a protein called EZH2, thereby preventing the proliferation of cancer cells. It has so far been approved as a monotherapy in certain situations for FL.

The goal of the SYMPHONY-1 study is to combine these three drugs. The study will therefore investigate the optimal dose, efficacy, and safety of the combination therapy of tazemetostat with lenalidomide and rituximab (Taz-R²) compared to treatment with a placebo (a drug without an active ingredient) and lenalidomide and rituximab (Placebo-R²). The SYMPHONY-1 study is therefore investigating whether adding tazemetostat to the standard R² treatment can improve treatment outcomes.

The study consists of several phases. In the first phase (Phase 1b, safety induction), the appropriate dosage of tazemetostat as well as the safety and tolerability of the Taz-R² combination were evaluated, and the recommended dose for the next phase was determined. This phase has already been completed. In the main phase (Phase 3), patients are randomly assigned to two groups. Group 1 receives the combination of tazemetostat, lenalidomide, and rituximab. Group 2 receives a placebo combined with lenalidomide and rituximab. This is a double-blind study, meaning that neither the medical staff nor the patients know which medication (tazemetostat or placebo) is being administered.

Treatment is administered over 12 cycles, each lasting 28 days. Tazemetostat (or placebo) is administered twice daily in tablet form. Lenalidomide is taken in tablet form on days 1 through 21 of each cycle, and rituximab is administered via a venous line (infusion) on days 1, 8, 15, and 22 of the first cycle, as well as on day 1 of cycles 2–5, via an intravenous line (infusion). After completing these 12 cycles, patients receive maintenance therapy: Group 1 receives tazemetostat daily, and Group 2 receives the placebo daily, for up to 2 years each. Follow-up as part of the study lasts for up to 72 months (6 years), during which the efficacy of the therapy and the occurrence of side effects from the various medications are evaluated. The key factor is whether or when the disease progresses again during treatment (progression-free survival).

Women and men aged 18 and older with FL are eligible to participate in this study. The FL must be either recurrent (relapsed) or refractory, and patients must have previously received at least one systemic therapy (e.g., immunochemotherapy).