A Phase 1b/3 Randomized, Double-Blind, 3-Stage Study of Tazemetostat or Placebo Plus Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma

Background: Relapsed/refractory (R/R) follicular lymphoma (FL) remains a challenging disease necessitating novel treatment strategies. Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator that catalyzes the histone 3 lysine 27 trimethylation (H3K27m3) gene suppressive mark, which is essential for BCL6-driven germinal center formation. FL is generally dependent on EZH2 function, either in conjunction with other epigenetic modulators or when gain-of-function EZH2 mutations are present. Tazemetostat, a selective, oral EZH2 inhibitor, has demonstrated durable, single-agent antitumor activity in R/R FL patients with mutant (MT) or wild-type (WT) EZH2. This study (NCT04224493) will determine and assess the recommended phase 3 dose (RP3D), efficacy, and safety of rituximab, lenalidomide, and tazemetostat (R² + tazemetostat) vs rituximab, lenalidomide, and placebo (R²) in patients with R/R FL.

Study Design and Methods: This global multicenter study will enroll patients aged ≥18 years with histologically confirmed FL (grades 1–3A; WT or MT EZH2 status) treated previously with ≥1 line of chemotherapy, immunotherapy, or chemoimmunotherapy. All patients are required to provide written informed consent.

Stage 1 of the study (phase 1b) will evaluate safety and tolerability and establish the maximum tolerated dose and/or the RP3D of tazemetostat + R² in 3–18 patients with R/R FL. Using a standard 3+3 design, tazemetostat will be evaluated at 3 dose levels (400 mg, 600 mg, and 800 mg orally twice daily). The RP3D will be selected at the dose level with a dose-limiting toxicity rate <33%. Rituximab (375 mg/m²) will be administered intravenously on days 1, 8, 15, and 22 of cycle 1, then day 1 of cycles 2–5. Lenalidomide (20 mg) will be administered orally once daily on days 1–21 every 28 days (up to 12 cycles). Dose reductions/modifications are allowed per protocol.

In stage 2 (phase 3), approximately 500 patients will be randomly assigned (1:1) to receive tazemetostat (administered twice daily at the RP3D from stage 1) + R² (dosing as in stage 1) or placebo + R². Enrollment of patients with MT EZH2 status will be capped at 150–210 patients (up to 30%) to reflect real-world prevalence. Randomization will be stratified by EZH2 status (WT or MT), response to prior systemic therapy (sensitive or refractory), and number of prior treatment lines (1 or ≥2). Combination treatment will continue for up to 12 cycles or until relapse/intolerability. After 12 months of treatment, patients will receive up to 2 years of maintenance therapy with tazemetostat 800 mg twice daily or placebo. The primary endpoint is investigator-assessed progression-free survival (PFS) per the 2014 Lugano Classification. Secondary endpoints will include PFS by independent review committee, objective response rate (ORR), duration of response, duration of complete response, disease control rate, overall survival, quality of life, pharmacokinetics, and safety.

The study design includes two interim futility analyses; the first will be initiated when 100 patients are evaluable for ORR. The second interim futility analysis, based on PFS, is planned for 2.5 years after the first patient is enrolled. Sample size may be reestimated based on PFS to ensure early detection of clinical benefit and adequate powering. Both analyses will be carried out first on patients with EZH2 MT FL, followed by patients with EZH2 WT disease. An optional stage 3 for patients with EZH2 MT status only will be executed if efficacy in stage 2 fails for all patients but is sufficiently promising for patients with EZH2 MT status.