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: Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator that is essential for BCL6-driven germinal center (GC) formation. Relapsed/refractory (R/R) follicular lymphoma (FL) is derived from GC B-cells and is generally dependent on EZH2 function. EZH2 mutations are observed in ∼20% of patients with FL; however, as FL is commonly reliant on other epigenetic modulator mutations, EZH2 is relevant in both mutant (MT) and wild-type (WT) EZH2 FL. Tazemetostat (TAZ), a selective, oral EZH2 inhibitor, has demonstrated durable single-agent antitumor activity in MT or WT EZH2 R/R FL. Aims: Study EZH-302 (NCT04224493) will determine the recommended phase 3 dose (RP3D) and assess efficacy and safety of rituximab, lenalidomide, and TAZ (R2+TAZ) versus rituximab, lenalidomide, and placebo (R2) in R/R FL. Methods: Patients aged ≥18 years with histologically confirmed FL (grades 1–3A; WT or MT EZH2 status) previously treated with ≥1 line of chemotherapy, immunotherapy, or chemoimmunotherapy will be enrolled. Phase 1b (safety run-in; stage 1) will evaluate safety and tolerability and establish the maximum tolerated and/or RP3D of TAZ+R2 in 3–18 patients. TAZ will be evaluated at 3 escalating dose levels (400 mg, 600 mg, and 800 mg orally twice daily) if no dose-limiting toxicities are observed. 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 for up to 12 cycles. Phase 3 (stage 2) will be a 1:1 randomized study of ∼500 patients receiving TAZ (twice daily at the RP3D)+R2 (dosed per stage 1) or placebo+R2. Enrollment with MT EZH2 status will be capped at 150–210 patients (≤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). Primary endpoint is investigator-assessed progression-free survival per 2014 Lugano Classification. An interim futility analysis will be initiated when 100 patients are evaluable for objective response rate.