Background: First-line treatment options for patients with MZL include single-agent immunotherapy, chemotherapy, or chemoimmunotherapy. While chemoimmunotherapy has a higher toxicity profile than immunotherapy alone, it may lead to longer progression-free survival (PFS). Rituximab, an anti-CD20 antibody, is FDA approved for the first-line treatment of follicular lymphoma but not specifically for advanced MZL. Ibrutinib is a Bruton’s tyrosine kinase inhibitor approved in the United States for patients with MZL who require systemic therapy and have received ≥1 prior anti-CD20-based therapy. The combination of ibrutinib and rituximab has proven effective and is well tolerated in other B-cell lymphomas; it may serve as an effective chemotherapy-free option for the treatment of previously untreated MZL. Methods: NCT04212013 is a multicenter, double-blind, placebo-controlled, randomized, phase 3 study designed to compare the efficacy of ibrutinib + rituximab vs placebo + rituximab in patients with previously untreated MZL. Adults (≥18 y) with histologically documented MZL (splenic, nodal, and extranodal subtypes), no prior systemic treatment for MZL (prior splenectomy or other local surgical or radiation treatment allowed), measurable disease on CT scan, documented evidence of need for treatment, and Eastern Cooperative Oncology Group performance status ≤2 are eligible. Patients will be randomly assigned 1:1 to receive ibrutinib 560 mg once daily or placebo; all patients will also receive rituximab 375 mg/m² on days 1, 8, 15, and 22 of cycle 1. Subcutaneous dosing after dose 1 is allowed. Treatment with ibrutinib or placebo will continue for 30 mo or until disease progression, unacceptable toxicity, patient or investigator decision to withdraw, noncompliance, death, or study termination. Clinical assessments will occur every 4 weeks until week 13, at week 25, and then every 6 mo thereafter. Imaging assessments will be conducted at week 13, at week 25, and then every 6 mo thereafter. Response will be investigator assessed per the revised International Working Group for Non-Hodgkin Lymphoma (RECIL) criteria. At month 30, patients who have a complete response (CR) will discontinue treatment; patients who have a partial response (PR) or stable disease may continue treatment at investigator discretion. Safety will be assessed throughout the study and for 30 days after the last dose of study treatment. The primary endpoint is CR rate at month 30. Secondary endpoints include overall response rate (CR + PR), duration of response, PFS, overall survival, and safety. Enrollment has started and will continue until approximately 138 patients are enrolled. Clinical trial information: NCT04212013