Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. A limited number of chemotherapy-free options exist for patients with treatment-naïve (TN) FL who are older or who have comorbidities. Single-agent rituximab is considered a treatment option for elderly or infirm patients. In a phase 2 study, frontline treatment with ibrutinib in combination with rituximab for 4 weekly doses without maintenance resulted in an ORR of 85% (CR, 35%) with a median follow-up of 22 months and an 18-month PFS rate of 87% (Fowler Blood 2016). The phase 2 study serves as the basis for the randomized, double-blind, placebo-controlled phase 3 PERSPECTIVE (PCYC-1141-CA) trial. PERSPECTIVE will be conducted in two parts and will uniquely test (1) whether frontline treatment with ibrutinib in combination with rituximab results in prolongation of PFS compared to rituximab alone, and (2) whether continuous versus finite treatment with ibrutinib affects PFS outcomes. Methods: In the ongoing PERSPECTIVE trial, approximately 440 patients with TN FL meeting at least one Groupe d'Etude des Lymphomes Folliculaires (GELF) criterion will be randomized if they also meet one of the following criteria: age ≥70 years or age 60 to 69 with one or more comorbidities (creatinine clearance 30-59 mL/min or ECOG performance status of 2). Patients will be randomized to receive either ibrutinib or oral placebo once daily. All patients will be given rituximab for 4 weekly doses followed by maintenance. After at least 2 years of treatment in Part 1, patients randomized to ibrutinib who still remain on ibrutinib will be re-randomized in Part 2 to continue ibrutinib or switch to placebo. Key exclusion criteria include any prior treatment for FL, evidence of CNS involvement, or transformation. Analyses will be conducted in two distinct parts, both with a primary endpoint of PFS. The study is open for enrollment with sites planned in the US, EU, and Asia Pacific. Clinical trial information: NCT02947347