PERSPECTIVE: A Randomized, Phase 3 Study of Ibrutinib-Rituximab Versus Placebo-Rituximab Combination Therapy for First-Line Treatment of Follicular Lymphoma

Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma originating from germinal-center B cells. There are very few chemotherapy-free treatment options available for previously untreated patients with FL, particularly those who are older or with comorbidities. Single-agent rituximab is used as a chemotherapy-free treatment option for the first-line treatment of elderly, frail patients or those with low tumor burden. Ibrutinib is a once-daily Bruton’s tyrosine kinase inhibitor approved in the United States (US) for the treatment of various B-cell malignancies. In a phase 2 trial, ibrutinib and rituximab combination therapy was evaluated for the treatment of FL in the first-line setting. Oral ibrutinib given once-daily until disease progression or unacceptable toxicity was administered in combination with once-weekly doses of intravenous rituximab for 4 weeks. At a median follow-up of 34 months, an objective response rate of 85% and a complete response rate of 40% were observed. The progression-free survival (PFS) rate was 67%, and the overall survival rate was 97% at 30 months [1]. Based on the clinical activity and durable responses observed in the phase 2 study, the phase 3 PERSPECTIVE study (PCYC-1141-CA, NCT02947347) was designed to further evaluate the efficacy and safety of ibrutinib and rituximab combination therapy for FL in the first-line setting. The two objectives of this study are: (1) to compare PFS outcomes with ibrutinib-rituximab combination therapy versus placebo-rituximab, and (2) to evaluate differences in PFS outcomes between continuous ibrutinib versus fixed-duration ibrutinib treatment.

Trial Design / Design and Methods: PERSPECTIVE is an ongoing, multicenter, randomized, double-blind, placebo-controlled phase 3 study with a planned enrollment of approximately 440 previously untreated patients with FL. Patients who meet at least one of the Groupe d'Etude des Lymphomes Folliculaires criteria [2] are being enrolled in the trial. Eligible patients are either ≥70 years or 60–69 years with one or more of the following comorbidities: creatinine clearance 30–59 mL/min or ECOG performance status of 2. Exclusion criteria include patients with a history of any prior treatment for FL or any evidence of central nervous system involvement or transformed lymphoma. In Part 1 of the study, eligible patients are randomized to two treatment arms. Patients in Arm A receive once-daily oral ibrutinib in combination with rituximab; patients in Arm B receive oral daily placebo in combination with rituximab. In both treatment arms, patients will receive rituximab as 4 weekly doses, which are followed by maintenance rituximab therapy. In Part 2 of the study, patients randomized to Arm A (ibrutinib-rituximab combination arm) who have continued ibrutinib treatment for at least 2 years will be re-randomized to continue receiving once-daily oral ibrutinib or switch to once-daily oral placebo. For both parts of the study, the primary endpoint is PFS.

Status: PERSPECTIVE is currently enrolling patients in multiple regions, including the US, Europe, and Asia Pacific. Funding: Pharmacyclics LLC, an AbbVie Company.

References

1. Fowler NH, Nastoupil L, De Vos S, et al: The combination of ibrutinib and rituximab demonstrates activity in first-line follicular lymphoma. Br J Haematol 189(4):650-60, 2020. 2. Solal-Céligny P, Lepage E, Brousse N, et al: Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. N Engl J Med 329(22):1608-14, 1993.