Ongoing clinical efforts are focused on evaluating the efficacy and tolerability of targeted therapies in patients with follicular lymphoma (FL). Previous trials have separately demonstrated the safety and antitumor activity of the combination of rituximab with the immunomodulatory drug lenalidomide (R2) and the Bruton’s tyrosine kinase inhibitor ibrutinib in patients with relapsed/refractory FL.1,2 Based on these promising results, the Alliance for Clinical Trials in Oncology is currently evaluating the triplet combination of ibrutinib plus rituximab and lenalidomide in a phase 1 dose-escalation study as a frontline regimen for patients with FL, preliminary results of which were reported by Ujjani and colleagues at the ASH 2015 meeting.3
In this trial, a total of 22 patients were enrolled in 3 dose cohorts using the standard 3+3 dose-escalation design from a starting dose level DL0 (lenalidomide 15 mg; ibrutinib 420 mg; n = 3) to DL2 (lenalidomide 20 mg; ibrutinib 560 mg; n = 16); following determination of phase II dose, patients were enrolled into a 10-patient expansion cohort. Patients also received allopurinol 300 mg daily for tumor lysis syndrome prophylaxis. The median age of the total patient cohort was 53.5 years, and the majority had stage IV disease and an intermediate- or high-risk Follicular Lymphoma International Prognostic Index score. Lenalidomide 20 mg and ibrutinib 560 mg was determined to be the recommended phase 2 dose. In terms of safety, grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), and anemia (4.5%). Notably, rash (all grades) occurred in 82% of patients; 36% was of grade 3 severity and occurred at significantly higher rates than previously reported with R2 or Ibrutinib therapy. Grade 1/2 rash resolved spontaneously without dose modifications, while grade 3 rash was managed with supportive care. No protocol-defined dose-limiting toxicities (DLTs) were reported at any dose level; grade 3 rash that resolved to <grade 2 in 10 days with supportive care was not as defined as a DLT in this trial. Also, the potential role of concomitant allopurinol with incidence of rash was evaluated; however, no correlation could be ascertained. Other grade 3 nonhematologic adverse events (AEs) included atrial fibrillation/chest pain, diarrhea, febrile neutropenia, periorbital edema, arthralgia, and neoplasms. In the overall population, the triplet combination resulted in an overall response rate of 95%, including a complete response rate of 63%; the 12-month progression-free survival was 84%. Based on these results, the authors concluded that the triplet combination of lenalidomide/rituximab/ibrutinib showed similar antitumor activity as the R2 regimen in this setting; however, the incidence of rash was higher.
