Avadomide (CC-122), a Novel Cereblon Modulating Agent, Plus Rituximab in Patients with Relapsed or Refractory Follicular Lymphoma

Introduction:The prognosis is poor for patients with follicular lymphoma (FL) who experience early relapse within 2 years of initial diagnosis and for those who are double refractory to both rituximab and chemotherapy (Casulo et al. J Clin Oncol 2015). Avadomide, a cereblon-modulating agent that promotes degradation of the hematopoietic transcription factors Aiolos and Ikaros, is being examined in this setting. Avadomide demonstrated promising clinical activity in combination with obinutuzumab or rituximab in relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and FL (Michot et al. Blood 2017; Ribrag et al. Blood 2017). Herein, we report FL subgroup analyses for the avadomide plus rituximab combination (Arm D) of the CC-122 DLBCL-001 study in both lenalidomide-naïve and treated patients. Methods: CC-122-DLBCL-001 (NCT02031419) is aphase Ib dose escalation/expansion study of avadomide, CC-223, and CC-292 given orally as doublets, and as triplets in combination with rituximab, as well as avadomide plus rituximab doublets, in patients with R/R DLBCL or FL after ≥1 prior line of therapy. In the dose expansion phase of the study, patients received avadomide once daily (QD) for 5 days/week (5/7 d), with a fixed dose of intravenous rituximab 375 mg/m2/cycle (28-day cycle). The study endpoints were safety, tolerability, pharmacokinetics, preliminary efficacy (overall response rate [ORR] and complete response [CR]), and blood pharmacodynamic markers of avadomide. Results: As of May 1, 2018, 37 patients with FL were enrolled in the Arm D expansion group, including 29 in cohort 1 (no prior lenalidomide) and 8 in cohort 2 (≥2 cycles of prior lenalidomide). Baseline patient characteristics were similar between the two cohorts. In the total FL population, the median age was 61 years (range, 41-81 years), 54% were male, and 46% had an Eastern Cooperative Oncology Group performance status of 1. The median number of prior systemic anticancer regimens was 3 (range, 1-8). At disease diagnosis, three patients (8%) had bulky disease (≥7 cm in single dimension) and 7 (19%) had high Follicular Lymphoma International Prognostic Index scores. Twenty-three patients (62%) were refractory to rituximab and 11 (30%) were double-refractory to rituximab and an alkylating agent. As of the data cutoff, 27 patients (71%) were ongoing and no evaluable patients had experienced a dose-limiting toxicity. The most common (≥10%) any-grade adverse events (AEs) were neutropenia (46%)