Kurzfassung: 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%) and anemia (24%). Grade 3/4 AEs occurring in 〉 1 patient were neutropenia (32%); fatigue, dizziness, and anemia (8% each); febrile neutropenia and diarrhea (5% each). Six patients (16%) experienced serious AEs related to study drugs. One patient died during the study (sepsis considered possibly related to study treatment). Avadomide dose reduction occurred in 7 (19%) patients. Among all FL patients, the ORR was 65% with 8 patients (22%) achieving a CR. Response rates appeared to be independent of prior lenalidomide treatment, with an ORR of 62% (CR=14%) in cohort 1 and an ORR of 75% (CR=50%) in cohort 2. The median follow up for progression-free survival (PFS) was 6.3 months and 49% of patients had 〈 6 months of PFS follow up. In the total FL population, 6-month and 12-month PFS rates were 83 (95% CI, 64-93) and 66 (37-84), respectively. Conclusions: Avadomide combined with rituximab was well tolerated. AEs were generally consistent with the known safety profile of avadomide and toxicities associated with rituximab. Moreover, this combination showed promising efficacy in patients with R/R FL independent of prior treatment with lenalidomide. These findings support the role of avadomide plus an anti-CD20 antibody as a novel chemotherapy-free treatment for this difficult to treat patient population. Disclosures Nastoupil: TG Therappeutics: Research Funding; Karus: Research Funding; Novartis: Honoraria; Merck: Honoraria, Research Funding; Juno: Honoraria; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Research Funding; Spectrum: Honoraria; Genentech: Honoraria, Research Funding. Ribrag:Amgen: Research Funding; Roche: Honoraria, Other: travel; epizyme: Consultancy, Honoraria; MSD: Honoraria; Infinity: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel; Servier: Consultancy, Honoraria; pharmamar: Other: travel; Gilead: Consultancy, Honoraria; Incyte Corporation: Consultancy; argenX: Research Funding. Chavez:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Humanigen: Consultancy; Merck: Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Andorsky:AstraZeneca: Consultancy; Genentech: Consultancy; Celgene: Research Funding; CTI BioPharma: Consultancy, Research Funding. Corradini:Janssen: Honoraria, Other: Lecturer; Amgen: Honoraria, Other: Advisory Board & Lecturer; Gilead: Honoraria, Other: Advisory Board & Lecturer; Celgene: Honoraria, Other: Advisory Board & Lecturer; Roche: Honoraria, Other: Advisory Board & Lecturer; Takeda: Honoraria, Other: Advisory Board & Lecturer; Sanofi: Honoraria, Other: Advisory Board & Lecturer; Novartis: Honoraria, Other: Advisory Board & Lecturer; Abbvie: Honoraria, Other: Advisory Board & Lecturer; Sandoz: Other: Advisory Board. Flinn:ArQule: Research Funding; Agios: Research Funding; TG Therapeutics: Research Funding; Calithera: Research Funding; BeiGene: Research Funding; Verastem: Consultancy, Research Funding; Janssen: Research Funding; Curis: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Trillium: Research Funding; Forty Seven: Research Funding; Kite: Research Funding; Pfizer: Research Funding; Verastem: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Merck: Research Funding; Portola: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Constellation: Research Funding; Forma: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Infinity: Research Funding. Sangha:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; BI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Uttamsingh:Celgene Corporation: Employment, Equity Ownership. Hagner:Celgene Corporation: Employment, Equity Ownership. Gandhi:Celgene Corporation: Employment, Equity Ownership. Chen:Celgene Corporation: Employment, Equity Ownership. Hege:Mersana: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; SITC: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: multiple; Arcus Biosicences: Membership on an entity's Board of Directors or advisory committees. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Kuruvilla:Celgene: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Lundbeck: Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Merck: Consultancy, Honoraria; Amgen: Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; Leukemia and Lymphoma Society Canada: Research Funding.

Kurzfassung: There is a need for additional treatment options for patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC‐122), the selective, ATP‐competitive mammalian target of rapamycin kinase inhibitor CC‐223, and the potent, selective, covalent Bruton tyrosine kinase inhibitor CC‐292 in patients with relapsed/refractory (R/R) DLBCL. In the multicenter, phase Ib CC‐122‐DLBCL‐001 study (NCT02031419), the dose‐escalation portion explored combinations of CC‐122, CC‐223, and CC‐292 administered as doublets or triplets with rituximab in patients with chemorefractory DLBCL. Primary endpoints were safety, tolerability, and dose‐limiting toxicities; additional endpoints included pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy. As of December 1, 2017, 106 patients were enrolled across four cohorts. The median age was 65 years (range 24–84 years), and patients had a median of 3 (range 1–10) prior to regimens. A total of 101 patients (95.3%) discontinued, most commonly due to disease progression (49.1%). The most common any‐grade adverse events (AEs) across treatment arms were gastrointestinal and hematologic; the most common grade 3/4 AEs were hematologic. CC‐122 was well tolerated, with no unexpected safety concerns. Preliminary efficacy was observed in three of four treatment arms. CC‐122 plus rituximab was considered suitable for dose expansion, whereas CC‐223 and CC‐292 combinations were associated with enhanced toxicity and/or insufficient improvement in responses. CC‐122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi‐arm dose‐finding design.