Abstract: Background: CC-122, a pleiotropic pathway modifier, modulates the cullin 4 ring E3 ligase complex, which results in recruitment and degradation of Aiolos and Ikaros. This substrate degradation results in cell autonomous anti-lymphoma and immunomodulatory effects on T- and NK-cell function (Gandhi, ASH 2012). The anti-CD20 monoclonal antibody, obinutuzumab, improves direct cell killing and antibody-dependent cell-mediated cytotoxicity (ADCC) activity compared to rituximab (Mössner, 2010; Niederfellner, 2011). The combination of obinutuzumab with CC-122 revealed synergistic effects in follicular lymphoma (FL) and additive effects in diffuse large B-cell lymphoma (DLBCL) in in vivo models when compared to either as single agents (Hsiling Chiu, ASH 2015). CC-122 monotherapy has shown encouraging activity against DLBCL and FL in a Phase I clinical trial (Rasco, ASH 2013). Obinutuzumab has demonstrated efficacy in patients with relapsed/refractory indolent non-Hodgkin lymphoma (iNHL) (Salles, 2013) and DLBCL (Morschhauser, 2013) and has been approved by the FDA and the European Medicinal Agency for patients with previously treated FL. The current study was designed to evaluate the safety and efficacy of escalating doses of CC-122 in combination with obinutuzumab in patients with relapsed/refractory DLBCL and iNHL (NCT02417285). Methods: Subjects with relapsed/refractory DLBCL and iNHL (FL and marginal zone lymphoma [MZL]) were enrolled in this phase 1b study of CC-122 given orally on 5 out of 7 days per week (5/7 days) for 28 day cycles. Subjects were enrolled in cohorts of escalating dose levels of CC-122 (1.0 mg [n=4] , 2.0 mg [n = 4], 3.0 mg [n = 7] , 4.0 mg [n = 6]), with a fixed dose of obinutuzumab. Obinutuzumab is administered as an intravenous (IV) infusion at a dose of 1000 mg on Days 2, 8, and 15 of Cycle 1 and on Day 1 of Cycles 2 through 8. The initial 4 dose levels evaluated active ingredient in capsule (AIC) CC-122 formulation. In Cohort 5 (3.0 mg, [n = 5] ), subjects received CC-122 formulated capsules. Prophylaxis with granulocyte-colony stimulating factor (G-CSF) was not allowed during Cycle 1. As the study is ongoing, the CC-122 dose will be escalated until the maximum tolerated dose (MTD) is established on the CC-122 formulated capsule, using a modified 3+3 design. Subjects are evaluated for efficacy every 2 cycles(c) through c6 then every 3 cycles through c12, then every 6 cycles. Results: As of 1 June 2016, 26 subjects with relapsed/refractory DLBCL or iNHL were enrolled; all were evaluable for safety. The median age was 60 years and 84.6% were male. Thirteen subjects had DLBCL (50%), 13 (50%) had iNHL (12 FL [46.2%], 1 had MZL [3.8%] ). All subjects were ECOG 0-1. One subject experienced a dose-limiting toxicity (DLT) of Grade 4 neutropenia (Cohort 3) and no dose was considered a non-tolerated dose (NTD). The most common (≥ 10%) study drug-related treatment emergent adverse events (TEAEs) were neutropenia (50%), thrombocytopenia (30.8%), diarrhea, chills, and increased ALT (11.5% each). Seventeen subjects (65.4%) experienced at least one NCI CTCAE grade 3-4 TEAE related to study treatment (most common [≥ 10%] were neutropenia [42.3%] , thrombocytopenia [15.4%], and increased ALT [11.5%] ). Seven subjects experienced at least one serious AE suspected to be related to study treatment by the investigator (infusion related reaction [3 subjects], febrile neutropenia, neutropenia, thrombocytopenia, and pneumonia, [1 subject each] ). The overall response rate (ORR) for the 26 subjects enrolled, as of the efficacy cut off of 7 July 2016, was 53.8% (14/26); 8 of 12 (66.7%) FL, 5/13 (38.5%) DLBCL, and 1/1 MZL. Responses are ongoing in 12 of 14 of these subjects. ORR in the pooled higher dose cohorts of CC-122 (eg, a dose of 3 mg or higher, cohorts 3, 4, and 5) was 66.7% (12 of 18 subjects). Conclusion: The combination of CC-122 and obinutuzumab was well-tolerated in subjects with relapsed-refractory DLBCL and iNHL. AEs observed were consistent with the toxicity profile of CC-122 or obinutuzumab. Response rates observed were promising in this heavily pretreated population. Response rate appears higher in patients with FL however this warrants further investigation in a larger population. An NTD has not been reached and the MTD has not yet been established. Disclosures Michot: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Vitolo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria; Gilead: Honoraria; Takeda: Honoraria. Zinzani:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kersten:Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Chiappella:Teva: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Speakers Bureau; Roche: Speakers Bureau; Celgene: Speakers Bureau. Sarmiento:Celgene CITRE: Employment, Equity Ownership. Zuraek:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership. Nikolova:Celgene International: Employment, Equity Ownership. Ribrag:BMS: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; NanoString: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

Abstract: Background: CC-90009 is a cereblon (CRBN) E3 ligase modulator (CELMoD) and a first-in-class small molecule that drives the binding of a novel target protein, G1 to S phase transition 1 (GSPT1), to CRBN, resulting in the proteasome-dependent degradation of GSPT1. GSPT1 plays a central role in mRNA translation, and loss of GSPT1 activates an integrated stress response that leads to AML cell death (Matyskiela ME, et al. Nature. 2016;535:252-7; Zhouravleva G, et al. EBMO J. 1995;14:4065-72). In preclinical testing, CC-90009 is active across a range of AML cell lines and primary AML patient (pt) samples in vitro and in vivo and exerts its GSPT1- and CRBN-dependent effects through rapid induction of apoptosis. Here we share the first clinical results in pts with R/R AML. Methods: Adult pts with R/R AML enrolled in the dose-finding phase of this first-in-human, multicenter, open-label phase 1 study to evaluate tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of CC-90009; and to establish the recommended phase 2 dose and schedule (RP2D) (CC-90009-AML-001; NCT02848001). Dose escalation proceeded via a modified 3 + 3 design. Treatment was by daily intravenous administration on either Days 1-5 (D1-5) or Days 1-3 and 8-10 (D1-3/8-10) of a 28-day cycle. Treatment response was assessed after Cycles 1, 2, and 4 by modified International Working Group 2003 criteria. Safety and preliminary response data are presented for all treated pts. PK and PD were analyzed for evaluable pts. Results: As of May 15, 2019, 45 pts with R/R AML had been treated, including 35 pts on the D1-5 and 10 pts on the D1-3/D8-10 schedule. Median age was 66 years (range 27-81); 73% were male. Most pts (n = 36; 80%) were refractory to their last therapy and 17 pts (38%) were refractory to all prior therapy; 14 pts (31%) had secondary AML. Pts were treated at dose levels from 0.3 to 3.6 mg. Dose-limiting toxicities (DLTs) reported (only in dose levels from 2.4 to 3.6 mg) included hypotension, systemic inflammatory response syndrome (SIRS), hyperbilirubinemia, pneumonitis, and pericarditis with tamponade. Exploration of the 3.6 mg dose level is ongoing; the RP2D has not yet been determined. CC-90009-related grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 23 pts (51%); those occurring in & gt;1 pt were hypocalcemia (22%); hypotension (13%); and hyperbilirubinemia, hyperglycemia, hypophosphatemia, pneumonitis, sepsis, thrombocytopenia, and tumor lysis syndrome (4%). Preclinically identified hypocalcemia was confirmed as a CC-90009 on-target toxicity in the clinic; it was reversible, manageable and did not lead to any treatment discontinuations. The majority of treated pts experienced ≥1 serious TEAE (80%); most were infections (47%). Two (4%) pts experienced TEAEs leading to permanent discontinuation of the study drug. Dose interruptions due to TEAEs occurred in 12 pts (27%) and dose reductions in 2 pts (4%). Of 40 pts who discontinued treatment, 24 (60%) discontinued due to progressive disease or lack of efficacy. Seven pts discontinued treatment due to death; 4 deaths were secondary to progression from AML, 2 due to sepsis and 1 due to hyperglycemic hyperosmolar nonketotic syndrome. Responses to single-agent treatment were observed in pts treated at 3.0 or 3.6 mg on the D1-5 schedule, with a best response of complete remission (CR; n = 1), morphologic CR with incomplete blood count recovery (CRi; n = 1) and morphologic leukemia-free state (MLFS; n = 1). A dose-dependent decrease in GSPT1 levels in peripheral blood blasts and T cells was observed, with a & gt;90% decrease observed for higher dose levels. Evidence of antileukemic activity (decreases in bone marrow and/or peripheral blasts) was seen in pts treated with CC-90009 at 1.2 mg and above with a trend to more sustained reductions at the highest dose levels. Plasma PK analysis demonstrated dose-dependent exposure. Conclusions: In this phase 1 study of CC-90009, a first-in-class agent, evidence of deep GSPT1 degradation, on-target activity and promising antileukemic activity was observed. The observed TEAEs, in addition to those expected in this heavily pretreated R/R AML pt population, were generally well manageable. The study is ongoing with further optimization of dose, schedule and toxicity mitigation. Expansion cohorts in R/R AML and higher-risk myelodysplastic syndromes are planned. Disclosures Uy: GlycoMimetics: Consultancy; Curis: Consultancy; Astellas: Consultancy; Pfizer: Consultancy. Montesinos:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. DeAngelo:Blue print Medicines: Consultancy, Research Funding; Celgene Corporation: Consultancy; Shire: Consultancy; Pfizer, Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Incyte Corporation: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; GlycoMimetics: Research Funding; AbbVie, Inc.: Research Funding; Takeda Pharmaceuticals: Consultancy; Amgen: Consultancy. Altman:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead; France Foundation: Speakers Bureau; PeerView: Speakers Bureau; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Cancer Expert Now: Consultancy; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; prIME Oncology: Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Koprivnikar:Amgen: Speakers Bureau; Pfizer: Honoraria; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. Vyas:Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding; Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Fløisand:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Novartis: Honoraria. Gjertsen:BerGenBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; EU Horizon 2020: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; The Norwegian Cancer Society: Research Funding; KinN Therapeutics AS: Equity Ownership; ACTII AS: Equity Ownership; ERA PerMed: Research Funding; Helse Vest Health Trust: Research Funding; Research Council of Norway: Research Funding. Esteve:Astellas: Consultancy, Speakers Bureau; Amgen: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Buchholz:Celgene Corporation: Employment, Equity Ownership. Couto:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Fan:Celgene Corporation: Employment, Equity Ownership. Hanna:Celgene Corporation: Employment, Equity Ownership. Li:Celgene Corporation: Employment, Equity Ownership. Pierce:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Zeidan:Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Cardinal Health: Honoraria; Daiichi Sankyo: Honoraria; Novartis: Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Astellas: Honoraria.

Abstract: Background: Relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL), remains a clinical challenge with limited second- and third-line treatment options. Patients (pts) with follicular lymphoma (FL) experiencing early relapse (ER) within 2 years of initial diagnosis and those double refractory (DR) to both rituximab and chemotherapy have particularly poor outcomes (Casulo et al. J Clin Oncol 2015; Gopal et al. N Engl J Med 2014).Avadomide (CC-122) is a cereblon modulating agent that promotes degradation of transcription factors Aiolos and Ikaros, resulting in potent antilymphoma and immunomodulatory effects on T- and NK-cell function. Phase I clinical data from the CC-122-NHL-001 study (NCT02417285) revealed promising activity with avadomide plus obinutuzumab in pts with R/R B-cell NHL (Michot et al. Blood 2017). Herein, we report results from CC-122-NHL-001 in pts with R/R FL. Methods: CC-122-NHL-001 is a phase Ib, open-label, dose escalation/expansion study of avadomide in combination with obinutuzumab. Eligible pts were aged ≥18 y with histologically or cytologically confirmed CD20+ B-cell NHL after ≥1 prior regimen for FL/marginal zone lymphoma (MZL). Upon informed consent, pts received escalating doses of avadomide for 5 out of 7 d/wk in 28-d cycles plus a fixed dose of intravenous obinutuzumab 1000 mg on d 2, 8, and 15 of cycle 1 (C1), and d 1 of C2-8. Avadomide active ingredient in capsule (AIC) formulation at doses of 1, 2, 3, and 4 mg and avadomide formulated capsules (F6) of 3 and 4 mg were evaluated in separate cohorts. Primary endpoints included safety and tolerability, non-tolerated dose, and maximum-tolerated dose. Response was assessed using the Cheson 2007 criteria every 2 cycles to C6, every 3 cycles to C12, and every 6 cycles thereafter. Results: As of May 1, 2018, 58 pts with R/R B-cell NHL were treated in the study, including 19 with R/R DLBCL,38 with R/R FL, and 1 with R/R MZL. Among the 38 pts with R/R FL, 18 were treated in the dose escalation phase (median of 16.5 cycles; 78% initiated ≥6 cycles) and 20 were treated in the expansion phase (median of 4 cycles; 40% initiated ≥6 cycles). Of the 38 pts, 36 pts received 3 mg of 4 mg of avadomide (F6 or AIC); 2 pts received 2 mg of avadomide (AIC). The median age among R/R FL pts was 60 y (range, 41-83), 22 pts (58%) were male, and 32 (84%) had stage III/IV disease. The median number of prior antilymphoma therapies was 3 (range, 1-8), and 12 (32%) pts had 1 prior autologous stem cell transplant. As of data cutoff, 19 pts (50%) were ongoing treatment. One pt experienced a dose-limiting toxicity, consisting of grade 4 neutropenia (avadomide 3 mg AIC). Among the 38 pts in the dose escalation/dose expansion phases, the most common (≥25%) any-grade treatment-emergent adverse events (TEAEs) were neutropenia (66%), thrombocytopenia (29%), and pyrexia (29%). The most common (≥10%) grade 3/4 TEAEs were neutropenia (58%) and thrombocytopenia (11%). Nine pts (24%) had ≥1 serious TEAE related to avadomide; only cytokine release syndrome (11%) and infusion related reactions (8%) occurred in 〉 1 pt. Avadomide dose reduction and temporary interruption occurred in 10 pts (26%; all due to AEs), and 27 pts (71%; 25 pts due to AEs), respectively. Median duration of interruption due to AEs was 15 d (range, 2-48). The overall response rate (ORR) among all R/R FL pts (n=38) was 68%, with 16 pts (42%) achieving complete response (CR). Median duration of response was 19.4 mo (95% CI, 8.4-not reached). Median progression-free survival (mPFS) was 16.6 mo (95% CI, 11.4-24.9) with a median follow up time for PFS of 5.4 mo. Subgroup analysis examined activity of the combination in standard-risk and high-risk (ER and/or DR) FL pts (Table). Both response rates and mPFS were similar in standard-risk and high-risk FL pts (ORR: 70% vs 67%, P=0.83; CR: 40% vs 44%, P=0.78; mPFS: 16.6 mo [95% CI, 5.4-not reached] vs 21.2 mo [3.7-24.9] , P=0.60). The median duration of PFS follow up in the expansion phase (n=20/38) is 3.5 mo. Updated data will be presented at ASH. Conclusions: Avadomide given in combination with obinutuzumab was well-tolerated and demonstrated promising clinical activity, with encouraging response rates and mPFS observed in pts with R/R FL, irrespective of their disease risk status. Avadomide plus obinutuzumab may provide a new chemotherapy-free treatment option for pts with R/R FL failing standard therapies. Disclosures Vitolo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Gilead: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kersten:Millennium/Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Kite/Gilead: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria. Chiappella:Roche: Other: lecture fees; Amgen: Other: lecture fees; Nanostring: Other: lecture fees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Teva: Other: lecture fees. Zinzani:Astra Zeneca: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees. Salles:ACERTA: Honoraria; SERVIER: Honoraria; TAKEDA: Honoraria; GILEAD: Honoraria; CELGENE: Honoraria, Research Funding; AMGEN: Honoraria; JANSSEN: Honoraria; MERCK: Honoraria; MORPHOSYS: Honoraria; PFIZER: Honoraria; ABBVIE: Honoraria; EPIZYME: Honoraria; NOVARTIS: Consultancy, Honoraria; ROCHE: Honoraria, Research Funding. Sarmiento:Celgene Institute for Translational Research Europe: Employment, Equity Ownership. Mosulen:Celgene Institute for Translational Research Europe: Employment, Equity Ownership. Mendez:Celgene Institute for Translational Research Europe: Employment, Equity Ownership. Uttamsingh:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Hege:Arcus Biosicences: Membership on an entity's Board of Directors or advisory committees; SITC: Membership on an entity's Board of Directors or advisory committees; Mersana: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: multiple. Li:Celgene Corporation: Employment. Nikolova:Celgene International Sarl: Employment, Equity Ownership. Ribrag:argenX: Research Funding; Infinity: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel; epizyme: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; pharmamar: Other: travel; MSD: Honoraria; Gilead: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Roche: Honoraria, Other: travel; Amgen: Research Funding; Incyte Corporation: Consultancy.

Abstract: 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.

Abstract: Background: CC-122 is a first in class PPMTM pleiotropic pathway modifier compound with multiple biological activities including potent anti-proliferative activity against B lineage cells, anti-angiogenic activity and immunomodulatory effects. CC-122 binds cereblon, and promotes ubiquitination of lymphoid transcription factors Ikaros and Aiolos, leading to their subsequent degradation resulting in activation of T cells. The immunological properties of CC-122 including effects on T cell subset number in vivo and T cell cytokine production ex vivo was explored in subjects with advanced aggressive non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM) enrolled in a Phase 1b trial (NCT01421524) at 3 mg QD and 4 and 5 mg 5/7 days dosed in 28 day cycles until disease progression. Methods: As of June 25, 2015, 76 total DLBCL and MM subjects were enrolled in the expansion phase of the study. Assessments for T cell subset numbers were performed at screening (baseline), cycle 1 day 15 (C1D15), cycle 1 day 22, cycle 2 day 15 and cycle 2 day 22 by flow cytometric immunophenotyping of fresh whole blood. Ex vivo whole blood T cell activation as measured by IL-2, IL-6, IFNg and GM-CSF cytokine production was performed using the anti-CD3 TruCulture Assay. Changes from baseline were evaluated using the t test with p 〈 0.05 considered significant. Results: T cell subsets which were significantly changed are shown in italics in Table 1. In MM subjects (n=19-21) and DLBCL subjects (n=30-31), CC-122 treatment significantly expanded several T cell activator and memory T cell subsets while decreasing naïve T cells. A single dose of CC-122 on C1D1 activated T cells as measured in an ex vivo T cell activation assay in MM subjects (n=6-13) and DLBCL subjects (n=5-12) (Table 2). In addition, we evaluated potential correlations of clinical outcome with baseline biomarker and biomarker changes upon CC-122 treatment. Table 1. MM n=19-21 NHL n=30-31 T cell Parameter Phenotype Baseline cells/mm3 Median % Change at C1D15 from Baseline P Baseline cells/mm3 Median % Change at C1D15 from Baseline P Total T cells ABS CD3+ 636.9 17.733 0.24747 522.94 43.83 0.03638 Total T helper ABS CD3+/CD4+/CD8- 275.38 18.333 0.07812 238.96 13.428 0.09893 T helper Activated ABS CD3+/CD4+/CD8-/HLA-DR+ 62.34 105.769 0.00238 57.11 78.571 0.01567 T helper Total Naïve ABS CD3+/CD4+/CD8-/45RA+/45RO- 69.07 -54.545 0.0038 47.94 -47.841 0.03159 T helper Effector CD62L+ ABS CD3+/CD4+/CD8-/45RA+/62L+ 117.62 0 0.16621 93.74 -6 0.14611 T helper Effector CD62L- ABS CD3+/CD4+/CD8-/45RA+/62L- 21.38 -25.862 0.15196 28.44 -20.161 0.08548 T helper Total Memory ABS CD3+/CD4+/CD8-/45RA-/45RO+ 137.93 41.176 0.05373 119.15 36 0.01915 T helper Central Memory ABS CD3+/CD4+/CD8-/45RA-/62L+ 91.9 47.451 0.01953 75.74 37.143 0.01275 T helper Effector Memory ABS CD3+/CD4+/CD8-/45RA-/62L- 44.17 18.147 0.17768 41.07 19.375 0.04749 Total T cytotoxic ABS CD3+/CD4-/CD8+ 334.07 18.044 0.27499 265.7 43.823 0.0127 T cytotoxic Activated ABS CD3+/CD4-/CD8+ /HLA-DR+ 176.76 100 0.20781 121.3 96.454 0.00686 T cytotoxic Total Naïve ABS CD3+/CD4-/CD8+ /45RA+/45RO- 173.69 -35.714 0.15126 116.04 -32.667 0.89774 T cytotoxic Effector CD62L+ ABS CD3+/CD4-/CD8+ /45RA+/62L+ 127.28 20.727 0.24151 93.43 17.419 0.09599 T cytotoxic Effector CD62L- ABS CD3+/CD4-/CD8+ /45RA+/62L- 151.72 -14.286 0.28394 120.98 -18.301 0.18068 T cytotoxic Total Memory ABS CD3+/CD4-/CD8+ /45RA-/45RO+ 55.03 167.402 0.26292 54.13 184.615 0.01034 T cytotoxic Central Memory ABS CD3+/CD4-/CD8+ /45RA-/62L+ 26.83 160.417 0.00013 18.78 264.087 0.00169 T cytotoxic Effector Memory ABS CD3+/CD4-/CD8+ /45RA-/62L- 28.14 133.333 0.00107 32.59 100 0.01939 Table 2. MM n=6-13 NHL n=5-12 Cytokine Baseline cells/mm3 Median % Change from Baseline P Baseline cells/mm3 Median % Change from Baseline P IL-2 98.71 603.509 0.01329 104.5 437.194 0.01761 IL-6 131.84 124.108 0.03426 99.64 21.68 0.2692 GM-CSF 90.24 636.207 0.06608 212.96 144.601 0.16744 IFNg 271.85 404.98 0.0056 554.64 162.451 0.03024 Conclusions: CC-122 significantly increases the proportion of several cytotoxic and helper T cells subsets while decreasing naïve T cells in both DLBCL and MM subjects. CC-122 also significantly activates T cells ex vivo as measured by cytokine production. These results indicate that CC-122 is a potent modulator of T cell numbers and activation and this may serve as rationale for combinations with other immunotherapies. Disclosures Gandhi: Celgene: Employment, Equity Ownership. Off Label Use: CC-122 is a first in class PPM(TM) pleiotropic pathway modifier with multiple biological activities against B lineage cells. Vincent:Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Carpio:Celgene: Research Funding. Stoppa:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gharibo:Celgene: Research Funding. Damian:Celgene: Research Funding. Rasco:Celgene: Research Funding; Asana BioSciences, LLC: Research Funding. Ysebaert:Celgene: Research Funding. Cordoba:Celgene: Research Funding. Edenfield:Celgene: Research Funding. Pinto:Celgene Corporation: Honoraria; Takeda: Honoraria, Research Funding; Spectrum: Honoraria. López-Martín:Celgene: Research Funding. Sancho:Celgene: Research Funding. Panizo:Janssen: Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau; Celgene: Research Funding. Wei:Celgene: Employment, Equity Ownership. Hagner:Celgene: Employment, Equity Ownership. Waldman:Celgene: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership. Chopra:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene: Employment.

Abstract: Treatment options for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are limited, with no standard of care; prognosis is poor, with 4- to 6-month median survival. Avadomide (CC-122) is a cereblon-modulating agent with immunomodulatory and direct antitumor activities. This phase 1 dose-expansion study assessed safety and clinical activity of avadomide monotherapy in patients with de novo R/R DLBCL and transformed lymphoma. Additionally, a novel gene expression classifier, which identifies tumors with a high immune cell infiltration, was shown to enrich for response to avadomide in R/R DLBCL. Ninety-seven patients with R/R DLBCL, including 12 patients with transformed lymphoma, received 3 to 5 mg avadomide administered on continuous or intermittent schedules until unacceptable toxicity, disease progression, or withdrawal. Eighty-two patients (85%) experienced ≥1 grade 3/4 treatment-emergent adverse events (AEs), most commonly neutropenia (51%), infections (24%), anemia (12%), and febrile neutropenia (10%). Discontinuations because of AEs occurred in 10% of patients. Introduction of an intermittent 5/7-day schedule improved tolerability and reduced frequency and severity of neutropenia, febrile neutropenia, and infections. Among 84 patients with de novo R/R DLBCL, overall response rate (ORR) was 29%, including 11% complete response (CR). Responses were cell-of-origin independent. Classifier-positive DLBCL patients (de novo) had an ORR of 44%, median progression-free survival (mPFS) of 6 months, and 16% CR vs an ORR of 19%, mPFS of 1.5 months, and 5% CR in classifier-negative patients (P = .0096). Avadomide is being evaluated in combination with other antilymphoma agents. This trial was registered at www.clinicaltrials.gov as #NCT01421524.

Abstract: Background: Approximately 40% of patients (pts) with non-Hodgkin lymphoma (NHL) have disease that will relapse or is refractory to chemotherapy and/or immunotherapies; management of these pts remains a challenge. Although follicular lymphoma (FL) generally responds well to first-line treatment (tx), this disease is characterized by frequent relapses with shorter intervals between tx lines. Pts with early relapse (ER) (progressive disease & lt;2 y after initial diagnosis) and those who are double-refractory (DR) to both rituximab and chemotherapy, have particularly poor outcomes. Avadomide (CC-122) is a small molecule oral agent that induces cereblon-mediated degradation of the transcription factors Ikaros and Aiolos and promotes antilymphoma activity. Results from the dose-escalation part of the CC-122-NHL-001 study demonstrated preliminary antitumor activity of avadomide in combination with obinutuzumab in pts with relapsed and/or refractory (R/R) FL. Here, we report long-term safety and efficacy results from the dose-escalation and dose-expansion parts of the CC-122-NHL-001 study in pts with R/R FL. Methods: CC-122-NHL-001 (NCT02417285) is an ongoing, open-label, phase 1b study of avadomide in combination with obinutuzumab conducted at 8 sites in 3 European countries with dose-escalation and dose-expansion parts in R/R FL. Eligible pts (age ≥18 y) had histologically confirmed, CD20-positive R/R NHL. Pts with FL (grade 1, 2, or 3a) had ≥1 prior standard regimen. Avadomide active ingredient in capsule (1.0-4.0 mg) or formulated capsules (3.0 or 4.0 mg) was administered orally once daily on days 1-5 followed by 2 days off (5/7-day schedule) every week of each 28-day cycle. Obinutuzumab 1000 mg was given intravenously on days 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-8. Primary objectives were to determine the safety and tolerability of the combination, including the non-tolerated dose, maximum tolerated dose, and recommended phase 2 dose (RP2D). Response was assessed using Cheson 2007 criteria every 2 cycles to cycle 6, then every 3 cycles to cycle 12, and every 6 cycles thereafter. Median duration of response (mDOR) and median progression-free survival (mPFS) were assessed by Kaplan-Meier estimates. Results: As of January 10, 2020, 73 pts with R/R NHL were enrolled and treated, including 19 with R/R diffuse large B-cell lymphoma, 1 with marginal zone lymphoma, and 53 with R/R FL; all 35 pts in the dose-expansion part of the study had R/R FL. The median age among treated pts was 61 y (range, 26-83), the median number of prior antilymphoma therapies was 3 (range 1-11), and 26 pts (36%) had prior autologous stem cell transplantation. As of July 14, 2020, tx was ongoing in 3/38 pts (8%) in dose-escalation (all ongoing in cycle & gt;24, 1 pt ongoing in cycle & gt;40). In the dose-expansion, tx was ongoing in 15/35 pts (43%); of these pts, all were ongoing in cycle & gt;21 and 1 was ongoing in cycle 30. The RP2D of avadomide was established as 3.0 mg formulated capsule. In the expansion part of the study, pts received a median of 15 tx cycles (range, 1-33), and median tx duration was 60 wk (range, 1-132). The most common (≥10%) grade 3/4 TEAEs were neutropenia, reported in 19 pts (54%) and thrombocytopenia, reported in 7 pts (20%). Sixteen pts (46%) had a serious TEAE; only pyrexia (11%) and sepsis (9%) occurred in & gt;2 pts. The objective response rate (ORR) among the 35 pts with R/R FL in the dose-expansion part of the study was 71%, including 40% with a complete response (CR). The mDOR was 14.6 mo (95% CI, 14.6-not estimable [NE]), and mPFS was 16.4 mo (95% CI, 8.3-NE). The median duration of PFS follow-up in dose-expansion was 14.4 mo (range, 0.8-30.3). Two pts had CRs lasting 13.7 mo and 15.3 mo before discontinuation owing to receiving allogeneic stem cell transplantation. Response rates were similar among all 53 R/R FL pts in both parts of the study (dose escalation and dose expansion) and in high-risk (ER and/or DR) FL pts (Table). Conclusions: Long-term follow-up results demonstrate that avadomide plus obinutuzumab has a manageable safety profile and durable responses in patients with R/R FL. The antitumor activity of cereblon modulators plus next-generation anti-CD20 antibodies in heavily pretreated R/R NHL warrants further investigation as a novel chemotherapy-free option. Disclosures Michot: Genentech: Research Funding; Abbvie: Research Funding; Forma: Research Funding; Eisai: Research Funding; Debiopharm: Research Funding; Daiichi Sankyo: Research Funding; Kyowa: Research Funding; AstraZeneca: Other, Research Funding; Gustave Roussy: Honoraria, Other: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 bio, Research Funding; Janssen: Other, Research Funding; Celgene: Other; Mundi Pharma: Other; Eos: Research Funding; AZD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Medimmune: Research Funding; Lytix Biopharma: Research Funding; Lysarc: Research Funding; Lilly: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Argen-x: Research Funding; Amgen: Research Funding; Agios: Research Funding; Xencor: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other; Exelixis: Research Funding. Doorduijn:Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Boccomini:SC Ematologia, ASOU Città della Salute e della Scienza di Torino, Turin, Italy: Current Employment. Kersten:Takeda: Research Funding; Miltenyi Biotech: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen/Cilag: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); MSD: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Chiappella:Servier: Honoraria; Takeda: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead-Kite: Honoraria; Celgene: Honoraria; Iqone: Honoraria. Zinzani:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salles:Abbvie, Autolus, BMS/Celgene, Debiopharm, Genmab, Kite/Gilead, Epizyme, Janssen, Karyopharm, Morphosys, Novartis, F. Hoffmann-La Roche, Takeda: Consultancy; Abbvie, Amgen, Celgene, Gilead, Janssen, Kite, Morphosys, Novartis, Roche, Takeda: Other: Participation to educational events; Abbvie, Autolus, BMS/Celgene, Debiopharm, Genmab, Kite/Gilead, Epizyme, Janssen, Karyopharm, Morphosys, Novartis, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie, Amgen, Celgene, Gilead, Janssen, Kite, Morphosys, Novartis, F. Hoffmann-La Roche, Takeda: Honoraria. Hentrup:Neuronetics, Inc: Current equity holder in publicly-traded company, Ended employment in the past 24 months; BMS Consultant: Current Employment. Rhee:I own stocks for publicly-traded companies: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current Employment. Hagner:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Klein:Roche: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Pourdehnad:Celgene: Ended employment in the past 24 months, Patents & Royalties: Various CC-122 patents; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Various CC-122 patents. Hege:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties: numerous, Research Funding; Celgene (acquired by Bristol Myers Squibb): Ended employment in the past 24 months; Mersana Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences (Former Board of Directors): Divested equity in a private or publicly-traded company in the past 24 months. Dobmeyer:BMS: Consultancy. Nikolova:Celgene, A Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Ribrag:nanostring: 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; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; gustave roussy comprehensive cancer center: Current Employment; servier: Consultancy; pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; argenX: Research Funding; epizyme (EPZ): Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; EPZ: Honoraria, Membership on an entity's Board of Directors or advisory committees; AZD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This is a phase I study evaluating the safety and efficacy of avadomide in combination with obinutuzumab in patients with R/R B-cell NHL. Avadomide is an investigational agent and has not yet been approved in the US.

Abstract: 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.

Abstract: Background: Relapsed/refractory (R/R) DLBCL remains an unmet medical need with no approved or standard therapy in the third-line setting. Several new promising classes of drugs are being developed based on emerging understanding of the molecular pathology of DLBCL. These include CC-122, a pleiotropic pathway modifier that promotes CRBN-dependent Aiolos and Ikaros degradation, CC-223, a potent selective ATP-competitive inhibitor of mTOR kinase, and CC-292, a highly selective irreversible-inhibitor of Btk. Early phase studies with these compounds indicated single-agent activity in B cell malignancies including DLBCL. CC-122-DLBCL-001 is a Phase 1b dose escalation and expansion study of CC-122, CC-223 and CC-292 administered orally as doublets, and as triplets in combination with rituximab (R), as well as a CC-122 plus R doublet, in subjects with high risk R/R DLBCL. Methods: The dose escalation phase of the study explores combinations of one or more doses for each novel agent using a modified 3+3 dose escalation design with higher dose cohorts including the addition of a fixed dose of rituximab 375 mg/m2 IV Q28 days. CC-122 1mg, 2mg, 3mg, or 4mg is given orally QD or for 5 out of 7 days/week (5/7d). CC-223 15mg, 20mg, or 30mg is given orally QD. CC-292 500mg is given orally BID. Subjects were treated until progression or intolerable side effects. Study endpoints were: safety, tolerability, PK, PD and preliminary efficacy [overall response rate (ORR) and complete response (CR)]. Subjects were considered efficacy evaluable if they received at least one cycle of treatment and had one post-baseline tumor assessment. Peripheral blood PD biomarkers on treatment were compared to baseline levels by flow cytometry for CC-223 mTOR pathway targets p4EBP1 and pAKT and CC-122 target Aiolos. CC-292 500mg BID was previously demonstrated to result in 〉 90% Btk receptor occupancy at 24 hours (Blood 2013 122:4169). Results: As of May 02, 2016, a total of 102 subjects were enrolled into the ongoing dose escalation phase of the study. The median no. of prior anti-lymphoma regimens was 3 (range, 1-10), 30% had prior ASCT and 30% were refractory to any prior therapy. Arm A (CC-122 + CC-223 +/- R) enrolled 31 subjects (28 treated) on 5 dose levels. As of the data-cutoff, the MTD had not been established. The most common ( 〉 10%) related grade 3/4 adverse events (AEs) were neutropenia (43%), thrombocytopenia (14%), diarrhea (18%), and rash (11%). Arm B (CC-122 + CC-292 +/- R) enrolled 28 (27 treated) subjects on 5 dose levels. The MTD was determined to be CC-122 1mg 5/7d + CC-292 500mg BID + R. The most common ( 〉 10%) related grade 3/4 AEs were neutropenia (37%), thrombocytopenia (22%), anemia (11%) and febrile neutropenia (15%) Arm C (CC-223 + CC-292) included 14 enrolled (all treated) subjects on 2 dose levels. A tolerable dose demonstrating sufficient PD biomarker inhibition was not established. The most common ( 〉 10%) related grade 3/4 AEs were neutropenia (14%), thrombocytopenia (29%) and diarrhea (14%). Arm D (CC-122 + R) included 29 subjects enrolled (28 treated) on 5 dose levels. As of the data-cutoff, the MTD had not been established. The most common ( 〉 10%) related grade 3/4 AEs were neutropenia (32%). Generally, response rates of interest were noted in Arms A, B and D (Table 1). ORR increased at higher dose levels and responses were durable. Preliminary PD data (Table 2) demonstrated differential effects of CC-223 20mg dose on p4EBP1 inhibition between Arms A and C and differential effects of low and high dose CC-122 dosing on Aiolos inhibition between Arms A, B and D. Preliminary PK analysis for drug-drug interactions will be presented. Conclusions: Preliminary data from this ongoing novel-novel dose escalation study indicate that safe and tolerable combinations of CC-122 with CC-223, CC-292, and/or rituximab can be achieved. Combination effects on toxicity, efficacy and PD biomarkers were seen. The observed signals of efficacy are encouraging in this R/R DLBCL population and will be further explored in dose expansion of selected arms at the optimized doses. Disclosures Ribrag: Infinity: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding; Pharmamar: Membership on an entity's Board of Directors or advisory committees; NanoString: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Chavez:Janssen: Speakers Bureau. Kaplan:Janssen: Research Funding; Seattle Genetics: Research Funding. Vitolo:Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria; Celgene: Honoraria. Santoro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; ArQule: Membership on an entity's Board of Directors or advisory committees. Corradini:Servier: Honoraria; Sanofi: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Takeda: Consultancy, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Gentium: Honoraria, Speakers Bureau. Cassier:Celgene Corporation: Research Funding; AstraZeneca: Research Funding; MSD: Research Funding; Merck Serono: Research Funding; Roche: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Eli Lilly: Research Funding; Bayer: Research Funding; Amgen: Honoraria. Flinn:Janssen: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Advani:Janssen: Research Funding; Celgene: Research Funding; Merck: Research Funding; Kura: Research Funding; Millennium: Research Funding; Infinity: Research Funding; Kyowa Hakko Kirin: Consultancy, Honoraria; FortySeven: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Sutro: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Stanford University: Employment; Seattle Genetics: Research Funding; Regeneron: Research Funding; Agensys: Research Funding; Pharmacyclics: Research Funding. Sangha:Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria; Eli-Lilly: 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; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Hagner:Celgene Corporation: Employment, Equity Ownership. Trowe:Celgene Corporation: Employment, Equity Ownership. Gandhi:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Kuruvilla:BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria.