Abstract: 3015 Background: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that control expression of genes involved in cell growth and oncogenesis. CC-90010 is an oral, potent and reversible BET inhibitor that showed promising activity in lymphoma and solid tumor cell lines and reduced tumor growth in xenograft models. Methods: CC-90010-ST-001 (NCT03220347; 2015-004371-79) is a phase I, first-in-human study of CC-90010 in patients (pts) with advanced solid tumors and R/R NHL. Three schedules and 11 dose levels were evaluated (Table). Primary objectives were to determine safety, maximum-tolerated dose and/or recommended phase II dose (RP2D). Secondary objectives were the identification of early activity signals, pharmacokinetics and pharmacodynamics (PD). Results: As of 10 Dec 2018, 69 pts were enrolled, 67 with solid tumors and 2 with R/R NHL. Data shown are from all pts (N = 69). The median age was 57 y (range, 21–80), 38 (55%) were male, and the median number of prior systemic anticancer regimens was 3 (range, 1–9). The RP2Ds were dose cohorts 3A and 4B. Dose-limiting toxicities (n = 6) occurred in dose cohorts 3A, 3C, and 4B. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 17 pts (25%), most commonly (≥2 pts) thrombocytopenia (7%), platelet count decreased (4%), fatigue (3%), and increased alanine aminotransferase (3%). No deaths from toxicity occurred. Two pts (endometrial carcinoma and astrocytoma) had a partial response (PR); 1 occurred after the data cutoff. Seven pts had prolonged stable disease (SD) 〉 9 mo. Exposures and PD marker regulation increased with dose in each dosing schedule; terminal half-life was ~ 73 h. Conclusions: Most of the TRAEs observed were mild or moderate in severity, reversible, and manageable by dose adjustments and/or supportive care. Promising ongoing anticancer activity with prolonged SD and PRs were observed. The preliminary clinical data provide the rationale for dose expansion of CC-90010 in pts with selected advanced malignancies. Clinical trial information: NCT03220347. [Table: see text]

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: Bromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR]  + stable disease [SD] of ≥4 months’ duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion co horts (parts B [N = 25] and C [N = 41] ). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8–33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0–8.6) and a CBR of 31.7% (95% CI, 18.1–48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents.

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.