Abstract: Abstract 1317 Introduction: Allogeneic stem cell transplantation offers potentially curative therapy for selected patients with hematopoietic malignancies or bone marrow failure states. Only 20–25% of transplantation candidates have compatible related donors, and thus the majority of patients require stem cells from unrelated individuals matching their human leukocyte antigen (HLA) genes. Unrelated donor transplantation (NMUDT) is associated with higher rate of acute and chronic graft versus host disease (aGVHD and cGVHD, respectively) resulting in significant treatment related morbidity and mortality. Severe aGVHD (grade III/IV) occurs in 30–40% of patients and many of these patients eventually die from the complications. The incidence of cGVHD following unrelated transplantation was reported to occur up to 80%. Treatment-related mortality in the first 100–180 days post-transplant ranges from 30–60% depending on the patient/donor age, disease status at time of transplant and HLA mismatch. This compares to a treatment-related mortality of approximately 20–30% for patients receiving sibling-donor transplants. More aggressive conditioning including total body irradiation is believed to result in severe organ toxicities fueling subsequent GVHD in the NMUDT patients. In this study we evaluated chemotherapy only based preparative therapy (busulfan and fludarabine) and tacrolimus plus methotrexate as the GVHD prophylaxis. Also the donors and recipients were matched with strict HLA compatibility. Patients and Method: Thirty-five patients meeting eligibility criteria for NMUDT were prospectively enrolled. Diagnoses included:14 AML, 6 NHL, 6 MDS, 5 ALL, 2 MPD, 2 CML. The median age was 46 years (18-61); 20 males and 15 females. Preparative therapy consisted of Fludarabine (F) 30mg/m2 daily for 5 doses, Busulfan (Bu) 0.8mg/kg IV q6 hrs for 16 doses. All patients received stem cells from allele-matched unrelated donors; 7/8 (n=1), 8/10 (n=1), 9/10 (n= 7) or 10/10 (n= 26) at HLA A, B, C, DR and DQ. 9 patients received bone marrow and 26 patients received G-CSF mobilized peripherial blood stem cells. All patients received TAC (target 5–10 ug/L), MTX (5mg/m2 d1,3,6,11) for GVHD prophylaxis. Infectious disease prophylaxis included; G-CSF, acyclovir, anti-bacterials, voriconazole, and CMV pre-emptive therapy. Results: The engraftment was documented as follows: ANC 〉 1.0 median: day 12 (SD3.5), Plt 〉 50×10e9/L median: day 16 (SD 7.2), Plt 〉 100×10e9/L median: day 20 (SD 40.7). The frequent ( 〉 20%) toxicities included bone marrow suppression (grade 4 100%) mucositis (gr≥1 91%), enteritis (gr≥1 43%); elevated AST (gr 1 27%), elevated total bilirubin (gr 1 20%) and alkaline phosphatase (gr1 40%). Other significant toxicities (gr ≥3) included neutropenic fever (20%), bacteremia (11%), infections (including pneumonia, fungal pneumonia, CMV viremia) (26%), enteritis 6%, ARF 9%, rash 9%, respiratory failure 14%. The incidence of aGVHD (Gr II-IV) was 43%. The incidence of cGVHD was 60% (90% extensive cGVHD). The 100 day non-relapse mortality (NRM) was 9% (2 GVHD, 1 VOD). The late TRM (beyond 100 days) was 11% (3 GVHD, 1 infection). Cumulative relapse related mortality was 17% at 6 months, 26% at 9 months and 31% at 24 months. Overall mortality at 1 year was 44%. Overall survival is currently 40% with median follow-up of 4.4 years. Conclusions: In this prospective study of 35 patients undergoing matched unrelated donor transplantation, the busulfan/fludarabine preparative regimen is safe and resulting in reasonably low TRM and comparable GVHD rates. Disease relapse remains the most significant cause of death. Disclosures: No relevant conflicts of interest to declare.

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: Introduction: Chimeric antigen receptor (CAR) T cell therapy directed against B cell maturation antigen (BCMA) has shown promising results for the treatment of relapsed refractory multiple myeloma (RRMM) in several phase 1 studies. Persistence of CAR T cells post infusion may be one determinant of duration of response. bb21217 is a next-generation anti-BCMA CAR T cell therapy based on investigational therapy idecabtagene vicleucel (bb2121) (Friedman 2018, Hum Gene Ther 29:585) that uses the same lentiviral CAR T design as bb2121, but adds the phosphoinositide 3-kinase inhibitor bb007 during ex vivo culture to enrich the drug product for memory-like T cells. Evidence suggests that CAR T cells with this phenotype may be more persistent and more potent than unselected CAR T cells. CRB-402 is a first-in-human study of bb21217 in patients with RRMM designed to assess safety, pharmacokinetics, efficacy and duration of effect. Methods: CRB-402 (NCT03274219) is an ongoing, multi-center phase 1 dose escalation trial of bb21217 planning to enroll 74 patients with RRMM who received ≥ 3 prior regimens, including a proteasome inhibitor and an immuno-modulatory agent, or are double-refractory to both classes. During dose escalation, enrollment is restricted to patients with ≥ 50% BCMA expression by IHC on malignant plasma cells. Peripheral blood mononuclear cells are collected via leukapheresis and sent to a central facility for transduction, expansion and release testing prior to being returned to the site for infusion. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days, then receive bb21217 as a single infusion. Planned dose levels are 150, 450, 800, and 1,200 x 106 CAR+ T cells and intermediate dose levels are allowed. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures are quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria, evaluation of minimal residual disease (MRD), progression-free and overall survival, and quantification of CAR+ T cells in blood. Results: Asof April 20, 2019, 22 patients (median age 63 [min;max 42 to 74]) have received bb21217 (12 at 150, 6 at 300 and 4 at 450). Eleven had high tumor burden, defined as ≥ 50% bone marrow plasma cells pre-infusion. Patients had a median of 7 (min;max 4 to 17) prior lines of therapy and 18/22 had prior autologous stem cell transplant; 7/22 had high-risk cytogenetics. Of the 22 patients, 19 received prior daratumumab, 13 received prior Bort/Len/Car/Pom/Dara. Median follow-up after bb21217 infusion was 23 weeks ( & lt;1 to 77 weeks). As of data cut-off, 13/22 patients developed cytokine release syndrome (CRS; 5 G1, 7 G2, 1 G3) and responded to supportive care, tocilizumab and/or corticosteroids. Five patients developed neurotoxicity [1 G1, 2 G2, 1 G3 (vertigo/dizziness), 1 G4 (encephalopathy, previously reported)]. For the 1 patient with G4 neurotoxicity, G3 CRS was also reported; both have resolved. A total of 18 patients were evaluable for response with ≥ 2 months of follow up or PD within 2 months. Fifteen (83%) patients demonstrated clinical response per IMWG criteria. Six of these subjects subsequently progressed. Nine patients remained in response, including 2 patients with ongoing response at months 15 and 18. MRD negative results at 10-5 nucleated cells or better were obtained by NGS in 10/10 evaluable responders at month 1. Overall, 6/8 patients evaluable at 6 months and 2/2 patients evaluable at 12 months had detectable CAR T cells in blood. Updated data from this study will be presented, including extended follow-up on the initial patients treated and early clinical and CAR T cell persistence data from at least 15 additional patients treated with up to 450 x 106 CAR+ T cells. Conclusions: The adverse events observed to date were manageable and consistent with known toxicities of CAR T therapies. Initial efficacy results with bb21217 CAR T therapy in heavily pretreated RRMM are encouraging, with 83% of patients demonstrating clinical response. Emerging data demonstrate long-term persistence of CAR T cells in long-term responders. Updated data to be presented will help determine whether treatment with bb21217 results in sustained CAR T cell persistence and durable clinical responses, and whether bb21217 is tolerated at higher doses. Disclosures Berdeja: AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Alsina:Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau. Shah:Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jagannath:Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Merck: Consultancy. Madduri:Abbvie: Consultancy; Celgene: Consultancy; Takeda: Consultancy; undation Medicine: Consultancy. Kaufman:Janssen: Honoraria; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Winship Cancer Institute of Emory University: Employment; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Celgene: Consultancy. Munshi:Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Celgene: Consultancy; Adaptive: Consultancy; Abbvie: Consultancy. Rosenblatt:BMS: Other: Advisory Board ; Parexel: Consultancy; Imaging Endpoint: Consultancy; Partner Tx: Other: Advisory Board; Dava Oncology: Other: Education; BMS: Research Funding; Amgen: Other: Advisory Board; Celgene: Research Funding; Merck: Other: Advisory Board. Turka:bluebird bio: Employment. Lam:bluebird bio: Employment. Massaro:bluebird bio: Employment. Campbell: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; Arcus Biosciences: 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. Petrocca:bluebird bio: Employment. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: 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: Increased understanding of the local injection site infiltrate in response to tumor vaccines may facilitate more effective anti-cancer vaccination strategies. A pilot vaccination strategy was developed to determine if K562/GM-CSF immunotherapy could enhance T cell reactivity and clinical responses in CML patients undergoing therapy with imatinib mesylate. K562/GM-CSF is a tumor vaccine derived from a CML cell line that expresses several defined CML associated antigens and has been genetically modified to secrete GM-CSF. We undertook a correlative project comparing the cellular infiltrates from pre- and post-vaccination skin biopsies in this immunotherapy trial. GM-CSF producing tumor vaccines are effective in recruiting antigen presenting cells (APCs), however alone they are insufficient to initiate APC maturation. Because topical imiquimod (a Toll-like receptor 7 agonist) is known to enhance the in vivo maturation of the recruited APCs, the vaccines (1 x 10*8 cells distributed over 10 injection sites) were given with or without topical 5% imiquimod cream. Imiquimod was applied 4 hrs post-vaccination and then 3d and 5d post-vaccination to injection sites, with at least 1 site left without imiquimod treatment. A series of 4 vaccines were administered in 3 wk intervals. Six mm punch biopsies were taken at baseline, and 3d following the 1st and 4th vaccination. Biopsies were performed at the imiquimod site with the largest area of induration, as well as a site not exposed to imiquimod. Immunohistochemistry of CD3, CD4, CD8, CD1a (Langerhans cell (LC)), factor XIIIa (dermal dendritic cell), and CD68 (monocyte/macrophage) and Geimsa staining was performed. Staining is reported as number of live cells per mm2 in the epidermis and dermis for CD1a+ cells and dermis for the remaining stains. Fifteen subjects agreed to the procedures as part of the clinical trial. Mean area of induration of imiquimod sites was increased significantly compared to the non-imiquimod sites after both the first (p=0.005) and fourth vaccinations (p=0.068). Geimsa staining revealed significant increases in proportion of neutrophils, eosinophils, and mononuclear cells to total number of staining cells after the 1st vaccination in the sites treated with imiquimod compared to the pre-vaccination biopsies while the increases at the sites without imiquimod treatment did not reach statistical significance. We observed increases in CD3+, CD4+, and CD8+ cells at post-vaccination sites. Interestingly, the total number of CD1a+ LCs in the area measured did not appear to be affected by the administration of imiquimod and was constant after vaccinations. However, distribution of CD1a+ LCs shifted from the epidermis to the dermis after vaccination. In addition we observed recruitment of factor XIIIa+ dermal dendritic cells and CD68+ macrophages to the vaccination site that was increased by imiquimod. Epidermal APCs known as LCs migrate to the dermis, yet maintain homeostasis of the total LCs following vaccination independent of Imiquimod application. A correlation across subjects between these histologic features and clinical response to vaccination is on-going.

Abstract: Background: Cluster of differentiation 47 (CD47), a widely expressed cell-surface ligand,is overexpressed in various malignancies and is correlated with worse outcomes in NHL. Interaction of CD47 and signal regulatory protein-α (SIRPα) delivers an antiphagocytic 'don't eat me' signal to promote tumor cell evasion from macrophages. CC-90002 is a humanized IgG4-PE CD47 antibody that inhibits CD47-SIRPα interaction and enabled phagocytosis across a panel of cancer cell lines (Narla et al. AACR.2017). In addition to high binding affinity, CC-90002 is potentially differentiated from other CD47 immunotherapies by its lack of ability to induce hemagglutination of red blood cells or hemolysis in nonclinical studies. CD47 antibodies can synergize with the CD20 antibody rituximab to induce phagocytosis of NHL cells in vitroand to eliminate lymphoma in mouse models (Chao et al. Cell.2010). We therefore examined CC-90002 plus rituximab for treatment of R/R NHL. Methods: This 2-part, phase I, multicenter study (CC-90002-ST-001; NCT02367196) is evaluating CC-90002 in subjects with advanced solid and hematologic malignancies. Part B of the study (reported here) is examining CC-90002 in combination with rituximab in subjects with CD20-positive R/R NHL. Dose escalation followed a modified 3+3 design. Subjects received escalating doses of CC-90002 intravenously at 4, 8, 15, 20, or 30 mg/kg every 2 weeks (Q2W) on days 1 and 15 plus rituximab 375 mg/m2 given on days −15, −8, and −1 and day 8 of cycles 1-6, 8, 10, and 12 in 28-day cycles. Primary endpoints are dose-limiting toxicities (DLTs), nontolerated dose (NTD), and maximimum tolerated dose. Secondary endpoints are pharmacokinetics, preliminary efficacy per International Working Group Response Criteria for NHL (Cheson et al. J Clin Oncol.2014), and frequency of antidrug antibodies. Results: Overall, 28 subjects have been enrolled and 24 were treated. As of July 5, 2019, 20 subjects had discontinued the study, most commonly for progressive disease (PD; n=9) or death (n=7). The median age at enrollment was 64 years (range, 27−81), and subjects had received a median of 3 prior systemic therapies (range, 2−9). Subjects received a median of 2 cycles of CC-90002 plus rituximab (range, 1−18). There were no CC-90002 dose reductions but 7 subjects had their dose interrupted, mostly because of thrombocytopenia and neutropenia. The NTD was established as 30 mg/kg Q2W.DLTs occurred in 3 subjects; 1 subject developed dyspnea attributed to an infusion-related reaction at 15 mg/kg Q2W CC-90002 and 2 subjects had grade 3 thrombocytopenia requiring platelet transfusion occurring at 30 mg/kg Q2W CC-90002. The most common adverse events (AEs) were hematologic (Table). Although anemia was common, there was no evidence of hemolysis. The most frequent grade 3/4 AEs were neutropenia (38%) and thrombocytoenia (21%). Seven deaths occurred on study or in follow-up, 6 from PD or complications related to NHL and 1 due to an AE (cytokine release syndrome in a subject who discontinued CC-90002 for PD and enrolled in another trial within the follow-up period). There were no treatment-related deaths. The overall response rate was 13% (95% CI, 2.7−32.4) and the disease control rate was 25% (95% CI, 9.8−46.7; Figure). One subject achieved a durable complete response (8 mg/kg; ongoing in cycle 18) and 2 had partial responses (15 mg/kg and 20 mg/kg); 3 subjects had stable disease. Among responders, the median duration of response was 3.9 months (95% CI, 1.9−3.9). CC-90002 exhibited linear pharmacokinetics at doses ≥15 mg/kg, suggesting target saturation at 15 mg/kg. In addition, a longer half-life was observed at higher (≥15 mg/kg) versus lower doses (t1/2≈ 3−7 days vs 1 day). Conclusions: The CD47-SIRPα checkpoint inhibitor, CC-90002,plus rituximab demonstrated tolerability and modest clinical activity in this early-phase study of heavily pretreated R/R NHL subjects. AEs were predominantly grade 1/2; cytopenias were the most common AEs with dose-limiting thrombocytopenia observed at 30 mg/kg Q2W. In contrast to other CD47-targeting immunotherapies and consistent with results of preclinical studies of CC-90002, hemolysis at a starting dose of up to 30 mg/kg CC-90002 was not observed. These preliminary data support further evaluation of targeting the CD47-SIRPα pathway in combination with rituximab in NHL. Disclosures Abrisqueta: Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. Sancho:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: Advisory board; Novartis: Honoraria; Kern Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Celltrion: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squib: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cordoba:Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Kyowa-Kirin: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; FUNDACION JIMENEZ DIAZ UNIVERSITY HOSPITAL: Employment; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy. Persky:Sandoz: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy. Andreadis:Juno: Research Funding; Pharmacyclics: Research Funding; Roche: Equity Ownership; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Research Funding; Kite: Consultancy; Gilead: Consultancy; Merck: Research Funding; Genentech: Consultancy, Employment. Huntington:Pharmacyclics: Honoraria; Genentech: Consultancy; Bayer: Consultancy, Honoraria; DTRM Biopharm: Research Funding; AbbVie: Consultancy; Celgene: Consultancy, Research Funding. Carpio:University Hospital Vall D'Hebron: Employment. Morillo Giles:Hospital Universitario Fundacion Jimenez Diaz: Honoraria. Wei:Celgene Corp.: Employment, Equity Ownership. Li:Celgene Corp.: Employment, Equity Ownership. Zuraek:Celgene Corp.: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Burgess:University of California: Other: Volunteer clinical faculty, without salary, Patents & Royalties: Patent - T315A and F317I mutations of BCR-ABL kinase domain; Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Patent - CD47 antibodies and methods of use thereof. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; 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. Martín:iQone: Consultancy; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Kiowa Kirin: Consultancy; Servier: Honoraria, Other: Travel Expenses; Teva: Research Funding; Janssen: Honoraria, Other: Travel Expenses, Research Funding.

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: Introduction: Idecabtagene vicleucel (ide-cel, bb2121) is a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T cell therapy under investigation in the KarMMa trial as a treatment for patients with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies. In the phase 2 KarMMa trial, ide-cel demonstrated a favorable benefit-risk profile in this patient population (Munshi NC, et al. J Clin Oncol 2020;38:8503). Ide-cel also demonstrated clinically meaningful improvements in the key health-related quality of life (HRQoL) symptoms associated with MM (Delforge M, et al. HemaSphere 2020;4:EP1000). Translating HRQoL data to health state utility values (HSUVs)/HRQoL weights is key to understanding the HRQoL impact of a treatment in relation to that of a healthy general population and is an important consideration in clinical decision making and health technology assessments. HSUVs are scored between 0 and 1, where 0 is death and 1 is perfect health. In the general population, individuals of a similar age range to patients with MM have HSUV scores of 0.83 in the USA, 0.80 in the UK, and 0.84 in Canada (Guertin JR, et al. CMAJ 2018;190:E155-161; Janssen MF, et al. Eur J Health Econ 2019;20:205-216). This analysis aimed to determine HSUVs for patients treated in the KarMMa study according to their progression status. Methods: HRQoL assessment in the KarMMa study (NCT03361748) included the European Quality of Life-5 dimensions 5 levels (EQ-5D-5L) health state classifier performed at specified time points: prior to receiving lymphodepleting chemotherapy (baseline), day of infusion (Day 1), Months 1, 2, 3, 6, 9, 12, and 15, inclusive of disease progression/relapse or complete remission. Using US, UK, and Canadian weights, HSUVs were estimated for the KarMMa trial at an aggregate level. A longitudinal mixed-effects model was used with health state as a fixed effect, and a random intercept term. Three models were run using different health states. Model 1 considered 3 health states: baseline, pre-progression, and post-progression. In Model 2, the pre-progression health state was split into 2 time periods: Day 1 to the end of Month 1, and Month 2 onward. In Model 3, 2 pre-progression health states were defined based on the quality of response to treatment, thus capturing the difference in HRQoL for patients achieving at least a very good partial response (≥ VGPR) or patients who did not achieve a VGPR ( & lt; VGPR). Results: The HSUVs derived from the 3 different models using US, UK, and Canadian tariffs are summarized (Table). In all 3 models, patients in the pre-progression state experienced an increase in HRQoL from baseline. In Model 1, the increment ranged from +0.05 to +0.08. On progression, patients experienced a decrement (−0.01 to −0.03), but their HSUV remained above the baseline value by +0.04 to +0.05, indicating that ide-cel treatment was associated with an improvement in HRQoL, with some of the benefit remaining even upon disease progression. When HSUV in the pre-progression state was analyzed in Model 2 at Month 1 and then Month 2 onward, patients also experienced an increase in their HRQoL from baseline. While this increase was small in Month 1 (+0.02 to +0.04), the subsequent increase from baseline (i.e. from Month 2 onward) was more pronounced (+0.07 to +0.10) reflecting the benefits of a one-off administration of ide-cel and the associated treatment-free interval. A further analysis of the pre-progression HSUV by the quality of response in Model 3 showed that patients who achieved ≥ VGPR had a greater improvement in HRQoL (+0.08 to +0.11) than patients who achieved & lt; VGPR. Both response levels were associated with an improvement in HRQoL compared with baseline, with HRQoL for patients achieving ≥ VGPR approaching that of the general population (Figure). Conclusions: Results of this analysis indicate that ide-cel provides clinically meaningful improvements in HRQoL for patients with triple-class-exposed RRMM. The benefit is particularly marked in patients who achieve ≥ VGPR, in whom HRQoL approaches that of the general population. Disclosures Delforge: Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Amgen: Honoraria. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Rodriguez-Otero:Celgene-BMS: Consultancy, Honoraria; Mundipharma: Research Funding; Janssen, BMS: Other: Travel, accommodations, expenses; BMS, Janssen, Amgen: Honoraria; Janssen, BMS, AbbVie, Sanofi, GSK, Oncopeptides, Kite, Amgen: Consultancy, Honoraria. Hari:Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy; BMS: Consultancy; Incyte Corporation: Consultancy; Takeda: Consultancy. Braverman:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Trigg:Adelphi Values: Current Employment. Patel:BMS: Current Employment. Huang:BMS: Current Employment, Current equity holder in publicly-traded company. Hege:Arcus Biosciences: Divested equity in a private or publicly-traded company 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; BMS: Current Employment, Current equity holder in publicly-traded company, Other: Travel, accommodations, expenses, Patents & Royalties: Numerous, Research Funding. Dhanasiri:BMS: Current Employment, Current equity holder in publicly-traded company.

Abstract: Introduction: Chimeric antigen receptor (CAR) T cell therapies have demonstrated robust and sustained clinical responses in several hematologic malignancies. Data suggest that achieving acceptable benefit:risk profiles depends on several factors, including the specificity of the antigen target and characteristics of the CAR itself, including on-target, off-tumor activity.To test the safety and efficacy of CAR T cells in relapsed and/or refractory multiple myeloma (RRMM), we have designed a second-generation CAR construct targeting B cell maturation antigen (BCMA) to redirect T cells to MM cells. BCMA is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells. bb2121 consists of autologous T cells transduced with a lentiviral vector encoding a novel CAR incorporating an anti-BCMA scFv, a 4-1BB costimulatory motif and a CD3-zeta T cell activation domain. Methods: CRB-401 (NCT02658929) is a multi-center phase 1 dose escalation trial of bb2121 in patients with RRMM who have received ≥ 3 prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have ≥ 50% BCMA expression on malignant cells. Peripheral blood mononuclear cells are collected via leukapheresis and shipped to a central facility for transduction, expansion, and release testing prior to being returned to the site for infusion. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days then receive 1 infusion of bb2121. The study follows a standard 3+3 design with planned dose levels of 50, 150, 450, 800, and 1,200 x 106 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures were quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria for Multiple Myeloma, evaluation of minimal residual disease (MRD), overall and progression-free survival, quantification of bb2121 in blood, and quantification of circulating soluble BCMA over time. Results: Asof May 4, 2017, 21 patients (median 58 [37 to 74] years old) with a median of 5 (1 to 16) years since MM diagnosis, had been infused with bb2121, and 18 patients were evaluable for initial (1-month) clinical response. Patients had a median of 7 prior lines of therapy (range 3 to 14), all with prior autologous stem cell transplant; 67% had high-risk cytogenetics. Fifteen of 21 (71%) had prior exposure to, and 6 of 21 (29%) were refractory to 5 prior therapies (Bort/Len/Car/Pom/Dara). Median follow-up after bb2121 infusion was 15.4 weeks (range 1.4 to 54.4 weeks). As of data cut-off, no DLTs and no treatment-emergent Grade 3 or higher neurotoxicities similar to those reported in other CAR T clinical studies had been observed. Cytokine release syndrome (CRS), primarily Grade 1 or 2, was reported in 15 of 21 (71%) patients: 2 patients had Grade 3 CRS that resolved in 24 hours and 4 patients received tocilizumab, 1 with steroids, to manage CRS. CRS was more common in the higher dose groups but did not appear related to tumor burden. One death on study, due to cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history, was observed while the patient was in sCR and was assessed as unrelated to bb2121. The overall response rate (ORR) was 89% and increased to 100% for patients treated with doses of 150 x 106 CAR+ T cells or higher. No patients treated with doses of 150 x 106 CAR+ T cells or higher had disease progression, with time since bb2121 between 8 and 54 weeks (Table 1). MRD negative results were obtained in all 4 patients evaluable for analysis. CAR+ T cell expansion has been demonstrated consistently and 3 of 5 patients evaluable for CAR+ cells at 6 months had detectable vector copies. A further 5 months of follow up on reported results and initial data from additional patients will be presented. Conclusions: bb2121 shows promising efficacy at dose levels above 50 x 106 CAR+ T cells, with manageable CRS and no DLTs to date. ORR was 100% at these dose levels with 8 ongoing clinical responses at 6 months and 1 patient demonstrating a sustained response beyond one year. These initial data support the potential of CAR T therapy with bb2121 as a new treatment paradigm in RRMM. CT.gov study NCT02658929, sponsored by bluebird bio and Celgene Disclosures Berdeja: Teva: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; BMS: Research Funding; Takeda: Research Funding; Vivolux: Research Funding; Amgen: Research Funding; Constellation: Research Funding; Bluebird: Research Funding; Curis: Research Funding. Siegel: Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. Jagannath: MMRF: Speakers Bureau; Bristol-Meyers Squibb: Consultancy; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau. Turka: bluebird bio: Employment, Equity Ownership. Lam: bluebird bio: Employment, Equity Ownership. Hege: Celgene Corporation: Employment, Equity Ownership. Morgan: bluebird bio: Employment, Equity Ownership, Patents & Royalties. Quigley: bluebird bio: Employment, Equity Ownership, Patents & Royalties. Kochenderfer: Bluebird bio: Research Funding; N/A: Patents & Royalties: I have multiple patents in the CAR field.; Kite Pharma: Research Funding.

Abstract: 3006^ Background: The mammalian target of rapamycin (mTOR) signaling pathway is frequently activated in cancer. The mTOR kinase exists in two multi-protein complexes, TORC1 and TORC2, which drive key cellular metabolic and proliferative functions.  TORC1-selective inhibitors can induce feedback upregulation of TORC2 and treatment resistance.  CC-223 is an oral, potent, selective, ATP-competitive inhibitor of both TORC1 and TORC2, selected to address this escape mechanism. Methods: Subjects with advanced solid and hematologic cancers were enrolled using an accelerated (1+5) dose escalation design.  CC-223 was administered orally once daily (QD) in 28 day cycles until disease progression.  Safety, pharmacokinetic, pharmacodynamic and clinical endpoints were evaluated. Results:   28 subjects were treated across 5 dose levels:  7.5 (n=1), 15 (n=2), 30 (n=9), 45 (n=7) and 60 mg (n=8).  The most common ( 〉 20%) related adverse events (all grades) were fatigue (64%), nausea (50%), hyperglycemia and diarrhea (43% each), mucositis (39%), anorexia and vomiting (32% each) and rash (29%).  Dose-limiting toxicity (all grade 3) occurred in 4 subjects:  hyperglycemia (30 mg), rash (45 mg), fatigue (60mg), and mucositis (60 mg).  The maximum tolerated dose (MTD) was 45 mg QD. Dose proportional exposure was observed with a terminal half life of 4 to 8 hrs (mean steady state C max 485 ng/mL, AUC 0-24 2371 ng x hr/mL at 45 mg).  Inhibition of TORC1 (pS6, p4EBP1) and TORC2 (pAKT) biomarkers in blood cells was characterized to be exposure-dependent and described by an E max model.   Near maximal inhibition of both TORC1 and TORC2 biomarkers was achieved at the peak concentrations of 30 or 45mg QD.  Target inhibition was predicted to last 8 to 20 hours at 45mg QD. Tumor responses included: 1 partial response lasting 9 months (ER+ breast) and 7 subjects with stable disease (SD) lasting 8+ weeks (range 8 to 23.3). Conclusions:   CC-223 was well tolerated with toxicities comparable to other drugs in this class.  Evidence of TORC1/TORC2 pathway inhibition was observed as well as preliminary signals of anti-tumor activity, including one durable PR.  Expansion cohorts in selected hematologic and solid tumors will evaluate CC-223 at the MTD of 45 mg QD.