Citations

Abstract Introduction: Plamotamab (XmAb13676) is a humanized bispecific antibody that binds both CD20 and CD3 to recruit cytotoxic T cells to kill CD20 expressing malignant cells. Interim results of an ongoing first-in-human (FIH), dose-escalation study (XmAb13676-01; NCT02924402) in subjects with relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL) are reported. Methods: The study is an FIH, multi-center, open-label, phase 1, dose-escalation study in subjects with R/R NHL with a standard 3 + 3 design. The primary objectives are to determine safety, tolerability, and the maximum tolerated dose (MTD) or recommended dose of plamotamab. Secondary objectives include preliminary anti-tumor activity and pharmacokinetics/pharmacodynamics of plamotamab. This study has 3 Parts: Part A, escalating dose cohorts that establish an initial priming dose as part of repeated weekly infusions at a fixed, weight-based dose in a 28-day cycle; Part B, with a dosing schedule consisting of a priming dose on Cycle 1 Day 1, established in Part A, followed by step-up dosing (SUD) on subsequent weeks; and Part C is an SUD regimen with flat and less frequent dosing. Cytokine release syndrome (CRS) prophylaxis with dexamethasone, antihistamine, and acetaminophen was mandated prior to each administration of plamotamab. Treatment was continued for 2 cycles or longer if there was evidence of therapeutic benefit. Results: At data cut-off (01Jul2021), 80 subjects with NHL have been treated. Subjects had a median age of 62 years (range 32-89), a median of 4 prior therapies (range 1-10), and had been diagnosed a median of 28 months (range 6-353) prior to treatment in the study. The most common treatment-related adverse event was CRS. Overall, 50 subjects (62.5%) experienced CRS, with 4 (5.0%) experiencing Grade ≥ 3 CRS. No related neurotoxicity >Grade 2 has been observed. Treatment responses for NHL were assessed by the Lugano criteria or International Working Group criteria for Waldenström Macroglobulinemia. There have been 23 objective responses (43.4% overall response rate [ORR]) and 13 (38.2%) at doses of ≥ 80 µg/kg or flat dosing in all evaluable subjects with NHL and diffuse large cell B-cell lymphoma, respectively. In the efficacy-evaluable, follicular lymphoma population, at doses of 80-360 µg/kg or flat dosing, objective responses were observed in 8/10 (80%) subjects. After implementation of flat dosing, as opposed to weight-based dosing, a 50% ORR (4/8 evaluable subjects) has been observed in NHL subjects in that cohort. An MTD has not been reached, and dose escalation is ongoing. Overall, 4 out of 16 (25%) evaluable subjects with prior CAR-T therapy responded to plamotamab. Conclusions: Plamotamab demonstrated evidence of clinical activity in heavily pretreated subjects with R/R NHL. CRS was generally manageable with premedication. The study is ongoing with further optimization of dose and schedule. Figure 1 Figure 1. Disclosures Patel: Kite Pharma: Consultancy, Speakers Bureau; Genentech: Consultancy; Morphosys: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; BeiGene: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; MEI Pharma: Consultancy; ADC Therapeutics: Consultancy; Lilly: Consultancy. Michot: GSK: Honoraria; Celgene: Honoraria; MSD: Consultancy, Honoraria; Innate Pharma: Research Funding; Incyte: Research Funding; H3 biomedecine: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Gamamabs: Research Funding; Forma: Research Funding; Exelixis: Research Funding; Eos: Research Funding; Eisai: Research Funding; Debiopharm: Research Funding; Daiichi Sankyo,: Research Funding; Clovis: Research Funding; Chugai: Research Funding; Boeringer Ingelheim: Research Funding; Celgene: Research Funding; Blueprint: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Argen-x: Research Funding; Amgen: Research Funding; Agios: Research Funding; Aduro: Research Funding; Abbvie: Research Funding; ASTEX: Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Research Funding; Roche: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Chanan-Khan: Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; Ascentage: Research Funding; Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BeiGene, Jansen, Ascentage: Honoraria; BieGene, Jansen, Ascentage: Consultancy. Ghesquieres: Janssen: Honoraria; Mundipharma: Consultancy, Honoraria; Roche: Consultancy; Celgene: Consultancy, Honoraria; Gilead Science: Consultancy, Honoraria. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Portell: Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; SeaGen: Research Funding; Targeted Oncology: Honoraria; Aptitude Health: Honoraria; Abbvie: Research Funding; Pharmacyclics: Honoraria; Kite: Honoraria, Research Funding; Merck: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Morphosys: Honoraria; TG Therapeutics: Honoraria, Research Funding; Genentech: Research Funding; VelosBio: Research Funding. Solh: Jazz Pharmaceuticals: Consultancy; Partner Therapeutics: Research Funding; BMS: Consultancy; ADCT Therapeutics: Consultancy, Research Funding. Wierda: Loxo Oncology, Inc.: Research Funding; GSK/Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; Gilead Sciences: Research Funding; KITE Pharma: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma Inc.: Research Funding; Xencor: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Karyopharm: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Johnson: Xencor: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Garcha: Xencor: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Promedim: Ended employment in the past 24 months. Ribrag: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees. Liebowitz: Xencor: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Phillips: Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding.

Abstract Background: Mcl-1 is an anti-apoptotic protein in the Bcl-2 family that contributes to the pathophysiology of certain B-cell malignancies and AML. Dependence on Mcl-1 is associated with poor prognosis, and increased Mcl-1 levels is a common mechanism of resistance to venetoclax. Voruciclib (VORU), a potent oral CDK9 inhibitor (Ki <10 nM), was shown to decrease Mcl-1 protein expression in preclinical models, supporting its evaluation as a single agent and in combination with venetoclax in AML and B-cell malignancies. In two dose escalation phase 1 studies of VORU in patients (pts) with solid tumors, the maximum tolerated dose (MTD) was established at 350 mg when administered daily continuously and 600 mg when administered on days 1 to 14 in a 21-day cycle. Based on concentrations needed for antitumoral activity in preclinical models, pharmacokinetic (PK) results predict a dose of ~200 mg could be sufficient for target inhibition. The present phase 1 study is the first to evaluate the MTD, recommended Phase 2 dose (RP2D), dose-limiting toxicities (DLT), safety, PK, and preliminary efficacy of VORU in pts with relapsed/refractory hematologic malignancies (NCT03547115). Methods: Pts with relapsed B-cell lymphoma, chronic lymphocytic leukemia (CLL), or AML were eligible if age ≥18 years, ECOG performance status ≤1, disease progression after failure of standard therapies, adequate hepatic and renal function, and no prior CDK9 therapy. Dose escalation started at 50 mg, followed a 3+3 design, and DLTs were assessed in Cycle 1. Initially VORU was administered once daily continuously in a 28-day cycle (Group I). After 2 DLTs were observed at 100 mg, administration was changed to once daily on days 1 to 14 in a 28-day cycle (Group II), patients with prior allogeneic transplant were excluded, and dose escalation (100, 150, 200 mg) proceeded in separate cohorts for AML and B-cell malignancies. Disease response was assessed by the Lugano, iwCLL, and 2017 ELN criteria. Results: To date 28 pts have been enrolled: 14 AML, 7 diffuse large B-cell lymphoma (DLBCL), 3 follicular lymphoma (FL), 2 CLL and 2 mantle cell lymphoma. Group I enrolled 16 pts, 8 each at 50 mg and 100 mg. Group II enrolled 12 pts, 10 with AML administered VORU at 100, 150 or 200 mg and 2 pts with B-cell malignancies administered VORU at 100 mg. Dose escalation in AML is completed. Median age was 71 years (range 40-90) and 54% of pts were male. Pts were generally heavily pretreated, with a median of 3 prior therapies (range 1-8). Median number of VORU cycles administered was 2 (range 1-4). Drug-related serious adverse events (SAEs) were reported in Group I only and consisted of 2 DLT of Gr 3 pneumonitis at 100 mg, both in AML pts treated with allogeneic transplant followed by GVHD in the preceding 12 months, one of whom also had a concurrent Gr 3 differentiation syndrome (DS), and 1 SAE not meeting DLT criteria, a Gr 3 hypoxemic respiratory failure in Cycle 4 in a pt with DLBCL at 50 mg. One AML pt developed ischemic bowel thought to be due to disease progression. Symptoms consistent with DS were observed in 4 AML pts. In Group II, no DLTs have been observed to date and there were no Gr 3-5 drug-related adverse events reported. There is no evidence of significant drug-related neutropenia in pts with B-cell malignancies. To date, in Groups I and II combined, 1 AML pt achieved a morphologic leukemia-free state, 2 AML pts achieved stable disease (SD), and 3 pts with B-cell malignancies had a best response of SD, including 1 FL pt who achieved a 42% reduction in SPD, and 1 CLL pt with relapsed disease after chemoimmunotherapy, venetoclax, and ibrutinib who had stable blood counts. Conclusions: VORU at doses up to 200 mg administered on 14 consecutive days in a 28-day cycle was well tolerated with no DLTs observed. Consistent with the phase 1 studies in solid tumors, no significant myelosuppression was seen in pts with B-cell malignancies. The safety profile does not indicate overlapping toxicities with venetoclax. Disease stabilization was observed in heavily pretreated pts and differentiation syndrome was observed in AML indicating biologic activity. Enrollment at 200 mg will continue in an expansion cohort in AML. A forthcoming protocol amendment will evaluate VORU in combination with venetoclax in pts with relapsed AML to exploit the dual inhibition of Bcl-2 and Mcl-1. Disclosures Konopleva: Sanofi: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; KisoJi: Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Stemline Therapeutics: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; AstraZeneca: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding. Brander: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; BeiGene: Research Funding; DTRM: Research Funding; Genentech: Consultancy, Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; TG Therapeutics: Consultancy, Research Funding; Ascentage: Research Funding; LOXO: Research Funding; AstraZeneca: Research Funding; MEI Pharma: Research Funding; ArQule: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Verastem: Consultancy; Novartis: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy. Patel: TG Therapeutics: Consultancy, Speakers Bureau; Curis, Inc: Research Funding; Xencor: Research Funding; Kite: Consultancy, Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; Juno Pharmaceuticals: Consultancy; Fate Therapeutics: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; MEI Pharma: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy; Abbvie: Consultancy; Aptevo Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Sunesis Pharmaceuticals: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding, Speakers Bureau; Velos Bio: Research Funding; Millenium/Takeda: Research Funding. Diefenbach: Celgene: Research Funding; Trillium: Research Funding; IMab: Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Gilead: Current equity holder in publicly-traded company; AbbVie: Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; IGM Biosciences: Research Funding; MEI: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Alvarado: BerGenBio: Research Funding; MEI Pharma: Research Funding; CytomX Therapeutics: Consultancy; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; Sun Pharma: Consultancy, Research Funding. Al Malki: Rigel Pharma: Consultancy; Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Hansa Biopharma: Consultancy; CareDx: Consultancy. Danilov: Bayer Oncology: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; SecuraBio: Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; Rigel Pharm: Honoraria; Bristol-Meyers-Squibb: Honoraria, Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria. Abedin: Pfizer: Research Funding; Amgen: Honoraria; Helsinn: Research Funding; Astellas Pharma Inc.: Research Funding; Agios: Honoraria; Actinium: Research Funding; AltruBio: Research Funding. Ghalie: MEI Pharma: Current Employment, Current equity holder in publicly-traded company. Davids: Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy. OffLabel Disclosure: Vorucicilb is an investigational CDK inhibitor being evaluated in patients with hematologic malignancies, specifically relapsed AML and B-cell malignancies. The abstract submitted to ASH 2021 reports the results of the completed dose escalation portion of a phase 1 study.

7541 Background: FT516 is an investigational, NK cell cancer immunotherapy derived from a clonal master iPSC line. FT516 is engineered with a novel hnCD16 Fc receptor, demonstrated preclinically to maximize antibody-dependent cellular cytotoxicity (Zhu et al. Blood 2020). FT516 can be mass produced and made available off-the-shelf for broad pt access and multi-dose administration. Methods: This is a Phase I trial of FT516 combined with rituximab (R) in pts with R/R BCL. Treatment consists of 2 cycles, each with 3 days lympho-conditioning (fludarabine 30 mg/m 2 and cyclophosphamide 500 mg/m 2 ) and 1 dose of R followed by 3 weekly infusions of FT516 (planned doses 30-900 million/dose) with IL-2 (6 MIU after each FT516 dose). The primary objective is to identify the incidence of dose-limiting toxicity (DLT)/dose cohort and the recommended Phase II dose using a standard 3+3 design. Additional objectives include safety, tolerability, preliminary activity, pharmacokinetics, and immunogenicity. Results: Six pts (5 DLBCL, 1 FL, median age 65.5 y) have completed (5) or discontinued (1) study treatment after the DLT period (data cutoff 9 Dec 2020): 2 received 30 million cells/dose, 3 received 90 million cells/dose, and 1 received 300 million cells/dose. All pts received > 1 prior R-containing regimen, and median number of prior therapies was 3 (range 2-6), including CAR-T in 3 pts. FT516 was primarily administered in the outpatient setting. No FT516-related Grade ≥3 adverse events (AEs) or serious AEs, and no events of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) of any grade were reported. DLT (Grade 4 neutrophil count decreased, not recovered to baseline by D29) was reported in the first pt at 30 million cells/dose and R dosing of 375 mg/m 2 weekly x 4/cycle, resulting in modification of R dosing to once/cycle; no DLTs were observed with modified R dosing. Most common all grade AEs in ≥3 pts: fatigue (4 pts) and decreased appetite, nausea, neutrophil count decreased, and headache (3 pts each). Grade ≥3 AEs in ≥2 pts: neutrophil count decreased (3 pts) and febrile neutropenia and platelet count decreased (2 pts each); none considered related to FT516. Host anti-product B- or T-cell immunogenicity was not observed. Three of 4 pts treated at ≥90 million cells/dose achieved objective response (2 complete responses [CRs] and 1 partial response). Conclusions: Administration of up to 6 doses of FT516 cells, including up to 300 million cells/dose, appears to be safe and tolerable, without CRS, ICANS, or GvHD. Activity was observed, including CRs, in heavily pretreated pts. Dose escalation is ongoing. Updated clinical and translational data will be presented. Clinical trial information: NCT04023071.

Introduction: Interleukin-1 receptor-associated kinase 4 (IRAK4) is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in immune cells including B lymphocytes. It forms the Myddosome complex with the MYD88 adaptor protein, with IRAK4 being essential for downstream signaling, maximal activation of NFkB with inflammatory and immune response and tumor promotion [Treon 2012; Rhyasen 2015]. CA-4948 is a novel small molecule, oral inhibitor of IRAK4, first-in-class and only suppressor of the TLR pathway currently tested in hematological malignancies. When combined with the BTK inhibitor ibrutinib that blocks parallel BCR signaling and NF-kB activating pathway, it has shown synergy in in-vivo B-cell NHL models, providing strong rationale for clinical evaluation [Booher 2018]. Recent preclinical studies demonstrated the role of IRAK4 activation as a driver of secondary, adaptive tumor resistance and survival mechanisms of hematological and solid tumor malignancies [Melgar 2019] that could be blocked by CA-4948 to delay or reverse resistance. Study Design and Methods: This is a multicenter, open-label trial of oral CA-4948 combined with ibrutinib in adult patients with relapsed or refractory hematologic malignancies. (NCT03328078). It has 2 parts: a dose escalation (Part A2), and expansion basket of 4 cohorts (Part B). Part A2: Is a truncated 3+3 design: CA-4948 starting is 200 mg BID with subsequent escalation to 300 mg BID. Both dose are safe and active against NHL as seen in the nearly completed monotherapy Part A1 of this trial Patients will receive CA-4948 with ibrutinib at the labeled dose for the respective NHL subtype (560 mg or 420 mg) until toxicity or progression. Primary objectives are safety/tolerance (MTD, RP2D); 2nd objectives are pharmacokinetics and preliminary efficacy; exploratory objectives include biomarker correlations (e.g., MYD88-L265P mut, IRAK4 pathway, NFκB inhibition). Part B basket has four cohorts: 1 -MZL, 2 - ABC-DLBCL, 3 - PCNSL, and 4 - NHL with adaptive ibrutinib resistance. Cohorts 1-3 must be BTK-inhibitor naïve. Cohort 4 includes ibrutinib treated NHLs after developing adaptive, secondary resistance. All will receive the combination of ibrutinib and CA-4948. Cohort 4 patients will be allowed a <3 weeks gap since prior ibrutinib therapy. Primary objectives include CR or ORR and DOR compared to (matched) historical controls (closely matched if possible). 2nd objectives include tolerance/safety, PFS, and pop-PK sampling for CA-4948. Exploratory objectives; response correlation with biomarkers including MYD88-L265P or other genetic mutations, gene expressions, cell of origin, IRAK4 signaling, and resistance. Treatment: CA-4948 at RP2D+ibrubinib at labelled doses; 21-day cycles to be repeated in the absence of toxicity or progression. Samples sizes, statistical considerations: Approx. 18 patients in Part A2. In Part B, a Simon 2-Step design will be applied to each cohort. Early stopping rule for futility after approx. 20 patients in Stage 1: full accrual with Stage 2 will add about 25 patients. Successful signal efficacy identification in a cohort may support further expansion or a subsequent controlled trial. The safety population will include all patients in the study who received any test dose. The efficacy population will have a valid baseline and post-baseline disease assessment. Safety assessments include TEAEs, safety labs, vitals, physical exams, PK, and ECGs; efficacy assessments: tumor imaging, para-protein determination, and histo/cyto-morphologic examinations. Part A2 inclusion: Histopathologically confirmed B-cell NHL as per the WHO 2016 classification. Eligible NHL subtypes: FL, MZL, MCL, DLBCL (including extranodal lymphomas of leg, testicle, or other sites, excluding mediastinal lymphoma), CLL/SLL, primary or secondary CNS lymphoma, and WM/LPL. Patients with FL, MCL, MZL, WM/LPL, or CLL/SLL should meet clinical treatment criteria. Part B inclusion: Cohorts 1-3 include patients with MZL, ABC-DLBCL, or PCNSL who are BTK-inhibitor naïve. Cohort 4 will include ibrutinib pre-treated MCL, MZL, CLL/SLL, WM/LPL, ABC-DLBCL, or PCNSL with adaptive resistance. Exclusions for both Parts A2 and B: Significant acute or chronic toxicity from prior anti-cancer therapy that has not resolved to Grade ≤ 1, as determined by NCI CTCAE v 4.03 within 7 days prior to start of study or serious co-morbidities. Disclosures Nowakowski: NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Kymera: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees. Leslie:TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Lunning:Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; TG Therapeutics: Research Funding; Verastem: Consultancy, Honoraria; Acrotech: Consultancy; ADC Therapeutics: Consultancy; Legend: Consultancy; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Curis: Research Funding; Gilead: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Patel:Adaptive Biotechnologies: Consultancy; Kite: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Landsburg:Takeda: Research Funding; Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Fenske:Medical College of Wisconsin: Current Employment. Ramchandren:Merck, Seattle Genetics, Janssen, Genentech: Research Funding; Seattle Genetics, Sandoz-Novartis, Pharmacyclics, an AbbVie Company, Janssen, Bristol-Myers Squibb: Consultancy. Skarbnik:Alexion: Consultancy; Beigene: Speakers Bureau; Verastem: Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: 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; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tun:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding.

Introduction CA-4948 is a novel oral small molecule inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 is part of the Myddosome signaling pathway, and is essential for signaling downstream of toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family in immune cells including B lymphocytes. . Dysregulated signaling in these pathways is frequently observed in Non-Hodgkin Lymphomas (NHL), particularly in ABC-subtype of Diffuse Large B-Cell Lymphoma (DLBCL) and Waldenström macroglobulinemia (WM)[1]. Furthermore, IRAK4 activation has recently been identified as a driver of an adaptive resistance mechanism of malignancies [2]. CA-4948 is the first clinical candidate targeting IRAK4 to be evaluated in cancer patients. Here we present Phase I results of CA-4948 in patients with relapsed/refractory hematologic malignancies. Method CA-4948-101 is a phase I trial dose escalation trial with a 3 + 3 design. Seven dosing cohorts were assessed including 50 and 100 mg daily (QD), and 50, 100, 200, 300, or 400 mg twice daily (BID) continuous oral monotherapy in 21-day cycles. Objectives included safety and tolerance (primary), pharmacokinetic (PK), pharmacodynamics (PD) and early efficacy (secondary), and biomarker correlations (exploratory). As of July 2020, 30 patients with relapsed or refractory, NHL have been enrolled, including DLBCL (n=14), FL (n=6), transformed HGBL (n=1), WM (n=3), LPL (n=2), MZL (n=2) and MCL (n=2). Median age is 68.5 (range 50 - 87; 5 female / 25 male). Median number of prior treatments is 4 (range 1 - 8, incl. 5 CAR-T-cell or ASCT treatments). Results CA-4948 has been generally well tolerated. Eight patients were exposed at the highest dose level of 400 mg BID: 2 of 5 DLT-evaluable patients had Grade 3 rhabdomyolysis (DLTs), without complications and reversible after treatment interruption and hydration / analgesic treatment - both subsequently continued treatment at lower doses of 200 or 300 mg BID, respectively. Six patients have tolerated 300 mg BID well without DLT. Most non-hematologic TEAEs were Grade 1 or 2 and manageable, including diarrhea, vomiting, fatigue, dyspnea, and myalgia. Hematologic TEAEs including neutropenia, anemia, thrombocytopenia was mild/moderate and without complications. There were only 4 Grade 3 combined episodes in 18 patients at dose levels ranging between 200 and 400 mg BID without complications (Table 1). Drug discontinuation occurred in only 3 cases for rash, fatigue, and asymptomatic amylase/lipase elevation at lower dose levels. No toxic deaths occurred. Favorable and predictable PK characteristics included rapid absorption with Tmax at 2-3 hours, T1/2 of 6 hours (supporting bid dosing), moderate accumulation, and dose-proportional increases in exposure. Dose proportional PD changes were shown for inflammatory cytokine reductions. Treatment duration ranged between 15 days and 19+ months with sustained disease control. Eight of 28 evaluable patients experienced overall tumor burden decreases of ≥20% from baseline - more at higher doses (Table 2). A WM patient with 6 prior lines of treatment, sustained PR underwent intra-patient dose escalation and had a dose/response relationship and very good treatment tolerance (Figure 1). The median duration at doses of 200 or 300 mg bid was >6 months (range 1-19+; including 3 cases of 11, 14, and 19+ mo.). Downstream pharmacodynamic markers of IRAK4 and molecular characteristics including cell-of-origin will be presented. Conclusion CA-4948 demonstrates good safety profile, desirable pharmacokinetic properties, and preliminary clinical activity. Enrollment is ongoing to support the anticipated RP2D of 300 mg bid. These encouraging results provide clinical validation of IRAK4 as a viable, novel therapeutic target in B-cell malignancies will lead to clinical combinations with synergistic drugs including BTK or BCL2 inhibitors [3] in patients with advanced hematological malignancies. Clinical trial: NCT03328078. References: 1. Treon, S. P. et al., 2012. N Engl J Med, 367: 826-33 2. Melgar, K. et al., 2019. Sci Transl Med, 11: eaaw8828 3. Booher R, Grayson D., 2019. Waldenstrom Roadmap Symposium, www.Curis.com Disclosures Nowakowski: Curis: Consultancy; MorphoSys: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; Kymera: Consultancy; Seattle Genetics: Consultancy. Leslie:TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Younes:Curis: Consultancy; Daiichi Sankyo: Consultancy; HCM: Consultancy; Epizyme: Consultancy; Takeda: Consultancy; Novartis: Consultancy; BioPath: Consultancy; BMS: Consultancy; Janssen: Consultancy; AstraZeneca: Current Employment. Lunning:Gilead: Consultancy, Honoraria; Curis: Research Funding; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Legend: Consultancy; ADC Therapeutics: Consultancy; Acrotech: Consultancy; Verastem: Consultancy, Honoraria; TG Therapeutics: Research Funding. Patel:Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Genentech: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Landsburg:Takeda: Research Funding; Seattle Genetics: Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding. Tun:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding.

7520 Background: We report results of a phase 2, open-label study of durvalumab (durva) in combination with R-CHOP or R2-CHOP (R-CHOP + lenalidomide) in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL). Methods: Subjects (≥18 y; ECOG 0–2) with previously untreated, high/high-intermediate risk DLBCL (IPI ≥3/NCCN-IPI ≥4) were stratified to durva + R-CHOP (Arm A, GCB DLBCL) or R2-CHOP for 6–8 cycles (Arm B, ABC DLBCL) based on cell of origin identified by gene expression followed by durva consolidation up to month 12 from start of induction. After FDA placed clinical holds on trials including combination therapy with checkpoint inhibitors and immunomodulatory agents, the study was revised to include both ABC and GCB in Arm A (durva + R-CHOP). The primary endpoint was complete response rate (CRR) at end of induction; secondary endpoints were rate of subjects continuing to consolidation, safety, and response in biological. Results: A total of 46 subjects were treated (safety; A/B, n=43/3); median age, 62/66 y; male, 61%/67%; ECOG 2, 19%/33%; Ann Arbor stage IV, 79%/33%; bulky disease: 49%/67%; double/triple-hit lymphoma, 30%/33%. As of Aug 2, 2018, 30/3 (A/B) had completed induction therapy, and 19 subjects (A) were ongoing. CRR (95% confidence interval) at end of induction was (A) 54% (37%-71%) and (B) 67% (9%-99%); 68%/67% (A/B) continued to consolidation therapy and were progression free at month 12. Safety profile was as expected for the components of the combination regimen with no new safety signal identified. Frequent treatment-emergent adverse events (TEAEs; ≥25%; A+B) included fatigue (61%), neutropenia (52%), peripheral sensory neuropathy (50%), nausea (46%), diarrhea (28%); constipation, decreased appetite, insomnia, pyrexia (24% each); and alopecia, dizziness, dyspnea, headache, stomatitis (22% each). Grade 3/4 TEAEs occurred in 84%/100% of subjects (A/B), and 3 subjects (2/1) died with no death related to study treatment. Follow-up for efficacy and safety is ongoing. Conclusions: Durva + R-CHOP combination therapy is safe and demonstrates encouraging response rates in subjects with high-risk DLBCL including double-hit lymphoma. Clinical trial information: NCT03003520.

e19055 Background: IRAK4 is a signaling modulator of Toll-like receptors (TLRs) and members of the IL-1R family. TLR/IL-1R activity is frequently dysregulated in NHL, including DLBCL and Waldenström macroglobulinemia (WM). CA-4948, an oral inhibitor of IRAK4, has demonstrated anti-tumor activity in preclinical models. Methods: Dose finding cohorts (3+3 design) will test QD or BID dosing schedule in pts with R/R NHL. Dose expansion will occur in 2 cohorts of R/R NHL with or without MYD88 mutation at the RP2D or MTD. Key eligibility criteria: age ≥ 18 years, ECOG ≤1, and adequate organ function. Objectives: safety, MTD and RP2D (primary); PK and anti-tumor activity (secondary); exploratory biomarkers and PD effects. Plasma cytokine levels are being evaluated post ex-vivo TLR stimulation in whole blood. Results: 13 pts have been treated (6 at 50 mg QD; 3 at 100 mg QD; 4 at 50 mg BID). Tumor types included DLBCL (7), FL (5), WM (1). The most frequent treatment-emergent AEs (≥10% of pts) were fatigue (23%), conjunctivitis, constipation, neutrophil count decrease, white blood cell count decrease (each 15%). One pt treated at 100 mg QD experienced Gr 3 rash which resolved following oral steroid treatment; dose reduction to 50 mg QD was tolerated without flare up. One SAE of disease progression occurred. 9 pts completed the DLT evaluation period thru Cycle 2 including 2 ongoing in Cycle 4 and 6. Preliminary PK showed that CA-4948 is rapidly absorbed with maximum plasma concentration observed 1.0 to 4.0 hrs post administration. T1/2 in plasma was about 6 hrs. Minimal to no accumulation was observed following multiple doses. Plasma exposures were dose proportional. Preliminary PD data showed, similar to murine studies, on target reduction of NF-kB-associated factors such as IL-6 post-treatment from pts with complete sample sets (N = 8). Conclusions: Current dose/schedule is well tolerated with preliminary PK and PD effects at the initial dose level. MTD has not been reached. Clinical trial information: NCT03328078.

Introduction and Purpose IRAK4 kinase activity is essential for signaling downstream of toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family in a variety of myeloid and lymphoid cell types. Dysregulated signaling in these pathways is frequently observed in NHL, particularly in ABC-subtype of Diffuse Large B-Cell Lymphoma (DLBCL) and Waldenström macroglobulinemia (WM). A phase 1 trial in patients with NHL is being conducted to determine safety, pharmacokinetics, and preliminary efficacy of CA-4948 as monotherapy. Patients and Methods At the 18-Jul-2019 data cut-off date, 22 patients have been treated with single-agent CA-4948. Five dose-escalation cohorts from 50 mg QD to 200 mg BID have been tested and cleared; a cohort of patients treated at 400 mg BID dose is currently being evaluated. Patients were diagnosed with relapsed or refractory NHL, including DLBCL (n=13), FL (n=5), HGBL with MYC and BCL2 and/or BCL6 rearrangement (n=1), WM (n=1), LPL (n=1) and MCL (n=1), had a performance status of 0 or 1 (ECOG) at baseline, and were treated in 21-day cycles until progression of disease or unacceptable toxicity, lost to follow-up or death. 5 patients had prior autologous bone marrow transplants. Results CA-4948 has been generally well tolerated. Grade 3/4 treatment-related adverse events included amylase/lipase increased, diarrhea, neutrophil count decreased, rash, rhabdomyolysis. Pharmacokinetics has shown favorable characteristics with dose-proportional increases in exposure. Five patients have been on treatment through the end of Cycle 4, including one patient in Cycle 10 on study for over 7 months. Five patients experienced overall tumor burden decreases of ≥20% from baseline, including at least 2 of 4 patients treated at 200 mg BID. Downstream pharmacodynamic markers of IRAK4 activity are being evaluated. Molecular characteristics including cell-of-origin will be presented. Conclusion CA-4948 demonstrates preliminary clinical activity. Enrollment is on-going and the MTD has not been reached. These encouraging results warrant further clinical testing in patients with advanced hematological malignancies. Clinical trial: NCT03328078. Disclosures Younes: Roche: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; AstraZeneca: Research Funding; Syndax: Research Funding; Abbvie: Honoraria; Epizyme: Consultancy, Honoraria. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Tun:Mundi-pharma: Research Funding; DTRM Biopharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Lunning:Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Curis: Research Funding; Juno Therapeutics: Consultancy, Research Funding; MiRagen: Research Funding; TG Therapeutics: Consultancy, Research Funding; Spectrum: Consultancy; VANIUM: Consultancy; Verastem: Consultancy; DAVA: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Kite: Consultancy; Gilead Sciences, Inc.: Consultancy; Seattle Genetics: Consultancy; Portola: Consultancy; OncLive: Consultancy; Novartis: Consultancy. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Martell:Curis, Inc.: Employment. Patel:AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Speakers Bureau; Sunesis: Consultancy.

Background: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adult patients who have relapsed/refractory large B cell lymphoma (LBCL) and have had ≥ 2 prior systemic therapies. In ZUMA-1, the registrational study of axi-cel in patients with refractory LBCL, the objective response rate was 83% (complete response rate, 58%), with ongoing responses in 39% after a median follow-up of 27.1 months (Locke FL, et al. Lancet Oncol. 2019). Despite the success of axi-cel, approximately 60% of patients have no response or relapse after treatment, indicating that additional strategies are needed for patients with relapsed/refractory LBCL. Preclinical murine studies have shown that rituximab augmented the tumor-suppressing effects of anti-CD19 CAR T cells, and the combination led to higher rates of tumor reduction (Mihara K, et al. Br J Haematol. 2010; Rufener GA, et al. Cancer Immunol Res. 2016). The IMiD® immunomodulatory agent lenalidomide has shown activity in patients with relapsed/refractory diffuse large B cell lymphoma and has also been shown to enhance the antitumor functions of anti-CD19 and anti-CD20 CAR T cells in mice (Otahal P, et al. Oncoimmunology. 2016). In ZUMA-14, the aim is to investigate the efficacy and safety of axi-cel in combination with rituximab or lenalidomide in adult patients with refractory LBCL. Methods: This Phase 2 study (NCT04002401) has a planned enrollment of approximately 60 patients aged ≥ 18 years with refractory LBCL, defined as a response of either progressive disease or stable disease to previous chemotherapy or progressive disease or relapse ≤ 12 months after an autologous stem cell transplant. Patients with prior IMiD® treatment, including lenalidomide, prior CAR T cell therapy, and/or prior CD19-targeted therapy are excluded. After leukapheresis, patients will be assigned 1:1 to receive axi-cel with either rituximab (Cohort 1) or lenalidomide (Cohort 2). Patients will receive lymphodepleting chemotherapy of fludarabine (30 mg/m2) and cyclophosphamide (500 mg/m2) on days -5 to -3 before axi-cel infusion (2 × 106 cells/kg) on Day 0. Cohort 1 will receive rituximab (375 mg/m2) every 28 days starting on Day -5 for a total of 6 doses. Cohort 2 will receive lenalidomide (10 mg) daily starting 7 days after leukapheresis through Day 3 and for 5 additional cycles (20 mg, first 21 days of each 28-day cycle) beginning after axi-cel infusion starting on Day 21. Patients may not receive any therapy other than conditioning therapy and rituximab or lenalidomide, as specified by cohort, between leukapheresis and axi-cel infusion. The primary endpoint is investigator-assessed complete response rate per the Lugano classification (Cheson BD, et al. J Clin Oncol. 2014). Key secondary endpoints include safety, objective response rate, duration of response, progression-free survival, overall survival, and pharmacokinetics (levels of blood CAR T cells over time). Exploratory endpoints for both cohorts include pharmacodynamic assessment of cytokine profiles and the rate of CD19-negative relapses. An additional exploratory endpoint for Cohort 2 is to investigate immunomodulation of the tumor microenvironment, including the number and activation of T cells and natural killer cells. Enrollment is expected to start in September 2019. Disclosures Neelapu: Cell Medica: Consultancy; Pfizer: Consultancy; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; Acerta: Research Funding; Karus: Research Funding; Incyte: Consultancy; Merck: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellectis: Research Funding; Allogene: Consultancy; Poseida: Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. Krish:Celgene: Consultancy, Research Funding, Speakers Bureau; Genetech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Takeda: Research Funding; Curis: Research Funding; MEI Pharma: Research Funding; Bristol Meyers Squibb: Research Funding; Xencor: Research Funding; Roche: Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Sunesis: Consultancy, Research Funding. Reshef:BMS: Consultancy; Shire: Research Funding; Incyte: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Atara: Consultancy, Research Funding; Magenta: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding. Riedell:Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Stiff:Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding. Goyal:Kite, a Gilead Company: Employment. Kawashima:Kite, a Gilead Company: Employment, Equity Ownership. Milletti:Roche: Employment, Equity Ownership, Other: Travel Expenses, Patents & Royalties; Gilead: Employment, Equity Ownership, Other: Travel Expenses, Patents & Royalties; Kite, a Gilead Company: Employment. Oliva:Kite, a Gilead Company: Employment. Sun:Kite, A Gilead Company: Employment. Munoz:Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding. OffLabel Disclosure: ZUMA-14 is a clinical trial evaluating the investigational combination of axicabtagene ciloleucel with either rituximab or lenalidomide in refractory large B cell lymphoma

Introduction: XmAb13676 is a humanized bispecific antibody that binds both CD20 and CD3 in order to recruit cytotoxic T cells to kill CD20 expressing malignant cells. Interim results of an ongoing first-in-human, dose-escalation study (XmAb13676-01; NCT02924402) in subjects with relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) are reported here. Methods: The study is a first-in-human, multi-center, open-label, phase 1, dose-escalation study in subjects with R/R NHL and R/R CLL with a standard 3 + 3 design. The primary objectives are to determine safety, tolerability, and the maximum tolerated dose (MTD) or recommended dose of XmAb13676. Secondary objectives include preliminary anti-tumor activity and PK/PD of XmAb13676. This study is designed in two parts: Part A, escalating dose cohorts that establish an initial priming dose as part of repeated weekly infusions at a fixed dose in a 28-day cycle; and Part B, with a dosing schedule consisting of a priming dose on C1D1 , established in Part A, followed by escalated dose(s) on subsequent weeks. Cytokine Release Syndrome (CRS) prophylaxis with dexamethasone was mandated prior to each administration of XmAb13676. Treatment was continued for 2 cycles or longer if there was evidence of therapeutic benefit. Results: At data cut-off, 44 subjects have been treated, 36 with NHL and 8 with CLL. NHL: Subjects with R/R NHL had a median age of 61.5 years (range 32-89), a median of 3.5 prior therapies (range 1-9) and had been diagnosed a median of 24.6 months (range 6.3-181.2) prior to treatment in the study. Treatment-emergent adverse events (TEAEs) related to treatment occurring in ˃ 3 subjects are shown in Table 1A. Nine treatment-related serious adverse events (SAE) occurred in 6 subjects. The most common treatment-related SAE was CRS, which occurred in 4 (11.1%) subjects with 1 of the events being Grade 4 and the other events being ≤ Grade 2. Treatment responses were assessed by the Lugano criteria or International Working Group criteria for Waldenström Macroglobulinemia (WM). There have been 7 objective responses: 2 complete responses (CR; DLBCL), 1 Very Good PR (VGPR; WM), and 4 partial responses (PR; 1FL, 3 DLBCL) at doses of 20-125 µg/kg. In the efficacy-evaluable population, at doses of 80-125 µg/kg, objective responses were observed in 6/18 patients. A priming dose of 45 µg/kg has been chosen for Part B. An MTD has not been reached and dose escalation is ongoing in Part B in NHL. CLL: Subjects with R/R CLL had a median age of 76 years (range 62-81), a median of 4.5 prior therapies (range 2-6) and had been diagnosed a median of 76.1 months (range 17.5-328.9) prior to treatment in the study. Treatment-related TEAEs occurring in ˃ 1 subject are shown in Table 1B. Three treatment-related serious adverse events (SAE) occurred in 2 subjects. The treatment related SAEs were CRS (Grade 3), hepatocellular injury (Grade 3), and jaundice cholestatic (Grade 2), each of which occurred in 1 (12.5%) subject. There has been 1 CR reported (Richter transformation) in 5 subjects at 20 µg/kg, the highest dose administered thus far. The treatment response was assessed by the Lugano criteria. An MTD has not been reached and dose escalation is ongoing in Part A in CLL. Conclusions: XmAb13676 demonstrated evidence of clinical activity in heavily pretreated subjects with R/R NHL and R/R CLL treated at doses between 20 and 125 µg/kg. CRS was generally manageable with premedication. The study is ongoing with further optimization of dose and schedule. Disclosures Patel: AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Speakers Bureau; Sunesis: Consultancy. Chanan-Khan:AbbVie: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding. Salles:Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; BMS: Honoraria. Cartron:Gilead: Honoraria; Jansen: Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Thomas:Celgene: Research Funding; Amgen: Research Funding; Xencor: Research Funding; BMS: Research Funding. Wierda:KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; GSK/Novartis: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Juno Therapeutics: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Pharmacyclics LLC: Research Funding; Xencor: Research Funding; Janssen: Research Funding. Liebowitz:Xencor: Employment, Equity Ownership. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Ribrag:MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel, accommodations, and expenses ; Nanostring: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses ; Incyte: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding. Saville:Xencor: Employment, Equity Ownership. Johnson:Xencor: Employment, Equity Ownership. Ly:Xencor: Employment, Equity Ownership. Phillips:Pharmacyclics: Consultancy, Research Funding; Bayer: Consultancy; Abbvie: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees.