ALBERT

Description: 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.

Description: Abstract 1953 Poster Board I-976 CD80 is a member of the B7/CD28 family of regulatory proteins. B7/CD28 proteins are expressed on the surface of cells of the adaptive and innate immune system (i.e. lymphocytes, monocyte/macrophages, dendritic cells, myeloid-derived suppressor cells). These proteins function to establish a biologically optimal and dynamic balance between immune activation and inhibition or self-tolerance. Interactions between CD80 and its receptors, which include CD28, CTLA4 and PD-L1, contribute to both stimulatory as well as inhibitory or homeostatic regulation. Galiximab, an antibody directed against CD80, is currently under investigation for the treatment of follicular NHL. Initial clinical trials demonstrated that galiximab is well tolerated and suggest that combining galiximab with rituximab may provide clinical benefit. While expression of CD80 by malignant B cells in non-Hodgkin's lymphoma (NHL) has been reported, these studies utilized poorly quantitative immunohistochemical methods. To gain further understanding of the potential role of CD80 as a therapeutic target in NHL, CD80 expression was evaluated by six-color flow cytometric analysis of primary lymphoma cell suspensions generated from diagnostic biopsies of patients presenting with lymphadenopathy. Results obtained to date confirm that CD80 is uniformly expressed by malignant cells in a large majority of cases of follicular lymphoma (N=63), diffuse large B cell lymphoma (N=38), mantle cell lymphoma (n=7), marginal zone lymphoma (n=12) and small lymphocytic lymphoma (n=9). Furthermore, CD80 expression was also observed on tumor-infiltrating, non-malignant T cells. These results confirm the nearly ubiquitous expression of CD80 by malignant B cells in follicular, diffuse and other low grade NHL. Furthermore, these data demonstrate expression of CD80 by non-malignant cells (e.g. T cells) that define the tumor microenvironment. Further work to expand this dataset and to evaluate the expression of CD80 in non-T, non-B cells is ongoing. The expression of CD80 by malignant cells as well as non-malignant cells in NHL provides an opportunity to not only employ therapeutic antibodies to direct anti-tumor effector function such as antibody-dependent cellular cytotoxicity, but to also potentially interfere with interactions involving CD80 that might be involved in establishing an immune suppressive microenvironment supportive of tumor growth. Disclosures: No relevant conflicts of interest to declare.

Description: MGd is a novel anti-cancer agent that induces apoptosis in NHL cell lines in part by targeting oxidative stress related proteins and has been shown in solid tumor studies to enhance ionizing radiation. We reasoned that response rates could be improved by combining MGd concurrently with RIT in NHL. We conducted a phase I/II trial for patients (pts) with relapsed/refractory NHL using fixed-dose Zevalin® with increasing doses of MGd (2.5 mg/kg, 3.5 mg/kg, 5.0 mg/kg). Pts received 8 MGd doses on days 1 to 4 (111Indium-Zevalin day 1) and days 8 to 11 (90Y-Zevalin day 8). Restaging CTs were performed 4 weeks after MGd/ 90Y-Zevalin. Response was assessed by the International Workshop NHL response criteria (Cheson, 1999). 30 pts enrolled, and 28 are evaluable for toxicity and response (see table). 23 of 28 pts (82%) were rituximab-refractory (Rit-Ref) (defined as no response or time to progression (TTP) of age 75 60 (47–85) 77 (48–87) Median prior treatments (range) 3 (1–5) 3 (1–4) 2 (1–4) Stage III/IV at study entry 19/28 (68%) 11/14 (79%) 7/10 (70%) Bulky disease (〉5cm) at study entry 15/28 (54%) 9/14 (64%) 4/10 (40%) Elevated LDH at study entry 10/28 (36%) 6/14 (43%) 4/10 (40%) Best ORR (CR rate) 57% (46% CR) 86% (64% CR) 20% (20% CR) ORR (CR rate) at 4 Weeks 57% (21% CR) 86% (21% CR) 20% (20% CR) TTP, months (range) 9 (2–31+) 10 (2–31+) 4 (2–29+) 2-year OS 76% 93% 50%

Description: Objective: To report a cohort of patients with lymphoid tumors of the orbit, including 1 with benign lymphoid hyperplasia of the orbit whose disease responded to immunotherapy with rituximab alone or rituximab followed by Zevalin (yttrium-90 ibritumomab tiuxetan) radioimmunotherapy. Methods: Between October 2002 and January 2005, 8 patients with low-grade non-Hodgkin’s lymphoma and 1 with benign lymphoid hyperplasia of the orbit were treated with monoclonal antibodies against CD20. Five patients with low-grade lymphoma of the orbit (3 with follicular B cell or 2 with MALT) received rituximab followed by yttrium-90 ibritumomab tiuxetan, 2 patients with low-grade orbital lymphoma (1 with follicular B-cell and the other with small lymphocytic lymphoma) and 1 patient with benign lymphoid hyperplasia received rituximab alone. Three out of the 5 patients who received yttrium-90 ibritumomab tiuxetan were part of a prospective trial evaluating the efficacy of yttrium-90 ibritumomab tiuxetan for low-grade B-cell lymphoma of the orbit; the other 2 had been treated in other open label trials at M. D. Anderson Cancer Center. For each patient, clinical records and imaging studies were reviewed to establish the diagnosis and document response. Results: Three men and 5 women in this cohort were between the age of 23 and 83 years old (median age, 63 years). Of the 7 patients with orbital lymphoma, 4 had stage IE and the other 3 had stage IVE, and 6 had previously untreated disease. All 8 patients experienced resolution of the orbital tumor in response to treatment with monoclonal antibodies against CD20. Follow-up time ranged from 6 months to 32 months (mean, 12 months) after completion of immunotherapy. There were no serious systemic or ocular side effects during the study period. The most commonly experienced side effect was mild fatigue. All 5 patients treated with yttrium-90 ibritumomab tiuxetan had transient pancytopenia, which normalized as expected within 3 months after treatment. One patient who received yttrium-90 ibritumomab tiuxetan developed shingles 6 weeks after treatment. There were no sequelae from this infection, which resolved with the usual course of oral antiviral therapy. Conclusions: Rituximab and yttrium-90 ibritumomab tiuxetan may be considered as alternative treatment modalities to external beam radiation therapy for low-grade B-cell follicular non-Hodgkin’s lymphoma or MALT of the orbit. Systemic targeted immunotherapy may potentially have the advantage of lower rate of distant (out-of-field) relapse and less ocular toxicity compared with external beam radiotherapy; these potential advantages would have to be verified in long-term studies and in larger numbers of patients.

Description: There are limited data on the relative efficacy of initial therapies for follicular NHL, in part due to the large sample size and prolonged follow-up required for comparative trials of induction regimens, and now complicated by the use of maintenance rituximab. To gain perspective in the comparison of different induction regimens (separate from rituximab maintenance), we performed a meta-analysis of trials in frontline indolent NHL, focusing on the clinical outcome measure of complete response rate (CRR) and its relation to disease progression. A literature search of clinical trials in untreated follicular NHL published from 2001–2006 was performed on Medline, Embase, Current Contents, and Biosis. Baseline characteristics, ORRs, CRRs, and time-to-event rates (TTP, PFS, EFS) were extracted. Studies were included only if they reported follicular-specific data. Therapies were induction and/or consolidation therapy, excluding trials with rituximab maintenance. Treatment categories were chemotherapy combinations without fludarabine (CHEMO); rituximab as a single-agent or in combination with chemotherapy (R±CHEMO); fludarabine as a single-agent or in combination (FLU); and ibritumomab tiuxetan or tositumomab as single agents or in combination (RIT). The Kruskal-Wallis test was used to compare baseline characteristics. CRRs were analyzed using the fixed effect model (Mantel-Haenszel) and the random effect model (DerSimonain and Laird). Reported time-to-event rates required a conversion to a standard monthly event rate (HR), assuming an exponential distribution. The Pearson correlation (rho) between the CRR and HR was estimated. 32 treatments from 25 publications with 2421 patients met the inclusion criteria—8 CHEMO, 13 R±CHEMO, 5 FLU and 6 RIT. Only median age and disease stage were consistently reported. Median age and proportion of stage 3–4 disease did not differ between treatment groups. Heterogeneity among the treatments was analyzed using an analog of ANOVA. There was a significant difference in CRRs between CHEMO, R±CHEMO, FLU and RIT (P=0.03). Random effect estimation showed a CRR of 37% with CHEMO (95% CI: 18%–57%), 53% with R±CHEMO (34%–71%), 68% with FLU (49%–87%), and 79% with RIT (73%–85%) (fig 1). There was a highly significant linear correlation between the CRR and HR for disease progression with all treatments (rho= −0.79; 95% CI: −0.57 to −0.91; P

Description: Background: Blasts and leukemic stem cells of acute myeloid leukemia (AML) as well as several other hematologic malignancies express CD123, potentially providing a target for novel therapies. XmAb14045 (also known as SQZ622) is a potent bispecific antibody targeting both CD123 and CD3 that stimulates targeted T cell-mediated killing of CD123-expressing cells, regardless of T cell antigen specificity. It is a full-length immunoglobulin molecule designed to be dosed intermittently, in contrast to smaller constructs that are referred to as "DART" or "BiTE" bispecific antibodies that require a continuous infusion. Methods: Patients with relapsed or refractory AML, B cell acute lymphoblastic leukemia (B-ALL), blast phase chronic myelogenous leukemia, or blastic plasmacytoid dendritic cell neoplasm were eligible to enroll on this first-in-human, multicenter, open-label phase 1 dose-escalation study (XmAb14045-01) with standard 3+3 design. The primary objective was to estimate the maximum tolerated dose (MTD) or recommended dose and schedule of XmAb14045. Secondary objectives included safety, preliminary antileukemic activity, and pharmacokinetics/pharmacodynamics of XmAb14045. Treatment was administered weekly in 28 day cycles, using a weight-based dose with a single dose level in Part A and, in Part B, an initial priming dose on Day 1 followed by an escalated dose on subsequent weeks. Premedication to prevent cytokine release syndrome (CRS) was instituted as needed and included a steroid, acetaminophen, and diphenhydramine. Patients were premedicated at all XmAb14045 doses ≥0.075 µg/kg. Therapy was continued for as long as tolerated and there was continuing evidence of therapeutic benefit in the opinion of the investigator. Treatment response was assessed by the 2017 European LeukemiaNet (ELN) criteria after Cycle 1 and after each odd-numbered cycle. CRS was graded using the CRS revised grading system (Lee et al., Blood, 2014). Results: At data cut-off, 64 patients have been treated to date, 63 with relapsed/refractory AML and 1 with B-ALL. Patients had a median age of 61 years and were heavily pretreated (median of 3 prior therapies [range 1-8], including 19 [30%] who had undergone prior allogeneic stem cell transplantation). The recommended dose for Part A was 1.3 µg/kg after a single dose-limiting toxicity of Grade 4 CRS at 2.3 µg/kg; no MTD has been identified. CRS or its component symptoms was the most common treatment-emergent adverse event (TEAE). CRS episodes began within approximately 1-4 hours of the start of drug infusion and occurred in 49 of 64 patients (77%). Seven patients (11%) developed Grade ≥3 CRS, the majority of these on the first dose. There were no CRS-related deaths. Excluding CRS-related events, additional TEAEs occurring in 〉10% of patients included fatigue (31%), febrile neutropenia (30%), peripheral edema (30%), cough (23%), elevated hepatic transaminases (19%; all recovered without sequelae), pneumonia (17%), stomatitis (14%), hyperglycemia (13%), and sepsis (11%). No myelosuppression requiring dose modification or evidence of tumor lysis syndrome was seen. In Part A, single agent antileukemic activity was documented with a best response of CR (2) or CRi (1) in 3/13 AML patients (CR/CRi rate 23%) treated at the two highest dose levels studied to date (1.3 and 2.3 µg/kg weekly); no CR, CRi, or morphologic leukemia-free state (MLFS) responses were seen at lower doses. Antileukemic activity occurred quickly; all responders had achieved at least an MLFS response after 4 doses (1 cycle). Two responders were bridged to stem cell transplantation, and the third was ineligible for medical reasons but remains in remission at 14+ weeks after initiating therapy. Conclusions: XmAb14045 demonstrated evidence of antileukemic activity in heavily pretreated patients with relapsed/refractory AML treated in Part A at the 1.3 and 2.3 µg/kg doses administered once weekly, with a 23% CR/CRi rate. CRS was the most common toxicity but was generally manageable with premedications. The study is ongoing with further optimization of dose, schedule, and premedication regimen for CRS anticipated during accrual to dose escalation cohorts in Part B. ClinicalTrials.gov Identifier: NCT02730312 Disclosures Ravandi: Xencor: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding. Foran:Xencor, Inc.: Research Funding; Agios: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Mawad:Swedish Cancer Institute: Employment. Blum:Astellas: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Research Funding; Forma: Research Funding; Xencor: Research Funding; Tolero: Research Funding. Saville:Xencor, Inc.: Employment, Equity Ownership. Johnson:Xencor, Inc.: Employment, Equity Ownership. Vanasse:Novartis: Employment, Equity Ownership. Ly:Xencor, Inc.: Employment, Equity Ownership. Mims:Novartis: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: Since rituximab is known to rapidly deplete B lymphocytes in the blood for 6–12 months after administration, there has been interest in determining whether this results in a clinically significant impact on humoral responses to common vaccines. Therefore, we designed a trial in patients with lymphoma to study vaccination response to recall and novel antigens and to document any changes in antibody titers to specific common antigens following rituximab treatment. Vaccination of healthy control subjects served as a control for vaccine effectiveness. Design: The trial evaluated responses to neoantigen (keyhole limpet hemocyanin, KLH) as well as a recall antigen (tetanus) in 2 groups: rituximab-treated subjects with relapsed/refractory indolent non-Hodgkin’s lymphoma (NHL) and an age-matched control group of untreated healthy volunteers. Rituximab was dosed at 375 mg/m2 weekly × 4 in the NHL group, and immunization occurred 36 weeks later (or immediately in the control subjects) with tetanus (0.5 mg single dose) and KLH (1 mg weekly × 2). Titers were evaluated 28 days after the start of vaccination in all subjects. In addition, titers to a selected panel of bacterial and viral antigens were measured in the NHL subjects from pre-treatment through 40 weeks follow-up. Endpoints: Primary-- the proportion of subjects in each group with either a doubling of titers to tetanus toxoid from baseline, or if the baseline was