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TPS2659 Background: Leukocyte-Associated Immunoglobulin-like Receptor (LAIR)-1 and LAIR-2 are members of the Leukocyte Receptor Complex (LRC) (An & Brodsky, 2016). LAIR-1 is a co-inhibitory receptor expressed on several subsets of immune cells, and functions to delimit immune responses (Meyaard et al., 1997). LAIR-2 is a secreted protein with homology to the transmembrane protein LAIR-1 (Lebbink et al., 2008). In cancer, it is hypothesized that LAIR-1 expression on several subsets of leukocytes prevents optimal immune responses by limiting both innate and adaptive immune functionality. LAIR-1 serves to suppress anti-tumor immunity through the inhibition of stimulatory signaling pathways. Specifically, LAIR-1 is a checkpoint and adhesion receptor on T cells that limits T cell activation and increases adhesion to collagens (Meyaard, 2008). LAIR-2 is capable of blocking LAIR-1 functional interactions with ligands, resulting in improved immune function on multiple immune cell subsets. Dysregulation of LAIR-1 ligands in the tumor microenvironment results in excessive production of collagens and complement C1q as well as altered forms of collagens, that leads to immune inhibition through binding to LAIR-1+ immune cells. NC410 is a dimeric form of the LAIR-2 protein fused to a human Fc domain of the immunoglobulin (Ig) subtype IgG1. The rationale for developing NC410 as a cancer therapeutic is based on nonclinical data demonstrating LAIR-1 signaling blockade can improve the immune response. Because LAIR-2 binds to ligands shared with LAIR-1 with increased affinity, NC410 acts as a decoy receptor for LAIR-1 ligands releasing suppression from myeloid cells and T cells and promoting anti-tumor immunity. NC410 may also mediate remodeling of the tumor extracellular matrix, further contributing to anti-tumor activity. Methods: This is a multi-center, first in human, phase 1/2, open-label, single-armed study to determine the safety and tolerability, define maximum tolerated dose (MTD) and/or pharmacologically active dose, assess preliminary efficacy, and explore predictive and pharmacodynamic biomarkers of NC410 in subjects with advanced or metastatic solid tumors. Key eligibility criteria include measurable disease based on RECIST v1.1 and being able to consent for collection of biopsies at screening and on treatment. Phase 1 is a classic 3+3 dose escalation design to determine the safety, tolerability, DLT, MTD and recommended phase 2 dose (RP2D) (NCT04408599). Ongoing exploratory analyses include the assessment of predictive biomarkers associated with treatment benefit, and pharmacodynamic markers associated with study drug activity. Phase 2 is going to enroll ovarian, colorectal, NSCLC, H&N, and gastric carcinomas and other tumors depending on biomarker data available from the Phase 1 part of the study. Clinical trial information: 04408599.

Abstract Abstract 586 Background: Dacetuzumab (SGN-40), a humanized monoclonal antibody that targets CD40, mediates antitumor activity through multiple mechanisms of action, including effector cell functions (ADCC/ADCP) and direct apoptotic signal transduction. Ongoing evaluation of the molecule has led to 2 additional key findings: a gene signature that predicts sensitivity to single-agent dacetuzumab, and upregulation of the pro-apoptotic and chemosensitizing transcription factor TAp63αa when dacetuzumab is combined with rituximab (R) and gemcitabine (GEM). In prior single-agent dacetuzumab trials, several patients who were immediately treated with GEM after progressing achieved unexpected responses. These observations provided rationale for further analysis of the combination of dacetuzumab, R and GEM. Methods: A phase 1b dose-escalation study to evaluate the safety and adverse event profile of dacetuzumab, R and GEM was conducted in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Patients received dacetuzumab at cohort-specific doses of 8 or 12 mg/kg IV weekly in combination with R (375 mg/m2 IV for 1 cycle, then once/28-day cycle) and GEM (1000 mg/m2 IV weekly or biweekly) in a 3 + 3 dose-escalation scheme. A maximum number of 8 cycles was permitted. Eligible patients included those with de novo DLBCL, including transformed lymphoma and follicular grade 3, who failed potentially curative therapy. Results: Thirty-one patients with a median age of 68 years (range 29–80) were enrolled and treated in the study (3 patients in each of 3 cohorts + 22 in an expansion cohort). The median number of prior regimens was 3 (range 1–18); 10 patients (32%) had transformed histology and 4 (13%) had prior ASCT. The median number of cycles received was 3 (range 1–8), although 11 patients are still on treatment. Three patients in the first cohort required dose reduction of GEM due to transient, non-dose-limiting thrombocytopenia. The protocol was thus amended to administer GEM on a biweekly schedule. No dose-limiting toxicity was observed, and MTD was not defined. Based on pharmacokinetic modeling suggesting no significant difference in exposure between dose levels, 8 mg/kg of dacetuzumab was chosen as the dose for the expansion cohort. The combination of dacetuzumab, R and GEM was generally well tolerated. Across all cohorts, the most common adverse events (> 15%) were nausea (42%), thrombocytopenia (35%), fatigue (32%), headache (29%), anorexia (19%), dyspnea (19%), pyrexia (19%), diarrhea (16%), and neutropenia (16%), the majority of which were Grade 1 or 2. Grade 3/4 adverse events related to dacetuzumab occurred infrequently. One patient experienced Grade 3 stress cardiomyopathy that resolved; this patient had a history of congestive heart failure. One patient developed pneumonitis in the left lung and acute respiratory distress syndrome, and subsequently died due to pulmonary toxicity; this patient had received prior radiation therapy to the left chest. There was preliminary evidence of antitumor activity. Of the 28 patients with response assessments, 7 patients achieved CR, 8 PR, 7 SD, and 6 PD per investigator assessment of response, yielding an objective response rate of 54%. Of interest, 1 patient who previously failed ASCT achieved a CR and was able to undergo allogeneic transplant. To date, this patient remains in CR. Conclusion: The combination of dacetuzumab, R and biweekly GEM was generally well tolerated. Evidence of antitumor activity with this combination is encouraging as multiple responses were observed in a population with heavily pre-treated patients. Further investigation with a randomized trial is warranted to more fully characterize safety and efficacy and to determine if sensitivity to this combination correlates with the previously identified single-agent predictive gene signature. Disclosures: Forero-Torres: Seattle Genetics, Inc.: Research Funding. Off Label Use: Gemcitabine has not been FDA approved for treatment of lymphoma. Dacetuzumab is an investigational agent.. Bartlett:Seattle Genetics, Inc.: Research Funding. Nasta:Seattle Genetics, Inc.: Research Funding; Genentech: Speakers Bureau. Northfelt:Seattle Genetics, Inc.: Research Funding. Beaven:Seattle Genetics, Inc.: Research Funding. Myint:Seattle Genetics, Inc.: Research Funding. Whiting:Seattle Genetics, Inc.: Employment, Equity Ownership. Drachman:Seattle Genetics, Inc.: Employment, Equity Ownership. Moskowitz:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background and Aims A platelet count ≤100,000/µL is regarded as an independent prognostic marker for the development of leukemia and is associated with inferior survival in myelofibrosis (MF) (Huang et al. 2008). The approved JAK2 inhibitor, ruxolitinib, is associated with treatment-emergent thrombocytopenia, and patients with platelets ≤100,000/µL were excluded from the phase III COMFORT trials. Efficacy and safety data are limited in patients with MF and platelets ≤100,000/µL treated with ruxolitinib. Pacritinib (SB1518), an oral JAK2/FLT3 inhibitor, did not appear to be associated with clinically significant treatment emergent anemia or thrombocytopenia during early phase studies in patients with myeloid and lymphoid malignancies. This integrated analysis was performed to further evaluate the safety and efficacy of pacritinib in MF patients with baseline platelet counts of ≤100,000/µL. Methods The databases from 2 phase I/II clinical trials of pacritinib in advanced myeloid malignancies and MF were integrated to evaluate the rate of adverse events (AEs) and favorable spleen responses in patients with MF and thrombocytopenia. Results One hundred twenty-nine patients with advanced myeloid malignancies and MF were treated with pacritinib in phase I and II clinical trials. Sixty-five patients with MF were treated with 400 mg orally once daily in 2 phase II studies. Of these, 28 patients with MF [21 primary MF (75%), 5 post-polycythemia vera-MF, 2 post-essential thrombocytosis-MF] had baseline platelet counts of ≤100,000/µL (median: 58,500/µL, range: 15,000/µL – 97,000/µL). The median age was 69 years. Twenty three (82%) patients had the JAK2V617F mutation. During the phase 2 studies, spleen volume responses were assessed by MRI and are shown for all patients (Figure 1) and for patients with platelets ≤100,000/µL (Figure 2). Thirty-seven percent and 43% of all evaluable patients and patients with ≤100,000/µL platelets, respectively, had ≥35% reduction in spleen volume from baseline (Table). Among the 21 informative patients with allelic JAK2V617F quantification at more than 1 study visit, 3, including 2 patients with homozygous mutations, had ≥35% reduction in spleen volume and substantial reductions in allelic burden from baseline (mean reduction 64%, range 44 to 88%). In the 11 (17%) patients with MF and baseline platelet counts ≤50,000/μL, overall spleen volume reduction was 38% (3/8) in evaluable patients and the median decline in platelet count observed at study end was 6,000/µL. Integrated safety analysis for all 129 patients with advanced myeloid malignancies showed the most common adverse events (AEs) were gastrointestinal (GI), predominantly diarrhea, and most of these were grade 1 (43%) and grade 2 (26%). The time to onset of diarrhea was ≤30 days in the majority of those affected, but only 2% had drug discontinuation as a consequence. Among the 129 patients in the phase 1 and 2 trials, 57 patients had ≤100,000 platelets; of these 26 (46%) had no CTC grade change in hemoglobin (Hb) and platelet counts from baseline values. Hb and platelet counts improved by one grade in 16% and 18% of patients, respectively. One grade worsening was seen in 28% and 30% in Hb and platelet counts, respectively. Conclusions Pacritinib was well-tolerated in patients with MF, regardless of their baseline platelet counts. Grade 1 or 2 GI toxicities, particularly diarrhea, were the most common AEs. Spleen responses were similar in patients regardless of baseline platelet counts (≥100,000/µL vs. ≤100,000/µL). Notably, even patients with initial platelet counts ≤50,000/µL tolerated therapy and the majority maintained stable hemoglobin and platelet counts. A phase III trial will evaluate pacritinib versus best available therapies in patients with MF and platelet counts ≤100,000/µL. Disclosures: Dean: Cell Therapeutics, Inc: Employment. Cernohous:Cell Therapeutics, Inc: Employment. Mesa:Incyte, CTI, Gilead, Celgene, Genetech, NS Pharma, Lilly: Research Funding. Campbell:Cell Therapeutics, Inc: Employment. Caldwell:Cell Therapeutics, Inc: Employment. Wang:Cell Therapeutics, Inc.: Employment. Myint:Cell Therapeutics, Inc: Employment.