scholarly journals Administration of KER-047, a Novel ALK2 Inhibitor, Elicited Robust and Sustained Increases in Serum Iron in Healthy Participants

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-13
Author(s):  
Claudia Ordonez ◽  
Snyder Ben ◽  
Rachel Barger ◽  
Timna Serino ◽  
Claire C Tseng ◽  
...  
Keyword(s):  
Multiple Dose ◽  
Serum Iron ◽  
Phase 1 ◽  
Transferrin Saturation ◽  
Liquid Formulation ◽  
Publicly Traded ◽  
Hemoglobin Content ◽  
Phase 1 Study ◽  
The Past ◽  
Healthy Participants

Background: Hepcidin is the master regulator of iron homeostasis. Its expression is controlled, in part, by signaling through TGF-β receptors including activin receptor-like kinase-2 (ALK2). As part of a negative feedback loop, high hepcidin levels increase expression of matriptase-2, which cleaves the ALK2 co-receptor hemojuvelin from the cell surface and suppresses ALK2 signaling. Dysregulation of the negative feedback system results in high hepcidin, which mobilizes iron from storage tissues and leads to insufficient iron for red blood cell production in the bone marrow, resulting in anemia. KER-047 is a selective ALK2 inhibitor that has the potential to normalize ALK2 signaling and the downstream sequalae that results in anemia as a result of elevated hepcidin. Aims: The objective of this Phase 1 study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of single and multiple ascending dose levels of KER-047 in healthy participants. Methods: In Part 1, two formulations of KER-047 were evaluated in single ascending oral doses ranging from 1 mg to 300 mg of a capsule formulation, and 30 mg to 450 mg of a liquid formulation or placebo. In Part 2, the liquid formulation was evaluated in multiple ascending doses (50 mg, 100 mg, 200 mg and 350 mg) of KER-047 or placebo, administered daily for up to 7 days. Endpoints included adverse events (AEs) and pharmacokinetic and pharmacodynamic parameters. Informed consent was obtained from all participants prior to enrollment in the study. Results: Part 1 enrolled 80 participants; 60 received a single dose of KER-047 and 20 received placebo. Part 2 enrolled 41 participants; 32 received KER-047 and 9 received placebo daily for up to 7 days. There were no serious adverse events in either part of the study. In Part 1, 3 (9.4%) participants discontinued the study; none discontinued due to AEs. In Part 2, 3 (9.4%) participants administered KER-047 and 1 (11.1%) placebo discontinued the study; of these, 2 participants discontinued due to an AE (one in the 200 mg group and one on placebo). In Part 2, 1 of 8 (12.5%) administered 200 mg and 4 of 8 (50%) participants administered 350 mg discontinued study drug due to AEs. The majority of AEs observed in participants administered KER-047 were mild or moderate in severity; severe AEs were reported only at the 350 mg multiple dose in 1 of 8 (12.5%) participants. AEs reported in ≥2 of participants administered KER-047 and higher than placebo were: headache, nausea, vomiting, diarrhea, gastroenteritis, chills, pyrexia, myalgia, decreased appetite, lymphopenia, neutropenia, and liver enzyme increases. Decreases in lymphocyte and neutrophil counts were observed at 200 mg and 350 mg. Mean KER-047 AUC and Cmax increased linearly, with greater than dose-proportional increases observed across multiple doses from 50-200 mg. Half-life values ranged from approximately 10 to 15 hours. Administration of KER-047 elicited rapid, robust and sustained dose-related increases in serum iron and transferrin saturation. Increases in serum iron and transferrin saturation were observed beginning on Day 2 after single doses and were sustained after multiple doses. Decreases in ferritin were also observed. Decreases in serum hepcidin post-dose were also observed in all the multiple dose cohort in which changes were evaluated. Reticulocyte hemoglobin content increased starting on Day 3 post-dosing indicating increased iron availability in the bone marrow. Summary: In healthy participants, administration of KER-047 elicited rapid, robust and sustained dose-related increases in serum iron and transferrin saturation that were associated with decreases in ferritin and hepcidin. The observed decrease in ferritin and hepcidin coupled with increases in reticulocyte hemoglobin content are indicative of increased iron mobilization, resulting in increased iron incorporation into hemoglobin. The tolerability profile of KER-047 in healthy participants has been characterized in this Phase 1 study. KER-047's unique pharmacologic effect on hepcidin and iron mobilization has the potential to treat anemia that results from elevated hepcidin. Table Disclosures Ordonez: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company; Ackea Therapeutics: Ended employment in the past 24 months. Ben:Nucleus Network: Current Employment. Barger:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Serino:BioBridges: Ended employment in the past 24 months; Keros Therapeutics: Current Employment. Tseng:Mitobridge: Current equity holder in private company; Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Rovaldi:Keros Therapeutics: Consultancy. Lachey:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Seehra:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Abstract 2899: Multiple-dose phase 1 study of 3,3′-diindolylmethane (DIM): Pharmacokinetics and biological effects

2010 ◽  
Author(s):  
Gregory A. Reed ◽  
Jean M. Sunega ◽  
Kevin Latinis ◽  
John Gray ◽  
James A. Crowell ◽  
...  
Keyword(s):  
Multiple Dose ◽  
Biological Effects ◽  
Phase 1 ◽  
Phase 1 Study

scholarly journals Cedar Trial in Progress: A First in Human, Phase 1/2 Study of the Correction of a Single Nucleotide Mutation in Autologous HSCs (GPH101) to Convert HbS to HbA for Treating Severe SCD

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1864-1864
Author(s):  
Julie Kanter ◽  
John F. DiPersio ◽  
Patrick Leavey ◽  
David C. Shyr ◽  
Alexis A Thompson ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Gene Correction ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
The Past ◽  
Adult Hemoglobin

Abstract Background Sickle cell disease (SCD) is a recessive monogenic disease caused by a single point mutation in which glutamic acid replaces valine in Codon 6 of the human beta-globin gene (HBB) leading to the production of abnormal globin chains (HbS) that polymerize and cause erythrocytes to sickle. This results in hemolytic anemia, vaso-occlusion and organ damage, which leads to lifelong complications and early mortality. Allogeneic hematopoietic stem cell transplant (allo-HSCT) is the only known cure for SCD, however, its use is limited by the lack of well-matched donors, need for immunosuppression, risk of graft versus host disease and graft rejection. GPH101 is an investigational, autologous, hematopoietic stem cell (HSC) drug product (DP) designed to correct the SCD mutation in the HBB gene ex vivo using a high fidelity Cas9 (CRISPR associated protein 9) paired with an AAV6 (adeno-associated virus type 6) delivery template, efficiently harnessing the natural homology directed repair (HDR) cellular pathway. This approach has the potential to restore normal adult hemoglobin (HbA) production while simultaneously reducing HbS levels. In preclinical studies, HBB gene correction in SCD donor HSCs resulted in ≥60% of gene-corrected alleles in vitro with minimal off-target effects. Gene corrected cells were successfully differentiated toward the erythroid lineage and produced ≥70% HbA in vitro. Long-term engraftment of gene-corrected HSCs was demonstrated in vivo, following transplant into immunodeficient mice, with multi-lineage allelic gene correction frequencies well above the predicted curative threshold of 20%, with potential of this approach to be equivalent or superior to allo-HSCT. In addition, HSC-based correction in an SCD mouse model led to stable adult hemoglobin production, increased erythrocyte lifespan and reduction in sickling morphology, demonstrating the therapeutic potential of this gene correction platform as a curative approach in SCD. Study Design and Methods CEDAR (NCT04819841) is a first-in-human, open-label, single-dose, multi-site Phase 1/2 clinical trial in participants with severe SCD designed to evaluate safety, efficacy and pharmacodynamics (PD) of GPH101. Approximately 15 adult (18-40 years) and adolescent (12-17 years) participants will be enrolled across 5 sites, with adolescent enrollment proceeding after a favorable assessment of adult safety data by a Safety Monitoring Committee. Participants must have a diagnosis of severe SCD (βS/βS), defined as ≥ 4 severe vaso-occlusive crises (VOCs) in the 2 years prior and/or ≥ 2 episodes of acute chest syndrome (ACS), in 2 years prior with at least 1 episode in the past year. Participants on chronic transfusion therapy may be eligible if required VOC and ACS criteria are met in the 2 years prior to the initiation of transfusions. Key exclusion criteria include availability of a 10/10 human leukocyte antigen-matched sibling donor, or prior receipt of HSCT or gene therapy. After eligibility confirmation including screening for pre-treatment cytogenetic abnormalities, participants will undergo plerixafor mobilization and apheresis, followed by CD34+ cell enrichment and cryopreservation, undertaken locally at each trial site before shipment to a centralized manufacturer for GPH101 production. After GPH101 release, participants will undergo eligibility reconfirmation prior to busulfan conditioning and DP infusion. Safety, efficacy and PD measurements will occur for 2 years post-infusion; a long-term follow up study will be offered to participants for an additional 13 years of monitoring. The primary endpoint for this study is safety, measured by the kinetics of HSC engraftment, transplant related mortality, overall survival and frequency and severity of adverse events. Secondary endpoints will explore efficacy and PD, including levels of globin expression as compared to baseline, gene correction rates, clinical manifestations of SCD (including VOC and ACS), laboratory parameters, complications and organ function. In addition, cerebral hemodynamics and oxygen delivery will be assessed by magnetic resonance techniques. Key exploratory endpoints include evaluation of patient-reported outcomes, erythrocyte function, on-target and off-target editing rates, and change from baseline in select SCD characteristics. Disclosures Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy. Thompson: Agios Pharmaceuticals: Consultancy; Graphite Bio: Research Funding; Vertex: Research Funding; Beam Therapeutics: Consultancy; Celgene: Consultancy, Research Funding; Biomarin: Research Funding; Baxalta: Research Funding; CRISPR Therapeutics: Research Funding; Global Blood Therapeutics: Current equity holder in publicly-traded company; bluebird bio: Consultancy, Research Funding; Novartis: Research Funding. Porteus: Versant Ventures: Consultancy; CRISPR Therapeutics: Current equity holder in publicly-traded company; Allogene Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Ziopharm: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Intondi: Graphite Bio: Current Employment, Current equity holder in publicly-traded company; Global Blood Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Lahiri: Graphite Bio: Current Employment, Current equity holder in publicly-traded company. Dever: Graphite Bio: Current Employment, Current equity holder in publicly-traded company. Petrusich: bluebird bio: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Graphite Bio: Current Employment, Current equity holder in publicly-traded company. Lehrer-Graiwer: Global Blood Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Graphite Bio: Current Employment, Current equity holder in publicly-traded company.

Siltuximab Treatment Increases Hemoglobin (Hb) Levels: Preliminary Results From a Prospective Phase 1 Study In Refractory Solid Tumors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5150-5150
Author(s):  
R. Kurzrock ◽  
E. Angévin ◽  
S. Cohen ◽  
J. Van Laethem ◽  
B. Rijnbeek ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Research Funding ◽  
Serum Iron ◽  
Binding Capacity ◽  
Iron Status ◽  
Phase 1 ◽  
Transferrin Saturation ◽  
Maximum Increase ◽  
Baseline Serum ◽  
Clinically Significant

Abstract Abstract 5150 Introduction: Siltuximab is a chimeric monoclonal antibody with high affinity for the inflammatory cytokine, IL-6, which is currently being studied in hematologic, solid malignancies and multicentric Castleman's disease (MCD). In addition to representing a therapeutic target, IL-6 is reported to play a key role in the etiology and symptoms of anemia of cancer. A possible mechanism is through up-regulation of hepatic production of hepcidin, the central iron-regulatory hormone. Siltuximab treatment has previously been shown to be associated with clinically significant Hb increases in MCD (a disorder caused by deregulated IL-6 production) and renal cell carcinoma. We have prospectively studied the Hb response in the context of a phase I study with siltuximab in patients with advanced solid tumors. Patients and Methods Siltuximab was administered intravenously to patients with any advanced solid tumor at increasing dose levels (2.8 or 5.5 mg/kg every 2 weeks, 11 or 15 mg/kg every 3 weeks). Hepcidin (C-ELISA), Hb, CRP (marker for inflammation) and iron status (serum iron, ferritin, transferrin saturation, total iron binding capacity) were measured at baseline and serially during treatment. IL-6 was not measured since interference of the drug with assay performance prevents accurate measurement of bioactive IL-6. The relationships between these biomarkers and Hb response (defined as a maximum Hb increase of ≥1 g/dL during treatment) were evaluated. Results: Forty-four pts (18 colorectal, 12 ovarian, 5 pancreatic, 9 other) received a median of 3 siltuximab cycles (range 1 – 25). Eight patients were excluded from analysis because they received blood transfusions or ESAs. There were no objective tumor responses (CR or PR). Baseline Hb ranged from 9.4–15.3 g/dL (median 12.2). All 36 evaluable patients had an increase in Hb (median 1.35 g/dL; range 0.1–3.2). Eleven (31%) patients had a maximum increase of ≥2 g/dL. Maximum Hb levels did not exceed the upper limit of normal. Baseline hepcidin (median 118.6 ng/mL; range 9.5–493.3) was positively correlated with baseline CRP (median 13.6 mg/L; range 0.42–152.0) (p<0.05) and ferritin (median 346 pmol/L; range 74.2–8543.1) (p<0.05) but not with baseline Hb or Hb response. For subjects with a Hb response of more than 2 g/dL an association was found with Day 8 hepcidin (p = 0.03) when controlled for baseline serum iron. Early hepcidin percentage change was not correlated with Hb response. Conclusion: Siltuximab treatment was associated with clinically meaningful Hb response in this moderately anemic refractory cancer population. The exact mechanism of action remains uncertain, however correlation with additional markers (e.g., soluble transferrin receptor, inflammatory markers such as IL-6) might also be important to identify patients most likely to respond to treatment and should be evaluated further in randomized trials. Disclosures: Kurzrock: Johnson & Johnson: Research Funding. Angévin:Johnson & Johnson: Research Funding. Cohen:Johnson & Johnson: Research Funding. Van Laethem:Johnson & Johnson: Research Funding. Rijnbeek:Johnson & Johnson: Employment. Vermeulen:Johnson & Johnson: Employment. Tromp:Johnson & Johnson: Employment. Li:Johnson & Johnson: Employment. Reddy:Johnson & Johnson: Employment. Cornfeld:Johnson & Johnson: Employment. Tabernero:Johnson & Johnson: Research Funding.

scholarly journals SLN124, a GalNAc Conjugated 19-Mer Double-Stranded SiRNA Reduces Iron and Increases Hepcidin Levels of Healthy Volunteers in a Phase 1 Clinical Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2009-2009
Author(s):  
John B. Porter ◽  
Alison Scrimgeour ◽  
Alberto Martinez ◽  
Leo James ◽  
Manuela Aleku ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stock Options ◽  
Serum Iron ◽  
Phase 1 ◽  
Transferrin Saturation ◽  
Beta Thalassemia ◽  
Advisory Committees ◽  
Treatment Groups ◽  
The Mean ◽  
Privately Held

Abstract Background Hepcidin, a peptide hormone consisting of 25-amino-acids, is the central regulator of systemic iron homeostasis. It is synthesized predominantly in hepatocytes, and dysregulation of its production leads to a variety of disorders of iron metabolism, including iron overload as well as congenital or acquired iron-loading anaemias. These conditions are a major source of morbidity and mortality. SLN124 increases hepatic hepcidin synthesis and hence plasma hepcidin by silencing its repressor, TMPRSS6. SLN124 has been shown to lower serum iron levels for at least 6 weeks after single administration in mice and has also been shown to increase haemoglobin in a mouse model of beta-thalassemia. Here we report results from a randomised, double-blind, placebo-controlled phase 1, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneously (sc) administered SLN124 in healthy volunteers. Objectives The primary objective was to evaluate the safety and tolerability of single ascending doses of SLN124 in healthy subjects. In addition, PK parameters of SLN124 and PD biomarkers of iron metabolism were evaluated. Methods Each subject received a single dose of SLN124 or placebo given by sc injection into their abdomen. Dose levels of 1 mg/kg, 3 mg/kg and 4.5 mg/kg were evaluated. At each dose level, 6 subjects received SLN124 and 2 received matching placebo. Results Three cohorts of 8 subjects (6:2) were included in the study. The mean age of subjects was 31.3 years (SD 7.8) and 71% were male. There were no serious adverse events or severe treatment emergent adverse events (TEAEs) or TEAEs leading to withdrawal. The majority of TEAEs were mild, including transient mild injection site reactions, which resolved without intervention. No dose limiting toxicities were observed. Plasma hepcidin levels at baseline were (mean ± SD) 2.3±1.1, 2.5±1.8 and 2.7±2.0 nM in the three treatment groups, respectively. After a single administration of 1, 3 or 4.5 mg/kg of SLN124, levels were increased by 3.1±2.7, 5.8±2.6 and 7.8±2.9 nM on day 29 and by 2.6±2.6, 2.8±1.4 and 3.5±1.8 nM day 57 post dosing, respectively. Serum iron was reduced by mean (±SD) 32% (26), 40% (14) ,46% (21) on day 8 and by 42% (20), 48% (14) and 47% (26) on day 29 for single doses of 1, 3 and 4.5 mg/kg, respectively. Average percentage changes in all three treatment groups were also still reduced from baseline at day 57. The mean (±SD) percent transferrin saturation (TSAT) was reduced from baseline levels in all single dose administration groups with maximum decreases observed at day 29 but reductions still observed at day 57. (Table 1). The observed PK is consistent with the PK model based on preclinical data. Thus, whereas the effects of SLN124 on plasma hepcidin show clear increments across the dose range tested, the effect on lowering serum iron and transferrin saturation shows something of a plateau effect at the highest dose. In future studies in patients with raised baseline transferrin saturations, it will be of note to determine whether transferrin saturation continues to decrease at the highest SLN124 doses. Conclusion/summary In summary, SLN124, a GalNAc conjugated siRNA targeting TMPRSS6, effectively reduces serum iron levels and has the potential as a therapeutic for patients with alpha and beta-thalassemia, myelodysplastic syndromes, hereditary hemochromatosis and other related disorders. The effect on hepcidin levels at the end of study, day 57, suggest a prolonged duration of action. The encouraging efficacy signal on serum iron and transferrin saturation and the expected benign safety profile of SLN124 supports further development. The GEMINI II trial (NCT04718844) is currently recruiting and wil l evaluate single and multiple doses of SLN124 in patients withthalassemia and myelodysplastic syndromes. Figure 1 Figure 1. Disclosures Porter: bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria; Protagonism: Honoraria; La Jolla Pharmaceuticals: Honoraria; Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees. Scrimgeour: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Martinez: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. James: Silence Therapeutics: Consultancy. Aleku: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Wilson: Silence Therapeutics: Consultancy. Muckenthaler: Silence Therapeutics: Research Funding. Schaeper: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Campion: Silence Therapeutics: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company.

scholarly journals A Phase 1 Study of NKX019, a CD19 Chimeric Antigen Receptor Natural Killer (CAR NK) Cell Therapy, in Subjects with B-Cell Malignancies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3868-3868
Author(s):  
Michael Dickinson ◽  
Nada Hamad ◽  
Christian E Bryant ◽  
Gautam Borthakur ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Nk Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Publicly Traded ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Car T

Abstract Background: B-cell lineage cancers are a worldwide healthcare burden. Over 500,000 new cases of non-Hodgkin lymphoma (NHL) and 50,000 new cases of acute lymphoblastic leukemia (ALL) are diagnosed world-wide each year (seer.cancer.gov, Smith 2015, Solomon 2017). Despite progress in treatment, many patients diagnosed with this heterogeneous group of cancers still succumb to their disease. Recently approved autologous chimeric antigen receptor (CAR) T cells specific for CD19 have altered the treatment landscape for some patients with relapsed or refractory (R/R) B-cell malignancies, though significant toxicities associated with T-cell expansion and the necessity for bespoke manufacturing have limited their use. Natural killer (NK) cells, part of the innate immune system, efficiently recognize transformed cells and are particularly suited to address limitations of the approved CAR T products (Marcus 2014, Morvan 2016). Lacking a T-cell receptor and the consequent clonal expansion, non-engineered NK cells have been safely administered after lymphodepletion without side effects typically associated with T-cell therapies, such as severe cytokine release syndrome or neurotoxicity (Bachier 2020). Allogeneic NK cell-based therapies allow off-the-shelf use, obviating the necessity to wait for manufacture of autologous T-cell therapies. CD19-directed CAR NK cells have been administered safely, with promising preliminary efficacy (Liu 2020). NKX019 is a cryopreserved product, composed of expanded NK cells engineered to express a humanized CAR against CD19, fused to co-stimulatory (OX40) and signaling (CD3ζ) domains to enhance their intrinsic antitumor activity. NKX019 also expresses a membrane-bound interleukin-15 (IL-15) to serve as an autocrine growth factor and thereby increase NKX019 persistence, with an in vivo half-life of over up to 28 days without systemic IL-2 support. Preclinical characterization has shown that NKX019 cells are 10 times more effective at killing CD19+ target cells than non-engineered NK cells, resulting in greater suppression of xenograft tumor models (Morisot 2020). Further, NKX019, unlike CD19 CAR T cells, retained cytotoxicity even when CD19 antigen density was reduced &gt;50x on target cells. Hence, clinical evaluation of NKX019 is being undertaken in this Phase 1 study in subjects with R/R NHL or ALL. Methods: This is a multicenter, open-label, Phase 1 study of NKX019 (Figure). The study will be conducted in 2 parts: Part 1 (dose finding) to determine the recommended Phase 2 dose (RP2D) of NKX019 separately in adult patients with CAR T naïve R/R NHL or B-ALL, utilizing a "3+3" enrollment schema. Part 2 (dose expansion) will further evaluate safety and tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PDn), and antitumor activity of NKX019 using RP2D with separate expansion cohorts for patients with ALL as well as different subtypes of NHL, including a cohort of CAR T pretreated large B-cell lymphoma. NKX019 is being manufactured from NK cells obtained from healthy adult donors. The study evaluates two dose levels of NKX019: 3 × 10 8 and 1 × 10 9 viable CAR+ NK cells. NKX019 will be administered on Days 0, 7, and 14 of a 28-day cycle following standard fludarabine/cyclophosphamide lymphodepletion (Table). Up to 5 total cycles may be administered based on response and tolerability assessed at the end of each cycle. The primary endpoint is incidence of adverse events, dose-limiting toxicities, clinically significant laboratory abnormalities, and determination of the RP2D. Secondary endpoints include evaluation of standard cellular PK parameters, PDn, immunogenicity, and antitumor responses. Subjects will be assessed for efficacy using disease-specific criteria: Lugano classification with LYRIC refinement for pseudo-progression (NHL), 2018 International Workshop (IW) criteria (CLL), 6th IW criteria (Waldenström macroglobulinemia [WM]), and National Comprehensive Cancer Version 1.2020 (B-ALL) (Cheson 2006, Cheson 2014, Hallek 2018, Owen 2013, Brown 2020). Enrollment across multiple sites in the US and Australia is expected to start in the second half of 2021. Figure 1 Figure 1. Disclosures Dickinson: Celgene: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bryant: Jansen, BMS/Celgene, Skyline Diagnostics: Consultancy; Amgen: Honoraria. Borthakur: Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Shook: Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tan: Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rajangam: Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Liu: SITC: Honoraria; BMS; Karyopharm; Miltenyi: Research Funding; Agios; NGM Biopharmaceuticals; BeiGene: Consultancy. McSweeney: Kite-Gilead: Consultancy; Kite-Gilead, Autolus, Novartis: Research Funding; Kite-Gilead: Honoraria, Speakers Bureau. Hill: Novartis: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; AstraZenica: Consultancy, Honoraria; Beigene: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Gentenech: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.

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