1549TiP DeLLphi-303: Phase Ib first-line combination study of tarlatamab, a DLL3-targeting half-life extended bispecific T-cell engager (HLE BiTE®), with carboplatin, etoposide, and PD-L1 inhibition in extensive stage small cell lung cancer (ES-SCLC)

Background: The inhibitory Notch ligand, delta-like ligand 3 (DLL3), is a compelling therapeutic target due to its aberrant expression on the cell surface in most small cell lung cancer (SCLC). Tarlatamab (AMG 757) is a half-life extended bispecific T-cell engager (HLE BiTE®) molecule designed to specifically bind DLL3 on target cancer cells and CD3 on T cells, resulting in T cell-dependent killing of tumor cells. Data from an ongoing first-in-human monotherapy study show acceptable safety with evidence of tarlatamab efficacy in patients with relapsed/refractory SCLC (NCT03319940). Adding programmed death ligand 1 (PD-L1) inhibitors to first-line platinum chemotherapy is the emerging standard-of-care (SOC) in ES-SCLC and preclinical data suggests increased antitumor activity of BiTE molecules when combined with PD-1/PD-L1 inhibition or chemotherapy.1 These data support a clinical trial of tarlatamab combined with frontline carboplatin, etoposide, and PD-L1 inhibition in ES-SCLC. Trial design: This is a phase 1b, multicenter, open-label study evaluating tarlatamab in combination with first-line SOC chemo-immunotherapy in subjects with ES-SCLC. Tarlatamab will be evaluated in two separate settings: A) In combination with carboplatin, etoposide, and a PD-L1 inhibitor followed by maintenance cycles of tarlatamab plus PD-L1 inhibitor, and B) In combination with PD-L1 inhibitor following SOC chemo-immunotherapy as a maintenance only approach. Key eligibility criteria include patients with histologically or cytologically confirmed ES-SCLC with no prior systemic treatment (except as specified in protocol) and ECOG performance status ≤1. The primary objective is to evaluate the safety, tolerability, and determine the recommended phase 2 dose and/or maximum tolerated dose of tarlatamab in combination with PD-L1 inhibition with or without chemotherapy. Secondary endpoints are objective response rate, duration of response, disease control, progression-free survival, overall survival, and pharmacokinetics

Metabolic profiling of HepG2 cells incubated with S(−) and R(+) enantiomers of anti-coagulating drug warfarin

Warfarin is a commonly prescribed oral anticoagulant with narrow therapeutic index. It achieves anti-coagulating effects by interfering with the vitamin K cycle. Warfarin has two enantiomers, S(−) and R(+) and undergoes stereoselective metabolism, with the S(−) enantiomer being more effective. We reported the intracellular metabolic profile in HepG2 cells incubated with S(−) and R(+) warfarin by GCMS. Chemometric method PCA was applied to analyze the individual samples. A total of 80 metabolites which belong to different categories were identified. Two batches of experiments (with and without the presence of vitamin K) were designed. In samples incubated with S(−) and R(+) warfarin, glucuronic acid showed significantly decreased in cells incubated with R(+) warfarin but not in those incubated with S(−) warfarin. It may partially explain the lower bio-activity of R(+) warfarin. And arachidonic acid showed increased in cells incubated with S(−) warfarin but not in those incubated with R(+) warfarin. In addition, a number of small molecules involved in γ-glutamyl cycle displayed ratio variations. Intracellular glutathione detection further validated the results. Taken together, our findings provided molecular evidence on a comprehensive metabolic profile on warfarin-cell interaction which may shed new lights on future improvement of warfarin therapy

Hematologic Chaos in Lupus Flare: A Case of Fulminant and Simultaneous Antiphospholipid, Anti-ADAMTS13, and Red Blood Cell Autoantibodies

Systemic lupus erythematosus may present with several distinct autoimmune phenomena simultaneously. We report a patient presenting with three serious hematologic disorders: thrombotic thrombocytopenic purpura, catastrophic antiphospholipid syndrome, and warm-type IgG red cell autoantibodies. The case is an example of the complex clinical nature of lupus and the importance of accurately identifying individual complications in order to optimize management