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Abstract Background There is an unmet need for antithrombotic treatments for venous thromboembolic disease that do not increase bleeding risk. Selectins are cell adhesion molecules that augment thrombosis by activating immune cells to initiate the coagulation cascade. GMI‐1271, a potent small‐molecule E‐selectin antagonist, has been shown in mouse models to decrease thrombus burden with a low risk of bleeding. Methods A first‐in‐human study of GMI‐1271 was conducted to assess its safety, tolerability, and pharmacokinetic (PK) profile. As a secondary end point, biomarkers of coagulation, cell adhesion, and leukocyte/platelet activation were evaluated. Aims 1 and 2 were performed in healthy volunteers and evaluated single and multiple doses of the study drug, respectively. Aim 3 included 2 patients with isolated calf‐level deep vein thrombosis (DVT). Results GMI‐1271 showed consistent PK parameters for doses ranging from 2 to 40 mg/kg. Plasma levels increased in a linear manner with respect to dose, while clearance, volume of distribution, and half‐life were not dose dependent. No accumulation was seen with multiple consecutive doses. No serious adverse events (grade 3 or 4) were reported. Biomarker analysis demonstrated a trend in reduction of soluble E‐selectin (sEsel) levels with GMI‐1271 exposure, while exposure did not impact laboratory testing of coagulation. Two patients with calf vein DVT were treated with GMI‐1271 and demonstrated rapid improvement of symptoms after 48 hours, with repeat ultrasound showing signs of clot resolution. Conclusions We demonstrate that GMI‐1271 is safe in healthy volunteers and provide proof of concept that an E‐selectin antagonist is a potential therapeutic approach to treat venous thrombosis.

The T-cell lymphoproliferative disorders are a heterogeneous group of non-Hodgkin’s lymphomas (NHL) for which current therapeutic strategies are inadequate, as most patients afflicted with these NHL will succumb to disease progression within 2 years of diagnosis. Appreciation of the genetic and immunologic landscape of these aggressive NHL, including PD-L1 (B7-H1, CD274) expression by malignant T cells and within the tumor microenvironment, provides a strong rationale for therapeutic targeting this immune checkpoint. While further studies are needed, the available data suggests that responses with PD-1 checkpoint blockade alone will unlikely approach those achieved in other lymphoproliferative disorders. Herein, we review the unique challenges posed by the T-cell lymphoproliferative disorders and discuss potential strategies to optimize checkpoint blockade in these T-cell derived malignancies.

Pancreatic neuroendocrine tumors (PNETs) are relatively rare tumors that arise in the endocrine cells of the pancreas. Historically, somatostatin analogues have been used in this disease primarily for symptom control and, to a limited extent, disease stability. More recently, sunitinib and everolimus have been approved for advanced stage PNETs based on a survival benefit. However, both agents have a