Safety and efficacy of HLA-G–targeted CAR T cells (IVS-3001) in patients with advanced HLA-G–positive solid tumors: Clinical trial in progress.

Journal of Clinical Oncology · 2025-05-28 · 2 citations

TPS2679 Background: Immunotherapies have transformed cancer treatment, yet only a small proportion of patients experiences durable responses. IVS-3001 is an innovative autologous chimeric antigen receptor (CAR) T-cell therapy specifically targeting Human Leukocyte Antigen (HLA-G). HLA-G is an immune-modulatory checkpoint molecule expressed on various solid tumors, positioning it as an ideal a tumor-specific targeted antigen. Our third-generation CAR construct features enhanced T cell activation and persistence against HLA-G. By harnessing IVS-3001 to target HLA-G and revitalize immune cells, we aim to overcome the suppressive tumor microenvironment and improve antitumor activity, potentially leading to better outcomes for patients with advanced solid tumors who otherwise have no standard options known to confer clinical benefit. Methods: Study NCT05672459 is a First-in-Human, phase 1/2a, safety and efficacy study of IVS-3001 in subjects with previously treated advanced HLA-G-positive solid tumors. Phase 1 (n≤24 patients) is a Bayesian Optimal Interval Design (BOIN) with primary objective to determine the safety, tolerability and the recommended phase 2 dose. The primary objective for phase 2 (n≤90 patients) is to evaluate the anti-tumor activity of IVS-3001. The secondary objectives of the study are to evaluate i) pharmacokinetic profile of IVS-3001 (persistence, expansion); ii) the clinical activity of IVS-3001 in selected HLA-G+ solid tumor types; iii) assess the long-term safety of IVS-3001. Exploratory endpoints include functionality of CAR-T cells, immune biomarker changes, and relationships with clinical response. Key inclusion criteria: adults with advanced solid tumors expressing HLA-G; ECOG < 2; adequate organ function. Key exclusion criteria: uncontrolled brain metastasis; prior exposure to HLA-G targeted therapy. Subjects undergo lymphodepletion with fludarabine and cyclophosphamide on days -5 to -3, followed by CAR-T cell infusion on day 0 and a 28-day monitoring period for dose limiting toxicity. Response assessment per RECIST criteria. Study is currently accruing at Dose level 3. Active recruitment and enrollment are ongoing at The University of Texas MD Anderson Cancer Center, Houston, Texas. Clinical trial information: NCT05672459 .

Abstract CT200: Safety and efficacy of HLA-G-targeted CAR T cells (IVS-3001) in patients with advanced HLA-G-positive solid tumors: Clinical trial in progress

Cancer Research · 2025-04-25 · 1 citations

Abstract Background: Immunotherapies have transformed cancer treatment, yet only a small proportion of patients experiences durable responses. IVS-3001 is an innovative autologous chimeric antigen receptor (CAR) T-cell therapy specifically targeting Human Leukocyte Antigen (HLA-G). HLA-G is an immune-modulatory checkpoint molecule expressed on various solid tumors, positioning it as an ideal tumor-specific targeted antigen. Our third-generation CAR construct features enhanced T cell activation and persistence against HLA-G. By harnessing IVS-3001 to target HLA-G and revitalize immune cells, we aim to overcome the suppressive tumor microenvironment and improve antitumor activity, potentially leading to better outcomes for patients with advanced solid tumors who otherwise have no standard options known to confer clinical benefit. Study Design and Study: NCT05672459 is a First-in-Human, phase 1/2a, safety and efficacy study of IVS-3001 in subjects with previously treated advanced HLA-G-positive solid tumors. Phase 1 (n≤24 patients) is a Bayesian Optimal Interval Design (BOIN) with primary objective to determine the safety, tolerability and the recommended phase 2 dose. The primary objective for phase 2 (n≤90 patients) is to evaluate the anti-tumor activity of IVS-3001. The secondary objectives of the study are to evaluate i) pharmacokinetic profile of IVS-3001 (persistence, expansion); ii) the clinical activity of IVS-3001 in selected HLA-G+ solid tumor types; iii) assess the long-term safety of IVS-3001. Exploratory endpoints include functionality of CAR-T cells, immune biomarker changes, and relationships with clinical response. Key inclusion criteria: adults with advanced solid tumors expressing HLA-G; ECOG<2; adequate organ function. Key exclusion criteria: Uncontrolled brain metastasis; prior exposure to HLA-G targeted therapy. Subjects undergo lymphodepletion with fludarabine and cyclophosphamide on days -5 to -3, followed by CAR-T cell infusion on day 0 and a 28-day monitoring period for dose limiting toxicity. Response assessment per RECIST criteria. Study is currently accruing at Dose level 3. Active recruitment and enrollment are ongoing at The University of Texas MD Anderson Cancer Center, Houston, Texas.Not applicable. Citation Format: Samer A. Srour, Nizar Tannir, Amir Jazaeri, Matthew T. Campbell, Yago Nieto, Cara Haymaker, Ying Yuan, Israa Salih, Yali Yang, Valerie Doppler, Julie Garibal, Marie Escande, Melissa Yang, Jake Kushner, Jake Kushner, Jane Koo, Serdar A. Gurses, David S. Hong, Siqing Fu, Funda Meric-Bernstam, Aung Naing. Safety and efficacy of HLA-G-targeted CAR T cells (IVS-3001) in patients with advanced HLA-G-positive solid tumors: Clinical trial in progress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT200.

Unsupervised Anomaly Detection to Characterize Heterogeneity in Type 2 Diabetes

PubMed Central · 2023-06-16 · 1 citations

Diabetes is associated with heterogeneous behaviors affecting patients’ clinical characteristics and trajectories. This study includes 21,288 patients with type 2 diabetes (women, ages 30 to 65). The cohort was filtered through a set of preprocessing heuristics in order to assure the cohort exhibited a similar clinical trajectory. Anomalous characteristics were then identified using dimensionality reduction and anomaly detection methods. Compared to the majority of the cohort, patients classified as anomalous were twice as likely to be admitted into the hospital (7.94[7.59 8.28] versus 3.12[3.06 3.17] times), have a higher incidence of comorbidities (2[1.64 2.36] times more), and be prescribed more insulin and less new and more expensive diabetes medications (such as Sodium glucose co-transporter 2 inhibitors). Patients with these anomalous characteristics may benefit from additional or specialized interventions to avert their risk for adverse outcomes.

Clinical and Laboratory Predictors of Dehydration Severity in Children With Diabetic Ketoacidosis

Annals of Emergency Medicine · 2023-04-05 · 9 citations

Diabetic Ketoacidosis and Related Events With Sotagliflozin Added to Insulin in Adults With Type 1 Diabetes: A Pooled Analysis of the inTandem 1 and 2 Studies

2020-09-14

<b>Objective: </b>To evaluate incidence and risk factors for diabetic ketoacidosis (DKA) and related adverse events (AEs) in adults with type 1 diabetes treated with sotagliflozin adjunctive to insulin. <p><b>Research Design and Methods: </b>Data from two identically designed, 52-week, randomized studies were pooled and analyzed for DKA, changes in beta-hydroxybutyrate (BHB), and percentage of patients with BHB >0.6 and >1.5 mmol/L; patients were administered placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg once daily. </p> <p><b>Results:</b> A total of 191 ketosis-related AEs were reported; 98 underwent adjudication. Of these, 37 (36 patients) were adjudicated as DKA, with an exposure-adjusted incidence rate of 0.2, 3.1, and 4.2 events per 100 patient-years for placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg. No patient died from a DKA event. From a baseline BHB of ~0.13 mmol/L, sotagliflozin treatment led to a small median increase over 52 weeks (≤0.05 mmol/L at all time points). Approximately 47% and 7% of sotagliflozin-treated patients had ≥1 BHB measurement >0.6 mmol/L and >1.5 mmol/L (vs 20% and 2% of placebo-treated patients). Subsequent to the implementation of a risk mitigation plan, annualized DKA incidence was lower versus pre-implementation in both the sotagliflozin 200-mg and 400-mg groups. </p> <p><b>Conclusion:</b> In patients with type 1 diabetes, confirmed DKA incidence increased when sotagliflozin was added to insulin compared with insulin alone. A lower incidence of DKA was observed following the implementation of an enhanced risk mitigation plan, suggesting that this risk can be managed with patient education.</p>

Diabetic Ketoacidosis and Related Events With Sotagliflozin Added to Insulin in Adults With Type 1 Diabetes: A Pooled Analysis of the inTandem 1 and 2 Studies

2020-09-14

<b>Objective: </b>To evaluate incidence and risk factors for diabetic ketoacidosis (DKA) and related adverse events (AEs) in adults with type 1 diabetes treated with sotagliflozin adjunctive to insulin. <p><b>Research Design and Methods: </b>Data from two identically designed, 52-week, randomized studies were pooled and analyzed for DKA, changes in beta-hydroxybutyrate (BHB), and percentage of patients with BHB >0.6 and >1.5 mmol/L; patients were administered placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg once daily. </p> <p><b>Results:</b> A total of 191 ketosis-related AEs were reported; 98 underwent adjudication. Of these, 37 (36 patients) were adjudicated as DKA, with an exposure-adjusted incidence rate of 0.2, 3.1, and 4.2 events per 100 patient-years for placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg. No patient died from a DKA event. From a baseline BHB of ~0.13 mmol/L, sotagliflozin treatment led to a small median increase over 52 weeks (≤0.05 mmol/L at all time points). Approximately 47% and 7% of sotagliflozin-treated patients had ≥1 BHB measurement >0.6 mmol/L and >1.5 mmol/L (vs 20% and 2% of placebo-treated patients). Subsequent to the implementation of a risk mitigation plan, annualized DKA incidence was lower versus pre-implementation in both the sotagliflozin 200-mg and 400-mg groups. </p> <p><b>Conclusion:</b> In patients with type 1 diabetes, confirmed DKA incidence increased when sotagliflozin was added to insulin compared with insulin alone. A lower incidence of DKA was observed following the implementation of an enhanced risk mitigation plan, suggesting that this risk can be managed with patient education.</p>

Diabetic Ketoacidosis and Related Events With Sotagliflozin Added to Insulin in Adults With Type 1 Diabetes: A Pooled Analysis of the inTandem 1 and 2 Studies

Diabetes Care · 2020-09-14 · 37 citations

OBJECTIVE: To evaluate the incidence and risk factors for diabetic ketoacidosis (DKA) and related adverse events (AEs) in adults with type 1 diabetes treated with sotagliflozin adjunctive to insulin. RESEARCH DESIGN AND METHODS: Data from two identically designed, 52-week, randomized studies were pooled and analyzed for DKA, changes in β-hydroxybutyrate (BHB), and percentage of patients with BHB >0.6 and >1.5 mmol/L. The patients were administered placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg once daily. RESULTS: A total of 191 ketosis-related AEs were reported, and 98 underwent adjudication. Of these, 37 events (36 patients) were adjudicated as DKA, with an exposure-adjusted incidence rate of 0.2, 3.1, and 4.2 events per 100 patient-years for placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively. No patient died of a DKA event. From a baseline BHB of ∼0.13 mmol/L, sotagliflozin treatment led to a small median increase over 52 weeks (≤0.05 mmol/L at all time points). Of sotagliflozin-treated patients, approximately 47% and 7% had ≥1 BHB measurement >0.6 mmol/L and >1.5 mmol/L, respectively (vs. 20% and 2%, respectively, of placebo-treated patients). Subsequent to the implementation of a risk mitigation plan, annualized DKA incidence was lower versus preimplementation in both the sotagliflozin 200 and 400 mg groups. CONCLUSIONS: In patients with type 1 diabetes, confirmed DKA incidence increased when sotagliflozin was added to insulin compared with insulin alone. A lower incidence of DKA was observed following the implementation of an enhanced risk mitigation plan, suggesting that this risk can be managed with patient education.

Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes

UNC Libraries · 2020-04-22

BACKGROUND: In most patients with type 1 diabetes, adequate glycemic control is not achieved with insulin therapy alone. We evaluated the safety and efficacy of sotagliflozin, an oral inhibitor of sodium-glucose cotransporters 1 and 2, in combination with insulin treatment in patients with type 1 diabetes. METHODS: In this phase 3, double-blind trial, which was conducted at 133 centers worldwide, we randomly assigned 1402 patients with type 1 diabetes who were receiving treatment with any insulin therapy (pump or injections) to receive sotagliflozin (400 mg per day) or placebo for 24 weeks. The primary end point was a glycated hemoglobin level lower than 7.0% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis after randomization. Secondary end points included the change from baseline in glycated hemoglobin level, weight, systolic blood pressure, and mean daily bolus dose of insulin. RESULTS: A significantly larger proportion of patients in the sotagliflozin group than in the placebo group achieved the primary end point (200 of 699 patients [28.6%] vs. 107 of 703 [15.2%], P<0.001). The least-squares mean change from baseline was significantly greater in the sotagliflozin group than in the placebo group for glycated hemoglobin (difference, -0.46 percentage points), weight (-2.98 kg), systolic blood pressure (-3.5 mm Hg), and mean daily bolus dose of insulin (-2.8 units per day) (P≤0.002 for all comparisons). The rate of severe hypoglycemia was similar in the sotagliflozin group and the placebo group (3.0% [21 patients] and 2.4% [17], respectively). The rate of documented hypoglycemia with a blood glucose level of 55 mg per deciliter (3.1 mmol per liter) or below was significantly lower in the sotagliflozin group than in the placebo group. The rate of diabetic ketoacidosis was higher in the sotagliflozin group than in the placebo group (3.0% [21 patients] and 0.6% [4], respectively). CONCLUSIONS: Among patients with type 1 diabetes who were receiving insulin, the proportion of patients who achieved a glycated hemoglobin level lower than 7.0% with no severe hypoglycemia or diabetic ketoacidosis was larger in the group that received sotagliflozin than in the placebo group. However, the rate of diabetic ketoacidosis was higher in the sotagliflozin group. (Funded by Lexicon Pharmaceuticals; inTandem3 ClinicalTrials.gov number, NCT02531035 .).

Effects of Sotagliflozin Combined with Intensive Insulin Therapy in Young Adults with Poorly Controlled Type 1 Diabetes: The JDRF Sotagliflozin Study

Diabetes Technology & Therapeutics · 2020-07-09 · 20 citations

Background: Young adults with type 1 diabetes (T1D) tend to have higher A1C than older adults and are at increased risk for diabetic ketoacidosis (DKA). Oral adjuncts to insulin have not been previously studied in this population. Methods: In this phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, adults aged 18–30 years with T1D and A1C ≥9.0% were randomly assigned to placebo ( n = 42) or sotagliflozin 400 mg ( n = 43), in addition to insulin for 12 weeks. Insulin doses were adjusted to meet glucose targets (preprandial 80–130 mg/dL, postprandial &lt;180 mg/dL). The primary endpoint was change from baseline in A1C at week 12. Results: From a baseline of 9.8%, mean A1C decreased by 1.0% with placebo and 1.3% with sotagliflozin (−0.4% [95% confidence interval (CI): −0.8 to 0.1]; P = 0.10 vs. placebo). In the prespecified A1C ≤10.0% subgroup, the treatment difference was −0.8% (−1.3 to −0.2; P = 0.006), favoring sotagliflozin. Overall, relative to placebo, postprandial glucose (PPG) decreased by 56.6 mg/dL (−89.7 to −23.6; P &lt; 0.001) and weight decreased by 2.37 kg (−3.5 to −1.2; P &lt; 0.001). More patients achieved an A1C &lt;7.0% with sotagliflozin (16.3%) than placebo (2.4%; P = 0.026). Rates of documented hypoglycemia and severe hypoglycemia were similar between groups. One DKA event occurred with placebo, and none occurred with sotagliflozin. Conclusions: In young adults with T1D and suboptimal glycemic control, sotagliflozin plus insulin for 12 weeks numerically improved A1C and significantly improved A1C goal attainment, PPG, and body weight. Sotagliflozin plus insulin was generally well tolerated without any episodes of DKA (NCT02383940).

International Consensus on Risk Management of Diabetic Ketoacidosis in Patients With Type 1 Diabetes Treated With Sodium–Glucose Cotransporter (SGLT) Inhibitors

Diabetes Care · 2019-02-06 · 355 citations

Sodium-glucose cotransporter (SGLT) inhibitors are new oral antidiabetes medications shown to effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure, and body weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes. However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with near-normal blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of DKA and potentially delaying treatment. Several SGLT inhibitors are currently under review by the U.S. Food and Drug Administration and European regulatory agencies as adjuncts to insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to the medical community to mitigate the associated DKA risk. This Consensus Report reviews current data regarding SGLT inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with type 1 diabetes.