GRACE: A Phase 1/2a Study of VTRU200 in Relapsed/Refractory AML, High-risk MDS, DLBCL Post CART Failure and Advanced Solid Tumors

Relapsed or refractory (R/R) acute myeloid leukemia (AML), higher-risk myelodysplastic syndromes (HR-MDS), and diffuse large B-cell lymphoma (DLBCL) after chimeric antigen receptor (CAR) T-cell therapy remain associated with poor clinical outcomes despite recent therapeutic advances. Although targeted therapies and immunotherapies have improved outcomes for some patients, treatment failure frequently occurs because of disease heterogeneity, antigen loss, immune escape, and treatment resistance. Therefore, novel therapeutic approaches capable of recognizing shared cancer-associated features across genetically diverse tumors are needed.

VTRU200 is a first-in-class, investigational trispecific T-cell engager (TCE) designed to redirect endogenous T cells toward malignant cells through simultaneous binding of CD3 on T cells and two stress-associated tumor surface markers: aberrant high-mannose glycans and phosphatidylserine (PS). These glycan and lipid structures are enriched on many malignant cells and cells within the tumor microenvironment as a consequence of altered glycosylation, metabolic stress, oxidative stress, endoplasmic reticulum stress, impaired membrane asymmetry, rapid proliferation, and resistance to therapy. In contrast, these targets are minimally exposed on most normal healthy tissues, providing the rationale for selective tumor targeting.

Preclinical studies demonstrated that VTRU200 binds tumor cells expressing these stress-associated surface markers and mediates potent T-cell activation and cytotoxicity across multiple AML models. In nonclinical studies, VTRU200 exhibited antitumor activity in vitro and in vivo, demonstrated minimal cytokine release relative to conventional CD3-engaging therapies, showed no detectable binding to normal human peripheral blood leukocytes or hematopoietic stem and progenitor cells, and did not bind an FDA-recommended panel of normal human or cynomolgus monkey tissues. Repeat-dose animal studies demonstrated a favorable therapeutic window supporting clinical evaluation.

This is a first-in-human, multicenter, open-label Phase 1/2a study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary antitumor activity of VTRU200 administered by intravenous infusion.

The Phase 1 dose-escalation portion will determine the maximum tolerated dose (MTD), if reached, and identify the recommended Phase 2 dose (RP2D). Dose escalation will begin with an accelerated titration design using sentinel participants at the lowest dose levels, followed by a Bayesian Optimal Interval (BOIN) design after evidence of acceptable safety. Escalation decisions will be based on predefined safety criteria and review by the Safety Review Committee.

Following determination of the RP2D, the Phase 2a dose-expansion portion will further characterize the safety profile and evaluate preliminary clinical activity in disease-specific cohorts. Adult participants with R/R AML and HR-MDS will constitute the primary efficacy population, with additional exploratory cohorts enrolling participants with DLBCL following CAR T-cell therapy failure. Adolescent and pediatric participants with AML may be enrolled after establishment of an acceptable safety profile and appropriate adult exposure.

Safety evaluations will include monitoring of adverse events, serious adverse events, infusion-related reactions, immune-mediated toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), clinical laboratory testing, vital signs, electrocardiograms, physical examinations, and concomitant medications.

PK assessments will characterize serum concentrations of VTRU200, while immunogenicity assessments will evaluate anti-drug antibodies (ADA). PD analyses will assess biomarkers of immune activation, cytokine responses, target engagement, and changes within peripheral blood and bone marrow, where applicable.

Preliminary antitumor activity will be evaluated using disease-specific response criteria, including the European LeukemiaNet (ELN) recommendations for AML, International Working Group (IWG) criteria for HR-MDS, and Lugano Classification criteria for DLBCL. Additional efficacy endpoints include measurable residual disease (MRD), duration of response, progression-free survival, overall survival, and other clinically relevant measures of disease control.

This study is designed primarily to establish the safety profile, appropriate dose, and biologic activity of VTRU200 while providing an initial assessment of its clinical activity in patients with relapsed or refractory hematologic malignancies for whom effective treatment options remain limited.