671 A first-in-human study evaluating safety, tolerability and efficacy of TEV-56278, as monotherapy and in combination with pembrolizumab in participants with locally advanced or metastatic solid tumors

Background

Direct immune stimulation using cytokines, including interleukin-2 (IL-2), drives immune-mediated cytotoxic cancer responses.¹ Toxicity of high-dose IL-2 limits its activity and clinical utility. Preclinical studies show that targeting IL-2 to specific cell subsets substantially increases its therapeutic index. In multiple cancers, tumor-infiltrating T-cells display higher levels of programmed cell death protein (PD-1) relative to circulating and tissue-resident T-cells,^2–4 making PD-1 a target for selective delivery of IL-2. TEV-56278 is a human antibody-cytokine fusion protein comprised of an antibody targeting PD-1 and attenuated IL-2. TEV-56278 is designed to deliver IL-2 selectively to PD-1+ T cells, thus amplifying anti-tumor T-cell activity while minimizing off-target systemic toxicities. Furthermore, its binding to PD-1 receptors does not block ligand binding and does not compete for binding with known PD1-blocking antibodies, allowing for use in combination. Here, we describe a phase 1a/1b trial design evaluating TEV-56278 as monotherapy and in combination with pembrolizumab.

Methods

This multicenter, open-label, Phase 1, first-in-human, dose-escalation, dose-expansion study is being conducted in 3 parts (figure 1). Patients >18 years of age with various locally advanced or metastatic solid tumors who have progressed on or were intolerant to standard of care therapies and resistant to anti-PD-(L)1 treatment will be included. The primary objective of dose escalation is to assess safety, tolerability and determine the recommended Phase 2 dose (RP2D) of TEV-56278 alone and in combination with pembrolizumab. Secondary objectives include assessment of pharmacokinetics (PK) and anti-tumor activity. Determination of the maximum tolerated dose will be based on a Bayesian optimal interval (BOIN) design.⁵ Additional pharmacodynamic (PD) and biomarker data, including biomarkers of IL-2 signaling and activation of PD-1+ T cells, will be collected during backfill of monotherapy dose cohort(s). After determination of the monotherapy RP2D, 2 cohorts of patients with locally advanced or metastatic primary and secondary resistant melanoma (A&B) and 2 cohorts of primary and secondary resistant non-small cell lung cancer (NSCLC; [C&D]) will be accrued to evaluate the primary objective of anti-tumor activity. The Simon two-stage admissible design^6–8 will be used for Cohort B (RP2D and a dose <RP2D), while a Bayesian approach will be used for A, C, and D with RP2D. The objective response rate (ORR) and duration of response (DOR) will be assessed based on Response Evaluation Criteria in Solid Tumors (RECISTv1.1). Secondary objectives include safety, tolerability, PK and other efficacy measures. This study is open for participant enrollment, targeting up to 240 patients.

Acknowledgements

The study is funded by Teva Pharmaceuticals. Software that is freely available to the public was used for the BOIN design (mdanderson.org) and the Simon two-stage admissible design (unc.edu).

Trial Registration

ClinicalTrials. gov Identifier: NCT06480552.

References

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Ethics Approval

Central and local/site Institutional Review Board approval has been obtained prior to study initiation. All enrolled subjects must provide signed informed consent prior to any study related procedures being completed.