Abstract CT254: Trial in progress: a first-in-human, phase 1, multicenter dose escalation and dose expansion study of WTX-330 in adult patients with advanced or metastatic solid tumors or non-Hodgkin lymphoma

Background: Interleukin-12 (IL-12) is a potent proinflammatory cytokine with activating effects on both innate and adaptive immune cells. Though recombinant IL-12 (rIL-12) causes tumor regression with antitumor immune memory formation in a range of immunocompetent mouse models, clinical development of rIL-12 was limited by serious toxicities resulting in several patient deaths. WTX-330 is an engineered cytokine prodrug composed of a wild-type IL-12 heterodimer fused via proprietary cleavable linkers to an inactivation domain and to a half-life extension domain. In the circulation and in normal tissues, WTX-330 is designed to remain inactive and not bind to high-affinity IL-12 receptors. In contrast, proteolytic activation of WTX-330 in the tumor microenvironment is expected to liberate the IL-12 cytokine to stimulate antitumor immunity. Preclinical data show that WTX-330 is activated by a range of dissociated human tumors in vitro but not by normal human cells or by patient serum. Moreover, a WTX-330 murine surrogate molecule has potent antitumor activity as a monotherapy in multiple syngeneic mouse models, including in those resistant to anti-PD-1 therapy. In the MC38 model, the WTX-330 surrogate has a large therapeutic window of 49-fold compared to 5-fold for recombinant chimeric IL-12. Methods: This first-in-human, open-label phase 1 trial is investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity of WTX-330 administered as a monotherapy to patients with advanced or metastatic solid tumors or non-Hodgkin lymphoma (NCT05678998). All patients must have ≥ 1 measurable lesion per RECIST 1.1 and be refractory to all standard of care therapies for their indication. Dose escalation utilizes a Bayesian logistic regression model with overdose control with WTX-330 administered intravenously every two weeks in 28-day cycles. Dose expansion is anticipated to include two arms (A, B) of 20 patients each. Patients eligible for Arm A will have tumor types for which immune checkpoint inhibitors (ICIs) are indicated but demonstrate either primary or secondary resistance to this therapy. Primary resistance is defined as disease progression or SD < 6 months as the best response after at least 6 weeks of exposure to PD-(L)1 inhibitors. Secondary resistance is defined as disease progression ≥ 6 months after initiation of PD-(L)1 inhibitors in patients who received clinical benefit (i.e., CR, PR, or SD > 6 months). Pa