Phase I/II Study of Subasumstat (TAK-981) in Combination With Rituximab in Relapsed/Refractory Non-Hodgkin Lymphoma.

Background: Subasumstat (TAK-981) is an investigational, first-in-class, innate immunity enhancer that unlocks innate/adaptive immune responses in target tumor microenvironments through SUMOylation inhibition. Subasumstat enhanced antitumor activity of rituximab in preclinical xenograft models.

Patients and methods: This phase I/II study enrolled 34 patients (n = 31, phase I; n = 3, phase II) with CD20+-positive relapsed/refractory non-Hodgkin lymphoma (NHL); patients with indolent NHL had to be refractory to an anti-CD20 antibody. In phase I, patients received intravenous subasumstat (10-120 mg) once weekly (QW) (or twice weekly [BIW], 90 mg only) with intravenous rituximab 375 mg/m².

Results: No dose-limiting toxicities were reported, no maximum tolerated dose was identified up to 120 mg QW. Safety outcomes were comparable across QW dosing cohorts; grade ≥ 3 and serious adverse events (AEs) were more common in the BIW cohort. The most common AEs reported during dose escalation were pyrexia (55%), chills (39%), and fatigue (35%). Most AEs were transient and consistent with low-grade flu-like symptoms, indicative of interferon pathway activation. Overall, 8/29 evaluable patients receiving QW dosing achieved an objective response (2 complete responses; 6 partial responses); the overall best response rate was 27.6%. Pharmacodynamic analyses provided evidence of dose-dependent target engagement (subasumstat-SUMO adduct and SUMOylation pathway inhibition) in blood and skin. Induction of a type-I interferon response, demonstrated by gene expression analysis, increased plasma cytokines/chemokine levels, and activation of innate and adaptative immune response was also observed.

Conclusion: This study demonstrated a positive benefit-risk profile of subasumstat combined with rituximab in NHL.