Phase I/II Study of Subasumstat (TAK-981) in Combination With Rituximab in Relapsed/Refractory Non-Hodgkin Lymphoma
Sarit Assouline, Amitkumar Mehta, Walter Hanel, Stéphane Doucet, Patrick B. Johnston, Alexey V. Danilov, Brenda Cooper, Aleksander Chudnovsky, Junyu Ding, Tao Long, Dina Stroopinsky, Deborah Berg, Lapo Alinari
Abstract
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/m 2 . 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. Micro Abstract Subasumstat, an investigational SUMOylation inhibitor, was investigated in this phase I/II study in combination with rituximab in patients with relapsed/refractory CD20+ non-Hodgkin lymphoma. Subasumstat demonstrated a manageable safety profile and early clinical activity with an overall response rate of 27.6%. Pharmacokinetics analyses revealed limited impact of rituximab on subasumstat. Pharmacodynamic findings provided a proof-of-principle of SUMOylation inhibition in this patient population.