Phase 1/2 study of the novel SUMOylation inhibitor TAK-981 in adult patients (pts) with advanced or metastatic solid tumors or relapsed/refractory (RR) hematologic malignancies.

Abstract

TPS2667 Background: SUMOylation, a posttranslational modification analogous to ubiquitination, attaches a small, ubiquitin-like modifier (SUMO) to target proteins. SUMOylation plays a central role in regulating type I interferon (IFN-I)-dependent innate response and functions to constrain the innate immune response, which can impair tumor immune surveillance. TAK-981 is a first-in-class, small-molecule inhibitor of SUMO-activating enzyme subunit 2 (SAE2). Inhibition of SAE2 by TAK-981 disrupts SUMOylation, thereby allowing innate immune system activation. In ex vivo assays, TAK-981 increased phagocytic activity of monocyte-derived macrophages, increased natural killer cell cytotoxicity, and induced markers of dendritic cell activation and maturation via IFN-I signaling. In syngeneic mouse models, TAK-981 resulted in antitumor activity, including complete remissions, and a sustained, protective antitumor immune response. Methods: This first-in-human study of single-agent TAK-981 comprises two parts. Phase 1 primary objectives are to determine safety and tolerability, and to select a recommended phase 2 dose (RP2D); secondary objectives are to assess preliminary antitumor activity, characterize pharmacokinetics (PK), and explore pharmacodynamic (PD) biomarkers. This phase will enroll ̃70 pts with untreatable locally advanced or metastatic solid tumors or RR lymphoma. The phase 2 primary objective is to evaluate preliminary efficacy at the RP2D in ̃132 pts with non-squamous non-small cell lung cancer, cervical cancer, microsatellite-stable colorectal cancer, or CD20+ RR diffuse large B-cell lymphoma or follicular lymphoma. Pts receive TAK-981 via a 1-hour intravenous infusion on days 1, 4, 8, and 11 in 21-day cycles until unacceptable toxicity, pt withdrawal, or death. Dose escalation is proceeding from 3 mg, guided by an adaptive 3+3 design combined with Bayesian logistic regression modelling with overdose control, plus consideration of other safety, clinical, PK, and PD data. The RP2D will be based on the maximum tolerated dose (MTD) or on a biologically effective dose (BED) that is ≤MTD. The BED is defined as a dose at which there is evidence of drug-target engagement and inhibition of SUMOylation, plus: induction of cytokines/chemokines and/or IFN-I signature in tumor or blood; evidence of increased T cell infiltration in tumor; or antitumor activity. PK/PD modeling in the BED range is ongoing and will be used in RP2D determination. Clinical trial information: NCT03648372.