Dejan Juric, Daniel M. Anderson, Afshin Dowlati, Jordi Rodón, Iwona Ługowska, Sławomir Mańdziuk, Yuqin Song, Feng Jung Sherida H. Woei-A-Jin, Marc André, Joanna Góra‐Tybor, José‐Ángel Hernández‐Rivas, Razelle Kurzrock, Armando López‐Guillermo, David Schröder, Rafał Stec, Allison Berger, Bo Chao, Aleksander Chudnovsky, John P. Gibbs, Tao Long, Dina Stroopinsky, Qi Dong, Anthony J. Olszanski
PURPOSE: Subasumstat (TAK-981) is a first-in-class inhibitor of SUMOylation that can engage innate and adaptive immune responses in tumors by enhancing type I IFN (IFNI) production. We conducted a phase I/II dose-escalation/-expansion study (NCT03648372) to investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of subasumstat as a single agent in patients with advanced/metastatic solid tumors and relapsed/refractory hematologic malignancies. PATIENTS AND METHODS: Eligible patients received subasumstat intravenously at escalating doses twice weekly (days 1, 4, 8, and 11) or once weekly (days 1 and 8) in 21-day cycles until disease progression or unacceptable toxicity. RESULTS: A total of 109 patients were enrolled (solid tumors: n = 100; lymphomas, n = 9). In phase I, four patients reported dose-limiting toxicities of grade 3 alanine transaminase/aspartate transaminase elevation, pneumonitis, stomatitis, and cognitive disorder; 120 mg twice weekly was determined as the MTD. The most common adverse events were fatigue (47%), nausea (41%), diarrhea (36%), and pyrexia (36%). Pharmacodynamic analyses demonstrated target engagement and SUMOylation pathway inhibition, induction of an IFNI-regulated gene signature and cytokine production, and activation of innate and adaptive immune cells. Based on safety, pharmacokinetic, and pharmacodynamic findings, 90 mg twice weekly was proposed as the recommended phase II dosage. Overall, three and 26 patients achieved a partial response and stable disease, respectively. CONCLUSIONS: Subasumstat had a manageable safety profile, with evidence of innate and adaptive immune response engagement in patients with advanced/metastatic solid tumors and relapsed/refractory hematologic malignancies. Further studies are needed to determine the role of subasumstat in cancer treatment. SIGNIFICANCE: Identification of novel and effective therapies for patients who become refractory to standard anticancer treatments remains paramount. In this phase I/II study, subasumstat, a first-in-class SUMOylation inhibitor, had preliminary clinical activity and demonstrated target engagement, upregulation of IFN and plasma cytokines, and activation of innate and adaptive immune cells.