A first-in-human, open-label, phase I trial of daily oral zelenirstat, an NMT inhibitor, in patients with relapsed/refractory advanced cancer including gastrointestinal cancers.

129 Background: Myristoylation catalyzed by N-myristoyltransferases (NMT) 1 and 2 regulates membrane-bound signaling important in cancer, including Src and Src-family tyrosine kinases. Zelenirstat is a potent oral small molecule pan-NMT inhibitor. Transcriptomic analysis of zelenirstat treated cell lines identified an expression signature that predicts cancers most likely to be responsive to NMT inhibition; high sensitivity scores were seen in colorectal carcinomas and diffuse large B-cell lymphoma. The objectives of this phase I study were to determine the safety, tolerability, and maximum tolerated dose (MTD) of zelenirstat monotherapy in patients (pts) with refractory cancers. Methods: Pts with advanced solid malignancies or relapsed/refractory B-cell lymphomas were dose escalated with daily oral zelenirstat in 28-day cycles until progressive disease or dose-limiting toxicity (DLT). Results: Between September 2021 and July 2023, pts received 28-day cycles of zelenirstat ranging from 20 mg/d to 280 mg/d. In 21 evaluable patients, DLT was not observed up to and including the 210 mg/d cohort. Gastrointestinal DLTs were seen in the 280 mg/d cohort, establishing 210 mg/d to be the MTD. In doses up to and including 210 mg/d, gastrointestinal adverse events were the most common, reported in 29% of pts; these were primarily Gr 1 or 2 diarrhea, nausea or vomiting. Transient Gr 2 thrombocytopenia was seen in 3 pts. Zelenirstat did not induce neuropathy, alopecia, or prolong QT intervals. Plasma concentrations peaked between 1h and 4 h, terminal half-lives were 6.7 to 12 h, and steady state was achieved by day 8. Proton pump inhibitors lowered exposure and were prohibited in the higher dose cohorts. At 100 mg/d and higher, trough plasma concentrations exceeded the levels predicted to be therapeutic. Stable disease as best response was seen in 5 (30%) of 17 evaluable pts, including 1 patient with advanced refractory colon cancer who received 6 cycles of therapy at 140 mg daily dosing prior to PD. Another colon cancer patient with 5 prior lines of therapy continues 210 mg/d dosing after > 5 cycles of therapy, with non-RECIST criteria reductions of approximately 50% in CEA and tumor volumes. Conclusions: Zelenirstat was well-tolerated on a continuous daily oral schedule at doses as high as 210 mg/d, establishing the MTD to be 210 mg. The absence of severe toxicities, attainment of plasma concentrations highly active in preclinical models, and early evidence of clinical benefit in patients with refractory colon cancer warrant further trials. Updated data will be presented. Clinical trial information: NCT04836195 .