Final results of a first-in-human phase I dose escalation trial of daily oral zelenirstat, a n-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas.
Authors: Sangha Randeep S. , Jamal Rahima , Spratlin Jennifer , Kuruvilla John , Sehn Laurie Helen , Weickert Michael , Berthiaume Luc G. , Mackey John Robert 
Published: July 2024

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Background: Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, regulates multiple membrane-bound signal transduction pathways important in cancer cell biology, including Src and Src family of protein tyrosine kinases. This modification is catalyzed by two N-myristoyltransferases (NMT), NMT1 and NMT2. Zelenirstat is a first-in-class oral small molecule NMT inhibitor with strong affinity for both NMT1 and NMT2 proteins. Transcriptomic analysis of zelenirstat treated cell lines identified a myristoylation inhibition sensitivity signature in cancer cells most likely to respond to NMT inhibitor therapy; high sensitivity scores were seen in a range of solid cancers and diffuse large B-cell lymphoma. Based on tumor regression and safety in preclinical models, we hypothesized zelenirstat would be safe to administer and show anticancer activity. Methods: Patients (pts) with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in a multicenter, open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until disease progression or unacceptable toxicity (NCT04836195). The primary endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD). Secondary endpoints were to characterize the pharmacokinetic parameters of zelenirstat and assess anticancer activity. Results: Twenty-nine pts (17 females; 12 males; median age 65 years; median prior systemic treatments 4; 25 advanced solid tumor; 4 R/R B-cell lymphoma) were enrolled and 24 pts were DLT-evaluable. Dose cohorts ranged from 20 mg once daily (OD) to 280 mg OD without DLT until the 280 mg cohort where three DLTs were observed: Gr 3 diarrhea, Gr 3 diverticulitis, and Gr 3 dehydration. MTD and recommended phase 2 dose was established at 210 mg OD. Common adverse events were Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked between 1 and 4 hours across the cohorts with terminal half-lives ranging from 6.7 to 12 hours. Steady state was achieved by Day 8 to 15, and in the higher dose cohorts, trough concentrations exceeded the levels predicted to be therapeutic. Stable disease as best response was seen in 8 (28%) heavily pre-treated pts (3 colorectal, 2 ovarian, 1 pancreatic, 1 appendiceal, and 1 bladder). Progression-free survival, overall survival, and weighted health status were significantly better in pts receiving 210 mg OD compared to those receiving lower doses. Conclusions: Zelenirstat is well-tolerated, reaches plasma concentrations highly active in preclinical models, and shows preliminary signs of encouraging anticancer activity. NMT inhibition represents a new target for ongoing research efforts and further clinical development of zelenirstat is warranted. Clinical trial information: NCT04836195 .