Phase 1/2 Trial of Oral Zelenirstat Launches in Relapsed/Refractory AML

Acute myeloid leukemia (AML) cells in blood flow - isometric view 3d illustration | Image credit © LASZLO via Adobe Stock

A trial of oral zelenirstat (PCLX-001), a first-in-class N-myristoyltransferase inhibitor, dosed its first patient with relapsed/refractory acute myeloid leukemia (AML), according to a press release from Pacylex Pharmaceuticals.¹

The phase 1/2 dose-finding trial (NCT06613217) based at The University of Texas MD Anderson Cancer Center follows a phase 1 trial in patients with solid tumors and non-Hodgkin lymphoma as well as preclinical data supporting anti-AML activity of zelenirstat.

“Because preclinical results suggest AML cells are particularly sensitive to zelenirstat, we are eager to see it tested in people with AML,” John Mackey, MD, chief medical officer of Pacylex, stated in the press release.

N-myristoylation, the myristate modification of proteins, is linked to survival signaling and metabolism and is considered a potential target for AML.² Low expression of NMT2, which is involved in the catalyzation of N-myristoylation, was associated with poor outcomes in AML. Zelenirstat is a pan-NMT inhibitor that leads to multiple mechanisms of AML cell death.

The newly launched trial has 2 parts; in the dose escalation portion, a maximum of 15 patients will be enrolled and in the dose expansion portion, 20 evaluable patients will be treated with the minimum safe and biologically effective dose of zelenirstat.³

Eligible patients must have received at least 1 prior therapy for AML and must not be eligible for other therapies expected to have clinical benefit. Reasons for ineligibility include acute promyelocytic leukemia, history of cardiac disease, and moderate to severe hepatic impairment.

Zelenirstat is being given daily at dose levels of 40 mg, 70 mg, 100 mg, 140 mg, 210 mg, and 280 mg in 28-day cycles, with the 40-mg starting dose supported by results of an ongoing trial in solid tumors and lymphoma. The primary end point is determining a recommended phase 2 dose (RP2D) and observing dose-limiting toxicities (DLTs) for up to 18 months, with a secondary end point of measuring tumor response and progression of AML.

In the phase 1 study of 29 patients with heavily pretreated solid tumors and lymphoma (NCT04836195), patients were treated with doses of oral zelenirstat ranging from 20 mg to 210 mg daily without any DLTs, but in patients receiving 280 mg daily, gastrointestinal DLTs were observed.⁴ Five patients initially received 280 mg daily, but 2 were replaced due to progressive disease. Grade 3 AEs of diarrhea, diverticulitis, and dehydration were reported by 1 patient each at this dose level. The dose level of 210 mg was established as the RP2D dose for this study.

Adverse events commonly reported in the full trial population included decreased appetite, nausea, vomiting, diarrhea, and fatigue of grade 1 and 2. There was no evidence of drug-induced QT prolongation and no trend seen for increased QT duration as the dose level increased.

A best response of stable disease was observed in 8 patients (28%), including those with refractory ovarian cancer, metastatic appendiceal carcinoma, and metastatic colon adenocarcinoma. The patient with colon cancer was still being treated at 210 mg beyond 14 cycles with stable disease; he had been treated with 6 prior therapies.

“Our phase 1 dose escalation safety and tolerability study in solid tumor and lymphoma patients showed excellent safety and signs of efficacy even though these patients were less likely to respond to zelenirstat than those with AML,” stated Mackey in the press release.¹

_References:

_{1. Pacylex Pharmaceuticals Announces the first Acute Myeloid Leukemia (AML) patient dosed with zelenirstat in a new Phase 1/2 clinical trial. News release. Pacylex. March 17, 2025. Accessed March 19, 2025. https://pacylex.reportablenews.com/pr/pacylex-pharmaceuticals-announces-the-first-acute-myeloid-leukemia-aml-patient-dosed-with-zelenirstat-in-a-new-phase-1-2-clinical-trail}

_{2. Gamma JM, Liu Q, Beauchamp E, et al. Zelenirstat inhibits N-myristoyltransferases to disrupt Src family kinase signaling and oxidative phosphorylation, killing acute myeloid leukemia cells. Mol Cancer Ther. 2025;24(1):69-80. doi:10.1158/1535-7163.MCT-24-0307}

_{3. Study of Oral PCLX-001 in R/​R Acute Myeloid Leukemia. ClinicalTrials.gov. Updated March 10, 2025. Accessed March 19, 2025. https://clinicaltrials.gov/study/NCT06613217}

_{4. Sangha R, Jamal R, Spratlin J, et al. A first-in-human phase I trial of daily oral zelenirstat, a N-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas. Invest New Drugs. 2024;42(4):386-393. doi:10.1007/s10637-024-01448-w}