On June 10, 2024 Pacylex Pharmaceuticals Inc. (Pacylex) is a clinical-stage pharmaceutical company developing N-myristoyltransferase (NMT) inhibitors to treat hematologic cancers and solid tumors, reported the publication of Phase 1 clinical trial results in the journal Investigational New Drugs (Press release, Pacylex Pharmaceuticals, JUN 10, 2024, View Source [SID1234645047]). The report, titled: "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," describes effects of zelenirstat at various doses on cancer patients who exhausted all other therapeutic options.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
Myristoylation is a fatty acid modification critical to targeting certain proteins to cell membranes where they participate in activities essential to cancer cell survival and proliferation. Zelenirstat works by the unique mechanism of inhibiting the myristoylation required for the assembly, translocation, and function of EGFR, VEGFR, and the B-cell receptor. Last month Pacylex published in the Journal of Translational Medicine that zelenirstat also blocks Complex I formation in mitochondria of cancer cells to shut down oxidative phosphorylation, an energy generation process needed for metastases and cancer stem cell survival.
The Phase 1 dose escalation safety and tolerability study was conducted in 29 patients with refractory/relapsed (r/r) lymphoma and refractory solid tumors who averaged 4 lines of prior therapy. Zelenirstat, administered as a once daily oral medication, was well-tolerated in Phase 1 patients up to the recommended Phase 2 dose (RP2D) with no dose limiting toxicities observed in 6 dose levels. The most common treatment related adverse events were mild to moderate gastrointestinal side effects which were self-limiting and occurred in a minority of patients.
The study was designed and sponsored by Pacylex Pharmaceuticals and was conducted at the Cross Cancer Institute, Edmonton, AB, under the direction of Principal Investigator Dr. Randeep Sangha; the British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, BC, by Dr. Laurie Helen Sehn; Princess Margaret Cancer Centre, Toronto, ON by Dr. John Kuruvilla; and Université de Montréal’s hospital affiliated research centre, the CRCHUM, QC by Dr. Rahima Jamal.
The 7 patients receiving the recommended Phase 2 dose had significantly better progression free and overall survival than the 17 treated at lower doses; 57% had stable disease or better for six months or longer, including patients with ovarian, appendiceal, and colorectal cancer. The sole person with colorectal cancer receiving the RP2D had experienced only short-term benefit from any of the 6 prior lines of therapy, but continues to receive the zelenirstat 450 days after starting therapy and had reductions of approximately 50% in CEA (carcinoembryonic antigen) and tumor volumes.
"These Phase 1 results are as encouraging as any cancer study I have run with an oral cancer therapy", said Dr. Randeep Sangha. "The safety profile was consistent with long-term therapy and considering how many prior lines of therapy these patients had received, the signals of potential efficacy in several different types of solid tumor cancers was surprising."
"Given the outstanding safety of zelenirstat in Phase 1 and the prolonged stable disease or better seen in patients with refractory ovarian, appendiceal and colorectal cancer who received the RP2D, we are advancing zelenirstat into two Phase 2a studies that have begun dosing patients with refractory and relapsed B-cell non-Hodgkin’s lymphoma, and advanced refractory colorectal cancer", said Dr. John Mackey, CMO of Pacylex Pharmaceuticals.
"Zelenirstat is a very unique approach to treating cancer – it inhibits proteins that have been hijacked in cancer cells for survival and proliferation signaling, tumor blood supply, cell surface receptor recycling, and energy production, all with one drug", said Dr. Michael Weickert, CEO of Pacylex. "This explains how zelenirstat has potential as an important therapeutic option across many different cancers."
About zelenirstat (PCLX-001)
Zelenirstat (formerly identified as PCLX-001) is a first-in-class, oral, small molecule NMTi being developed to treat patients with leukemia, lymphoma, and solid tumors. Zelenirstat selectively killed cancer cells in vitro and in animal models has been shown to fully regress hematologic malignancies and inhibit the growth of lung and breast cancer tumors. In AML models, zelenirstat preferentially killed leukemic stem enriched cell populations and reduced the bone marrow leukemic burden.
About zelenirstat Phase 1 and 2 studies
Pacylex completed the dose escalation phase of a Phase 1 multiple ascending dose safety, tolerability, and pharmacokinetics study on zelenirstat in people with relapsed/refractory lymphoma and refractory solid tumors (NCT04836195). A recommended Phase 2 dose was determined. Zelenirstat demonstrated an acceptable safety and tolerability profile, pharmacokinetics consistent with once daily oral dosing, and early signs of efficacy.
Zelenirstat is currently being studied in a Phase 2a open-label study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of zelenirstat in patients with relapsed/refractory B-cell non-Hodgkin Lymphoma (NHL) and a separate Phase 2a cohort in patients with refractory metastatic colorectal cancer that has progressed despite all available standard therapies.