Novel, First-in-Human, Oral PCLX-001 Treatment in a Patient with Relapsed Diffuse Large B-Cell Lymphoma

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) face limited treatment options, especially if they are ineligible for transplantation or chimeric antigen receptor (CAR) T-cell therapy, highlighting the need for novel therapeutics. In a phase I dose-escalation trial, an 86-year-old woman with relapsed DLBCL became the first patient to receive a novel, first-in-class small molecule inhibitor of N-myristoyltransferase (NMT). She was treated with a daily oral dose of 20 mg PCLX-001 tablets, which showed a pharmacokinetic profile conducive to once-daily dosing—characterized by rapid oral absorption and an apparent elimination half-life of 16 hours, without systemic drug accumulation by day 15. Pharmacodynamic testing indicated no significant changes in the levels of NMT1, NMT2, or selected NMT substrates Lyn and HGAL proteins in normal circulating blood mononuclear cells, suggesting that higher doses may be necessary to observe normal tissue toxicity. The patient did not experience any dose-limiting toxicities but showed disease progression after 28 days of treatment. Dose escalation is ongoing in other patients in this first-in-human study of a new class of anticancer drug. The findings suggest that PCLX-001 oral monotherapy has favorable pharmacokinetic properties for dose escalation, and that higher doses are needed to achieve pharmacodynamic evidence of on-target activity in normal tissues. The current study protocol is well-designed to meet these objectives, and the trial is proceeding DDD86481 without modifications.