Background: Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, regulates multiple membrane-bound signal transduction pathways driving cancer cell biology. This modification is catalyzed by two N-myristoyltransferases (NMT), NMT1 and NMT2. Aberrant NMT expression has been identified in cancer cells and inhibition of myristoylation represents a novel anticancer treatment strategy. PCLX-001 is an oral, highly bioavailable, small molecule NMT inhibitor with strong affinity for both NMT1 and NMT2 proteins (IC₅₀ of 5nM and 8nM, respectively). In vitro, hematologic cancer cell lines were exquisitely sensitive to PCLX-001. PCLX-001 regressed subcutaneous tumors in xenograft models derived from lymphoma cell lines, as well as in a refractory DLBCL patient derived xenograft model. PCLX-001 also demonstrated anticancer activity in multiple solid tumor xenograft models. Based on pre-clinical data, we hypothesized that PCLX-001 would be safe, tolerable, and active as a novel oral cancer therapeutic. Methods: Patients with relapsed/refractory B-cell lymphomas and advanced solid tumors are being enrolled in a multicenter, open label, standard phase I dose escalation design to determine feasibility, maximum tolerated dose (MTD), and pharmacokinetics of PCLX-001 monotherapy. Seven dose levels are being studied: 20 mg, 40 mg, 70 mg, 100 mg, 140 mg, 200 mg, and 280 mg. Dose limiting toxicity (DLT) is defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, Gr 4 ANC ≥ 7 days, febrile neutropenia, or clinically significant > Gr 3 non-hematologic toxicity. Results: Eighteen evaluable patients (3 relapsed B-cell lymphoma; 15 advanced solid tumor) have been accrued through dose level six (200 mg cohort) without DLT. No attributable Gr 3 or 4 toxicities have been identified. Noncompartmental pharmacokinetic (PK) analyses demonstrate rapid oral absorption, a terminal half-life of approximately 10 hours, rapid achievement of steady state, and no induction of metabolism. PCLX-001 trough plasma concentrations at higher dose cohorts exceed the EC₉₀ required to inhibit cultured cancer cells. Conclusions: PCLX-001 is safe and well tolerated up to the 200 mg daily dose. Our results support the ongoing development of PCLX-001 as an oral daily therapy for the treatment of patients with cancer. Updated study results will be presented, summarizing the safety, MTD, and PK outcomes in PCLX-001 treated patients. Preliminary clinical activity will be determined in 20 patient dose expansion cohorts of relapsed/refractory B-cell lymphomas, and selected advanced solid tumors following the identification of PCLX-001 MTD. Clinical trial information: NCT04836195.