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) have limited treatment options, particularly if they are transplantation or chimeric antigen receptor (CAR) T-cell ineligible, and novel therapeutics are needed. An 86-year-old woman with relapsed DLBCL received a novel, firs...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Current Oncology |
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| Online Access: | https://www.mdpi.com/1718-7729/29/3/158 |
| _version_ | 1797472090083819520 |
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| author | Randeep Sangha Neal M. Davies Afshin Namdar Michael Chu Jennifer Spratlin Erwan Beauchamp Luc G. Berthiaume John R. Mackey |
| author_facet | Randeep Sangha Neal M. Davies Afshin Namdar Michael Chu Jennifer Spratlin Erwan Beauchamp Luc G. Berthiaume John R. Mackey |
| author_sort | Randeep Sangha |
| collection | DOAJ |
| description | Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have limited treatment options, particularly if they are transplantation or chimeric antigen receptor (CAR) T-cell ineligible, and novel therapeutics are needed. An 86-year-old woman with relapsed DLBCL received a novel, first-in-class small molecule inhibitor of N-myristoyltransferase (NMT) as the initial patient on a phase I dose escalation trial. Daily oral administration of 20 mg PCLX-001 tablets produced a pharmacokinetic profile suitable for single daily dosing: rapid oral absorption, followed by an apparent elimination half-life of 16 h, without systemic accumulation of drug by day 15. Pharmacodynamic tests showed no clear change in NMT1 and NMT2 levels or selected NMT substrate Lyn and HGAL protein levels in normal circulating blood mononuclear cells, suggesting a higher dose will be required for normal tissue toxicity. The patient did not experience any dose-limiting toxicities but had disease progression after 28 days of study therapy. Dose escalation continues in other patients in this first-in-human study of a new class of anticancer drug. We conclude that PCLX-001 oral monotherapy has suitable pharmacokinetic parameters for dose escalation, and that higher doses are required to achieve pharmacodynamic evidence of on-target activity in normal tissues. The current protocol is appropriately designed to achieve these ends, and the study proceeds without modification. |
| first_indexed | 2024-03-09T19:57:18Z |
| format | Article |
| id | doaj.art-bc7e32c7ed9e44a19c59822c4b50dbea |
| institution | Directory Open Access Journal |
| issn | 1198-0052 1718-7729 |
| language | English |
| last_indexed | 2024-03-09T19:57:18Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Current Oncology |
| spelling | doaj.art-bc7e32c7ed9e44a19c59822c4b50dbea2023-11-24T00:53:20ZengMDPI AGCurrent Oncology1198-00521718-77292022-03-012931939194610.3390/curroncol29030158Novel, First-in-Human, Oral PCLX-001 Treatment in a Patient with Relapsed Diffuse Large B-Cell LymphomaRandeep Sangha0Neal M. Davies1Afshin Namdar2Michael Chu3Jennifer Spratlin4Erwan Beauchamp5Luc G. Berthiaume6John R. Mackey7Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G1Z2, CanadaFaculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G2H1, CanadaDepartment of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2H7, CanadaDepartment of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G1Z2, CanadaDepartment of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G1Z2, CanadaPacylex Pharmaceuticals Inc., Edmonton, AB T5J4P6, CanadaDepartment of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2H7, CanadaDepartment of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G1Z2, CanadaPatients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have limited treatment options, particularly if they are transplantation or chimeric antigen receptor (CAR) T-cell ineligible, and novel therapeutics are needed. An 86-year-old woman with relapsed DLBCL received a novel, first-in-class small molecule inhibitor of N-myristoyltransferase (NMT) as the initial patient on a phase I dose escalation trial. Daily oral administration of 20 mg PCLX-001 tablets produced a pharmacokinetic profile suitable for single daily dosing: rapid oral absorption, followed by an apparent elimination half-life of 16 h, without systemic accumulation of drug by day 15. Pharmacodynamic tests showed no clear change in NMT1 and NMT2 levels or selected NMT substrate Lyn and HGAL protein levels in normal circulating blood mononuclear cells, suggesting a higher dose will be required for normal tissue toxicity. The patient did not experience any dose-limiting toxicities but had disease progression after 28 days of study therapy. Dose escalation continues in other patients in this first-in-human study of a new class of anticancer drug. We conclude that PCLX-001 oral monotherapy has suitable pharmacokinetic parameters for dose escalation, and that higher doses are required to achieve pharmacodynamic evidence of on-target activity in normal tissues. The current protocol is appropriately designed to achieve these ends, and the study proceeds without modification.https://www.mdpi.com/1718-7729/29/3/158N-myristoyltransferase inhibitorsPCLX-001non-Hodgkin lymphomaphase Ifirst-in-humandose escalation |
| spellingShingle | Randeep Sangha Neal M. Davies Afshin Namdar Michael Chu Jennifer Spratlin Erwan Beauchamp Luc G. Berthiaume John R. Mackey Novel, First-in-Human, Oral PCLX-001 Treatment in a Patient with Relapsed Diffuse Large B-Cell Lymphoma Current Oncology N-myristoyltransferase inhibitors PCLX-001 non-Hodgkin lymphoma phase I first-in-human dose escalation |
| title | Novel, First-in-Human, Oral PCLX-001 Treatment in a Patient with Relapsed Diffuse Large B-Cell Lymphoma |
| title_full | Novel, First-in-Human, Oral PCLX-001 Treatment in a Patient with Relapsed Diffuse Large B-Cell Lymphoma |
| title_fullStr | Novel, First-in-Human, Oral PCLX-001 Treatment in a Patient with Relapsed Diffuse Large B-Cell Lymphoma |
| title_full_unstemmed | Novel, First-in-Human, Oral PCLX-001 Treatment in a Patient with Relapsed Diffuse Large B-Cell Lymphoma |
| title_short | Novel, First-in-Human, Oral PCLX-001 Treatment in a Patient with Relapsed Diffuse Large B-Cell Lymphoma |
| title_sort | novel first in human oral pclx 001 treatment in a patient with relapsed diffuse large b cell lymphoma |
| topic | N-myristoyltransferase inhibitors PCLX-001 non-Hodgkin lymphoma phase I first-in-human dose escalation |
| url | https://www.mdpi.com/1718-7729/29/3/158 |
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