First-in-Human Dose-Escalation Study of the First-in-Class PDE3A–SLFN12 Complex Inducer BAY 2666605 in Patients with Advanced Solid Tumors Coexpressing SLFN12 and PDE3A
Gespeichert in:
| Titel: | First-in-Human Dose-Escalation Study of the First-in-Class PDE3A–SLFN12 Complex Inducer BAY 2666605 in Patients with Advanced Solid Tumors Coexpressing SLFN12 and PDE3A |
|---|---|
| Autoren: | Kyriakos P. Papadopoulos, Meredith McKean, Silvia Goldoni, Isabelle Genvresse, Marine F. Garrido, Rui Li, Gary Wilkinson, Christoph Kneip, Timothy A. Yap |
| Quelle: | Clin Cancer Res |
| Verlagsinformationen: | American Association for Cancer Research (AACR), 2024. |
| Publikationsjahr: | 2024 |
| Schlagwörter: | Male, Adult, Aged, 80 and over, Maximum Tolerated Dose, Dose-Response Relationship, Drug, Neoplasms, Humans, Clinical Trials: Targeted Therapy, Female, Antineoplastic Agents, Middle Aged, Cyclic Nucleotide Phosphodiesterases, Type 3, Aged |
| Beschreibung: | Purpose: The study aims to evaluate the safety, tolerability, and pharmacokinetics of BAY 2666605, a velcrin that induces complex formation between the phosphodiesterase PDE3A and the protein Schlafen 12 (SLFN12), leading to a cytotoxic response in cancer cells. Patients and Methods: This was a first-in-human phase I study of BAY 2666605 (NCT04809805), an oral, potent first-in-class PDE3A–SLFN12 complex inducer, with reduced PDE3A inhibition. Adults with advanced solid tumors that coexpress SLFN12 and PDE3A received BAY 2666605 at escalating doses starting at 5 mg once daily in 28-day cycles. Forty-seven patients were prescreened for SLFN12 and PDE3A overexpression, and five biomarker-positive patients received ≥1 BAY 2666605 dose. Results: The most common adverse event was grade 3 to 4 thrombocytopenia in three of the five patients treated. The long half-life (>360 hours) and associated accumulation of BAY 2666605 led to the selection of an alternative schedule consisting of a loading dose with a once-daily maintenance dose. The maximum tolerated dose was not established as the highest doses of both schedules were intolerable. No objective responses were observed. Due to the high expression of PDE3A in platelets compared with tumor tissues, the ex vivo dose-dependent inhibitory effect of BAY 2666605 on megakaryocytes, and the pharmacokinetic profile of the compound, alternative schedules were not predicted to ameliorate the mechanism-based thrombocytopenia. Conclusions: Despite the decreased PDE3A enzymatic inhibition profile of BAY 2666605, the occurrence of thrombocytopenia in treated patients, an on-target effect of the compound, precluded the achievement of a therapeutic window, consequently leading to trial termination. |
| Publikationsart: | Article Other literature type |
| Sprache: | English |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-24-2713 |
| Zugangs-URL: | https://pubmed.ncbi.nlm.nih.gov/39437010 |
| Rights: | CC BY NC ND URL: http://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
| Dokumentencode: | edsair.doi.dedup.....fbd844546a98c173796d8749acddc3fe |
| Datenbank: | OpenAIRE |
Nájsť tento článok vo Web of Science | Abstract: | Purpose: The study aims to evaluate the safety, tolerability, and pharmacokinetics of BAY 2666605, a velcrin that induces complex formation between the phosphodiesterase PDE3A and the protein Schlafen 12 (SLFN12), leading to a cytotoxic response in cancer cells. Patients and Methods: This was a first-in-human phase I study of BAY 2666605 (NCT04809805), an oral, potent first-in-class PDE3A–SLFN12 complex inducer, with reduced PDE3A inhibition. Adults with advanced solid tumors that coexpress SLFN12 and PDE3A received BAY 2666605 at escalating doses starting at 5 mg once daily in 28-day cycles. Forty-seven patients were prescreened for SLFN12 and PDE3A overexpression, and five biomarker-positive patients received ≥1 BAY 2666605 dose. Results: The most common adverse event was grade 3 to 4 thrombocytopenia in three of the five patients treated. The long half-life (>360 hours) and associated accumulation of BAY 2666605 led to the selection of an alternative schedule consisting of a loading dose with a once-daily maintenance dose. The maximum tolerated dose was not established as the highest doses of both schedules were intolerable. No objective responses were observed. Due to the high expression of PDE3A in platelets compared with tumor tissues, the ex vivo dose-dependent inhibitory effect of BAY 2666605 on megakaryocytes, and the pharmacokinetic profile of the compound, alternative schedules were not predicted to ameliorate the mechanism-based thrombocytopenia. Conclusions: Despite the decreased PDE3A enzymatic inhibition profile of BAY 2666605, the occurrence of thrombocytopenia in treated patients, an on-target effect of the compound, precluded the achievement of a therapeutic window, consequently leading to trial termination. |
|---|---|
| ISSN: | 15573265 10780432 |
| DOI: | 10.1158/1078-0432.ccr-24-2713 |