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A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia

Mivavotinib (TAK-659) is an investigational type 1 tyrosine kinase inhibitor with dual activity against spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 (FLT3). We conducted a phase Ib study to investigate the safety, tolerability, and efficacy of mivavotinib in patients with refractory a...

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Autores principales: Pratz, Keith W., Kaplan, Jason, Levy, Moshe, Bixby, Dale, Burke, Patrick W., Erba, Harry, Wise-Draper, Trisha M., Roboz, Gail J., Papadantonakis, Nikolaos, Rajkhowa, Trivikram, Hernandez, Daniela, Dobler, Iwona, Gregory, Richard C., Li, Cheryl, Wang, Shining, Stumpo, Kate, Kannan, Karuppiah, Miao, Harry, Levis, Mark
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973464/
https://www.ncbi.nlm.nih.gov/pubmed/36226495
http://dx.doi.org/10.3324/haematol.2022.281216
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author Pratz, Keith W.
Kaplan, Jason
Levy, Moshe
Bixby, Dale
Burke, Patrick W.
Erba, Harry
Wise-Draper, Trisha M.
Roboz, Gail J.
Papadantonakis, Nikolaos
Rajkhowa, Trivikram
Hernandez, Daniela
Dobler, Iwona
Gregory, Richard C.
Li, Cheryl
Wang, Shining
Stumpo, Kate
Kannan, Karuppiah
Miao, Harry
Levis, Mark
author_facet Pratz, Keith W.
Kaplan, Jason
Levy, Moshe
Bixby, Dale
Burke, Patrick W.
Erba, Harry
Wise-Draper, Trisha M.
Roboz, Gail J.
Papadantonakis, Nikolaos
Rajkhowa, Trivikram
Hernandez, Daniela
Dobler, Iwona
Gregory, Richard C.
Li, Cheryl
Wang, Shining
Stumpo, Kate
Kannan, Karuppiah
Miao, Harry
Levis, Mark
author_sort Pratz, Keith W.
collection PubMed
description Mivavotinib (TAK-659) is an investigational type 1 tyrosine kinase inhibitor with dual activity against spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 (FLT3). We conducted a phase Ib study to investigate the safety, tolerability, and efficacy of mivavotinib in patients with refractory and/or relapsed (R/R) acute myeloid leukemia (AML). Both daily (QD) and twice daily (BID) dosing regimens were evaluated. A total of 43 patients were enrolled, and there were 5 complete responses (4 with incomplete count recovery). In the QD dosing regimen, the maximum tolerated dose (MTD) was not reached up to 160 mg QD per protocol; 140 mg QD was identified as the recommended phase II dose. In the BID dosing regimen, the MTD was 60 mg BID. Thirty patients (70%) experienced a bleeding event on study; the majority were grades 1 or 2, were resolved without mivavotinib modification, and were not considered related to study treatment. Eleven patients (26%) experienced grade ≥3 bleeding events, which were observed most frequently with the 80 mg BID dose. We conducted platelet aggregation studies to investigate the potential role of mivavotinib-mediated SYK inhibition on platelet function. The bleeding events observed may have been the result of several confounding factors, including AML disease status, associated thrombocytopenia, and high doses of mivavotinib. Overall, these findings indicate that the activity of mivavotinib in R/R AML is modest. Furthermore, any future clinical investigation of this agent should be undertaken with caution, particularly in thrombocytopenic patients, due to the potential bleeding risk of SYK inhibition. ClinicalTrials.gov: NCT02323113.
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spelling pubmed-99734642023-03-01 A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia Pratz, Keith W. Kaplan, Jason Levy, Moshe Bixby, Dale Burke, Patrick W. Erba, Harry Wise-Draper, Trisha M. Roboz, Gail J. Papadantonakis, Nikolaos Rajkhowa, Trivikram Hernandez, Daniela Dobler, Iwona Gregory, Richard C. Li, Cheryl Wang, Shining Stumpo, Kate Kannan, Karuppiah Miao, Harry Levis, Mark Haematologica Article - Acute Myeloid Leukemia Mivavotinib (TAK-659) is an investigational type 1 tyrosine kinase inhibitor with dual activity against spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 (FLT3). We conducted a phase Ib study to investigate the safety, tolerability, and efficacy of mivavotinib in patients with refractory and/or relapsed (R/R) acute myeloid leukemia (AML). Both daily (QD) and twice daily (BID) dosing regimens were evaluated. A total of 43 patients were enrolled, and there were 5 complete responses (4 with incomplete count recovery). In the QD dosing regimen, the maximum tolerated dose (MTD) was not reached up to 160 mg QD per protocol; 140 mg QD was identified as the recommended phase II dose. In the BID dosing regimen, the MTD was 60 mg BID. Thirty patients (70%) experienced a bleeding event on study; the majority were grades 1 or 2, were resolved without mivavotinib modification, and were not considered related to study treatment. Eleven patients (26%) experienced grade ≥3 bleeding events, which were observed most frequently with the 80 mg BID dose. We conducted platelet aggregation studies to investigate the potential role of mivavotinib-mediated SYK inhibition on platelet function. The bleeding events observed may have been the result of several confounding factors, including AML disease status, associated thrombocytopenia, and high doses of mivavotinib. Overall, these findings indicate that the activity of mivavotinib in R/R AML is modest. Furthermore, any future clinical investigation of this agent should be undertaken with caution, particularly in thrombocytopenic patients, due to the potential bleeding risk of SYK inhibition. ClinicalTrials.gov: NCT02323113. Fondazione Ferrata Storti 2022-10-13 /pmc/articles/PMC9973464/ /pubmed/36226495 http://dx.doi.org/10.3324/haematol.2022.281216 Text en Copyright© 2023 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article - Acute Myeloid Leukemia
Pratz, Keith W.
Kaplan, Jason
Levy, Moshe
Bixby, Dale
Burke, Patrick W.
Erba, Harry
Wise-Draper, Trisha M.
Roboz, Gail J.
Papadantonakis, Nikolaos
Rajkhowa, Trivikram
Hernandez, Daniela
Dobler, Iwona
Gregory, Richard C.
Li, Cheryl
Wang, Shining
Stumpo, Kate
Kannan, Karuppiah
Miao, Harry
Levis, Mark
A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia
title A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia
title_full A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia
title_fullStr A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia
title_full_unstemmed A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia
title_short A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia
title_sort phase ib trial of mivavotinib (tak-659), a dual syk/flt3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia
topic Article - Acute Myeloid Leukemia
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973464/
https://www.ncbi.nlm.nih.gov/pubmed/36226495
http://dx.doi.org/10.3324/haematol.2022.281216
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