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Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results

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Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results. / Heuser, Michael; Palmisiano, Neil; Mantzaris, Ioannis; Mims, Alice; DiNardo, Courtney; Silverman, Lewis R; Wang, Eunice S; Fiedler, Walter; Baldus, Claudia; Schwind, Sebastian; Pardee, Timothy; Perl, Alexander E; Cai, Charles; Kaulfuss, Stefan; Lagkadinou, Eleni; Rentzsch, Christine; Wagner, Markus; Wilkinson, Gary; Wu, Bingyan; Jeffers, Michael; Genvresse, Isabelle; Krämer, Alwin.

in: LEUKEMIA, Jahrgang 34, Nr. 11, 11.2020, S. 2903-2913.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Heuser, M, Palmisiano, N, Mantzaris, I, Mims, A, DiNardo, C, Silverman, LR, Wang, ES, Fiedler, W, Baldus, C, Schwind, S, Pardee, T, Perl, AE, Cai, C, Kaulfuss, S, Lagkadinou, E, Rentzsch, C, Wagner, M, Wilkinson, G, Wu, B, Jeffers, M, Genvresse, I & Krämer, A 2020, 'Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results', LEUKEMIA, Jg. 34, Nr. 11, S. 2903-2913. https://doi.org/10.1038/s41375-020-0996-5

APA

Heuser, M., Palmisiano, N., Mantzaris, I., Mims, A., DiNardo, C., Silverman, L. R., Wang, E. S., Fiedler, W., Baldus, C., Schwind, S., Pardee, T., Perl, A. E., Cai, C., Kaulfuss, S., Lagkadinou, E., Rentzsch, C., Wagner, M., Wilkinson, G., Wu, B., ... Krämer, A. (2020). Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results. LEUKEMIA, 34(11), 2903-2913. https://doi.org/10.1038/s41375-020-0996-5

Vancouver

Heuser M, Palmisiano N, Mantzaris I, Mims A, DiNardo C, Silverman LR et al. Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results. LEUKEMIA. 2020 Nov;34(11):2903-2913. https://doi.org/10.1038/s41375-020-0996-5

Bibtex

@article{dd71ed5edf7c43608ae406b46a342111,
title = "Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results",
abstract = "The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49-8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9-8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1-7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.",
author = "Michael Heuser and Neil Palmisiano and Ioannis Mantzaris and Alice Mims and Courtney DiNardo and Silverman, {Lewis R} and Wang, {Eunice S} and Walter Fiedler and Claudia Baldus and Sebastian Schwind and Timothy Pardee and Perl, {Alexander E} and Charles Cai and Stefan Kaulfuss and Eleni Lagkadinou and Christine Rentzsch and Markus Wagner and Gary Wilkinson and Bingyan Wu and Michael Jeffers and Isabelle Genvresse and Alwin Kr{\"a}mer",
year = "2020",
month = nov,
doi = "10.1038/s41375-020-0996-5",
language = "English",
volume = "34",
pages = "2903--2913",
journal = "LEUKEMIA",
issn = "0887-6924",
publisher = "NATURE PUBLISHING GROUP",
number = "11",

}

RIS

TY - JOUR

T1 - Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results

AU - Heuser, Michael

AU - Palmisiano, Neil

AU - Mantzaris, Ioannis

AU - Mims, Alice

AU - DiNardo, Courtney

AU - Silverman, Lewis R

AU - Wang, Eunice S

AU - Fiedler, Walter

AU - Baldus, Claudia

AU - Schwind, Sebastian

AU - Pardee, Timothy

AU - Perl, Alexander E

AU - Cai, Charles

AU - Kaulfuss, Stefan

AU - Lagkadinou, Eleni

AU - Rentzsch, Christine

AU - Wagner, Markus

AU - Wilkinson, Gary

AU - Wu, Bingyan

AU - Jeffers, Michael

AU - Genvresse, Isabelle

AU - Krämer, Alwin

PY - 2020/11

Y1 - 2020/11

N2 - The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49-8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9-8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1-7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.

AB - The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49-8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9-8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1-7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.

U2 - 10.1038/s41375-020-0996-5

DO - 10.1038/s41375-020-0996-5

M3 - SCORING: Journal article

C2 - 32733012

VL - 34

SP - 2903

EP - 2913

JO - LEUKEMIA

JF - LEUKEMIA

SN - 0887-6924

IS - 11

ER -