Universität zu Köln

DiNardo, Courtney D., Hochhaus, Andreas, Frattini, Mark G., Yee, Karen, Zander, Thomas, Kraemer, Alwin, Chen, Xueying, Ji, Yan, Parikh, Nehal S., Choi, Joanne and Wei, Andrew H. (2023). A phase 1 study of IDH305 in patients with IDH1(R132)-mutant acute myeloid leukemia or myelodysplastic syndrome. J. Cancer Res. Clin. Oncol., 149 (3). S. 1145 - 1159. NEW YORK: SPRINGER. ISSN 1432-1335

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Abstract

Purpose Isocitrate dehydrogenase enzyme 1 (IDH1) mutations at 132nd amino acid residue (R132*) result in the cellular accumulation of the oncometabolite, 2-hydroxyglutarate (2-HG). IDH305 is an orally bioavailable, brain-penetrant, mutant-selective allosteric IDH1 inhibitor demonstrating target engagement in preclinical models. This first-in human study was designed to identify the recommended dose for expansion/maximum tolerated dose of IDH305 in patients with IDH1(R132)-mutant acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods IDH305 was given at doses 75-750 mg twice daily in 41 patients with IDH1(R132)-mutant AML/MDS. Dose escalation was designed using Bayesian hierarchical model with overdose control principle and relationship with dose-limiting toxicity. Results IDH305 exhibited rapid absorption with mean T-1/2 approximately 4-10 h across doses. Interpatient variability was moderate and exposure increased with dose in a less than dose proportional manner. Most patients (35/41) demonstrated target engagement with reduction in 2-HG concentration at all doses. Complete remission (CR) or CR with incomplete count recovery occurred in 10/37 (27%) patients with AML and 1/ 4 patients with MDS. Adverse events (AEs) suspected to be related to study drug were reported in 53.7% of patients: increased blood bilirubin (14.6%), nausea (14.6%), increased alanine aminotransferase and aspartate aminotransferase (12.2%, each); most frequent grade 3 or 4 AEs were differentiation syndrome and tumor lysis syndrome (n = 3; 7.3%, each). Hepatotoxicity was manageable with dose modification. Conclusion Due to potentially narrow therapeutic window, the study was prematurely halted and recommended phase 2 dose could not be declared.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code DiNardo, Courtney D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hochhaus, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Frattini, Mark G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yee, Karen UNSPECIFIED UNSPECIFIED UNSPECIFIED Zander, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Kraemer, Alwin UNSPECIFIED UNSPECIFIED UNSPECIFIED Chen, Xueying UNSPECIFIED UNSPECIFIED UNSPECIFIED Ji, Yan UNSPECIFIED UNSPECIFIED UNSPECIFIED Parikh, Nehal S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Choi, Joanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Wei, Andrew H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-693311
DOI:	10.1007/s00432-022-03983-6
Journal or Publication Title:	J. Cancer Res. Clin. Oncol.
Volume:	149
Number:	3
Page Range:	S. 1145 - 1159
Date:	2023
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-1335
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ISOCITRATE DEHYDROGENASE MUTATIONS; INTERNATIONAL WORKING GROUP; RESPONSE CRITERIA; IDH1; DIFFERENTIATION; RECOMMENDATIONS; DIAGNOSIS; GLIOMA; SERUM Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69331