A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias

K. W. Pratz; E. Cho; M. J. Levis; J. E. Karp; S. D. Gore; M. McDevitt; A. Stine; M. Zhao; S. D. Baker; M. A. Carducci; J. J. Wright; M. A. Rudek; B. D. Smith

doi:10.1038/leu.2010.132

A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias

K. W. Pratz, E. Cho, M. J. Levis, J. E. Karp, S. D. Gore, M. McDevitt, A. Stine, M. Zhao, S. D. Baker, M. A. Carducci, J. J. Wright, M. A. Rudek, B. D. Smith

School of Medicine

Research output: Contribution to journal › Article › peer-review

79 Scopus citations

Abstract

We report the results of a phase I dose escalation trial of the multikinase inhibitor sorafenib in relapsed and refractory acute leukemia patients using an intermittent dosing regimen. Fifteen patients with advanced leukemia (12 with acute myeloid leukemia, 2 with acute lymphoblastic leukemia, 1 with biphenotypic) and a median age of 63 (range 37-85) years were enrolled and treated on a dose escalation trial. Toxicities grade 3 were present in 55% of cycles and the maximum tolerated dose (MTD) was determined to be 400 mg b.i.d. × 21days in a 28-day cycle. Plasma inhibitory assays of kinase targets extracellular signal-regulated kinase (ERK) and FLT3-internal tandem duplication (ITD) showed excellent target inhibition, with FLT3-ITD silencing occurring below the MTD. The N-oxide metabolite of sorafenib seemed to be a more potent inhibitor of FLT3-ITD than the parent compound. Despite marked ex vivo FLT-3 ITD inhibition, no patients met the criteria for complete or partial response in this monotherapy study. Out of 15 patients, 11 experienced stable disease as best response. Although sorafenib showed only modest clinical activity as a single agent in this heavily treated population, robust inhibition of FLT3 and ERK suggests that there may be a potential important role in combination therapies.

Original language	English (US)
Pages (from-to)	1437-1444
Number of pages	8
Journal	Leukemia
Volume	24
Issue number	8
DOIs	https://doi.org/10.1038/leu.2010.132
State	Published - Aug 2010

Keywords

FLT3 targeted therapy
acute myeloid leukemia
clinical trial
signal transduction inhibitors

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

Access to Document

10.1038/leu.2010.132

Cite this

@article{46e32924e9974b328058ef68ec705c61,

title = "A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias",

abstract = "We report the results of a phase I dose escalation trial of the multikinase inhibitor sorafenib in relapsed and refractory acute leukemia patients using an intermittent dosing regimen. Fifteen patients with advanced leukemia (12 with acute myeloid leukemia, 2 with acute lymphoblastic leukemia, 1 with biphenotypic) and a median age of 63 (range 37-85) years were enrolled and treated on a dose escalation trial. Toxicities grade 3 were present in 55% of cycles and the maximum tolerated dose (MTD) was determined to be 400 mg b.i.d. × 21days in a 28-day cycle. Plasma inhibitory assays of kinase targets extracellular signal-regulated kinase (ERK) and FLT3-internal tandem duplication (ITD) showed excellent target inhibition, with FLT3-ITD silencing occurring below the MTD. The N-oxide metabolite of sorafenib seemed to be a more potent inhibitor of FLT3-ITD than the parent compound. Despite marked ex vivo FLT-3 ITD inhibition, no patients met the criteria for complete or partial response in this monotherapy study. Out of 15 patients, 11 experienced stable disease as best response. Although sorafenib showed only modest clinical activity as a single agent in this heavily treated population, robust inhibition of FLT3 and ERK suggests that there may be a potential important role in combination therapies.",

keywords = "FLT3 targeted therapy, acute myeloid leukemia, clinical trial, signal transduction inhibitors",

author = "Pratz, {K. W.} and E. Cho and Levis, {M. J.} and Karp, {J. E.} and Gore, {S. D.} and M. McDevitt and A. Stine and M. Zhao and Baker, {S. D.} and Carducci, {M. A.} and Wright, {J. J.} and Rudek, {M. A.} and Smith, {B. D.}",

note = "Funding Information: We thank Carol Hartke, Ping He, Aleksandr Mnatsakanyan, Yelena Zabelina and Linping Xu for their technical assistance; and Susan Davidson for quality assurance of the pharmacokinetic data. This work was supported by National Institutes of Health grants P30CA006973, U01CA70095, UL1 RR025005, NCI Leukemia SPORE P50 CA100632-06, R01 CA128864 and the by American Society of Clinical Oncology (MJL). MJL is a Clinical Scholar of the Leukemia and Lymphoma Society.",

year = "2010",

month = aug,

doi = "10.1038/leu.2010.132",

language = "English (US)",

volume = "24",

pages = "1437--1444",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Nature Publishing Group",

number = "8",

}

TY - JOUR

T1 - A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias

AU - Pratz, K. W.

AU - Cho, E.

AU - Levis, M. J.

AU - Karp, J. E.

AU - Gore, S. D.

AU - McDevitt, M.

AU - Stine, A.

AU - Zhao, M.

AU - Baker, S. D.

AU - Carducci, M. A.

AU - Wright, J. J.

AU - Rudek, M. A.

AU - Smith, B. D.

N1 - Funding Information: We thank Carol Hartke, Ping He, Aleksandr Mnatsakanyan, Yelena Zabelina and Linping Xu for their technical assistance; and Susan Davidson for quality assurance of the pharmacokinetic data. This work was supported by National Institutes of Health grants P30CA006973, U01CA70095, UL1 RR025005, NCI Leukemia SPORE P50 CA100632-06, R01 CA128864 and the by American Society of Clinical Oncology (MJL). MJL is a Clinical Scholar of the Leukemia and Lymphoma Society.

PY - 2010/8

Y1 - 2010/8

N2 - We report the results of a phase I dose escalation trial of the multikinase inhibitor sorafenib in relapsed and refractory acute leukemia patients using an intermittent dosing regimen. Fifteen patients with advanced leukemia (12 with acute myeloid leukemia, 2 with acute lymphoblastic leukemia, 1 with biphenotypic) and a median age of 63 (range 37-85) years were enrolled and treated on a dose escalation trial. Toxicities grade 3 were present in 55% of cycles and the maximum tolerated dose (MTD) was determined to be 400 mg b.i.d. × 21days in a 28-day cycle. Plasma inhibitory assays of kinase targets extracellular signal-regulated kinase (ERK) and FLT3-internal tandem duplication (ITD) showed excellent target inhibition, with FLT3-ITD silencing occurring below the MTD. The N-oxide metabolite of sorafenib seemed to be a more potent inhibitor of FLT3-ITD than the parent compound. Despite marked ex vivo FLT-3 ITD inhibition, no patients met the criteria for complete or partial response in this monotherapy study. Out of 15 patients, 11 experienced stable disease as best response. Although sorafenib showed only modest clinical activity as a single agent in this heavily treated population, robust inhibition of FLT3 and ERK suggests that there may be a potential important role in combination therapies.

AB - We report the results of a phase I dose escalation trial of the multikinase inhibitor sorafenib in relapsed and refractory acute leukemia patients using an intermittent dosing regimen. Fifteen patients with advanced leukemia (12 with acute myeloid leukemia, 2 with acute lymphoblastic leukemia, 1 with biphenotypic) and a median age of 63 (range 37-85) years were enrolled and treated on a dose escalation trial. Toxicities grade 3 were present in 55% of cycles and the maximum tolerated dose (MTD) was determined to be 400 mg b.i.d. × 21days in a 28-day cycle. Plasma inhibitory assays of kinase targets extracellular signal-regulated kinase (ERK) and FLT3-internal tandem duplication (ITD) showed excellent target inhibition, with FLT3-ITD silencing occurring below the MTD. The N-oxide metabolite of sorafenib seemed to be a more potent inhibitor of FLT3-ITD than the parent compound. Despite marked ex vivo FLT-3 ITD inhibition, no patients met the criteria for complete or partial response in this monotherapy study. Out of 15 patients, 11 experienced stable disease as best response. Although sorafenib showed only modest clinical activity as a single agent in this heavily treated population, robust inhibition of FLT3 and ERK suggests that there may be a potential important role in combination therapies.

KW - FLT3 targeted therapy

KW - acute myeloid leukemia

KW - clinical trial

KW - signal transduction inhibitors

UR - http://www.scopus.com/inward/record.url?scp=77955714871&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955714871&partnerID=8YFLogxK

U2 - 10.1038/leu.2010.132

DO - 10.1038/leu.2010.132

M3 - Article

C2 - 20535150

AN - SCOPUS:77955714871

SN - 0887-6924

VL - 24

SP - 1437

EP - 1444

JO - Leukemia

JF - Leukemia

IS - 8

ER -

A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this