A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia

J. E. Lancet, F. Ravandi, R. M. Ricklis, L. D. Cripe, H. M. Kantarjian, F. J. Giles, A. F. List, T. Chen, R. S. Allen, J. A. Fox, G. C. Michelson, J. E. Karp

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

This study of vosaroxin evaluated dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics (PK), clinical activity and pharmacodynamics in relapsed/refractory leukemia. Dosing was weekly (days 1, 8 and 15) or twice weekly (days 1, 4, 8 and 11). Seventy-three treated patients had a median age of 65 years, 85% had acute myeloid leukemia and 78% had refractory disease. Weekly schedule: 42 patients received 18-90 mg/m 2; MTD was 72 mg/m 2. Twice-weekly schedule: 31 patients received 9-50 mg/m 2; MTD was 40 mg/m 2. DLT was stomatitis; primary non-hematologic toxicity was reversible gastrointestinal symptoms and febrile neutropenia. Thirty-day all-cause mortality was 11%. Five patients had complete or incomplete remissions; median duration was 3.1 months. A morphologic leukemia-free state (bone marrow blast reduction to 5%) occurred in 11 additional patients. Antileukemic activity was associated with total dose or weekly time above 1 mol/l plasma vosaroxin concentration (P0.05). Vosaroxin exposure was dose proportional over 9-90 mg/m 2. The average terminal half-life was ∼25h and clearance was non-renal. No induction or inhibition of vosaroxin metabolism was evident. Vosaroxin-induced DNA damage was detected as increased intracellular γH2AX. Vosaroxin had an acceptable safety profile, linear PK and encouraging clinical activity in relapsed/refractory leukemia.

Original languageEnglish (US)
Pages (from-to)1808-1814
Number of pages7
JournalLeukemia
Volume25
Issue number12
DOIs
StatePublished - Dec 2011

Fingerprint

Quinolones
Leukemia
Maximum Tolerated Dose
Appointments and Schedules
Pharmacokinetics
Febrile Neutropenia
Stomatitis
Acute Myeloid Leukemia
DNA Damage
Half-Life
vosaroxin
Bone Marrow
Safety
Mortality

Keywords

  • acute leukemia
  • phase 1
  • quinolone derivative
  • relapsed/refractory
  • voreloxin
  • vosaroxin

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Lancet, J. E., Ravandi, F., Ricklis, R. M., Cripe, L. D., Kantarjian, H. M., Giles, F. J., ... Karp, J. E. (2011). A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia. Leukemia, 25(12), 1808-1814. https://doi.org/10.1038/leu.2011.157

A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia. / Lancet, J. E.; Ravandi, F.; Ricklis, R. M.; Cripe, L. D.; Kantarjian, H. M.; Giles, F. J.; List, A. F.; Chen, T.; Allen, R. S.; Fox, J. A.; Michelson, G. C.; Karp, J. E.

In: Leukemia, Vol. 25, No. 12, 12.2011, p. 1808-1814.

Research output: Contribution to journalArticle

Lancet, JE, Ravandi, F, Ricklis, RM, Cripe, LD, Kantarjian, HM, Giles, FJ, List, AF, Chen, T, Allen, RS, Fox, JA, Michelson, GC & Karp, JE 2011, 'A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia', Leukemia, vol. 25, no. 12, pp. 1808-1814. https://doi.org/10.1038/leu.2011.157
Lancet, J. E. ; Ravandi, F. ; Ricklis, R. M. ; Cripe, L. D. ; Kantarjian, H. M. ; Giles, F. J. ; List, A. F. ; Chen, T. ; Allen, R. S. ; Fox, J. A. ; Michelson, G. C. ; Karp, J. E. / A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia. In: Leukemia. 2011 ; Vol. 25, No. 12. pp. 1808-1814.
@article{1541957607004acba0c1aba8daafe339,
title = "A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia",
abstract = "This study of vosaroxin evaluated dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics (PK), clinical activity and pharmacodynamics in relapsed/refractory leukemia. Dosing was weekly (days 1, 8 and 15) or twice weekly (days 1, 4, 8 and 11). Seventy-three treated patients had a median age of 65 years, 85{\%} had acute myeloid leukemia and 78{\%} had refractory disease. Weekly schedule: 42 patients received 18-90 mg/m 2; MTD was 72 mg/m 2. Twice-weekly schedule: 31 patients received 9-50 mg/m 2; MTD was 40 mg/m 2. DLT was stomatitis; primary non-hematologic toxicity was reversible gastrointestinal symptoms and febrile neutropenia. Thirty-day all-cause mortality was 11{\%}. Five patients had complete or incomplete remissions; median duration was 3.1 months. A morphologic leukemia-free state (bone marrow blast reduction to 5{\%}) occurred in 11 additional patients. Antileukemic activity was associated with total dose or weekly time above 1 mol/l plasma vosaroxin concentration (P0.05). Vosaroxin exposure was dose proportional over 9-90 mg/m 2. The average terminal half-life was ∼25h and clearance was non-renal. No induction or inhibition of vosaroxin metabolism was evident. Vosaroxin-induced DNA damage was detected as increased intracellular γH2AX. Vosaroxin had an acceptable safety profile, linear PK and encouraging clinical activity in relapsed/refractory leukemia.",
keywords = "acute leukemia, phase 1, quinolone derivative, relapsed/refractory, voreloxin, vosaroxin",
author = "Lancet, {J. E.} and F. Ravandi and Ricklis, {R. M.} and Cripe, {L. D.} and Kantarjian, {H. M.} and Giles, {F. J.} and List, {A. F.} and T. Chen and Allen, {R. S.} and Fox, {J. A.} and Michelson, {G. C.} and Karp, {J. E.}",
year = "2011",
month = "12",
doi = "10.1038/leu.2011.157",
language = "English (US)",
volume = "25",
pages = "1808--1814",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "12",

}

TY - JOUR

T1 - A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia

AU - Lancet, J. E.

AU - Ravandi, F.

AU - Ricklis, R. M.

AU - Cripe, L. D.

AU - Kantarjian, H. M.

AU - Giles, F. J.

AU - List, A. F.

AU - Chen, T.

AU - Allen, R. S.

AU - Fox, J. A.

AU - Michelson, G. C.

AU - Karp, J. E.

PY - 2011/12

Y1 - 2011/12

N2 - This study of vosaroxin evaluated dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics (PK), clinical activity and pharmacodynamics in relapsed/refractory leukemia. Dosing was weekly (days 1, 8 and 15) or twice weekly (days 1, 4, 8 and 11). Seventy-three treated patients had a median age of 65 years, 85% had acute myeloid leukemia and 78% had refractory disease. Weekly schedule: 42 patients received 18-90 mg/m 2; MTD was 72 mg/m 2. Twice-weekly schedule: 31 patients received 9-50 mg/m 2; MTD was 40 mg/m 2. DLT was stomatitis; primary non-hematologic toxicity was reversible gastrointestinal symptoms and febrile neutropenia. Thirty-day all-cause mortality was 11%. Five patients had complete or incomplete remissions; median duration was 3.1 months. A morphologic leukemia-free state (bone marrow blast reduction to 5%) occurred in 11 additional patients. Antileukemic activity was associated with total dose or weekly time above 1 mol/l plasma vosaroxin concentration (P0.05). Vosaroxin exposure was dose proportional over 9-90 mg/m 2. The average terminal half-life was ∼25h and clearance was non-renal. No induction or inhibition of vosaroxin metabolism was evident. Vosaroxin-induced DNA damage was detected as increased intracellular γH2AX. Vosaroxin had an acceptable safety profile, linear PK and encouraging clinical activity in relapsed/refractory leukemia.

AB - This study of vosaroxin evaluated dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics (PK), clinical activity and pharmacodynamics in relapsed/refractory leukemia. Dosing was weekly (days 1, 8 and 15) or twice weekly (days 1, 4, 8 and 11). Seventy-three treated patients had a median age of 65 years, 85% had acute myeloid leukemia and 78% had refractory disease. Weekly schedule: 42 patients received 18-90 mg/m 2; MTD was 72 mg/m 2. Twice-weekly schedule: 31 patients received 9-50 mg/m 2; MTD was 40 mg/m 2. DLT was stomatitis; primary non-hematologic toxicity was reversible gastrointestinal symptoms and febrile neutropenia. Thirty-day all-cause mortality was 11%. Five patients had complete or incomplete remissions; median duration was 3.1 months. A morphologic leukemia-free state (bone marrow blast reduction to 5%) occurred in 11 additional patients. Antileukemic activity was associated with total dose or weekly time above 1 mol/l plasma vosaroxin concentration (P0.05). Vosaroxin exposure was dose proportional over 9-90 mg/m 2. The average terminal half-life was ∼25h and clearance was non-renal. No induction or inhibition of vosaroxin metabolism was evident. Vosaroxin-induced DNA damage was detected as increased intracellular γH2AX. Vosaroxin had an acceptable safety profile, linear PK and encouraging clinical activity in relapsed/refractory leukemia.

KW - acute leukemia

KW - phase 1

KW - quinolone derivative

KW - relapsed/refractory

KW - voreloxin

KW - vosaroxin

UR - http://www.scopus.com/inward/record.url?scp=83555165090&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=83555165090&partnerID=8YFLogxK

U2 - 10.1038/leu.2011.157

DO - 10.1038/leu.2011.157

M3 - Article

C2 - 21760592

AN - SCOPUS:83555165090

VL - 25

SP - 1808

EP - 1814

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 12

ER -