Abstract | PURPOSE: METHODS: Five patients with poor prognosis AML (newly diagnosed, relapsed or refractory) received barasertib 1,200 mg as a 7-day continuous infusion every 28 days. On Day 2 of Cycle 1 only, patients also received a 2-hour infusion of [(14)C]- barasertib. Blood, urine and feces samples were collected at various time points during Cycle 1. Safety and preliminary efficacy were also assessed. RESULTS:
Barasertib-hQPA was extensively distributed to tissues, with a slow rate of total clearance (CL = 31.4 L/h). Overall, 72-82 % of radioactivity was recovered, with approximately double the amount recovered in feces (mean = 51 %) compared with urine (mean = 27 %). The main metabolism pathways for barasertib were (1) cleavage of the phosphate group to form barasertib-hQPA, followed by oxidation and (2) loss of the fluoroaniline moiety to form barasertib-hQPA desfluoroaniline, followed by oxidation. One of the four patients evaluable for response entered complete remission. No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis. CONCLUSIONS: The PK profile of barasertib is similar to previous studies using the same dosing regimen in patients with AML. The majority of barasertib-hQPA clearance occurred via hepatic metabolic routes.
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Authors | Mike Dennis, Michelle Davies, Stuart Oliver, Roy D'Souza, Laura Pike, Paul Stockman |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 70
Issue 3
Pg. 461-9
(Sep 2012)
ISSN: 1432-0843 [Electronic] Germany |
PMID | 22864876
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
- Organophosphates
- Prodrugs
- Quinazolines
- AZD 1152-HQPA
- AURKB protein, human
- Aurora Kinase B
- Aurora Kinases
- Protein Serine-Threonine Kinases
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Topics |
- Adult
- Aged
- Aurora Kinase B
- Aurora Kinases
- Female
- Humans
- Infusions, Intravenous
- Leukemia, Myeloid, Acute
(drug therapy, pathology)
- Male
- Middle Aged
- Organophosphates
(adverse effects, pharmacokinetics, therapeutic use)
- Prodrugs
- Protein Serine-Threonine Kinases
(antagonists & inhibitors)
- Quinazolines
(adverse effects, pharmacokinetics, therapeutic use)
- Remission Induction
- Time Factors
- Treatment Outcome
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