Phase i study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors Journal Article

Authors: Schwartz, G. K.; Carvajal, R. D.; Midgley, R.; Rodig, S. J.; Stockman, P. K.; Ataman, O.; Wilson, D.; Das, S.; Shapiro, G. I.
Article Title: Phase i study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors
Abstract: Summary: The purpose of this study was to determine the maximum-tolerated dose (MTD), pharmacokinetics and safety profile for two different dosing regimens of barasertib, a selective inhibitor of Aurora B Kinase. In this Phase I trial, patients with advanced solid malignancies were treated with escalating doses of barasertib, administered as either a 48-h continuous infusion or as two 2-h infusions on consecutive days, both every 14 days of a 28-day cycle. Thirty-five patients were treated. The MTDs were 150 mg as a 48-h continuous infusion and 220 mg administered as two 2-h infusions (110 mg/day, days 1, 2, 15 and 16), with neutropenia the dose-limiting toxicity (DLT) of each schedule. Common Terminology Criteria of Adverse Events (CTCAE) grade ≥ 3 neutropenia (with or without fever) occurred in 34 % of patients overall. Other adverse events, many of hematologic or gastrointestinal etiology, were of mild or moderate intensity. No objective tumor responses were observed, although stable disease was observed in 23 % of patients. Systemic exposure to barasertib-hQPA, the more active moiety to which barasertib is converted, was observed by 1 and 6 h into the 2-h and continuous infusion, respectively, and exhibited linear pharmacokinetics. In summary, barasertib was generally well tolerated, with neutropenia the most frequent and dose-limiting toxicity, irrespective of schedule. Future development of barasertib will depend on better definition of its therapeutic index. © 2012 Springer Science+Business Media, LLC.
Keywords: adult; clinical article; human tissue; aged; aged, 80 and over; middle aged; unclassified drug; constipation; drug tolerability; fatigue; neutropenia; advanced cancer; area under the curve; diarrhea; drug dose comparison; drug dose reduction; drug safety; drug withdrawal; gastrointestinal hemorrhage; side effect; solid tumor; pancreas cancer; follow-up studies; antineoplastic agent; neoplasms; colorectal cancer; ki 67 antigen; melanoma; drug eruption; multiple cycle treatment; ovary cancer; cohort studies; anemia; leukopenia; nausea; dehydration; skin cancer; lung cancer; hemoglobin; tumor biopsy; antineoplastic activity; continuous infusion; dose-response relationship, drug; abdominal pain; arthralgia; drug dose escalation; drug fever; dyspnea; febrile neutropenia; hyperglycemia; pneumonia; hypoxia; immunoenzyme techniques; alkaline phosphatase; chemotherapy induced emesis; drug fatality; disease severity; drug distribution; tissue distribution; head and neck cancer; protein-serine-threonine kinases; vein thrombosis; colon cancer; histone h3; drug response; urinary tract infection; peripheral edema; drug clearance; pleura effusion; open study; alkaline phosphatase blood level; hyperbilirubinemia; maximum plasma concentration; time to maximum plasma concentration; drug metabolism; drug blood level; maximum tolerated dose; phase 1 clinical trial; drug half life; esophagus cancer; quinazolines; alopecia; rectum cancer; infusions, intravenous; gastrointestinal disease; proteinuria; hematologic disease; drug exposure; pharmacokinetics; solid tumors; aurora b kinase; hemoptysis; phase i; pleura cancer; decreased appetite; barasertib; soft tissue cancer; organophosphates; azd1152; barasertib hydroxyquinazoline pyrazole anilide; blood clotting time; eye melanoma; pityriasiform rash
Journal Title: Investigational New Drugs
Volume: 31
Issue: 2
ISSN: 0167-6997
Publisher: Springer  
Date Published: 2013-04-01
Start Page: 370
End Page: 380
Language: English
DOI: 10.1007/s10637-012-9825-7
PROVIDER: scopus
PUBMED: 22661287
Notes: --- - "Export Date: 19 July 2013" - "CODEN: INNDD" - "Source: Scopus"
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MSK Authors
  1. Gary Schwartz
    369 Schwartz
  2. Richard D Carvajal
    133 Carvajal