Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma Journal Article

   


Authors: Naing, A.; Aghajanian, C.; Raymond, E.; Olmos, D.; Schwartz, G.; Oelmann, E.; Grinsted, L.; Burke, W.; Taylor, R.; Kaye, S.; Kurzrock, R.; Banerji, U.
Article Title: Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma
Abstract: Background: This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of the first-in-class dual mammalian target of rapamycin complex (mTORC)1/mTORC2 inhibitor, AZD8055. Methods: Patients with advanced solid malignancies or lymphomas were recruited into this phase I, open-label, dose-escalation study of AZD8055 starting at 10 mg twice-daily oral dosing (BID). Results: Forty-nine patients received AZD8055. Dose-limiting toxicities were reported at 40 mg (n1), 90 mg (n1) and 120 mg (n3) BID; all were grade 3 rises in transaminases, reversible in all patients, apart from one who had liver metastases. The maximum tolerated dose was defined as 90 mg BID. The most frequent adverse events assessed to be related to AZD8055 were increased alanine aminotransferase (22%), increased aspartate aminotransferase (22%) and fatigue (16%). AZD8055 was rapidly absorbed (median t max 0.5 h) and exposure increased with increasing doses. Seven patients had stable disease for 4 months. Partial metabolic responses, assessed by fluorodeoxyglucose positron emission tomography, were observed at 40 mg BID (n8 at day 35).Conclusion:The maximum tolerated dose for AZD8055 is 90 mg BID. Apart from elevated transaminases, which occurred at most dose levels, the drug had an acceptable toxicity profile; however, no RECIST responses were seen. © 2012 Cancer Research UK All rights reserved.
Keywords: adult; clinical article; aged; middle aged; drug tolerability; fatigue; drug dose reduction; drug safety; side effect; solid tumor; positron emission tomography; neoplasms; cohort studies; nausea; stomatitis; drug administration schedule; dose-response relationship, drug; drug dose escalation; hyperglycemia; morpholines; lymphoma; fluorodeoxyglucose f 18; multiprotein complexes; maximum tolerated dose; phase 1 clinical trial; phase i; mammalian target of rapamycin complex 1; tor serine-threonine kinases; azd 8055; mammalian target of rapamycin complex 2; mtor inhibitors; azd8055
Journal Title: British Journal of Cancer
Volume: 107
Issue: 7
ISSN: 0007-0920
Publisher: Nature Publishing Group  
Date Published: 2012-09-25
Start Page: 1093
End Page: 1099
Language: English
DOI: 10.1038/bjc.2012.368
PROVIDER: scopus
PMCID: PMC3461162
PUBMED: 22935583
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84866928171&partnerID=40&md5=c05214ed0322234556114570bd3be1a9
Notes: --- - "Export Date: 2 November 2012" - "CODEN: BJCAA" - "Source: Scopus"
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MSK Authors
  1. Gary Schwartz
    385 Schwartz
  2. Carol A Aghajanian
    609 Aghajanian
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