TY - JOUR
T1 - Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma
AU - Naing, A.
AU - Aghajanian, C.
AU - Raymond, E.
AU - Olmos, D.
AU - Schwartz, G.
AU - Oelmann, E.
AU - Grinsted, L.
AU - Burke, W.
AU - Taylor, R.
AU - Kaye, S.
AU - Kurzrock, R.
AU - Banerji, U.
N1 - Funding Information:
Medical writing services were provided by Emma Burke of iMed Comms and were funded by AstraZeneca. The study was sponsored by AstraZeneca and supported by funding from Cancer Research UK (grant number: C309/A8274/A309/A11566; C51/ A6883); the Experimental Cancer Medicine Network (grant number: C51/A7401/C12540/A15573); and by a National Institute for Health Research Biomedical Research Centre grant, awarded jointly to The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research.
Funding Information:
Elisabeth Oelmann, Lynda Grinsted and Wendy Burke are all employees of AstraZeneca and hold AstraZeneca stocks or shares. Rosemary Taylor is a contractor employed by AstraZeneca. Dr Banerji has previously been a member of an AstraZeneca advisory board. Dr Kurzrock has received research funding from AstraZeneca. All remaining authors declare no conflict of interest.
PY - 2012/9/25
Y1 - 2012/9/25
N2 - 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.
AB - 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.
KW - AZD8055
KW - mTOR inhibitors
KW - phase I
UR - http://www.scopus.com/inward/record.url?scp=84866928171&partnerID=8YFLogxK
U2 - 10.1038/bjc.2012.368
DO - 10.1038/bjc.2012.368
M3 - Article
C2 - 22935583
AN - SCOPUS:84866928171
SN - 0007-0920
VL - 107
SP - 1093
EP - 1099
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 7
ER -