First-in-human phase I trial of the dual mTORC1 and mTORC2 inhibitor AZD2014 in solid tumors.

U Banerji, E Dean, M Gonzalez, A Greystoke, B Basu, M Krebs, M Puglisi, L Grinsted, E Oelmann, W Burke, E Harrington, S Green, M. Ranson

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    Abstract

    Background: AZD2014 is a potent, dual mTORC1/mTORC2 inhibitor with clear activity in in vivo and in vitro experimental models. Methods: This 2-part study consisted of "rolling six" dose escalation (Part A) and expansion (Part B) phases. Part A: 3–6 pts per cohort received an oral solution of AZD2014 BD starting at 50 mg. A further 6 pts were treated in Part A below the MTD to study changes in pharmacodynamic (PD) biomarkers. Part B: additional pts were dosed at the MTD, including a group of ER+/PR+ or HER2+ patients with breast cancer. Primary endpoint: safety and tolerability; secondary endpoints: pharmacokinetics (PK), PD and efficacy. Biomarkers assessed: mTORC1: pS6 (S235/236) and p4EBP1 (T37/46); mTORC2: pAKT (S473). Results: 50 pts have been enroled in this ongoing study and interim data are reported: Part A, n=23 (25 mg, n=6; 50 mg, n=8; 70 mg, n=5; 100 mg, n=4; all BD); Part B, n=27. The MTD was 50 mg BD. DLTs were seen at both 100 mg (Gr 2 and 3 lethargy/fatigue, n=4/4) and 70 mg (Gr 3 mucositis, Gr 2 lethargy, n=2/4); no DLTs were seen at 25 mg or 50 mg. The most common AEs in order of incidence were fatigue, stomatitis, decreased appetite, nausea and diarrhea. Seven SAEs (nausea, vomiting, lethargy, abdominal pain, mucositis) reported by 3 pts were considered ‘possibly related’ to the study drug by investigators. AZD2014 is rapidly absorbed following single and BD multiple doses with a short t1/2 of ~3 h. At 50 mg (n=32), preliminary data show geometric mean AUCss=7.4 µg.h/ml and Cmax ss=1.7 µg/ml. One pt with acinar pancreatic cancer had a RECIST partial response. pAKT and p4EBP1 reductions were observed between 2–8 h in platelet-rich plasma and peripheral blood mononuclear cells respectively. Target modulation in paired tumor biopsies was seen at the MTD. Reduction in the phosphorylation of S6 and 4EBP1 was evident in 8/10 and 3/9 paired biopsies respectively. pAKT was reduced in 3/6 evaluable paired biopsies. As opposed to rapalogs, pAKT was not upregulated in any of the evaluable post-treatment biopsies. Conclusions: The MTD for AZD2014 is 50 mg BD. Further clinical evaluation of AZD2014 is now warranted based on the safety, PK and proof-of-mechanism PD data, as well as its preliminary clinical activity. Updated results will be presented.
    Original languageEnglish
    JournalJ Clin Oncol
    Volume30s
    Issue numberabstr 3004
    Publication statusPublished - Jun 2012

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