Abstract CT233: A phase I study evaluating continuous and intermittent AZD2014 in combination with fulvestrant in patients with ER+ advanced metastatic breast cancer
Authors: Patel Manish , Hamilton Erika , LoRusso Patricia M. , Gluck W. Larry , Jones Suzanne F. , Kittaneh Muaiad , Cosulich Sabina , Harrington Elizabeth A. , Green Stephen , Burke Wendy , Strickland Donald K. , Oelmann Elisabeth , Burris Howard A. 
Published: August 2015

Abstract
Background: Preclinical and clinical (BOLERO 2) data suggest that pts with ER+ breast cancer become less sensitive to hormonal therapy over time with greater dependency on the mTOR pathway. AZD2014 is a selective dual mTORC1 and mTORC2 inhibitor that may offer additional benefit vs mTORC1 inhibitors through suppression of AKT via mTORC2. Preclinical data demonstrate that continuous or intermittent dosing schedules are equally effective in a model of ER+ breast cancer and the latter may achieve improved tolerability in pts. This Ph I trial assesses the safety, tolerability, PK, PD and preliminary efficacy of AZD2014 administered both continuously and intermittently in combination with fulvestrant (F); data are unvalidated and subject to change.
Methods: Adult pts with ER+ metastatic breast cancer were treated with continuous or intermittent AZD2014 in combination with F 500mg intramuscularly on day 1 of each 28 day cycle.
Results: In the continuous schedules, 43 pts have been treated in 4 cohorts: 50mg BD = 13; 35mg BD = 6; 100mg QD = 10; and 75mg QD = 14. In the intermittent schedules 23 pts have been treated on D1 and 2 (2 days out of 7) per week in 2 cohorts: 170mg BD = 8; 125mg BD = 15. DLTs on the continuous schedule included rash/stomatitis (1 pt) and hyperglycemia (1 pt) at 50mg BD; fatigue (1 pt) and stomatitis (1 pt) at 100mg QD; and rash (1 pt) at 75mg QD. There were no DLTs at 170mg or 125mg BD (D1&2) on the intermittent schedule. Treatment-related toxicities (any grade) in 66 pts include: nausea (58%), fatigue (52%), diarrhea (46%), stomatitis (41%), vomiting (32%), decreased appetite (30%), maculo-papular rash (26%), and hyperglycemia (15%). PK data show that AZD2014 is rapidly absorbed (median tmax 1-1.75h). The mean single dose terminal elimination t1/2 was 3.3-5.6h and increased following multiple and/or high dosing. There was no evidence that co-administration of F had a clinically relevant impact on AZD2014 exposure. Inhibition of both mTORC1 and 2 was observed in both surrogate and tumor tissue. In the 49 pts with measureable disease, 9 confirmed (duration 1.8-22 months) and 3 unconfirmed PRs were observed. Overall, CBR (CR+PR+SD &gt;24 weeks) was 29/66.
Conclusion: Continuous and intermittent dosing of AZD2014 in combination with F is tolerable with clinical benefit observed in 44% of all pts with clinical activity observed with both schedules. Toxicities observed with the continuous dosing schedule are broadly consistent with AEs observed in other trials with mTOR inhibitors. Notably, the intermittent schedule had a different AE profile with a lower incidence of rash. AZD2014 inhibited both mTORC1 and mTORC2 in surrogate and tumor tissue and the PK data were broadly consistent with previous findings for AZD2014 single agent. A randomized phase II trial of the combination comparing both the continuous and intermittent dosing schedules is ongoing.
Citation Format: Manish Patel, Erika Hamilton, Patricia M. LoRusso, W. Larry Gluck, Suzanne F. Jones, Muaiad Kittaneh, Sabina Cosulich, Elizabeth A. Harrington, Stephen Green, Wendy Burke, Donald K. Strickland, Elisabeth Oelmann, Howard A. Burris. A phase I study evaluating continuous and intermittent AZD2014 in combination with fulvestrant in patients with ER+ advanced metastatic breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT233. doi:10.1158/1538-7445.AM2015-CT233