Abstract P6-12-01: A phase I study evaluating AZD2014 in combination with fulvestrant in patients with ER+ advanced metastatic breast cancer
Authors: Burris III Howard , LoRusso Patricia , Gluck W  Larry , Jones Suzanne , Kittaneh Muaiad , Hamilton Erika , Green Stephen , Burke Wendy , Strickland Donald , Oelmann Elisabeth , Patel Manish 
Published: May 2015

Abstract
Background: Preclinical data suggest that patients with ER+ Breast Cancer become less sensitive to hormonal therapy by upregulation of the mTOR pathway. BOLERO-2 demonstrated that the combination of an allosteric mTOR inhibitor and an aromatase inhibitor improves progression-free survival in postmenopausal women with hormone resistant advanced breast cancer (NEJM 2012; 366:520-529). AZD2014 is a selective dual mTORC1 and mTORC2 inhibitor whilst fulvestrant is an estrogen receptor antagonist that is approved for the treatment of postmenopausal women with disease progression following antiestrogen therapy. This phase I trial assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of AZD2014 administered in combination with fulvestrant.
Methods: Continuous BID or QD dosing of AZD2014 was administered in combination with fulvestrant 500 mg intramuscularly on day 1 of each 28 day cycle. An additional 500 mg dose of fulvestrant was administered on day 15 of cycle 1 as per the approved dosing schedule. Single and multiple dose AZD2014 and fulvestrant pharmacokinetic samples were obtained. Optional tumor biopsies were also obtained.
Results: 43 patients (median age 61, range 32-82 years; prior chemo in the metastatic setting = 25; prior hormonal therapy = 43) have been treated in 4 dosing cohorts: 50 mg BID = 13; 35 mg BID = 6; 100 mg QD = 10; and 75 mg QD = 14. Patients have received 302+ treatment cycles (median 5 cycles/patient, range 1-21) and 4 patients continue on treatment. Review of preliminary unvalidated safety and Pk data revealed that dose-limiting toxicities included rash/mucositis (1 pt) and hyperglycemia (1 pt) at 50 mg BID; fatigue (1 pt) and mucositis (1 pt) at 100 mg QD; and rash (1 pt) at 75 mg QD. Treatment-related toxicities (any grade) include: fatigue (51%), mucositis (60%), rash (60%), nausea (47%), hyperglycemia (12%), and neutropenia (2%). Pharmacokinetic data show that AZD2014 is rapidly absorbed with a median time to maximum concentration of 1-1.75 hours and an estimated mean half-life of approximately 3.3-5.6 hours across the dose range. There is no evidence that co-administration of fulvestrant has a clinically relevant impact on exposure to AZD2014. In the 26 patients with measureable disease, 5 confirmed PRs have been observed (duration 4-18+ months) with an additional 14 patients experiencing stable disease for at least 6 months of treatment.
Conclusion: Continuous QD (75mg) and BID (35 and 50 mg) administration of AZD2014 in combination with fulvestrant is tolerable with clinical benefit observed in nearly half of the patients. Toxicities observed are broadly consistent with AEs observed in other trials with antihormonal agents and other mTOR inhibitors, but seem to be well manageable. There were no new or other additive toxicities, when the two drugs were combined and AZD2014 pharmacokinetic data are broadly consistent with what has been previously observed for AZD2014 single agent. A randomized phase II trial of the combination is ongoing and an intermittent weekly dosing schedule is being explored in additional patient cohorts in the current study.
Citation Format: Howard Burris III, Patricia LoRusso, W Larry Gluck, Suzanne Jones, Muaiad Kittaneh, Erika Hamilton, Stephen Green, Wendy Burke, Donald Strickland, Elisabeth Oelmann, Manish Patel. A phase I study evaluating AZD2014 in combination with fulvestrant in patients with ER+ advanced metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-12-01.