Abstract CT114: A phase II trial of exemestane and ruxolitinib for aI-resistant ER+ breast cancer: Interim safety, efficacy, and biomarker analysis
Authors: DeMichele Angela M. , Colameco Christopher B. , Kalota Anna , Troxel Andrea B. , Holmes Robin , Cimildoro Rebecca , Zafman Kelly , Fox Kevin R. , Domchek Susan M. , Gogineni Keerthi , Bradbury Angela R. , Matro Jennifer M. , Shih Natalie , Feldman Michael D. , Clark Amy S. , Hexner Elizabeth O. , Bromberg Jacqueline F. 
Published: August 2015

Abstract
Resistance to aromatase inhibitors in ER+ breast cancer leads to recurrence and progression in the metastatic setting. JAK/STAT pathway activation is a resistance mechanism that could potentially be overcome with the use of JAK inhibitor therapy.
Methods: We performed a phase II trial of exemestane, 25 mg daily, and ruxolitinib, 25 mg BID, in postmenopausal women with advanced, ER+ breast cancer who had progressed on a non-steroidal aromatase inhibitor and had either measureable or bone-only disease. A Simon 2-stage design was employed. A “go” decision to second stage would occur if fewer than 5/15 patients experienced any grade 3/4 toxicity requiring discontinuation from the study within the first treatment cycle.
Results: Fifteen patients were enrolled; during cycle 1, no patient discontinued for toxicity and 1 patient went off study for progression of bone disease. 36 grade 3 events occurred; anemia was most common (n = 5), requiring transfusion in all patients. 47% required dose reduction. No partial or complete responses occurred; 3/15 (20%) had stable disease ≥6 months (clinical benefit, CB). Baseline CRP ≥8 was significantly associated with CB (3/3 CB vs. 1/11 non-CB; p = 0.011); other markers, including baseline ESR, IL-6 genotype status and primary tumor phosphoSTAT3 expression were not associated with CB in this small sample, though high tumoral pSTAT3 was seen in 66% of CB and 33% of non-CB. A novel pharmacodynamic (PD) assay to assess STAT3 phosphorylation in peripheral blood mononuclear cells after ruxolitinib exposure demonstrated differential effects in patients with CB vs. those without CB.
Conclusions: The combination of exemestane and the JAK2 inhibitor ruxolitinib met safety criteria for continued enrollment. Anemia, an expected toxicity of R, was common and the high rate of severe anemia and need for dose reductions has led to a decision to reduce the starting dose of ruxolitinib to 15 mg BID moving forward. Promising predictive markers, including CRP, tumor pSTAT3 and a novel PD assay for pSTAT3 will be further evaluated.
Citation Format: Angela M. DeMichele, Christopher B. Colameco, Anna Kalota, Andrea B. Troxel, Robin Holmes, Rebecca Cimildoro, Kelly Zafman, Kevin R. Fox, Susan M. Domchek, Keerthi Gogineni, Angela R. Bradbury, Jennifer M. Matro, Natalie Shih, Michael D. Feldman, Amy S. Clark, Elizabeth O. Hexner, Jacqueline F. Bromberg. A phase II trial of exemestane and ruxolitinib for aI-resistant ER+ breast cancer: Interim safety, efficacy, and biomarker analysis. [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 CT114. doi:10.1158/1538-7445.AM2015-CT114