Abstract P2-19-03: Src Kinase Inhibition with AZD0530 Plus Anastrozole in Postmenopausal Hormone Receptor Positive (HR+) Metastatic Breast Cancer (MBC)
Authors: M Pegram, O Silva, C Higgins, K Tukia, E Avisar, M Stuart, J. Slingerland
Journal: Cancer Research (2010)

Abstract Background: p27 is a negative regulator of cell cycle that is frequently decreased in primary human breast cancer (BC) due to accelerated proteolysis. In HR+ BC, p27 function is required to promote G1 arrest following anti-estrogen treatment. cSrc is overexpressed/activated in up to 70% of BC. Src kinase phosphorylates p27 reducing its inhibitory function toward cyclin E-Cdk2, thereby facilitating p27 degradation. AZD0530 is a potent, orally available dual inhibitor of Abl and Src family kinases. Preclinical data indicate AZD0530 cooperates with anastrozole to inhibit BC cell growth in vitro and in vivo (Chen, et al., Clin Cancer Res 2009). We hypothesized that Src inhibition would augment p27 to promote antiproliferative effects of anastrozole in HR+ BC. Methods: This is an NCI funded investigator-initiated, open label phase IB clinical trial conducted under an investigator IND. Target population: postmenopausal HR+ relapsed or MBC who are candidates for aromatase inhibitor therapy. Key Inclusion: postmenopausal females, age ≥18, advanced or locally relapsed unresectable HR+ measurable/evaluable (RECIST) disease, ECOG 0-2, informed consent. Cohorts of 3 patients were initiated with AZD0530 175mg PO/day in combination with anastrozole 1mg PO daily in a planned dose de-escalation study design with subsequent cohort expansion to 12 subjects for PK assessment (both AZD0530 and anastrozole) performed at 6, 12, 24, 48, and 72 hours, 8, 15 and 22 days. Results: Among 12 patients enrolled, AZD0530 plus anastrozole was well tolerated (no dose limiting toxicities) without need for dose de-escalation. Drug related adverse events: grade 3 lymphopenia (N=3), neutropenia (N=2), anemia (N=1) and reversible grade 1/2 transaminase elevation (N=9). Serious adverse events were observed in 2 patients (urosepsis and CNS hemorrhage due to CNS metastasis), neither considered drug-related. Interstitial pneumonitis was not observed. PK assessment: mean day 21 serum concentration = 298±38.4 ng/ml for AZD0530 and 51±5.6 ng/ml for anastrozole, indicating no evidence for drug-drug interaction between the 2 agents. Clinical efficacy: There were no RECIST clinical responses in this heavily pretreated population. However, notably patients with bone metastasis reported improvement in bone pain, and 2 patients had prolonged disease stability (&amp;gt;7 and 10 months with improvement of PET and bone scans) despite prior hormone refractory disease. Conclusions: Src kinase inhibition with AZD0530 combined with anastrozole was well tolerated without significant PK interaction. The recommended phase II dose is AZD0530 175mg PO plus anastrozole 1mg PO daily. A randomized phase II study of this combination is currently underway in the neoadjuvant setting including complete PK/PD assessment and molecular correlative studies to evaluate predictors of response. Supported by NIH 1R21CA133884-01A1 Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-19-03.