Abstract P6-10-02: MLN8237 (alisertib), an investigational Aurora A Kinase inhibitor, in patients with breast cancer: Emerging phase 2 results
Authors: Alvarez RH , DeMichele A , Mailliez A , Benaim E , Fingert H , Schusterbauer C , Zhang B , Melichar B 
Published: August 2014

Abstract
Background: Aurora A Kinase (AAK) is a key mitotic regulator amplified or overexpressed in a variety of tumor types including pre-invasive and invasive breast cancer. In mouse mammary epithelium, AAK overexpression induces genetic instability and tumor formation. In breast cancer patients (pts), AAK overexpression is often associated with poor prognosis. Therefore, AAK is an attractive target in cancer treatment. MLN8237 is an oral, selective AAK inhibitor under evaluation in pts with different advanced tumors. An ongoing multi-indication phase 2 (NCT01045421) trial evaluates MLN8237 in pts with solid tumors; here we present preliminary phase 2 data on the breast cancer cohort.
Methods: Eligible pts were female ≥18 years of age with stage IV breast cancer, ECOG PS 0–1, measurable disease by RECIST, and ≤4 prior cytotoxic chemotherapy regimens. Stratification on receptor subtype was performed to ensure 8–10 pts with triple negative disease and 8–10 patients with HER2 positive disease. Oral MLN8237 50 mg was administered twice-daily for 7 days, followed by 14 days' rest in 21-day cycles. The primary objective was overall response rate; response was determined by RECIST v1.1. Secondary objectives included assessment of safety. A Simon's optimal 2-stage design was used; 20 pts were initially enrolled, and this cohort was expanded if ≥2 partial responses (PR) were observed in response-evaluable pts.
Results: In the first 20 pts, 2 had PR and the cohort was expanded to a total of 53 (data cut-off: March 29, 2012). Median age was 60 years (range 33–81). Pts received a median of 3 cycles (range 1–14) and 20 pts (38%) received ≥6 treatment cycles. Of 45 response-evaluable pts, 6 pts (13%) had a best response of PR and 26 (58%) had stable disease (SD). Median duration of SD was 68 days, of which 2 pts (4%) had SD for ≥6 months (clinical benefit rate [PR+SD ≥6 months] = 18%). One HER2+ patient with 2 prior lines of therapy (carboplatin/docetaxel/trastuzumab + trastuzumab maintenance; gemcitabine/lapatinib/ trastuzumab) had PR 6 months. Fifty-three pts were evaluable for toxicity. Drug-related adverse events (AEs) were reported in 49 pts (92%) and were commonly grade 1–2 in severity. The most frequent drug-related AEs included alopecia (n = 26, 49%), neutropenia (n = 25, 47%), diarrhea (n = 23, 43%), fatigue (n = 21, 40%), and stomatitis (n = 19, 36%). A total of 34 pts (64%) reported grade ≥3 drug-related AEs, including neutropenia (n = 23, 43%) and leukopenia (n = 8, 15%). Two pts (4%) discontinued due to AEs; there were no on-study deaths. Treatment is ongoing in 21 pts.
Conclusions: Emerging phase 2 data reported here provide preliminary evidence of antitumor activity of oral MLN8237 in pts with relapsed/refractory breast cancer. AEs were frequent but generally reversible and manageable by dose reduction and supportive care.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-10-02.