Abstract LB-170: Preliminary report of a phase I/II trial to assess safety and tolerability of an oral Aurora kinase A inhibitor, MLN 8237 (alisertib), in combination with erlotinib in patients with recurrent or metastatic non-small cell lung cancer (NSCLC).
Authors: Borghaei Hossein , Mehra Ranee , Litwin Samuel , Astsaturov Igor 
Published: August 2014

Abstract
Introduction: NSCLC is the leading cause of cancer related death in the US. Inhibitors of the epidermal growth factor receptor (EGFR) are active in only a subset of patients. Based on our recent observation of synergistic activity of dual inhibition of EGFR and Aurora-A pathways, we are investigating the combined activity of Aurora-A inhibition (MLN8237, Alisertib, A) and an EGFR antagonist (erlotinib, E) in patients with recurrent/refractory metastatic NSCLC.
Objectives: Our hypothesis is that blockade of Aurora A kinase will sensitize lung cancers to erlotinib, since the oncogenic proliferative effects of Aurora A kinase are downstream of the hyperactive EGFR-Ras-MAPK signaling axis.
The primary endpoints of the Phase 1 portion include: Safety and tolerability of the combination treatment and determining the maximum tolerated dose (MTD) of A when given with E. The phase II primary endpoint is progression free survival (PFS). The secondary endpoints include PK parameters, response rate and time to treatment failure.
Methods: Patients with EGFR wild type NSCLC who have progressed after at least one line of treatment were enrolled. The inclusion/exclusion criteria are as expected for a phase I/II study. This study consists of a single center Phase I run-in with the standard 3+3 design, followed by multi-center single arm phase II, with early stopping rule for futility. E is administered orally with continuous daily dosing and A is also oral, given BID for 7 days followed by 14 day rest. Treatment schema consists of 4 dose levels: 1) E 100 mg, A 30 mg, 2) E 150 mg, A 30 mg 3) E 150 mg, A 40 mg 4) E 150 mg, A 50 mg. Dosing on the Phase II portion is based on the MTD from the phase I, and will follow a two stage design that allows for early termination if the primary end point of PFS is not met.
Preliminary Data: To date we have completed the first three dose levels of the phase I portion of the study. One patient is enrolled in the final level of 50 mg dose of A. MTD has not been reached. In total, 10 patients (5 male/5 female) with a median age of 62 (Range: 30 to 74) have been enrolled. All patients have had multiple prior therapies (both chemotherapy and radiation). Two patients remained on study for six cycles of therapy; four patients progressed after three cycles and four patients after two cycles (treated at lower dose levels). Three patients remain on study. Two patients have experienced dose reductions of A due to fatigue which was not defined as DLT. Other toxicities include: alopecia (one patient, 50 mg of A), transient neutropenia and anemia. At least three patients have gone to receive other forms of therapy after progression on this trial. Seven patients treated on this protocol are alive.
Conclusion: The combination of E and A appears to be tolerable in patients with EGFR wild type advanced NSCLC. Dose escalation in the last cohort (50 mg po bid for seven days) continues.
Citation Format: Hossein Borghaei, Ranee Mehra, Samuel Litwin, Igor Astsaturov. Preliminary report of a phase I/II trial to assess safety and tolerability of an oral Aurora kinase A inhibitor, MLN 8237 (alisertib), in combination with erlotinib in patients with recurrent or metastatic non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-170. doi:10.1158/1538-7445.AM2013-LB-170