Phase I study combining the aurora kinase A (AURKA) inhibitor alisertib (Ali) with mFOLFOX in gastrointestinal (GI) cancer

2593 Background: Overexpression and cellular mis-localization of AURKA in GI cancers results in chromosomal instability, activation of several oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 causing cell death. Our preclinical data showed synergy of Ali and platinum agents in GI cells and xenografts, and suggested an optimal timing window of the combination. The purpose of this study was to assess safety of Ali + mFOLFOX, as this is a standard platinum-based therapy for GI cancers. Methods: This CTEP-sponsored, investigator-initiated, study (NCT02319018) used standard 3+3 dose escalation to determine the maximum tolerated dose (MTD) of Ali + mFOLFOX. Eligible patients (pts) had metastatic or unresectable GI cancer where standard therapies did not exist or were no longer effective, or for whom FOLFOX was appropriate. Pts received escalating doses of Ali starting at 10 mg twice daily (D1-3), with leucovorin + oxaliplatin (85 mg/m 2 ) on D2 followed by continuous 5FU (2400 mg/m 2 ) infusion on D2-4 in 14-day cycles. Dose-limiting toxicity (DLT) was any treatment-related non-hematologic ≥Gr3 toxicity (except diarrhea or nausea, vomiting, controllable with meds) or ≥Gr4 hematologic toxicity observed during the first 28 days. Results: 13 pts were enrolled and 2 dose levels explored; 2 pts were not evaluable for DLT and replaced. Zero DLTs observed in first 3 pts. Ali was escalated to 20 mg where 2/6 had a DLT [Gr3 fatigue (n = 2); Gr3 nausea, vomiting, dehydration with hospitalization (n = 1)]. Ali was de-escalated and 2 of 3 pts have been enrolled; 0 DLTs observed thus far. Most frequent toxicities (%) were nausea (54), fatigue (46), neuropathy (46), anorexia (38), and anemia (38), most ≤Gr2. One of 10 evaluable pts had a partial response, and 6 had stable disease for a 70% disease control rate. Conclusions: The MTD will be 10 mg Ali (D1-3) + oxaliplatin (D2, 85 mg/m 2 ) + continuous 5FU (D2-4, 2400 mg/m 2 ). The combination was tolerable, and preliminary clinical activity was seen in a majority of pts. Correlative biomarker studies to evaluate AURKA target inhibition are ongoing and will be reported. Clinical trial information: NCT02319018