The Investigational Aurora A Kinase Inhibitor MLN8237 in Combination with Vincristine Demonstrates Robust Anti-Tumor Activity in Preclinical B-Cell Non-Hodgkin's Lymphoma Models

Abstract 2733

Aurora A kinase (AAK) is a serine/threonine protein kinase that is essential for normal mitotic progression. MLN8237, an investigational, selective inhibitor of AAK, is being evaluated in multiple Phase 1 and 2 clinical studies in patients with solid cancers and hematological malignancies. In early clinical trials in heme-lymphatic malignancy, MLN8237 dosed as a single agent has demonstrated antitumor activity (Padmanabhan ASH 2010; Goldberg ASH 2010). In order to identify potential combination partners for MLN8237 for clinical evaluation, previous preclinical efforts demonstrated that MLN8237 combined with rituximab leads to significant antitumor activity in a panel of in vivo diffuse large B-cell lymphoma (DLBCL) models (Huck et. al. ASH 2008; Zhang et, al. AACR 2009). In the present preclinical studies, a novel combination treatment of MLN8237 and vincristine was tested in two xenograft models of DLBCL, WSU and OCI-LY19. Mice were dosed for three weeks with MLN8237 orally daily (QD) and with vincristine intravenously weekly (QW). In both tumor models, single agent dose dependent antitumor activity was observed with MLN8237 and vincristine; however, tumors gradually re-grew after the treatment. Combined MLN8237 and vincristine treatment led to additive or synergistic antitumor activity and resulted in significant tumor growth delay even after discontinuing treatment. In the OCI-Ly19 model, MLN8237 (20 mg/kg) with vincristine (0.5mg/kg or 1 mg/kg) resulted in complete cures with no tumor re-growth out to >120 day. In the WSU model, MLN8237 (20mg/kg) combined with vincristine (1mg/kg) led to tumor regression during the treatment period and significant tumor growth delay (TGD=38). Body weight loss (BWL) was observed in the combination arms in a dose dependent manner in an acceptable range (maximum ∼10%); however body weight recovered quickly after treatment termination. The plasma and tumor pharmacokinetic profiles of MLN8237 (20 and 3 mg/kg) and vincristine (1 mg/kg) in the WSU model demonstrated decreased MLN8237 exposure when co-administered with vincristine. Vincristine exposures were not affected by co-administration with MLN8237. Additional preclinical studies are planned to evaluate the antitumor activity of MLN8237 combined with vincristine and rituximab. Preclinical data showing the antitumor activity of the combination of MLN8237 and vincristine provides the basis for its clinical evaluation as a treatment option for aggressive DLBCL.