Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma

Abstract

The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL. Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 + 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 IHC was performed on available archival tissue. Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV ( = 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL). The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.

Comprehensive tumor profiling reveals unique molecular differences between peritoneal metastases and primary colorectal adenocarcinoma

“…These tumors were initially certified for adequate sample size and histological subtype by board‐certified pathologists. Corresponding formalin‐fixed paraffin‐embedded (FFPE) samples were then processed for analysis using one or more of the following profiling platforms: next‐generation sequencing (NGS), immunohistochemistry (IHC), or fusion analysis 17 . TMB, MSI, and copy number variation (CNV) analyses were performed using data from the NGS panel.…”

The LIV-1-GRPEL1 axis adjusts cell fate during anti-mitotic agent-damaged mitosis

“…Drugs such as the taxanes and the vinca alkaloids, which target microtubule dynamics, have successfully been used for the treatment of various human malignancies and have demonstrated outstanding therapeutic efficacy [2,3] . Moreover, novel antimitotic agents that target mitotic kinases and components other than microtubules have been developed [4][5][6] ; their benefits are currently under investigation in clinical trials [7][8][9][10][11][12][13] .…”

Therapeutic Rationale to Target Highly Expressed Aurora kinase A Conferring Poor Prognosis in Cholangiocarcinoma

“…Alisertib (MLN8237) is an orally available ATP-competitive, highly selective inhibitor of AURKA (40-fold selective for AURKA compared with AURKB) [24]. Clinical trials testing Alisertib as a single agent or in combination with conventional chemotherapies are ongoing for the treatment of various malignancies [14,[25][26][27][28][29][30][31][32][33]. Of the entire AURKA inhibitors, only Alisertib has proceeded to phase III evaluation [34].…”