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

Purpose: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin's 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. Experimental Design: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg BID days 1-7, plus IV rituximab 375 mg/m2 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) BID days 1-7 plus rituximab and vincristine (1.4 mg/m2 [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 immunohistochemistry was performed on available archival tissue. Results: Forty-five patients participated. The alisertib RP2D for MR was 50 mg BID. For MRV (n = 32) the RP2D was determined as 40 mg BID (1 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 (CRs), seven had partial responses (PRs); 9/20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non-germinal center B-cell (GCB) DLBCL. Conclusions: The combination of alisertib 50 mg BID plus rituximab or alisertib 40 mg BID plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.

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