SAN DIEGO, CA—Alisertib, an ATP-competitive, orally available inhibitor of aurora A kinase (AAK), was well-tolerated, with responses observed in heavily pretreated patients with aggressive non-Hodgkin’s lymphoma (NHL), including after autologous stem cell transplantation (ASCT), noted study investigators at the 53rd Annual Meeting and Exposition of American Society and Hematology.

Jonathan Friedberg, MD, from the James P. Wilmot Cancer Center, University of Rochester, Rochester, NY, and colleagues conducted a Phase 2 multicenter trial evaluating the investigational agent alisertib in adult patients with relapsed/refractory aggressive B-cell and T-cell NHL. Patients eligible for the study had ECOG PS 0–2, normal organ function, absolute neutrophil count (ANC) ≥1.25×109/L, platelets ≥75×109/L and no prior allogeneic transplant. Patients were treated with alisertib at a dose of 50mg twice daily for seven days of a 21-day cycle until disease progression or unacceptable treatment-related toxicity occurred.

The 48 patients enrolled had the following histologies: diffuse large B-cell lymphoma (DLBCL; n=21, 44%), mantle cell (MCL; n=13, 27%), transformed follicular (n=5, 10%) Burkitt (n=1, 2%), and peripheral T-cell (n=8, 17%). Patients had received a median of three prior therapies and 17, radiation therapy. Prior second-line regimens included ASCT (n=11), platinum-containing (n=31), and bendamustine (n=7). Median age of the patients was 67 years (range 32–85).

The overall response rate (complete response plus partial response) was 32% (95% CI: 0.18–0.48); response by histology was DLBCL, 3 patients (20%); MCL, 3 patients (23%), transformed follicular lymphoma, 2 patients (40%), Burkitt, 1 patient (100%), and T-cell lymphoma, 4 patients (57%).

Using fluorescent in situ hybridization (FISH), investigators assessed gene amplification in archived tumors by a dual assay that measured both AAK copy number on chromosome 20q13 and the ratio to a control probe located on chromosome 20q11. Immunohistochemistry (IHC) was performed on archived paraffin embedded diagnostic tissue using a dual assay that measured the protein levels of total AAK and phospho histone H3. No correlation was observed with AAK protein expression, pHH3 expression, or AAK copy number and best overall response in this patient population.

Neutropenia (63%; 7 of 30 patients had febrile neutropenia), thrombocytopenia (31%), stomatitis (15%), and fatigue (6%) were the most common Grade 3/4 adverse events. Four deaths occurred in the study. Two were attributed to progressive DLBCL, one to treatment-related sepsis (DLBCL at Day 14), and one due to an unknown cause. Common non-hematologic toxicities included fatigue (65%), diarrhea (60%), alopecia (48%), somnolence (44%), stomatitis (38%), and nausea/vomiting (33%).

Dose reduction to 40mg twice daily was required in 24 patients (50%), 17 of whom reduced in Cycle 2; an additional six patients required dose reduction to 30mg twice daily.

Toxicities of alisertib were generally manageable and reversible in patients with refractory aggressive lymphomas, Dr. Friedberg noted; while 19% of patients discontinued treatment due to adverse events, seven patients continued treatment for ≥1 year. These data suggest alisertib has anti-tumor activity in aggressive B-cell and T-cell NHL, including in heavily pretreated and post-ASCT patients, with favorable overall response rates in aggressive T-cell lymphoma.

Future clinical directions for alisertib in patients with T-cell lymphoma include a Southwest Oncology Group Phase 2 single agent study and a corporate-sponsored global Phase 3 global in relapsed/refractory disease and, in B-cell lymphoma, a Phase 1/2 trial of alisertib + rituximab + vincristine as well as other trials in development through US National Cancer Institute cooperative research agreements.