Phase II Study Shows Activity of Selective Aurora A Kinase Inhibitor Alisertib in Relapsed/Refractory Aggressive B- and T-Cell Non-Hodgkin Lymphoma
Aurora A kinase is overexpressed in aggressive lymphomas and may correlate with more histologically aggressive forms of disease. In a phase II study reported in Journal of Clinical Oncology, Jonathan W. Friedberg, MD, of University of Rochester Wilmot Cancer Center, and colleagues assessed the effects of the selective AAK inhibitor alisertib in patients with relapsed and refractory aggressive non-Hodgkin lymphoma (NHL). They found that the agent was generally well tolerated and exhibited activity that warrants further study.
Study Details
In the study, 48 patients with relapsed or refractory diffuse large B-cell lymphoma (n = 21), mantle cell lymphoma (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), or Burkitt’s lymphoma (n = 1) were treated with oral alisertib at 50 mg twice daily for 7 days in 21-day cycles. Patients had a median age of 67.5 years, 27% were female, 98% were white, 87% had Eastern Cooperative Oncology Group performance status of 0 or 1, and 48% had Ann Arbor disease stage IV. The median number of prior treatment regimens was 3 (range 1-9), 54% had received ≥ 3 regimens, 35% had received prior radiotherapy, and second-line regimen types consisted of autologous stem cell transplantation in 23%, platinum-containing regimens in 65%, and bendamustine in 15%.
Response Rate
The overall response rate was 27% (complete response in 10%), including responses in 3 of 21 patients with diffuse large B-cell lymphoma, 3 of 13 with mantle cell lymphoma, 4 of 8 with noncutaneous T-cell lymphoma, 2 of 5 with transformed follicular lymphoma, and 1 of 1 with Burkitt’s lymphoma. Three patients with T-cell lymphoma (2 with complete responses and 1 with partial response) continued therapy beyond 1 year. One patient with ALK-negative anaplastic large-cell lymphoma received > 40 cycles of study drug.
Adverse Events
The most common grade 3 or 4 adverse events were neutropenia (63%), leukopenia (54%), anemia (35%), thrombocytopenia (33%), stomatitis (15%), febrile neutropenia (13%), and fatigue (6%). Six cases of febrile neutropenia were considered treatment-related. Four deaths during the study were attributed to progressive diffuse large B-cell lymphoma (n = 2), treatment-related sepsis (n =1), and unknown cause (n = 1). Alopecia occurred in approximately half of patients, and other common grade 1 or 2 drug-related adverse events included somnolence, nausea and vomiting, and fever. Dose reduction to 40 mg twice daily was required in 25 patients, and further reduction to 30 mg twice daily was required in 6. One patient with angioimmunoblastic T-cell NHL developed myelodysplastic syndrome after 16 months of alisertib treatment; previous therapy in this patient included ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), ICE (ifosfamide, carboplatin, etoposide), and cyclosporine.
Pharmacokinetic analysis in 25 patients showed that alisertib steady-state trough concentrations exhibited expected variability, with a trend observed for a higher incidence of dose reductions for adverse events at higher trough concentrations.
Analysis of AAK gene amplification and total AAK protein showed no differences between histologies and no correlation with clinical response.
The investigators concluded: “[D]ata from this phase II study suggest that alisertib is clinically active in both B- and T-cell aggressive lymphomas, presenting an opportunity for a novel therapeutic strategy of AAK inhibition in these indications. On the basis of these results, several confirmatory single-agent and combination studies have been initiated using alisertib and other inhibitors of aurora kinases in lymphoma.”
Dr. Friedberg is the corresponding author for the article.
The study was supported by Millennium Pharmaceuticals and others.
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