Phase 2 Trial of Alisertib (MLN8237), An Investigational, Potent Inhibitor of Aurora A Kinase (AAK), in Patients (pts) with Aggressive B- and T-Cell Non-Hodgkin Lymphoma (NHL)

Aurora kinases are a family of oncogenic serine-threonine kinases that regulate multiple phases of the mitotic signaling cascade. Inhibition of aurora A kinase (AAK) leads to mitotic errors, followed by aneuploidy, apoptosis, and senescence. Investigational drug alisertib is an ATP-competitive, orally available inhibitor of AAK, that has been evaluated for safety and efficacy in Phase I hematological malignancies. We conducted the first phase II multicenter trial of alisertib in adult patients with aggressive B- and T- cell NHL. Methods: Eligible patients had normal organ function, ANC ≥1250/mm³, platelets ≥ 75,000/mm³ and no prior allogeneic transplant. Patients were treated with alisertib at a dose of 50mg twice daily for 7 days on 21 day cycles until either documented progression or unacceptable treatment-related toxicity. Using fluorescent in situ hybridization (FISH), gene amplification was assessed in archived tumors by a dual assay measuring AAK copy number on chromosome 20q13 as well as the ratio to a control probe located on chromosome 20q11. Immunohistochemistry (IHC) was performed on archived paraffin embedded diagnostic tissue using a dual assay measuring the protein levels of total AAK and that of phospho histone H3. PK sampling was performed with inclusion of steady-state trough plasma PK samples on the morning of Cycle 1 Day 8. Results: 48 pts were enrolled, including 41 response-evaluable. Histologies included DLBCL (n=21, 44%), mantle cell (MCL; n=13, 27%), peripheral T- cell (n=8, 17%), transformed follicular (n=5, 10%) and Burkitt (n=1, 2%). Median age was 68 y (range 32–85). Pts received median 3 prior regimens (range 1–11); 11 pts received prior ASCT. Most common Grade 3/4 adverse events were neutropenia (63%), thrombocytopenia (31%), stomatitis (15%), febrile neutropenia (13%) and fatigue (6%). Four deaths on study were attributed to progressive NHL (2), treatment-related sepsis (1), and unknown cause (1). 11 pts discontinued and 24 reduced dose due to adverse events (AEs). Evaluation of steady state trough concentration of alisertib (N=25) revealed that PK variability was consistent with that observed in other trials with alisertib, and there was a trend toward higher levels in patients who required AE-related dose reductions compared to those who did not (geometric mean 2375 nM [n=10, CV: 54%] vs. 1504 nM [n=15, CV: 35%]). FISH analysis for AAK gene amplification did not reveal differences between histologies (N=31). When total AAK protein was evaluated by immunohistochemistry (N=32), marked variability in both proportion of expression as well as intensity was observed both between and within histologies; there was no correlation of AAK protein expression and clinical response. The overall response rate (ORR) was 32% (95% CI 0.181–0.481); response by histology: DLBCL 20%; MCL 23% and T- cell NHL 57%. Conclusion: Current data suggests that alisertib is generally well-tolerated, with responses observed in heavily pretreated patients with aggressive NHL, including patients after ASCT. Emerging data supports single agent activity in several histologies, with proportionally more responses observed in relapsed/refractory T-cell NHL. Some patients have now been treated for up to two years with this agent, and the generally manageable toxicity profile suggests an opportunity to combine this drug with other agents. IHC of aggressive lymphoma histologies suggests heterogeneity in AAK protein expression and intensity. The geometric mean of alisertib steady-state trough concentration was 1.8 μM (CV= 47%, N = 25), which was above the 1 μM steady-state plasma concentrations associated with saturating levels of pharmacodynamics and antitumor activity in preclinical xenograft models. The observed trend for association between trough concentration of alisertib and AEs supports the dose modification scheme implemented in this trial. Based upon these results, planned future trials include a single-agent study in T-cell NHL, and a combination study exploring alisertib with rituximab and vincristine in aggressive B-cell NHL.

Friedberg:Genentech: Consultancy; astellas:; Lilly:; Abbott/Trubion:; Seattle Genetics: Honoraria; Cephalon: Consultancy. Off Label Use: novel agents for relapsed DLBCL. Jung:Millennium: Employment. Danaee:Millennium Pharmaceuticals Inc.: Employment. Zhou:millennium: Employment. Leonard:millennium: Employment.