Randomized Phase III Study of Alisertib or Investigator’s Choice (Selected Single Agent) in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma

Abstract

PURPOSE The aim of this open-label, first-in-setting, randomized phase III trial was to evaluate the efficacy of alisertib, an investigational Aurora A kinase inhibitor, in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL). PATIENTS AND METHODS Adult patients with relapsed/refractory PTCL—one or more prior therapy—were randomly assigned 1:1 to receive oral alisertib 50 mg two times per day (days 1 to 7; 21-day cycle) or investigator-selected single-agent comparator, including intravenous pralatrexate 30 mg/m2 (once per week for 6 weeks; 7-week cycle), or intravenous gemcitabine 1,000 mg/m2 or intravenous romidepsin 14 mg/m2 (days 1, 8, and 15; 28-day cycle). Tumor tissue (disease subtype) and imaging were assessed by independent central review. Primary outcomes were overall response rate and progression-free survival (PFS). Two interim analyses and one final analysis were planned. RESULTS Between May 2012 and October 2014, 271 patients were randomly assigned (alisertib, n = 138; comparator, n = 133). Enrollment was stopped early on the recommendation of the independent data monitoring committee as a result of the low probability of alisertib achieving PFS superiority with full enrollment. Centrally assessed overall response rate was 33% for alisertib and 45% for the comparator arm (odds ratio, 0.60; 95% CI, 0.33 to 1.08). Median PFS was 115 days for alisertib and 104 days for the comparator arm (hazard ratio, 0.87; 95% CI, 0.637 to 1.178). The most common adverse events were anemia (53% of alisertib-treated patients v 34% of comparator-treated patients) and neutropenia (47% v 31%, respectively). A lower percentage of patients who received alisertib (9%) compared with the comparator (14%) experienced events that led to study drug discontinuation. Of 26 on-study deaths, five were considered treatment related (alisertib, n = 3 of 11; comparator, n = 2 of 15). Two-year overall survival was 35% for each arm. CONCLUSION In patients with relapsed/refractory PTCL, alisertib was not statistically significantly superior to the comparator arm.

Role of HDACs in normal and malignant hematopoiesis

“…Hence, combining HDACis with other chemotherapeutic agents is considered to be an effective way to enhance tumor drug sensitivity by improving the cellular efficacy and toxicity of HDACis to tumor cells [116][117][118][119][120][121][122][123][124][125] (Table 3 and Table 4). To date, the different mechanisms of HDACis combined with chemotherapeutic agents such as topoisomerase inhibitors, platinumbased chemotherapeutics, proteasome inhibitors, tyrosine kinase pathway inhibitors and epigenetic modifiers for advanced or drug-resistant hematological malignancies include (1) acetylating histones and inducing p21-CDK-mediated cell cycle arrest; (2) inducing apoptosis by regulating the expression of pro-and antiapoptotic genes through the intrinsic or extrinsic pathway; (3) inducing DNA damage and oxidative stress; (4) activating BTK (in CLL) or inhibiting ERK (in MM) and AKT (in CML) signaling pathways; and (5) regulating the expression of drug resistance-related molecules, such as downregulating BCR-ABL and upregulating Bim in hematological malignancies and downregulating CD44 in multiple myeloma (MM), NF-κB in ALL, γ-catenin in CML, and BRCA1, CHK1 and RAD51 in AML [126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145]. Specific combination strategies and their corresponding mechanisms are summarized in Table 3 [146][147][148]…”

GATA‐3 in T‐cell lymphoproliferative disorders

“…Therefore, AAK inhibition has emerged as an attractive therapeutic strategy in the T‐cell lymphomas (reviewed in Reference ). In fact, the AAK inhibitor alisertib is associated with an overall response rate ≈30% in PTCL, which rivals the anticipated response rates observed with currently available agents . The extent to which the AAK/PLK1 axis, GATA‐3 itself, and/or c‐myc are predictive biomarkers for response to alisertib is unknown.…”

Biomarker-driven management strategies for peripheral T cell lymphoma

“…Consistent with earlier phase I data, myelosuppression was common (in up to 32% of patients) and was the most common reason for dose reductions. The phase III Lumiere trial compared single-agent alisertib to investigator's choice of single-agent of pralatrexate, gemcitabine, or romidepsin [63]. Alisertib showed similar results with an ORR of 33% with 16% CR, a median PFS of 2.7 months, and a median OS of 9.9 months.…”