Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer

Abstract

IMPORTANCE There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. OBJECTIVE This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). DESIGN, SETTING, AND PARTICIPANTS An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. INTERVENTIONS Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m 2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m 2 intravenously in 28-day cycles. MAIN OUTCOMES AND MEASURES Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received Ն1 dose of study drug). RESULTS The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P = .14; 2-sided P value cutoff = .20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. CONCLUSIONS AND RELEVANCE The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted.

Aurora A Inhibition Eliminates Myeloid Cell–Mediated Immunosuppression and Enhances the Efficacy of Anti–PD-L1 Therapy in Breast Cancer

“…Notably, neutropenia is one of the most common toxicities in clinical trials of alisertib in solid tumors (5,7,8,44). In line with these reports, we demonstrated myeloid cells are readily eliminated by alisertib in mouse mammary tumor.…”

“…The Aurora A kinase inhibitor alisertib has exhibited significant anticancer effects in preclinical studies and phase I and phase II clinical trials in multiple tumor types including refractory breast cancer (5)(6)(7)(8)44). However, it is unclear whether and how this compound directly modulates the immune microenvironment, which has been widely proved to play an important role not only in tumor progression but also in tumor therapy.…”

CCNB2 and AURKA overexpression may cause atypical mitosis in Japanese cortisol-producing adrenocortical carcinoma with TP53 somatic variant

“…The RT-qPCR results of our seven cases of cortisol-producing ACC and the results of ACC-TCGA dataset analysis showed that mRNA of AURKA is also highly expressed in adult ACC cases with TP53 somatic variants and with atypical mitotic figures. Alisertib, an AURKA inhibitor, is currently undergoing clinical trials for various cancers [55,56,57], and it may be useful for the treatment of ACC in the future. In aggressive cases with TP53 variants, it may be more effective to administer an AURKA inhibitor in combination with conventional mitotane and combined etoposide, doxorubicin, and cisplatin therapy as adjuvant therapy.…”

Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses

“…[18][19][20][21][22][23] Single-agent activity was demonstrated in a phase II study of patients with relapsed or refractory solid tumors, including SCLC (n ¼ 48); 23 in patients with SCLC, the objective response rate (ORR) was 21% and the median progression-free survival (PFS) was 2.1 months. 23 On the basis of preclinical evidence of synergy, alisertib plus paclitaxel (henceforth referred to as alisertib/paclitaxel) was evaluated in patients with breast and ovarian cancer 19 and showed promise over paclitaxel alone, with PFS and ORR trending in favor of the combination. 19 Preclinical data have also shown alisertib/paclitaxel synergy in SCLC; increased antitumor activity with the combination versus with the single agents was demonstrated in xenograft tumor models derived from human SCLC cell lines and human SCLC primary tumors (Takeda, data on file).…”

“…23 On the basis of preclinical evidence of synergy, alisertib plus paclitaxel (henceforth referred to as alisertib/paclitaxel) was evaluated in patients with breast and ovarian cancer 19 and showed promise over paclitaxel alone, with PFS and ORR trending in favor of the combination. 19 Preclinical data have also shown alisertib/paclitaxel synergy in SCLC; increased antitumor activity with the combination versus with the single agents was demonstrated in xenograft tumor models derived from human SCLC cell lines and human SCLC primary tumors (Takeda, data on file). The preclinical and clinical data thus provided justification for this phase II study of alisertib/paclitaxel as second-line therapy for relapsed or refractory SCLC.…”