%0 Journal Article
%A Owonikoko, Taofeek K
%A Niu, Huifeng
%A Nackaerts, Kristiaan
%A Csoszi, Tibor
%A Ostoros, Gyula
%A Mark, Zsuzsanna
%A Baik, Christina
%A Joy, Anil Abraham
%A Chouaid, Christos
%A Jaime, Jesus Corral
%A Kolek, Vitezslav
%A Majem, Margarita
%A Roubec, Jaromir
%A Santos, Edgardo S
%A Chiang, Anne C
%A Speranza, Giovanna
%A Belani, Chandra P
%A Chiappori, Alberto
%A Patel, Manish R
%A Czebe, Krisztina
%A Byers, Lauren
%A Bahamon, Brittany
%A Li, Cong
%A Sheldon-Waniga, Emily
%A Kong, Eric F
%A Williams, Miguel
%A Badola, Sunita
%A Shin, Hyunjin
%A Bedford, Lisa
%A Ecsedy, Jeffrey A
%A Bryant, Matthew
%A Jones, Sian
%A Simmons, John
%A Leonard, E Jane
%A Ullmann, Claudio Dansky
%A Spigel, David R
%A C14018 study investigators
%T Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses.
%D 2019
%U http://hdl.handle.net/10668/15444
%X We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC. In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated. A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths. Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted.
%K Alisertib
%K Aurora A kinase
%K Paclitaxel
%K Phase II
%K SCLC
%~