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Falchook G , Coleman RL , Roszak A , Behbakht K , Matulonis U , Ray-Coquard I , Sawrycki P , Duska LR , Tew W , Ghamande S , Lesoin A , Schwartz PE , Buscema J , Fabbro M , Lortholary A , Goff B , Kurzrock R , Martin LP , Gray HJ , Fu SQ , Sheldon-Waniga E , Lin HM , Venkatakrishnan K , Zhou XF , Leonard EJ , Schilder RJ
Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer A Randomized Clinical Trial
JAMA Oncol. 2019 Jan;5(1) :e183773
PMID: 30347019    PMCID: PMC6439781    URL: https://www.ncbi.nlm.nih.gov/pubmed/30347019
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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 >= 1 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.
Falchook, Gerald Coleman, Robert L. Roszak, Andrzej Behbakht, Kian Matulonis, Ursula Ray-Coquard, Isabelle Sawrycki, Piotr Duska, Linda R. Tew, William Ghamande, Sharad Lesoin, Anne Schwartz, Peter E. Buscema, Joseph Fabbro, Michel Lortholary, Alain Goff, Barbara Kurzrock, Razelle Martin, Lainie P. Gray, Heidi J. Fu, Siqing Sheldon-Waniga, Emily Lin, Huamao Mark Venkatakrishnan, Karthik Zhou, Xiaofei Leonard, E. Jane Schilder, Russell J. 2374-2445 JAMA Oncol. 2019 Jan 1;5(1):e183773. doi: 10.1001/jamaoncol.2018.3773. Epub 2019 Jan 10.