[Skip to Content]
[Skip to Content Landing]
Views 741
Citations 0
Original Investigation
January 10, 2019

Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial

Author Affiliations
  • 1Sarah Cannon Research Institute at HealthONE, Denver, Colorado
  • 2University of Texas, MD Anderson Cancer Center, Houston
  • 3Greater Poland Cancer Centre/University of Medical Sciences, Poznan, Poland
  • 4Department of Gynecologic Oncology, University of Colorado School of Medicine, Aurora
  • 5Gynecologic Oncology Program, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 6Centre Léon Bérard & University Claude Bernard, Lyon, France
  • 7Department of Oncology and Chemotherapy, L. Rydygiera District Hospital, Torun, Poland
  • 8University of Virginia Health System, Charlottesville
  • 9Memorial Sloan Kettering Cancer Center, New York, New York
  • 10Georgia Cancer Center at Augusta University, Augusta, Georgia
  • 11Centre Oscar Lambret, Lille, France
  • 12Yale University School of Medicine, New Haven, Connecticut
  • 13Arizona Oncology Associates PC, Tucson, Arizona
  • 14Institut Regional du Cancer, Montpellier, France
  • 15Centre Catherine de Sienne, Nantes, France
  • 16University of Washington, Seattle
  • 17San Diego Moores Cancer Center, La Jolla, California
  • 18Fox Chase Cancer Center, Philadelphia, Pennsylvania
  • 19Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachusetts
  • 20Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
JAMA Oncol. 2019;5(1):e183773. doi:10.1001/jamaoncol.2018.3773
Key Points

Question  Can oral alisertib in combination with paclitaxel improve progression-free survival (PFS) compared with paclitaxel alone in patients with breast or ovarian cancer?

Findings  In this open-label phase 1 trial of 191 patients and randomized phase 2 clinical trial of 142 patients with recurrent ovarian cancer or advanced breast cancer, median PFS was 6.7 months in the alisertib plus paclitaxel arm vs 4.7 months in the paclitaxel arm. The combination of alisertib plus paclitaxel demonstrated a manageable safety profile.

Meaning  Future studies of alisertib in combination with paclitaxel and other taxanes are warranted.


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/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 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.

Trial Registration  ClinicalTrials.gov identifier: NCT01091428