Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial | Breast Cancer | JAMA Oncology | JAMA Network
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Figure 1.  Phase 2 Study Design
Phase 2 Study Design
Figure 2.  Duration of Progression-Free Survival (PFS) in Phase 2 Response-Evaluable Population
Duration of Progression-Free Survival (PFS) in Phase 2 Response-Evaluable Population

A, RECIST and CA-125 criteria. B, RECIST alone.

aUnstratified log-rank test (2-sided P value cutoff = .20). Data are given as number (percentage) unless otherwise stated. HR indicates hazard ratio; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors.

Table 1.  Demographics and Baseline Disease Characteristics (Phase 2 Safety Population)
Demographics and Baseline Disease Characteristics (Phase 2 Safety Population)
Table 2.  Summary of Secondary Efficacy Endpoints (Phase 2 Response-Evaluable Population)
Summary of Secondary Efficacy Endpoints (Phase 2 Response-Evaluable Population)
Table 3.  Most Frequently Reported All-Cause and Drug-Related TEAEs Occurring in 10% or More of Patients Overall (Any Grade) With the Corresponding Grade 3 or Higher TEAEs (Phase 2 Safety Population)
Most Frequently Reported All-Cause and Drug-Related TEAEs Occurring in 10% or More of Patients Overall (Any Grade) With the Corresponding Grade 3 or Higher TEAEs (Phase 2 Safety Population)
1.
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Venkatakrishnan  K, Zhou  X, Ecsedy  J,  et al.  Dose selection for the investigational anticancer agent alisertib (MLN8237): Pharmacokinetics, pharmacodynamics, and exposure-safety relationships.  J Clin Pharmacol. 2015;55(3):336-347.PubMedGoogle ScholarCrossref
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Friedberg  JW, Mahadevan  D, Cebula  E,  et al.  Phase II study of alisertib, a selective Aurora A kinase inhibitor, in relapsed and refractory aggressive B- and T-cell non-Hodgkin lymphomas.  J Clin Oncol. 2014;32(1):44-50.PubMedGoogle ScholarCrossref
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Goldberg  SL, Fenaux  P, Craig  MD,  et al.  An exploratory phase 2 study of investigational Aurora A kinase inhibitor alisertib (MLN8237) in acute myelogenous leukemia and myelodysplastic syndromes.  Leuk Res Rep. 2014;3(2):58-61.PubMedGoogle Scholar
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Kelly  KR, Shea  TC, Goy  A,  et al.  Phase I study of MLN8237—investigational Aurora A kinase inhibitor—in relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia.  Invest New Drugs. 2014;32(3):489-499.PubMedGoogle ScholarCrossref
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Kampan  NC, Madondo  MT, McNally  OM,  et al.  Paclitaxel and its evolving role in the management of ovarian cancer.  Biomed Res Int. 2015;2015:413076-413097.Google ScholarCrossref
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Belotti  D, Vergani  V, Drudis  T,  et al.  The microtubule-affecting drug paclitaxel has antiangiogenic activity.  Clin Cancer Res. 1996;2(11):1843-1849.PubMedGoogle Scholar
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Baird  RD, Tan  DS, Kaye  SB.  Weekly paclitaxel in the treatment of recurrent ovarian cancer.  Nat Rev Clin Oncol. 2010;7(10):575-582.PubMedGoogle ScholarCrossref
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Lück  HJ, Roché  H.  Weekly paclitaxel: an effective and well-tolerated treatment in patients with advanced breast cancer.  Crit Rev Oncol Hematol. 2002;44(suppl):S15-S30.PubMedGoogle ScholarCrossref
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Markman  M, Blessing  J, Rubin  SC, Connor  J, Hanjani  P, Waggoner  S; Gynecologic Oncology Group.  Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study.  Gynecol Oncol. 2006;101(3):436-440.PubMedGoogle ScholarCrossref
20.
Huck  JJ, Zhang  M, Mettetal  J,  et al.  Translational exposure-efficacy modeling to optimize the dose and schedule of taxanes combined with the investigational Aurora A kinase inhibitor MLN8237 (alisertib).  Mol Cancer Ther. 2014;13(9):2170-2183.PubMedGoogle ScholarCrossref
21.
Eisenhauer  EA, Therasse  P, Bogaerts  J,  et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).  Eur J Cancer. 2009;45(2):228-247.PubMedGoogle ScholarCrossref
22.
Rustin  GJ, Timmers  P, Nelstrop  A,  et al.  Comparison of CA-125 and standard definitions of progression of ovarian cancer in the intergroup trial of cisplatin and paclitaxel versus cisplatin and cyclophosphamide.  J Clin Oncol. 2006;24(1):45-51.PubMedGoogle ScholarCrossref
23.
Yang  JJ, Li  Y, Chakravarty  A,  et al.  Preclinical drug metabolism and pharmacokinetics, and prediction of human pharmacokinetics and efficacious dose of the investigational Aurora A kinase inhibitor alisertib (MLN8237).  Drug Metab Lett. 2014;7(2):96-104.PubMedGoogle ScholarCrossref
24.
Thomas  H, Rosenberg  P.  Role of weekly paclitaxel in the treatment of advanced ovarian cancer.  Crit Rev Oncol Hematol. 2002;44(suppl):S43-S51.PubMedGoogle ScholarCrossref
25.
Graff  JN, Higano  CS, Hahn  NM,  et al.  Open-label, multicenter, phase 1 study of alisertib (MLN8237), an aurora A kinase inhibitor, with docetaxel in patients with solid tumors.  Cancer. 2016;122(16):2524-2533.PubMedGoogle ScholarCrossref
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Monk  BJ, Poveda  A, Vergote  I,  et al.  Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial.  Lancet Oncol. 2014;15(8):799-808.PubMedGoogle ScholarCrossref
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Pujade-Lauraine  E, Hilpert  F, Weber  B,  et al.  Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial.  J Clin Oncol. 2014;32(13):1302-1308.PubMedGoogle ScholarCrossref
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Havrilesky  LJ, Alvarez  AA, Sayer  RA,  et al.  Weekly low-dose carboplatin and paclitaxel in the treatment of recurrent ovarian and peritoneal cancer.  Gynecol Oncol. 2003;88(1):51-57.PubMedGoogle ScholarCrossref
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Linch  M, Stavridi  F, Hook  J, Barbachano  Y, Gore  M, Kaye  SB.  Experience in a UK cancer centre of weekly paclitaxel in the treatment of relapsed ovarian and primary peritoneal cancer.  Gynecol Oncol. 2008;109(1):27-32.PubMedGoogle ScholarCrossref
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Görgün  G, Calabrese  E, Hideshima  T,  et al.  A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma.  Blood. 2010;115(25):5202-5213.PubMedGoogle ScholarCrossref
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Aghajanian  C, Goff  B, Nycum  LR, Wang  Y, Husain  A, Blank  S.  Independent radiologic review: bevacizumab in combination with gemcitabine and carboplatin in recurrent ovarian cancer.  Gynecol Oncol. 2014;133(1):105-110.PubMedGoogle ScholarCrossref
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Niu  H, Shin  H, Gao  F,  et al.  Aurora A Functional Single Nucleotide Polymorphism (SNP) Correlates With Clinical Outcome in Patients With Advanced Solid Tumors Treated With Alisertib, an Investigational Aurora A Kinase Inhibitor.  EBioMedicine. 2017;25:50-57.PubMedGoogle ScholarCrossref
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.

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/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

Introduction

Aurora A kinase (AAK) plays a key role in mitosis and is required for centrosome function and maturation, spindle assembly, chromosome alignment, and mitotic entry.1,2 Overexpression and/or amplification of AAK has been linked with tumor progression and poor prognosis in various cancers, including ovarian and breast.2-5 Furthermore, blockade of aurora kinase signaling in preclinical models of ovarian cancer results in decreased proliferation and increased apoptosis.4

Alisertib (MLN8237) is an investigational, oral, selective AAK inhibitor.6 In xenograft models, alisertib showed potent AAK inhibition and antitumor activity across a range of tumor types.6 Phase 1 evaluation demonstrated that the pharmacodynamic effects of alisertib are consistent with AAK inhibition, with 7-day dosing resulting in exposure-related disruption of chromosome alignment and spindle bipolarity.7,8 Alisertib has demonstrated preliminary antitumor activity with manageable toxic effects in nonhematologic9-11 and hematologic malignant abnormalities.12-14

Paclitaxel is approved for treatment of various solid tumors, and is considered a standard of care in patients with platinum-resistant ovarian cancer.15 Weekly paclitaxel may have additional mechanisms of action vs the 3-weekly schedule, including apoptotic effects (independent of microtubule stabilization) and inhibition of angiogenesis.16 Studies of weekly dose-dense/dose-intense paclitaxel therapy have shown activity in advanced ovarian and breast cancer.17,18 In patients with both paclitaxel- (dosed every 3 weeks) and platinum-resistant ovarian cancer, single-agent weekly paclitaxel resulted in an overall response rate (ORR) of 20.9%, a median duration of response (DOR) of 3.6 months, and progression-free survival (PFS) of 7 months; serious adverse events (AEs) included grade 2 (21%) and 3 (4%) neuropathy.19

Alisertib has shown modest single-agent activity with an acceptable toxic effects profile in patients with platinum-resistant ovarian and breast cancer.10,11 Weekly administration of alisertib plus weekly paclitaxel had both additive and synergistic antitumor effects in 2 xenograft models of triple-negative breast cancer, whereas a translational exposure-efficacy model supported the potential for improved antitumor activity of alisertib when added to 60 mg/m2 to 80 mg/m2 paclitaxel.20 This phase 1/2 study therefore evaluated the activity of alisertib plus weekly paclitaxel in patients with advanced breast cancer (phase 1 only) and recurrent ovarian cancer.

Methods
Study Design and Patients

This multicenter, open-label phase 1/2 study enrolled patients at 33 sites (USA, France, and Poland) (Supplement 1). The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines and the protocol was approved by independent ethics committees in Poland and France and institutional review boards at each US site. All patients provided written informed consent.

The study enrolled women 18 years or older with Eastern Cooperative Oncology Group performance status of 0 to 1. For phase 1, patients with recurrent ovarian or breast cancer were eligible; for phase 2, only women with recurrent ovarian cancer were included. Additional eligibility criteria are listed in Supplement 1 (the trial protocol) and Supplement 2.

For phase 1, the primary objective was to assess the safety and tolerability of alisertib plus paclitaxel and to determine the recommended phase 2 dose (RP2D). Phase 1 also aimed to evaluate tumor response and characterize the pharmacokinetic (PK) profiles of alisertib and paclitaxel when administered concomitantly. The primary endpoint for phase 2 was investigator-assessed PFS. Secondary endpoints were: ORR, DOR, time to progression (TTP), and overall survival (OS). Safety and tolerability were also assessed.

In phase 1, patients received oral alisertib as an enteric-coated tablet starting at 10 mg twice daily on days 1 to 3, 8 to 10, and 15 to 17 in 28-day cycles, selected to maximize exposure overlap with paclitaxel while providing adequate treatment-free periods for recovery from toxic effects. Paclitaxel was administered at 80 mg/m2 intravenously on days 1, 8, and 15, in 28-day cycles. Alisertib doses were escalated in 10-mg twice daily increments using a 3 + 3 schema (eFigure 1 in Supplement 2) based on the occurrence of dose-limiting toxic effects (DLTs; defined in Supplement 1 and Supplement 2) in cycle 1 until the maximum tolerated dose (MTD) was reached. Alisertib doses yielding exposures previously associated with robust AAK inhibition (eg, ≥30 mg twice daily)8 were not achievable in combination with 80 mg/m2 paclitaxel, so the starting dose of paclitaxel was decreased to 60 mg/m2, to evaluate further escalation of the alisertib dose and determine an alternate MTD of the combination. In cycle 2, alisertib dosing was withheld on days 1 to 3 to allow characterization of paclitaxel PK in the absence of alisertib for comparison with cycle-1 paclitaxel PK in combination.

For phase 2, patients were randomized 1:1 to receive the RP2D of alisertib plus weekly paclitaxel, or weekly paclitaxel alone; stratified by platinum-free interval (refractory, 0-6 months or 6-12 months) and prior weekly taxane treatment (yes or no). Treatment was given for 2 years or less (unless agreed with the sponsor), until progressive disease (PD), unacceptable treatment-related toxic effects, or initiating another antineoplastic therapy.

Assessments

Best tumor response was assessed by investigators after every 2 cycles according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 and/or modified Gynecologic Cancer Intergroup (GCIC) CA-125 criteria.21,22 The ORR analyses were based on best overall combined response (eTable 1 in Supplement 2). Phase 1 PK parameters were determined by noncompartmental analysis of the concentration-time data using Phoenix WinNonlin 6.2. Plasma alisertib concentrations were measured using a validated liquid chromatography tandem mass spectrometry method.9 The PK sampling schedule is described in Supplement 2. Changes in health-related quality of life (HRQoL) were assessed using the EORTC QLQ-C30 and EORTC QLQ-OV28 questionnaires, administered on day 1 of every other cycle and of every cycle, respectively, before any treatment.

Safety was assessed by AE reporting (incidence, severity, and type) coded per Medical Dictionary for Regulatory Activities (MedDRA) and evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.02).

Statistical Analysis

Full statistical analyses are described in Supplement 2. A sample size of 136 patients was required to achieve a target hazard ratio (HR) for PFS of 0.67 (median PFS from 4-6 months; approximately 33.3% reduction in hazard rates) with the addition of alisertib to weekly paclitaxel. It was estimated that 110 events (PD or death) would be needed across both treatment arms to detect such an increase (1-sided α = .10; power = 80%; 2-sided P value cutoff = .20). Because this was a phase 2 trial, the α level was set to be higher because the criteria for success was less strict. All analyses were performed using SAS statistical software (version 9.1 or higher; SAS Institute, Inc).

Results

Forty-nine patients were enrolled and received treatment in phase 1 between May 2010 to August 2012, including 38 patients with ovarian cancer and 11 with breast cancer. On confirmation of the RP2D, 142 patients were randomized to receive alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in phase 2 between March 2012 to August 2013 (Figure 1). Patient baseline and disease characteristics for the phase 1 population are presented in eTable 2 in Supplement 2; characteristics for the phase 2 safety population are shown in Table 1.

In phase 1, 6 of 39 DLT-evaluable patients (80%) experienced a total of 7 DLTs: febrile neutropenia (n = 3), neutropenia (n = 1), stomatitis (n = 2), and diarrhea (n = 1) (eTable 3 in Supplement 2). Alisertib 10 mg twice daily plus paclitaxel 80 mg/m2 was established as the MTD (MTD1) and the cohort was expanded. Because systemic exposures of alisertib in the MTD1 cohort were not within a range sufficient to provide an optimal pharmacodynamic and antitumor effect, alisertib dose escalation recommenced in combination with paclitaxel 60 mg/m2. The maximum tolerated dose 2 (MTD2) was determined as alisertib 40 mg twice daily with paclitaxel 60 mg/m2, based on the occurrence of DLTs in 2 of 3 patients on alisertib 50 mg twice daily with paclitaxel 60 mg/m2. In the MTD2 cohort, 1 of 7 patients experienced a DLT (grade 4 febrile neutropenia). Alisertib and paclitaxel exposures at MTD1/MTD2 are summarized in eTable 4 and eTable 5 in Supplement 2, respectively. Based on PK and safety data, MTD2 was selected as the RP2D.

In phase 1, patients received a median of 6 treatment cycles (alisertib range, 1-37; paclitaxel range, 1-24). The median relative dose intensity for alisertib and paclitaxel was 95% and 96%, respectively. At data cutoff (August 12, 2014), treatment was ongoing in 2 patients and the investigator-assessed ORR was 49%; response data for phase 1 are summarized in Supplement 2 and eFigures 2 and 3.

Patients in phase 2 received a median of 6 cycles (range, 1-28) in the alisertib plus paclitaxel arm and 5 cycles (range, 1-14) in the paclitaxel-alone arm. Five patients receiving alisertib plus paclitaxel at the RP2D were ongoing at data cutoff. These patients completed 16, 24, 26, 28, and 30 cycles of treatment with alisertib plus paclitaxel and are now off study; reasons for discontinuation were PD (n = 3), complete response (CR) of approximately 2 years (n = 1), and stable response for longer than 1 year (n = 1).

At data cutoff, 107 patients (75%) had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm and 55 (80%) in the paclitaxel arm. Patient PFS (per RECIST 1.1 or CA-125) was improved with alisertib plus paclitaxel vs 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) in favor of alisertib plus paclitaxel. Median PFS was 6.7 months (80% CI, 5.8-7.6) vs 4.7 months (80% CI, 3.8-4.9) with alisertib plus paclitaxel vs paclitaxel (Figure 2A). Similar results were obtained when PFS was assessed by RECIST alone (Figure 2B).

Secondary efficacy endpoints for phase 2 are summarized in Table 2. Forty of 67 response-evaluable patients in the alisertib plus paclitaxel arm achieved CR, PR, or response by CA-125 for an ORR of 60% (80% CI, 51%-68%) vs 33 patients in the paclitaxel-alone arm for an ORR of 52% (80% CI, 43%-60%; P = .38). Median DOR per RECIST and CA-125 was 6.6 months in the alisertib plus paclitaxel arm vs 5.6 months in the paclitaxel-alone arm. Patient TTP as assessed by RECIST and CA-125 (modified intention to treat; mITT population) was longer with the addition of alisertib to weekly paclitaxel (median TTP 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel alone; HR, 0.76; P = .16, in favor of alisertib plus paclitaxel). Subgroup analyses of ORR and PFS according to platinum sensitivity were carried out in the mITT population of the phase 2 study (eTable 6 in Supplement 2). At the time of analysis, OS was not estimable in either treatment arm. Overall, 7 deaths had occurred (alisertib plus paclitaxel, n = 2; single-agent paclitaxel, n = 5). Median duration of follow-up was 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel-alone arm.

The addition of alisertib to weekly paclitaxel did not have any negative impact on HRQoL as measured by QLQ-C30 and OV28 in terms of mean global health status/QoL domain score (QLQ-C30) or mean change from baseline of individual domain scores (eFigure 4 in Supplement 2).

In phase 1, all 49 patients experienced a drug-related AE, and 38 (78%) experienced a grade 3 or higher drug-related AE (eTable 7 in Supplement 2). The most common (≥10%) grade 3 or higher drug-related AEs were neutropenia (59%), leukopenia (35%), anemia (16%), febrile neutropenia (16%), and stomatitis (14%). Nine patients (18%) experienced drug-related serious AEs, most frequently febrile neutropenia (12%). Eleven (22%) and 10 patients (20%) required a dose reduction of alisertib and paclitaxel, respectively, owing to AEs. Two patients discontinued the study permanently owing to AEs. There were no on-study deaths in phase 1.

In phase 2, a similar proportion of patients in each treatment arm experienced 1 or more AEs: all 73 patients in the alisertib plus paclitaxel arm and 66 (96%) patients in the paclitaxel-alone arm (Table 3). All patients in the alisertib plus paclitaxel arm vs 59 (86%) patients in the paclitaxel-alone arm experienced 1 or more drug-related AEs (Table 3). Grade 3 or higher AEs (any cause) occurred in 67 (92%) patients (drug-related, 63 [86%]) who received alisertib plus paclitaxel and 35 (51%) patients (drug-related, 14 [20%]) who received paclitaxel alone. Serious AEs occurred in 30 (41%) patients (drug-related, 21 [29%]) in the alisertib plus paclitaxel arm vs 19 (28%) patients (drug-related, 3 [4%]) in the paclitaxel-alone arm. A total of 54 (74%) patients in the alisertib plus paclitaxel arm had AEs leading to dose reductions (alisertib-related, 34 [47%] patients; paclitaxel-related, 42 [58%] patients), vs 17 (25%) patients in the paclitaxel-alone arm. Adverse events led to study drug discontinuation in 12 (16%) patients (most considered drug-related) who received alisertib plus paclitaxel and 4 (6%) patients (1 AE considered drug-related) who received paclitaxel alone. One patient in each arm died while in study; neither were considered related to study drug.

Discussion

The phase 1 portion of this study identified the MTD and RP2D for alisertib in combination with weekly paclitaxel in women with recurrent platinum- and taxane-pretreated ovarian cancer or previously treated advanced breast cancer. The encouraging antitumor activity seen with alisertib plus paclitaxel in phase 1 (49% ORR) provided the rationale for continuing with the randomized phase 2 study, which reported a statistically significant increase, given the .20 α level, in median PFS in patients with recurrent ovarian cancer who received alisertib plus paclitaxel relative to paclitaxel alone, thereby meeting the statistical criterion to be considered worthy of further investigation.

The phase 1 dose-escalation study identified 2 MTDs: MTD1 (alisertib 10 mg twice daily plus paclitaxel 80 mg/m2) and MTD2 (alisertib 40 mg twice daily with paclitaxel 60 mg/m2). The maximum tolerated dose 2 was selected as the RP2D based on PK and tolerability findings. Systemic exposures of alisertib at MTD1 were approximately 4 times lower than those at MTD2, and were not considered to be within the range associated with a robust pharmacodynamic (≥50% decrease in chromosome alignment/spindle bipolarity) and antitumor effect in the tumor types under investigation based on single-agent experience.7,8,23 In contrast, at MTD2, systemic exposures of alisertib were in the previously reported bioactive range.7,8 Furthermore, the clinical exposures of paclitaxel and alisertib achieved at MTD2 translated to a greater level of expected efficacy compared with those achieved at MTD1, as well as greater efficacy vs single-agent paclitaxel at the full dose of 80 mg/m2, when mapped onto an isobolographic framework constructed based on translational exposure-efficacy modeling in the MDA-MB-231 xenograft model.20 In addition, MTD2 was associated with an acceptable safety profile over multiple treatment cycles. Weekly paclitaxel at 60 mg/m2 was also better tolerated than at 80 mg/m2.17,18,24

In a recently published report25 of alisertib plus docetaxel (docetaxel 75 mg/m2 21 days and alisertib in a 7 days on/14 days off regimen), the MTD of alisertib was determined as 20 mg twice daily. This highlights the challenge of increasing the alisertib dose when combined with docetaxel in this regimen. Our findings confirm that the alisertib plus paclitaxel combination can be administered at doses associated with pharmacologically active exposures, such that further studies of alisertib in combination with paclitaxel in other cancer types as well as with related taxane therapies (eg, albumin-bound paclitaxel) are warranted. In addition, there may be a need to evaluate additional weekly taxane schedules, which may allow for higher doses of alisertib to be administered in combination or may offer greater tolerability.

In phase 2, median PFS was 2 months longer in the alisertib plus paclitaxel arm vs paclitaxel alone as assessed by RECIST or CA-125 (HR, 0.75; 80% CI, 0.58-0.96; P = .14; meeting the 2-sided P-value cutoff of 0.2 to be considered worthy of further investigation). The observation of longer median PFS for the alisertib plus paclitaxel combination (at the selected doses of 40 mg twice daily and 60 mg/m2, respectively) compared with the full dose of single-agent paclitaxel (80 mg/m2) provides important proof-of-principle for the translational exposure-efficacy model-based framework that guided interpretation of the results from the phase 1 part of this study to inform dose selection for phase 2. These data are in line with phase 3 studies in patients with recurrent ovarian cancer such as the TRINOVA-1 study, which reported a significantly longer median PFS with trebananib than placebo (7.2 months vs 5.4 months; HR, 0.66; 95% CI, 0.57-0.77; P < .001)26 and the AURELIA study, which demonstrated a median PFS of 6.7 months with bevacizumab-containing therapy vs 3.4 months with chemotherapy alone (HR, 0.48; 95% CI, 0.38-0.60; unstratified log-rank P < .001).27 In the phase 2 CARTAXHY study, the PFS reported for paclitaxel plus topotecan (5.4 months) or carboplatin (4.8 months) was numerically, not statistically, higher vs single-agent paclitaxel (3.7 months) (HR, 0.92; 95% CI, 0.77-1.1).28

However, these efficacy benefits must be considered in the context of relative safety profiles. The predominant toxic effects associated with paclitaxel are myelosuppression and neuropathy.17,18,29-31 Common toxic effects associated with alisertib, likely caused by inhibition of AAK activity,32 included cytopenia, gastrointestinal toxic effects, and mucositis.9-11 Although myelosuppression was common in our study, the incidence of neuropathy with the combination regimen was lower than expected. Importantly, the myelosuppression was reversible and did not limit treatment with alisertib plus paclitaxel because the selected dosing regimens of both alisertib (3 days on/4 days off) and paclitaxel (weekly) enabled adequate recovery of hematologic parameters at the end of each treatment cycle, while maintaining sufficient exposure overlap with weekly paclitaxel to enhance antitumor effects. Nevertheless, alisertib plus paclitaxel appeared less well tolerated than paclitaxel alone, as evidenced by higher rates of dose reductions and discontinuations owing to toxic effects; this may be partly associated with a slightly greater duration of treatment exposure. However, the differential safety profile appeared somewhat more pronounced than reported in TRINOVA-126 and AURELIA.27

Limitations

This study had a number of limitations; first, a lack of confirmation of response by independent review (IDR). Although several ovarian cancer studies have confirmed that IDR does not appreciably alter the magnitude or direction of a treatment effect at the study level (specifically in patients with resistant disease),33-36 discordance between investigators and IDR assessments can sometimes occur. Second, outcomes to alisertib treatment might have been improved if predictive markers of response to AAK inhibition were available to facilitate patient selection. A companion paper investigated the prognostic significance of 2 aurora A functional single nucleotide polymorphisms during alisertib therapy, and showed that the presence of VV alleles at a codon 57 single nucleotide polymorphism resulted in greater relative efficacy benefit with alisertib plus paclitaxel vs paclitaxel compared with the overall population (median PFS, 7.5 vs 3.8 months; HR, 0.62; P = .05).37 The data from the phase 2 patient population with ovarian cancer may not be applicable to other tumor types, although the inclusion of breast cancer patients in the phase 1 study may provide preliminary safety and efficacy information.

Conclusions

The combination of oral alisertib 40 mg twice daily plus weekly paclitaxel 60 mg/m2 showed promising antitumor activity with an increased but generally manageable safety profile in patients with recurrent ovarian cancer. Future studies of alisertib in combination with paclitaxel and other taxanes are warranted.

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Article Information

Corresponding Author: Gerald Falchook, MD, Sarah Cannon Research Institute at HealthONE, 1800 Williams St, Ste 300, Denver, CO 80218 (gerald.falchook@scresearch.net).

Accepted for Publication: June 1, 2018.

Published Online: October 18, 2018. doi:10.1001/jamaoncol.2018.3773

Author Contributions: All authors had full access to the study data on request and the lead authors (Gerald Falchook and Robert L. Coleman) had final responsibility for the decision to submit for publication. Drs Falchook and Coleman are co–first authors.

Study concept and design: Coleman, Tew, Martin, Venkatakrishnan, Zhou, Leonard, Schilder.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Coleman, Martin, Sheldon-Waniga, Venkatakrishnan, Zhou, Leonard.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Coleman, Sheldon-Waniga, Venkatakrishnan, Zhou.

Obtained funding: Lortholary, Schilder.

Administrative, technical, or material support: Coleman, Roszak, Matulonis, Tew, Buscema, Martin, Zhou, Leonard, Schilder.

Study supervision: Falchook, Coleman, Behbakht, Ghamande, Lortholary, Goff, Zhou, Leonard.

Conflict of Interest Disclosures: Employment: Drs Sheldon-Waniga, Lin, Venkatakrishnan, Zhou, and Leonard (Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited). Stock ownership: Dr Kurzrock reports ownership interest in CureMatch Inc; (Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited). Financial activity during the submitted work: Dr Falchook report grants from Millennium; Dr Coleman reports grants from Millennium; Dr Martin reports financial support to the institution for conduct of the study from Millennium Pharmaceuticals, Inc. Financial activity outside the submitted work: Dr Falchook reports grants from Millennium; Dr Coleman reports grants from Roche/Genentech, AstraZeneca, Merck, Clovis, Esperance, Johnson & Johnson and Abbvie; Dr Ghamande reports board consulting from Advaxis Inc; Dr Goff reports grants from Millennium; Dr Kurzrock reports research funding from Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant and consultant/advisory board fees from Actuate Therapeutics and XBiotech; Dr Martin reports financial support to the institution for conduct of the study from Novartis Pharmaceuticals Corporation, Aduro Biotech, Inc, Tetralogic Pharmaceuticals, Clovis Oncology Inc, Regeneron, Millennium Pharmaceuticals Inc, AbbVie, Amgen, and personal fees from Immunogen Inc; Dr Schilder reports personal fees from Merck, Celsion and Merck Serono. Other: Drs Falchook and Coleman report travel reimbursement to present trial results at ESGO 2013 and ESMO 2014; Dr Martin reports travel expenses for presentation of data at national meetings in November 2015 and March 2017; Intellectual property: Dr Venkatakrishnan is named inventor on published patent applications WO2103/142491 and US2013/0303519 titled “Methods of treating cancer using Aurora Kinase Inhibitors.” No other disclosures are reported. Russell J. Schilder was supported in part by NCI grant 5P30CA056036-17.

Funding/Support: The study was funded by Millennium Pharmaceuticals Inc, Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Part of this work was supported by the Judi Rees/Albert Pisani MD Ovarian Cancer Research Fund and the Ann Rife Cox Chair in Gynecology (Robert L. Coleman).

Role of the Funder/Sponsor: Millennium employees participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentations: This study was presented as a poster at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 24, 2012; Austin, Texas; at the Annual Meeting of the American Society of Clinical Oncology; June 1, 2012; Chicago, Illinois. Venkatakrishnan K et al poster presented at the Annual Meeting of the American Society of Clinical Oncology; May 31, 2013; Chicago, Illinois; as an oral presentation at the European Society of Gynaecological Oncology’s Biennial International Meeting 2013; October 19, 2013; Liverpool, England; and at the Annual Meeting of the European Society of Medical Oncology; September 26, 2014; Madrid, Spain.

Additional Contributions: The authors would also like to acknowledge writing support from Dawn L. Lee, PhD, and Helen Johns, PhD, of FireKite, an Ashfield company, part of UDG Healthcare plc, during the development of this manuscript, which was funded by Millennium Pharmaceuticals, Inc, and complied with Good Publication Practice 3 ethical guidelines. We thank all of the patients who participated in these studies and their families, as well as all the investigators and site staff who made these studies possible.

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