title: Phase II study of MLN8237 (Alisertib) in advanced/metastatic sarcoma.
abstract: Aurora kinase A (AURKA) is commonly overexpressed in sarcoma. The inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel oral adenosine triphosphate-competitive AURKA inhibitor.
  
  
  
  This Cancer Therapy Evaluation Program-sponsored phase II study of alisertib was conducted through the Alliance for Clinical Trials in Oncology (A091102). Patients were enrolled into histology-defined cohorts: (i) liposarcoma, (ii) leiomyosarcoma, (iii) undifferentiated sarcoma, (iv) malignant peripheral nerve sheath tumor, or (v) other. Treatment was alisertib 50 mg PO b.i.d. d1-d7 every 21 days. The primary end point was response rate; progression-free survival (PFS) was secondary. One response in the first 9 patients expanded enrollment in a cohort to 24 using a Simon two-stage design.
  
  
  
  Seventy-two patients were enrolled at 24 sites [12 LPS, 10 LMS, 11 US, 10 malignant peripheral nerve sheath tumor (MPNST), 29 Other]. The median age was 55 years; 54% were male; 58%/38%/4% were ECOG PS 0/1/2. One PR expanded enrollment to the second stage in the other sarcoma cohort. The histology-specific cohorts ceased at the first stage. There were two confirmed PRs in the other cohort (both angiosarcoma) and one unconfirmed PR in dedifferentiated chondrosarcoma. Twelve-week PFS was 73% (LPS), 44% (LMS), 36% (US), 60% (MPNST), and 38% (Other). Grade 3-4 adverse events: oral mucositis (12%), anemia (14%), platelet count decreased (14%), leukopenia (22%), and neutropenia (42%).
  
  
  
  Alisertib was well tolerated. Occasional responses, yet prolonged stable disease, were observed. Although failing to meet the primary RR end point, PFS was promising.
  
  
  
  NCT01653028.
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York Weill Cornell Medical College, New York dicksonm@mskcc.org.
authors: M A
authors: MA
authors: Dickson
authors: Biomedical Statistics & Informatics, Alliance Statistics and Data Center, Mayo Clinic, Rochester.
authors: M R
authors: MR
authors: Mahoney
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York Weill Cornell Medical College, New York.
authors: W D
authors: WD
authors: Tap
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York Weill Cornell Medical College, New York.
authors: S P
authors: SP
authors: D'Angelo
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York Weill Cornell Medical College, New York.
authors: M L
authors: ML
authors: Keohan
authors: Department of Internal Medicine, Washington University School of Medicine, Saint Louis.
authors: B A
authors: BA
authors: Van Tine
authors: Department of Hematology and Oncology, Northwestern University, Chicago.
authors: M
authors: M
authors: Agulnik
authors: Department of Medicine, Alliance for Clinical Trials in Oncology, Chicago.
authors: L E
authors: LE
authors: Horvath
authors: Department of Medicine, Columbia University Medical Center, New York, USA.
authors: J S
authors: JS
authors: Nair
authors: Department of Medicine, Columbia University Medical Center, New York, USA.
authors: G K
authors: GK
authors: Schwartz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000235:genetics; D001381:Azepines / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008080:Liposarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D064096:Aurora Kinase A
keywords: aurora kinase inhibitors; bone sarcoma; phase II clinical trials; soft tissue sarcoma