title: A Phase I Trial of BKM120 (Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer.
abstract: OBJECTIVE
  This trial was conducted to determine the maximum tolerated dose (MTD) and preliminary efficacy of buparlisib, an oral pan-class I PI3K inhibitor, plus fulvestrant in postmenopausal women with metastatic estrogen receptor positive (ER(+)) breast cancer.
  
  
  METHODS
  Phase IA employed a 3+3 design to determine the MTD of buparlisib daily plus fulvestrant. Subsequent cohorts (phase IB and cohort C) evaluated intermittent (5/7-day) and continuous dosing of buparlisib (100 mg daily). No more than 3 prior systemic treatments in the metastatic setting were allowed in these subsequent cohorts.
  
  
  RESULTS
  Thirty-one patients were enrolled. MTD was defined as buparlisib 100 mg daily plus fulvestrant. Common adverse events (AE) included fatigue (38.7%), transaminases elevation (35.5%), rash (29%), and diarrhea (19.4%). C-peptide was significantly increased during treatment, consistent with on-target effect of buparlisib. Compared with intermittent dosing, daily buparlisib was associated with more frequent early onset AEs and higher buparlisib plasma concentrations. Among the 29 evaluable patients, the clinical benefit rate was 58.6% (95% CI, 40.7%-74.5%). Response was not associated with PIK3CA mutation or treatment cohort; however, loss of PTEN, progesterone receptor (PgR) expression, or mutation in TP53 was most common in resistant cases, and mutations inAKT1 and ESR1 did not exclude treatment response.
  
  
  CONCLUSIONS
  Buparlisib plus fulvestrant is clinically active with manageable AEs in patients with metastatic ER(+)breast cancer. Weekend breaks in buparlisib dosing reduced toxicity. Patients with PgR negative and TP53 mutation did poorly, suggesting buparlisib plus fulvestrant may not be adequately effective against tumors with these poor prognostic molecular features.
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri. cma@dom.wustl.edu mjellis@bcm.edu.
authors.forename: Cynthia X
authors.initials: CX
authors.lastname: Ma
authors.affiliation: Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jingqin
authors.initials: J
authors.lastname: Luo
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Michael
authors.initials: M
authors.lastname: Naughton
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Foluso
authors.initials: F
authors.lastname: Ademuyiwa
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Rama
authors.initials: R
authors.lastname: Suresh
authors.affiliation: Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri. The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Malachi
authors.initials: M
authors.lastname: Griffith
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri. The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Obi L
authors.initials: OL
authors.lastname: Griffith
authors.affiliation: The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Skidmore
authors.affiliation: The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Spies
authors.affiliation: The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Avinash
authors.initials: A
authors.lastname: Ramu
authors.affiliation: The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Lee
authors.initials: L
authors.lastname: Trani
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Timothy
authors.initials: T
authors.lastname: Pluard
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Nagaraj
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Shana
authors.initials: S
authors.lastname: Thomas
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Zhanfang
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hoog
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.affiliation: Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri. The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri. Division of Genomics and Bioinformatics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Elaine
authors.initials: E
authors.lastname: Mardis
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Craig
authors.initials: C
authors.lastname: Lockhart
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. cma@dom.wustl.edu mjellis@bcm.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
mesh_terms: D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000493:pharmacokinetics; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone; D016896:Treatment Outcome
chemical_list: D000631:Aminopyridines; D014408:Biomarkers, Tumor; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000077267:Fulvestrant; D004958:Estradiol; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human