title: A phase 1 study of buparlisib and bevacizumab in patients with metastatic renal cell carcinoma progressing on vascular endothelial growth factor-targeted therapies.
abstract: BACKGROUND
  The phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is dysregulated in patients with metastatic renal cell carcinoma (mRCC). Buparlisib is a pan-PI3K inhibitor with activity in advanced solid tumors. The primary objective of the current study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of buparlisib and bevacizumab in patients with mRCC. Secondary objectives included efficacy, biomarker discovery, and additional toxicity.
  
  
  METHODS
  This was a standard 3 + 3 dose escalation study of buparlisib (at a dose of 60-100 mg/day) and bevacizumab (at a dose of 10 mg/kg every 2 weeks). After the MTD was defined, 15 patients were accrued to the expansion cohort.
  
  
  RESULTS
  Thirty-two patients were accrued (3 were treated at 60 mg/day, 21 were treated at 80 mg/day, 6 were treated at 100 mg/day, and 2 patients never received therapy). The majority of patients had clear cell histology (87%) and 50% had received ≥2 prior lines of therapy. The MTD of buparlisib was 80 mg/day and that of bevacizumab was 10 mg/kg every 2 weeks. A total of 28 patients discontinued therapy: 17 because of disease progression, 7 because of toxicity, and 4 for other reasons. Dose-limiting toxicities included rash/pruritis, elevated lipase/amylase, anorexia, and psychiatric disorders (suicidal ideation, depression, and cognitive disturbances). Of the 30 patients who received at least 1 dose, 13% achieved a partial response (95% confidence interval, 4%-31%). Two patients harboring activating PI3KA mutations achieved 42% and 16% maximal tumor shrinkage, respectively.
  
  
  CONCLUSIONS
  Buparlisib at a dose of 80 mg/day with bevacizumab was found to be a tolerable regimen with preliminary activity in vascular endothelial growth factor-refractory mRCC. The benefit of this combination may be of interest for future mRCC trials, possibly in a selected patient population. Cancer 2016;122:2389-2398. © 2016 American Cancer Society.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Rana R
authors.initials: RR
authors.lastname: McKay
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Guillermo
authors.initials: G
authors.lastname: De Velasco
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Lillian
authors.initials: L
authors.lastname: Werner
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Lauren
authors.initials: L
authors.lastname: Harshman
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sweeney
authors.affiliation: Deparment of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Michelle
authors.initials: M
authors.lastname: Hirsch
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Eliezer M
authors.initials: EM
authors.lastname: Van Allen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Meghara
authors.initials: M
authors.lastname: Walsh
authors.affiliation: Department of Hematology/Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Ulka
authors.initials: U
authors.lastname: Vaishampayan
authors.affiliation: Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D015415:Biomarkers; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology*; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000008:administration & dosage; D009362:Neoplasm Metastasis; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D000631:Aminopyridines; D015415:Biomarkers; D009025:Morpholines; C571178:NVP-BKM120; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab
keywords: bevacizumab; buparlisib; phase 1; phosphatidylinositol-3 kinase (PI3K) inhibitor; renal cell carcinoma