title: A phase 1 Bayesian dose selection study of bortezomib and sunitinib in patients with refractory solid tumor malignancies.
abstract: BACKGROUND
  This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination.
  
  
  METHODS
  Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25 mg and bortezomib 1 mg m(-2). Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50 mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria.
  
  
  RESULTS
  Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50 mg and bortezomib 1.3 mg m(-2) were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5 mg and bortezomib 1.9 mg m(-2). Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9 mg m(-2) and sunitinib 37.5 mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients.
  
  
  CONCLUSIONS
  Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. donald.harvey@emory.edu
authors: R D
authors: RD
authors: Harvey
authors: T K
authors: TK
authors: Owonikoko
authors: C M
authors: CM
authors: Lewis
authors: A
authors: A
authors: Akintayo
authors: Z
authors: Z
authors: Chen
authors: M
authors: M
authors: Tighiouart
authors: S S
authors: SS
authors: Ramalingam
authors: M P
authors: MP
authors: Fanucchi
authors: P
authors: P
authors: Nadella
authors: A
authors: A
authors: Rogatko
authors: D M
authors: DM
authors: Shin
authors: B
authors: B
authors: El-Rayes
authors: F R
authors: FR
authors: Khuri
authors: J S
authors: JS
authors: Kauh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001499:Bayes Theorem; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D011719:Pyrazines / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*; D000077210:Sunitinib; D013964:Thyroid Neoplasms / Q000188:drug therapy
chemical_list: D001897:Boronic Acids; D007211:Indoles; D011719:Pyrazines; D011758:Pyrroles; D000069286:Bortezomib; D000077210:Sunitinib