title: Sunitinib in combination with gemcitabine for advanced solid tumours: a phase I dose-finding study.
abstract: BACKGROUND
  This phase I, dose-finding study determined the maximum tolerated dose (MTD), safety, and pharmacokinetics of sunitinib plus gemcitabine in patients with advanced solid tumours.
  
  
  METHODS
  Two schedules with sunitinib (25-50 mg per day) and IV gemcitabine (750-1250 mg m(-2)) in escalating doses were studied. First, patients received sunitinib on a 4-weeks-on-2-weeks-off schedule (Schedule 4/2) plus gemcitabine on days 1, 8, 22, and 29. Second, patients received sunitinib on a 2-weeks-on-1-week-off schedule (Schedule 2/1) plus gemcitabine on days 1 and 8. The primary endpoint was determination of MTD and tolerability.
  
  
  RESULTS
  Forty-four patients received the combination (Schedule 4/2, n=8; Schedule 2/1, n=36). With no dose-limiting toxicities (DLTs) at maximum dose levels on Schedule 2/1, MTD was not reached. Grade 4 treatment-related AEs and laboratory abnormalities included cerebrovascular accident, hypertension, and pulmonary embolism (n=1 each), and neutropenia (n=3), thrombocytopenia and increased uric acid (both n=2), and lymphopenia (n=1). There were no clinically significant drug-drug interactions. Antitumor activity occurred across dose levels and tumour types. In poor-risk and/or high-grade renal cell carcinoma patients (n=12), 5 had partial responses and 7 stable disease ≥ 6 weeks.
  
  
  CONCLUSIONS
  Sunitinib plus gemcitabine on Schedule 2/1 with growth factor support was well tolerated and safely administered at maximum doses of each drug, without significant drug-drug interactions.
authors.affiliation: Massachusetts General Hospital Cancer Center, 55 Fruit Street, Yawkey 7, Boston, MA 02114, USA. dmichaelson1@partners.org
authors.forename: M D
authors.initials: MD
authors.lastname: Michaelson
authors.forename: A X
authors.initials: AX
authors.lastname: Zhu
authors.forename: D P
authors.initials: DP
authors.lastname: Ryan
authors.forename: D F
authors.initials: DF
authors.lastname: McDermott
authors.forename: G I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: L
authors.initials: L
authors.lastname: Tye
authors.forename: I
authors.initials: I
authors.lastname: Chen
authors.forename: P
authors.initials: P
authors.lastname: Stephenson
authors.forename: S
authors.initials: S
authors.lastname: Patyna
authors.forename: A
authors.initials: A
authors.lastname: Ruiz-Garcia
authors.forename: A B
authors.initials: AB
authors.lastname: Schwarzberg
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077210:Sunitinib; D000093542:Gemcitabine
chemical_list: D007211:Indoles; D011758:Pyrroles; D003841:Deoxycytidine; D000077210:Sunitinib; D000093542:Gemcitabine