title: A phase I study of sunitinib combined with modified FOLFOX6 in patients with advanced solid tumors.
abstract: OBJECTIVE
  This phase I study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor effects of sunitinib combined with modified FOLFOX6 (mFOLFOX6).
  
  
  METHODS
  Patients with advanced solid malignancies received mFOLFOX6 in 2-week cycles with escalating sunitinib doses (25, 37.5, and 50 mg/day) on three schedules: 2 weeks on, 2 weeks off (2/2); 4 weeks on, 2 weeks off (4/2); or continuous daily dosing (CDD). Patients received up to 8 treatment cycles (Schedule 2/2 and CDD schedule) or 6 cycles (Schedule 4/2). An expansion cohort enrolled patients with metastatic colorectal cancer at the Schedule 2/2 MTD.
  
  
  RESULTS
  Overall, 53 patients were enrolled, with 43 evaluable for dose-limiting toxicity (DLT). On Schedule 2/2 (n = 18), DLTs occurred in three patients at 50 mg/day (grade 4 neutropenia [n = 1]; grades 3 and 4 thrombocytopenia [n = 2]) and two patients achieved partial responses (PRs). On Schedule 4/2 (n = 13), 37.5 mg/day exceeded the MTD with two DLTs (febrile neutropenia and grade 4 hypokalemia, respectively). On the CDD schedule (n = 12), the MTD was 25 mg/day; one DLT (grade 3 stomatitis) was reported and two patients achieved PRs. The most common adverse events were neutropenia, fatigue, and thrombocytopenia. No clinically significant drug-drug interactions were apparent between sunitinib, its metabolite SU12662, and mFOLFOX6.
  
  
  CONCLUSIONS
  Sunitinib combined with mFOLFOX6 had acceptable tolerability. The MTDs were sunitinib 50 mg/day on Schedule 2/2 and 25 mg/day on the CDD schedule. A MTD for Schedule 4/2 was not established.
authors.affiliation: Medical Oncology, Developmental Therapeutics Program/GI Malignancies, University of Colorado Cancer Center, University of Colorado at Denver, Mail Stop 8117, 12801 E 17th Ave, Room 8120, Aurora, CO 80045, USA. stephen.leong@ucdenver.edu
authors.forename: S
authors.initials: S
authors.lastname: Leong
authors.forename: S G
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: E
authors.initials: E
authors.lastname: Chan
authors.forename: W A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: J
authors.initials: J
authors.lastname: Spratlin
authors.forename: D R
authors.initials: DR
authors.lastname: Camidge
authors.forename: S
authors.initials: S
authors.lastname: Diab
authors.forename: R
authors.initials: R
authors.lastname: Khosravan
authors.forename: X
authors.initials: X
authors.lastname: Lin
authors.forename: E
authors.initials: E
authors.lastname: Chow Maneval
authors.forename: A C
authors.initials: AC
authors.lastname: Lockhart
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077210:Sunitinib; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D007211:Indoles; D009944:Organoplatinum Compounds; D011758:Pyrroles; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil; D000077210:Sunitinib