title: A phase I study of sunitinib in combination with FOLFIRI in patients with untreated metastatic colorectal cancer.
abstract: BACKGROUND
  This study evaluated the maximum tolerated dose (MTD) of sunitinib, a multitargeted tyrosine kinase inhibitor, combined with FOLFIRI (irinotecan 180 mg/m2 given over 90 min i.v. and l-leucovorin 200 mg/m2 given over 120 min on day 1, followed by 5-FU 400 mg/m2 bolus and then 2400 mg/m2 infused over 46 h) in untreated metastatic colorectal cancer (mCRC).
  
  
  METHODS
  In this multicentre, phase I, open-label, dose-finding trial, FOLFIRI was administered every 2 weeks. Two sunitinib regimens were explored: Schedule 4/2 (4 weeks on, 2 weeks off; 37.5 and 50 mg/day) and continuous daily dosing (CDD; 37.5 and 25 mg/day). Dose-limiting toxic toxicities (DLTs) were evaluated during weeks 1-6. Efficacy was a secondary objective.
  
  
  RESULTS
  Thirty-seven patients were enrolled. The 37.5 mg/day Schedule 4/2 cohort had zero of six DLTs, was expanded by 15 patients and declared the MTD. The MTD was exceeded at all other sunitinib doses and schedules; DLTs included febrile neutropenia (n=1), grade 4 neutropenia (n=4) and grade 3 deep vein thrombosis with grade 4 neutropenia (n=1). At the MTD, non-haematologic grade 3/4 adverse events with a frequency of >10% were diarrhoea, vomiting and lethargy, and the objective response rate was 57.9% (95% confidence interval 33.5-79.7).
  
  
  CONCLUSIONS
  The MTD of sunitinib combined with FOLFIRI in chemotherapy-naive mCRC was 37.5 mg/day on Schedule 4/2. CDD of sunitinib at 37.5 or 25 mg/day plus FOLFIRI was not feasible.
authors: Department of Medicine, Royal Marsden Hospital, NHS Foundation Trust, London and Sutton, UK.
authors: N
authors: N
authors: Starling
authors: Medical Oncology Department, Elche University Hospital, Elche.
authors: F
authors: F
authors: Vázquez-Mazón
authors: Department of Medicine, Royal Marsden Hospital, NHS Foundation Trust, London and Sutton, UK. Electronic address: david.cunningham@rmh.nhs.uk.
authors: D
authors: D
authors: Cunningham
authors: Department of Medicine, Royal Marsden Hospital, NHS Foundation Trust, London and Sutton, UK.
authors: I
authors: I
authors: Chau
authors: Department of Medical Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: J
authors: J
authors: Tabernero
authors: Department of Medical Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: F J
authors: FJ
authors: Ramos
authors: Department of Medical Oncology, Southampton Oncology Centre, Southampton General Hospital, Southampton.
authors: T J
authors: TJ
authors: Iveson
authors: Department of Radiotherapy and Clinical Oncology, Christie Hospital, Manchester, UK.
authors: M P
authors: MP
authors: Saunders
authors: Department of Medical Oncology, Hospital Universitario Reina Sofia, Cordoba, Spain.
authors: E
authors: E
authors: Aranda
authors: Pfizer Oncology, Clinical Development.
authors: A M
authors: AM
authors: Countouriotis
authors: Pfizer Oncology, Clinical Pharmacology.
authors: A
authors: A
authors: Ruiz-Garcia
authors: Pfizer Oncology, Oncology Statistics, La Jolla, USA.
authors: G
authors: G
authors: Wei
authors: Pfizer Italia Srl, Clinical Development Oncology, Milan, Italy.
authors: J M
authors: JM
authors: Tursi
authors: Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, Spain.
authors: C
authors: C
authors: Guillen-Ponce
authors: Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, Spain.
authors: A
authors: A
authors: Carrato
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; 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; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D002955:Leucovorin; D005472:Fluorouracil; D000077210:Sunitinib; D002166:Camptothecin