title: Preclinical and clinical activity of sunitinib in patients with cisplatin-refractory or multiply relapsed germ cell tumors: a Canadian Urologic Oncology Group/German Testicular Cancer Study Group cooperative study.
abstract: BACKGROUND
  The objective of the study was to investigate the activity of sunitinib in a cell line model and subsequently in patients with cisplatin-refractory or multiply relapsed germ cell tumors (GCT).
  
  
  METHODS
  The effect of sunitinib on cell proliferation in cisplatin-sensitive and cisplatin-refractory GCT cell lines was evaluated after 48-h sunitinib exposure by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, and IC(50) (concentration that causes 50% inhibition of growth) doses were determined. Sunitinib was subsequently administered at a dose of 50 mg/day for 4 weeks followed by a 2-week break to 33 patients using a Simon two-stage design.
  
  
  RESULTS
  Sunitinib demonstrated comparable dose-dependent growth inhibition in cisplatin-sensitive and cisplatin-resistant cell lines, with IC(50) between 3.0 and 3.8 μM. Patient characteristics were as follows: median of 2 (1-6) cisplatin-containing regimens; high-dose chemotherapy 67%; late relapse 33%; and cisplatin refractory or absolute cisplatin refractory 54%. Toxic effects included fatigue (39%), anorexia (21%), diarrhea (27%), mucositis (45%), nausea (33%), hand-foot syndrome (12%), dyspepsia (27%), and skin rash (18%). No unexpected side-effects were observed. Thirty -two of 33 patients were assessable for response. Three confirmed partial responses (PRs) and one unconfirmed PR were seen for a total response rate of 13%. Median progression-free survival (PFS) was 2 months, with a 6-month PFS rate of 11%.
  
  
  CONCLUSIONS
  Sunitinib shows in vitro activity in cisplatin-resistant GCT cell lines. Modest clinical activity in heavily pretreated GCT patients was observed.
authors.affiliation: Division of Oncology, Hematology, Bone Marrow Transplantation and Section Pneumology, University Medical Centre Eppendorf, Hamburg University, Hamburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Oechsle
authors.affiliation: Division of Oncology, Hematology, Bone Marrow Transplantation and Section Pneumology, University Medical Centre Eppendorf, Hamburg University, Hamburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Honecker
authors.affiliation: Department of Oncology, Tom Baker Cancer Centre, Calgary, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Department of Medical Oncology, Hematology, Rheumatology, Immunology and Pulmonology, University of Tuebingen, Tuebingen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Mayer
authors.affiliation: Department Medical Oncology/Haematology, CancerCare Manitoba, University of Manitoba, Winnipeg.
authors.forename: P
authors.initials: P
authors.lastname: Czaykowski
authors.affiliation: Division of Medical Oncology, London Health Science Centre, London.
authors.forename: E
authors.initials: E
authors.lastname: Winquist
authors.affiliation: Division of Medical Oncology, Queen Elizabeth II Health Sciences Centre, Halifax, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Wood
authors.affiliation: Department of Hematology/Hemostaseology/Oncology/Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Fenner
authors.affiliation: Division of Oncology, Hematology, Bone Marrow Transplantation and Section Pneumology, University Medical Centre Eppendorf, Hamburg University, Hamburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Glaesener
authors.affiliation: Department of Medical Oncology, Hematology, Rheumatology, Immunology and Pulmonology, University of Tuebingen, Tuebingen, Germany.
authors.forename: J T
authors.initials: JT
authors.lastname: Hartmann
authors.affiliation: Division of Medical Oncology, British Columbia Cancer Agency, University of British Columbia-Vancouver Cancer Centre, Vancouver, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Chi
authors.affiliation: Division of Oncology, Hematology, Bone Marrow Transplantation and Section Pneumology, University Medical Centre Eppendorf, Hamburg University, Hamburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Division of Medical Oncology, British Columbia Cancer Agency, University of British Columbia-Vancouver Cancer Centre, Vancouver, Canada. Electronic address: ckollmannsberger@bccancer.bc.ca.
authors.forename: C
authors.initials: C
authors.lastname: Kollmannsberger
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D018572:Disease-Free Survival; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000401:mortality; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D000077210:Sunitinib; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D002945:Cisplatin; D000077210:Sunitinib