title: Efficacy and safety of motesanib, an oral inhibitor of VEGF, PDGF, and Kit receptors, in patients with imatinib-resistant gastrointestinal stromal tumors.
abstract: OBJECTIVE
  This multicenter phase 2 study assessed the tolerability and efficacy of motesanib, an oral inhibitor of Kit, platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptors (VEGFR), in patients with imatinib-resistant gastrointestinal stromal tumors (GIST).
  
  
  METHODS
  Patients with advanced GIST who failed imatinib mesylate after ≥8 weeks of treatment with ≥600 mg daily received motesanib 125 mg orally once daily continuously for 48 weeks or until unacceptable toxicity or disease progression occurred. The primary endpoint was confirmed objective tumor response per RECIST and independent review. Secondary endpoints included progression-free survival (PFS), time to progression (TTP); objective response by (18)FDG-PET and by changes in tumor size and/or density (Choi criteria); pharmacokinetics and safety.
  
  
  RESULTS
  In the patients evaluable for response (N = 102), the objective response rate was 3%; 59% of patients achieved stable disease, with 14% achieving durable stable disease ≥24 weeks; 38% had disease progression. Higher objective response rates were observed per (18)FDG-PET (N = 91) (30%) and Choi criteria (41%). The median PFS was 16 weeks (95% CI = 14-24 weeks); the median TTP was 17 weeks (95% CI = 15-24 weeks). The most common motesanib treatment-related grade 3 adverse events included hypertension (23%), fatigue (9%), and diarrhea (5%). Motesanib did not accumulate with daily dosing.
  
  
  CONCLUSIONS
  In this study of patients with imatinib-resistant GIST, motesanib treatment resulted in acceptable tolerability and modest tumor control as evident in the proportion of patients who achieved stable disease and durable stable disease.
authors.affiliation: Department of Sarcoma Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1400 Holcombe Blvd., Unit 450, Houston, TX 77030-4009, USA. rbenjami@mdanderson.org
authors.forename: Robert S
authors.initials: RS
authors.lastname: Benjamin
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Jörg Thomas
authors.initials: JT
authors.lastname: Hartmann
authors.forename: Allan
authors.initials: A
authors.lastname: Van Oosterom
authors.forename: Binh Nguyen
authors.initials: BN
authors.lastname: Bui
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.forename: Scott
authors.initials: S
authors.lastname: Schuetze
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.forename: Peter
authors.initials: P
authors.lastname: Reichardt
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.forename: Keith
authors.initials: K
authors.lastname: Skubitz
authors.forename: Sheryl
authors.initials: S
authors.lastname: McCoy
authors.forename: Yu-Nien
authors.initials: YN
authors.lastname: Sun
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Stepan
authors.forename: Laurence
authors.initials: L
authors.lastname: Baker
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D009841:Oligonucleotides; D010879:Piperazines / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D009841:Oligonucleotides; D010879:Piperazines; D011743:Pyrimidines; D009536:Niacinamide; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; C519562:imetelstat