title: Safety and pharmacokinetics of motesanib in combination with gemcitabine and erlotinib for the treatment of solid tumors: a phase 1b study.
abstract: BACKGROUND
  This phase 1b study assessed the maximum tolerated dose (MTD), safety, and pharmacokinetics of motesanib (a small-molecule antagonist of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) administered once daily (QD) or twice daily (BID) in combination with erlotinib and gemcitabine in patients with solid tumors.
  
  
  METHODS
  Patients received weekly intravenous gemcitabine (1000 mg/m2) and erlotinib (100 mg QD) alone (control cohort) or in combination with motesanib (50 mg QD, 75 mg BID, 125 mg QD, or 100 mg QD; cohorts 1-4); or erlotinib (150 mg QD) in combination with motesanib (100 or 125 mg QD; cohorts 5 and 6).
  
  
  RESULTS
  Fifty-six patients were enrolled and received protocol-specified treatment. Dose-limiting toxicities occurred in 11 patients in cohorts 1 (n = 2), 2 (n = 4), 3 (n = 3), and 6 (n = 2). The MTD of motesanib in combination with gemcitabine and erlotinib was 100 mg QD. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. Frequently occurring motesanib-related adverse events included diarrhea (n = 19), nausea (n = 18), vomiting (n = 13), and fatigue (n = 12), which were mostly of worst grade < 3. The pharmacokinetics of motesanib was not markedly affected by coadministration of gemcitabine and erlotinib, or erlotinib alone. Erlotinib exposure, however, appeared lower after coadministration with gemcitabine and/or motesanib. Of 49 evaluable patients, 1 had a confirmed partial response and 26 had stable disease.
  
  
  CONCLUSIONS
  Treatment with motesanib 100 mg QD plus erlotinib and gemcitabine was tolerable. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01235416.
authors.affiliation: Adelaide Cancer Center, Level 1, Tennyson Centre, 520 South Road, Kurralta Park, SA 5037, Australia. dkotasek@adelaidecancercentre.com.au
authors.forename: Dusan
authors.initials: D
authors.lastname: Kotasek
authors.forename: Niall
authors.initials: N
authors.lastname: Tebbutt
authors.forename: Jayesh
authors.initials: J
authors.lastname: Desai
authors.forename: Stephen
authors.initials: S
authors.lastname: Welch
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.forename: Sheryl
authors.initials: S
authors.lastname: McCoy
authors.forename: Yu-Nien
authors.initials: YN
authors.lastname: Sun
authors.forename: Jessica
authors.initials: J
authors.lastname: Johnson
authors.forename: Adeboye H
authors.initials: AH
authors.lastname: Adewoye
authors.forename: Timothy
authors.initials: T
authors.lastname: Price
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009841:Oligonucleotides; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: D007211:Indoles; D009841:Oligonucleotides; D011799:Quinazolines; D003841:Deoxycytidine; D009536:Niacinamide; D000069347:Erlotinib Hydrochloride; C519562:imetelstat; D000093542:Gemcitabine