title: Safety, pharmacokinetics, and pharmacodynamics of the DR5 antibody LBY135 alone and in combination with capecitabine in patients with advanced solid tumors.
abstract: OBJECTIVE
  We evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, biologic activity, and antitumor efficacy of the DR5 antibody, LBY135 ± capecitabine.
  
  
  METHODS
  Escalating LBY135 was administered every 21 days, alone (Arm1) or with capecitabine (Arm2), to patients with advanced solid tumors.
  
  
  RESULTS
  In Arm1 (n = 40), LBY135 (0.3-40 mg/kg) resulted in no dose-limiting toxicities (DLTs); adverse events (AEs) included fatigue, hypotension, abdominal pain, dyspnea, and nausea. Stable disease (SD) was observed in 21/38 (55.3 %) patients. In Arm2 (n = 33), LBY135 (1-40 mg/kg) plus capecitabine resulted in 3 DLTs (each grade 3): dehydration and mucosal inflammation (1 mg/kg), colitis (20 mg/kg), and diarrhea (40 mg/kg). AEs included fatigue, nausea, dyspnea, and vomiting. Partial response was observed in 2 patients (rectal and breast cancer) and SD in 12/27 (44.4 %) patients. Mean elimination half-life of LBY135 ± capecitabine at saturation of clearance (≥10 mg/kg) ranged between 146 h and 492 h. Immunogenicity was detected in 16/73 (22 %) patients, of which 6 patients experienced reduced LBY135 exposure with repeat dosing. M30/M65 levels were not predictive for LBY135 response. FDG-PET responses were not consistently associated with RECIST responses.
  
  
  CONCLUSIONS
  LBY135 was well tolerated up to 40 mg/kg, the maximal dose administered; no MTD for LBY135 ± capecitabine was defined. Clearance was saturated at doses ≥10 mg/kg.
authors.affiliation: Huntsman Cancer Institute, Division of Medical Oncology, University of Utah, 2000 Circle of Hope Drive, Suite 3380, Salt Lake City, UT, 84112, USA, Sunil.Sharma@hci.utah.edu.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.forename: Elisabeth G
authors.initials: EG
authors.lastname: de Vries
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Corina N
authors.initials: CN
authors.lastname: Oldenhuis
authors.forename: Jourik A
authors.initials: JA
authors.lastname: Gietema
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.forename: Sanela
authors.initials: S
authors.lastname: Bilic
authors.forename: Katie
authors.initials: K
authors.lastname: Parker
authors.forename: Michael
authors.initials: M
authors.lastname: Goldbrunner
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Scott
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D000069287:Capecitabine; D003710:Demography; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D019788:Fluorodeoxyglucose F18; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D049268:Positron-Emission Tomography; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*
chemical_list: D000906:Antibodies; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; C000592141:LBY135 monoclonal antibody; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D003841:Deoxycytidine; D019788:Fluorodeoxyglucose F18; D000069287:Capecitabine; D005472:Fluorouracil