title: Mapatumumab, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: results of a phase I and pharmacokinetic study.
abstract: OBJECTIVE
  A phase I study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor effect of mapatumumab, a fully-human agonist monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1, DR4), in combination with paclitaxel and carboplatin.
  
  
  METHODS
  Patients with advanced solid malignancies received 3, 10, or 20 mg/kg of mapatumumab with standard doses of paclitaxel and carboplatin every 21 days for up to six cycles in the absence of disease progression. Additional cycles of paclitaxel and/or mapatumumab were permissible in selected cases.
  
  
  RESULTS
  Twenty-seven patients (21 males), with a median age of 54 years, received mapatumumab in the following three cohorts: 3 mg/kg (n = 4), 10 mg/kg (n = 11), and 20 mg/kg (n = 12). The median number of cycles was four. Dose-limiting toxicities (DLTs) were grade 3 hypersensitivity reaction (n = 1) and neutropenic fever (n = 1), both at 10 mg/kg. Non-DLT treatment-related adverse events occurring in more than 10% of administered doses included alopecia, neutropenia, fatigue, nausea, anemia, thrombocytopenia, anorexia, and neuropathy. Paclitaxel and carboplatin exposures were similar in the presence or absence of mapatumumab. Plasma mapatumumab concentrations seemed similar to data from previous phase I monotherapy studies. Five patients (19%) achieved a confirmed radiologic partial response (including one pathologic complete response), and 12 patients (44%) had stable disease as their best response.
  
  
  CONCLUSIONS
  Mapatumumab is well-tolerated up to 20 mg/kg in combination with paclitaxel and carboplatin. There are no apparent pharmacokinetic interactions among the drugs. Preliminary anticancer activity demonstrated clinical benefit for the majority of these patients.
authors: Division of Medical Oncology, University of Colorado Health Sciences Center, 12801 E 17th Ave, Aurora, CO 80045, USA. stephen.leong@ucdenver.edu
authors: Stephen
authors: S
authors: Leong
authors: Roger B
authors: RB
authors: Cohen
authors: Daniel L
authors: DL
authors: Gustafson
authors: Corey J
authors: CJ
authors: Langer
authors: D Ross
authors: DR
authors: Camidge
authors: Kristin
authors: K
authors: Padavic
authors: Lia
authors: L
authors: Gore
authors: Margaret
authors: M
authors: Smith
authors: Laura Q
authors: LQ
authors: Chow
authors: Margaret
authors: M
authors: von Mehren
authors: Cindy
authors: C
authors: O'Bryant
authors: Sujatha
authors: S
authors: Hariharan
authors: Sami
authors: S
authors: Diab
authors: Norma Lynn
authors: NL
authors: Fox
authors: Renée
authors: R
authors: Miceli
authors: S Gail
authors: SG
authors: Eckhardt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000505:Alopecia / Q000139:chemically induced; D000740:Anemia / Q000139:chemically induced; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016190:Carboplatin; D017239:Paclitaxel; C507357:mapatumumab