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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

Stephen Leong, Roger B Cohen, Daniel L Gustafson, Corey J Langer, D Ross Camidge, Kristin Padavic, Lia Gore, Margaret Smith, Laura Q Chow, Margaret von Mehren, Cindy O'Bryant, Sujatha Hariharan, Sami Diab, Norma Lynn Fox, Renée Miceli, S Gail Eckhardt
Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2009 September 10, 27 (26): 4413-21

PURPOSE: 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.

PATIENTS AND 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.

CONCLUSION: 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.


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