Author of

• 11826

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  P2.14 - Poster Session 2 - Mesothelioma (ID 196)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Mesothelioma
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11829

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    P2.14-003 - Phase I and pharmacokinetic study of amatuximab, a novel chimeric antibody to mesothelin, in patients with advanced solid tumors (ID 1209)

    09:30 - 09:30  |  Author(s): T. Kurata
    • Abstract

    Background
    Amatuximab is a chimeric monoclonal antibody to mesothelin. Mesothelin, a membrane protein, is a potential target for molecular targeted therapy due to its high expressions in virtually all pancreatic cancers and mesotheliomas as well as several cancers, while showing little expression in normal tissues, except for normal mesothelium. Amatuximab inhibits the growth of mesothelin-expressing human tumors in vitro and in vivo xenograft model.

    Methods
    To investigate dose-limiting toxicities (DLTs) and estimate the maximum tolerated dose (MTD) of amatuximab in Japanese patients with advanced solid tumors. In addition, pharmacokinetics of amatuximab, human anti-chimeric antibody (HACA) and mesothelin expression by immunohistochemistry (IHC) were investigated. Patients with pancreatic cancers, mesotheliomas, or mesothelin-positive solid tumors as assessed by the IHC test, who have no other appropriate treatment were eligible in the study. Amatuximab was administered weekly until disease progression or occurrence of a DLT, and administered to 3 cohorts at 50, 100 and 200 mg/m[2] in a step-wise dose escalation manner. The pharmacokinetic parameters were calculated by model independent analysis and the dose proportionality was investigated on Cmax and AUC (0-t) values.

    Results
    58 patients were screened and a total of 17 patients were enrolled consisting of seven colorectal cancer, six pancreatic adenocarcinoma, two mesothelioma and two head and neck cancer (seven patients in 50 mg/m[2], three in 100 mg/m[2] and seven in 200 mg/m[2], respectively). Two DLTs were observed (grade 3 cytokine release syndrome in 50 mg/m[2] and grade 5 interstitial lung disease in 200 mg/m[2]). Treatment related adverse events were observed in 13 of 17 patients, and the most common events were grade 1 fatigue (five patients) and pyrexia (four patients). Amatuximab was eliminated from serum biphasically after reached Cmax. Estimated mean T1/2 on Cycle 1 Day 1 was 92.3 to 108 h and CL was 11.7 to 15.2 mL/h/m[2]. It was found that the Cmax and AUC (0-t) values on Cycle 1 Day 1 increased in an almost dose proportional manner and these were similar to those in US patients. HACA was detected in eight of 17 patients. Of 53 patients whose tissue samples were evaluated by IHC, 24 patients (45.3%) were mesothelin-positive (10 of 19 patients in colorectal cancer, four of eight in biliary cancer, four of five in pancreatic adenocarcinoma and six of 21 in other cancers).

    Conclusion
    Amatuximab was well tolerated in patients with advanced solid tumors, and MTD was not reached up to 200 mg/m[2]. Pharmacokinetic profile of amatuximab in Japanese patients was similar to that in US patients. Amatuximab is currently being investigated for its potential treatment of mesothelioma.