A phase II study evaluating the efficacy and safety of AMG 102 (rilotumumab) in patients with recurrent glioblastoma

Center for Neuro-Oncology, Dana Farber/Brigham and Women's Cancer Center, Shields Warren 430 D, Boston, MA 02115, USA.
Neuro-Oncology (Impact Factor: 5.56). 02/2011; 13(4):437-46. DOI: 10.1093/neuonc/noq198
Source: PubMed

ABSTRACT This phase II study evaluated the efficacy and safety of AMG 102 (rilotumumab), a fully human monoclonal antibody against hepatocyte growth factor/scatter factor (HGF/SF), in patients with recurrent glioblastoma (GBM). Patients with histologically confirmed, measurable recurrent GBM or gliosarcoma (World Health Organization grade 4) and ≤3 relapses or prior systemic therapies received AMG 102 (10 or 20 mg/kg) by infusion every 2 weeks. The primary endpoint was best confirmed objective response rate (central assessment) per Macdonald criteria. Of the 61 patients who enrolled, 60 received AMG 102. Twenty-nine patients (48%) had previously received bevacizumab. There were no objective responses per central assessment, but 1 patient had an objective response per investigator assessment. Median overall survival (95% CI) in the 10- and 20-mg/kg cohorts was 6.5 months (4.1-9.8) and 5.4 months (3.4-11.4), respectively, and progression-free survival (PFS) per central assessment was 4.1 weeks (4.0-4.1) and 4.3 weeks (4.1-8.1), respectively. PFS was similar among patients who had previously received bevacizumab compared with bevacizumab-naive patients. The most common adverse events were fatigue (38%), headache (33%), and peripheral edema (23%). AMG 102 serum concentrations increased approximately dose-proportionally with 2-fold accumulation at steady state. Plasma total HGF/SF and soluble c-Met concentrations increased 12.05- and 1.12-fold, respectively, from baseline during AMG 102 treatment. AMG 102 monotherapy at doses up to 20 mg/kg was not associated with significant antitumor activity in heavily pretreated patients with recurrent GBM.

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Available from: Michael Wolf, Sep 28, 2015
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    • "Prior bevacizumab treatment had no effect on the study endpoints. Fatigue (38%), headache (33%), and peripheral edema (23%) were the most common side effects.76 "
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    ABSTRACT: MET is located on chromosome 7q31 and is a proto-oncogene that encodes for hepatocyte growth factor (HGF) receptor, a member of the receptor tyrosine kinase (RTK) family. HGF, also known as scatter factor (SF), is the only known ligand for MET. MET is a master regulator of cell growth and division (mitogenesis), mobility (motogenesis), and differentiation (morphogenesis); it plays an important role in normal development and tissue regeneration. The HGF-MET axis is frequently dysregulated in cancer by MET gene amplification, translocation, and mutation, or by MET or HGF protein overexpression. MET dysregulation is associated with an increased propensity for metastatic disease and poor overall prognosis across multiple tumor types. Targeting the dysregulated HGF-MET pathway is an area of active research; a number of monoclonal antibodies to HGF and MET, as well as small molecule inhibitors of MET, are under development. This review summarizes the key biological features of the HGF-MET axis, its dysregulation in cancer, and the therapeutic agents targeting the HGF-MET axis, which are in development.
    OncoTargets and Therapy 06/2014; 7:969-83. DOI:10.2147/OTT.S40241 · 2.31 Impact Factor
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    • "Inhibition of MET, a frequently overexpressed receptor in GBMs, is also currently under evaluation in clinical trials [40]. Unfortunately, a phase II trial using an anti-MET antibody , AMG102, demonstrated no significant antitumor activity in patients with recurrent GBMs [41]. Overall, these therapeutic approaches have yielded at best marginally positive results and TMZ, the hallmark chemotherapeutic agent routinely used to treat GBMs, remains the primary therapeutic alternative. "
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    • "Although the effects of NK4 on antimyeloma immunity were not investigated, this study clearly indicates that molecular targeting of HGF by NK4 may prove beneficial in MM. Amgen has recently reported the generation of fully human monoclonal antibodies against HGF that exhibit therapeutic potential in mice bearing subcutaneous xenografts of human glioma cell lines with an HGF-dependent autocrine loop [27, 83, 84]. In particular, AMG102 (rilotumumab; Amgen) is a fully human neutralizing mAb against HGF and is currently under evaluation in patients with advanced solid tumors, both as monotherapy and in combination with other agents [83, 84]. "
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