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

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.

Figures

Fig. 1.

Progression-free survival (PFS) per central assessment (A) and overall survival (B). Tumor assessments that were taken after initiation of any non–AMG 102 antitumor therapy, tumor resection, or first tumor progression were excluded from PFS. All deaths were included. PFS was defined as the time in weeks from the first dose of AMG 102 to first progression by Macdonald criteria or death from any cause, whichever occurred first. Patients who did not progress or die were censored at the last evaluable radiograph. If a patient had no evaluable postbaseline radiograph and did not die, then the patient was censored at day 1.

Fig. 2.

Analysis of hepatocyte growth factor/scatter factor (HGF/SF) and c-Met as biomarkers. Plasma log total HGF/SF (A) and soluble c-Met (B) concentrations from week 1 until the end of treatment (EOT). (C) Representative images of high (maximum intensity scale of 3) versus low (maximum intensity scale of 1) cytoplasmic c-Met expression assessed by immunohistochemistry staining of patient archival tumor samples.