Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma.

PURPOSE To evaluate single-agent activity of bevacizumab in patients with recurrent glioblastoma. PATIENTS AND METHODS Patients with recurrent glioblastoma were treated with bevacizumab 10 mg/kg every 2 weeks. After tumor progression, patients were immediately treated with bevacizumab in combination with irinotecan 340 mg/m(2) or 125 mg/m(2) every 2 weeks, depending on use of enzyme-inducing antiepileptic drugs. Complete patient evaluations were repeated every 4 weeks. RESULTS Forty-eight heavily pretreated patients were accrued to this study. Thromboembolic events (12.5%), hypertension (12.5%), hypophosphatemia (6%), and thrombocytopenia (6%) were the most common drug-associated adverse events. Six patients (12.5%) were removed from study for drug-associated toxicity (five thromboembolic events, one bowel perforation). Thirty-four patients (71%) and 17 patients (35%) achieved radiographic response based on Levin and Macdonald criteria, respectively. Median progression-free survival (PFS) was 16 weeks (95% CI, 12 to 26 weeks). The 6-month PFS was 29% (95% CI, 18% to 48%). The 6-month overall survival was 57% (95% CI, 44% to 75%). Median overall survival was 31 weeks (95% CI, 21 to 54 weeks). Early magnetic resonance imaging response (first 96 hours and 4 weeks) was predictive of long-term PFS, with the Levin criteria being more predictive than Macdonald criteria. Of 19 patients treated with bevacizumab plus irinotecan at progression, there were no objective radiographic responses. Eighteen patients (95%) experienced disease progression by the second cycle, and the median PFS was 30 days. CONCLUSION We conclude that single-agent bevacizumab has significant biologic and antiglioma activity in patients with recurrent glioblastoma.

[1]  Timothy F Cloughesy,et al.  Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. , 2008, Neuro-oncology.

[2]  John Sampson,et al.  Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  Darell D. Bigner,et al.  Phase II Trial of Bevacizumab and Irinotecan in Recurrent Malignant Glioma , 2007, Clinical Cancer Research.

[4]  J. Buckner,et al.  The relationship between six-month progression-free survival and 12-month overall survival end points for phase II trials in patients with glioblastoma multiforme. , 2007, Neuro-oncology.

[5]  J. Delattre,et al.  Glioma in the elderly , 2006, Current opinion in oncology.

[6]  Susan M. Chang,et al.  A phase 2 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study. , 2006, Neuro-oncology.

[7]  M. van Glabbeke,et al.  RECIST vs. WHO: prospective comparison of response criteria in an EORTC phase II clinical trial investigating ET-743 in advanced soft tissue sarcoma. , 2005, European journal of cancer.

[8]  J. Berlin,et al.  Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  C. Kerr Bevacizumab and chemotherapy improves survival in NSCLC. , 2005, The Lancet. Oncology.

[10]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[11]  Susan M. Chang,et al.  Prognostic factors for survival of patients with glioblastoma: recursive partitioning analysis. , 2004, Neuro-oncology.

[12]  W. Welch,et al.  Monoclonal Antibodies to Vascular Endothelial Growth Factor (VEGF) And the VEGF Receptor, FLT-1, Inhibit the Growth of C6 Glioma in a Mouse Xenograft , 2001, Journal of Neuro-Oncology.

[13]  T. Mikkelsen,et al.  Phase 2 study of weekly irinotecan in adults with recurrent malignant glioma: final report of NABTT 97-11. , 2004, Neuro-oncology.

[14]  Jan C Buckner,et al.  Factors influencing survival in high-grade gliomas. , 2003, Seminars in oncology.

[15]  Young Suk Park,et al.  Measuring response in solid tumors: comparison of RECIST and WHO response criteria. , 2003, Japanese journal of clinical oncology.

[16]  M J Gleason,et al.  Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  J. Takahashi,et al.  Correlation of basic fibroblast growth factor expression levels with the degree of malignancy and vascularity in human gliomas. , 1992, Journal of neurosurgery.

[18]  S. Naber,et al.  Expression of angiogenic growth factor genes in primary human astrocytomas may contribute to their growth and progression. , 1991, Cancer research.

[19]  T. Cascino,et al.  Response criteria for phase II studies of supratentorial malignant glioma. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  D. Norman,et al.  Criteria for evaluating patients undergoing chemotherapy for malignant brain tumors. , 1977, Journal of neurosurgery.