Phase I Study of Vandetanib With Radiotherapy and Temozolomide for Newly Diagnosed Glioblastoma

Center for Neuro-Oncology, Dana Farber/Brigham and Women's Cancer Center, Boston, MA 02115, USA.
International journal of radiation oncology, biology, physics (Impact Factor: 4.26). 02/2010; 78(1):85-90. DOI: 10.1016/j.ijrobp.2009.07.1741
Source: PubMed


Increasing evidence has suggested that angiogenesis inhibition might potentiate the effects of radiotherapy and chemotherapy in patients with glioblastoma (GBM). In addition, epidermal growth factor receptor inhibition might be of therapeutic benefit, because the epidermal growth factor receptor is upregulated in GBM and contributes to radiation resistance. We conducted a Phase I study of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, in patients with newly diagnosed GBM combined with RT and temozolomide (TMZ).
A total of 13 GBM patients were treated with vandetanib, radiotherapy, and concurrent and adjuvant TMZ, using a standard "3 + 3" dose escalation. The maximal tolerated dose was defined as the dose with <1 of 6 dose-limiting toxicities during the first 12 weeks of therapy. The eligible patients were adults with newly diagnosed GBM, Karnofsky performance status of >or=60, normal organ function, who were not taking enzyme-inducing antiepileptic drugs.
Of the 13 patients, 6 were treated with vandetanib at a dose of 200mg daily. Of the 6 patients, 3 developed dose-limiting toxicities within the first 12 weeks, including gastrointestinal hemorrhage and thrombocytopenia in 1 patient, neutropenia in 1 patient, and diverticulitis with gastrointestinal perforation in 1 patient. The other 7 patients were treated with 100 mg daily, with no dose-limiting toxicities observed, establishing this dose as the maximal tolerated dose combined with TMZ and RT.
Vandetanib can be safely combined with RT and TMZ in GBM patients. A Phase II study in which patients are randomized to vandetanib 100 mg daily with RT and TMZ or RT and TMZ alone is underway.

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Available from: Stephanie Elizabeth Weiss, Feb 21, 2015
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    • "Following completion of a Phase I study of vandetanib, radiotherapy, and temozolomide in patients with newly diagnosed GBM, it was concluded that this inhibitor can be safely combined with radiotherapy. A Phase II study in which patients were randomized to receive vandetanib (100 mg) daily with radiotherapy and temozolomide or radiotherapy and temozolomide alone is currently underway [71]. "
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    ABSTRACT: Glioblastoma is a deadly brain disease and modest improvement in survival has been made. At initial diagnosis, treatment consists of maximum safe surgical resection, followed by temozolomide and chemoirradiation or adjuvant temozolomide alone. However, these treatments do not improve the prognosis and survival of patients. New treatment strategies are being sought according to the biology of tumors. The epidermal growth factor receptor has been considered as the hallmark in glioma tumors; thereby, some antibodies have been designed to bind to this receptor and block the downstream signaling pathways. Also, it is known that vascularization plays an important role in supplying new vessels to the tumor; therefore, new therapy has been guided to inhibit angiogenic growth factors in order to limit tumor growth. An innovative strategy in the treatment of glial tumors is the use of toxins produced by bacteria, which may be coupled to specific carrier-ligands and used for tumoral targeting. These carrier-ligands provide tumor-selective properties by the recognition of a cell-surface receptor on the tumor cells and promote their binding of the toxin-carrier complex prior to entry into the cell. Here, we reviewed some strategies to improve the management and treatment of glioblastoma and focused on the use of antibodies.
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    • "Recent reports suggest that directly targeting angiogenesis might increase the therapeutic ratio when being combined with irradiation (Beal et al. 2011). In accordance, the monoclonal antibody bevacizumab , which blocks angiogenesis by preventing the binding of VEGF to its respective receptor (Willett et al. 2004), significantly improves clinical outcome when combined with radiotherapy (Velenik et al. 2011; Shin et al. 2011; Niyazi et al. 2012a), and similar results were obtained for the VEGF-R inhibitor vandetanib and, primarily , for the antiangiogenetic peptide cilengitide (Albert et al. 2006; Williams et al. 2004; Brazelle et al. 2006; Drappatz et al. 2010; Yang et al. 2010). However, a recent phase III trial on cilengitide in combination with radiochemotherapy failed to show a significant increase in overall survival in glioblastoma patients. "
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    • "Based on this preclinical evidence, few Phase I studies have investigated the combination of vandetanib with RT in both newly diagnosed and recurrent gliomas (Table 1). Drappatz et al65 enrolled 13 patients with newly diagnosed GBM into a Phase I trial testing the combination of vandetanib with standard RT and TMZ. In the initial cohort, six patients were treated with vandetanib at 200 mg/day. "
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