Phase I study of vandetanib with radiotherapy and temozolomide for newly diagnosed glioblastoma.
ABSTRACT 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.
Article: Targeted therapy in gliomas.[Show abstract] [Hide abstract]
ABSTRACT: The survival outcome of patients with malignant gliomas is still poor, despite advances in surgical techniques, radiation therapy and the development of novel chemotherapeutic agents. The heterogeneity of molecular alterations in signaling pathways involved in the pathogenesis of these tumors contributes significantly to their resistance to treatment. Several molecular targets for therapy have been discovered over the last several years. Therapeutic agents targeting these signaling pathways may provide more effective treatments and may improve survival. This review summarizes the important molecular therapeutic targets and the outcome of published clinical trials involving targeted therapeutic agents in glioma patients.Current Oncology Reports 04/2014; 16(4):379. · 3.33 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Recent drug discovery developments in the field of small molecule targeted agents have led to much interest in combining these with radiotherapy. There are good preclinical data to suggest this approach worthy of investigation and in this review we discuss how this has translated into recent clinical trials. The outcome of clinical trials investigating radiotherapy/targeted drug combinations published in the last 5 years is discussed, as are trials in progress. The perceived future opportunities and challenges in the development of this exciting area are considered.Clinical Oncology 03/2014; · 2.86 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The discovery that malignant gliomas produce an excessive amount of VEGF, a key mediator of angiogenesis, has heightened interest in developing drugs that block angiogenic pathways. These antiangiogenic drugs tend to decrease vascular permeability, thereby diminishing tumor contrast enhancement independent of anti-tumor effects. This has made the determination of tumor response difficult, since contrast enhancement on post-contrast T1-weighted images is standard for assessing therapy effectiveness. In light of these unique challenges in assessing antiangiogenic therapy, new biomarkers have been proposed, based on advanced magnetic resonance techniques and PET. This article outlines the challenges associated with the evaluation of antiangiogenic therapy in malignant gliomas and describes how new imaging biomarkers can be used to better predict response.CNS oncology. 01/2013; 2(1):33-47.