Background: Glioblastoma, the most common primary brain tumor in adults, universally recurs with dismal prognosis. Treatment of recurrent disease with second-line chemotherapy has limited impact on progression-free and overall survival. To date, clinical trials with newly developed protein kinase inhibitors (PKIs) failed to demonstrate efficacy in glioblastoma despite the fact that essential signaling pathways responsible for tumor growth of glioblastoma are targeted by these agents. One of the main reasons hypothesized for this failure is due to the blood-brain barrier, which may prevent adequate drug accumulation in the tumor. However, in a pilot study we demonstrated that tumor concentrations of sunitinib, a multi-receptor PKI, in patients with newly-diagnosed glioblastoma are within the range of tumor concentrations measured in metastases from patients with other solid malignancies, such as colorectal cancer (NCT02239952, unpublished results). These data indicate that alternative resistance mechanisms are responsible for resistance to PKIs in glioblastoma. In addition, we demonstrated in a phase I/II study that an alternative schedule of high-dose, intermittent sunitinib, aiming at high intratumoral peak concentrations, was feasible and safe in patients with refractory solid tumors (Rovithi M, et al.J Clin Oncol 2018). Promising antitumor activity in these heavily pre-treated patients with cancer was observed, indicating that drug resistance can be overcome by an alternative, chemotherapy-like schedule of intermittent and high-dosed sunitinib, administered once weekly or once every two weeks. Based on these findings we initiated a randomized, phase II/III clinical trial with high-dose, intermittent sunitinib designed to achieve adequate tumor concentrations in patients with glioblastoma, aiming for significant clinical benefit compared to standard treatment with lomustine. Methods: Adult patients with unequivocal first progression of or secondary glioblastoma after first-line treatment are included in this randomized, phase II/III, multi-center, open-label clinical trial. The primary endpoint of this study is the six-month progression-free survival of treatment with high-dose sunitinib versus treatment with lomustine. Hundred patients will be randomized to receive either sunitinib 300 mg, administered orally once every week or lomustine 110 mg/m², administered orally on day 1 every 6 weeks. Response evaluation will be assessed by MRI according to a uniform neuro-oncology protocol every 6 weeks for the first 6 months, and every 12 weeks until documented progression. Secondary endpoints include safety and quality of life assessments. Lastly, an interim analysis for futility will be performed after inclusion of 25% of the patients. As of January 2019, 9% of the planned patients have been enrolled. Clinical trial information: NCT03025893. Citation Format: Cyrillo G. Brahm, Myra E. van Linde, Mariette Labots, Mathilde C. Kouwenhoven, Esther Sanchez Aliaga, Roelien H. Enting, Auke P. Appelman, Janine Nuver, Annemiek M. Walenkamp, Henk M. Verheul. A Phase II/III trial of high-dose, intermittent sunitinib in patients with recurrent glioblastoma: The STELLAR study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT117.
|Publication status||Published - 2019|
|Event||Annual meeting of the American Academy of Cancer Research - Atlanta, United States|
Duration: 29 Mar 2019 → 3 Apr 2019
|Conference||Annual meeting of the American Academy of Cancer Research|
|Period||29/03/2019 → 03/04/2019|