A Phase Ii/Iii Trial Of High-Dose, Intermittent Sunitinib In Patients With Recurrent Glioblastoma: The Stellar Study

Background Glioblastoma, the most common primary brain tumour in adults, universally recurs with dismal prognosis. To date, clinical trials with protein kinase inhibitors (PKIs) failed to demonstrate efficacy in glioblastoma, possibly due to the blood-brain barrier, which may prevent adequate drug accumulation in the tumour. However, in a pilot study we demonstrated that tumour concentrations of sunitinib, a multi-receptor PKI, in patients with newly-diagnosed glioblastoma are within the range of tumour concentrations measured in metastases from patients with other solid tumours (NCT02239952). 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, safe and showed promising antitumor activity in patients with refractory solid tumours (JCO; PMID 30586316). These results indicate 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. Therefore, we initiated a randomized, phase II/III clinical trial with high-dose, intermittent sunitinib designed to achieve adequate tumour concentrations in patients with glioblastoma, aiming for significant clinical benefit compared to treatment with lomustine. Trial design Adult patients with first progression of de novo or secondary glioblastoma after first-line treatment are included in this randomized, phase II/III, multi-centre, open-label clinical trial. The primary endpoint is the six-month progression-free survival of treatment with high-dose sunitinib versus 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 every 6 weeks for the first 6 months, and every 12 weeks until documented progression. Secondary endpoints include safety and quality of life assessments. An interim analysis will be performed after inclusion of 25 patients. As of May 2019, 16 patients have been enrolled. Clinical trial identification NCT03025893. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure M. Labots: Advisory / Consultancy: Bristol-Myers Squibb. A.M.E. Walenkamp: Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Ipsen. H.M.W. Verheul: Advisory / Consultancy, Research grant / Funding (self): Roche; Advisory / Consultancy, Research grant / Funding (self): Glycostem; Research grant / Funding (self): Immunovo. All other authors have declared no conflicts of interest.