Phase III Randomized Trial Comparing the Efficacy of Cediranib As Monotherapy, and in Combination With Lomustine, Versus Lomustine Alone in Patients With Recurrent Glioblastoma

Abstract

A B S T R A C T PurposeA randomized, phase III, placebo-controlled, partially blinded clinical trial (REGAL [Recentin in Glioblastoma Alone and With Lomustine]) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma. Patients and MethodsPatients (N ϭ 325) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 2:2:1 to receive (1) cediranib (30 mg) monotherapy; (2) cediranib (20 mg) plus lomustine (110 mg/m 2 ); (3) lomustine (110 mg/m 2 ) plus a placebo. The primary end point was progression-free survival based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted magnetic resonance imaging (MRI) brain scans. ResultsThe primary end point of progression-free survival (PFS) was not significantly different for either cediranib alone (hazard ratio [HR] ϭ 1.05; 95% CI, 0.74 to 1.50; two-sided P ϭ .90) or cediranib in combination with lomustine (HR ϭ 0.76; 95% CI, 0.53 to 1.08; two-sided P ϭ .16) versus lomustine based on independent or local review of postcontrast T1-weighted MRI. ConclusionThis study did not meet its primary end point of PFS prolongation with cediranib either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma, although cediranib showed evidence of clinical activity on some secondary end points including time to deterioration in neurologic status and corticosteroid-sparing effects.

EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma

“…44,45 The three strategies of medical treatment for glioblastoma recurring after TMZ/RT→TMZ most commonly used across Europe include nitrosourea-based regimens, alternative dosing regimens of TMZ, and bevacizumab. The activity of CCNU has been confirmed in the standard arms of randomized trials exploring the activity of the protein kinase C-β inhibitor, enzastaurin, 46 or the vascular endothelial growth factor (VEGF) receptor inhibitor, cediranib, 47 with progression-free survival rates at 6 months of 20%. Somewhat better control rates at 6 months have been reported with a continuous dosing regimen of TMZ, 48 but not in recent phase II trial exploring a 21 out of 28 days schedule.…”

Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation

“…Taken together, these observations suggest that anti-VEGF agents improve OS only in the subset of GBM patients who experience increased tumor perfusion and oxygenation and not in all patients. This finding may account for the failure of cediranib and bevacizumab to extend OS in randomized phase III trials conducted in unselected nGBM and rGBM patient populations (9,43,44). We also identified tissue markers, as well as circulating blood proteins that may serve as biomarkers of changes in tumor perfusion and oxygenation during anti-VEGF therapy.…”

Therapeutic options in recurrent glioblastoma—An update

“…Notably, in the randomized studies, lomustine as monotherapy showed comparable results with the investigational agents enzastaurin, cediranib, galunisertib or bevacizumab [52][53][54][55], pointing towards relevant single agent activity of the "control" agent or lack of efficacy of the experimental agents The combination of lomustine plus bevacizumab showed prolonged median PFS and OS and higher PFS-6 than the single agents in the BELOB phase II trial [54]. However, the combination treatment at least with the higher dose of lomustine with 110 mg/m 2 exhibited more hematological toxicity leading to the dose reduction to 90 mg/m 2 when combined with bevacizumab.…”

“…Nitrosoureas [52][53][54][55][56] and 1 trial with carmustine where data for patients treated with carmustine (n=29) were not separately reported but summarized in a common "control" arm with 27 patients receiving TMZ [57]. All but 3 trials were conducted at the first recurrence after TMZ-based standard radiochemotherapy.…”

“…The subsequent phase III trial of cediranib showed comparable but not better efficacy than lomustine. Still, it is surprising that cediranib which is supposed to be similarily active as bevacizumab did not show superiority in combination with lomustine [52]. Further, the clinical development of a placental derived growth factor antibody was stopped early for presumed lack of activity [107].…”