MONTREAL – The novel tyrosine kinase inhibitor cediranib performed short of expectations in REGAL, a randomized, parallel-group, multicenter phase III study in patients with recurrent glioblastoma.

Whether paired with lomustine or given as monotherapy, cediranib (Recentin) failed to improve progression-free survival, the study’s primary end point, or overall survival, a secondary end point, in comparisons with lomustine plus placebo.

"Our initial study was a 45-mg-per-day dose, and there is a dose-response curve with this agent," said Dr. Tracy T. Batchelor, who reported the findings at the annual meeting of the Society for Neuro-Oncology. "If there’s one thing I could go back and do [with this study], I might start with a higher dose."

The study randomized 325 patients with recurrent glioblastoma on a 2:2:1 ratio to three all-oral regimens: cediranib monotherapy, 30 mg/day (131 patients); a combination of cediranib, 20 mg/day, and lomustine, 110 mg/m2 once every 6 weeks (129 patients); or a control group of lomustine at the same dose and a cediranib-matched placebo, 20 mg/day (65 patients).

Participants came from 10 countries and had to have at least one prior regimen containing temozolomide (Temodar), but no prior treatment with an agent inhibiting vascular endothelial growth factor (VEGF) signaling.

Progression-free survival was determined by a centralized, independent review by a radiologist who was blinded to treatment status. For this outcome, the study found no statistically significant advantage of cediranib monotherapy (median, 92 days; P = .889) or combination therapy (median, 125 days; P = .162) compared with controls (median, 82 days).

"Although the trend was in the right direction, the P values were not statistically significant," said Dr. Batchelor, executive director of the Stephen E. and Catherine Pappas Center for Neuro-Oncology at Massachusetts General Hospital, Boston. "There is a suggestion of an early separation of the curves by about 3 months, but then they begin converging, and eventually cross over."

Similarly, there was no statistical difference between groups for overall survival, which ranged from 8 to 9.8 months, he said.

Two other secondary end points, steroid use and time to neurologic decline, did favor cediranib, either alone or in combination, reported Dr. Batchelor. There was a statistically significant reduction in steroid use in the cediranib monotherapy group (P = .006) and in the combination arm (P = .012) compared with controls. And time to neurologic decline was significantly prolonged in the combination therapy group compared with controls (P = .009).

Cediranib fell short, however, on the APF6 (the proportion of patients alive and progression free at 6 months), with a rate of 16%, vs. 34.5% in the combination group and 24.5% in the control group. Dr. Batchelor’s previously published, nonrandomized, noncontrolled study of cediranib monotherapy in a similar patient population reported a much higher APF6 of 25.8% (J. Clin. Oncol. 2010;28:2817-23).

"I think the dosing in that study – 45mg compared with 30 mg – is a contributing factor to this difference," he said in an interview.

Cediranib is an oral, pan-VEGF receptor tyrosine kinase inhibitor (TKI), and "the concern with TKIs is that the toxicities you see with this classic drug may compromise dose intensity or the agent or of chemotherapy combined with it," explained Dr. Batchelor. Trial sponsor AstraZeneca recommended the lower dose, he explained.

Adverse events occurred at a similar rate across all arms, 60.9% with monotherapy, 79.7% with combination therapy, and 60.9% with controls. The profile of toxicities with cediranib was consistent with what has been previously reported and included fatigue (16.4%), hypertension (14.1%), and diarrhea (6.3%). However, of note, was that "there was no compromise of cediranib dose intensity based on toxicity," he said. "In fact the cediranib dose intensity was maintained in 95% of patients, while in those who received more than one dose of lomustine, about half had a reduction in dose in the control arm, and 70% required some reduction in the combination arm."

When asked to comment on the findings, Dr. Kenneth D. Aldape, conference chair, said, "It is a negative study and these initial results were somewhat disappointing; however I don’t think we want to throw in the towel for this particular drug." "Higher doses could be considered, and I think in current and future trials, [investigators] will be using higher doses in the hopes of increasing efficacy of this agent," said Dr. Aldape, professor of pathology at the University of Texas M.D. Anderson Cancer Center in Houston.

Dr. Aldape also noted that the trial enrolled patients with recurrent glioblastoma for whom previous treatments had failed. "Newer trials will look at newly diagnosed patients who are treatment naive. So it’s possible that a drug that doesn’t work in recurrent disease might have some efficacy in newly diagnosed patients, especially if the dose is increased."

Dr. Batchelor has received research funding and honoraria from AstraZeneca, which sponsored the trial and is developing cediranib.

Cediranib Falls Short in Phase III Glioblastoma Trial