Lomustine monotherapy has been used as a comparator arm but there have been no trials comparing it to best supportive care (BSC).
In a phase III, randomised, multicentre international open-label study trial involving 266 patients comparing the efficacy of enzastaurin with lomustine alone in patients with recurrent intracranial glioblastoma (WHO grade 4).r
Between March 2006 and August 2007, 174 patients were enrolled to receive enzastaurin (500 mg/d with 1,125 mg loading dose, day 1) and 92 patients were randomised to receive lomustine (100-130 mg/m2 day 1 every 6 weeks).
The primary end point was progression free survival and secondary end points were overall survival, objective response, safety, and patient-reported outcomes.r
Enzastaurin was well tolerated and had a better haematological toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma.
Another study, the REGAL trial (Recentin®/Cediranib in Glioblastoma Alone and with Lomustine) was a randomised phase III, placebo-controlled, partially blinded clinical trial conducted to determine the efficacy of cediranib (VEGF inhibitor) either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma. 325 patients were randomised 2:2:1 to (1) cediranib 30 mg, (2) cediranib 20 mg plus lomustine 110 mg/m2, or (3) lomustine 110 mg/m2 plus placebo.r
The primary endpoint was progression free survival which was not statistically different for either cediranib-containing arm versus lomustine on review of postcontrast T1-weighted MRI.r
The median follow-up time for surviving patients was 8.7 months. After a planned interim analysis for futility was set after enrolment of 266 patients, the median PFS was not statistically different with 1.5 months in enzastaurin vs 1.6 months in the lomustine group (HR=1.28; 95% CI, 0.97 to 1.70 ; p=0.08). The 6 month PFS rate was 11.1% for enzastaurin and 19% for lomustine (p=0.13). The median OS was also not statistically significant (6.6 versus 7.1 months, HR=1.2, 95% CI 0.88 to 1.65; p=0.25).r
(A) Progression-free survival and (B) Overall survival by treatment arm for the intent-to-treat populationr
© Journal of Clinical Oncology 2010
Patients with a high KPS (90 to 100) had better PFS (2.8 vs 1.5, p=0.02) and longer OS (10.3 vs 7.4 months, p=0.20). There was no significant difference in objective response rates (2.9 vs 4.3%).
Time to deterioration of physical and functional well-being and symptoms did not differ between arms (HR 1.12, p=0.54). 91.4% of patients on enzastaurin and 89.1% on lomustine participated in the time to deterioration analysis (using the Functional Assessment of Cancer Therapy-Brain questionnaire) and there was no statistical difference between the arms with a 6-month deterioration rate of 18% vs 29% (HR = 1.12, 95% CI, 0.77 to 1.63; p=0.54).
The REGAL trial
The median PFS for cediranib 30 mg, cediranib 20 mg plus lomustine, and lomustine arm was 92 days, 125 days, and 82 days respectively.r
© Journal of Clinical Oncology 2013
There were eleven patients (6.6%) on enzastaurin and four patients (4.8%) on lomustine who died from treatment. Four of the eleven deaths on enzastaurin were related to AEs and one related to a drug-related cerebral haemorrhage. All four deaths on lomustine were related to disease progression. Twelve patients discontinued enzastaurin because of adverse events and four patients discontinued lomustine. There was no significant difference in the incidence of serious AEs between the arms except for neutropaenia, thrombocytopaenia, and leukopenia which occurred in significantly fewer patients on enzastaurin.r
© Journal of Clinical Oncology 2010