External beam radiation therapy (XRT) with concomitant temozolomide and 6 cycles 
of adjuvant temozolomide (5/28-day schedule) improves survival in patients with 
newly diagnosed glioblastoma compared with XRT alone. Studies suggest that 
dose-dense temozolomide schedules and addition of cytostatic agents may further 
improve efficacy. This factorial design phase I/II protocol tested dose-dense 
temozolomide alone and combined with cytostatic agents. Patients with newly 
diagnosed glioblastoma received fractionated XRT to 60 Gy concomitant with 
temozolomide (75 mg/m²)/day for 42 days). In the phase I portion, patients with 
stable disease or radiologic response 1 month after chemoradiation were 
randomized to adjuvant temozolomide alone (150 mg/m²/day, 7/14-day schedule) or 
with doublet combinations of thalidomide (400 mg/day), isotretinoin (100 
mg/m²/day), and/or celecoxib (400 mg twice daily), or all 3 agents. Toxicity was 
assessed after 4 weeks. Among 54 patients enrolled (median age, 52 years; median 
Karnofsky performance status, 90), adjuvant treatment was not administered to 12 
(22%), primarily because of disease progression (n = 10). All combinations were 
well tolerated. Grade 3/4 lymphopenia developed in 63% of patients, but no 
related infections occurred. One patient treated with temozolomide plus 
isotretinoin plus thalidomide had dose-limiting grade 3 fatigue and rash, and 1 
patient receiving all 4 agents had dose-limiting grade 4 neutropenia. Venous 
thrombosis occurred in 7 patients, 4 of whom received thalidomide. From study 
entry, median survival was 20 months and the 2-year survival rate was 40%. 
Multiple cytostatic agents can be safely combined with dose-dense temozolomide. 
The factorial-based phase II portion of this study is currently ongoing.