The activity of single-agent targeted molecular therapies in glioblastoma has 
been limited to date. The North American Brain Tumor Consortium examined the 
safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a 
small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, 
and platelet-derived growth factor receptor-β, and temsirolimus (CCI-779), an 
inhibitor of mammalian target of rapamycin. This was a phase I/II study. The 
phase I component used a standard 3 × 3 dose escalation scheme to determine the 
safety and tolerability of this combination therapy. The phase II component used 
a 2-stage design; the primary endpoint was 6-month progression-free survival 
(PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum 
tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and 
temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the 
dose-limiting toxicity. Eighteen patients were treated in the phase II 
component. At interim analysis, the study was terminated and did not proceed to 
the second stage. No patients remained progression free at 6 months. Median PFS 
was 8 weeks. The toxicity of this combination therapy resulted in a maximum 
tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. 
Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 
2 combined agents.