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Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings.
Vol 23, No 16S (June 1 Supplement), 2005: 1505
Phase II trial of CCI-779 in recurrent glioblastoma multiforme (GBM): Updated results and correlative laboratory analysis
E. Galanis, J. C. Buckner, M. J. Maurer, M. Hidalgo, J. I. Kreisberg, J. Peralba, R. B. Jenkins and D. J. Walsh
Mayo Clinic Coll of Medicine, Rochester, MN; Mayo Clinic, Rochester, MN; Johns Hopkins Univ, Baltimore, MD; UTHSCSA, San Antonio, TX; North Central Cancer Treatment Group, Rochester, MN
1505
Background:
CCI-779 is a small molecule inhibitor of the mammalian target of rapamycin (mTOR), and represents a rational therapeutic target in GBM. Methods: Recurrent GBM pts with 1 chemo regimen for progressive disease were eligible. CCI-779 dose was 250 mg IV q wk. Results: 52 pts were treated. Treatment was well tolerated: grade 3+ non-hematologic toxicity was observed in 49% and consisted mostly of hyperlipidemia, rash, and stomatitis, and grade 3+ hematologic toxicity was seen in 10%. Review of pre- and post-treatment MRI scans was performed in 40 pts. Of them, 16 (40%) had evidence of improvement in neuroimaging, consisting of significant decrease in T2 signal abnormality+/- decrease in T1 gad enhancement on stable or reduced steroid doses. Median progression free survival (PFS) for all pts was 68 days and PFS6 was 10%. PFS was significantly longer for responders (146 days) vs non-responders (55 days), (p=0.05). The incidence of grade 2 or higher hyperlipidemia in the first 2 treatment cycles was significantly higher among responders as compared to non-responders(75% vs 30%, p=0.01). The presence of PTEN deletion or EGFR amplification by FISH and the phosphorylation status of AKT in baseline tumor samples did not correlate with outcome. Decreased p70s6 kinase activity in peripheral blood mononuclear cells post treatment was not predictive of antitumor response. In contrast, a significant correlation between the presence of phosphorylated p70s6 kinase, a downstream indicator of mTOR pathway activation, in baseline tumor samples by immunohistochemistry and the likelihood of response was observed (p=0.03).
Conclusions;
CCI-779 is well tolerated in recurrent GBM pts. Radiographic response in CCI-779 treated pts is associated with significantly longer PFS. Development of grade 2+ hyperlipidemia on treatment appears to be a surrogate marker of radiographic improvement. High levels of phosphorylated p70s6 kinase, determined by IHC in baseline tumor samples appear to predict a patient population more likely to derive benefit from treatment. These preliminary observations are hypothesis generating and should be confirmed in other ongoing and future studies of mTOR inhibitors.
© 2005 American Society of Clinical Oncology