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N997B: Phase II Trial of CCI-779 in
Recurrent Glioblastoma Mutiforme (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, 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
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.
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