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NCCTG phase II trial of
CCI-779 in recurrent glioblastoma multiforme (GBM)
E. Galanis, J. C. Buckner, M. Maurer, K. Ballman, M. Hidalgo, J. I.
Kreisberg, J. Boni, C. D. D. James, R. B. Jenkins, D. J. Walsh
Mayo Clinic College of Medicine, Rochester, MN; Johns Hopkins
University, Baltimore, MD; UTHSCSA, San Antonio, TX; Wyeth, Collegeville, PA;
North Central Cancer Treatment Group, Rochester, MN.
Background. CCI-779 is a
small molecule inhibitor of the mammalian target of rapamycin (mTOR).
mTOR is a rational therapeutic target in GBM, being downstream from
important pathways such as EGFR and PTEN.
Study aims: to determine the efficacy of CCI-779 in recurrent GBM, to
assess toxicity, to evaluate the pharmacokinetics (PK) of CCI-779 for pts on
p450 inducing anticonvulsants (EIAC), to define the pt population most likely to
benefit from treatment (Rx), and to determine whether CCI-779 successfully
interacts with the target pathway.
Methods. Recurrent GBM pts
with ≤ 1 chemo regimen for progressive disease, stable steroid dose for
≥ 1 wk prior to baseline scan, acceptable hematologic, renal, liver
function, cholesterol and triglyceride levels were eligible.
CCI-779 dose was 250 mg iv q wk.
Results. 41 pts were
treated.
Rx was well tolerated: grade 3+ hematologic toxicity was observed in 12
%, and grade 3+ non-hematologic toxicity in 51%, and consisted mostly of
hypercholesterolemia (15%), hypertriglyceridemia (12%), hyperglycemia (10%),
rash (5%), stomatitis (5%), fatigue (2%).
Sirolimus metabolite trough concentration, AUC and AUC sum
(CCI+sirolimus) were decreased in EIAC pts by 65%, 50%, and 40% respectively,
but they were still within the therapeutic range of preclinical models.
Assessment of tumor Akt and p70s6 kinase phosphorylation (PHOS) pre-Rx,
demonstrated activation of the Akt and p70s6k in the majority of pts (14/17 and
11/17 pts respectively).
Analysis of p70s6k PHOS in peripheral blood mononuclear cells (PMBC),
showed post-Rx inhibition in 7/10 pts.
Although there were no objective partial responses in the first 31 pts,
evidence of antitumor activity was observed, with significant decrease in T2
signal abnormality in 5 pts and modest decrease in T1 Gad enhancement in 3
pts.
Conclusions. CCI-779 is well
tolerated in recurrent GBM pts.
Despite the impact of EIAC on CCI-779 metabolism, therapeutic levels were
achieved.
There is preliminary evidence of antitumor activity, as well as
inhibition of the target pathway in post-Rx PBMCs.
Assessment of the PTEN and EGFR tumor status, Akt and p70s6k PHOS pre-
and post-Rx and correlation with response and toxicity is ongoing.
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-00848,00.asp
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