Thema: News: CCI-779 in recurrent glioblastoma multiforme
News: CCI-779 in recurrent glioblastoma multiforme
Karen[a]
08.06.2004 22:51:39
NCCTG phase II trial of CCI-779 in recurrent glioblastoma multiforme (GBM).
Abstract No: 1503
Author(s): 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.
Event: 2004 ASCO Annual Meeting
Presenter: Evanthia Galanis, MD
Abstract No: 1503
Author(s): 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.
Event: 2004 ASCO Annual Meeting
Presenter: Evanthia Galanis, MD
Karen[a]
