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A phase II trial of LY317615 in
patients with recurrent high grade gliomas
H. A. Fine, L. Kim, C. Royce, S. Mitchell, J. P. Duic, P. Albert, L. Musib,
D. Thornton
Neuro-Oncology Branch, NCI and NINDS, NIH, Bethesda, MD;
Biometrics Branch, NCI, Bethesda, MD; Eli Lilly, Indianapolis, IN
Background. Gliomas are amongst the most
angiogenic of all solid tumors and experimental evidence suggests that
angiogenesis inhibition can be an effective approach for inhibiting glioma
growth in vivo.
PKC-ß2 is an important signaling molecule in the induction of, and signaling
through the VEGF pathway, thus making PKC-ß2 an attractive therapeutic
target.
LY317615 is a macrocytic bisindolylmaleimide which disrupts the intrinsic
phosphotransferase activity of conventional and novel PKC isoforms via an
interaction at the ATP binding site and displays selectivity in inhibiting the
beta isoform.
Preclinical studies demonstrate potent antiangiogenic activity of
LY317615.
A normal volunteer and a phase I trial in solid tumor patients (pts) demonstrate
the drug is very well tolerated at doses that achieve a biologically active
serum concentration.
Based on the dependence of glioma growth on VEGF-mediated angiogenesis, and the
promising preclinical and clinical data, we have initiated a phase II trial of
LY317615 in pts with recurrent and progressive high grade gliomas following
standard therapy.
Methods.
Treatment consists of oral
LY317615 administered daily on an every 6 week cycle after which pts undergo a
complete physical/neurological, biochemical and radiographic reevaluation.
We stratified pts based on those taking enzyme inducing antiepileptic drugs
(EIAED; Group B) and those not taking EIAED (Group A) and conducted
pharmacokinetic studies.
Results.
To date 32 pts (17 pts in Group
A and 15 pts in Group B) have been accrued to the trial and 28 pts were
evaluable for response.
Treatment has been well tolerated with only one possible case of drug-related
toxicity > grade 1 (Grade 2 thrombocytopenia).
11 pts have received more than 1 cycle of treatment (6 pts in Group A and 5 pts
in Group B) and several pts have been stable on treatment for greater then 3
months and a number of other pts continue treatment with LY317615.
Objective radiographic responses have been seen in 5 pts.
Conclusion. LY317615 appears to have
antitumoral activity against recurrent malignant gliomas.
The trial continues to accrue additional pts and mature clinical and
pharmacokinetic data will be presented at the meeting.
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_19-003784,00.asp
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