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Results from phase II trial of Enzastaurin (LY317615) in patients with
recurrent high grade gliomas
H. A. Fine, L. Kim, C. Royce, D. Draper, I.
Haggarty, H. Ellinzano, P. Albert, P. Kinney, 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 PKC-ß2 inhibitor with a
potent antiangiogenic activity.
We presented the preliminary result of
phase II LY317615 clinical trial on 32 patients (pts) with recurrent
malignant gliomas last year that demonstrated the antitumoral activity
of LY 317615. (JCO, 2004 ASCO Ann. Meet. Proc., Vol 22, No 14S, 2004:
1511).
We now report updated data on 85 pts (including original 32
pts) who were treated with LY317615.
Methods. Treatment
consists of oral LY317615 (fixed dose of 500 mg/day) administered
daily on an every 6 week cycle.
We stratified pts based on those
taking enzyme inducing antiepileptic drugs (EIAED; Group B) and those
not taking EIAED (Group A) and conducted pharmacokinetic (PK) studies.
Results. To date 85 pts (70 pts in Group A and 15 pts in Group
B) have been accrued to the trial and 79 pts were evaluable for
response (72% GBM).
Treatment (Tx) has been well tolerated with
minimal drug-related toxicity > grade 1 (hematologic Grade (Gr) 2:
4 pts, Gr 3: 2 pts, Gr 4: 1 pt; hepatotoxic Gr 2: 1 pt).
36 pts have
received more than 1 cycle of Tx (31 pts in Group A and 5 pts in Group
B) and 13 pts have been stable on Tx for > 3 months and a number of
other pts continue Tx with LY317615.
Objective radiographic responses
have been seen in 14 pts (10 GBM pts) that includes 1 complete
response who is still receiving Tx 13 months after the enrollment.
The
Group B arm is closed and the accrual for GBM pts in Group A arm will
be completed soon.
Conclusion. LY317615 is well tolerated and
appears to have promising antitumoral activity in a significant
percentage of highly pretreated patients.
We are still accruing pts to
the trial and will present additional clinical and PK data to the ASCO
meeting.
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