Results from phase II trial of enzastaurin (LY317615) in patients with recurrent high grade gliomas

Abstract

1504 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-β2 is an important signaling molecule in the induction of, and signaling through the VEGF pathway, thus making PKC-β2 an attractive therapeutic target. LY317615 is a PKC-β2 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. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly