Thema: News: LY317615 in patients with high grade gliomas
News: LY317615 in patients with high grade gliomas
Karen[a]
08.06.2004 22:07:33
A phase II trial of LY317615 in patients with recurrent high grade gliomas.
Abstract No: 1511
Author(s): 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.
Event: 2004 ASCO Annual Meeting
Presenter: Howard A. Fine, MD
Session: Central Nervous System Tumors
Abstract No: 1511
Author(s): 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.
Event: 2004 ASCO Annual Meeting
Presenter: Howard A. Fine, MD
Session: Central Nervous System Tumors
Karen[a]
