New Phase 3 Trial of Targeted Therapy for Newly Diagnosed Glioblastoma
The UCSF Brain Tumor Center is leading a new randomized, double-blind, placebo-controlled, phase 3 clinical trial of enzastaurin combined with temozolomide and radiation therapy in patients with newly diagnosed glioblastoma (GBM) who are positive for the biomarker DGM1.
The trial will enroll patients globally at more than 10 institutions, and UCSF neuro-oncologist Nicholas Butowski, MD, serves as the global principal investigator.
Enzastaurin is a protein kinase C beta inhibitor that has been shown to repress tumor cell survival and proliferation, as well as interfere with tumor-induced angiogenesis. While a previous UCSF Phase 2 study of the same treatment regimen for GBM patients only showed mild improvement in median overall survival, several of the patients enrolled in the study did go on to survive 5 years or longer, indicating significant activity in a certain subpopulation of patients.
"A major challenge with clinical trials of targeted drugs is being able to identify the subpopulations of patients who will really benefit," says Butowski. "We now have a biological marker that may be able to predict response to enzastaurin and we hope selecting for those patients will extend their survival."
Enriched Patient Population
The biomarker was discovered by study sponsor Denovo Biopharma as part of its bid to identify pharmacogenomic biomarkers for oncology drugs by scanning the genome for single nucleotide polymorphisms that can predict drug efficacy. In the case of enzastaurin, they recently identified the germline polymorphism DGM1 as predictive of response to treatment.
In a retrospective analysis of DNA samples from the patients enrolled in UCSF's phase 2 trial of enzastaurin, temozolomide and radiation therapy for glioblastoma, patients with the DGM1 biomarker were found to have a longer median overall survival time than those who were DGM1-negative.
Similar findings emerged from retrospective analyses of patients with diffuse large B-cell lymphoma who had been treated with enzastaurin in clinical trials.
Better data have also emerged regarding how enzastaurin is metabolized and absorbed in the body. Food is now understood to significantly increase the exposure to enzastaurin and its metabolites, and patients will need to take the drug soon after eating as part of the new protocol. The new trial will also test a higher dose (375mg), which may be more effective.
"I am excited to see if applying this biomarker, optimal biological dosing and a better stratification of patients can result in more long-term survivors," says Butowski. "This trial is a very promising option for a disease that remains highly resistant to other therapies."
For More Information on Enrollment: