AZD7451 for Recurrent Gliomas

BACKGROUND: Recurrent glioma patients have very limited treatment options. A major cause of gliomarelated morbidity and mortality is the extensive infiltrative and invasive nature of glioma cells. Thus, inhibition of glioma invasion is a potentially promising strategy. Work in the Neuro-Oncology Branch laboratory of Dr. Howard Fine has identified TrkA as an important signaling receptor for mediating glioma cell invasion. Both genetic and pharmacological inhibition of Trk potently inhibits glioma invasion and tumor progression in vitro and in vivo. AZD7451 is a first in-class inhibitor of Trk. OBJECTIVES: To establish the maximally tolerated dose (MTD) of continuous twice a day AZD7451 dosing in patients with recurrent glioblastoma not on enzyme-inducing anti-epileptic drugs (EIAED). To generate pharmacokinetic data on continuous twice a day AZD7451 dosing. ELIGIBILITY: Patients with histologically proven glioblastoma are eligible for this study. Patients should have failed prior standard treatment with radiotherapy. DESIGN: This study will accrue up to 60 evaluable patients. Cohorts of 3 to 6 patients will receive continuous AZD7451 twice a day orally for 28 days. The MTD will be based on the tolerability observed during the first 4 weeks of treatment only. Up to three patients may be enrolled simultaneously at each dose level. The dose of AZD7451 can be progressively escalated if only 0/3 or 1/6 patients experience a dose limiting toxicity at the prior dose level. At the end of Cycle 1, patients may choose to continue to receive AZD7451 until disease progression or until they experience unmanageable drug related toxicity, as long as they are continuing to derive clinical benefit and do not fulfill any of the criteria for removal from protocol therapy. Each cycle during this extension period will last 28 days.