Background:
In vivo experiments have documented the ability of ZD6474 to inhibit tumor growth in various
preclinical tumor models. Given the pronounced neovasculature associated with malignant
gliomas, and abundant published data demonstrating the dependence of glioma growth on the
maintenance and proliferation of this neovasculature, ZD6474 represents a potentially
promising new therapeutic approach to these otherwise refractory tumors.
Thus, we now propose a phase I trial of ZD6474 in patients with recurrent and progressive
low-grade gliomas who are on P450-inducing anti-epileptic drugs and a phase II trial for
patients with recurrent gliomas not taking P450-inducing anti-epileptic drugs.
Objective:
Phase I - To establish the maximally tolerated dose of ZD6474 and to obtain preliminary
information regarding the spectrum of toxicities of ZD6474, and to obtain pharmacokinetic
data to patients taking EIAED.
Phase I - To obtain preliminary information regarding potential anti-tumor activity of ZD6474
in patients taking EIAED.
Phase II - To establish data regarding the anti-tumor activity of ZD6474 and to collect
information regarding the spectrum of toxicities in patients not taking EIAEDs.
Eligibility:
Patients with histologically proven malignant primary gliomas will be eligible for this
protocol. Additionally, patients with progressive low-grade gliomas and patients with
infiltrative brain stem gliomas, diagnosed radiographically rather than by biopsy will also
be eligible.
Design:
Phase I - Group B patients will be accrued to the formal dose-escalation phase I trial.
Groups of patients with recurrent high-grade gliomas will be accrued to increasingly higher
doses of ZD6474 until the MTD is established.
Phase II - Patients will be treated at a dose of 300 mg day, every day, on a 4-week cycle.