NABTC phase I/II trial of ZD-1839 for recurrent malignant gliomas and unresectable meningiomas

Abstract

1510 Background: We update this trial evaluating ZD-1839(Iressa) for treatment of malignant gliomas recurring after radiation therapy and for unresectable benign or anaplastic meningiomas (MEN) progressing after radiation therapy. Methods: In the phase II component, patients who were not receiving enzyme inducing anticonvulsants (EIAED) or corticosteroids, were treated with 500mg/ day. The dose in patients receiving corticosteroids was escalated in two increments of 250mg to 1000mg/day. Phase II study was limited to patients with 2 or less relapses. For patients on EIAEDs, a phase 1 component began at 500mg/day and was escalating in 250mg increments. Subjects in the phase 2 component were evaluated for radiological response, time to progression (TTP), and percentage without progression at 6 months (%PFS-26wk). Results: The MTD for patients on EIAEDs is 1500mg/day. As of 11/19/03, 38 glioblastoma(GBM), 17 anaplastic glioma(AG), and 10 MEN patients had entered phase 2 study. The median TTP for GBM is unchanged at 8 weeks (95%CI:7–12weeks). The median TTP for AG is shortened at 12 weeks (95%CI:7-ND). For both GBM and AG, %PFS-26wk is unchanged at 9%(95%CI:3–27%), and 33%(95%CI: 13–81%). However, 1 GBM patient had SD for 66wks, and 1 is progression free at 93 wks; 4 AG patients had SD for over 50wks. Partial responses (not centrally confirmed) were seen in 5 GBM, 1 AO and 1 anaplastic oligoastrocytoma. No MEN has responed. Skin rash, transaminase elevations, fatigue, diarrhea, and hypokalemia were the most common toxicities. No pulmonary interstitial fibrosis was observed. Conclusion: The MTD for ZD-1839 in patients receiving EIAEDs is 1500mg/day. With complete accrual in both GBM and AG cohorts, ZD-1839 does not prolong TTP compared to historical controls, but subgroups of both GBM and AG demonstrated prolonged TTP. Microdisection based genotyping and determination of EGFR expression is in progress to determine if these tumors are distinguishable from those demonstrating rapid progression. No significant financial relationships to disclose.