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Phase I study of ZD1839 plus temozolomide in patients with malignant glioma. A study of the North American Brain Tumor Consortium
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2004
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PharmacotherapyHigh-grade GliomasBrain LesionGliomaTreatment VerificationNeuro-oncologyRadiation MedicineEligible PtsMetronomic TherapyRadiopharmaceutical TherapyNeurologyBrain PathologyClinical Radiation OncologyDiagnostic SciencesTreatment StrategiesRadiation OncologyCancer ResearchHealth SciencesRadiation TherapyMedicineMalignant GliomaCancer TreatmentNeurological AssessmentBrain Tumor BiologyZd 1839NeuroscienceOncology
1504 Background: To define the MTD of ZD1839 in combination with Temodar in patients with malignant glioma, without (Group A) or with (Group B) enzyme-inducing antiepileptic drugs (EIAEDs). Methods: Eligible pts were > 17 years of age, had KPS ≥60 with stable or progressive malignant glioma, with acceptable laboratory baseline tests. Radiation was completed at least 3-weeks prior to registration. No more than 3 prior chemotherapy regimens allowed. Treatment: Patients started on a continuous dose of ZD1839 (day 1) beginning at 500 mg/day. Temodar started (day 8) at an oral dose of 150 mg/m2/day for 5 days after the ZD1839 and was repeated every 28 days. Temodar could be escalated to 200 mg/m2/day after cycle 1. DLT was defined as any grade 3 or greater non-hematological or any grade 4 hematological toxicity using CTC v 2.0 during the first 35 days of therapy. 3 patients per cohort (Group A or Group B) were enrolled. The dose of ZD 1839 was escalated by 250 mg increments assuming no DLT in each 3-patient group. If 1 DLT was seen in 3 patients, 3 additional patients were enrolled at that dose. The MTD was the dose level at which 0/3 or 1/6 patient experienced DLT with the next higher dose having at least 2/3 or 2/6 patients with DLT. Patients could continue treatment indefinitely until tumor progression or unacceptable toxicity. Results: 28 pts enrolled (12 in Group A, 16 in Group B); 20 had GBM, rest with grade-3 tumors; all had prior XRT, 9 were chemo naïve. For Group A pts, the MDT of ZD 1839 was 250 mg/day, one dose level lower than the starting dose. DLT's at 500 mg were grade 3 diarrhea and ALT elevations. There were no DLTs at 250 mg/day. For Group B pts, the MTD of ZD 1839 was 1000 mg/day. DLT's at 1250 mg included grade 3 diarrhea, vomiting, hyponatremia and weakness, and grade 4 hypokalemia. Skin rash was always ≤ Grade 2. Conclusion: The recommended phase-2 dose of ZD1839 plus Temodar in patients on EIAEDs is 1000 mg/day, and 250 mg/day for patients not on EIAEDs. No significant financial relationships to disclose.