Phase I study of temozolomide and escalating doses of oral etoposide for adults with recurrent malignant glioma

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Abstract
BACKGROUND Although temozolomide is active against recurrent malignant glioma, responses in many patients are modest and short‐lived. Temozolomide may prove more effective in combination with other agents. Therefore, combination oral chemotherapy for these patients is a particularly attractive approach. METHODS The authors conducted a Phase I study of temozolomide in combination with escalating doses of oral etoposide (VP‐16) to determine the maximum tolerated doses of these two agents when given together. The temozolomide dose was fixed at 150 mg/m2 per day on Days 1–5. The oral VP‐16 was escalated in cohorts of 3 to 6 patients by numbers of days of VP‐16 administered: 50 mg/m2 per day, Days 1–5 (dose level 1), Days 1–8 (dose level 2), Days 1–12 (dose level 3), Days 1–16 (dose level 4), and Days 1–20 (dose level 5). Therapy was given in 28‐day cycles. RESULTS Of the 29 patients enrolled, 26 were fully evaluable and 3 were partially evaluable for toxicity. The 29 patients received a total of 92 cycles. The median age of the patients was 49 years (range, 28–76 years). Diagnoses included glioblastoma (n = 19), gliosarcoma (n = 3), anaplastic astrocytoma (n = 5), and anaplastic oligoastrocytoma (n = 2). The median time from diagnosis to disease recurrence was 8 months (3–188 months). Twenty patients were treated at the first disease recurrence, seven at the second, and two at the third. Twenty‐four patients (83%) were receiving anticonvulsants and 24 were receiving dexamethasone. All patients had received previous radiation, and 25 of 29 had been treated with chemotherapy previously. Of the 3 patients at dose level 1, none had dose‐limiting toxicity (DLT). Of the 6 patients at dose level 2, 1 patient had DLT: Grade 3 thrombocytopenia resulting in a > 2‐week delay in starting the next cycle of chemotherapy. Of the 6 patients at dose level 3, 1 patient had DLT: death due to pneumonia. There were 2 DLTs in the 7 patients at dose level 4: fever, neutropenia, and herpes zoster infection in 1 patient and death due to pneumonia in another. Seven patients had been started at dose level 5 when DLT was established at dose level 4: of the 5 fully evaluable and 2 partially evaluable patients at dose level 5, there was no DLT. CONCLUSIONS The maximum tolerated dose of temozolomide and oral VP‐16 in this heavily treated group of patients with recurrent malignant glioma is temozolomide 150 mg/m2 per day for 5 days and oral VP‐16 50 mg/m2 per day for 12 days. Cancer 2003;97:1963–8. © 2003 American Cancer Society. DOI 10.1002/cncr.11260

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