1559 Background: Gimatecan (GT) is an orally available camptothecin analogue with potent preclinical antitumor activity. A phase I trial was conducted to determine the maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics (PK) of GT in patients (pts) with recurrent malignant glioma. Methods: GT was given orally once daily for 5 days every 28 days. The starting dose, 1.6 mg/m2 over 5 days, was independently escalated in pts who were and were not concurrently receiving enzyme inducing antiseizure drugs (±EIASD). PK samples were obtained up to 24 after dosing on day 1 and 168 h after dosing on day 5 of cycle 1. Results: A total of 43 pts were enrolled, 18 in the +EIASD arm and 25 in the -EIASD arm, with a median age of 51 years (range, 23–70) and median KPS of 80 (range, 60–100). All pts had prior irradiation and 84% had prior chemotherapy. Dose levels evaluated were 1.6, 3.2, 5.3, 8.0, 11.2, and 15.0 mg/m2 in the +EIASD arm and 1.6, 3.2, 5.3, 6.1, and 8.0 mg/m2 in the -EIASD arm. No dose-limiting toxicities (DLTs) occurred during 49 cycles of therapy in the +EIASD arm with dose escalation terminated at 15.0 mg/m2. Grade 3–4 myelosuppression was the DLT in the -EIASD arm, occurring in 1/11 pts at the MTD of 6.1 mg/m2, and 2/3 pts at 8.0 mg/m2. Gastrointestinal disorders, the most common side effects, were grade >3 in only 7% of pts. Pts in the +EIASD arm received a median of 6 cycles of therapy and there were 2 partial responses and 6 pts with stable disease. Pts in the -EIASD arm received a median of 2 cycles of therapy and 11 pts had stable disease. GT exhibited linear PK. EIASDs significantly affected the PK, decreasing the biological half-life 2-fold from 53 ± 25 to 25 ± 12 h (mean ± SD) and increasing the apparent oral clearance (CL/F) nearly 5-fold from 1.3 ± 1.7 L/h to 6.2 ± 4.3 L/h. CL/F was independent of body surface area. Conclusions: The MTD of GT for pts not receiving EIASDs is 6.1 mg/m2 and an MTD was not established for pts receiving EIASDs due to practical limitations on dose administration. Median duration of disease stabilization or response was 6 cycles for 44% of +EIASD pts and 2 cycles for 44% of -EIASD pts. [Table: see text]
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