Phase I C linical T rial o f I ntrathecal T opotecan i n P atients With N eoplastic M eningitis

Purpose: A phase I trial of intrathecal (IT) topotecan was performed to determine the optimal dose, the dose-limiting toxic effects, and the incidence and severity of other toxic effects in patients 3 years and older with neoplastic meningitis. Patients and Methods: Twenty-three assessable patients received IT topotecan administered by means of either lumbar puncture or an indwelling ventricular access device (Ommaya reservoir). Intrapatient dose escalation from 0.025 mg to 0.2 mg was performed in the first cohort of patients. Subsequent cohorts of patients were treated at fixed dose levels of 0.2 mg, 0.4 mg, or 0.7 mg. Serial samples of CSF for pharmacokinetic studies were obtained in a subset of patients with Ommaya reservoirs. Results: Arachnoiditis, characterized by fever, nausea, vomiting, headache, and back pain, was the dose-limiting toxic effect in two of four patients enrolled at the 0.7 mg dose level. The maximum-tolerated dose (MTD) was 0.4 mg. Six of the 23 assessable patients had evidence of benefit manifested as prolonged disease stabilization or response. Conclusion: The MTD and recommended phase II dose of IT topotecan in patients who are 3 years or older is 0.4 mg. A phase II trial of IT topotecan in children with neoplastic meningitis is in progress. J Clin Oncol 21:143-147. © 2003 by American Society of Clinical Oncology. I NTRATHECAL ADMINISTRATION of anticancer drugs has been an effective strategy for the primary treatment and prevention of leptomeningeal leukemias and lymphomas, but it has not been effective in patients with neoplastic meningitis or in patients with refractory meningeal leukemias. These limitations result in part from the limited number of agents available for intrathecal (IT) administration. Therefore, it is essential to develop new IT agents with novel mechanisms of action. Topotecan is a topoisomerase I poison that has anticancer activity against a variety of adult and childhood solid tumors. Studies to evaluate the CSF pharmacokinetics of topotecan following systemic administration in a nonhuman primate model demonstrated that the CSF penetration of the active lactone form of topotecan was approximately 30%. 1,2 These findings were subsequently confirmed in children with brain tumors who were receiving continuous infusion topotecan. 3 As a result of the excellent CSF penetration, the lack of neurotoxicity after systemic administration, and its novel mechanism of action, studies were performed to evaluate the feasibility of IT topotecan in a nonhuman primate model. These preclinical studies demonstrated that a 0.1 mg intraventricular dose (equivalent to 1.0 mg in humans) was well tolerated. Furthermore, following direct intraventricular topotecan administration, a 450-fold greater CSF exposure could be achieved with 1/100 th of the systemic dose. 1 The results of these preclinical studies served as the basis for the initiation of a phase I study of IT topotecan in patients with neoplastic meningitis.