Intrathecal mafosfamide: a preclinical pharmacology and phase I trial.

PURPOSE: Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. PATIENTS AND METHODS: In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. RESULTS: The cytotoxic target exposure for mafosfamide was 10 micromol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 micromol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. CONCLUSION: The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

Phase I and pharmacokinetic study of thalidomide with carboplatin in children with cancer.

PURPOSE: Tumor growth and metastasis is believed to depend on the tumor's ability to induce neovascularization. Recent studies have indicated that thalidomide inhibits angiogenesis. We performed a phase I and pharmacokinetic study of thalidomide with carboplatin in children with refractory solid tumors. PATIENTS AND METHODS: Carboplatin was administered as a single intravenous dose once every 21 days at a target area under the concentration-time curve of 6 mg/mL.min. Thalidomide was administered daily by mouth. The initial dose level was 100 mg/m(2)/d with intrapatient dose escalation to a maximum dose of 300 mg/m(2)/d. The next cohort of patients started at a dose of 300 mg/m(2)/d, with intrapatient dose escalation to a maximum dose of 500 mg/m(2)/d. Standard response and adverse event criteria were used. Serial blood samples for thalidomide pharmacokinetics studies were obtained after the first dose. RESULTS: Twenty-two patients received 56 cycles of therapy. The maximum tolerated thalidomide dose was 400 mg/m(2)/d. The dose-limiting toxicity was somnolence. There were no objective responses. Thalidomide's apparent clearance was 55 +/- 16 mL/min/m(2) and the terminal half-life was 5.9 +/- 2.8 hours. There was no evidence of dose-dependent pharmacokinetics in the narrow range studied. CONCLUSION: Thalidomide at a dose of 400 mg/m(2)/d can be safely administered to children with solid tumors in combination with carboplatin. Somnolence is the major toxicity. In addition, we have characterized the pharmacokinetic behavior of thalidomide in children. This study can serve as the basis for future investigation of thalidomide as an anticancer agent in children.

Pharmacokinetics of phenylacetate administered as a 30-min infusion in children with refractory cancer.

PURPOSE: Phenylacetate (PAA), a deaminated metabolite of phenylalanine, suppresses tumor growth and induces differentiation in preclinical tumor models. We performed a pharmacokinetic study, as part of a phase I trial, of PAA in children with refractory cancer. METHODS: PAA was administered as a 30-min i.v. infusion at a dose of 1.8 or 2.5 g/m2. Serial plasma samples were collected for up to 24 h after the end of the infusion in 27 children. The concentrations of PAA and its inactive metabolite, phenylacetylglutamine (PAG), were measured using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection. RESULTS: PAA and PAG concentrations were best described by a two-compartment model (one compartment for each compound) with capacity-limited conversion of PAA to PAG. The half-life of PAA was 55+/-18 min at the 1.8 g/m2 dose and 77+/-22 min at the 2.5 g/m2 dose. The half-life of PAG was 112+/-53 min at the 1.8 g/m2 dose and 135+/-75 min at the 2.5 g/m2 dose. The clearance of PAA was 66+/-33 ml/min per m2 at the 1.8 g/m2 dose and 60+/-24 ml/min per m2 at the 2.5 g/m2 dose. The Michaelis-Menten constants describing the conversion of PAA to PAG in the model (Vm and Km) were (means+/-SD) 18.4+/-13.8 mg/m2 per min and 152+/-155 microg/ml, respectively. The volumes of distribution for PAA and PAG (V(d-PAA) and V(d-PAG)) were 7.9+/-3.4 l/m2 and 34.4+/-16.1 l/m2, respectively. The first-order elimination rate constant for PAG (k(e-PAG)) was 0.0091+/-0.0039 min(-1). CONCLUSIONS: The capacity-limited conversion of PAA to PAG has important implications for the dosing of PAA, and the pharmacokinetic model described here may be useful for individualizing the infusion rate of the drug in future clinical trials.