Phase I and Pharmacokinetic Evaluation of Thiotepa in the Cerebrospinal Fluid and Plasma of Pediatrie Patients: Evidence for Dose-dependent Plasma Clearance of Thiotepa

A Phase I trial of thiotepa (II) administered as an i.v. bolus was performed in 19 children with refractory malignancies. The starting dose was 25 mg/m2 with escalations to 50, 65, and 75 mg/nr. Seven additional patients were treated with 8-h infusions at 50 or 65 mg/m2. The maximum tolerated bolus dose was 65 mg/m2. Reversible myelosuppression was the dose-limiting toxicity. The plasma and cerebrospinal fluid (CSF) pharmacokinetic parame ters of TT and its major active metabolite tepa (TP) were also evaluated. When the bolus or infusion methods of TT administration were compared, there was little difference observed in any pharmacokinetic parameter for either TT or TP. The plasma disappearance of TT was rapid and biphasic with half-lives of 0.14 to 0.32 and 1.34 to 2.0 h. Dose-dependent pharmacokinetics was demonstrated by steadily declining plasma clear ance with increasing TT dose. Clearance values declined from 28.6 liters/ m2/h at the 25-mg/m2 dose to 11.9 liters/mz/h at the 75-mg/m2 dose. The half-life of TP was longer than that of TT and ranged between 4.3 and 5.6 h. There was evidence of the saturation of TP production. TT and TP both exhibited excellent penetration into the CSF, produc ing lumbar and ventricular concentrations which were nearly identical to simultaneous plasma concentrations. In one patient with a Rickham reservoir, the CSF:plasma area under the (concentration x time) curve ratios for TT and TP were 1.01 and 0.95, respectively. The above data indicate that TT can be safely administered to pediatrie patients at doses higher than conventionally used. The favorable CSF penetration of TT and TP suggests that Phase II studies of TT be considered in patients with central nervous system tumors. INTRODUCTION TT2 is a polyfunctional alkylating agent which has been in clinical use for more than 30 yr. It is currently used i.v. in adult oncology for the treatment of ovarian and breast cancer, as well as being administered intravesically for the treatment of bladder cancer, and intrathecally for meningeal carcinomatosis. In ad dition, high-dose TT has been used as preparative chemother apy for autologous bone marrow transplantation in patients with refractory malignancies (1-5). The observation that TT displays excellent CSF penetration in the nonhuman primate following i.v administration suggests that TT may also be of some clinical utility in the treatment of central nervous system malignancies (6). In vivo, TT is metabolized to TP, a molecule which retains TT's three aziridine rings and is itself a potent alkylator (Fig. 1). Although recent publications have described the human Received 8/30/88; accepted 10/25/88. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ' To whom requests for reprints should be addressed, at Building 10. Room 13N240, Pediatrie Branch. National Cancer Institute. Bethesda. MD 20892. 2The abbreviations used are: TT, thiotepa (JV,Ar',A"'-triethylenethiophosphoramide); TP, tepa (/V.A",Ar"-triethylenephosphoramide); AUC, area under the (concentration x time) curve; CSF, cerebrospinal fluid; MTD. maximum tolerated dose; CT, computerized tomography; CNS, central nervous system. plasma pharmacokinetics of TT, only limited information re garding TP is available (1,7-11). Similarly, little exists regard ing the pharmacokinetics of these agents in human CSF (12). In spite of its long clinical history, the optimal dose of TT has never been established in pediatrie patients. Conventional doses of TT in adults range from 12.5 to 25 mg/m2. However, TT is known to have a steep dose-response curve. This infor mation, together with the knowledge that the administration of very high dose TT is feasible with autologous bone marrow transplantation, suggested that it might be possible to safely administer TT in higher than conventional doses without au tologous bone marrow rescue. The present report details the results of a Phase I study of higher than conventional dose TT in children. In addition, we describe the clinical pharmacology and pharmacokinetics of TT and its major active metabolite, TP, in human plasma and CSF. MATERIALS AND METHODS Patient Eligibility. Patients between 1 and 21 yr of age with malig nancies refractory to conventional therapy were eligible for this trial. Prior to treatment all patients were required to have histological con firmation of their diagnosis, an Eastern Cooperative Oncology Group performance level of 3 or less, and a life expectancy of at least 8 wk. Prior to entry, patients were required to have fully recovered from the toxic effects of antineoplastic therapy and to have adequate hepatic (bilirubin less than 2 mg/dl and serum transaminases less than 1.5 times normal) and renal function (creatinine less than 1.5 mg/dl or creatinine clearance greater than 60 ml/min/1.73 m2), as well as a normal coagulation profile, serum electrolytes, and uric acid. Patients with solid tumors (without bone marrow involvement) were also re quired to have adequate peripheral blood counts (a granulocyte count greater than 1,500/mm3 and a platelet count greater than 100,000/ mm3) prior to treatment. All patients or their legal guardians signed a document of informed consent consistent with federal and local institutional guidelines stating that they were aware of the investigational nature of this trial. Study Design. Two different methods of TT administration were studied in this trial. Nineteen patients were administered a 5-min i.v. bolus dose and seven patients an 8-h continuous i.v. infusion of TT. The drug was given every 3 wk or as soon thereafter as recovery from the hematological effects of prior TT doses permitted. One dose con stituted one course of therapy. The starting bolus dose of 25 mg/m2 was the conventionally used dose in adults. Drug escalations to 50, 65, and 75 mg/m2 were carried out once at least three patients évaluable for toxicity had been accrued at the prior dose level. Patients were allowed to escalate to the next higher dose level if they had shown some evidence of response and did not have Grade III or IV toxicity at their prior dose level. Only one escalation was allowed in an individual patient. Escalated patients were évaluablefor toxicity only at their initial dose level. Patients were monitored weekly with complete blood counts, physical exams, and measurement of any palpable lesions. Bone marrow examinations, radiographie studies, and CT or magnetic reso nance imaging scans, as appropriate, were obtained prior to treatment