Purpose: The ability of growth factors to stimulate marrow recovery suggests their potential for use in dose intensification of cytotoxic drugs. We performed a phase I study of the alkylating agent thiotepa in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), with the goal of dose-escalation of thiotepa. Thiotepa was selected based on its capacity for dose escalation to more than 1 g/m2 in the marrow transplantation setting.
Patients and methods: The starting dose of thiotepa (75 mg/m2) was the highest dose evaluated in our previous phase I trial. Thirteen patients received 22 courses of thiotepa and GM-CSF. The dose of GM-CSF was 10 micrograms/kg subcutaneously daily in six patients and 5 micrograms/kg in seven patients.
Results: Three patients (23%) developed grade 3 to 4 neutropenia on the first course, with a recovery to more than 1000/mm3 in 4.7 days (mean). Recovery was as rapid with the 5 micrograms/kg as it was with the 10 micrograms/kg GM-CSF dose. Thrombocytopenia grade 3 to 4 affected seven of 13 (54%) patients in the first course; counts recovered to more than 50,000/mm3 in a median of 15 days. GM-CSF at either dose did not influence markedly the severity or duration of thrombocytopenia, and did not permit dose escalation of thiotepa. Among the seven patients who received a second cycle of treatment, six of seven experienced grade 3 or 4 thrombocytopenia that lasted a median of 15.5 days. Five had thrombocytopenia that lasted more than 35 days after one to three cycles of treatment. Plasma concentrations of thiotepa and tepa were measured by gas chromatography in eight patients. The plasma elimination of thiotepa fit a two-compartment open model with a harmonic mean terminal half-life of 2.44 hours. The mean total body clearance was 217.9 mL/min/m2, and the mean steady-state volume of distribution (Vdss) was 36.8 L/m2. The half-life of tepa was 7.98 hours, and the ratio of the area under the plasma concentration versus time curve (AUC) of tepa to that of thiotepa was 0.79.
Conclusions: These data were consistent with our previous observations at this dose, and indicated that the severity of toxicity in these patients was not explained by aberrant pharmacokinetic indices. We conclude that, independent of effects on neutropenia, severe and cumulative platelet toxicity precludes further escalation of thiotepa dose despite the use of GM-CSF.