Phase I and pharmacologic study of 9-aminocamptothecin given by 72-hour infusion in adult cancer patients

Purpose: To conduct a phase I and pharmacologic study of the new topoisomerase I inhibitor, 9-aminocamptothecin (9-AC). Patients and Methods: A 72-hour infusion of 9-AC was administered every 14 days to 48 solid-tumor patients at doses of 5 to 59 μg/m²/h without granulocyte colony-stimulating factor (G-CSF) and 47 to 74 Hg/m²/h with G-CSF. Results: Without G-CSF, two of eight patients who received 47 μg/m²/h had dose-limiting neutropenia in their initial cycle, as did both patients who received 59 μg/m²/h (with a platelet count < 25,000/μL in one). With G-CSF, zero of seven patients treated with 47 μg/m²/h had dose-limiting neutropenia in their first cycle, while dose-limiting neutropenia occurred in six of 14 patients (with platelet count < 25,000/μL in five) entered at 59 μg/m²/h. Among 39 patients entered at ≥ 25 μg/m²/h 9-AC with or without G-CSF, fatigue, diarrhea, and nausea/vomiting of grade 2 severity ultimately occurred in 54%, 30%, and 38%, respectively, while grade 3 toxicity of each type occurred in 8% of patients. Steady-state 9-AC lactone concentration (Css) increased linearly from 0.89 to 10.6 nmol/L, and correlated strongly with leukopenia (r = .85). Conclusion: The recommended phase II dose of 9-AC given by our infusion every 2 weeks is 35 μg/m²/h without G-CSF or 47 μg/m²/h with G-CSF support. Dose escalation in individual patients may be possible according to their tolerance.