PHASE-I AND PHARMACOLOGICAL 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 topoi somerase I inhibitor, 9-aminocamptothecin (9-AC). Patients and Methods : A 72-hour infusion of 9-AC was administered every 14 days to 48 soli d-tumor patients at doses of 5 to 59 mu g/m(2)/h without granulocyte c olony-stimulating factor (G CSF) and 47 to 74 mu g/m(2)/ h with G-CSF. Results: Without G-CSF, two of eight patients who received 47 mu g/m( 2)/h had dose-limiting neutropenia in their initial cycle, as did both patients who received 59 mu g/m(2)/h (with a platelet count < 25,000/ mu L in one). With G-CSF, zero of seven patients treated with 47 mu g/ m(2)/h had dose-limiting neutropenia in their first cycle, while dose -limiting neutropenia occurred in six of 14 patients (with platelet co unt < 25,000/mu L in five) entered at 59 mu g/m(2)/h. Among 39 patient s entered at greater than or equal to 25 mu g/ m(2)/h 9-AC with or wit hout G CSF, fatigue, diarrhea, and navsea/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 l actone concentration (Css) increased linearly from 0.89 to 10.6 nmol/L , and correlated strongly with leukopenia (r = .85). Conclusion: The r ecommended phase II dose of 9-AC given by 72-hour infusion every 2 wee ks is 35 mu g/m(2)/h without G-CSF or 47 mu g/m(2)/h with G-CSF suppor t. Dose escalation in individual patients may be possible according to their tolerance.