A PHASE-I STUDY OF TOPOTECAN FOLLOWED SEQUENTIALLY BY DOXORUBICIN IN PATIENTS WITH ADVANCED MALIGNANCIES

Inhibitors of topoisomerase I and topoisomerase II have demonstrated s ynergy when administered sequentially in several tumor models while ha ving a diminished antitumor effect when given concurrently, To explore the potential for clinical sequence-dependent synergy, we instituted a Phase I study of topotecan (a topoisomerase I inhibitor) followed by doxorubicin (a topoisomerase II inhibitor) in patients with advanced malignancies, Thirty-three patients with advanced malignancies or mali gnancies for whom no standard therapy exists were entered into the stu dy, Topotecan was administered in escalating doses by 72-h continuous infusion on days 1, 2, and 3, followed by a bolus of doxorubicin given on day 5, To explore the hematological toxicity associated with this sequence, bone marrow aspirates were obtained both prior to the topote can infusion and immediately prior to the doxorubicin in 10 patients t o determine by fluorescence-activated cell sorting analysis whether CD 34+ cell synchronization was occurring using this sequential schedule, Dose-limiting hematological toxicity occurred at the first dose-level in three of six patients, Therefore, we defined the maximum-tolerated dose (MTD) below our starting dose-level, Further dose-escalation and a new MTD were defined with the addition of granulocyte-colony stimul ating factor (G-CSF), The MTD was, therefore, topotecan 0.35 mg/m(2)/d ay continuous i,v, infusion on days 1, 2, and 3, followed by doxorubic in 45 mg/m(2) on day 5 without G-CSF, whereas the MTD with G-CSF was t opotecan 0.75 mg/m(2)/day by 72-h continuous i,v, infusion, followed b y doxorubicin 45 mg/m(2) i,v, bolus on day 5, Ten patients with paired bone marrow aspirates obtained before topotecan and before doxorubici n administrations were available for evaluation, In 7 of 10 patients, there was an increase (16.6 +/- 2.9% to 25.0 +/- 3.5%; P < 0.02) in th e proportion of CD34+ cells in S-phase 24 h after the topotecan infusi on and prior to doxorubicin compared to the pretreatment values, where as 1 patient had a decrease in the proportion of CD34+ cells in S phas e and 2 patients had no change, Topotecan and doxorubicin with this se quence and schedule can be given safely; the dose-limiting toxicity is hematological toxicity. Alterations in the fraction of hematopoietic progenitor CD34+ cells in S-phase may account for the increased granul ocytopenia and thrombocytopenia observed at relatively low dose levels of the combination with and without G-CSF.